CA2078590A1 - 2-hydroxymethylpyridines, the corresponding pyridine n-oxides and their derivatives, processes for their preparation and their use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE: HOE 91/F 291K

2-Hydroxymethylpyridines, the corresponding pyridine N-oxides and their derivatlves, processes for their preparation and their use 2-Hydroxymethylpyridines and their pyridine N-oxides according to formula I, and their use as pharmaceuticals for administration as fibrosuppressants and for influenc-ing the metabolism of collagen and collagen-like substances.

Description

2~78~9~
- ~ 'HST AKTIE~GES~LLSCHAFT HOE 91/~ 291 K Dr. Fi/St Description 2-Hydro~ymethylpyridines, the corresponding pyridine N-oxides and their derivatives, processes for their preparation and their use Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase cause a very selective inhibition of collagen bio~ynthesis by affecting the colla~en-specific hydroxylation reactions. In its course, protein-bound proline or lysine is hydroxylated by th~ enzymesproline hydroxylase or lysine hydroxyla~e. If this reac-tion is suppressed by inhibi~ors, a non-functional, underhydro~ylated collagen molecule results, which can be dissipated into the extracellular space by the cells only in a small amount. The underhydroxylated collag~n can additionally not be incorporated into the collagen matrix and is very easily degraded by proteolysis. As a conse-quence of these effects, the amount of extracellularly deposited collagen is as a whole decreased.

It is known that the enzyme proline hydroxylase is - effectively inhibited by pyridine-2,4- and -2,5-dicar-boxylic acid (K. Majamaa et al., Eur. J~ Biochem. 138 (1984) 239-245). In cell culture, however, these com-pounds are only active as inhibitors in very high concen-trations (Tschank, G.. et al., Biochem. J. 238 (1987) 625-633).

In EP-A-0,176,7411 pyridine-2,4- and -2,5~dicarboxylic acid diesters having 1-6 carbon atoms in the ester alkyl moiety are described as pharmaceuticals for the inh.ibi-tion of proline hydroxylase and lysine hydroxyla~e. Theselow-alkylated diesters, however, have the disadvantage that they are rapidly cleaved in the body to give the acids and do not pass in sufficiently high concentration to their site of action in the cell and are thus little suited for possible administration as a pharmaceutical.

- 2 20~8~0 EP-A~0,278,453, EP-A-0,27~454 and EP-A-0,278,452 des-cribe in yeneral form mixed esters/amide~ and higher alkylated diesters and diamides of pyxidine-2,4- and -2,5-dicarboxylic acid which effectively inhibit collagen biosynthesi~ in the animal model.

Thus, EP-A-0 r 27B,453 describes, inter alia, ~he ~ynthe~i~
ofN,N'-bis(2-methoxyethyl)pyridine-2,~-dicarboxamideand N~N~-bis(3-isopropoxypropyl)pyridine-2~4-dicarbox~mlde.

European Patent Application EP-A-0,353,668 proposes an Lmproved process for the pxeparation of N,N'-bis(2 methoxyethyl)pyridine-~,4-dicarboxamide. European Patent Application ~P-A-0,409,119 proposes novel N,N'-bis-(alko~yalkyl)pyridine-2,4-dicarboxamides.

German Patent Application P 40 01 002.3 propose~ pyri-dine-~,4- and -2,5-dicarboxylic acid di(nitroxyalkyl)-amides for the inhibition of colla~en biosynthesis.

The necessity existed to ~eek other compounds whi~h have a stronger antifibrotic activity.

Surprisingly, it has now been ound that pyridine deriva-tives which have a methyl ox a hydroxymethyl group,optionally protected by an alcohol protective group, in the 2-position possess a stronger antifibrotic action.

The invention therefore relates to pyridine derivatives of the formula I

~ ~ (I) ()n in which - 3 - ~07~90 Rl, R4 and one of the two radicals R2 or R3 are identical or different and are hydrogen, halogen, in particular fluorine, chlorine or bromine, cyano, nitro, trifluoromethyl, (cl-cl2)-alkyl, hydroxyl, ~Cl-C6)-hydroxyalkyl, (cl-c,2)-alkoxy~
O-[CHz-]~C HsZ~+l-~)F8~ -OCF2Cl, -O-CF2-CHFCl, ~C1-C8)-alkylmercapto, (C1-Ca)alkylsulfinyl, (Cl-C~)-alkyl-sulfQnyl, (Cl-C~-alkylcarbonyl, (C~ 6)-alkoxy-carbonyl, carb~moyl, N (cl-c43-alkylc~rbamoyl~
N,N-di-( Cl-c4 ) ~alkylcarbamoyl, ( Cl-C3 )-alkyl_ carbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzylr phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenyl~ulfinyl, or -NR -R , (Cl-Cl2)~alkoxy-(Cl-Cl2)-alkYl or (Cl-Cl2)-alkoxy-(Cl-Cl2)-alkoxy, or an unsubstitu~ed or substituted (C6-Cl2)-aryloxy radical or (c~-c~ aralkyloxy radical which carries 1, 2, 3, 4 or 5 identical or different substituents from the series comprising halogen, cyano, nitro, trifluoromethyl, (Cl-C6)-alkyl, (C1-C6)-hydroxyalkyl, (~1~C6)-alkoxy, -O- ~ CH2- ]xC H~2~ 8)F~ CF2Cl ~ -0-~2-CHFCl t (Cl-C6)-alkylmerc:apto, (C~ ::6)-alkylsulfinyl, tCl-C6)-alkylsulfonyl, ~C1-C6)-alkylcarbonyl, (Cl-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-carbamoyl, N,N-di-(Cl-C4)-alkylcarb~moyl, (C~-C6~-alkylcarbonyloxy, (C3-C83-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenyl-3Q mercapto, phenylqulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-di-(cl-c4)-alkylsulfamoyl/ in particular up to 3 of the abovementioned identical or different sub-stikuents, in the aryl moiety, and the other radical, R2 or R3, corresponds to the following formula II

~ 4 ~ 2~78~

X R~
f~ ~
-~-N (II) in which X is O or 5, R5 is a branched or unbranched (cl-cl2)-alkyl radi-cal, (C1-C~2)-alkenyl radical or 5Cl-C,~)-alkynyl radical which is monosubstituted ar polysub-stituted by halogen, hydroxyl, cyano, amino, ~ar-boxyl (Cl-C10)-alkoxy, (Cl-Cl2)-alkoxyc3rbonyl9 (C3-CB)-cycloalkoxycarbonyl, ~C7-C,6) aralkoxycarbonyl, 1 O ( C6_~12 ) _arY1XYCaXbO~Y1~ ( C~-C12 )-alkylcarbonyloxy, (C~-C~2)-alkanoylamino, ( C3_CB )-cycloalkanoylamino, (C~-Clz)-hydroxyalkanoylamino,(C6-Cl2)-aroyl~nina, (C7-Cll)-aralkanoylamino, ~Cl-C8)-alkoxy-tC~-Cl2)-alkanoylamino, (Cl-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy~(Cl-C~)-alkoxycarbOnylOxy~ ( C6_C12 )-arYloXY-carbonyloxy, (C7-C,1)-aralkyloxycarbonyloxy, ( C7_ C11)-aralkylcarbonyloxy, (C6-C~2)-arylcarbonyloxy, (C3-C8)-alkenylcarbonyloxy, (c3-cE~)-alkynyl-carbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (Cl-C,2)-alkoxy-(Cl-C~2)-alkoxy, (C,-Cl2)-alkoxyamino, (C~-C12)-alkoxy-N-(C1-C6)-alkylamino, (Cl-cl2)-alkox~-N,N-(C1-C6)-dialkylamino, carbamoyloxy, N-(c~-ca)-alkylcarbamoyloxy~ N~N~Di~(Cl~C8)~alkYl~
carbamoyloxy, N- ( ~3_CB ) -CYC loalkylcarbamoyloxy~
(Cl-CB)-alkylmercapto, (Cl~Ca)-alkylsulfinyl, (Cl-CB )-alkylsulfonyl/ (C1-C~)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,nitro,trifluoromethyl,phenyl-mercapto, phenylsulfonyl, phenylsulfinyl, sul-famoyl, N-(C1-C6)-alkylsulfamoyl, N,N-di-(Cl-C6)-alkylsulfamoyl, tCl-C8)-alkylsulfonamido, arylsul-fonamido, carbamoyl, N-(Cl~C8)-alkylcarbamoyl, 2~78~
N,N-di-(Cl-C8)-alkylcarbamoyl~ ~-[c3-ca~-cycloalkylcarbamoyl, N-l CB-C12 )-arylcarbamoyl, N-(C,~C16)-aralkylcarbamoyl, N-(cl-clo)-a~yl-N-( ~6-C 12 ) -arylcar~amoyl, N-(cl-clo)-~lkyl-N-( C7_~1B ) ~
aralkylcarbamoyl, N-(( C1-CB )-alkoxy-(C1-C4)-alkyl)-carbamoyl, N-~(C1-C4)-hydroxyalkyl)carbamoyl or an O-acylated derivative thereof, or by a subætituted (C6-Cl2)-aryl radical, a (C7-C~
aralkyl radic 1 or a heteroaryl radical which carries 1, 2, 3, 4 or 5 identical or different substitu~nts from the series compri~ing hydroxyl, halogen, cyano, nitro, (Cl-C6) alkyl, (C1-C6)-alkoxy, trifluoromethyl, (Cl-C6)-hydroxyalkyl, -O-[CH2-]XCf~(2ffl-8)F~, OCF2Cl, ~OCFa-CHFCl, (Cl-C6)-alkylmercapto, ( C1-C6 ) -alkylsulfinyl, ~ C1-C6 ) ~
alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C8)^
alkoxycarbonyl, carbamoyl, N-(C1-C8)-alkyl-carbamoyl, N,N-di-( C1-C B )-alkylcarbamoyl, (C1-C~)-alXylcarbonyloxy, ( C3_C~ )-cycloalkyl, phenyl/
benzyl, phenoxy, benzyloxy, NR~ R~ phPnyl-mercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(Cl-C4)-alkylsulfamoyl and N,N-di ( C~-C4 )-alkylsulfamoyl, in particular up to three of the abovementioned identical or different substituents, in the aryl moiety, or by a substituted, (C6-Cl2)-aryloxyradical, (C7-Cll)-aralkyloxy radical or a heteroaryloxy radical which carries 1, 2, 3, 4 or 5 identical or dif-ferent substituents from the series comprising hydroxyl, halogen, cyano, nitro, ( C1_CB )-alkyl, (cl-c6)-alkoxy~ trifluoromethyl, (Cl-C6)-hydroxy-alkyl, -O- E CH2- ] ,~CfH(2f~l-8~F3 ~ -~CF2Cl, -OCF2-C~FCl, (cl-c6)alkylmercapto~ (Cl~C6)-alkyl~ulfinyl, (Cl-Cfi ) -alkylsulfonyl, (Cl-C6)-alkylcarbonyl, (Cl-C6)-alkoxycarbonyl, carbamoyl, N-(Cl-C4)-alkyl-carbamoyl, N,N-di-(Cl-C4)-alkylcarbamoyl, - 6 - 2~7~59~
~Cl-C6)-alkylcarhonyloxy, ( C3-C~ ~ -CyC loalkyl, phenyl, benzyl, phenoxy, benæyloxy, NR'-R", phenylmercapto, phenyl 8U1 fonyl, phenyl~ulfinyl, sulfamoyl, N-(Cl-C4)-alXyl 8ul famoyl an~ N,N-di-(Cl-C4)-alkylsulfamoyl, in particular up to three of the abovemen~ioned identical or different substituents, in t~le aryl moiety, R6 is a (C1-Cl2)-alko~y radic l~ (C3-C~)-cycloalko~y r~dical or a (C6-Cl2)-aryl radical, (c7-cll3-ar~lk radical or a heteroaryl radical, which carries 1, 2, 3, 4 or 5 identical or different ~ub-stituents from the series comprising hydro~l, halogen, cyano, nitro, ( Cl-C6 ) -alkyl, ( C1-C6 ) -alkoxy, trifluoromethyl, (C1-C6)-hydroxyall~l, -O-~CH2-]xc~H(z~+l-8)F8~ -OCF2Cl, ~OCF2 CHFCl, (Cl-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, ~Cl-C6)-alkylsulfonyl, ~Cl-C6)-alkylcarbonyl, ~Cl-C6)-alkoxycarbonyl, carbamoyl, N-(C1-Ca)-al~
: carbamoyl, N,N~di-(C1-C~)-alkylcarbamoyl, N-( C3-2 0 C6 ) -cycloalkylcarbamoyl, N- ( C6-Cl2 ) -arylcarbamoyl, N- ( C7-Cl6 ) -aralkylcarbamoyl, N- ( Cl-C10 ) -alkyl-N- ( C6-Cl2 ) -arylc arbamoyl, N- ( Cl-C10 ) -alkyl -N- ( C7-Cl6 ) -aralkylcarbamoyl, (C1-C6)-alkylcaxbonyloxy, (C3-c8)-cycloalkyl~ phenyl, benzyl, phenoxy, ben-zyloxy, NR'-R", phenylmercapto, phenyl~ulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsul~
famoyl and N,N~di-(Cl-C4)-alkylsulfamoyl, in par-ticular up to three of the abovementioned identi-cal or different sub~tituents, in the aryl moiety, in which in each case R' and R" are identical or different and are hydrogen/ (C6-C~ aryl, (Cl-C8)-alkyl, (Cl-C8)-aminoalkyl, N-(cl-ca)-alkylamino-(cl-c 12 ) -alkyl, N~N-di-(C1-c8)-alkylamino-(cl-c~2)-alkyl~ 1 C7-C14 ) -aralkyl, or are together -[CH2~n-, in which one CH2 group can be replaced by 0, S, N-(C~-C4)-alkanoylimino ~ 7 ~ 2~ 7~ ~ 0 or N-~C1-C~)-alkoxycarbonylamino, and R6 can be substituted by a radical of the formula III

~ ~ Z (III) in which Z is an amino acid or a derivative thereof/ bonded via its acyl radical, or R5, or by a radical of the formula IV

- CO - V ~IV) in which U is a polypeptid~ bonded via the amino group, preferably a tripeptide or a dipeptide, or an amino acid derivative bonded via the amino group, preferably an L-amino acid derivative, in parti-cular an L-alanine or a glycine derivakive, R7 independently of RB, can be hydr~gen or R6, where the radicals R5 and R7, together with the nitrogen atom, also form a 5-, 6- or 7-membered saturated heterocyclic ring, which heterocyclic ring can also contain a second nitrogen atom and which heterocyclic ring for its part can be substituted by phenyl or phenyl-Cl-C3-alkyl, Y is methyl or CH-oR5, in which 25 R5 is hydrogen, Z or the radical of a physio-logically tolerable alcohol protective group which can preferably be removed in ~he liver or under physiological conditions, and - 8 - 2~78~
n is 0 or 1 f is 1 to 8, preferably 1 to 5, g is 0 or 1 to (2f+1) and x is 0, 1, 2 or 3, preferably 0 or 1, plus all derivatives which have a protective group in the corresponding amino or hydroxyl group, and ~he physio-logically active salts.

