AU600084B2

AU600084B2 - Pyridine-2,4- and -2,5-dicarboxylic acid derivatives, processes for their preparation, the use thereof and medicaments based on these compounds

Info

Publication number: AU600084B2
Application number: AU11450/88A
Authority: AU
Inventors: Martin Bickel; Dietrich Brocks; Harald Burghard; Volkmar Gunzler; Hartmut Hanauske-Abel; Stephan Henke
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1987-02-10
Filing date: 1988-02-09
Publication date: 1990-08-02
Anticipated expiration: 2008-02-09
Also published as: PT86734A; FI880554A0; AU1145088A; FI880554A; IE67446B1; NO173184B; IL85361A; NO880556D0; EP0278452A2; DK66088D0; IL85361A0; NO173184C; DK90992A; FI91524B; DK170245B1; FI91524C; DK90992D0; KR880009935A; AR247816A1; EP0278452A3

Description

A-

600C84 1 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Application Number: Lodged: I t. Class 'Cmplete Specification Lodged: Accepted: Published: Priority: s~,t.

9 ,f Rlated Art: *Name of Applicant: Address of Applicant Actual Inventor., Address for Service HOECHST AKTILENGESELLSCHAFT 45 Bruningstrasse, D-623O Frankfurt/Main 80, Federal Republic of Germany MvARTIN BICKEL, DIETRICH BROCKS, HARALD BURGHARD, VOLKMAR CUNZL ER, STEPHAN HJEN'.1(E, HARTMUT HAZNAUSKE-ABEL EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: PYRIDINE-2,4- AND -2,5-DI2CARBOXYbIC ACID DERIVATIVES, PROCESSES FOR THEIR PREPARATION, THE USE THE~REOF AND MEDICAMENTS BASED ON THESE COMPOUNDS The following statement Is a full description of this Invention, Including the best method of perforfr.~g It known to us 1;

I~

I I- 1 HOECHST AKTIENGESELLSCHAFT HOE 87/F 040 Dr.WN/St 0 0 0 00 a 0 4 o o 00 0 0 00 i 0 0 0 0 Description Pyridine-2,4- and -2,5-dicarboxylic acid derivatives, processes for their preparation, the use thereof and medicaments based on these compounds Compounds which inhibit proline hydroxylase and lysine hydroxylase effect very selective inhibition of collagen biosynthesis by influencing collagen-specific hydroxylation reactions. In the course of these, protein-bonded proline or lysine is hydrolyzed by the enzymes proline hydroxylase and lysine hydroxylase. If this reaction is suppressed by inhibitors, a hypo-hydroxylated collagen molecule which is not capable of functioning and is released by the cell into the extracellular space in only a small amount is formed. The hypo-hydroxylated collagen 15 also cannot be incorporated into the collagen matrix and is very readiltydegraded.pro.teolytically. As a consequence of these effects, the total amount of extracellularly deposited collagen is reduced.

It is known that inhibition of proline hydroxylase by known inhibitors, such as a,a'-dipyridyl, leads to an inhibition of the clq-biosynthesis of macrophages Muller et al., FEBS Lett. 90 (1978), 218; and Immunbiology 155 (1978) 47). There is thus a loss of the classical route of complement activation. Inhibitors of proline hydroxylase therefore also act as immunosuppressanks, for example in immunity complex diseases.

It is known that proline hydroxylase is inhibited effectively by pyridine-2,4- and -2,5-dicarboxylic acid Mayama et al., Eur. J. Biochem. 138 (1984) 239-245).

However, these compounds are active as inhibitors in the celL culture only in very high concentrations Gunsler et al. Collagen and Rel. Research 3, 71 1983).

.4 4 0 4 .4 .4 -ZI 410 .4 0 .4 t1)t, 14 .4 14 .4 ~.4 o .4 o '0 .414 .4 4~~ 14 00 .414 0 O ,,14 00 1) .4 .4, .4 1,14 .40 40 .4 .4.4 tt.4 .4 2- DE-A-3,432,094 describes pyridine-2,4- and Lic acid dliesters with 1-6 carbon atoms in -the ester aLkyL part as medicaments for inhibiting proline hydroxy- Lase and Lysine hydroxylase.

Ho!-ever, these Lower alkyL diestirs have the disadvantage that they are split too rapidly in the organism to give the acids and do not arrive at their site of action in the cell in a sufficiently high concentration, and therefore are not particularly suitable for possible admninistration as medicaments.

Surprisingly, it has now been found that tho mixed ester/ amides of pyridine-2,4- and -2,5-dicarboxyLic acid and Likewise the higher aLkyLated dliesters are excellent inhibitors of collagen biosynthesis in the animal model.

15 The actual active compound, the pyridine-2,4- or dlicarboxyLic acid, is first formed in the cell by hydro- -l.ysi.sof.the sters-,or ester/amides. -On- the-basis of their higher LipophiLicity and the fact that, surpr singLy, they are hydrolyzed only very slowly during trans- 20 portation, the esters and ester/amides can be transported into the celLs. OnLy here is the actual active compound, the pyridine-2,4- or -2,5-dicarboxyLic acid, released.

The invention thus relates to; 1. Pyridine-2,4- and -2,5-dicarboxyLic acid derivatives of the formula I 0 0 0

C.-X-R

1 0 0 in whi~oh Rdenotes brandied or unbranched Cl-C 1 2 -aLkyl which 2 4444 4 4 9 44 4 no r 494 4 4444 4 4I 444444 4 4L 4 44O 4 44 -3is optionally monosubstituted or, in the case of the

C

2

-C

12 -aky radicals, also polysubstituted bI halogen, hydroxyl, cyano, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyLoxy or alkyt- or dialkylamino, the alkyl radicals containing 1-4 carbon atoms and, in the case of the C 3 and C 4 -alkyL radicals, it also being possible for them to be branched, phenyl, which is in turn optionalty mono-, di- or trisubstituted by halogen, nitro, C 1

-C

4 -alkyL or

C

1

-C

4 -alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C 3 and C 4 -alky radicals, for these to be branched, 15 or R denotes saturated C 5

-C

7 -cycloakyl, whicli is optionally benzo-fused, or R denotes aryl or heteroaryl, which in turn is optionally mono-, di- or trisubstituted by halogen,

C

1 -C4-atkyL-or eC 1

-C'

4 -alkoxy, it .also being 20 possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the

C

3 and C 4 -alkyl radicals, for these to be branched, or R' denotes 2-oxo-1,3-dioxolylmethyl, which is optionally also methyl-substituted, or R, if X is nitrogen, denotes hydrogen, and 2 1 1 R independently of denotes hydrogen or R it also being possible for R 2 to be identical to R II and X denotes oxygen or R-substituted nitrogen, in which R is hydrogen or Cl-C 6 -alkyl or, together with

