NO173184B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRIDINE-2,4- AND 2,5-DICARBOXYLIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to the production of therapeutically effective pyridine-2,4- and 2,5-dicarboxylic acid derivatives. Compounds that inhibit proline and lysine hydroxylase cause a very effective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. During their course, protein-bound proline is hydroxylated by the enzyme proline or lysine hydroxylase. If this reaction is prevented by means of inhibitors, then a non-functional, under-hydroxylated collagen molecule is produced which can only be released by the cell in small quantities in the extracellular space. Furthermore, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily degraded proteolytically. As a result of this effect, the overall amount of the extracellularly stored collagen is reduced.

It is known that the inhibition of proline hydroxylase by means of known inhibitors, such as α,α'-dipyridyl, leads to an inhibition of Clq biosynthesis by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1978) 47). This results in an outcome of the classical pathway for complement activation. Inhibitors for the proline hydroxylase therefore also act as immunosuppressants, e.g. in immune complex diseases.

It is known that proline hydroxylase is effectively inhibited by pyridine-2,4- and 2,5-dicarboxylic acid (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245). However, these compounds are only effective as inhibitory substances in very high concentrations in the cell culture (V. Gtinsler et al. Collagen and Re. Research 3, 71 1983).

DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic acid diesters with 1-6 C atoms in the ester alkyl part as drugs for inhibiting proline and lysine hydroxylase.

However, these low-alkylated diestes have the disadvantage that they break down too quickly in the body into acids and do not reach the site of action in the cell 1 in a sufficiently high concentration, and are consequently less suitable for possible administration as medicine.

Surprisingly, it has now been found that the mixed ester/amides of pyridine-2,4- and -2,5-dicarboxylic acids and also the higher alkylated diesters are excellent inhibitors of collagen biosynthesis in animal models.

The actual active substance, the pyridine-2,4- or 2,5-dicarboxylic acid, is first produced by hydrolysis of the ester or ester/amide in the cell. Due to their higher lipophilicity and the fact that they are hydrolysed very slowly during transport, the ester or ester/amide can be transported to the cells. Only here is the actual active substance, pyridine-2,4- or -2,5-dicarboxylic acid, released.

The invention therefore relates to the production of:

Pyridine-2,4- and -2,5-dicarboxylic acid derivatives of formula I'

in which

r<!>' is branched or unbranched C^-C^-alkyl, which is optionally monosubstituted, or in the case of C2-Cfc-alkyl also polysubstituted, with alkoxy, alkoxycarbonyl, whereby the alkyl residues exhibit 1-4 C atoms, and whereby in the case of C3- and C4~alkyls these can also be branched, or phenyl, whereby the substituents in the case of multiple substitutions can also be different from each other

or

R<1>' stands for phenyl which is optionally singly or doubly substituted with nitro, C^-C^alkyl, whereby the substituents in the case of multiple substitutions can also be different from each other and whereby in the case of C3- and C4-alkyls these can also be branched,

or

R<1>' stands for 2-oxo-1,3-dioxolylmethyl which is optionally methyl substituted,

or

R<1>' stands for hydrogen when X' is nitrogen,

and

R<2>' stands, independently of R<1>', for hydrogen or R*', whereby R<2>' can also be identical to R<*>',

and

X' stands for oxygen or with R<3>' substituted nitrogen, whereby R<3>' is hydrogen or C^-C^-alkyl and optionally together with R<1>' forms a piperazine ring, whereby the heterocyclic ring again may be substituted with phenyl or phenyl-C1-C3-alkyl,

as well as physiologically tolerable salts thereof,

except for those compounds in which X' stands for oxygen and R<1>' and R<2>' are simultaneously unsubstituted C^-C^-alkyl.

Particularly preferred is the preparation of pyridine-2,4- and -2,5-dicarboxylic acid derivatives of formula I' in which R<*>' stands for branched or unbranched C₁-C₂ alkyl which is substituted with an alkoxycarbonyl, whereby the alkyl residues exhibit 1 -3 C atoms which in the case of C3~alkyl residues can also be branched, and R<2>' independently of R<1>' stands for hydrogen or R<1>', whereby R<2>' can also be identical to R<1>' and X' stand for oxygen, as well as physiologically tolerable salts thereof.

Among other things, these compounds have a special activity when used orally, as also the particularly preferred pyridine-2,4- and -2,5-dicarboxylic acid derivatives of formula I', in which R<1>' and R<2>' are 1- isopropoxycarbonylethyl groups and X' stands for oxygen (such as pyridine-2,5-dicarboxylic acid bis-(1-isopropoxycarbonylethyl)ester (Example 3) or pyridine-2,4-dicarboxylic acid bis(1-isopropoxycarbonylethyl) -ester (Example 29)), as well as their physiologically tolerable salts.