Halogen is understood as meaning fluorine, chlorine, bromine and iodine, aryl as meaning phenyl and naphthyl and heteroaryl as meaning 5- and 6-membered aromatic rings having 1, 2 or 3 ni~rogen and/or oxygen and~or sulfur atoms which can optionally also be benzo-fused; in particular, the heteroaryl radicals are pyridyl, pyri-dazyl, pyrimidyl, pyrazyl, 1,3,5~triaæyl, pyrrolyl, pyrazolyl, Lmidazolyl, triazolyl, thienyl, o~azolyl and thia~olyl radicals and optionally their benzo-fused derivatives.

An alkyl radical is understood as meaning a linear, branched or cyclic radical having 1-12 carbon atoms. If cyclic alkyl radicals are present, these have 3-10, preferably 5 or 6 carbon atoms. Branched alkyl radical~
are all the more frequently preferred, the larger the number of carbon atoms.

The alkyl radicals can al~o be monounsaturated or poly-unsaturated. Saturated al~yl radicals, however, are preferred. If, however, unsaturated radicals are present, they are preferably linear unbranched radicals.

Said alkyl radicals can contain both chiral, and achiral, carbon atoms.

2~78~
The radical ~C~-C~ aralkyloxy is preferably understood as meaning a sub6tituted ph~nylalkyloxy radical of the formula V
R~ R7 --I~H2~

Rl~ ~9 (~) in which R6, R7, R8 and R10 are identical or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1 C6)-alkyl, (cl-c6)-alkoxy/ -O-`~C~2-~xcf~2f~l-4)F8r -OCF2Cl, -O-CF2-CHFCl,(Cl-C6)-alkylmercapto,~C~-C6)-a~kylsulfirly~, (Cl-C6)-alkylsulfonyl, (cl-c6)~a~ carborlyl; (Cl-c6)-alko~ycarbonyl, carbamoyl, N-(Cl-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (Cl-C6)-alkylcarbonyloxy, (C3-C6)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'R~, ~uch as amino, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(Cl C4)-alkylsulfamoyl or N,N-di-~Cl-C4)-alkylsul~amoyl, or two adjacent substituents are ~ogether a chain ~~C~~]n or -CH=CH-CH=C~ , where one CH2 group of the chain is optionally replaced by 0, 5, SO, SO2 or NR~, and v = 1, 2, 3, or 4, preferably O and 1.

Preferred compounds of the formula I are those in which R1, R4 and one of the two radical6 R~ or R3 are identi-cal or different and are hydrogen, halogen, in particular fluorine, chlorine or bromine, ~C1-C5)-alkyl, hydroxyl, (Cl-C53-alko~y, (Cl-C5)-alkoxy-~5 carbonyl, (Cl-C8)-alkylcarbonyloxy, NR'-R", (Cl-C4 ) -alkoxy-(cl-c6)-alkyl~ tc~-c6)-alkoxy-(cl-c6)-alkoxy or a substituted (C6-C12)-aryloxy or ( C7-Cl,)-aralkyloxy radical which carries, 1, 2 or 3 identical or different substituents from the lo 2~78~9~
series comprising halogen, in particul~r fluorine or chlorlne, cyano, tri1uoromethyl, (C1-C5)-alkyl, (cl-c6)-alkoxy~ ( Cl-c5 3-alkyl~arbOnYl, tC1-C5 )-alkoxycarbonyl, in which S R~ and ~ are identical or different and ~re hydrogen, (C6-C~2)-aryl, ~C,-Ca)-alky1 or ~C1-C6)-alkyl carbonyl, n is O or 1 and the o~her radical R2 or R3 corresponds to the formula II, in which X is Q, Y is CH2-oR5, R6 is a branched or unbranched ~C~-CB)-alkyl radical which is monosubstituted or disubstituted, in par~icular monosubstitutedl by hydroxyl, (C1-C~O)-alkoxy, ~Cl-Ca)-alkoxycarbonyl~ (C3-C8)-cyclo~
alkoxycarbonyl, (C~-C12)-aralkoxycarbonyl, ~C6-C1O)-aryloxycarbonyl, carbamoyl, N-~(C1_CB)_ alkoxy~Cl-C2)-alkyl)carbamoyl,N-t(Cl-C4)~hydroxy-alkyl)carbamoyl or an O-acylated derivative thereof, (C,-Cl2)-alkylcarbonyloxy, carboxyl, ~Cl-C6)-alkoxycarbonyloxy, ~C6-Cl2)-aryloxycarbonyloxy, ~ C7-c11~ -aralkyloxycarbonyloxy, ( C7-c11 )-aralkyl~
carbonyloxy, (C~-Cl2)-arylcarbonyloxy, (C -C )-cycloalkylcarbonyloxy, carbamoyloxy, N-(Cl-C6j-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkyl-carbamoyloxy, N-(C3-Ca)-cycloalkylcarbamoyloxy, (Cl-C9)-alkylcarbonyl,(C3-C8)~cycloalkylcarbonyl, NR'R" or the acyl radical of an N-deriva~ized amino acid, or by a substituted ~C~-C12)-aryl radical which contains one or two substituents from the series compris-ing halogen, in particular fluorine, chloxine, 2~378~9~
trifluorometh~1, hydroxyl, (~ 4 )-alkoxy~ (Cl-C5) -~lkyl, (Cl-CB)-alkylcarbonyloxy, (C1-Cs)-alkoxycarbonyl, tCl-C4~-hydroxyalkyl, or by a substituted ~c~-cl2)-aryloxy radical, (C7-Cll)-aralkyloxy radical or a heteroa~yloxy radical, in particular a phenoxy radical or a benzyloxy radical, which contains one or two ~ub~tituents from the series comprising hydro~yl, ( Cl-C4 ) -alkoxy, (Cl-C5)-alkyl, (C~-C6)-alkylcarbonylo ~, ( Cl-C6 ) -alkoxycarbonyl, ( Cl-C4 )-hydroxyalkyl, R6 is a (C6-Cl2)-aryl r~dical which is substituted once r twice or three times by hydroxyl, halogen, in particular chlorine or bromine, cyano, nitro, ~C1-C6)-alkyl, (C1-C~)-alkoxy, trifluoromethyl, (C1-C6)-hydroxyalkyl, -0-[CH2~scfH~2f~l8)Fg~ -OCF2Cl~
OCF2-CHFC1, (C1-C6)-alkylcarbonyl, (Cl-C6)-alkoxy-carbonyl, carbamoyl, N~(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, (C1-C6)-alkyl carbonyloxyr phenyl, benzyl, phenoxy, benzyloxy and/or NR~R", R7, independently of R6, can be hydrogen or (C1-C5)-alkyl, Rs can be H or an alcohol protective group, where ORs is in particular a substituted or unsub~
stituted methyl ether, a substituted or unsub-stituted ethyl ether, a substituted or unsub-stituted benzyl ether, a 8ilyl ether, an ester, a carbonate, a carbamate or a 6ulfonate.

The following alcohol protective groups can be used:

A8 substituted methyl ethers:
methoxymethyl, methylthiome~hyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxyme~hyl, (4-methoxyphenoxy)-methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl~

- 12 - ~78~
siloxymethyl, 2-methoxyethoxymethyl, 2,2,~-trichlor~
etho~ymethyl, bis(2-chloroethoxy)me~hyl, ~-(trimethyl-silyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetra-hydropyranyl,tetrahydrothiopyranyl,l-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-me~hoxytetr2hydrothio-pyranyl, 4-metho~ytetrahydrothiopyranyl-S,S-dioxo, 1-[~-chloro-4-methyl)-phenyl]-4-methoxypiperidin-4-yl/ 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl.

As substituted ethyl ethers~
l-Pthoxyethyl, 1-(2-chloroe~ho~y~ethyl, l-methyl 1-meth-oxyethyl, 1-methyl-l-benzyloxyethyl, l--methyl l-benzyl-oxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trLmethyl-silylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl.

As substituted benzyl ethers:
p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl~ p-halobenzyl, 2,6-dichlorobenzyl, p-cyano-benzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl-N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, triphenylmethyl, ~-naphthyldiphenylmethyl, p-methoxy-phenyldiphenylmethyl, di-tp-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)-phenyldiphenylmethyl, 4/4',4'l-tris(4,5-dichlorophthalLmi-dophenyl)methyl, 4,4',4"-tris(levulinooxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazole-1,4'-methyl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)~ pyrenylmethyl,9-anthryl,9-(9 phenyl)-xanthenyl, 9-(9-phenyl-lO-oxo)anthryl.

As silyl ethers:
trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, dieth~lisopropylsilyl, dimethyl-hexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, di-phenylmethylsilyl, t-butylmethoxyphenylsilyl.

_ 13 - 207~9~
As esters:
formates, benzoylformates, amino acid esters, acstate~, chloroacetate, dichloroaceta~e, trichloroacetate, tri-fluoroaceta~e, methoxyaceta~e, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p--P phenyl-acetate, 3-phenylpropionate, 4-oxopentanoate (le linate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4~methoxycrotonate, ben~oate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate).

As carbonates:
methyl, 9-fluorenylmethyl, ethyl r 2 ~ 2,2-trichlorethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(~riphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxy-benzyl, o-nitrobenzyl, p-nitrobenzyl, s-benzyl thiocar-bonates, 4-ethoxy-1-naphthyl, methyl dithiocarbonates.

Other esters:
2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylhutyl)phenoxyacetate, 2,4-bis(l,1-dimethylpropyl)phenoxyacetate/ chloro~iphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, (tigloate), O-(methoxycarbonyl)benzoate, p-P-benzoate, ~-naphthoate, nitrate, alkyl N,N,N~,N~-tetramethylphos-phorodiamidate, N-phenylcarbamate, borates, dimethylphos-phinothioyl, 2,4-dinitrophenylsulfenate.

As sulfonates:
sulfates, methanesulfonate (mesylate), benzylsulfonate, tosylates.

The following protective groups are particularly prefer-red as R5:
(cl-c6)-alkanoyl~ (Cl-C~)-alkylcarbamoyl, di-(Cl-C~ alkyl-carbamoyl, N-( C3-C~ ) -cyc loalkylcarbamoyl, (Cl-C6)-alkoxy-carbonyl, (C6 C12)-aryloxycarbonyl, (C,-C11)-aralkyloxy-carbonyl, in particular benzyloxycarbonyl, - 14 - 20~9~
(C6-C12)-arylcarbonyl, (C7-C~ aralkylcarbOnyl, ~Cl-C6)-alkyl~ (Cl-c6)-alkoXy-(cl-c6)-alkyl~ c~rbamoyl-(Cl-C~)-alkyl esters, (c1-C1Q)-acyloxy-(C1-C6)-alkyl~ preferably (C1-C10) alkanoyloxy-(Cl-C6)-alkyl, benzyloxy-(C,-C6)-alkyl~ benzyl-5 oxycarbonyloxy-(Cl-C6)-alkyl, tCl-C6)-alkoxycarbonyloxy-(Cl-C6)-alkyl, phenyl, benzyl, where the phenyl can optionally be substituted, amino acid ~sters or tetra-hydropyrsnyl.

Amino-protective gro~ps are described in R. Geiger and W. ~onig ~The Peptides~ Volume 31 ~Protection of Functional Groups in Peptide Synthesis", E.G. Gross, J. Meienh~fer Edit, Academic Press, New York (1981), in particular pages 7-46.