R

1 optionally forms a heterocyclic saturated 6- or 7-ring, it also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible for the heterocyclic ring in 4turn to be substituted by phenyl or phenyl-Cl-C 3 a Lk yL, and physiologically tolerated saLts thereof for use as miedi caments, excluding the compounds in which X denotes oxygen and R 1 and R2at the same time denote unsubstituted Cl-C 6 5-aLkyL The invention particularLy relates to pyridine-2,4- and acid derivatives according to formula 1, in which Rdenotes branched or unbranched Cl-C 4 -aLkyL which is optionally ronosubstituted or, in the case of the 0998C 3 nd C-aLkyL radicals, also pp~ysubstituted by Cl-C 3 -aLkoxy and/or Cl-C3-aLIkoxycarbonyL, it also 15 being possible for the C 3 -aLkyl radicals to be 0 00 0a 4branched, and/or phenyL, a 9 1 or R denotes C 5 or C 6 -cycLoaLkyL, which is option- 8a L aL-vy benz'o-f used, o r Rldenotes phenyL, which is optionally mono-, dli- or 9~,'20 trisubstituted by nitro, or R 1 denotes 3- cr 4-pyridyL, naphthyl, 2- or 3thienyL., pyrazolyL, imidlazoLyL or thiazoLyL, or Rdenotes 5-methyL-2-oxo-1,3-dioxoL-4-yL-methyL and

R

2 indlependlently of R 1 denotes hydrogen or R 1,t also being possible f or R~ to be identical to R, and 3_ X denotes oxygen or R -substituted nitrogen, in which Ris hydrogen or Cl-C 3 -aLkyL or, together with R1, optionaLly forms a heterocycLic saturated 6ring, it also being possible for the heterocycLic 6ring to include a second nitrogen atom and to be subst i toted in turn by phenyL or phenyL-Cl-C 3 -aLkyL, and i:A i ltgicaLty to( 4 eratedl satts thereof, for use as medir.iments, excLuding the compounds in which X clenolues oxygen and Rland R2at the same time ara~ unsubstituted Cl-C 4 -atkyL.

C--

The invention also relates to pyridine-2,4- and dicarboxylic acid derivatives of the formula I' 0 2' II R I' C X'

R

I,

0 in which R denotes branched or unbranched C 1

-C

12 -akyL which is optionally monosubstituted or, in the case of C 2

C

1 2 -alkyl, also polysubstituted by halogen, hydroxyL, cyano, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy or alkyl- or dialkylamino, the alkyl radicals containing 1-4 carbon atoms and it also being possible, oo0 in the case of the C 3 and C 4 -alky radicals, for 0000 o, these to be branched, phenyl, which is in turn optionally mono-, di- or trisubstituted by haLogen, C 1 -C4- -aLko y--or C 1-4-aLky L, .i t alsob e i ng po s i b Le for the C 3 and C 4 -alkyl radicals mentioned to be 0* branched and it also being possible, in the case of d. polysubstitution, for the substituents to differ independently of one another, 1 or R denotes saturated C 5

-C

7 -cycLoaky, which is optionally benzo-fused, or R denotes aryl or heteroaryt, which is in turn .optionally mono-, di- or trisubstituted by halogen, nitro, C 1

-C

4 -alkyL or C 1

-C

4 -alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C 3 and C 4 -alkyL radicals, for these to be branched, 1' or R denotes 2 -oxo-1,3-dioxoylmethyL, which is optionally methyL-substituted, or R if X' is oxygen, denotes hydrogen, and

R

2 independently of R 1 denotes hydrogen or R1, it also being possible for R to be identical to R, -6and XI denotes oxygen or 1substituted nitrogen, in which R3 is hydrogen or Cl-C 6 -aLkyL or, together with R 1,optionally forms a heterocyclic, saturated 6- or 7-ring, it also being possible for the heterocycLic ring to incLude a second nitrogen atom and it being possible for the heterocycLic ring in turn to be substituted by phenyL or phenyL-Cl-C3a Lk y L, and physiologically tolerated salts thereof, excluding the compounds in which X' denotes oxygen and R tand R1at the same time are unsubstit'jted C 1

C

12 -aLkyL or methyl or ethyl which is substituted by chlorine, hydroXyL or phenyL.

15 Preferred pyridine-2,4- and -2,5-dicarboxyLic acid derivatives according to formula 1' are those in which 1 4* 44 4 1*4 4 *44* 4*44 441$, 4 4 41~44 S

S

S 45 p 4 44 4 4 44 RII denotes branched or unbranched Cl-C 4 which 'is opt ionaL-Lymonosubsti tuted or,- in the cas.: )f the

C

2

-C

4 -aLkyL radicals, also poLysubstituted by aLkoxy or alkoxycarbonyL, the aLkyL radicals 'ontaining 1-3 carbon atoms and it also being pozsibLe, in the case of the C 3 -aLkyL compounds, for these to be branched, or phenyL #45w 4 4

'S

25 or R 0denotes optionally or R 1denotes by 1, 2 or or R tdenotes imidlazoly L It' cycLopentyL or cyclohexyL, which are benzo-fused, phenyl, which is optionalkLy substituted 3 nitro groups, or naphthyL, 3- or 4-pyridyL, 3-thienyL, pyrazoLyL, or thiazoLyL, 5-methyL-2-oxo-1,3-dioxoL-4-yL-methyL or R aenmates and 21 1

R

2 indc,,pendentLy of R denotes hydrogen or R ,it aLso boing possible for R 2 1 to be idienticaL toR and X' deotesoxyge or substituted nitroge.n, in which 3-7 is hydrogen or C 1

-C

3 -alkyl or, together with R optionally forms a heterocyclic, saturated 6ring, it also being possible for the heterocyclic 6ring to include a second nitrogen atom and in turn to be substituted by phenyl or phenyL-C 1

-C

3 -alkyL, and physiologically tolerated salts thereof, exci, ding the compounds in which X' denotes oxygen and R and R 2 at the same time are unsubstituted Cl-C 4 alkyl or phenyl-substituted methyL or ethyL.

Particularly preferred pyridine-2,4- and lic acid derivatives of the formula I are those in which R1 is branched or unbranched C 1

-C

4 -aky, which is substituted by alkoxycarbonyl, the alkyl radicals containing 1 3 carbon atoms and it also being possible, in the case of the C 3 -alky radicals, for these to be branched, and 21 independenty of R' denotes hydrogen or R it 20 also being possible for R to be identical to R ,and X f denot e s to'xygen, and physiologically tolerated salts thereof.

