CA2013783A1 - Substituted 1,8-naphthyridines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase which are 1,8-naphthyridines of the formula in which A - represents a 3- to 7-membered heterocycle which is optionally substituted, or aryl which is optionally substituted, B - represents cycloalkyl or alkyl which is optionally substituted, aryl which is optionally substituted, D and E are identical or different and - represents hydrogen, halogen, mercapto, hydroxyl, alkoxy, alkyl which is optionally substituted, or a group of the formula -NR1R2, aryl, aryloxy or arylthio having 6 to 10 carbon atoms, which is optionally substituted, Y - represents a group of the formula or in which J - denotes hydrogen, hydroxyl, mercapto or halogen, or alkyl, alkoxy or alkylthio which are option-ally substituted, aryloxy, benzyloxy or arylthio or a group of the formula -NR1R2, Z - denotes oxygen or sulphur, G - denotes hydrogen, alkyl or alkenyl which is optionally substituted, Le A 26 759 X - represents a group of the formula -CH2-CH2- or -CH=CH-, and R - represents a group of the formula or in which R5 - denotes hydrogen or alkyl, and R6 _ denotes hydrogen or alkyl, which may be substituted by phenyl, or - denotes aryl or a cation, and their salts.

Le A 26 759

Description

20~37~3 The invention relates to new substituted 1,8-naphthyridines, to intermediate~ or their preparation, and to their preparation and their use in medicaments It is known that lactone derivatives isolated from fungal cultures ~re inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) ~mevinolin, EP-A 22,478; US 4,231,9381 Moreover, certain indole derivatives or pyrazole derivatives ~re inhibitors of HMG-CoA reductase tEP-A 1,114,027; US Patent 4,613,610]
New substituted 1,8-naphthyridines o$ the general formula (I) E D A

~- R
B
in which A - repre~ents a 3- to 7-membered heterocycle which lS m~y contain up to 4 sulphur, oxyqen or nitroqen heteroatoms and which is optionallY
monosubstituted to trisubstituted by identic~l or different ~ubstituents from the erie- comprl~ing halogen, trlfluoromethyl, trlfluorometho~y, tralght-chaln or br~nched alkyl, alkoxy or ~lko ycarbonyl ln ach ca-e havlng up to 8 carbon atoms or by ~ryl h~vlng 6 to 10 carbon atoms, or ~e A 26 759 - 1 -20~3783 A - repre~ents aryl having 6 to 10 carbon atom~ which is optionally monosubstituted to pentasubstituted by identical or different substituents from the series comprising straight-chain or branched S alkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl in each ca~e having up to 10 carbon atoms, which may in turn be substltuted by hydroxyl, ~lkoxy having up to 6 c~rbon atoms, phenyl or by a group of the formula -NRlR2, in which Rl and R2 ar~ identical or different and - denote hydrogen, aryl or arylsu1phonyl having 6 to 10 carbon atoms, straight-chain or branched alkyl or alkyl~ulphonyl having up to 8 carbon atom~, where the last mentioned radicals are optionally sub~tituted by aryI having 6 to 10 carbon ~toms, - or denote a group of the formula -CoR3 in which R3 - denotes str~ight-ch~in or br~nched aIkyl or ~lkoxy having up to 8 carbon ~tomR, or phenyl, or the ~ryl i9 substituted by aryl, aryloxy, arylthlo or Aryl-ulphonyl h~vlng 6 to 10 c~rbon ~toms, or by halogen, nltro, cyano, trlfluoromethyl, 6 7$~ - 2 -2~ 3 ~g3 trifluoromethoxy, trifluoromethylthio, benzyloxy or a group of the formul~ -NRlR2, in which Rl and R2 have the ~bovementioned meaning, 5 B - represents cyclo~lkyl having S to 8 carbon atoms, straight-chain or br~nched alkyl having up to 12 carbon atoms, which i~ optionally substituted by halogen, trifluoromethyl or alkylthio havlng up to 8 carbon atoms, - represents aryl having 6 to 10 carbon atoms, - which is optionally substituted by halogen, cyano, nitro, trifluoromethyl, straight-chain or branched ~lkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, or amino, D and E are identical or different and - represent hydrogen, halogen, mercapto, hydroxyl, a}koxy having up to 8 carbon atoms, str~ight-chain or branched alkyl having up to 10 carbon ~toms, which is option~lly substituted by :~ hydroxyI, phenoxy, halogon, trifluoromethyl or ~lkylthio h~ving up to 8 carbon ~toms, or repre-: sent a group of the fonmula -NRlR2, ln whlch Rl ~nd R2 h~v the ~bovqmentloned mean$ng, or D and E each independently Le A 26 ?S9 3 20~37~3 - repre6ent aryl, aryloxy or arylthio having 6 to lO carbon atom6, which is optionally sub~tituted by halogen, cyano, nitro, trifluoromethyl, straight-chain or branched alkyl, alkoxy or S alkoxycarbonyl in each case having up to 8 carbon atoms, or amino, Y - represent~ a group of the formula -frN- or J Z G

in which lO J - denotes hydrogen, hydroxyl, mercapto or halogen, or denote~ straight-chain or branched alkyl, alkoxy or alkylthio having up tolO carbon atoms, which are optionally ~ubstituted by phenyl, or denotes aryloxy, benzyloxy or arylthio having 6 to 10 carbon atom~ or a group of the formula - in which Rl and R2 have the ~bov~mentioned meaning, Z - donote~ oxyg n or ulphur, G - d not-~ hydrog n, tr~iqht-chain or branched alkyl or alkenyl in -ach ca-e ha~ing up to lO
carbon atoms, which 1~ optionally ~ubst$tutQd by ~e A 26 759 _ 4 _ 20~ 3~3 halogen, cyano, alkoxy having up to 8 carbon atoms, benzyloxy, aryl or aryloxy having.6 to 10 carbon atoms, by a 5- to 7-membered heterocycle having up to 4 nitrogen, oxygen or sulpur heteroatoms or by a group of the formula -NRlR2, -COR~ or -COOR~, in which R1, R2 and R3 have the abovementioned meaning, R~ - denotes hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, phenyl, halogen or cyano, _ or R~ denotes aryl having 6 to 10 ~rbon atoms, which may in turn be substituted by halogen, amino, hydroxyl, nitro or cyano, X - represents a group of the formula -CH2-CH2- or -CH=CH-, and R - represents a group of the formula 7H CH2 7-CH2-COoR6 or HO
OH OH
$n wh$ch e A 26 759 - 5 -2 ~ 1 3 r~l ~ 3 Rs _ denotes hydro~en or ~traight-chain or branched alkyl having up to lQ carbon atoms and R5 _ denstes hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by phenyl, or - denote~ aryl having 6 to lO carbon atoms or a cation, and their salts have now been found.
If R~ forms an ester radical with the carboxyl group, then a physiologically tolerable e~ter radical, which i8 ea~ily hydrolyzed in vivo to give a free car-boxyl group and a corresponding physiologically tolerablealcohol, io preferably meant by this. These include, for example, alkyl e~ter~ (C1 to CE) and aralkyl ester6 (C~ to C10), preferably (C~-C~)-alkyl esters and benzyl esters.
Moreover, the following e~ter radical~ may be mentioneds methyl e~ter~, ethyl e~ter~, propyl esters and banzyl e6ters.
If RB represents a cation, then ~ physiologically tolerable metal cation or a~monium cation ~8 psefer~bly meant. Preferred cations in this connection ~re alkali metal or al~aline earth aetal oatlon~ uch as, for ex~mple, ~odium, pota~ium, aagne~lum or calcium cations, and al~o aluminum or ammonium cation~, and non-toxic .

Le ~ 2 ~ 7~2 - 6 -2~3 3r~3 sub6tituted ammonium cations of a~ines such a~ (Cl-C~)-dialkylamines, Cl-C~)-trialkylamines, procaine,.diben-zylamine, N,N~-dibenzylethylenedi~mine, N-benzyl-~-phenylethylamine, N-methylmorpholine or N-ethylmorpho-line, l-ephenamine, dihydro~bietylamine, N,N'-bi~-dihydroabietylethylenediamine, N-lower alkyl piperidine and other amines which may be used for the formation of salts.
Surprisingly, the substituted 1,8-naphthyridines according to the invention show a ~uperior inhibitory action on HNG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reducta~e).
In the context of the general formula (I), compounds of the general formula (Ia) and (Ib) ~ and ~-R