Such groups ar2 als~ described in A. Hubbuch, Schutzgruppen in der Peptidsynthese (Protective Groups in Peptide Synthesis)l Rontakte 3/79, pages 19-23.

The following amino protective groups are particularly preferred:
acetamidomethyl l-adamantyloxycarbonyl ~ adamantyl)-1-methyl-ethoxycarbonyl allyloxycarbonyl tert-butoxycarbonyl 1-~4-biphenylyl)-1-methyl-ethoxycarbonyl dicyclohexylcarbodiimide ~,~-dimethyI-3,5-dimethoxybenzyloxycarbonyl 4-dihydroxyborylbenzylcarbonyl 9-fluorenylmethoxycarbonyl l-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2l3-benzotriazine isobornyloxycarbonyl l-methyl-cyclobutoxycarbonyl 4-methoxybenzyloxycarbonyl methylsulfonylethoxycarbonyl 4-pyridylmethoxycarbonyl lS -2078~
2,2,2-trichloro-tert-butoxycarbonyl benzyloxycarbonyl halogen-substituted benzyloxycarbonyl 4-nitro~benzyloxycarbonyl 2-phosphonomethoxycarbonyl phenylsulfonylethoxycarbonyl toluenesulfonylethoxycarbonyl 2,3,5-trimethyl-4~methoxy-phenylsulfonyl benzotria ol-1-yl-oxy-tris(dimethylamino)phosphonium parafluorophosphate.

R5 is very particularly preferably hydrogen, tC1-C8)-alkyl, benzyl, (C1-C6)-alkylcarbonyl, phenylcarbonyl and the carbamoyl derivatives which are mentioned above.

Particularly preferred compounds of the formula I are those in which Y is CH2ORs, n = 0 and R1 and R4 and one of the radicals R2 or R3 are hydrogen, ( C,-C5 ) - alkyl, luorine, chlorine, (C1~C5)-alkoxy, and the other radical, R2 or R3, corresponds to the formula II in which 20 X is O, R6 is branched or unbranched (C1-C3)-alkyl which is monosubstituted by hydroxyl, (C~-C4)-alkoxy, (Cl-C~)-alkoxycarbonyl, (C3-C6)-cycloalkoxycarbonyl, benzyloxycarbonyl, (C1-C4)alkylcarbonyloxy and/or (((Cl-C~)-alkoxycarbonyl)methyl~carbamoyl or R6 is (C6-Cl2)-aryl which is monosubstituted or disubstituted by hydroxyl, halogen, (Cl-C6)-alkoxy, (Cl-C6)-alkyl, trifluoromethyl, (Cl-C6)-hydroxyalkyl, -O-[CH2]~CfH~2f~1~)F8and/or NR'R", and 30 R7 is hydrogen.

- 16 - 2~78~0 Preferred compounds are those in which R6 is in each case substituted in the end position.

Very particularly preferred compounds of ~he formula I
are those in which R1, R4 and one of the two radicals R2 or R3 are hydrogen.

The following compounds are particularly to be used.

N-(3-Methoxypropyl)-6-hydroxymethylp~ridine-4-carboxamide N-(3-Hydroxypropyl)-6-hydroxymethylpyridine-4-carboxamide N-(3-Hydroxypropyl)-6-methoxymethylpyridine-4-carboxamide N-(2-Hydroxyethyl)-6-hydroxymethylpyridine-4-carboxamide N-(2-Hydroxyethyl)-6-hydroxymethylpyridine-3-car~oxamide The invention furthermore relates ~o the use of compounds of the formula I and the physiologically tolerable salts for the production of a pharmaceutical ha~ing anti-fibrotic activity.

Finally, the invention relates to the compounds of theformula I for use as pharmaceuticals.

In partlcular, the invention relates to the compounds of the formula I for use as fibrosuppressants and for influencing the metabolism of collagen and collagen-like substances.

The invention furthermore relates to processes for the preparation of compounds of the formula I.

Compounds of the formula I are obtained either 25 a) from appropriately subst~tuted pyridine-4- (or -5-) carboxylic acids or their esters of the farmula VI (shown here as 5-carboxylic acids) by the known methods of amide synthesis (for example by the methods of peptide synthesis or the - 17 - 2~7 ~ ~0 aminolysis of esters), optionally wi~.h subsequent Gxidation to the pyrldine N-oxide, ~3 R~ O
R ~ CO2H(oikyl) ~ ~ N / R~

Y R~ y ~ ~ Rl R
or (Vt) ()~ (I) b) from pyxidine-4- (or -s-) carboxamide derivatives S of the formula VII in which Y~ is a ~u~stituen which can be converted int~ a radical -CX2-oR5/
optionally with ~ubseguent oxidation to the pyridine N-oxide R3 o R3 o R ~ O - C H z ~N
( V I I ) t ) n ( I ) where 10 b,) compounds of the formula VII in which Y~ is CH3 and n is 0, are halogenated to give compounds of the formula VII in which Y~ is -CH2W (W denotes halogen, chlorine or bromine) and these are subsequently reacted with xeagents of the formula MORs in which M is hydrogen, an alkali me~al atom or an alkaline earth metal atom, or b2) compounds of the formula YII in which Y' is CH3 and n is 1 are reacted as in scheme 1 with Ac20/AcOH to give compounds of the formula I in which Y is -CH2-OAc, or b3) compounds of the formula VII in which Y' is -C02H, -CO2-alkyl or -CHO and n is O are reduced by methods known to the person skilled in the art to give compounds of the formula I in which Y is - lB - 2078590 -CHzOH (cf. scheme 2).

Th~ following reaction scheme 1 give8 a general idea of specific compounds according to formula I
2 R3 ~ R3 R ~R4 ox Id~ion R ~R~
R ' N C H 3 Step I `~

V 111 step 2 ~ AC2~ACOH

step 1' ~2 ~ R4 HalogenationR ~l~C H 2 A c ~ W Holog~n1 step ~

R2~,R~ ~oR5 ~ ~R"

R ~J~NJ~ C H W ~-- R 1 N~C H 2 ~ R 5 X Oxldo110n ¦ step 4 R 2~R 4 R~ l CH20R
~ I

The pyridine derivatives VIII and I are converted to the corresponding pyridine N-oxides IX and I according to steps 1 and 4.

This oxidation is achieved most simply by adding oxidants such as, fox example, hydrogen peroxide or peracids, ~uch as peracetic acid, perfluoroacetic acid, perbenzoic acid or metachloroperbenzoic acid in golvents, ~uc~
inated hydrocarbons, for example methylene chloride, chloroform, tri- or tetrachloroe~hylene, benzene or toluene to the pyridine compounds to be oxidized which can likewise be dissolved in the abovementioned ~olvents, and stirring at temperatures between -30 and ~40C, preferably O and ~5C, for between 30 minutes and 3 days. The end of the reaction can be determined by means of thin layer chromatography. Preferably, the compounds I accordin~ to the invention can be prepared by employing the pyridine derivative ancl the oxidant in equimolar amounts or up to an approxLmately S-fold excess of oxidant.

Optionally, the excess of pPracid can also be eliminAted by passing, for example, gaseous ammonia into the reac-tion solution and separating off the resulting precip-itate from the reaction solution by filtration~

Optionally, the working up of the products can be carried out, for example, by extraction or by chromatosraphy on silica gel. The isolated product can be recrystallized.

A general procedure for this oxidation method is also described, for example, in ~E. Xlingsberg, Pyridine and its Derivatives, Interscience Publishers, New York, 1961, Part 2, 93ll.

Oxidation with hydrogen peroxide is described, for example, in "E. Ochiai, J. Org. Chem. 18, 534 (1953)".

The compounds according to the invention can also be prepared by means of oxidation according to the simul-taneously filed German Patent Applications P 41 31 217.1 and P 41 31 220.1.

The preparation of the different pyridine derivatives necessary for the oxidation described i6 mentioned in the - 20 - ~7 8 ~ 90 patent applications already cited as prior art. Those which may be men~ioned are D~ 3~826~471? 3,828,140, 3,924,093 and P 40 01 002.3 and DE-A-3,703,959, 3,703,962 and 3,703l963.

S Step 2 describes the conversion of the pyridine N oxide IX to the pyridine compound 1. This conversion i6 carried out with trifluoroacetic anhydride a~ O~C or with acetic anhydride, optionally in the presence of an acid, ~uch as/ for example, glacial acetic acid, at 8Q-120C and the acetates of the formula I are obtained. The conversion is also described by Katritzky, A.R., L~gowsXi, J.M. in:
~Chemistry of the Heterocyclic N-oxides~, Academic Press:
New York, 1972, IV. 2, pages 352-365.

The hydrolysis according to step 3 is carried out by known methods. In particular, alkali metal hydroxides or carbonates in methanol, ethanol, water or the like are used for this purpose.

Step 1~

Compounds of ~he formula I in which Rs is hydrogen, n is 0 and Rl to R4 have the meaning given can be prepared by halogenation of the corresponding 2-picolines of the formula VIII with N-haloamides such as N-bromosuccinimide or N-chlorophthalimide or with trichloroi~ocyanuric acid (cf. Chem. Ber. 120, 649 651 (1987)).

Step 2~

The reaction of the 2-picolyl halides of the ~ormula X
thus obtained with hydroxyl-containing salts in the manner familiar to the person skilled in the art leads to the compounds of the formula I according to the inven-tion.

- 21 - 2078~9~
The title compounds of ~he formula I where R5 = H can also be prepared by reaction of compounds of the formula I, in which oR5 is an oxygen-containing leaving group such as tosylate, brosylate, mesylate or triflate and n is 0, with hydroxyl-containing bases.

The preparation of derivatives, which can also be substi-tuted on the pyridine ring, is illustrated below in reaction scheme 2.

Pyridine-2,4-(and -~,5-)dicarboxylic acid diesters having various substituents R2 (~3) such as, for example, halogen, hydroxyl, alkoxy, amino, 4-butyn-1-ol, alkoxy-carbonylalkyl, hydroxyalkyl and 3 propyn-1-ol, are known from the application DE-A-3,707,429.

The selective hydrolysis of the ester group in the 2-position, for example the Cu sal~-mediated ester cleavage of J. Delarge, Pharm. Acta Helv. 44, pp. 637-643, 1969, enables the differentiation of the ~wo ester groups and leads to the compounds of the formula XII. The amLnolysis of these compounds leads to the 4-carboxamides of the formula XIII, whose reduction leads, by reduction methods familiar to the person skilled in the art such as, for example, with BH3 . THF, borane, tetrahyrofuran or boxane-dimethyl sulfide complex, to the compounds of the formula I.

The following reaction scheme 2 serves for clarification for the pyridine-4-carboxylic acids 2~78~

R ~R ' ~ C o 2 ~

X I X ~ I Aminolysls o~N ~R ~ o~N ~R 2 R ~C H z O R 5 R ~C t)2 H
Reduction X ~ I I

~ R6 m-CPBA
2 o~ 'N`RR'~

R'~CH20Rs ()n The compounds of the formula I in which R5 is H and n is O can furthermore be obtained by reduction of the corres-ponding pyridine-2-aldehydes or the pyridine-2-carboxylic acid esters by methods familiar to the person ~killed in the art.

Suitable reductants arel for example, lithium aluminum hydride, lithi~m borohydride, sodium borohydride and diborane derivatives.
The compounds of the formula I according to the invention have useful pharmacological properties and in particular - ~3 - 2~7~9~
show activlty as inhibitors of prolinehydroxylaSe and lysine hydroxylase, and as a fibrosuppressant, immunosup-pres 5 ant and antiatherosclerotic.

The antifibrotic action can be determined in the model of carbon tetrachloride-induced liver fibro~is. For this purpose, rats are treated with CC14 (1 ml/kg) - dissolved in olive oil - twice weekly. The test substance i~ admin-istered daily, if appropriate even twice daily, orally or intraperitoneally - di~solve~ in a suitable tolerable solvent. Ths extent of liver fibro~is i~ determined by histology and the proportiQn of collagen in the liver per hydroxyproline dstermination - as described in Kivirikko et al. (~nal. Biochem. l9t249 f. ~1967)) - is analyzed.
The activity of fibrogenesis can be determined by radio-immunological determination of collagen fragments andprocollagen peptides in the serum. ~he compound~
according ~o the invention are ac~ive in this m~del in a concentration of 1-100 mg/kg.

The activity of fibrogenesis can be determined by radio-immunological determination of the N terminal propeptides of collayen type III or of the N- or C-terminal cross-linking domain of collagen type IV (7s-collagen or type IV collagen-NCl) in the serum.

For this purpose, the hydroxyproline, px~collagen III
peptide, 7s-collagen and type IV collagen-NC concentra-tions in the liver of a) untreated rats (control) b) rats to whom carbon tetrachlvride was adminis-tered (CCl4 control) 30 c) rats to whom first CCl4 and then a compound according to the invention was administered were measured (this test method i5 described by Rouiller, C., experimental toxic injury of the }iver; in The Liver, C. Rouiller, Vol. 2, 5. 335-476, New York, Academic Press, 1964).

- 24 - 2~7~5~0 ~nother mo~el for the evaluation of the antibiotic action is that of bleomycin-induced pulmonary fibrosis as described in Xelley et al. (J. Lab Clin. Med. 96, 954, ~1980)). For ~he evalua~ion of the action of the com-pounds according to the invention on the granulationtissues, the model of cotton pellet granuloma, as described in Meier et al., Experientia 6, 463 (1950) can be used.