These compounds have, inter alia, a particular activity on oral administration, as do the especially preferred pyridine-2,4- and -2,5-dicarboxyLic acid derivatives of the lormula 1 in which R and R are 1-isopropoxycarbonylethyl groups and X' denotes oxygen (such an, for example, bis(1-isopropoxycarbonylethyL) dicarboxylate \avmple 3) or bis(1-isopropoxycarbonyLethyl) pyridine-2,g-dicarboxylate (Example 30), and physioLogically tolerated salts thereof.

By halogen there are understood fLuorine, chlorine, bromine and iodine, by aryl there are understood phenyL and naphthyl and by heteroaryl there are understood and 6-membered aromatic rings which contain 1, 2 or 3 nitrogen and/or oxygen and/or suLfur atoms and can optionally also be benzo-fused; the heteroaryl radicals are, in particular, pyridyl, pyridazyL, pyrimidyl, pyrazyl, 8 1,3,5-triazyL, pyrolyl, pyrazolyl, imidazolyL, triazolyl, thienyl, oxazoLyl and thiazolyl radicats and where appropriate benzo-fused compounds thcreof.

"Polysubstituted" above and below means that at least 2 and at most all of the hydrogen atoms present in the alkyl radicals are replaced by the substituents mentioned.

It is preferably a matter here of one substituent per methyl or methylene group.

In the case of polysubstitution, the substituents can also differ independently of one another.

The invention furthermore relates to a process for the preparation of compounds of the formula 1i, which compr iis es 4 aa) reacting a compound of the formula II 0 R 1o

O

with a compound of the formula III 411 in which R 1

R

2 and XO have the meanings given in the case of formula 11 and Y is halogen or hydroxyL, or b) reacting a compound of the formula IV 9- I V) 0 with a compound of the formula V HO-R 2 in which R 1 0, R 2 0 and XI have the meanings given in the case of formula I' and Z is halogen, or 0 9 9 9 9 9 9 o 0o '3 9 ~,0 00 9 0 0 -39 c) reacting a compound of the formula VI VI f. IAoq!ft,; C- z with an alcohol HO-R 2 or an alcohol of the formuLa VII HO-R 1 (VI I 9090 0 '0 wherein R 1 1 and R 2 0 have the meanings given in the case of formula I I and Z is halogen, or d) reacting an alkali1 metaL salt of pyridine-2,4- or acid with a halide of the f ormula V II I z (VI II) wherein R 1 has the mean ings @i~Ven in the case of f ormula I I and Z, is haLogen, and, if appropriate, convert ing the. react ion, products into their physioLogicaLLy tolerated salts.

10 The preparation of compounds according to formula I and the preparation of the starting substances required for this where they are not commercially available are described in more detail below.

The compounds according to the invention are most easily prepared by mixing the two components, the pyridine derivative according to formula (IV) or (VI) and the amine or alcohol according to formuLa (III), or (VII), in equimoLar amounts or with up to an approximately 5-fold excess of III, V or VII, and reacting them at temperatures between -30 and 1500C, preferably at 20 to 100 0 C, until the reaction has ended. The end of the reaction can be determined by means of thin layer chromatography (TLC control). One variant of this process S, 15 comprises carrying out the reaction in a suitable solvent, uch as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons, such as methyene S chloride, chloroform or tri- or tetrachtoroethylene, benene; toLovene*Orpoear sotvents, such as .dimethyformamide, acetone or dimethyl sulfoxide. An excess of amine/ 0 9alcohol according to formula (III), or (VI)O, which can be up to 5 times the amnount, Can also be used here.

The reaction temperatures here are bef,-' -iom temperature and the boiling point of the soly. t, t peratures in the range from room temperature to 1 e4in particularly preferred, If appropriate, the reaction can also be carried out in the presence of bases. Possible additiona bases are inorganic acid-trapping agents, suchl as carbonates or bicarbonates, for example sodium carbonate, potassium carbonate, sodium bicarbonate Or potassiumt bicarbonate, or organic acid-trapping agents, such as tertiary amines, such as triethylaminhe, tributyamine or ethyl diisopropyLa8ine, or hatet ydtio amines, uc as i-a4kyLmorphotines, pyridine, quohline or dtakylanlines.

The reaction of the compounds acaorci4ig to formula (fi0 4494 9 4 4444a 4 441 44 4 lt94 4 4 4t 4 4 11 with alcohols according to formula (III) 0) is preferably carried out with the addition of a dehydrating agent, such as a dialkylearbodiiuide, the alkyl radicaLs containing 1 to 8 carbon atoms and it also being possible, in the case of the C 3

-C

8 -compounds, for these to be branched or cyclic; dicycLohexyLcarbodiimide is preferably used. A corresponding method is described in Houben-Weyl, Volume XV/2, pages 103-111, Methoden der Organischen Chemie (Methods of Organic Chemistry), 4th edition, Georg Thieme Verlag, Stuttgart, 1974.

If appropriate, the products can be worked up, for example by extraction or by chromatography, for example over silica gel. The isolated products can be recrystallized and if appropriate reacted with a suitable acid to give a physiologically tolerated salt. Examples of possible suitable acids area mineral acids, such as hydrochloric and hydrobromic acid, as well as sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such a tflracttci;caette,-4propionicm-succinic, .gLy.coLic a c t i c, 20 raalic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesufonic, toluenesufonic, oxalic, 4aminobenzoic, naphthaene-1,5-disufonic or ascorbic acid.

The starting compounds of the formula (III), and (VII), where they are not commercially available, can be synthesized in a simple manner (for example Organikum, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry), 15th edition, VEB beutscher Verlag der Wissenschaften, 1976; a review of the various possibilities is to be found in the method register; AlcohoLs: page 821, Amines: page 822).

The starting compounds of the forYmula (II) are obtained, for exariple, by converting pyridine-2,4- or boxylic acid into the corresponding pyridine-2,4- or acid halide preferably the chloride (by processes which arc enown from the literature, for examp a Organikum, Organisch Chemisches ur 12 Grundpraktikum (Basic Practical Organic Chemistry), edition, VEB Deutscher Verlag der Wissenschaften, 1976, page 595 et seq.), which is then reacted with an alcohol of the forrl--a R -OH to give the corresponding 2,4- or 2,5-diester. Selective hydrolysis of the ester in the 2-pnsition of the pyridine derivative (for example by a copper complex, see Pharm, Acta Helv. 44 1969, page 637) or partial alkaline hydrolysis (see J. Org. Chem.

39 1974, page 1158) gives the pyridine-4- or carboxylic acid ester-2-carbo'yLic acid, which is either used directly (II, Y=OH) or can be converted into the acid halide (II, Br or preferably the acid chLoride.