"Multi-substituted" in the preceding and following means that at least 2 and at most all of the hydrogen atoms present in the alkyl residues have been replaced by the aforementioned substituents. Preferably, this involves one substituent per methyl or methylene group.

In the case of multiple substitutions, the substituents can also be different from each other.

The invention relates to a method for the preparation of compounds of formula I' which is characterized in that one

a) reacts a compound of formula II

with a compound of formula III

whereby R*' , R<2>' and X' have the meanings indicated by formula I' and Y is halogen or hydroxy or

b) reacts a compound of formula IV

with a compound of formula V

whereby R<1>', R<2>' and X' have the meanings given by formula I' and Z is halogen or

c) reacts with a compound of formula VI

with an alcohol HO-R<2>' or an alcohol of formula VII whereby R<1>' and R<2>' have the meanings given by formula I' and Z is halogen or d) reacts an alkali salt of pyridine-2 ,4- or -2,5-dicarboxylic acid with a halide of formula VIII

whereby R<1>' has the meaning given by formula I' and Z is halogen,

optionally, a diester of formula I' obtained by the method is hydrogenated to a monoester of formula I',

and optionally transfers the reaction products to their physiologically tolerable salts.

In the following, the preparation of compounds of formula I, and the preparation of the starting materials required for this purpose - provided they are not commercial goods - are described in more detail.

The preparation of the compounds of formula I' takes place most simply by mixing both components, the pyridine derivative - according to formula II, IV or VI and the amine, respectively the alcohol of formula III, V or VII, in equimolar amounts or up to a 5-fold excess of III, V or VII and is reacted at temperatures between -30 to 150°C, preferably at 20 to 100°C until the reaction is finished. The reaction conditions can be determined by means of thin-layer chromatography (DC control). A variant of this method consists in working in a suitable solvent, such as diethyl ether or dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, tri- or tetrachloroethylene, benzene, toluene or also polar solvents such as dimethylformamide or acetone or dimethylsulfoxide. Here too, an excess of amine/alcohol according to formula III, V or VII which can be up to the 5-fold amount.The reaction temperatures are between room temperature r and the boiling point of the solvent, whereby temperatures in the range from room temperature to 130°C are particularly preferred.

If necessary, turnover can also take place in the presence of bases. As additional bases, inorganic acid scavengers such as carbonates or bicarbonates come into consideration, e.g. sodium or potassium carbonate or sodium or potassium bicarbonate, or organic acid scavengers such as tertiary amines, such as triethylamine, tributylamine, ethyldiisopropylamine or heterocyclic amines such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.

Preferably, the reaction of compounds of formula II with alcohols of formula III (X'=0) takes place with the addition of a water-splitting agent such as dialkylcarbodiimide, whereby the alkyl residues exhibit 1 to 6 C atoms, which in the case of C3-Cfc compounds can also be branched or cyclic; dicyclohexylcarbodiimide is preferably used. A similar method is described in Houben-Weyl, volume XV/2, pages 103-11, "Methoden der Organischen Chemie", 4th edition, Georg Thieme Verlag, Stuttgart, 1974.

Optionally, the preparation of the products can take place, for example, by extraction or by chromatography, e.g. over silica gel. The isolated product can be recrystallized and optionally reacted with a suitable acid to a physiologically tolerable salt. Examples of suitable acids include the following: mineral acids, such as hydrochloric acid and hydrobromic acid, as well as sulphurous, phosphoric, nitric or perchloric acid or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid , fumaric acid, phenylacetic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, oxalic acid, 4-aminobenzoic acid, naphthalene-1,5-disulfonic or ascorbic acid.

The starting compounds of the formulas III, V and VII, as long as they are not commercial products, can be easily synthesized (e.g. "Organikum, Organisch Chemisches Grundpraktikum", 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976; an overview of the various possibilities can be found in the method register; alcohols: page 821, amines: page 822).