The compounds of the ~ormula I can be used as medicaments in ~he form of pharmaceutical preparations~ which option-ally contain tolerable pharmaceutical excipients. The compounds can be used as medicines, for ex.~mple in the form of pharmaceutical preparations, which contain these compounds mixed with a pharmaceutical, organic or inor lS ganic excipient suitable for enteral, pexcutaneous or parenteral administration, such as, for ex~mple, water, gum arabic, gelatinel lactose, starch, magnesium stear-ate, talc, vegetable oils, polyalkylene glycols, petroleum jelly etc.

For this purpose, they can be administered orally in doses of 0.1 - 25 mg~kg/day, preferably 1 - 5 mg/kg/day or parenterally in doses of 0.01 - 5 mg/kg/day, prefer-ably 0.01 - 2.5 mg/kg/day, in particular 0.5 1.0 mg/kg/day. The dosage can also be increased in severe 2S cases. In many cases, however, relatively low doses are also sufficient. These data relate to an adult of weight about 7~ kg.

rrhe invention furthermore compri es the use of the compounds according to the invention in the production of 3~ pharmaceuticals which are employed for the txeatment and prophylaxis of the abovementioned metabolic disorders.

'rhe invention further xelates to pharmaceuticals which contain one or more com~ounds of the formula I according to the invention and/or their physiologically tolerable ~78~0 salts.

The pharmaceuticals are prepared by methods which are known per se and familiar to the person skilled in the art. As pharmaceuticals, ~he pharmacologically actîve compounds according to the invention (- active ~ubstance) are either employed as such or preferably co~bined with sui~able pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsule~, ~uppositories, emulsions, ~uspensions or solutions, the active sub~tance content being up to about 95 %, advantageously between 10 and 75 %.

In addition to solvents, gelling agents, suppository ba~es, tablet auxiliaries and other active substance carriers, suitable auxiliaries or excipients for the desired pharmaceutical ormulation are also, for example, antioxidants, dispersants, emulsifiers, antifoam agents, flavour modifiers, preservatives, solubilizers or color-ants.

The following examples are intended to illustrate the invention.

Inter alia, methyl 2-hydroxymethylpyridine-4-carboxylate is used as a startin~ substance. It is prepared as described by T. Sugiyama et al., Chem. hett. 1982, 917-920 by photochemical hydroxymethylation or from methyl 2-methylpyridine-4-carboxylate, as described by J.K.
Seydel et ~1., J. Med. Chem. 1976, 19, 483-492.

Example 1:
N-t2-Methoxyethyl)-6-hydroxymethylpyridine-4-carboxamide 10.O g (59.8 mmol~ of methyl 2-hydroxymethylpyridine-4-3~ carboxylate are heated at reflux for 5 h in 150 ml of 2-methoxyethylamine. The mixture is allowed to cool to room temperature and excess amine is distilled off in - 26 - 2~78~0 vacuo. The residue is ohromatographed on silica gel using ethyl acetate/methanol (5:1).

A colorless oil, Rf Z O . 27, results Empirical formula: C1oHl4N2O3 M5: m/e = 211.2 (M~H) Example 2:
N-(3-Methoxypropyl) 6-hydroxymethylpyridine-4-CarbOXamide The title compound i5 prepared from 1.6~ g (10 mmol) of methyl 2-hydroxymethylpyridine-4-carboxylate and 20 ml of 3-methoxypropyl~mine analogously to Bxample 1.

1.7 g of colorless oil, Rf ~ O . 36, result Empirical formula: C1l~lsN23 MS: m/e = 225.3 (M + H) Example 3:
N-(2-~ydroxyethyl)-6-hydroxymethylpyridine-4-carboxamide 1.67 g (10 mmol) of methyl 6-hydroxymethylpyridine-4-carboxylate are stirred at 105-110C for 3 h in 15 ml of 2-aminoethanol. Ths excess amine is distilled off in vacuo and the-crude product is chromatographed on silica gel using ethyl acetate/methanol (5:1), (R~ ~ 0.16).

2 g of an oily crude product results, which i~ crystal-lized using ethyl aceta~e, m.p. 81-82C.

Example 4:
N-(3-Hydroxypropyl)-6-hydroxymethylpyridine-4 carboxamide The title compound is prepared fxom 10 g (59.8 mmol) of methyl 6~hydroxymethylpyridine-4-carboxylate and 30 ml of l-aminopropan-3-ol t4 h, 120-125C) analogously to Example 3.

~ ~7 ~ 207 ~ 9 0 After chromatography using ethyl acetate~methanol (5:1), lQ.4 g of a colorless oily product, R2 ~ 0.16, result.
Empirical formula: CloH14N2O3 MS: m/e = 211 (M+ + H) Example 5:
N-t2-Methoxyethyl~-6-hydro~ymethylpyridine-4~carboxamide N-oxide O.7 g (3.3 mmol) of the title compound rom Example 1 is treated with 1.2 g (4.~5 mmol) of m-chloroperbenz~ic acid (70 ~), with stirring, in 50 ml of dichloromethane. 3-Chlorobenzoic acid i~ precipitated by passing in ga~eous ammonia and filtered off with suction. The filtrat~ is concen~rated and cry~tallized using diisopropyl ether. It was possible to obtain 0.66 g of colorle~s c~ystals, m.p.
101-103~C.
Empirical formula: C1oH14N24 MS: m/e = 227 (M~ + H) Example 6:
N-(2-Methoxyethyl)-6-me~hoxymethylpyridine-4-carboxamide 20 a) With stirring, 3.0 ml of th~onyl chloride SOC12, dissolved in 5 ml of dichloromethane, are added dropwise with ice-cooling to a solution of 1.5 g of methyl 6-hydro~ymethyl pyridine-4-csrboxylate in 50 ml of dichloromethane. After warming to room temperature, the mixture is stirred for a further 1 h and concentrated i.n vacuo, and the residue i6 treated with diethyl ether and fil-tered off with suction. It was pQssible to obtain 1.8 g of methyl 6-chloromethyl pyridine-4-carboxylate hydrochloride as colorless cryqtals.

M.p. 116-118C

- 28 - 2~8~
b) 2.2 g (10 mmol) of the compound from Example 6a) are dissol~ed in 50 ml of anhydrous methanol and treated at 20C with stirring with 3.6 ml ~20 mmol of 5.5 molar sodium meth~late solution.
After the mixture has been heated a r~flux for 6 h, it is allowed to cool ~o 20C and is concentrated in vacuo, treated with wster and extracted three times with dichloromethane. After distilling off the ~ol~ent, 1.0 g of methyl 2-methoxymethylpyridine-4-carboxylate i5 obtained as an oily crude product.

c) O.g g (50 mmol) of the compound fr~m example 6b) is heated at reflux for 3 h in 20 ml of 6-meth-oxyethylamine. After coolin~, the mixture is concentrated in vacuo snd the oill~ residue is chromatographed on silica gel u~ing ethyl acetate/methanol (10:1~. 0.85 g of the title com-pound results as a colorless oil, R~ - 0.40.

Empirical fo~mula: CllHl6N203 MS: m/e = 225.3 (M+ + H) Example 7:
N-(2-Acetoxyethyl)-6-acetoxymethylpyridine-4-carboxamide 0.63 g (3.3 mmol) of the title compound from Example 3 is suspended in 50 ml of 1,4-dioxane and 20 ml of dichloro-methane. 0.1 g of 4-N,M-dimethylaminopyridine and 1.1 ml (8 mmol) of triethylamine are ~ubsequently added. 0.47 ml (6.6 mmol) of acetyl chloride are then added dropwise and the mixture i~ stirred at 20C for 2 h. It is concen-trated, the residue is treatsd with water, the mixture is extracted with dichloromethane, and the extract is dried and freed of 901~ent. 0.21 g of a colorleRs oil results.
R~ = 0.40 (ethyl acetate/methanol (5:1J) 2V78~90 Empirical formula: C13H~5N2O5 MS: m~e = 281 (~ ~ H) Exampl2 8:
N-(2-Methoxyethyl) -6-benzoyloxymethylpyridine-4-carboxamide 100 mg of 4-N,N-dimethylaminopyridine and 0.54 ml (4 mmol) of triethylamine are added to 0.7 g (3.3 mmol3 of the title compound from Example 1 in 5Q ml of dichloromethane. ~fter 0.39 ml t3.3 mmol) of benzoyl chloride has been added dropwise, the mixture is stirred at 20C for 2 h and concentrated in vacuo, the re~idue is treated with water, the mixture is extracted with dichloromethane, the organic phase is dried, the solvent is evaporated in vacuo and the re~idue is crystallized using diethyl ether.

It was possible to obtain 0.65 g of colorless crystals of melting point m.p. = 81-82C.
EmpiriCal formula: Cl7HlaN24 Example 9:
N-t3-Methoxypropyl)-6-methoxymethylpyridine-4-carboxamide a) 6 ml of thionyl chloride in 20 ml of dichloro-methane are added dropwise with ice-cooling to 2.0 g of (~.93 mmol) of the title compound from example 2 in 80 ml of dichloromethane. After 0.5 hours, the mixture is concentra~ed in vacuo, the residue is crystallized using diethyl ether and 2.3 g of N-t3-methoxypropy)-6-chloromethyl-pyridine-4-carboxamide hydrochloride are obtained as a colorless, crystalline substance, m.p. 128-130C.

b) 1.7 g (6.1 mmol) of the compound from 9a) are treated with 2.8 ml of 5.5 molar ~odium methylate - 30 - ~ ~7~90 solution in 50 ml of me~thanol and at 20C. The mixture is then heated at xeflux for 5 hours and concentrated in vacuo, ths residue i~ treated with 50 ml of aqueous ammonium chloride solution, the mixture i8 extracted with dichloromethane, the extract is dried and concentrated and 1.4 g of the oily title compound are obtained.

Empirical ormula: C12H~8N203 MS: m~e = 239 (~ + H~

Example lO:
N-(3-Hydroxypropyl)-6-methoxymethylpyridine-4~carboxamide 2.7 g (14.9 mmol) of methyl 6-metho~ymethylpyridine-4-carboxylate (compound from Example 6b) are heated to 80C
for 1.5 hours in lO ml of 3-aminopropanol. After concen-trating in vacuo and chromatographing with ethyl acetate/methanol (93:7) on silica gel, the title compound is obtained as a pale yellow oil; R~ ahout 0.17.

Empirial formula; C~lHl6N203 MS: m/e = 2~5 (M~ + H) Example ll:
N-(3-Methoxypropyl)-6-(N-cyclohexylcarbamoylo~ymethyl)-pyridine-4-carboxamide 1.1 g (4.9 mmol) of N-~3 methoxypropyl~6-hydroxymethyl-pyridine-4-carboxamide ttîtle compound from Example 2) are treated dropwise with ~tirring at 0C with 3.5 ml (25 mmol) of cyclohexyl isocyanate in 50 ml of dichloro-methane and the mixture is heated at reflux for 2 hours.
After cooling, it i8 treated with 20 ml of water and the organic phase is separated off; after distilling off the solvent, an oily crude product is obtained which is crystallized using diethyl ether.

2~78~

1.3 g of colorlQ~s crystals of melting ~oint m.p. = 117 -119 C result.
Empirical fo~mula: ClRH~7N304 Example 12:
S N-(3-Methoxypropyl)-6-benzyloxymethylpyridine-4-carboxamide The title compound can be prepared from N-(3-methoxy-propyl)-6 chloromethylpyridine-4-carboxamide hydro-chloride, benzyl alcohol and sodiuni analogously to Examples 6a) and b); colorless oil.

Empirical formula:Cl3H22N203 : MS: m/e = 315 ~M~ + H) Example 13 N-(2-Methoxyethyl)-6-benzyloxymethylpyridine-4-carboxamide The preparation is analogous to Example 12.