The starting compounds of the formula (IV) can be syn- 0 90 I o 15 thesized, for example, as follows: 0400 Reaction of the pyridine-2,4- or -2,5-dicarboxylic acid halide, preferably the chloride, with benzyl alcohoL to 0 give pyr.idine-2,4- or--2 5-,dicarboxyLic-acid be zyL ester; subsequent selective hydrolysis of the ester in 20 the 2-position (for example in the presence of a coppr *0 catalyst, Loc.cit.Pharm. Acta Helv.), conversion of the 4 00 free acid in the 2-position into the acid halide, reac- 1 oo tion with a compound of the formula HX'-R 1 (III) to give the pyridine-4- or -5-carboxylic acid benzyI ester- 2-carboxylic acid (R 1 ester or -amide, hydrogenoLytic 0 t splitting off of the benzyl protective group which remains (for example with H 2 /Pt, see Houben-Wey' Volume IV/lc (1980), pages 381-82) and subsequent conversion of the free acid in the 4- or 5-position of the pyridine ring into the acid halide (IV).

The pyridine-2,4- or -2,5-dicarboxylic acid halide according to formula VI can be obtained by known methods, f'or example by reaction of pyridine-2,4- or boxytic acid with a phosphorus trihalide (see, for example, Organikum, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry), 15th edition, VEB 4 4, 4 3 4 4.r 444"' 4r* 4 4 44 4 4i 44r 4. 44 44 4 4. 44 44 43 4., 4. 44 13 Deutscher Verlag der Wissenschaften, 1976, pages 527 and 595 et seq.).

The reaction of alkali metal salts of the pyridine-2,4or -2,5-dicarboxylic acid with a halide of the formula VIII is carried out by processes which are known from the literature (see, for example, Organikum, Organisch Chemisches Grundpraktikum (Banic Practical Organic Chemistry), 15th edition, VEZ Deutscher Verlag der Wissenschaften, 1976, page 255 et seq.).

The compounds of the formula I and I' according to the invention have useful pharmacological properties, and in particular show an activity as inhibitors of proine hydroxylase and lysine hydroxylase and as fibrosuppressants and immunosuppressants.

The activity of the fibrogenase can be determined by radioimmunologica assay of the N-terminal propeptide of cbl'agen type-III or the -N--or C-terminaL, crossLinking domains of collagen type IV (7s-collagen or type IV collagen-NCI) in the serum.

20 For this purpose, the hydroxyproine, procoLLagen III, peptide, 7s-collapen and type IV collagen-NC 1 concentrations in the liver of a) untreated rats (controL) b) rats to which carbon tetrachloride had been administered (CCL4 control) c) rts to which first CCL 4 and then a compound according to the invention had been administered were measured (this test method is described by Rouiller, Experimental toxic injury of the Liver; in The Liver, C. Rouitler, Volume 2, pages 335-476, New York, Academic Press, 1964).

The pharmacological activity of the substances according to the invention has been investigated in a series of experiments (see Table A clear inhibition of proline _1 I_ I 14 hydroxylase and Lysine hydroxylase was thereby found.

Table 1 Substance Dosage Hydroxyproline ProcolLagen 7s-coLagen type IV from Example ,g/mg of liver III peptide ng/mL collagenng/nl

NC

1 ng/m 4 2 x 0.482 37.2 121.4 100.8 mg

CC

4 control 0.773 73.9 308.7 168.4 control 0.289 11.1 22.8 23.5 ci' The compounds of the formula I and I' can be used as Ottmedicaments in the form of pharmaceutical preparations iw hich contain them, if appropriate together with tolerated pharmaceutical excipients. The compounds can be used as medicines, for exampe in the form of pharmaceutical preparations whicmh contain these, compounds- as a mixture with a pharmaceutical organic or inorganic excipient hid suitable for enteraL, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable 4 t oils, polyalkylene glycols, vas'line and the like- The pharmaceutical preparations can be in the solid form, for example as tablets, coated tablets, suppositories or capsules; in the semi-solid form, for example as ointments, or in the liquid form, for example as solutions, suspensions or emulsions. If appropriate, they are sterilized and/or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for modifying the osmotic pressure or buffers.

They can furthermore also contain other therapeutically active substances.

The invention is illustrated in more detail with the aid of examples below: 7 i i 1 i 15 Examples 1. Bis(1-methoxycarbonylethyl) g of pyridine-2,5-dicarboxyic acid are taken ir ml of dry methylene chloride, arnd 80 ml of freshly distilled thionyl chloride and 2 mL of dry dimethylformamide are added. The mixture is boiled under refLux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toLuene. A solution of 12.5 g of methyl lactate, dissolved in methylene chloride, is added dropwise to the reaction mixture at -30 to -20 0 C. The mixture is *too allowed to warm slowly to room temperature and is stirred overnight at room temperature, and the solu- 15 tion is washed with sodium bicarbonate solution.

After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate-as't-hemobiephas-e. iThe.product is recrystal- Lized fpom isopropanoL.

S 20 Melting point 78oC; yield 7.2 g 2. Bis(1-ethoxycarbonylethy) I ii g of pyridine-2,5-dicarboxylic acid are taken in mL of dry methyene chLoride, and 80 mL of freshly distilled thionyl chloride and 2 mL of dry dimethylformamide are added. The mixture is boited under refLux for three hours, the excess thiony chloride and the methylene chloride are distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 14.1 g of ethyl lactate, dissolved in 1 L of methylene chloride, is added dropwist to the reaction mixture at -30 to -20 0 C. The mixture is allowed to warm slowl, to room temperiture and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate

I

16 as the mobile phase. The product is precipitated as an oil.

Y eld 16.6 g 3. Bis(1-isopropoxycarbonyethyl) late g of pyridine-2,5-dicarboxyic acid are taken in mL of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 mL of dry dimethylformamide are added. The mixture is boiled under refLux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 15.8 g of isopropyl lactate, 19 dissolved in 100 mL of methylene chloride, is added to the reaction mixture at -30 to -200C. The mixture S" is allowed to warm slowly to room temperature and is stirred overnight at room temperature, and the solution is washed with sodium bicarbonate soLution.

*.After :drying, the organirc..phase is freed -from the solvent and stirred with diisopropy ether. The monoester is separated off and the mother liquor is chromatogr'phed over silica gel with a mixture of four 49 parts of toluene and one part of ethyl acetate as the mobile phase. The oily product soiwly crystallizes completely.

Melting point 52 53 0 C Yield 13.5 g 4. Bis(2-methoxycarbony-2,2-dimethyLethyL dicarboxylate 10 g of pyridine-2,5-dicarboxyLic acid are taken in ml of dry methyene chloride, and 80 mL of freshly distilled thionyl chloride and 2 mL of dry dimethylformamide are added. The mixture is boiled under reflux for three hours, the excess thionyL chloride and the methytene chloride are then distilled off and the residue is evaporated, with fuming, once with dry hi'-_

I

17toluene. A solution of 15.8 g of methyl 2,2-dimethyL- 3-hydroxypropionate, dissolved in 100 ml of methylene chloride, is added *o the reaction mixture at -30 to -200C. The mixture is allowed to warm slowLy to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution.