(I~) (Ib) in which A, B, D, E, X, Y and R have the ~bovementioned meaning, are preferred.
Preferred compounds are those of the general formula (Ia) and (Ib), in which A - represents pyridyl or pyrimidyl, which i~ option-ally monosubst$tuted or disubstituted by e A 26 759 - 7 -2~3783 identical or different subst$tuents from the series comprising fluorine, chlorine, bromine, trifluoromethyl, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, S ~ or A represents phenyl or naphthyl which is oPtion-ally monosubstituted to tetrasubstituted by identical or different ~ubstituents from the series comprising straight-chain or branched alkyl, alkylthio, alkylsulphonyl, alko~y or alkoxycarbonyl in e~ch case having up to 8 carbon atoms, which may in turn be sub~tituted by hydroxyl, alkoxy having up to 4 carbon atoms, phenyl or by ~ group of the formula -NR~R2, in which Rl and R2 are identic~l or different and - denote hydrogen, phenyl, phenylsulphonyl, ~traight-chain or branched alkyl or alkylsulphonyl h~ving up to 6 carbon atom~, benzyl or benzylsulphonyl, or - denote ~ group of the formula -CoR3, in which R3 - denote~ straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms or phenyl, or the phenyl or naphthyl is optionally mono- to tetrasubstituted by i- ub-tituted by phenyl, phenyloxy, fluorine, chlorine, bromine, nitro, ¢yano, trifluoromethyl, trlfluoromethoxy, ben~yloxy or by a group of the e A 26 759 - 8 -~0137~3 formula -NRlR2, in which R~ and R2 have the abov~mentioned meaning, B - repre~ents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, - repre~ents straight-chain or branched alkyl having up to 10 carbon atoms, which may option-ally be substituted by fluorine, chlorine, bromine, trifluoromethyl or methylthio, D and E are identical or different and - represent hydrogen, hydroxyl, alkoxy having up to 6 carbon atom~, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or a group of the formula -NRlR2, in which R~ and R~ have the abovementioned meaning, Y - repre-ents a group of the formula -C~N- -C-N-I or ll l J z G

ln wh$ch J - denotes hydrogen, hydro yl, mercapto, Le A 26 759 - 9 -2~ 37~3 fluorine, chlorine or bromine, or denotes ~traight-chain or branched alkyl, alkoxy or alkylthio having up to 8 carbon atoms, which are optionally substituted by phenyl, or denotes phenoxy, benzyloxy or a group of the formula -NRlR2, in which Rl and R2 have the abovementioned meaning, Z - denote~ o~ygen or sulphur, 10 G - denote~ hydrogen, straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, which iB optionally sub~tituted by fluorine, chlorine, bromine, cyano, alkoxy having up to 6 carbon atoms, phenyl, phenoxy, benzyloxy, lS pyrryl, furyl or by a group of the formula -NRlRZ, -CoR3 or -COOR~, in which Rl, R2 ~nd R3 h~ve the ~bovementioned meaning, R~ - denotes hydrogen, str~ight-ch~$n or branched alkyl having up to 8 carbon ~toms, which 1~ opt$on~11y ~ubstituted by hydroxyl, phenyl, fluor~ne, chlor$ne or bromine, - denote- phenyl whl¢h aay ln turn be 2S ub-tltuted by fluor$n , ohlor$ne, bromlne Le A 26 759 - 10 -2~3~v3 or hydroxyl, x - represents a group of the formula -CH2-C~2- or -CH=CH-and S R - represents a group of the formula -ICH-cH2-l_c~2_cOOR or HO
OH OH
in which R5 - denotes hydrogen or traight-chain or branched alkyl having up to 8 carbon atoms and R6 _ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or benzyl, or - denotes phenyl or a cation and their ~alts.
Part$cularly preferred compounds of the general formulae ~Ia) and ~Ib) are tho~e in wh$ch A - represents phenyl wh$ch 1- opt~onally Le A 26 ~2 - 11 -2~ 37v3 monosubstituted to trisubstituted by identical or different substituent~ from the ~eries comprising ~traight-chain or branched alkyl having up to 6 carbon atoms, which may in turn be substituted by hydroxyl, methoxy, ethoxy, propoxy or phenyl, or the phenyl is substituted by~phenyl, phenoxy, fluorfne, chlorine, bromine or benzyloxy, B - represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, - represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl or trifluoromethyl, D and E are identical or different and - represent hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy, 15 Y - represent~ a group of the formula _fsN_ or -Il- 1-J Z G
in which J - denotes hydrogen, hydroxyl, fluorine or chlorine, or denotes ~traight-chain or branched alkyl, alkoxy or ~lkylthio having up to ~ c~rbon atom~, wh$ch ~re optionally ub~t$tuted by phenyl, or denote- benzyl-oxy or a group of the formula -NRlR2, Le A 26 759 - 12 -2~13~3 in which R1 and R2 are identical or different and - denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or benzyl, Z - denotes oxygen or ~ulphur, G - denote~ hydrogen, straight-chain or branched alkyl having up to 6 carbon atom~, wh~ch is optionally substituted by fluorine, chlorine, cyano, alkoxy having up to 4 carbon atoms, phenyl, benzyloxy or by a group of the formula -CoR3 or -COOR~, in which R3 - denotes straight-chain or branched alkyl or phenyl, R~ - denote~ hydrogen, straight-chain : or branched alkyl ha~ing up to 6 carbon atoms or phenyl, X - repre~ents a group -CH~CH- or -CH2-CH2-and R - repre~ents a group of the for~ula e A 26 759 - 13 -2~137~3 I R5`_~A~G~o -IH-cH2-l-cH2-cooR6 or Ho ~ T
OH OH

in which R~ - denotes hydrogen, methyl, ethyl, propyl, $sopropyl, butyl, isobutyl or tert.butyl S and R6 _ denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, i~obutyl, tert.butyl or benzyl, or - denotes a sodlum, pota~sium, calcium, magnesium or ammonlum ion and their ~alts.
The substituted 1,8-naphthyridines of the general formula (I) according to the invention have several asymmetric carbon atoms and can therefore exlst in various stereochemical form~. The invention relates both to the individual ~omers ~nd to thelr mixtures.
Depending on the meaning of the group X or the radical R, different stereoisomars result, which are intended to be lllu-trated in more detail ~n the following~
a) if the group -S- repr-sent~ a group of the formula -CH-CH-, the ¢ompound~ ~ccordlnq to the lnvention Le A 26 759 - 14 -20~37~3 can exi8t in two stereoisomeric forms which can have the E configuration (II) or Z configuration ~III) on the double bond:

E~ D A (II) E form E D A

~ R
~ (III) Z form (A, B, D, E and R have the abovementioned meanin~).
Preferred compounds of the genersl formula (I) are those which have the E configur~tion (II).
b) If the radical -R- represents a group.of the formula -IH-cH2-cl-cH2-cooR6 OH OH

the compounds of the general formuls ~I) have at least two a~ymmetric carbon ~tom~, n~mely the two carbon atom~ to whlch the hydroxyl group~ are bonded. Dopendin9 on the r l~ti~e po~ltlon of the~e hydroxyl groups to one another, the compounds Le A 26 759 - 15 -20~37~3 according to the invention msy be present in the erythro configuration ~IV) or in the threo con-figuration (v).

E D A
~ ~H CH2-~-cH2-cooR6 erythro form (IV) E D A
~X- CH- CH2 - C - CH2 - COOR6 S ~ OH OH threo form (V) In turn, two enantiomers each exist both of the compounds in the erythro and in the threo configu-ration, namely the 3R,SS-isomer or the 3S,SR-isomer (erythro form) ~nd the 3R,SR-isomer and 3S,5S-isomer (threo form).

In this connection, the isomers in the erythro configuration are preferred, particularly preferably the 3R,5S-isomer ~nd the 3R,SS-3S,SR-racemate.

c) If the radical -R- reprooents a group of the formula HO ~
,?<
15 the ub~tituted 1,8-naphthyridino~ have at loaot two ~e A 26 759 - 16 -2013~3 a~ymmetric carbon atoms, namely the carbon atom to which the hydroxyl group i8 bonded, and thç carbon atom to which the radical of the formula E ~ A

i8 bonded Depending on the po~ition of the hydroxyl group to the free v~lency on the l~ctone ring, the substituted 1,8-naphthyridines may be present as cis-lactones (VI) or ~ trans-lactones (VII) , HO~ \R

cis-lactone (VI) H0",~ R5 E~ tr~n~-l~cton (VII~

In turn, two isQmers each exi~t of the cis-lactone and the tr~ns-lactone, namely the 4R,6R-isomer or the 4S,6S-i-omer ~ci~ ctone), ~nd tho 4R,6S-i-omer or 4S,6R-l~omer (tr~n~ ctone) Pref-rred l~omers ~re the tr~n~ ctono~ ~he 4R,6S-lsQmer ~tran-) ~nd the 4R,6S-4S,6R-r~com~te ~re p~rtlcul~rly preferred Le A 26 759 - 17 -2~13783 in this connection.

For example, the following isomeric forms of the substituted 1,8-naphthyridines may be mentioned:

A
E D ~ I
~\\\`~0'' ~o A R ~ OH
E D ¦ ¦ ¦
~0~0 Le A 26 759 - 18 -20~37~3 A ~
~ o~o A ~
~lo~o A OH OH
~H C ~ 5 6 A OH OH
E D I C ~
~CH - CH2 - CR5 - CH2 - COOR6 B

A OH OH
~-CH2-CR5-CH2-CooR6 A OH OH
E D I . ~
~CH-CH2- CR5 -CH2-COOR6 ~B

~ ~/H-CH2-~R5-CH2-COOR6 I.e A 26 759 - 19 -2~137~3 B OH OH
E D I - ~
~CH - CH2 - CRS - CH2 - COOR6 ~A
B OH OH
~CH-CH2-CR5-CH2-CooR~

B OH OH
~ ~U-CH2-CR5-CH2-CooR6 In addition, a process for the preparation of the substituted 1,8-naphthyridines of the general formula ~I) ~ -R (I) in which A, B, D, E, ~, Y and R have the abovementioned meaning, has been found, which i~ characterized in that ketone~ of the general formula tVIII) O
E CHSCH-CH-CH2-C-CH2-CooR7 (VIII j in which Le A 26 759 - 20 -20137~3 A, B, D, E and Y have the abovementioned meaning, and R7 - represents alkyl, are reduced, in the case of the preparation of the acid~ the esters are hydrolyzed, in the case of the preparation of the lactones the carboxylic acids are cyclized, in the case of the preparation of the 8alt~ elther the esters or the lactones are hydrolyzed, in the case of the preparation of the ethylene compounds (x = -CH2-CH2-) the ethene compounds (X - -CH~CH-) are hydrogenated according to customary method~, and, if appropriate, isomers are separated.
The proces~ according to the invention can be illustrated by the following equations Le A 26 759 - 21 -20137~3 CH 2C OOCH :3 ~OH

reductl on 0~
¦ hydrolysis COOeN~

~ ~ OH

hCOOH
cycl l ~ atl on ~ ~ ~OH

~ .