EmpiriCal formula : Cl7H20N203 MS: m/e = 301 (M+ + H) Example 14 N-(2-Hydroxethyl)-6-benzyloxymethyl-pyridine-4-carbox~nide:

a) Methyl 6-chloromethylpyridine-4-carboxylate hydrochloride With stirring, 30 ml of thionyl chloride, dissolved in 70 ml of dichloromethane, are added dropwise with ice-cooling to a solution o~ 16.7 g (0.01 mol) of methyl 2-hydroxymethylpyridine-4-carboxylate in 500 ml of dichloromethane. After warming to room temperature, the mixture is stirred for 1 h and concentrated in vacuo, the residue is treated with diethyl ether and 23 ~ of the - 32 - ~ ~78~90 product are obtained in the form of colorles6 crystals, m.p. 116-118C.

b) 6-Benzyloxymethylpyridine-4-carbo~ylic acid 60 ml (0.6 mol) of benzyl alcohol are treated in portions with 14.4 g (about O.5 mol) of 80 ~ ~odium hydride in 500 ml of N,N-dimethylacetamide. The mixture i8 ~tirred at 60C for 30 min and cooled to 20C, 23 g (0.1 mol) of the compound from Example 2a are ~dded in portions, and the mixture is stirred at 75C for 2 h. 300 ml of water are subsequently added, the dark solution is concentrated in ~acuol a fl1rther 100 ml of water are added, the mixture is treated with 2N NaOH to give a clear solution and filtered, and the filtrate is brought to pH 4 with 2N
HCl, the precipitate is filtered off with æuction, washed with water and dried, and 10.8 g of product are obtained, m.p. 173-175C.

c) 1.8 g (7.5 mmol) of the above compound are dissolved in 100 ml of anhydrous tetrahydrofuran and treated at 0C with stirring with 1.1 ml (8 mmol) of triethylamine and 0.8 ml (8 mmol) of ethyl chlorofo~mate.
After 30 min at 0C, 0.5 ml t8 mmol) of ethanolamine is added dropwise and the mixture is stirred for a further hour at 0C. After TLC checking, it is concentrated, 100 ml of saturated aqueous NaHCO3 solution are added, the mixture is extracted three times with dichloromethane, and the organic phase is dried and concentrated. 2.5 g of the oily residue are purified on silica gel usiny ethyl acetate, Rf = a . 32.
1.8 g of the title compound are obtained as a colorless oil.
Empirical formula: Cl3H1~N203 MS: m/e (k~ + H) ~ 33 ~ 2~78~9~
Example 15 N-(2-Hydroxyethyl)-6-methoxymethylpyridine-3-carboxamide a) Methyl 6-methoxymethylpyridine-3-carbo~ylate 52 g (0.28 mol) of methyl 6-chloromethylpyridine-3-carboxylate (prepared by chlorination of m~thyl 6-methyl-pyridine-3-carboxylate with ~richloroisocyanuric acid, cf. Chem. Ber. 120, 64g-651 (1987)) are treated with 54 ml (about 0.3 mol) of 30 ~ s~rength sodium methylate solution and 4.5 g of sodium iodide in 500 ml of methanol and the mixture is hsated at reflux for 3 h. The reaction mixture is concentrated in vacuo, the residue is extracted with warm diisopropyl ether and the extract is chromatographed on silica gel using n-heptane/ethyl acetate (2sl).
42.8 g of product/ m.p. 34-3&~C (from petroleum ether) b) 4.8 g ~26.5 mmol) of the ~bove compound are stirred at 50C for S h in 100 ml of 2-aminoethanol. The mixture is concentrated in vacuo, the residue is chromatographed on silica gel usin~ ethyl acetate/
methanol (5:1) and 4.3 g of the title compound ara obtained as colorless crystals, m.p. 102-103C.
Empirical formula: C1oH~4N2O3 MS: m/e = 211 ~+H) : Example 16 N-~2-Hydxoxye*hyl)-6-hydroxymethylpyridine-3-car~oxamide 1 g (4.8 mmol) of methyl 6-acetoxymethylpyridine-3-carboxylate (prepared from methyl 6-methylpyridine-3-: carboxylate N-oxide and a mixture of glacial acetic acid/acetic anhydride at 110-115C, m.p~ 92-93C (from diisopropyl ether)) is stirred at 80C for 2 h in 5 ml of 2-aminoethanol. Excess amine is distilled off in vacuo and the residue is crystallized with ethyl acetate~
ethanol (10:1). 0.7 g of the title compound is obtained, ~78~9~
m.p.: 131-133C.
Empirical formula: C~Hl2N203 MS: m/e = 197 (Mt + H) Example 17 3-~((4-Ethoxyphenyl)amino)carbonyl~-6-hydroxymethyl-pyridine a) 6-Chloromethylpyridine-3-carboxylic acid 2.8 g (15.0 mmol~ of methyl 6-chloromethylpyridine-3-carboxylate (prepared by chlorination of methyl 6-methyl-pyridine-3-carboxyla~e with trichloroisocyanuric acid) are treated with O.6 g (15 mmol) of NaOH, dissolved in 20 ml of water, in 100 ml of 1,4-dioxane and the mixture is stirred at 20C for 2 h, TLC checking. A further 5 ml of 1 N aqueous NaOH are added, the mixture is stirred at 20C for 0.5 h and concentrated in vacuo, the precipitate is filtered off with suctisn, washed with water and dried, and 1.7 g of product are obtained, m.p. 159-161C.

The a~ueous filtrate is extrac~ed twice with ethyl acetate, the organic phase is dried and concentrated, and the residue is crystallized using diisopropyl ether/ethyl acetate (4:1~. A further 0.8 g of product is obtained, m.p. 159-161C.

b) 3-[(4-Ethox~phenylamino)carbonyl]-6-chloromethyl-pyridine 2.6 g (15 mmol) of the above compound are dis~olved in 100 ml of anhydxous tetrahydrofuran and traated with 2.4 ml (17 mmol) of triethylamine at -5C. After O.5 h, 2.1 ml (17 mmol) of pivaloyl chloride and, after a further hour at this temperature, 2.2 ml (17 ~mol) of p-phenetidine are added dropwise, and the mixture is stirred at 0C for 1 h and allowed to warm to 25C.

21~78~90 It is concentrated .in vacuo, the re~idue is treated with water and the precipitated substance is filtered off with suction. The latter is dis~olYed in dichloromethane, and the solution is shaken with 2N aqueous ~Cl and then with S saturated aqueous ~aHCO3 ~olution. It is sub~eguently dried and dichloromethane i6 distilled off in vacuo. The residue is treated at 20C with 100 ml of ethyl acetate, and the crystalline product i~ filtexed off wi h ~uction and washed with ethyl acetate and dried, 1.4 g, m.p. 172-174C.

c) The ti~le compound is obtained by warming 0.g g(3 mmol) of the above compound at 60C for 3 h with stirring with 20 ml of lN aqueou~ NaOH ~olution in 50 ml of 1,4-dioxane. After coolingl the mixture i~ concen-trated in vacuo, the residue is treated with agueous 2N
hydrochloric acid, the crystalline precipitate i8 filtered off with suction and dried, and 0.6 g of crude product is obtained, m.p. about 220C, which is treated with acetone~tetrahydrofuran (1:1) until white. 0.4 g of product is obtained, m.p. 234~235C. It can additionally be recrystallized from methanol or N,N-dimethylformamide, m.p. 236-238C.

Example 18 3-t(4-Methoxyphenylamino)carbonyl]-6-hydroxy-methylpyridine Example 19 3-~(4-n-Hexyloxyphenylamino)carbonyl]-6-hydroxy-methylpyridine Example 20 3-~(4-(4-Fluorophenoxy)phenylamino)carbonyl]-6-hydroxy-methylpyridine - 36 - 2078~
Example 21 3-~2-Methoxyphenylamino)carbonyl]-Ç-hydroxy-methylpyridine Example 22 3~ r ( 4-n-Butylphenylamino)carbonyl]-6-hydroxy-methylpyridine Example 23 3-[((3-Trifluoromethyl)phenylamino)carbonyl]-6-hydroxy-methylpyridine Example 24 3-[(4-Chlorophenylamino)carbonyl]-6-hydroxymethylpyridine Exhmple 25 3-[(4 Fluorophenylamino)carbonyl]-6-hydroxymethylpyridine Example 26 :~ 15 3-~(2-Fluorophenylamino)carbonyl]-6~hydroxy-methylpyridine ~ Example 27 ~ 3-[(Phenylamino)carbonyl]-6-hydroxymethylpyridin~
.
~:. Example 28 : 20 3-~(3-Chlorophenylamino)carbonyl]-6-hydroxymethylpyridine Example 29 3-[(4-(N,N-Dimethylamino)phenylamino)carbonyl]-6-hydroxy-methylpyridine Example 30 25 3-[(4-(2,2,2-Trifluoroethoxy)phenylamino)carbonyl~-6-hydroxymethylpyridine 2~78~i9V