After drying, the organic phase is freed from the solvent and the product is recrystatlized from isopropanol.

Melting point 114-5 0 C Yield 18.6 g Bis(2-methoxycarbony-2,2-dimethylethyL) pyridine-2,4dicarboxylate g of pyridine-2,5-dicarboxyLic acid are taken in 45 mL of dry methylene chloride, and 60 nL of freshly distilled thionyl chloride and 2 mL of dry dimethylformamide are added. The mixture is boiled under r ef u x ;f.or t h r e e .hoursIthe excess -thionyL chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry touene. A solution of 11.) g of methyl 2,2-dimethyl- 3-hydroxypropionate, dissolved in 100 ml of methylene chloride, is added to the reaction mixture at -30 to The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution.

After drying, the organic phase is freed from the solvent and chromvtographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oiL. Yield, 6.7 g.

6. Bis(1-ethoxycorbonyethyL) pyridine-2,4-dicarboxylate g of pyridine-2,4-dicarboxylic acid are taken in mL of dry methylene chloride, and 60 mL of freshly distilled thionyl chloride and 2 mL of dry dimethyl- 18 formamide are added. The mixture is boiled for three hours, the excess thiony chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 10.6 g of ethyl lactate, dissoCved in 100 mt of methylene chloride, is added dropwise to the reaction mixture at -30 to -20 0 C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washeed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oil, which slowly crystallizes completely.

Melting point 59 60 0 C Yield 3.7 g.

7. Bis(5-methyL-2-oxo-1,3-dioxol-4-yLmethyL) pyridine- 2,4-dicarboxyate 63gof pyridine-2;4- dic-arboxyi-c- acid sodium salt are boiled under reflux with 14.3 g of 5-methyl-2-oxo- 1,3-dioxoL-4-yL-metiyL bromide and 4.5 g of potassium carbonate in 125 mL of dry acetone for 40 hours. The carbonate is filtered off and the solution is chromatographed over silica gel with a 4:1 mixturr of toluene and ethyl acetate.

Melting point 113 0 C Yield 2.6 g Oli 8. Methyl 2-(4-(2-phenylethyLi)piperazinocarbonyL)-pyridineg of methyl pyridine-2-(carboxyic boxylate are heated under reflux with 22.5 mL of freshly distilled thionyl chLoride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 mL of dry methylene chloride, the mixture is added to a solution of 3.15 g of 1-(2-phenylethyl)-piperazine in 8 ml of methylene chloride and the 19 components are subsequently stirred at room temperature for five minutes and freed from the solvent.

The residue is recrystallized from isopropanoL, with the addition of a little active charcoaL. The product is obtained as the hydrochoride.

MeLting point 201 203 0 C Yield 2.6 g 9. Methyl g of methyl pyridine-2-(carboxylic boxylate are heated under reflux vith 22.5 mL of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 mL of dry methyene chloride, the mixture is added dropuise to a solution of 1.15 g of benzylamine in 8 mL of methylene chloride and the components are subsequently stirred at room temperatu r f or five minutes and freed fromthe solvent.

lhe residue is recrystallized from isopropanol, with S 20 the addition of a little active charcoal.

Melting point 215 2160C Yield 1.9 g Methyl Z (N-benzyL-N-methylaminocarbonyl)-pyridineg of methy pyridine-2-(carboxyLic boxylate ore heated under reflux With 22.5 mi of freshly distilled thiony chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 2.0 g of Nmethylbenzylamine in 8 mL of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent.

The residue is chromatographed over silica gel with 1 a mixture of 7 parts of methylene chloride and 3 parts of acetone.

The product is obtained as an oil.

11. Methyl 2 1.5 g of methyl pyridine-2-(carboxylic boxylate are heated under reflux with 22.5 mL of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off competely. The residue is taken up in 15 mL of dry methylene chloride, the mixture is added dropwise to a solution of 1.79 g of benzylalcoho in 8 mL of methyene chloride and the components are subsequently stirred at room tempera- 15 ture for five minutes and freed from the solvent.

The residue is recrystallized from isapropano, with the addition of a little active charcoaL.

'"Melting "point"iT04 0 C 'Yield 1.5 g 12. Methyl 2-phenyLaminocarbonyLpyridin 1.5 g of methyl pyridine-2-(carboxyic boxylate are heated under reflux with 22.5 mL of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 mL of dry methylene chlorid., the mixture is added dropwise to a solution of 1.54 g of aniline in 8 ml of methyene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent.

The residue is recrystallized from isopropanol, with the addition of a little active charcoal.

Melting point 167 0 C Yield 1.5 g 4444 4 4O #494r 4c #4 4 4-94 49* 4 4 4 4O *1 4* 21 13. Methyl 2-(2,2-diphenylethylamino)carbonylpyridine-5carboxylate g of methyl pyridine-2-(carboxylic boxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The tesidue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 3.27 g of diphenylethylamine in 8 mL of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent.

Melting point 147 0 C Yield 1.8 g 14. Methyl c arboxylate 25.5 g of methyl pyridine-2-(carboxylic boxylate gre heated under reflux with 380 mL of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour arnd the thionyl chloride is distilled off completely. The residue is taken up in 250 ml of dry methylene chloride, the mixture is added dropwise to a solution of 30 g of N-methylaniline in 150 ml of methylenechloride and the compornents are subsequently stirred at room temperature for five minutes and freed from the solvent.

The residue is recrystallized from isopropanol, with the addittion of a Little active charcoal.

Melting point 123 0 C Yield 30 g 9i 4 4 4 4 *4- *44 9 4 4 s~ r i i 22 Methyl g of methyl pyridine-2-((arboxyic boxylate are heated under reflux with 225 mi of freshly distilled thionyl chloride untiL a clear solution hAs formed. The solution is subsequently stirred at room temperature for one hour and the thionyL chLoride is distilled off completely. The residue is taken up in 70 mL of dry methytene chloride, the mixture is added dropWise to a solution of 13.7 g of ProrY (Sie kenn 150 mL of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the soLvent.

The residue is chromatographed over silica gel with a mixture of 7 parts of methylene chloride and 3 parts of acetone as the mobile phase.