The starting compounds of formula II are obtained, for example, by reacting pyridine-2,4- or -2,5-dicarboxylic acid to the corresponding pyridine-2,4- or -2,5-dicarboxylic acid halide VI, preferably the -chloride (according to methods known from the literature, e.g. "Organikum, Organisch Chemisenes Grundpraktikum", 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976, page 595 ff), which is then reacted with an alcohol of the formula R<2>'-OH (V) to the corresponding 2,4- or 2,5-diester. By selective saponification of the ester at the 2-position of the pyridine derivative (e.g. over a copper complex, see Pharm. Acta Heiv. 44 1969, page 637) or partial alkaline saponification (see J. Org. Chem. 39 (8) 1974, page 1158) one obtains pyridine-4 or -5-carboxylic acid ester-2-carboxylic acid, which is either used directly (II, Y=OH) or can be transferred to the acid halide (II, Y=C1, Br, J), preferably the acid chloride .

The starting compounds of formula IV can, for example, be synthesized in the following way: Reaction of the pyridine-2,4- or -2,5-dicarboxylic acid halides, preferably the -chlorides, with benzyl alcohol, to pyridine-2,4- or -2,5-dicarboxylic acid benzyl ester ; then follows selective saponification of the esters in the 2-position (e.g. in the presence of a copper catalyst, Loe.eit.Pharm. Acta Heiv.) transfer of the free acid in the 2-position to the acid halide, reaction with a compound of formula HX ^R<1>' (III) to pyridine-4- or -5-carboxylic acid benzyl ester-2-carboxylic acid-fR<1>')-ester respectively -amide, hydrogenolytic cleavage of the remaining benzyl protecting group (e.g. . with H2/Pt, see Houben-Weyl, vol. IV/lc (1980), pages 381-82) and then the following transfer of the free acid to the 4- or 5-position of the pyridine ring in the acid halide IV.

The pyridine-2,4- or -2,5-dicarboxylic acid halide according to formula VI can be obtained by known methods, e.g. by reaction of pyridine-2,4- or -2,5-dicarboxylic acid with phosphorus trihalide (see e.g. "Organikum, Organisch Chemisches Grundpraktikum", 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976, pages 527 and 595ff).

The reaction of alkali salts of pyridine-2,4- or -2,5-dicarboxylic acid with a halide of formula VIII takes place by methods known from the literature (see, for example, "Organikum Organisch Chemisches Grundpraktikum", 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976, page 255 ff.)

The compounds of formula I' produced according to the invention have valuable pharmacological properties and show particular activity as inhibitors of proline and lysine hydroxylase, as fibrosuppressants and immunosuppressants.

The activity of the fibrogenase can be determined by radioimmuno-logical determination of the N-terminal propeptide of collagen type III or the N- or C-terminal cross-linking domain of collagen type IV (7s-collagen or type-IV-collagen-NCi) in serum .

For this purpose, the hydroxyproline, procollagen-III peptide, 7s-collagen and type-IV-collagen-NC^ concentration in the liver of

a) untreated rats (control animals)

b) rats that had been given carbon tetrachloride (CC^ control animals) c) rats that had first been given CCI4 and then a compound prepared according to the invention

measured (this experimental method is described by Rouiller, C, "Experimental toxic injury of the liver"; in "The Liver", C. Rouiller, volume 2, pages 335-476, New York, Academic Press, 1964 ).

The pharmacological activity of the substances produced according to the invention was examined in a series of experiments (see table 1). This showed a clear inhibition of the proline and lysine hydroxylase.

The compounds of formula I' can be used as medicines in the form of pharmaceutical preparations containing them, possibly together with pharmaceutically acceptable carriers. The compounds can be used as healing agents, e.g. in the form of pharmaceutical preparations containing these compounds in admixture with a pharmaceutical, organic or inorganic carrier suitable for enteral, percutaneous or parenteral administration, such as e.g. water, gum arabic, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.

The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories or capsules; in semi-solid form, e.g. as ointments, or in liquid form, e.g. as solutions, suspensions or emulsions. Optionally, they are sterilized and/or contain auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically active substances.

In the following, the invention will be described in more detail by means of examples:

Examples

1. Pyridine-2.5-dicar "bok svi acid bis(1-methoxycarbonylethyl)-ester 10 g of pyridine-2,5-dicarboxylic acid are placed in 60 ml of dry methylene chloride and mixed with 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide . The mixture is boiled for three hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off, and the residue is evaporated once together with dry toluene. To the reaction mixture is added dropwise a solution of 12.5 g of lactic acid methyl ester, dissolved in methylene chloride, at -30 to -20° C. The mixture is slowly warmed to room temperature, stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and chromatographed over silica gel with ethyl acetate as eluent. The product is recrystallized from isopropanol.

Melting point 78°C; yield 7.2 g.