Example 3 1 3~~ (4-t (2/2,3,3,4,4,4-Heptafluorobutyl)OXy)phenyl~
amino ) carbonyl ~ -6-hydroxymethylpyridine Exampl e 3 2 5 3- [ ( 4 -Etho~yphenylamino~ carbonyl ] -6-methoxy~
methylpyridine Example 33 3 - [ ( 4 -n-Hexyloxyphenylamino ) carbonyl ] - 6 -methoxy-methylpyridine 10 Example 34 3- [ ( 4- ( 4-Fluorophenoxy)phenylamino)carbonyl ~ -6-methoxy~
methylpyridine Example 35 3 - [ ( 2 -Methoxyphenylamino ) carbonyl ] -6-methoxy-15 methylpyridine Example 36 3 - [ ( 4 -n-Butylphenylamino ) carbonyl ] - 6 -methoxy-methylpyridine Example 37 20 3-[ ( (3-Trifluoromethyl)phenylamino)carbonyl]-6 methoxy-methylpyridine Example 3 8 3- [ ( 4 -Chlorophenylamino ) carbonyl ] -6-methoxymethylpyridine Example 39 2 5 3 - [ ( 4 -Fluorophenylamino ) carbonyl ] - 6 -methoxymethylpyridine Example 4 0 3- [ ( 2-Fluorophenylamino ) carbonyl ] -6-methoxymethylpyridine Example 41 3-[(Phenylamino)carbonyl]-6-methoxymethylpyridine Exampla 42 3-[(3-Chlorophenylamino)carbonyl]-6-methoxymethylpyridine S Ex~mple 43 3-[(4-(N,N-Dimethylamino)phenylamino)carbonyl]-6-methoxymethylpyridine Example 44 3-~(4-((2,~,2-Trifluoroethyl)oxy)phsnylamino)carbonyl]-6-methox~methylpyridine Example 45 3-[(4-((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)phenyl-amino)carbonyl]-6-methoxymethylpyridine Example 46 3-[(4-Ethoxyphenylamino)carbonyl]-6-ethoxy-methylpyridine Example 47 3-[(4-n-Hexyloxyphenylamino)carbonyl3-6-ethoxy-methylpyridine Example 48 3-~(4-(4-Fluorophenoxy)phenylamino)carbonyl] 6-ethoxy-methylpyridine Example 49 3-~(2-Methoxyphenylamino)carbonyl]-6-ethoxymethylpyridine Example 50 3-~(4-n-Butylphenylamino)carbonyl]-6-ethoxymethylpyridine Example 51 3-[((3-Trifluoromethyl)phenylamino)carbonyl]-6-ethoxy-methylpyridine ~ 39 ~ 2~78~
Example 52 3-[(4-Chlorophenylamino)carbonyl]-6-ethoxymethylpyridine Example 53 3-[(4-Fluorophenylamino)carbonyl~-6-ethoxymethylpyridine S Example 54 3-[(2-Fluorophenylamino)carbonyl]-6-ethoxymethylp~ridine Example 55 3-~tphenyl~mino)carbonyl3-h-e~hoxymethylpyridine Ex~mple 56 3-[(3-Chlorophenylamino~carbonyl3-6-ethoxymethylpyridine Example 57 3-[(4-(N,N-DLmethylamino)phenylamino)carbonyl]-6~etho~y-methylpyridine Example 58 3-[(4-(2,2,2-Trifluoroethoxy)phenylamino)carbonyl~-6-ethoxymethylpyridine Example 59 3-[(4-((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)phenyl-amino)carbonyl~-6-ethoxymethylpyridine Example 60 3-[(4-Ethoxyphenylamino)carbonyl]-6-benzyloxy-methylpyridine Example 61 3 - E ( 4 -n-Hexyloxyphenylamino)carbonyl]-6-benzyloxy-methylpyridine Example 62 3- E (4-(4-Fluorophenoxy)phenylamino)carbonylJ-6-benzyloxy-methylpyridine - 40 - ~7 Ex~ple 63 3- [ ( 2-Me~hoxyphenylamino ) carbonyl]-6-benzyloxy-methylpyridlne Example 64 3-~(4-n-Butylphenylamino)carbonyl]-6-benzyloxy-methylpyridine Exampl e 65 3-[((3-Trif luoromethyl )phenylamino)carbonyl ]-6-~nzylo~-methylpyridine 10 Example 6 6 3~[(4 -Chlorophenylamino ) carbonyl I -6-benzyloxy-methylpyridine Example 6 7 3 - [ ( 4 -Fluorophenylamino ) carbonyl ~ -6-benzyloxy-15 methylpyridine Exampl e 6 8 3 [ ( 2 -Fluorophenyl amino ) carbonyl ] -6 -benzyloxy-methylpyridine Exampl e 6 ~
2 0 3- [ ( Phenylamino ) carbonyl ~ -6-benzyloxymethylpyridine Example 70 3-[( 3-Chlorophenylamino)carbonyl ]-6-benzyloxy-methylpyridine Example 7 1 3-[(4-(N, N-Dimethylamino ) phenylamino ) carbonyl ] -6-benzyloxymethylpyridine Example 7 2 3- [ ( 4 - ( 2, 2, 2-Tri:Eluoroethoxy ) phenylamino ) carbonyl ] -6-benzylox~7methylpyridine - 41 - 2078~0 Example 73 3-[(4-((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)phenyl-amino)carbonyl]-6benzylox~methylpyridine Example 74 3-[(4-Ethoxyphenylamino)carbonyl]-6-acetoxymethylpyridine Example 75 3-[(4-n-Hexyloxyphenylamino~carbonyl]-6-acetoxy-methylpyridine Example 76 3-[(4-(4-Fluorophenoxy)phenylamino)carbonyl]-6~acetoxy-msthylpyridine Example 77 3-[(2-Methoxyphenylamino)carbonyl]-6-acetoxy-methylpyridine : 15 Example 78 3-~(4-n-Butylphenylamino)carbonyl]-6-acetoxy-methylpyridine Example 79 3-[((3-Trifluo.romethyl)phenylamino)carbonyl]-6-acetoxy-methylpyridine Example 80 3-[(4-Chlorophenylamino)carbonyl]-6-acetoxymethylpyridine ~xample 81 3-[(4-Fluorophenylamino)carbonyl]-6 acetoxymethylpyridine Example B2 3-~(2-Fluorophenylamino)carbonyl]-6-acetoxymethylpyridine Example 83 3-[(Phenylamino)carbonyl]-6-acetoxymethylpyridine 42 2078~9~
Example 84 3-[(3-Chlorophenylamino)carbonyl]-6-acetoxymethylpyridine Example 85 3-[(4-(N,N-Dimethylamino)phenylamino)caxbonyl]-6-acetoxy-methylpyridine Example 86 3-[(4-(2,2,2-Trifluoroethoxy)phenylamino)carbonylJ-6-acetoxymethylpyridine Example 87 3-[~4~((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)phenyl-amino)carbonyl-6-acetoxymethylpyridine Example 3a 3-[(4-Ethoxyphenylamino~carbonyl]-6-benzoyloxy-methylpyridine Example 89 3-[(4-n~Hexyloxyphenylamino)carbonyl]-6-benzoy~oxy-methylpyridine Example 90 3-[(4-t4-Fluorophenoxy)phenylamino)carbonyl]-6-ben~oyl-oxymethylpyridine Example 91 3-[(2-Nethoxyphenylamino~carbonylJ-S-benzoyloxy-methylpyridine Example 92 3-~(4-n-Butylphenylamino)carbonyl]-6-benzoyloxy-methylpyridine Example 93 3-[((3-Trifluoromethyl)phenylamino)carbonyl]-6-benzoyl-oxymethylpyridine ~ ~3 _ ~ ~78~9~
Example 94 3-[(4-Chlorophenylamino) carbonyl]-6-n-butoxy msthylpyridine Example 95 3-[(4-Fluorophenylamino)carbonyl]-6-n-butoxy-methylpyridine Example 96 3~[(2-Fluorophenylamino)carbonyl]-6-n-butoxy-methylpyridine Example 97 3-[(Phenylamino)carbonyl~-6-n-butoxymethylpyridine Example 98 3-[(3-Chlorophenylamino)carbonyl-6-n-butoxymethylpyridine Example 99 3-[(4-(N,N-Dimethylamino)phenylamino)carbonyll-6--n-butoxymethylpyxidine Example 100 3-[(4-(2,2,2-~rifluoroethoxy~phenylamino)carbonyll-6-~2-propoxy)methylpyridine Example 101 3-~(4-((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)phenyl-amino)carbonyl]-6-(2-propoxy)methylpyridine Example 102 3-[(4-Ethoxyphenylamino)carbonyl3-6-cyclohexanoyloxy~
methylpyridine Example 103 3-[(4-n-Hexyloxyphenylamino)carbonyl]-6-(2-methyl-benzoyl)methylpyridine ~ 44 ~ 2~78~9~
Example 104 3- ~ ( 4- ( 4-Fluorophenoxy)phenylamino)carbonyl]-6-( 2-methyl-benzoyl )methylpyridine Example l 05 5 3- [ ( 2 -Methoxyphenylamino ) carbonyl ] - 6- ~ 2 -methylpropionyl-oxy ) methylpyxidine Example 106 3-[(4-n-Butylphenylamino)carbonyl]~ 6-propionyloxy-methylpyridine 10 Example 107 3-~ ( (3-Trifluoromethyl)phenylamino)carbonyl]-6-propio:~yl-oxymethylpyridine Example 108 3-[ (4-Chlorophenylamino)carbonyl]-6-(2-methyl-15 propionyl ) oxymethylpyridine Example lO9 3- [ ( 4 -Fluorophenylamino ) carbonyl ~ -6- ( 2 methyl-propionyl ) oxymethylpyridine Example 110 20 3- [ ( 2 -Fluorophenylamino ) carbonyl ] -6- ( 2-methyl-propionyl ) oxypyridine Example 11 1 3 - [ ( Phenylamino ) carbonyl ] -6- ( 2-methylbenzoyl ) oxy-methylpyridine 2 5 Example 112 3 - [ ( 3 -Chlorophenylamino ) carbonyl ] -6- ( 2-methyl-propionyl ) oxymethylpyridine ~ 45 ~ 2~78~9~
Example 113 3-~(4-(N,N-Dimethylamino)phenylamino)carbonyl]-6-butanoyloxymethylpyridine Example 114 3-[t4-(2,2,2~Trifluoroethoxy)phenylamino)carbonyl}-6-butanoyloxymethylpyridine Example 115 3~ E ( 4-((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)ph~nyl-amino)carbonyl]-6~butanoyloxym~thylpyridine Example 116 N-(Methoxycarbonylmethyl)-6-benzyloxymethylpyridine-4-carboxamide 3.6 g (15 mmol) of 6-benzyloxymethylpyridine-4-carboxylic acid are suspended in 80 ml of acetonitrile and st.~rred at 20C for 20 h with 1.9 g (15 mmol) of glycine methyl ester hydrochloride, 3.8 ml (30 mmol) of N-athyl-morpholine, 2.2 g (1~.5 mmol) of l-hydroxy-lH-benzotria-zole hydrate and 3.1 g (15 mmol) of N,N-dicyclohexyl-carbodiLmide. The insolubles are filtered off with suction and washed with acetonitrile, the filtrate is concentrated in vacuo, the residue is taken up in dichloromethane, the organic phase is extracted with saturated aqueous NaHCO3 solution and then with aqueous NH4Cl solution, the organic phase is dried and concentrated, and the residue (4.5 g) i8 chromatographed on silica gel usin~ ethyl scetate. 3.3 g of the title compound are obtained as a colorless oil, Rf = 0.5.
Empirical formula: C17H18N2O4 MS: m/e = 315 (Mt ~ H).

- 46 - 2 ~7 8~ 9 0 Example 117 N-Benzyloxycarbonylmethyl)-6_methoxymethylpyridine-3-carboxamide a) 6-Methoxymethylpyridine-3-carboxylic acid 6.2 g (34.2 mmol) of methyl 6-methoxymethylpyridine-3-carboxylate (cf. example 15a) are hydrolyzed in 200 ml of methanol and 34.3 ml of lN aqueou~ ~odium hydroxide solution. After concentrating and acidifying with hydro-chloric acid, ~he mixture is extracted with ethyl acet-ate, yield 4.3 g.

b) 4.3 g (25.7 mmol) of the above compound are treated at 5C with 7.9 ml (56.5 mmol) of triethylamine in 100 ml of anhydrous tetrahydrofuran. After 20 min, 3.47 ml (28.6 mmol) of pivaloyl chloride are added dropwise and the mixture is stirred for a further 2 h at 0-5C. 9.65 g (28.6 mmol) of glycine benzyl ester tosy-late are then added, the mixture is ~tirred at 0C for 30 min, allowed to warm to 20C and stirred for 16 h, 400 ml of ethyl acetate are added, ~he mixture is washed with water and then with saturated NaHCO3 solution and dried, and the residue is chromatographed on silica gel using ethyl acetate/n-heptane ~3:1~. 2 g of the title compound are obtained as colorless crystals, m.p. 75-76C.
Empirical formula: C~~Hl8N2O4 MS: m/e c 315 (Mt ~ H).

Example 118 N-(Ethoxycarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide Example 119 N-~2-Propoxycarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide - 47 - 207 8~ 90 Ex~mple 120 N-(3-Pentyloxycarbonylmethyl) 6-ethoxymethylpyridine-3-carboxamide Example 121 S N-(4-Heptyloxycarbonylmethyl)-6-ethoxymethylpyridinQ-3-carboxamide Example 122 N-(5-Nonyloxycarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide Example 123 N-(2,5-Dimethyl-3-pentyloxycarbonylmethyl)-6-e~hQxy-methylpyridine-3-carboxamide Example 124 N-(3-Methyl-3-pentyloxycarbonylmethyl)-6-ethoxy-methylpyridine-3-carboxamide ; Example 125 N-((R)-2-Butoxycarbonylme~hyl)-6-ethoxymethylpyridine-3-carboxamide Example 126 N-((S)-2-Butoxycarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide Example 127 N-(Cyclohexyloxycarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide Example 128 N-(Cyclopentyloxycarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide - 48 - 2~78~9~
Example 129 N-~Methoxycarbonylmethylaminocarbonylmethyl)-6-ethoxymethylpyridine-3-carboxamide Example 130 N-(2-Propoxycarbonylmethylaminocarbonylmethyl~-6-ethoxy-methylpyridin~-3-carboxamide Example 131 N-(Ethoxycarbonylmethyl)-6-acetoxymethylpyridine-3-carboxamide Example 132 N-(2-Propoxycarbonylmethyl)-6-acetoxymethylpyridine-3-carboxamide Example 133 N-(3 Pentyloxycarbonylmethyl)-6-acetoxymethylpyridine-3-carboxamide Example 134 N-(4-Heptyloxycarbonylmethyl) 6-acetoxymethylpyridine-3-carboxamide Example 135 N-(5-Nonyloxycarbonylmethyl)-6-acetoxymethylpyridine-3-carboxamide Example 136 N-(2,5-Dimethyl-3-pentyloxycarbonylmethyl)-6-acetoxy-methylpyridine-3 carboxamide Example 137 N-(3~Methyl-3-pentyloxycar~onylmethyl)-6-acetoxy-methylpyridine-3-carboxamide 2~78~go Example 138 N- ( ( R) -2-Butoxycarbonylmethyl)-6-acetoxymethylpyridine-3-carboxamide Example 139 N-((S)-2-Butoxycarbonylmethyl)-6-acetoxymethylpyridine-3-carboxamide Example 140 N-(Cyclohexyloxycarbonylmethyl~-6-acetoxymethylpyridine-3-car~oxamide Example 141 N-(Cyclopentyloxycarbonylm~thyl)-6-acetoxymethylpyridine-3-carboxamide Example 142 N-(Methoxycarbonylmethylaminocarbonylmeth~1)-6-ace~oxy-methylpyridine-3-carboxamide Example 143 N-(2-Propoxycarbonylmethylaminocarbonylmethyl)-6-acetoxy-methylpyridine-3-car~oxamide Example 144 N-(Ethoxycarbonylmethyl~-6-hydroxymethylpyridine~3-carboxamide Example 145 N-(2-Propoxycarbonylmethyl)-6-hydroxymethylpyridine-3-carboxamide Example 146 N-(3-Pentyloxycsrbonylmethyl)-6-hydroxymethylpyridine 3 carboxamide ~ 50 - ~078~
Ex~mple 147 N-(4-Heptyloxycarbonylmethyl)-6-hydroxyme~hylpyridine-3-carboxamide Example 148 N-(5-Nonyloxycarbonylmethyl)-6-hydroxymethylpyridine~3-carboxamide Example 149 N-(2,5-Dimethyl-3-pentyloxycarbonylmethyl)-6-hydroxy-methylpyridine-3-carboxamide Example 150 N-(3-Methyl-3-pentyloxycarbonylmethyl)-6-hydro~y-methylpyridine-3-car~oxamide Example 151 N-((R)-2-Butoxycarbonylmethyl)-6-hydroxymethylpyridine 3-carboxamide Example 152 N-((S)-2-Butoxyca.rbonylmethyl)-6 hydro~ymethylpyridine-3-carboxamide Example 153 N-(Cyclohexyloxycarbonylmethyl)-6-hydroxymethylpyridine-3-carboxamide Example 154 N-(Cyclopentyloxycarbonylmethyl)-6-hydroxymethylp~ridine 3-carboxamide Example 155 N-(Methoxycaxbonylmethylaminocarbonylmethyl)-6-hydroxy-methylpyridine-3-carboxamide 2~78~9~