Melting point 88 0 C Yield 12.6 g 16. Di(4-nitro-pheny) 4 44 a,20 1r 4 4 4 4 4444 25 4 41 4 16.7 g of pyridine-2,5-dicarboxyic acid are taken in 100 ml of dry tiethylene chloride, and 135 mL of freshly distilled thiony chloride and 3 ml of dry dimethylformamide are added. The mixture is bOoLed under reflux for three hours, the excess thionyl chloride and the methyene chloride are then distilled off and the residue is evaporated, with fuming, once With dry toluene. A solution of 27.8 g of 4-nitrophenoL in 50 mL of pyridine is added dropwise to the reaction mixture at -30 to -20 0 C. The mixture is atllowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution.

After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl adetate as the mobile phase.

Melting point 190 0 C Yield 12.5 g a.

-23 17. Bis(5-methyL-2-oxo-1,3-dioxoL-4-yL-methiyL) pyridinelate AnalogousLy to ExampLe 7, 6.3 g of carboxylic acid sodium salt are rea~cted with 14.3 g of 5-methyL-2-oxo-1,3-dioxo L-4-yl-me thy L bromide and the mixture is boiled under refLux in acetone for hours. After chromatography cver silica gel with ethyl acetate as the mobiLe phase, the product is recrystallized from hot ethyL acetate.

Melting point 118 0 C Yield 0.23 g 18. Di-(a-methoxycarbonyLbenzyL Late AnaLogously to Example 1, 10 g of pyridine-12,5-dlcarboxyLic acid are converted into the acid chLoride and this is reacted with 19.9 g of methyl (+)-mandeLa te. After extraction, working up is carried out by chromatography ov.er.si~LcageL witha mixture of toLuene and ethyl acetate as the mobile phase.

Melting point 125 0 C Yield 0.5 g 19. Methyl g of methyl pyridine-2-(carboxyLic, carboxyLate are converted into the acid ehiorid4 with 200 g of thionYL chloride as described int xampLe~ 8.

The acid chLoride is dissolved in chLoroforne and ammonia gas is passed over, the suspensiti, with vigorous stirring. The mixture is Left to stand for two days and the product is fiLtered off with suttion and washed with water.

Metting point 195-197 0 C Yield 15.6 g 20. DibenzyL Anatogously te, ExampLe 10 20 g of dicarbouytic acid are converted into the acid ch~oridd t I a I, Z4 with 160 ML of th I'hyi Fihk'r ide and this is reacted with 25.9 g of ir j, nohoL. The product is recrystaL L ized f rap,,ok~y Aq tate, wi th the addit ion of active charcoai, Melting point 11iUD Yied, ZQ.4 g 21. BenzyL pyridine-Z-( or'bxylic ac 17 g of dlibenzyL pyridline-2,5-dlicarboxyLate are suspended in methanol and~ the suspension is added to a suspension of 12.1 g of copper(II) nitrate. The mixture is boiLed under refLux for one hour and, after cooLing, the copper compLex is filtered off. The compLex is suspended in dioxane, and hydrogen suLfidle is passed in up to a weight increase o f 4 g. The copper sulfidle is separated off and the organic phase is concentrated. The product is recrystalLized from toIu en e, Melting point 132 0 C YiJeld 10.2 g 22. BenzyL pyridi'ne-2-(.3-isopropoxy- propyL )carboxamidearboxy Ia te AnaLogously to Example 8, 8 g of 5-benzy( pyridline- 2-carboxylate are converted into the acid chloride with 90 ml of thionyL chloride and this is reacted with 3 -isopropoxy-propyLamine to give the amidle. For purification, the product is chromatographed over silica gel with a mixture of cycLohexane/ethyL acetate Melting point 41 0 C Yiel 6.4 g 23. Pyridine-5-carboxyLic acid 2-(3-isopropoxy-propyl)carboxamide 5.3 g of benzyL pyridine-2-(3-isopropoxy-propyL)are hydrogenated in dioxane under normal pressure in the presence of a palladium" on-charcoal catalyst for live hours. When the uptake 1~20 II 25 if hydrogen has ended, the catalyst is filtered off with suction vnd the~ solvent is stripped off.

Melting point 129 0 C Yield 2.4 gi 24. BenzyL pyridine-2-C3-isopropoxy-propyL )carboxamiderboxy late In accordance with Example 8, 1 g of carboxyLic acid 2 -(3-isopropoxy-propyL)amide are converted into the acidl chloride (20 ml of thionyL chLoridle) and this is then reacted with 2 ml of benzyL alcohol to give benzyL pyridine-2-(isopropoxycarboxy Late. Fc~r purification, the prcgluct is chromatographed ovei siLica gel with a mixtu.;,e of cycLohexane/ethyL acetate Melting point 41 0 C Yield 0.9 g 25,. 1i 5-methyL-2-nitro-benzyL) rpyr idine-2,5-di carbqo' late Ana.logousl y. to. Ex.ai'p Le 1 5 g OfL py r~i ine-2 ,5-dli carboxyLic acid are converted into the acid chloridle with 40 ml of thionyL chloride in 30 mL of methyLene chloride and this is reacted with lo g of 2-nitro-benzyL alcohol in 50 ml of methyLene chloridle.

The reaction mixture is stirred overnight at room temperature, sodium bicarbonate solution is then added, the mixture is extracted with methylene chloride and the organic phase is dried. After the soL- 215 vent has been stripped off, the resid'ue is stirred with PthyL acetate, filtered, off with suction and recrystallized twice from methyLene chloridle.

Melting point 182 0 C Yie~Ld Z.9 g 26. Bis(2-ethoXy-ethyL) pyridine-2.,S-dicarboxy Late Analogously to Example 1, 10 g of carboxyLic acid are converted into the acid chloridle with 80 ml of thionyL chloride in 60 ml of methyLeje sqhLoride and this is reacted with 10.78 g of ethylene 26 glycol inonomethyL ether in 100 mL of methylene chloridcn Working up is by adding sodium bicarbonate solution, sParating off the organic phase and stripping off the solvent. The product is chromatographed twice over silica gel with ethyl actitate and dissolved in hot ethyl acetate, and the solution is clarified with active charcoal and freed from the solvent. The product precipitates as an oil.

Yield 7.2 g 27. Bis(2-methoxy-ethyl) Analogously to Example 26, 10 g of dicarboxylic acid are converted into the acid chloride and this is reacted with 9.1 g of ethylene glycol monomethyL ether. Working up is carried out in accordance with Example 26. The product is obtained as an oil.

Yield 6.5 g 28. Bis(2-ethoxy-ethyL) pyridine-2,4-dicarboxylate As described in Example 26, 10 g of pyridine-2,4dicarboxylic acid are reacted with ethylene glycol monoethy ether via the acid chloride. The reaction mixture is work'Ld up analogously to Example 26. The product is obtained as an oil.

Yield 7.2 g 29. 2-Methoxycarbony-2-methyl-propyl Late-2-N-(3-isopropoxy-propy)carboxamide 1 g of pyridine-5-carboxylic acid 2-(3-isopropoxypropyl)carboxamide are boiled under reflux in 20 mL of thionyl chloride until a solution is obtained.