~e A 26 759 - 22 -20~37~3 ~' H

The reductlon can be carried out u~ing the customary reducing agentE, preferably those which are suitable for the reduction of ketone~ to hydroxy com-pounds. Reduction u~ng metal hydrides or complex met~l hydrides in inert solvents is particularly suitable in thi6 connection, if appropriate in the pre3ence of a trialkylborane. Preferably, the reduction is carried out using complex metal hydride~ such as, for example, lithium borohydride, sodium borohydride, poeassium borohydride, zinc borohydride, lithium trialkylboro-hydrides, sodium trialkylborohydrides, sodium cyanoboro-hydride or lithium aluminum hydride. Very particularly preferably, the reduction is carried out using ~odium borohydride in the presence of triethylborane.
Suitable solventQ in this connection are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as, for example, diethyl ether, d~oxane, tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons uch as, for example, dichloromethane, tr~chloromethane, tetra-chlorometh~ne, 1,2-dichloroethane, or hydrocarbons ~uch as, for example, benz-ne, toluene or xylene. It is lik~wi-e pos~ble to employ mixture- of the olvents Le A 26 759 - 23 -~0~3~$3 mentioned.
Particularly pre$erably, the reduction of the ketone group to the hydroxyl group i8 carried out under conditions in which the customary functional groups such S as, for example, the ~lkoxycarbonyl group do not change.
The use of ~odium borohydride as ~ reducing agent in the presence of triethylborane in inert solvents such ~, preferably, ethers is particularly suitable for this purpose.
The reduction is in general carried out in a temperature range from -80-C ~o +30-C, preferably from -78C to O-C.
The proce~s according to the invention is in general carried out at ~tmospheric pressure. However, it is also possible to carry out the proces~ at reduced pressure or at elevated pressure (for ex~mple in a range from 0.5 to 5 bar).
In general, the reducing agent i~ employed in an ~mount from 1 to 2 moles, preferably from 1 to 1.5 moles, relative to 1 mole of the keto compound.
Under the abovementioned reaction conditions, the carbonyl group i8 in general reducad to the hydroxyl group without reduction of the double bond to a ~ingle bond taking plAce.
In order to prepare compound~ of the general formula (I), in which ~ repre~ent~ an ethylene grouping, the reduction of the ketone~ (III) c~n be c~rried out under those condition- under ~hich both the carbonyl group ~nd the double bond are r duced.
Noreover, $t 1~ o po-~lble to o~rry out the Le A 26 7~9 - 24 -201 37~3 reduction of the carbonyl group and the reduction of the double bond in two separate steps.
The carboxylic acids in the context of the general formula (I) correspond to the formula (Ic) E D A l5 ~ -ICH-CH2-Cl-CH2-COOH ~Ic) ~ OH OH
in which B
A, B, D, ~, and R5 have the abovementioned meaning.
The carbo~ylic ~cid ester~ in the context of the general formula (I) correspond to the formula (Id) ~ -ICH-cH2-l-cH2-cooR7 (Id) in which A, B, D, E, Y and R5 have the abovementioned meaning, and R7 - represents alkyl.
The s~lts of the compounds in the context of the general formula (I) according to the in~ention correspond to the formul~ (Ie) ~ -CIH-CH2-cl-cH2-coo ~ Mn- (I.) I,e A ~b 7~2 - 25 -in which A, B, D, E, Y and R5 have the abovementioned meanLng, and Mnt represents a cation, where n indicates the valency.
The lactones in the context of the general formula (I) corre6pond to the formula (If) HO~y~R5 E D A ~ ~
~0~

in which A, B, D, E, Y ~nd Rs h~ve the ~bovementioned mean$ng.
In order to prepare the carboxylic acids of the general formul~ (Ic) according to the invention, the carboxylic acid e~ters of the general formula (Id) or the lactones of the general formula (If) are in general hydrolyzed according to cu~tomary method~. Hydrolysi~ i~
in general carried out by treating the e~ters or the lactones in inert ~olvents with cu-tomary bases, in qeneral the salts of the general formula (Ie) initially resulting, which c~n aub~equently be converted in a second step by treating wlth acid into the free acids of the general formula ~Ic).
Suitable base~ for hydroly-is are the cu~tomary inorg~nic baae-. Theoe pref-rably lnclude alkali metal hydroxidea or alkaline earth etal hydroxlde- uch aa, for example, ~odium hydroxide, pota~aium hydroxlde or ; 25 barium hydroxide, or alkali metal c~rbonate~ ~uch a8 .

Le A 26 759 - 26 -20137~3 sodium carbonate or potassium carbonate or sodium hydro-gen carbonate, or alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium methoxide, potassium ethoxide or potassium tert. butoxide. Sodi~m S hydroxide or potassium hydroxide are particularly prefer-ably employed.
Suitable solvents for hydrolysis are water or the organic solvents customary for hydrolysi~. These pre-ferably include water, alcohols ~uch as ~ethanol, ethanol, propanol, i-opropanol or butanol, or ethers such as tetrahydrofuran or dio~ane, or dimethylformamide or dimethyl sulphoxide. Particularly preferably, methanol, tetrahydrofuran or water are used. It is al~o possible to employ mixtures of the solvents mentioned.
The hydrolysis is in general carried out in a temperature range from O-C to +lOO~C, preferably from +20C to +80-C.
In general, the hydrolysis is carried out at atmospheric pressure. Nowever, it is also possible to work at reduced pressure or elevated pre~sure (for example from 0.5 to 5 bar).
When carrying out the hydrolysis, the ba~e i~ in general employed in an amount from 1 to 3 moles, pre-ferably from 1 to 1.5 moles, relative to 1 mole of the ester or the lactone. Molar amounts of the reactants are particularly preferably u~ed.
When carry$ng out the reactlon, the alt- of the compounds (Ie) accordlng to the lnv ntlon ~ro fonmed ln the fir~t ~tep ~ lntermedlato- ~hlch c~n bo l~olat-d.
The acids ~Ic) according to the inventlon are obtained by Le A 26 759 - 27 -2~:137~3 treating the salts (Ie) with customary inorganic acids.
These preferably include mineral acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid. It has proved advantageous in S this connection in the preparation of the carboxylic acid~ (Ic) to acidify the basic reaction mixture from the hydroly~i~ in a second step without isolation of the salts. The acids can then be i~olated in a customary manner.
In order to prepare the lactone~ of the formula ( If ) according to the invention, the carboxylic acids (Ic3 according to the invention are in general cyclized according to customary methods, for example by heating the corresponding acid in inert organic solvents, if appropriate in the presence of mo}ecular sieve.
Suitable solvents in this connection are hydro-carbons such as benzene, toluene, ~ylene, mineral oil fractions, or tetralin or diglyme or triglyme. Benzene, toluene or xylene are preferably employed. It i~ also possible to employ mixture~ of the sol~ent~ mentioned.
Hydrocarbons, in particular toluene, in the presence of molecular sieve are particularly preferably u~ed.
The cyclizatinn 18 in general carried out in a temperature range from -40-C to +200-C, proferably from -25-C to +50-C.
The cycllzation i8 in general carried out at atmospheric pre-sure, but lt i~ al~o po88ib1e to carry out the proce~ at reduced pre~ure or at elevated pres~ure ~for example in a range from 0.5 to 5 bar).
Moreo~er, the cy~lization i~ aIso carriod out in Le A 26 759 - 28 -20 ~ 37~3 inert organic solvents, with the _id of cyclizing or dehydrating _gents Carbodiimides _re preferably used as dehydrating agents in this connection N,N~-dicyclohexyl-carbodiimide paratoluenesulphonate, N-cyclohexyl-N'-~2-(N'-methylmorpholinium)ethyl]carbodiimide or N-(3-di-methylaminopropyl~-N~-ethylc_rbodiimidehydrochlorideare preferably employed _8 C_rbodiimideB.
Suit_ble solvents in thi~ connection _re the customary org_nic ~olvents The~e preferably include ethers such a8 diethyl ether, tetrahydrofur_n or dioxane, or chlorinated hydroc_rbons such _8 methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene or miner_l oil fractions Chlorinated hydrocarbons such a8, for example, methylene chloride, chloroform or c_rbon tetr_chloride, or hydro-carbons such as benzene, toluene, xylene or mineral oil fractions are particularly preferred Chlorinated hydro-carbons such as, for ex_mple, methylene chloride, chloroform or carbon tetr_chloride _re particularly preferably employed The re~ction i8 in gener_l carried out in _ temper_ture r_nge from O C to +80 C, preferably from +lO C to +50 C
When carrying out the cycliz_tion, it h_s proved advant_geous to employ the cycli~ation method with the aid of carbodiimides _8 dehydratinq _g nts ~ he re-olution of the i-o~or- lnto the ~tereoi~omerlcally uniform con-titu-nt- i- in gen r_l c_rried out by cu-tomary method- uch a- ar- de~cribed, for e~_mple, by E L ~liel, Ster~ochemi-try of C_rbon Le A 26 759 - 29 -2~37~3 Compounds, McGraw Hill, 1962. Resolution of the isomers in the racemic ester Btep iB preferred in this con-nection. The racemic mixture of the trans-lactones (VII) is particularly preferably converted in this case by treating either with D-(+)- or L-(-)-~-methylbenzylamine by customary methods into the diastereomeric dihydroxy-amides (Ig) 1~ IH3 E D A ~ -cH2-coNH-cH-c6H5 ~ ~ H (Ig) which can then be resolved into the individual dia~tere-omers as i~ customary by chromatography or crystal-lization. Subsequent hydrolysis of the pure dia~tere-omeric amides by customary methods, for ex~mple by treating the dia~tereomeric amides with inorganic base~
such as sodium hydroxide or potassium hydro~ide in water and/or organic solvents such a8 alcohols, for example methanol, ethanol, propanol or isopropanol, gives the corresponding enantiomerically pure dihydroxy acids tIc) which can be converted lnto the enantiomerically pure lactones by cyclization as descrlbed above. In general, it is true for the prep~ration of the compounds of the general formula (I) according to the invention in enan-t~omerically pure form that the configur~tlon of the final product- accordlng to the method descrlbed ~bove is dependent on the configuratlon of the t~rtlnq ub-stances.