Example 156 N~(Glycyl-~2-propoxycarbonylmethylaminocarbonylmethyl)-6-hydroxymethylpyridine 3-carboxamide Example 157 N-(Ethoxycarbonylmethyl)-6-acetoxymethylpyridine 4-carboxamide Example 158 N-~2-Propoxycarbonylmethyl) 6-acetoxymethylpyridine-4-carboxamide Example 159 N-(3-Pentyloxycarbonylmethyl)-6-acetoxymethylpyridine-4-carboxamide Example 160 N-~4-Heptyloxycarbonylmethyl)-6-acetoxymethylpyridine-4-carboxamide Example 161 N-(5-Nonyloxycarbonylmethyl)-6-acetoxymethylpyridine-4-carboxamide Example 162 N-~2,5-Dimethyl-3-pentyloxycarbonylmethyl)-6-aceto2y-methylpyridine-4-carboxamide Example 163 N-(3-Methyl-3-pentyloxycarbonylmethyl)-6-acetoxy-methylpyridine-4-carboxamide Example 164 N-((R)-2-Butoxycarbonylmethyl)-6-acetoxymethylpyridine-4-carboxamide - 52 - 2~785~0 Example 165 N-~S)-2-Butuxycarbonylmethyl)-5-acetoxymethylpyridine 4-carboxamide Example 166 S N-(Cyclohexyloxycarbonylmethyl)-6-acetoa~ymethylpyridine-4-carboxamide Example 167 N-(Cyclopentyloxycarbonylmethyl)-6-acetoxymethylpyridine-4-carboxamide Example 158 N-(Methoxycarbonylmethylaminocarbonylmethyl)-6-acetoxy-methylpyridine-4-carboxamide Example 1Z9 N-((2-Propoxycarbonylmethylaminocarbonylmethyl)-6-acetoxymethylpyridine-4-carboxamide Example 170 N-~Ethoxycarbonylmethyl)-6-hydroxymethylpyridine-4-carbox~mide Example 171 N-(2-Propoxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Example 172 N-(3-Pentyloxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Example 173 N-~-Heptyloxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide - 53 - ~07~90 Example 174 N-(5~Monyloxycarbonylmethyl)-6-hydroxymethylpyridine-4 carboxamide Example 175 N-~2,5-Dimethyl-3-pentyloxycsrbonylmethyl)-6-hydroxy-methylpyridine-4-carboxamide ~xample 176 N-(3-~e~hyl-3-pentyloxycarbonyle~hyl)~6-hydroxy-methylpyridine-4-carboxamide Example 177 N- ( ( R )-2-Butoxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Example 178 N-((S)-2-Butoxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Example 179 N-(Cyclohexyloxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Example 180 N-(Cyclopentyloxycarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Example 181 N-(Methoxycarbonylmethylaminocarbonylmethyl)-6-hydro~-methylpyridine-4-carboxamide Example 182 N-(Glycyl-(2-propoxycarbonylmethylaminocarbonylmethyl)-6-hydroxymethylpyridine-4-carboxamide Other examples within the meaning of the invention, which were prepaxed analogously, where Et is ethyl, Me is 54 2~7859~

methyl, Bu is butyl, Hex is hexyl, Ph i5 phenyl and c i6 ~yclo .
X

l) ~33 = -Ca' R5 N
~' Y = CH2oR5 X = O
. ~_ j,; , . == ~ ~ ~, . . _ . _ ___ ¦ n R' F~7 Fl4 Rs Rs R' I _ _ _ ~ , _, . _ ~
¦ O H H H Et tl CH2ClH20Me !-- ~ ~ .. _ ¦ O H H H Et H ::H2CH20H
.. ~ .. _. . . _ O H H tl Et H CHaC:H;; CH;?C)Me I_ . . . . , ....... ___ _ . ... __ O H H H Et H C:H2GH2cH2oH
_ . ~ . ~ ~ ~ _ _ _ _ _ _ O H H H ~u H CH2cH2c~2oMe ~-- _ ___ ¦ O H H H Bu H CH2CH~CH20H
~ ~ ~ ~ . .. =.=.c .. ~.= _ l O H H H Ph H CH2CH2C)M~
,~ _ ~
O H H H Ph H CH2CH20H
, _ _ _ ; ~ _ O H Cl H Me H CR,CRnMe ¦ O H Cl H H H CH2CH20Me _ . . ~ . ~
O H Cl H H H CH,C~OH
O H Me H H H CH2CH2CH20Me _ , _, ~
O H Me H H H GH2C:H2C:H20H
_ . _ _ ~ . .. .... _ -O H H H CO-2-Me-Ph H CH2CH2CH20Me _ ._ _ . . _ _ .

O H H H C0 2-M~ Ph H CH,C11,C-,DH
O H H H CO-c-Hex H CH2CH2CH~OM0 _ -- .. ~................ _ _ _ _ H H H CO-c Hex H CH,CHzCH20H

2078~9~

O H H H H H CH2CH20-CO-n-Bu __ . ~ ,.
O H H H H H ~2~Hz~CO-Et ~ . _ O H H H H H CP,Ch,~COoR~
O H H H It H CH2CH2CH;~O-CO-2-Me-Ph _ _ _. _ . _ O H H H _ H Cff2C: ~O-GO-NHEt _ _. . ~ - __ s~ ~_ n R' R2 R~ Rs R~ R7 ..... _ . ~ ~ ~
O H H H H H CH2CH20-CO-NHnBu _ _ _ ~ ~ = ~ .
O H H H H H C:H2CHa~t:;O-NH-c-Hex . __ _ . ~ _ , O H H H Me H CH2CH20-~C~n-Bu ~ _ . . _~ -- . .
O H H H Me H CH2CH20~CO-Ph , ,, _ _ O H H H Me H ::H20- ::0-2-M~-Ph _ . _ . _ O H H H H ~ GH2CH2CH20-CO-OEt __ ~ .
O H H H ~ _ - H C~H2C H2CH20-CO O-C H~x . _ , , ,-~ ,~ ....... ~
L~ _ R2 R' R5 R~
¦ ~ H H H Et H Cl12CH20M~
I _ _ . . . _~_ ~ . ~
¦ 1 H H H Et H CH2CH20H
~ _ ._.
1 H H ~ Et H CH2t:~1 12CH20Me _ _ . ~ ,,_ 1 H H H Et H CH2 ::H2CH20H
1 H H H Bu H CH2CH2cH
_ _ _ 1 H H H Bu tl C~zCH2~H20H
_ __ _ _ . ..
1 H H H Ph H CH2CHzOM~
_ __ . .. _, _ H . H Ph H C~l,C-,OH

_ _ . __ 1H Cl H M~ H CH;~CH20Me ~ . , ~ ~ ~ . . ~ . .~_ ~ .. . . - ...... _ . .
1 H Cl H H H CH2CH2C)Me I ~r_____ .... __ __ _ . _ __ ___ 1 H Cl H H H CH,CH,t)H

. ~1 ~: rm.~ ~ = -~ ~
n R' R2 R' Rs R R7 . . . , . _ 1 H Me H H H CH;I :;H ~CH20Me _ ~ ~ . . . _ _~ I
1 H Me H H H CH~CH2C:H20H
. ~ ~ _ ~ ~
l 1 H H ~ CO-2-Me-Ph H CH20H2CH20Me l _ __ . . ~ _ . ~
1 H h H CO-2-Me-Ph H H~CH2CH20H
1 H H H C~c-Hex H Cl 12GHa~H29M~ ¦
._ ........ ~ _ _,, . ,, 1 H H H CO-c-Hex H CH2CHzCH2~H
_ . _ ~ _ _ .. ..... . .. .. . . _ _ 1 H H t~ H tl CH20H2~C~n-Bu I ... .. ~ . _ ¦ 1 H H H H H CH2CH2~C~Et I . . ~ ~ ,,... . _ _ .... __ 1 H H H H H CH2CH20-CO-c H~x _ ~ , .. _ _ _ 1 H H H H H CH2CH2CH2C: -CO-2-Me-Ph I ._ . ~ . , ~._ 1 H H H H H CH2CH20-OO-NHEt I ... _ ,.. ~ .. ..... _ .
¦ 1 H H H H H CH2CH20-~NH-n-Bu , . .__ 1 H H H H H CH2CH20-CO-NH~-H~x I ~ _ 1 H H H Me H CH2CH20-CO-n ~u . _ . ~
1 H H H Me H CH2CH20-C~Ph _ , . _ __ .
1 H H _ Me H CH,~CO*M~
1 H H H H H CH2CH2~::H2~CO-OEt _ _ ~ . ~
¦ 1 H H H H H CH2CH2CH20-CO-~c-Hex . . =5 _ _ _ . , . . _ . .

2~78~9~
-- s R2 = ~ R~
N

R' Y = CH~ORs X ~ O

- ~_ ., . == __ ___ ~_ ea~= ____ l n R' R3 R4 Rs R~ R' I ~ _ . ~ _ _ ~ _~
O H H H Ft H CH2CH20M~
_ ~ ~ , .
O H H H Et H CH2CH20H
. ~ _ ~ ~ _ ~ . ., .
l O H H H E~ H C;H2C:H2~H20Me .. . . _ ~ ~ . ,~
O H H H Et H CH2C:H2CH20H
. ~ _ _ .
0 H H H Bn H Ctl,Ch,CI l,OM~
O H H H Bn H CH2CH2 H20 _ . __ ~ . . ~
O H H H Ph H C~,CH,OM~
D H H H Ph H CH2CH20H
_ _ _ . . . .
O H Cl H Me H CHzt::H20M~
0 H Cl H H H CH2CH20M0 O H Cl H H H C~l,Ch,l~
O H Me H H H CH2CH2CI 120M~
_ ~ . . ~
O H I~Ae H H H CH2CH2CHzOH
0 H H H C~2-Me-Ph H CH2CH2CH20M~
0 H H H CO-2-Me-Ph H CH2CH2CH20H
I _ ~ _ --------- ~
O H H H CO-c-Hex H CH2CH2CH20M~

~ ,.~ = ==_ _~ ~_ _~ ~__ l n R' ~p R~ R5 R R' I . __ ...._ ~ _ _ ¦ O H H H CO-c-Hex H ~H2~H2~H2O~
~ _ .. _ _ ~ ~ . .............. . _ _ _ O H H H H H CH2CH20-CO~n-Bu _ . ~ _,, .... _ .
O tl H H H H CH2eH20-CQ-Et _ .
O H H H H H C:H2GH20-CO-c-Hex . ... ,. ~ ~
l O H H H ~ H C~12CH2C:H20-CO-2-Me-Ph _ .. . ~ _ . . . . ~
O H t 1 H H H CH2CH2~CC~NHEt _ . ~ . _~
O t I H H H H C:H2CH2~CO NH~Bu _ ~ ~ ~ ~ _ . _ O H H H H H CH2C:H20-CC~-NH-c-Hex _ ~ _ . .
O H H H Me H CH2C:H20-CO-n-Bu l _ . _ . ~ . ~
O H H H Me HCH2CH70-CO-Ph . . _ ___ _ . ~ -., _ , _ ~
O H H H Me HCH20-CO-2 Me-Ph . _ _ ~
O H H H H H CH2CH2CH20-CO~OEt _ ~ . , . ~
O H H H ;__ __ H CH2CH2CH20 CO O-c Hex ,_ _ r = - _ _ __~__ _ .. ~
n F R3 R~ Rs R~ R' _ , . _ . _ __ I
1 H H H Et H CH2t;H20Me _____ _ ~__ _ I
1H H H Et H GH2CH20tl _ _ ~
1 H H H Et H CH2CH2CH2 :)Me . _ _ . _ .. _ ~
_ __ 1 HH H Et H CH2CH2CH20H
_ ... ~ .. _ 1 H H H Bu H CH2CH2CH20Me 2078~9~

=:~ = == ~= _~ ~_ ~ a ~__ n Rl R3 R4 Rs R~ F,7 ,...... __. _ __ 1H H H Bu H GH2C HaC~20H
_ _ ~ ~ _ 1 H H H Ph H CH2CH20Me .. _ ~ .. ____ 1 H H H Ph H CH2CH20H
. . . _ _ . ~ .
1 H Cl H M~ H ~ H2CH20Me _ . _ ,, ~ ~ _~
1 ~1 Cl H H H CH2CH20Me _ . . . . _ ~
1 H Cl H H H CH2CH20~i . ~ ~ ~ . ., . , ... __ 1 l l Me tl H H CH2CH2CH20M~
~ ~ . ~
1 H Me H 11 t 1 CH2CH2CH20H
. -, ., ~ . . ., , .............. ~
1 ~1 H H C0 2 Ma Ph H CH2CH2CH~OMe . ... _ ~ H H H CO-2-Me-Ph H CH2CH2CH20H
_ . . ~
1 H H H C:O-c-Hex H CH2CH2CH2C)Me ~ _ _ , , , , _. _ 1 H H H CO-c-Hex H Ctl2Ctl2CH20H
_ m ._ _ _ _ ~ __ 1 H H tl H tl CH2CH20-CO-n-Bu . . , . __ . .. ,. -- -1 H H H W H ~H2C:H20-CO-Et . , ~ _, - __ 1 H H H H H CH2CH20-CO-c-Hex _ _ . . . _ _ .-- v~, _,.
1 H H H H H C~12CH2CH20-CO-2-Me-Ph _ -- T - _ 1 H H tl H H CH2CH20~NHEt _ _ _ _ _ . _ __ ~
1 H H H H H CH2CH20-CO~NH-n-Bu _ _ .
1 H H H H H CH2CH20-CO-NH-c-Hex _ ~
1 H H H Me H CH2CH20-CO-n Bu _ _ _ ~
1 H H H Me H CH2CH20-CO-Ph _ _ _ , 1 H H H Me H CH20-CO-2-Me-Ph - 60- 2~78~9~

=,== =~3 ~ ~_ ~ ~_ n R' R3 R~ Rs R~ R' _ . ~ ~ ~
1 H H H H H CH~Ctl2CH2O CO-OEt ~ _ . A__ _ ~__ ~
1 H H H H H CH2CH;~CH2O~O-O-c-H~x == _ ~ _ _=:=C _r.-

Claims (14)