The solution is left to stand at room temperature for one hour, the thionyl chloride is distilled off, the residu! is dissolved in 10 mL of dry methyiene chLoride and a solution of 0.5 g of methyl 27 2,2-di ethyl-3-hydroxypropiorate in 20 ml of dry methylene chloride is added dropwise. When the reaction has ended, the solvent is stripped off and the product is chromatographed over silica gel with ethyl acetate.

Yield 0.15 g Bis(l-isopropoxycarbonylethyl) pyridine-2,4-dicarboxylate g of pyridine-2,4-dicarboxy ic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 15.8 g of isopropyl lactate dissolved in 100 ml of methylene chloride, is added -dropwise to -the react ion mixture at -30 to -20 0

C.

The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and stirred with diisopropyl ether.

The onoester is separated off and the mother liquor is chromatographed over silica gel with a mixture of four parts of toluene and one part of ethyl acetate as the mobile phase. The product is obtained as an oil.

Yield: 11.2 g

Claims

1. A method of treatment for patients requiring inhibition of their proline hydroxylase or lysine hydroxylase levels, fibrosuppression, immunosuppression, influence of or treatment for disturbances in their metabolism of collagen or collagen-like substances or their biosynthesis of Clq, comprising administering to such a patient a pharmaceutically effective amount of a pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula I 0 R (I) o" C-X-R 1 which is optionally monosubstituted or, in the case of the C -alkyl radicals, also polysubstituted by halogen, .hydroxyl, cyano, carboxyl, alkoxy, alkoxy-carbonyl, alkylcarbonyloxy or alkyl-or dialkyl-amino, the alkyl radicals containing 1-4 carbon atoms and, in the case of the C and C 4 alkyl radicals, it also being possible for them j *to be branched, phenyl, which is in turn optionally mono-, di- or trisubstituted by halogen, nitro, C -C 4-alkyl or SC -C -alkoxy, it also being possible, in the case of a 4 0" polysubstitution, for the substituents to differ "o independently of one another and it also being possible, in the case of the C- and C 4-alky radicals, for these to be A. S I I 29 branched, or R 1 denotes saturated C 5 -C 7 -cycloalkyl, which is optionally benzo-fused, or R 1 denotes aryl or heteroaryl as hereinbefore defined which in turn is optionally mono-, di- or trisubstituted by halogen, C 1 -C 4 -alkyl or C-C 4 -alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C 3 and C -alkyl radicals, for these to be branched, or R 1 denotes

2-oxo-l,3-dioxolylmethyl, which is optionally also methyl-substituted, or R 1 if X is nitrogen, denotes hydrogen, and R 2 independently of R denotes hydrogen or R, 2 1 it also being possible for R to be identical to R and X denotes oxygen or R3-substituted nitrogen, in which R 3 is hydrogen or C -C -alkyl or, together with R 1 optionally forms a heterocyclic saturated 6- or 7-ring', it also being possible for the heterocyclic ring to include a second a* nitrogen atom and it being possible fof the heterocyclic ring in turn to be substituted by phenyl or phenyl-C -C 3 -alkyl, or a physiologically tolerated salt thereof but excluding the compounds in which X denotes oxygen and R1 and R at the same time denote unsubstituted S C-C -alkyl. 2. A method of treatment for patients requiring inhibition of their proline hydroxylase or lysine hydroxylase levels, fibrosuppression, immunosuppression, influence of or treatment for disturbances in their metabolism of collagen or collagen-like substances or their biosynthesis of Cl comprising administering to such a patient a pharmaceutically effective amount of a pyridine-2,4- or -2,5-dicarboxylic acid derivative according to formula I, in which .4 29a- 0 R 2 (I) 9 0 C-X-R R 1 denotes branched or unbranched C -C4-alkyl which is optionally monosubstituted or, in the case of the and C 4 -alkyl radicals, also polysubstituted by C -C -alkoxy I. o, and/or Ci-C -alkoxycarbonyl, it also being possible for the a a0 C3-alkyl radicals to be branched, and/or phenyl, or R 1 denotes C- or C-cycloalkyl, which is optionally benzo-fused, or R denotes phenyl, which is optionally mono-, di- or trisubstituted by nitro, or R denotes 3- I or 4-pyridyl, naphthyl, 2- or 3- thienyl, pyrazolyl, imidazolyl or thiazolyl, or R 1 denotes

5-methyl-2-oxo-l,3-dioxol-4-yl-methyl and R 2 independently of R 1 denotes hydrogen or R 1 it also being possible for R 2 1 to be identical to R and X denotes oxygen or R -substituted nitrogen, in which R 3 is hydrogen or !i io C 1 -C -alkyl or, together with R, optionally forms a heterocyclic saturated 6-ring it also being possible for the heterocyclic 6-ring to include a second nitrogen atom and to ou be substituted in turn by phenyl or phenyl-C -C -alkyl, or a S. physiologically tolerated salt thereof, excluding the SU compounds in which X denotes oxygen and R 1 and R 2 at the same time are unsubstituted C 1 -C 4 -alkyl. /C yg I ~1 30 3 Y L is hydrogen or Cl-C 3 alkyl, together with optionally forms a het ,ocvcl ic saturated 6- ring, it also being po-sisbLe for the heterocycLic 6- ring to include a .econd nitrogen atom and to be substituted in ,t'urn by phenyl or phenyL-Cl-C3-aLkyL, or a physiologica lly tolerated salt thereof, for use as a medicament, excluding the compounds in which X denotes oxygen and R 1and R 2at the same time are unsubstituted 3. A pyridine-2,4- or -2,5-dicarboxyL ic acid derivative of the formula V' Cr64 6* 6 *66 6 *696 6 4 I I I 0 2' 1 1 R 002 X' R 10 II in which R denotes branched or unbranched Cl-C 12 -aL1kyL which is optionalLy monosubstituted or, in the case Of C 2 C 1 2 -aLkyL, also polysubstituted by lhalogen, hydroxyl, *6 cyano, carboxyL, aLkoxy, aLkoxycarbonyL, aLkyLcarbon- ytoxy or alkyL- or diaLkylamino, the aLkyL radicaLs containing 1-4 carbon atoms and it also being possibLe, in the case of the C 3 and C 4 -aLkyL radicals, for these to be branched, phenyl, which is in turn option- ally mono-, dli- or trisubstituted by halogen, C 1 -C 4 aLkoxy or Cl-C 4 -aLkyL, it also being possible for thie C 3 and C 4 -alkyL radicals mentioned to be branched and it also being possible, in the cas.2 ol poLysubstitUtioi, for the substituents to differ indle- pendently of one another, or R 1 denotes saturated C5-C7-cycLoaLkyl, which is optionally benzo-fused, h\ or d o r R denotes aryL or heteroaryl which is in turn optionally mono-, dli- or trisubstituted by halogen, 31 nitro, C 1 -C 4 -aky or C 1 -C 4 -akoxy, it also being possible, in the case of poLysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C 3 and C 4 -alkyL radicals, for these to be branched, or R 1denotes 2-oxo-1,3-dioxolylmethyl, which is option- ally methyl-substituted, 1 n A) or R if X is e+ denotes hydrogen, and 2'1' 1' R independently of R denotes hydrogen or R it also being possible for R to be identical to R, and X' denotes oxygen or R -substituted nitrogen, in which R' is hydrogen or C 1 -C 6 -alky or, together with 1' *oR optionally forms a heterocyclic, saturated