Le A 26 7S9 - 30 -20137~3 The resolution of isomers is intended to be illustrated by way of example in the following ~cheme:

'~

~ A.~6 ~59 - 31 -20~37~3 ~ COOCH3 erythro racQmate ~I ~ H2N-CH-C6HS

F OH IH
H2-CO-NH-CH-c6~5 "`~OH

H~ mixture of diastereomers 1) separation of diastereomers 2) hydroly~is 3) l~ctoniz~tion F ~H F

Le A 26 75~ - 32 -2~ 37~3 The ketones (VIII) employed as starting sub-stances are new.
A process for the preparation of the ketones of the general formula (VIII) according to the invention o E D A ¦¦
~ CH=CH-IH_CH2_C_CH2_COOR7 (VIII) in which A, B, D, E, Y ~nd R7 have the abovement~oned meaning, has been found, which i~ characterized in that aldehydes of the general formula (IX) R
E D A ~
~ (IX) in which A, B, D, ~ ~nd Y h~ve the abovementioned meaning, sre reacted in inert solvents with ~cetoacetic e~ters of the general formula (X) 7 ~X) 15 in which H3c-c-cH2-cooR
R7 has the abovementioned meaning, in the pre~ence of base~.
~ he process according to the invention c~n be illu~trated, for e~mple, by the followlng equatlont Le A 2~ 75~_ 33 _ 2al137~3 ~ 1lH
o ~ ~ H3C-C-CH2-COOCH3 ~ ¦ B~

Suit~ble b~ses in this connection ~re the CU8-tomary 6trong b~sic compounds. These preferably include organolithium compounds such as, for example, N-butyl lithium, sec. butyllithium, tert. butyllithium or phenyl lithium, or amides uch a~, for ex~mple, lithium diiso-propylamide, sodium ~mide or pot~ssium ~mide, or lithium hexamethyldisilyl~mide, or ~lkali met~l hydr~des such a~
sodium hydride or pot~ssium hydride. It is likewise possible to ~mploy mixture~ of the b~ses mentioned.
N-butyllithlum or ~odium hydride or ~ mlxture thereof i8 p~rtlcul~rly pref-r~bly employed.
Addition- of met~l h~lide~ uch ~8, for ex~mple, Le A 26 752 - 34 -20137~3 magnesium chloride, zinc chloride or zinc bromide may be advantageous. The addition of zinc halides iB particu-larly preferred.
Suitable solvents in this connection nre the customary organic solvents which do not change under the reaction conditions. These preferably include ether~ such as diethyl ether, tetrahydrofuran, dioxane or dimethoxy-ethane, or hydrocarbons ~uch as benzene, toluene, ~ylene, cyclohexane, hexane or mineral oil fractions. It i8 likewise possible to employ mixture~ of the solvents mentioned. Ethers such às d$ethyl ether or tetrahydro-furan are part$cularly preferably used.
The reaction is in general carried out in a temperature range from -80-C to +50-C, preferably from -20-C to room temperature.
The process is in general carried out at atmospheric pressure, but it is al~o possible to carry out the process at reduced pressure or elevated pressure, for example in a range from 0.5 to 5 bar.
When carrying out the process, the acetoacetic ester is in general employed in an amount from 1 to 5, preferably from 1 to 3, moles, relative to 1 mole of the aldehyde.
The acetoacetic e-ters of the formula (~) employed as ~tarting ubstances are known or can be prepared by known method~ ~eilstein's Handbuch der organi~chen Chemie ~eil-t-in~ Handbook of Organic Chemistry) ~I~, 632t ~381-Example- of ao-toac-tlc -t-r- for th proce~s according to the invention which ~ay be mention d aret Le A 26 759 - 35 -201378~

methyl acetoacetate, ethyl acetoacetate, propyl aceto-acetate and i~opropyl acetoacetste The preparation of the aldehydes of the general formula (IX) employed a~ ~tarting substances is intended to be illustrated below by way of ex~mple for the 1,8-naphthyridines of the type (Ia) [A]

~COOR8 ~ CHzC)H

(XI~/X~b) ~XII) A A H 'CHO
r 2 ] ~CHO ~ 3 ~ ~H

~X2II ) ~ IX) ~ .
In this connection, ~ccording to ~ch~me A, 1,8-naphthyridines of the formula (XI), ln which R~ represent~
an alkyl radical having up to 4 carbon atoms, are reduced to the hydroxymethyl compound~ (XII) in the first step [1] in inert olvent- uch a- eth r-, for x~mple di-ethyl-ther, tetrahydrofur~n or dloxane or hydroc~rbon-~uch a- toluene, pr-f-r~bly toluene, u-lng ~et~l hydrlde~
15 ~B r duclng ~gent-, for x~mpl- lithlu~ aluminum hydrlde, odium cyanoborohydride, odlum aluminum ~e A 26 759 - 36 -2~137~3 hydride, dii~obutylaluminum hydride or sodium bi~(2-methoxyethoxy~-dihydro~luminate, in temperature ranges from -75-C to +lOO-C, preferably from -80-C to room temperature, or from room temperature to -78-C depending on the reducing agent u~ed. Preferably, the reduction i8 carried out using diisobutylaluminum hydride in tetra-hydrofuran or toluene in a temperature range from -78-C
to room temperature. The hydroxymethyl compounds (XII) are oxidized by cu~tomary methods to the aldehydes ~III) in the second ~tep [21. The o~id~t$on c~n be c~rried out, for example, with pyridinium chlorochromate, if appropri-ate in the presence of ~lumina, in inert solvents such as chlorinated hydrocarbon~, preferably methylene chloride, in a temperature range from O-C to 60-C, preferably at room temperature, or else are carried out usinq di~ethyl sulphoxide by the customary method~ of Swern oxidation.
The aldehyde~ (XIII) are reacted to give the aldehydes ~IX) in the third step [3] using diethyl-2-(cyclohexyl-amino)-vinylphosphonate in the presence of sodium hydride in inert solvents ~uch a~ ether~, for example diethyl-ether, tetrahydrofuran or dio~ane, preferably in tetra-hydrofuran, in a temperature range from -20-C to +40-C, prefer~bly from -5-C to room temper~ture.
The 1,8-naphthyridines of the formula (XI) employed as ~tarting subst~nces in this connection are new.
Compound~ of th formula (XIa), ln which Y
repre~ent~ the group of th for~ul~
-C-N-Z G