1. A pyridine derivative of the formula I
(I) in which R1, R4 and one of the two radicals R2 or R3 are identical or different and are hydrogen, halogen, in particular fluorine, chlorine or bromine, cyano, nitro, trifluoromethyl, (C1-C12)-alkyl, hydroxyl, (C1,-C6)-hydroxyalkyl, (C1-C12)-alkoxy, -O-[CH2-]xC H(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C8)-alkylmercapto, (C1-C8)alkylsulfinyl, (C1-C8-alkylsulfonyl, (C1-C8)-alkylcarbonyl, (C1-C8) alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-carbamoyl, N,N-di.-(C1-C4)-alkylcarbamoyl, (C1-C8)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methyl anilino, phenylmercapto, phenylsulfonyl, phenyl-sulfinyl, or -NR'-R", (C1-C12)-alkoxy-(C1-C12)-alkyl or (C1-C12)-alkoxy-(C1-C12)-alkoxy, or an unsubstituted or substituted (C6-C12)-aryloxy radical or (C7-C11) aralkyloxy radical which carries 1, 2, 3, 4 or 5 identical or different substituents from the series comprising halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy,-O-[CH2-]xC H(2f+1-g)Fg,-OCF2Cl,-O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C8) alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkyl-carbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-di (C1-C4)-alkylsulfamoyl, in particular up to 3 of the abovementioned idPntical or different substi-tuents, in the aryl moiety, where a CH2 group of the alkyl chain of the aralkyloxy radical is optionally substituted by O, S, SO, SO2 or NR', and the other radical, R2 or R3, corresponds to the following formula II
(II) in which X is O or S, R6 is a branched or unbranched (C1-C12)-alkyl radi-cal, (C1-C12) alkenyl radical or (C1-C12)-alkynyl radical which is monosubstituted or polysub-stituted by halogen, hydroxyl; cyano, amino, carboxyl (C1-C10)-alkoxy, (C1-C12)-alkoxycarbonyl,(C3-C8) cycloalkoxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C8-C12)-aryloxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C1-C12)-alkanoylamino, (C3-C8 )-cycloalkanoylamino, (C1-C12)-hydroxyalkanoylamino,(C6-C12)-aroylamino, (C7-C11)-aralkanoylamino, ( C1-C8)-alkoxy-(C1-C12) alkanoylamino, (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryl-oxycarbonyloxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkylcarbonyloxy,(C3-C12)-arylcarbonyl-oxy, (C3-C8)-alkenylcarbonyloxy, (C3-C8)-alkynyl-carbonyloxy, (C3-C8 )-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N-(C1-C6)-alkylamino, (C1-C12)-alkoxy-N,N-(C1-C6)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyloxy, (C1-C8)-alkylmercapto, (C1-C8)-alkylsulfinyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, trifluoromethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkylsul-famoyl, N,N-di-(C1-C6)-alkylsulfamoyl, (C1-C8)-alkylsulfonamido, arylsulfonamido, carbamoyl, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C8)-alkyl-carbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl, N-((C1-C8)-alkoxy-(C1-C4)-alkyl)carbamoyl, N-((C1-C4)-hydroxy-alkyl)carbamoyl or an O-acylated derivative thereof, or by a substituted (C8-C12)-aryl radical, a (C7-C11)-aralkyl radical or a heteroaryl radical which carries 1, 2, 3, 4 or 5 identical or different substituents from the series comprising hydroxyl, halogen, cyano, nitro, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, (C1-C6)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, OCF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C8)-alkyl-carbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenyl-mercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-di-(C1-C4)-alkylsulfamoyl, in particular up to three of the abovementioned identical or different substituents, in the aryl moiety, or by a subatituted, (C6-C12) aryloxy radical, (C7-C11)-aralkyloxy radical or a heteroaryloxy radical which carries 1, 2, 3, 4 or 5 identical or dif-ferent substituents from the series comprising hydroxyl, halogen, cyano, nitro, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, (C1-C6)-hydroxy-alkyl, O-[CH2-]xCfH(2f+1g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C8)alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenyl-mercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-di-(C1-C4)-alkylsulfamoyl, in particular up to three of the abovementioned identical or different substituents, in the aryl moiety, R6 is a (C1-C,2)-alkoxy radical, (C3-Ca)-cycloalkoxy radical or a (C6-C12)-aryl radical, (C7-C11)-aralkyl radical or a heteroaryl radical, which carries 1, 2, 3, 4 or 5 identical or different sub-stituents from the series comprising hydroxyl, halogen, cyano, nitro, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, (C1-C6)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg -OCF2C1, -OCF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C8)-alkyl-carbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, N-( C3-C8)-cycloalkylcarbamoyl,N-(C6-C10)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C12)arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl,(C1-C6)-alkylcarbonyloxy,(C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenyl-sulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-di-( C1-C4)-alkylsulfamoyl, in particular up to three of the abovementioned identical or different substituents, in the aryl moiety, in which in each case R' and R" are identical or different and are hydrogen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8) aminoalkyl, N-(C1-C8)-alkylamino-(C1-C12)-alkyl, N,N-di-(C1-C8)-alkylamino-(C1-C12)-alkyl, (C7-C14)-aralkyl, or are together -[CH2]n-, in which one CH2 group can be replaced by O, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)- alkoxycarbonylamino, and R6 can be substituted by a radical of the formula III
- O - Z (III) in which Z is an amino acid or a derivative thereof, bonded via its acyl radical, or R5, or by a radical of the formula IV
- CO - U (IV) in which U is a polypeptide bonded via the amino group, preferably a tripeptide or a dipeptide, or an amino acid derivative bonded via the amino group, preferably an L-amino acid derivative, in parti-cular an L-alanine or a glycine derivative, R7, independently of R6, can be hydrogen or R8, where the radicals R6 and R7, together with the nitrogen atom, also form a 5-, 6- or 7-membered saturated heterocyclic ring, which heterocyclic ring can also contain a second nitrogen atom and which heterocyclic ring for its part can be substituted by phenyl or phenyl-C1-C3-alkyl, Y is methyl or CH-OR5, in which R5 is hydrogen, Z or the radical of a physio-logically tolerable alcohol protective group which can preferably be removed in the liver or under physiological conditions, and n is 0 or 1 f is 1 to 8, preferably 1 to 5, g is 0 or 1 to (2f+1) and x is 0, 1, 2 or 3, preferably 0 or 1, plus all derivatives which have a protective group in the corresponding amino or hydroxyl group, and the physio-logically active salts.

2. A compound as claimed in claim 1, in which R1, R4 and one of the two radicals R2 or R3 are identical or different and are hydrogen, halogen, in particular fluorine, chlorine or bromine, (C1-C5)-alkyl, hydroxyl, (C1-C5)-alkoxy, (C1-C5)-alkoxy-carbonyl, (C1-C8)-alkylcarbonyloxy, NR'-R", (C1-C4)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy or a substituted (C6-C12)-aryloxy or (C7-C11)-aralkyloxy radical which carries, 1, 2 or 3 identical or different substituents from the series comprising halogen, in particular fluorine or chlorine, cyano, trifluoromethyl, (C1-C5)-alkyl, (C1-C8)-alkoxy, (C1-C5)-alkylcarbonyl, (Cl-C5)-alkoxycarbonyl, in which R' and R" are identical or different and are hydrogen, (C6-C12)-axyl, (C1-C8)-alkyl or (Cl-C6)-alkylcarbonyl, n is 0 or 1 and the other radical R2 or R3 corresponds to the formula II, in which X is 0, Y is CH2OR5, R5 is a branched or unbranched (Cl-C8)-alkyl radical, which is monosubstituted or disubstituted, in particular monosubstituted, by hydroxyl, (Cl-C10)-alkoxy, (C1-C8)-alkoxycarbonyl, (C3-C8)-cyclo-alkoxycarbonyl, (C,-C12)-aralkoxycarbonyl, (C6-C10)-aryloxycarbonyl, carbamoyl, N-(Cl-C8)-alkoxy(Cl-C2)-alkyl)carbamoyl,N-((Cl-C4)-hydroxy-alkyl)carbamoyl or an O-acylated derivative thereof, (C1-C12)-alkylcarbonyloxy, carboxyl, (Cl-C8)-alkoxycarbonyloxy; (C6-Cl2)-aryloxycarbonyloxy, (C7-C11)-aralkyloxycarbonyloxy, (C,-Cll)-aralkyl-carbonyloxy, (C6-Cl2)-arylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, carbamoyloxy, N-(Cl-C6)-alkylcarbamoyloxy,N,N-di-(Cl-C8)-alkylcarbamoyl-oxy, N-(C3-C8)-cycloalkylcarbamoyloxy, (Cl-C8)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, NR'R"
or the acyl radical of an N-derivatized amino acid, or by a substituted (C6-Cl2)-aryl radical which contains one or two substituents from the series compris-ing halogen, in particular fluorine, chlorine, trifluoromethyl, hydroxyl, (Cl-C4)-alkoxy, (Cl-C5 )-alkyl, (Cl-C6)-alkylcarbonyloxy, (Cl-C6)-alkoxycarbonyl, (Cl-C4)-hydroxyalkyl, or by a substituted (C6-C12)-aryloxy radical, (C7-C11)-aralkyloxy radical or a heteroaryloxy radical, in particular a phenoxy radical or a henzyloxy radical, which contains one or two substituents from the series comprising hydroxyl, (Cl-C4)-alkoxy, (Cl-C5)-alkyl, (Cl-C6)-alkylcarbonyloxy, (Cl-C6)-alkoxycaxbonyl, (Cl-C4)-hydroxyalkyl, R6 is a (C6-C12)-aryl radical which is substituted oncer twice or three times by hydroxyl, halogenr in particular chlorine or bromine, cyano, nitro, (Cl-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, (C1-C6)-hydroxyalkyl, -O-[CH2]xCfH(2f+1g)Fg, -OCF2Cl, OCF2-CHFCl, (Cl-C5)-alkylcarbonyl, (Cl-C6)-alkoxy-carbonyl, carbamoyl, N-(Cl-C8)-alkylcarbamoyl, N,N,di-(C1-C8)-alkylcarbamoyl, (Cl-C6)-alkyl-carbonyloxy, phenyl, benzyl, phenoxy, benzyloxy and/or NR'R", R7, independently of R6, can be hydrogen or (C1-C5)-alkyl, R5 can be H or an alcohol protective group, where OR5 is in particular a substituted or unsub-stituted methyl ether, a substituted or unsub-stituted ethyl etherr a substituted or unsub-stituted benzyl ether, a silyl ether, an esterr a carbonater a carbamate or a sulfonate.

3. A compound as claimed in claims 1 or 2, in which R5 is hydrogen, (Cl-C8)-alkyl, benzyl, (Cl-C8)-alkyl-carbonyl, phenylcarbonyl or carbamoyl.

4. A compound as claimed in any of claims 1 to 3, in which n is 0 and Y is CH2OR5, R1 and R4 and one of the radicals R2 or R3, in particular R2, are hydrogen, (C1-C5)-alkyl, fluorine, chlorine, (Cl-C5)-alkoxy, and the other radical, R2 or R3, in patricular R3, corresponds to the formula II in which X is 0, R6 is branched or unbranched (C1-C3)-alkyl which is monosubstituted by hydroxyl, (Cl-C4)-alkoxy, (Cl-C9)-alkoxycarbonyl, (C3-C6)-cycloalkoxycarbonyl, benzyloxycarbonyl, (Cl-C4)-alkylcarbonyloxy and/or (((C1-C8)-alkoxycarbonyl)methyl)carbamoyl or R6 is (C6-C12)-aryl which is monosubstituted or disubstituted by hydroxyl, halogen, (Cl-C6)-alkoxy, (Cl-C5)-alkyl; trifluoromethyl, (C1-C6)-hydroxyalkyl, -O-[CH2]xCfH(2f+1-g)F8and/or NR'R", and R7 is hydrogen.

5. A compound as claimed in any of claims 1 to 4, in which R6 is in each case substituted in the end position.

6. A compound as claimed in any of claims 1 to 5, in which R1, R4 and one of the two radicals R2 or R3 are hydrogen.

7. A process for the preparation of compounds as claimed in any of claims 1 to 6, which comprises reacting pyridine-4- or -5-carboxylic acid or their esters accord-ing to formula VI

or VI VI

with an amine to give compounds of the formula I.

8. The process for the preparation of compounds as claimed in any one of claims 1 to 6, in which Y is -CH2-OR5 and as claimed in claim 7, wherein pyridine-4- or -5-carboxylic acids of the formula VII

or VII

in which Y' is a substituent which can be converted to a radical -CH2-OR5, a) if Y' is CH3 and n is 0, are halogenated to give compounds of the formula VII in which Y' is CH2W, in which W is halogen, in particular chlorine or bromine, and these compounds for their part are reacted with reagents of the formula MOR5 to give compounds of the formula I, in which M is hydrogen, an alkali metal atom or an alkaline earth metal atom, or b) if Y' is CH3 and n is 1, are reacted with AC2O/ACOH to give compounds of the formula I in which Y is -CH2-OAc, or c) if Y' is -CO2H, -CO2alkyl or -CHO and n is 0, are reduced to give compounds of the formula I in which Y is CH2OH.

9. A compound as claimed in any of claims 1 to 6 for use as a fibrosuppressant.

10. A compound as claimed in any of claims 1 to 6 for influencing the metabolism of collagen and collagen-like substances.

11. A pharmaceutical containing a compound of the formula I and a tolerable pharmaceutical excipient.

12. The use of a compound of the formula I for influencing the metabolism of collagen and collagen-like substances.

13. The use of compounds of the formula I as fibrosuppressants.

14. A process for the production of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances, wherein the pharmaceutical contains a compound of the formula I.