2. Pyridine-2.5-dicarboxylic acid bis(1-ethoxycarbonylethyl) ester 10 g of pyridine-2,5-dicarboxylic acid are placed in 60 ml of dry methylene chloride and mixed with 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is boiled for three hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off and the residue is evaporated once with dry toluene. A solution of 14.1 g of lactic acid ethyl ester dissolved in methylene chloride at -30 to -20°C is added dropwise to the reaction mixture. The mixture is slowly warmed to room temperature, stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and chromatographed over silica gel with ethyl acetate as eluent. The product is obtained as an oil.

Yield 16.6 g.

3. Pyridine-2.5-dicarboxylic acid-bis(1-isopropoxycarbonyl-ethyl ester) 10 g of pyridine-2,5-dicarboxylic acid are placed in 60 ml of dry methylene chloride and mixed with 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is boiled for three hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off, and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise a solution of 15.8 g of lactic isopropyl ester dissolved in 100 ml of methylene chloride at -30 to -20°C. The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature and the solution washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and stirred with diisopropyl ether. It is separated from the monoester and the mother liquor is chromatographed over silica gel with a mixture of four parts toluene and one part ethyl acetate which eluent The oily product crystallizes through slowly.

Melting point 52-53°C; yield 13.5 g.

4. Pyridine-2.5-dicarboxylic acid bis(2-methoxycarbonvl-2.2-dimethylethyl ester) 10 g of pyridine-2,5-dicarboxylic acid are placed in 60 ml of dry methylene chloride and mixed with 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is boiled for three hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added a solution of 15.8 g of 2,2-dimethyl-3-hydroxypropionic acid methyl ester dissolved in 100 ml of methylene chloride at -30 to -20° C. The mixture is slowly warmed to room temperature, stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and the product is recrystallized from isopropanol.

Melting point 114-115°C; yield 18.6 g.

5. Pyridine- 2. 4- dicarboxylic acid- bis( 2- methoxycarbonyl- 2. 2-dimet<y>let<y>llester

7.5 g of pyridine-2,4-dicarboxylic acid are placed in 45 ml of dry methylene chloride and mixed with 60 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is boiled for three hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added a solution of 11.9 g of 2,2-dimethyl-3-hydroxypropionic acid methyl ester dissolved in 100 ml of methylene chloride at -30 to -20° C. The mixture is slowly warmed to room temperature, stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and chromatographed over silica gel with ethyl acetate as eluent. The product occurs as an oil.

Yield 6.7 g.

6. Pyridine-2. 4-dicarboxylic acid-bis(l-ethox.vcarbonvletyl ester) 7.5 g of pyridine-2,4-dicarboxylic acid is placed in 45 ml of dry methylene chloride and mixed with 60 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is boiled for three hours and then distilled off the excess thionyl chloride and methylene chloride and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise a solution of 10.6 g of lactic acid ethyl ester dissolved in 100 ml of methylene chloride at -30 to -20° C. The mixture is slowly warmed to room temperature, stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and chromatographed over silica gel with ethyl acetate as eluent. The product occurs as an oil which slowly crystallizes through.

Melting point 59-60°C; yield 3.7 g.

7 . Pyridine-2. 4- dicarboxylic acid- bis( 5- methyl- 2- oxo- 1. 3-dioxole- 4- yl methyl ester

6.3 g of pyridine-2,4-dicarboxylic acid sodium salt is boiled for 40 hours under reflux with 14.3 g of 5-methyl-2-oxo-1,3-dloxol-4-yl-methyl bromide and 4.5 potassium carbonate in 125 ml of dry acetone. The solution is filtered off from carbonate and chromatographed over silica gel with a 4:1 mixture of toluene and acetate.

Melting point 113°C; yield 2.6 g.

8. 2-( 4-( 2- PhenylethylIpiperazinocarbonyl) pyridine- 5- carboxylic acid methyl ester

1.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester is heated with 22.5 ml of freshly distilled thionyl chloride under reflux until a clear solution is formed. It is then stirred for one hour at room temperature and the thionyl chloride is completely distilled off. The residue is taken up in 15 ml of dry methylene chloride and added dropwise to a solution of 3.15 g of 1-(2-phenylethyl)-piperazine in 8 ml of methylene chloride, stirred for 5 minutes at room temperature and freed of solvent. The residue is recrystallized with the addition of a little activated carbon from isopropanol. The product occurs as hydrochloride.

Melting point 201-203°C; yield 2.6 g.