Le A 26 759 _ 37 _ 2~37~3 in which G and Z have the abovementioned meaning, can be obtained by oxidizing 3,4-dihydro-1,8-naphthyridines of the formula (XIV), in which A, B, D, E, G, Z and R~ have the abovementioned meaning, according to scheme lBl The oxidation can carried out, for example, with chromic oxide or sodium nitrite $n glacial acetic acid, with nitric acid in a aqueous suspension, with cerium salts such as, for example, ~mmonium cerium nitrate in a solvent mixture of acetonitrile and water, or with dichlorodicyano-p-benzoguinone in the abovementioned inert solvents, in a temperature range from -20 C to +150 C A
ooR8 G COOR8 ~XIV) (%~) lS The 3,4-dihydro-1,8-naphthyridines of the general formula (XIV) employed as starting substances in this connection are new They ~re obt~ined according to ~cheme ~C] by reaction of suitably sub~tituted ~ un~aturated carboxylic acid e~ter~ of the general formula (XV), $n which A, B and R have the abovementioned meaning, with substituted 6-~mino-2-pyridone~ of the general formula (XVI), in whlch D, E, G and ~ hav the abo~ementioned meaning, Th r action can be illu-trated by th following e A 26 759 - 38 -2~37~3 equation [C] A D A
oOR8 B z ~ NI~l~NH2z ~ N~l~N~'~B
G G
~XV) ~XVI) (XIV~) The process can be carried out in ~ubst~ncQ or in a high-boiling solvent such a~, for example, ethylene S glycol or dimethylform~mide, if appropriate in the presence of acetic acid, at room temperature to ~200 C
Reaction in sub~tance or dimethylformamide at +120 C to +160 C is preferred In addition, compounds of the general formula (I) in which Y represents the group of the formula -C-N-11 1 .
Z G
and G denote~ a C1-C6-~lkyl radical, can be prepared by alXylating compounds of the general formulae (XIII), (XIV) or tI), in which G repre~ents hydrogen, with Cl-C6-~lkyl halides, uch as, for example, methyl iodide in the presence of bases, ~uch as, for example, pot~ssium tert butoxide, in the ~bovementioned olvents, preferably in dimethylformamide at room temperature Compound- of the formula ~XIb), in which Y
represent- the group of th formul~
-I-N-L~_A_~ 152 - 39 -2~ 37~3 in which J has the abovementioned me_ning, can be pre-pared by reacting compounds of the formula (XIa) by methods known from the literature [cf. L.F. Pieser, M. Fieser, Reagent6 for Organic Synthesis, Vol. l, p.1232 5(1967)l either with trialkyloxonium salts, preferably with trimethyloxonium tetrafluoroborohydride at room temperature, or with bases such as, for example, potas-sium tert.butoxide or sodium hydride and C1-C~-alkyl halides such as, for ex_mple, methyl iodide, ethyl iodide lOor isopropyl iodide, preferably with isopropyl iodide, in the abovementioned solvents at roo~ temperature. It i8 also possible first to carry out a chlorination reaction with phosphorus chlorides, such as, for example, phos-phorus oxychloride, $n the presence of C1-C~-dialkyl-15anilines at O-C to +lOO-C and then to $ntroduce the group F by nucleophilic substitution.
The compounds of the general formula (I) accord-ing to the invention possess useful pharmacological properties and can be employed in medic_ments. In par-20ticul_r, they _re inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reduct_se and, aB a result of this, inhibitors of cholesterol biosynthesis. They can therefore be employed for the treatment of hyperlipo-proteinaemia, lipoproteinaemia or atherosclerosis. The 25active substances according to the invention additionally cause a lowering of the cholesterol content in the blood.
The enzyme aetivity dete-m~n~tlon wa- earried out as modified by G.C. Ne~- et al., Arehiv ~ of Bioehemi-try _nd Blophy~ics 197, ~93 ~ ~99 E 1979~ le Rleo rats 30(body weight 300 - ~00 g) were treated for ll d_ys with 29~37~3 sltromin powdered feed to which 40 g of cholestyramine/kg of feed had been added. After decapitation, the liver was removed from the animals and placed on ice. The liver6 were comminuted and homogenized 3 times in 3 ~olumes of S 0.1 M ~ucrose, 0.05 M ~Cl, 0.04 M R~ pho~phate, 0.03 M
ethylenediaminetetraacetic acid, 0.002 m dithiothreitol tSPEI buffer pH 7.2 $n a Potter-Elve~em homogenizer. The mixture was then centrifuged at 15,000 g for 15 minutes and the sediment was discarded. The supernatant was sedimented at 100,000 g for 75 minute~. The pellet i~
taken up in 1/4 volume~ of SPE buffer, homogenized once more and then centrifuged again at 100,000 g for 60 minutes. The pellet iB taken up using a 5-fold amount of its volume of SPE buffer, homogenized and frozen and ~tored at -78-C (- enzyme ~olution).
For testing, the test compound~ (or mevinolin a~
a reference substance) were di~olved in dimethylfor-mamide with the addition of 5 vol.-% of 1 N NaOH and, u~ing 10 ~1, employed in the enzyme test in various concentrations. The test wa~ started after preincubation of the compound~ with the enzyme at 37-C for 20 minutes.
The test batch was 0.380 ml and contalned 4 ~col of gluco~e-6-phosphate, 1.1 mg of bovlne ~erum albumin, 2.1 ~mol of dithiothreitol, 0.35 ~mol of NADP, 1 unit of glucose-6-phosphate dehydrogenase, 35 ~mol of R~ phos-phate pH 7.2, 20 ~1 of enzyme preparation ~nd 56 nmol of 3-hydro~y-3-methyl-glutaryl-coenzyme A (glutaryl-3-1~C~
100,000 dpm.
After lncubating for 60 minutes ~t 37-C, the batch wa~ centrlfuged and 600 ~1 of the ~upernatant was Le A 26 759 - 41 -applied to a 0.7 x 4 cm column packed with a 5-chloride 100-200 mesh (anion exchanger). The column W48 sub-sequently wa~hed with 2 ml of di~td. water and 3 ml of Aquasol were added to runnings plus washing water and c~unted in an LRB scintillation counter. IC50 value~ were determined by intrapolation by plotting the percentage inhibition against the concentration of the compound in the test. In order to determine the relative inhibitory potency, the IC~ value of the reference ~ubstance mevino-lin was set at 1 and compared with the s~multaneouslydetermined IC50 value of the test compound.
The new active substances can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suit~ble excipient~ or solvents. In this connection, the therapeutically active compound ~hould in each ca~e be present in a concen-tration of about 0.5 to 98% by weight, preferably 1 to 90~ by weight, of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the act$ve compounds with solvent~ and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, lf appropriate organic olvents can be u~ed a- auxiliary olv nt-.
Example~ of auxillarie- which may be mentloned aret Le A 26 759 - 42 -2~37~3 water, non-toxic organic solvents, such as paraffins (for example mineral oil fractions), vegetable oils (for example groundnut~sesame oil), alcohol~ (for example:
ethyl alcohol, glycerol), excipients, such as, for example, ground natural minerals (for example kaolins, clays, talc, chalk), ground synthetic minerals (for example highly disperse silica, silicates), sugars (for example sucrose, lacto~e and dextrose), emulsifier~ (for example polyoxyethylene fatty acid esters, polyoxy-ethylene fatty alcohol ethers, alkylsulphonate~ andarylsulphonates), dispersing agents (for example lignin-sulphite waste liguors, methylcellulo~e, st~rch and poly-vinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
lS Admini~trstion is carried out in a customary manner, preferably ornlly, parenterally, perlLngually or intravenously. In the case of oral administration, t~blet~ may of course also contain additions, such as sodium citrate, calcium carbonate and dicalcium phosphate together with vsrious additives, such as starch, prefer-ably potato starch, gelatin and the like in addition to the excipients mentioned. Furthermore, lubricants, such as magnesium stearate, ~odium lauryl sulphate and talc can addition~lly be u~ed for t~bleting. In the case of agueous ~uspensions, variou8 flavor enhancers or colorants may be added to the active compounds in addi-tlon to the abovementionod auxiliaries~
In tho ca~e of parenteral administration, olu-tion~ of the active compounds u~lng ~ultable liquid excipient~ may be employed.

Le A 26 75~ - 43 -2~ 37~3 In general, it ha~ proved advantageou~ on in-travenous administrat$on to admin$ster amounts of about 0 001 to 1 mg~kg, preferably about 0 01 to O S mg/kg of body weight to attain effective results, and on oral S administration the dosage is about 0 01 to 20 mg/kq, preferably 0 1 to 10 mg/kg of body we~ght In ~pfte of thi~ it may be nece~sary to deviate from the amounts mentioned, depending on the body weight or the type of adm$ni~tration route, on individual behavior towards the medicament, the manner of its formulation ~nd the point $n time or interval ~t which administration takes place Thus in some cases it may be ~ufficient to manage with less than the minimum amount previously mentioned, lS whereas in other cases the upper limit mentioned must be exceeded In the case of the admini~tration of larger amounts, it may be advisable to divide these $nto a number of individual doses over the day Preparation examples Example 1 E,Z-2-Ethoxycarbonyl-1-(4-fluorophenyl)-4-methyl-pent-1-en-3-one F ~ ~COOCH2CH3 lCI~

O
A olution of 20 ml ~0 2 1) of piperidine and 12 ml (0 21 ~mol) of acetic ac~d ln 200 ~1 of i-opropanol is addod to 554 g (3 5 mol) of thyl l-obutyryl aoet~te and 434 g (3 5 mol) of 4-fluoroben~ldehyde ln 1 8 1 of Le A 26 759 - ~4 -2~L3~3 isopropanol. The mixture i8 ~tirred at room temperature for 1 day and concentrated in vacuo, and the residue is distilled in a high vacuum.
Yield: 796 g (86~ of theory) of yellowish oil S b.p.: 135 - 140-C (0.2 mbar) Example 2 6-Ethoxycarbonyl-5-(4-fluorophenyl)-1,2-dihydro-7-i~o-propyl-2-oxo-1,8-naphthyridine F

~COO~:H2CH~
~ N ~
66 g (0.6 mol) of 6-~mino-pyridin-2-one tO.A. Seide, A.I. Titow, 8er. dtsch. Chem. Ges. 69, 1884 (1936)] and 159 g (0.6 mol) of the compound from Example 1 are stirred at lOO-C for 3 h in 50 ml of dimethyl-formamide. All volatile constituents are then distilled off up to a b~th temperature of 200-C and a pressure of 0.3 mbar. The dark re~idue is filtered through 1 kg of silica gel u~ing chloroform and chloroform/methanol (10:1). After stripping off the olvent, a brown foum (60 g) rem~ins.
This crude product i- di-~olved in 0.7 1 of dichloromethane, 39.7 g (0.175 mol) of d~chloro-dicyano-p-benzoquinone ~r- ~dd d and th ml~ture 1- tlrred at room temperatur- for 1 h. After fllt-rlng off the pre-cipitate with uction from the reactlon mirture ~nd .
.