6- or 7-ring, it also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible for the heterocyclic ring in turn to be substituted by phenyl or phenyl-Cl-C 3 alky, or a physiologically tolerated salt thereof, excluding the compounds in which X! denotes oxygen and R1 and R21 at the same time are unsubstituted C 1 C12-alkyl or methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl. 4. A pyridine-2,4- or -2,5-dicarboxyic acid derivative according to formula 11' as claimed in claim 3, in which R1' denotes branched or unbranched C 1 -C4-alkyL, which is optionally monosubstituted or, in the case of the C 2 -C 4 -akyl radicals, also polysubstituted by aLkoxy or aLkoxycarbonyl, the alkyL radicals contain- ing 1-3 carbon atoms and it also being possible, in the case of the c 3 -aky compound, for these to be branched, or phenyLI or R 11 denotes cyclopenty or cyclohexyl, which are optionaly benzo-fused, a a aat a ao 32 1' or R denotes phenyl, which is optionally substituted by 1, 2 or 3 nitro groups, or naphthyl, or R denotes 3- or 4-pyridyL, 3-thienyL, pyrazolyl, imidazolyl or thiazolyl, or R denotes 5-methyl-2-oxo-1,3-dioxoL-4-yl-methyl and R 2 independently of R' denotes hydrogen or R it aLso being possible for R 2 to be identical to R and X' denotes oxygen or R3'-substituted nitrogen, in which R is hydrogen or C 1 -C 3 -alkyL or, together with R optionally forms a heterocyclic, saturated 6- ring, it also being possible for the heterocyclic 6- ring to include a second nitrogen atom and in turn to be substituted by phenyl or phenyl-C 1 -C 3 -alkyl, or a physiologically tolerated salt thereof, excluding the compounds in which X' denotes oxygen and 1' R 2 Sand R at the same time are unsubstituted C 1 -C 12 alkyl or methyl or ethyl which is substituted by chlorine, hydroxyl- or phenyl. i. A process for the preparation of a compound of the formula I' as claimed in claim 3, which comprises a) reacting a compound of the formula II 0 2 11 R-c S- (II) N C-Y II 0 with a compound of the formula III HX'-R 1 (II) in which R 1 R 2 and X' have the meanings given in the case of formula I' and Y is halogen or hydroxyL, or b) reacting a compound of the formula IV 0 U Z-CIV I C-X -R1 0 with a compound of the formula V HO-R 2 (V) in which R 1 R 2 and X' have the meanings given in the case of formula I$ and Z is halogen, or c) reacting a compound of the formula VI 0 N Z-C- (VI) I -J 'N7 0 with an alcohol HO-R2 or an alcohol of the formula VII HO-R (VII) wherein R and R2 have the meanings given in the case of formula I' and Z is halogen, or d) reacting an alkali metal salt of pyridine-2,4- or acid with a halide of the formtlt VIII R z (VI I) wherein R 1 has the meanings given in the case of formula 1' and Z is halogen, and, if appropriate, converting the reaction product into one of its physiologically tolerated salts. 34 6. The process as claimed in claim 5, wherein, in process variant the reaction is carried out with simultaneous addition of a dialkylcarbodiimide, the dialkyl radicals containing 1 to 8 carbon atoms and it also being possible, in the case of the C 3 -C,-compounds, for these to be branched or cyclic.

7. A method of inhibiting proline hydroxylase and lysine hydroxylase comprising administering to a patient requiring such treatment and pharmaceutically effective amount of a compound as claimed in claim 3 or 4.

8. A method of fibrosuppression and immunosuppresion comprising administering to a patient requiring such treatment a pharmaceutically effective amount of a compound as claimed in claim 3 or 4, 0 9. A medicament containing a compound of the formula I or I' as hereinbefore defined in adjunct with tolerated S pharmaceutical excipients, i0. A method of influencing the metabolism of collagen and collagen-like substances or biosynthesis of Clq, comprising administering to a patient requiring such oon treatment a pharmaceutically effective quantity of a Sars .O*S herO<i\Ne3ore hQke\ compound of the formula I

11. A method of treating disturbances in the metabolism "r *of collagen and collagen-like substances or the biosynthesis of Clq comprising administering to a patient requiring such treatment a pharmaceutically effective quantity of a componid of the formula I).

12. A process for the preparation of a medicament for influencing the metabolism of collagen and collagen-like 4 F 4y -34a- substances or the biosynthesis of Cl q ,which comprises combining a compound of the formula I or V' as hereinbefore defined with a pharmaceutically acceptable carriers or excipierits.

13. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula I, 0 0 0 A 4in which R1' is branched or unbranched C 4 -alkyl, which is substituted by alkozycar bonyl, the alkyl radicals containing 1 3 carbon atoms and it also being possible, in. the case of the C 3 -alk~yl radicals, for these to bp branched, and independently of Rj denotes hydrogen or R' it also being osbefr 2to be identioal to ',and XI denotes oxygen, or a physiologically tolerated salt thereof but exccluding the compounds in which Xf denotes oxygen and Rl' and R 2 1 at the same time are unsubstituted C 1 -Cr1 2 alkyl or methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl, 35

14. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula If, 0 2 1 It R 0 C X i 0 C 00 o in which R" and R 2 1 are l- isopropoxyca rbonyl ethyl groups and XI denotes oxygen, or a physiologic ally tolerated salt thereof, but exciluding the compounds int which X0 de'notes oxygen and R 1 1' and R 2 at the same time are unsubst,'tuted C 1 -Ci,-alkyl or methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl,. DATED this 18th day of May, 1990. HOECHST AKTIENGESELLSCHIAFT 0 rJ~~ 0 00 00 0 WATERMAR(, PATENT TRADEMARK~ ATTORN4EYS# 290 BORWOOD ROAD, -AWTflORNP VIC 3122. AUSTRAIA, 3.4 ;SC(KRJS) 41 0 0 0 04 4f