Le A 26 759 _ 45 -2 ~ 3 concentrating the filtrate, a residue r~main~ which i8 filtered through 1 kg of silica gel u~ing petroleum ether/ethyl acetate (S 1) to (2 1) The residue obtained from the filtrate is recrystallized from ethyl acetate/-S ether Yield: 21 7 g (10~ of theory) of colorless crystals m p 182 C
Example 3 5-(4-Fluorophenyl)-1,2-dihydro-6-hydroxy-methyl-7-iso-propyl-2-oxo-1,8-naphthyridine F

H ~
200 ml of a 1 5 molar ~olution of diisobutyl alumlnum hydride in toluene are added dropwi~e at -78 C
during the course of 2 h to a ~olution of 21 7 g (61 mmol) of the compound from ~xample 2 in 700 ml of anhydrous toluene and the mixture 18 stirred for a further hour at thi~ temperature It i8 then allowed to warm slowly to room temperature, during which 200 ml of water are cautiously added dropwise The mixture is filtered off with ~uction through ~ieselguhr and wa~hed with ethyl ac-tate, and the ~ie-elguhr 18 boilod ag~in with ethyl acetate Tho organic pha-e 1~ ~a~hed with ~odium chloride olutlon, drled over odium ulph~te and concentrated to dryne~ ~nd the re-idue i~ cry-tallized Le A 26 759 - ~6 -2~733 from ethyl acetate/ether.
Yield: 18.8 g (97~ of theory) of colorless crystals m.p.: 230-C (from ethyl acetate) Example 4 5-(4-Fluorophenyl)-6-formyl-1,2-dihydro-7-isopropyl-2-oxo-1,8-naphthyridine ¢~ ' ' ~
H
12.3 g of alumina and 25.9 g (120 mmol) of pyridinium chlorochromate are added to a ~olution of 18.8 g ~60 mmol) of the compound from Example 3 in 300 ml of tetrahydrofuran and the mixture iB ~tirred at room temperature for 1 h. It is filtered through 500 g of silica gel and washed with 1 1 each of dichloromethane, petroleum ether~ethyl acetate (lsl) and ethyl acetate.
The filtrate is concentrated on a rotary evaporator and the residue i~ cry~tallized from methanol.
Yields 13.3 g (71% of theory) of colorless cry~tals m.p.s 223-C

~ A 26 759 - 47 -20~37g3 Example S
(E)-3-[5-(4-Fluorophenyl)-1,2-dihydro-7-isopropyl-2-oxo-1,8-naphthyridin-6-yl]-prop-2-enal ~q ~ ~CHO

A ~olution of 13.1 g (S0 mmol) of diethyl 2-S (cyclohexylamino)-vinyl-phosphonate in 80 ml of tetra-hydrofuran is added dropwise at O-C under argon to a suspension of 3.0 g (100 mmol) of 80% strength ~odium hydride in 80 ml of anhydrous tetrahydrofuran and the mixture is stirred at this temperature for 30 min. A
solution of 13.0 g ~42 mmol) of the compound from Example 4 in 80 ml of tetrahydrofuran is then added dropwise at O-C-5-C and the mixture is then heated under reflux for 1 h. 200 ml of water are added cautiously and the mixture i8 extracted three times with ethyl acetate. After con-centrating the organic phases, the residue i8 heated under reflux for 2 h with a mixture of 500 ml of toluene, 500 ml of water and 27.5 g (218 mmol) of oxalic acid dihydrate. The toluene phase is concentrated and the residue i- treated with ethyl acetate. 11.35 g (80~ of theory) of colorless ory-tal~ of m.p. 261-C are obta~ned.

Le A 26 759 - 48 -20~L3r~33 Example 6 Methyl erythro-(E)-7-~5-~4-fluorophenyl)-1,2-dihydro-7-isopropyl-2-oxo-1,8-naphthyridin-6-yl]-3,s-dihydroxy-hept-6-enoate F

~ ~ COOCH3 ~' 5.47 g (50.7 mmol) of methyl acetoacetate in 5 ml of tetrahydrofuran are added dropwi~e at -5-C to O-C
under argon to a ~uspension of 1.69 g (56.4 mmol) of 804 strength sodium hydride in SO ml of anhydrous tetrahydro-furan. After 15 min, 41 ml (67.6 mmol) of 15% ~trength butyl lithium in hexane are added dropwise at the same temperature and, after a further 15 m$n, a ~olution of 5.68 g (16.9 mmol) of the compound from Example S in 150 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour, then 11.2 g of acet$c acid in 120 ml of water are caut$ou~1y added dropwise and the mixture i~ extracted three t~s with ethyl acetate. The organic pha~e~ are wa~hed with ~aturated ~odium hydrogen carbonate and sodium chlor$de solution, dr~ed over ~od~um ~ulphate and concentrated. 7.8 g of crude methyl-(~)-7-t5-(4-fluorophenyl)1,2-dihydro-7-i-opropyl-2-oxo-1,8-n~phthyridin-C-yll-5-hydroxy-3-oxo-h pt-6-enoate are obtained a- orange oll.
This crude product i~ dl~olved under argon in Le A 26 759 - 49 -2~137~3 100 ml of anhydrous tetrahydrofuran, 20.3 ml of a 1 M
solution of triethylborane in tetrahydrofuran are added and air iB passed through the solution for 5 min. The mixture i8 cooled to -78-C, 767 mg (20.3 mmol) of sodium borohydride are added, then 11 ml of meth~nol are 810wly added dropwise and the mixture is stirred for a further hour at -78-C to -75-C. The m~xture i~ then allowed to warm to room temperature, 53 ml of 30~ ~trength hydrogen peroxide and 50 ml of water being added dropwi~e from about -30-C. The mixture i~ extracted three time~ with ethyl acetate, and the organic phase~ are dried over sodium sulphate and concentrated. The residue is chro-matographed on 120 g of silica gel (230 - 400 mesh) using ethyl acetate/petroleum ether (2:1) to ~4:1). A color-less foam (4.09 g) i~ obtained, which is recrystallized from methanol/water.
Yield: 2.32 g (30% of theory) of colourless crystals m.p.: 148-C
Example 7 Sodium erythro-(E)-7-tS-(4-fluorophenyl)-1,2-dihydro-7-isopropyl-2-oxo-1,8-naphthyridin-6-yl]-3,5-dihydroxy-hept-6-ene-c~rboxylate F

~00~

100 mg (0.22 mol) of the oompound from E~ample 6 L5LJL;~i~Za~ - 50 2~13~3 are fitirred at room temperature for 1 h in 2.2 ml of tetrahydrofuran and 2.2 ml of 0.1 N sodium hydroxide solution. The solvent is ~tripped off and the residue is dried over phosphoru~ pentoxide in a high vacuum.
Yield: 85 mg of colorless crystals m.p.: from 170-C (dec.) Example 8 ~ethyl erythro-(E)-7-15-(4-fluorophenyl)-1,2-dihydro-7-isopropyl-l-methyl-2-oxo-1,8-naphthyridin-6-yl]3,5-dihydroxy-hept-6-enoate F

~ ~ COOCH3 A solution of 275 mg (0.6 mol) of the compound from Example 6 in 5 ml of d$methylformamide and 86 mg (0.6 mol) of methyl iodide ~re added to ~ ~olution of 69 mg (0.6 mmol) of pot~ssium tert.-butoxide in 5 ml of dimethylformamide ~nd the mixture iB stirred ~t room temperature for 4 h. A further 138 mq (1.2 rmol) of potas~ium tert.-butoxide ~nd 344 mg (2.4 mmol) of methyl iodide ~re then ~dded ~nd the mixture is ~tirred over-night. 2he mixture i~ poured into water ~nd extrscted three times wlth ethyl ~cet~te, ~nd the organlc ph~e is dried ~nd concentr~ted ~0.28 g of yellow oil). Column chrom~togr~phy on 20 g of llic~ gel ~230-~00 ~e-h) u-ing petroleum ether~ethyl ~cet~te (1~ nd ethyl ~cet~te ~e A 26 759 - Sl -20137~3 gives 52 mg (18~ of theory) of a colorless oil.

H-NMR (CDCl3)s ~ - 1.25 - 1.45 (m, 8H, CH(Ç~b)2 + 4-H);
2.45 (m, 2H, 2-X); 3.07 (d, lH, OH);
3.45 (sept~ lH, ~(CH3)2); 3.53 (d, S lH, OH); 3.72 (8, 3H; O-CH3); 3.9 (8, 3H, N-CH3); 4.1 (m, lH, C-H); 4.35 (m, lH, C-H); 5.3 (dd, lH, 6-H); 6.43 (d, lH, 7-H); 6.6 (d, lH, 3'-H); 7.13 (m, 4H, ~rom~tic-H); 7.28 (d, lH, 4'-H) ppm.
~xample 9 (E)-3-~1-Ethyl-5-(4-fluorophenyl)-1,2-dihydro-7-i~o-propyl-2-oxo-1,8-n~phthyridin-6-yl~-prop-2-enal ¢~ HO
~., lH2 1.0 g (3 mmol) of the compound from Ex~mple 5 ~re suspended in 20 ml of dimethylform~mide ~nd ~ ~olution of 366 mg (3.3 m~ol) of pot~ssium tert.-butoxide in 5 ml of dimethylform~mide ~nd 510 mg (3.3 mmol) of ethyl iodide in 1 ml of dimethylform~mide ~re ~uccessively ~dded dropwi~e. ~he mixture i- ~tirrod ~t 60-C for 90 min, poured $nto 150 ml of lc- w~t-r ~nd xtracted three tlmes with ethyl ~cet~te. The org~nlc ph~-es ~re drlod ~nd concentr~ted, ~nd the re~idue i- chrom~togr~phed on 30 g Le A 26 759 - 52 -2013 ~83 of ~ilica gel (230-400 mesh, column di~meter 2.5 cm) using petroleum ether/ethyl acetste (5sl) ~nd (3:1).
Yield: 850 mg (78%), colorless cryst~ls of melting point: 123-C.
S In analooy to example 9 are prepared starting from the compound of example 5:
F

~ HO

No. R Rea~ent m.p. Yield ExamDle C~2~ Esr-CH2--~3 164 8 X

11 --~ `CH

Example 12 Methyl erythro-(~)-7-[1-ethyl-5-(4-fluorophenyl)-1,2-dihydro-7-ieopropyl-2-oxo-1,8-n~phthyr~dln-6-yl]-3.5-dihydroxy-hept-6-enoate . F

¢1 ~OOCH3 J~, f~2 C}~3 Le A 26 759 - 53 -2~37~33 830 mg (2.3 mmol) of the compound from E~ample 9 are reacted analogously to the procedure of E~ample 6, 103 mg (3.4 mmol) of sodium hydride, 0.27 ml (2.5 mmol) of ethyl acetate ~nd 2.79 ml (4.6 mmol) of 15% butyl lithium being used.
Yield: 155 mg (14%) colorless crystal8, melting point llO-C
(crystallized from ether ~nd petroleum ether).

In analogy to example 12 are prepared:
F

OH OH

~N ~

No. R Starting m. p . lH-NMR
r~Example ¦ ¦ (Exarnple) l _I(COC13) 2,45 tm,2H) 1~ CH2 ~ 10 3 7 ~s 3H) 4,1 (m,lH) 4,35 (n,lH) 5,3 tdd,lH) 5,8 (5,2H) 6,4 (d,lH) 14 ~ 11 - 6,6 td,4H) Le A 26 759 - 54 -2~137~3 Example =I5 Sodium erythro-(E)-7-[l-ethyl-5-(4-fluorophenyl)-l~2-dihydro-7-isopropyl-2-oxo-1,8-naphthyridin-6-yl]3,5-dihydroxy-hept-6-ene-carboxylate ¢l ~oo N.'' 100 mg (0.2 mmol) of the compound from Example 12 are reacted analogously to the procedure of Example 7.
Yield: 82 mg (81%), colorless foam FAB-MA: 513 (100%, M + Na + H, 491/20~, M + H) ,Example 1~
trans-6-~2-[5-(4-(Fluorophenyl)-7-isopropyl-2-oxo-1,2-dihydro-1,8-naphthyridin-6-yl]-ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one F OH

92S mg ~2 mmol) of tho compound from ~xample 7 ~re dissolved in 20 ml c THF and 20 81 of wat-r, the solution is ot at pH S u-ing 1 N HCl, 384 mg ~2 ~mol) of N-(3-dimethyl d nopropyl)-N'-ethyloarbodi~mide are added ,e,, A 26 759 - 55 -2~137~3 and the mixture i~ stirred at room temperature for 1 day.
A further 192 g (1 mmol) of the carbodiimide are added and the mixture is stirred for 2 more days. Extraction is carried out with ethyl acetate; drying of the organic phase and chromatography are carried out on 30 q of silica gel (230 to 400 me6h) usinq chloroform and chloroform/methanol ~Ssl), and crystallization from chloroform/ether/petroleum ether gi~es 179 mg (2~%) of colorless cry~tal~ of m.p.s 233-C.
Example 17 tran~-6-{2-~ enzyl-5-~4-fluorophenyl)-7-isopropyl-2-oxo-1,2-dihydro-1,8-n~phthyridin-6-yl]-ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one OH

f~2 A solution of 73 mg ~0.65 mmol) of potassium - 15 tert.-butoxide in 1 ml of DMF and a ~olution of 110 mg ~0.65 mmol) of benzyl br~mide in 1 ml of DMF are added to a su6pension of 250 mg ~0.59 mmol) of the compound from ~x~mple 16 in 5 ml of DMF and the mixture i- tirred at 60-C for 2.5 h. Working up a- ln Fxamplo 8 ~ive- llS mg (38~) of colorless foam.

e A 26 759 - 56 -20137.~3 H-NMR (CDC13)s 6 - 1.25 ~d, 6H); 1.3 - 1.7 (m, 2H); 2.6 (m~ 2H); 3.4 (sept~ lH); 4.2 (m, lH);
5.1 (m, lH); 5.3 (dd, 3H); 5.8 (5, 2H); 6.5 (d, lH); 6.6 (d, lH); 7.0 -7.3 (m, 8H); 7.5 (m, 2H).
Example 18 trans-6-{2-tl-cy~nomethyl-5-(4-fluorophenyl)-7-isoprop~l-2-oxo-1,2-d~hydro-1,8-nnphthyridln-6-yl]-ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyr~n-2-one OH

~, l H2 CN
The title compound i8 prep~red analogously to the procedure of Ex~mple 8 from 120 mg (0.28 mmol) of the compound from Ex~mple 7, 57 mg (0.5 mmol) of potas~ium tert.-butox~de and 38 mg (0.5 mmol) of chloroaceto-nitrile.
Yield: 68 mg (53~) of beige oil.

H-NMR (CDC13) 6 - 1.37 (d, 6H); 1.4 - 1.8 ~m, 2H~; 2.25 ~b, lH); 2.65 ~m, 2H); 3.45 ~sept, lH)t 4.25 ~m, lH); S.lS ~m, lH)~ 5.38 (dd, lH)~ 5.47 (-, 2H)~ 6.03 (d, lH)~
6.12 (d, lH)~ 7.13 (m, 4H); 7~38 (d, 2~137~3 Example 19 (E)-3-~2-Chloro-5-(4-fluorophenyl)-7-i~opropyl-1,8-naphthyridin-6-yl]-prop-2-enal F

~3 Cl ~ CH0 7.8 g (23 mmol) of the compound from Example S
are heated to 75-C in 20 ml of phosphorus oxychloride.
After a clear solution has formed, the mixture i~ con-centrated in vacuo, the residue iB di~solved in ethyl acetate, and the solution i8 poured into ice water and stirred vigorously. The ~queous phase i~ extracted twice with ethyl acetate, the combined organic phase~ are dried and the solvent i~ ~tripped off. 5.78 g (71S) of color-less crystal~ of m.p.s 142-C cry~tallize from ether.
The compounds shown in ~able 1 are prepared by the following procedure or by ~nalogous methodss A solution of 167 mg (1.55 mmol) of benzyl alcohol in 1 ml of IHF is added dropwi~e at O-C to a suspen~ion of 46 mg (1.55 mmol) of 80S strength sodium hydride in 5 ml of THF and the mixture i~ stirred for 15 min~
A olutlon of 0.5 g (1.4 mmol) of the compound from ~xample 19 in 5 ml of THF 1- added dropwl-e at the ~me temperature ~nd the mixture 1- then tlrred at room temperature for 2.5 h. 1.6 ml of acetic acld in 20 ml of e A 26 759 - 58 -2~ 1 37~3 water are added, the mixture is extracted twice with 20 ml of ethyl acetate, the combined organic pha~es are dried and concentrated, and the residue is chromato-graphed on 20 g of silica gel 230-400 mesh using S petroleum ether/ethyl acetate 6~ 3:1.
286 mg (49%) of colorless crystals of m.p.:
182C crystallize from ether/petroleum ether.

Lç_~ 26 759 - 5S - .

20137~3 _ 65L9Z ~r ~_ O~
!~ _ ~ N N 'O ~ .

~ 0 N ~ 2 ~, à~ 2' ~ -O ~ 8. 0 `C~

8 u ~ , U ~ , u x;
U ` ~ U ` ~
o ~ ~ ~ ~ ~ Z--U X
8 ~ z ~ Z N ~ ~ s _ u ~ u u 0 O _I N ~ ~t E-1~; z ~ N (~

2~137~3 The compounds shown in Table 2 were prep~red from the compounds of Examples 19, 20, 21, 22, 23 and 24 in analogy to the procedure of Example 12.

Table 2: 1 OH OH
~ ~ COOCH3 Example R m.p. (-C) lH-NNR
No. solvent (CDCl3) _ 25 -O-CHz~C0Hs 170 ether 26 -OCH3 155 ether/
petroleum ether 27 -O-CH2-C(CH3)3 amorphous 1.08 (~, 9H);
2.45 (m, 2H);
3.73 (8~ 3H);
4.1 (m, lH);
4.3 (8, 2H);
4.36 (m, lH);
6.57 (d, lH);
7.15 (m, 4H);
7.58 (d, lH) 28 -S-CH2-C~Hs 165 29 -N-CH2-C~H5 134 ether CH~
Cl 207 ether Le A 26 759 - 20137~3 The compounds shown in Table 3 were prepared in analogy to the procedure of Example 7.

Table 3: F

~ ~ COO Na ~ . -Example Y Starting Yield m.p. FAB-MS
No. Compound (%~ C
_ _ _ _ _ _ _ _ _ 31 Cl-C=N- 30 92 decomposi-tion from 32 ~ CH2-O-C=N- 25 100 amorphous 575 ~M+Na`
553 (M+Na) 33 o l N~ 10 92 Tt.~ e a~preci~t.e~ that the instant. snecifica~ion : anc claims are set forth by way of illustration and not li-mitation, and that various modifications and changes may be made without departing from the spirit and scope of the pre-sent invention.

Ie A 26 759 - 62 -

Claims (9)

1. A substituted 1,8-naphthyridine of the formula in which A - represents a 3- to 7-membered heterocycle which contains 1 to 4 sulphur, oxygen or nitrogen heteroatoms and which is optionally substituted by identical or different substituents said substituents being halogen, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, or A
- represents aryl having 6 to 10 carbon atoms which is optionally substituted by identical or differ-ent substituents said substituents being straight-chain or branched alkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl in each case having up to 10 carbon atoms, which may in turn be substituted by hydroxyl, alkoxy having up to 6 carbon atoms, phenyl or by a group of the formula -NR1R2, in which Le A 26 759 -63-R1 and R2 are identical or different and - denote hydrogen, aryl or arylsulphonyl having 6 to 10 carbon atoms, straight-chain or branched alkyl or alkylsulphonyl having up to 8 carbon atoms, where the last mentioned radicals are optionally substituted by aryl having 6 to 10 carbon atoms, - or R1 and R2 each independently denote a group of the formula -COR3 in which R3 - denotes straight-chain or branched alkyl or alkoxy having up to 8 carbon atoms, or phenyl, or the A aryl substituent may be aryl, aryloxy, arylthio or arylsulphonyl having 6 to 10 carbon atoms, or halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, benzyloxy or a group of the formula -NR1R2, in which R1 and R2 have the abovomentioned meaning, B - represents cycloalkyl having 3 to 8 carbon atoms, - represents straight-chain or branched alkyl having up to 12 carbon atoms, which is optionally substituted by halogen, trifluoromothyl or alkylthio having up to 8 carbon atoms, Le A 26 759 - 64 -- or B represents aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, cyano, nitro, trifluoromethyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, or amino, D and E are identical or different and - represent hydrogen, halogen, mercapto, hydroxyl, alkoxy having up to 8 carbon atoms, straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, phenoxy, halogen, trifluoromethyl or alkylthio having up to 8 carbon atoms, or repre-sents a group of the formula -NR1R2, in which R1 and R2 have the abovementioned meaning, or D and E each independently - represent aryl, aryloxy or arylthio having 6 to 10 carbon atoms, which is optionally substituted by halogen, cyano, nitro, trifluoromethyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, or amino, Y - represents a group of the formula or Le A 26 759 - 65 -in which J - denotes hydrogen, hydroxyl, mercapto or halogen, or denotes straight-chain or branched alkyl, alkoxy or alkylthio having up to 10 carbon atoms, which are optionally substituted by phenyl, or denotes aryloxy, benzyloxy or arylthio having 6 to 10 carbon atoms or a group of the formula -NR1R2, in which R1 and R2 have the abovementioned meaning, Z - denotes oxygen or sulphur, G - denotes hydrogen, straight-chain or branched alkyl or alkenyl in each case having up to 10 carbon atoms, which is optionally substituted by halogen, cyano, alkoxy having up to 8 carbon atoms, benzyloxy, aryl or aryloxy having 6 to 10 carbon atoms, by a 5- to 7-membered heterocycle having 1 to 4 nitrogen, oxygen or sulphur heteroatoms or by a group of the formula -NR1R2, -COR3 or -COOR4, in which R1, R2 and R3 have the abovementioned meaning, R4 - denotes hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by Le A 26 759 - 66 -hydroxyl, phenyl, halogen or cyano, - denotes aryl having 6 to 10 carbon atoms, which may in turn be substituted by halogen, amino, hydroxyl, nitro or cyano, X - represents a group of the formula -CH2-CH2- or -CH=CH-, and R - represents a group of the formula in which R5 - denotes hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms and R6 - denotes hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by phenyl, or R6 - denotes aryl having 6 to 10 carbon atoms or a cation, and their salts.

Le A 26 752 - 67 -

2. A substituted 1,8-naphthyridine according to claim 1 of the formula or in which A - represents pyridyl or pyrimidyl, which is optionally substituted by identical or differ-ent substituents said substituents being fluorine, chlorine, bromine, trifluoromethyl, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, - or A represents phenyl or naphthyl, which is optionally substituted by identical or differ-ent substituents said substituents being straight-chain or branched alkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, which may in turn be substituted by hydroxyl, alkoxy having up to 4 carbon atoms, phenyl or by a group of the formula -NR1R2, in which R1 and R2 are identical or different and - denote hydrogen, phenyl, phenylsulphonyl, straight-chain or branched alkyl or alkylsulphonyl having up to 6 carbon Le A 26 759 - 68 -atoms, benzyl or benzylsulphonyl, or - denote a group of the formula -COR3, in which R3 - denotes straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms or phenyl, or the phenyl or naphthyl may be substituted by phenyl, phenyloxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy, benzyloxy or by a group of the formula -NR1R2, in which R1 and R2 have the abovementioned meaning, B - represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, - represents straight-chain or branched alkyl having up to 10 carbon atoms, which may option-ally be substituted by fluorine, chlorine, bromine, trifluoromethyl or methylthio, D and E are identical or different and - represent hydrogen, hydroxyl, alkoxy having up to 6 carbon atoms, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or a group of the formula -NR1R2, Le A 26 759 - 69 -in which R and R2 have the abovementioned meaning, Y - represents a group of the formula or in which J - denotes hydrogen, hydroxyl, mercapto, fluorine, chlorine or bromine, or denotes straight-chain or branched alkyl, alkoxy or alkylthio having up to 8 carbon atoms, phenyl, or denotes phenoxy, benzyloxy or a group of the formula -NR1R2, in which R1 and R2 have the abovementioned meaning, Z - denotes oxygen or sulphur, G - denotes hydrogen, straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, cyano, alkoxy having up to 6 carbon atoms, phenyl, phenoxy, benzyloxy, pyrryl, furyl or by a group of the formula -NR1R2, -COR3 or -COOR4, Le A 26 759 - 70 -in which R1, R2 and R3 have the abovementioned meaning, R4 - denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine or bromine, - denotes phenyl which may in turn be substituted by fluorine, chlorine, bromine or hydroxyl, X - represents a group of the formula -CH2-CH2- or -CH=CH-and R - represents a group of the formula or in which R5 - denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms and Le A 26 759 - 71 -R6 - denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or benzyl, or - denotes phenyl or a cation and their salts

3 A substituted 1,8-naphthyridine according to Claim 1, in which A - represents phenyl which is optionally substituted by identical or different substituents said substituents being straight-chain or branched alkyl having up to 6 carbon atoms, which may in turn be substituted by hydroxyl, methoxy, ethoxy, propoxy or phenyl, or is substituted by phenyl, phenoxy, fluorine, chlorine, bromine or benzyloxy, B - represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, - represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl or trifluoromethyl, D and E are identical or different and - represent hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy, Y - represents a group of the formula Le A 26 759 -72- or in which J - denotes hydrogen, hydroxyl, fluorine or chlorine, or denotes straight-chain or branched alkyl, alkoxy or alkylthio having up to 6 carbon atoms, which are optionally substituted by phenyl, or denotes benzyl-oxy or a group of the formula -NR1R2, in which R1 and R2 are identical or different and - denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or benzyl, Z - denotes oxygen or sulphur, G - denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by fluorine, chlorine, cyano, alkoxy having up to 4 carbon atoms, phenyl, benzyloxy or by a group of the formula -COR3 or -COOR4, in which R3 - denotes straight-chain or branched alkyl or phenyl, Le A 26 759 - 73 -R4 _ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, X - represents a group -CH=CH- or -CH2-CH2-and R - represents a group of the formula or in which R5 - denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.butyl and R5 - denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl or benzyl, or - denotes a sodium, potassium, calcium, magnesium or ammonium ion and their salts.

Le A 26 759 - 74 -

4. A substituted 1,8-naphthyridine according to claim 1, in the form of a racemate or as an individual stereoisomer or enantiomer.

5. A pharmaceutical composition useful as an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase comprising at least one substituted 1,8-naphthyridine according to claim 1 and an inert, non-toxic pharmaceutically suitable excipient or solvent.

6. A pharmaceutical composition useful for the treatment of hyperlipoproteinaemia, lipoproteinaemia or atherosclerosis or for lowering blood cholesterol content comprising at least one substituted 1,8-naphthyridine according to claim 1 and an inert, non-toxic pharmaceutically suitable excipient or solvent.

7. A method of inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase activity comprising ad-ministering to a patient in need of such an inhibiting treatment an effective amount of at least one substituted 1,8-naphthyridine according to claim 1.

8. A method of teating hyperlipoproteinaemia, lipo-proteinaemia or atherosclerosis comprising administering to a patient in need of such treatment an effective amount of at least one substituted 1,8-naphthyridine according to claim 1.

9. A method of lowering blood cholesterol content in a patient comprising administering to a patient requiring lowering of blood cholesterol content an effective amount of at least one substituted 1,8-naphthyridine according to claim 1.
Le A 26 759