9. 2-Benzylaminocarbonyl-pyridine-5-carboxylic acid methyl ester 1.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester is heated with 22.5 ml freshly distilled thionyl chloride under reflux until a clear solution is formed. It is then stirred for one hour at room temperature and the thionyl chloride is completely distilled off. The residue is taken up in 15 ml of dry methylene chloride and added dropwise to a solution of 1.15 g of benzylamine in 8 ml of methylene chloride, stirred for 5 minutes at room temperature and freed of solvent. The residue is recrystallized with the addition of a little activated carbon from isopropanol.

Melting point 215-216°C; yield 1.9 g.

10. 2-(N-benzyl-N-methylaminocarbonyl)pyridine-5-carboxylic acid methyl ester

1.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester is heated with 22.5 ml of freshly distilled thionyl chloride under reflux until a clear solution is formed. It is then stirred for one hour at room temperature and the thionyl chloride is completely distilled off. The residue is taken up in 15 ml of dry methylene chloride and added dropwise to a solution of 2.0 g of N-methyl-benzylamine in 8 ml of methylene chloride, it is then stirred for 5 minutes at room temperature and freed of solvent. The residue is chromatographed over silica gel with a mixture of 7 parts methylene chloride and 3 parts acetone. The product turns into an oil. 11. 2-Benzyloxycarbonylpyridine-5-carboxylic acid methyl ester 1.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester is heated with 22.5 ml freshly distilled thionyl chloride under reflux until a clear solution is formed. It is then stirred for one hour at room temperature and the thionyl chloride is completely distilled off. The residue is taken up in 15 ml of dry methylene chloride and added dropwise to a solution of 1.79 g of benzyl alcohol in 8 ml of methylene chloride, it is then stirred for 5 minutes at room temperature and freed of solvent. The residue is recrystallized with the addition of a little activated carbon from isopropanol.

Melting point 104"C; yield 1.5 g.

12. 2-phenylaminocarbonylpyridine-5-carboxylic acid methyl ester 1.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester is heated with 22.5 ml freshly distilled thionyl chloride under reflux until a clear solution is formed. It is then stirred for one hour at room temperature and the thionyl chloride evaporates completely. The residue is taken up in 15 ml of dry methylene chloride and added dropwise to a solution of 1.54 g of aniline in 8 ml of methylene chloride, stirred for 5 minutes at room temperature and freed of solvent. The residue is recrystallized with the addition of a little activated carbon from isopropanol.

Melting point 167°C; yield 1.5 g.

13. 2-( 2. 2- diphenvletylaminolcarbonylpyridine- 5- carboxylic acid methyl ester

1.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester is heated with 22.5 ml of freshly distilled thionyl chloride under reflux until a clear solution is formed. It is then stirred for one hour at room temperature and the thionyl chloride is completely distilled off. The residue is taken up in 15 ml of dry methylene chloride and added dropwise to a solution of 3.27 g of diphenylethylamine in 8 ml of methylene chloride, it is then stirred for 5 minutes at room temperature and freed of solvent. The residue is recrystallized with the addition of a little activated carbon from isopropanol.

Melting point 247°C; yield 1.8 g.

14. 2-(N-methyl-N-phenylaminoIcarbonylpyridine-5-carboxylic acid methyl ester

25.5 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester are heated with 380 ml of freshly distilled thionyl chloride under reflux until a clear solution is formed. It is stirred for one hour at room temperature and the thionyl chloride is distilled off completely. The residue is taken up in 250 ml of dry methylene chloride and added dropwise to a solution of 30 g of N-methylaniline in 150 ml of methylene chloride, it is then stirred for 5 minutes at room temperature and freed of solvent. The residue is recrystallized with the addition of a little activated carbon from isopropanol.

Melting point 123°C; yield 30 g.

15. 2-N-propylamino-carbonylpyridine-5-carboxylic acid methyl ester 15 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester are heated with 225 ml freshly distilled thionyl chloride under reflux until a clear solution is formed. It is stirred for one hour at room temperature and the thionyl chloride is distilled off completely. The residue is taken up in 70 ml of dry methylene chloride and added dropwise to a solution of 13.7 g of propylamine in 150 ml of methylene chloride, which is then stirred for 5 minutes at room temperature and freed of solvent. The residue is chromatographed over silica gel with a mixture of 7 parts methylene chloride and 3 parts acetone as eluent.

Melting point 88'C; yield 12.6 g.

16. Pyridine-2.5-di(4-nitrophenylcarboxylic acid ester) 6.3 g of pyridine-2,5-dicarboxylic acid are placed in 100 ml of dry methylene chloride and mixed with 135 ml of freshly distilled thionyl chloride and 3 ml of dry dimethylformamide. The mixture is boiled for 3 hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise a solution of 27.8 g of 4-nitrophenol in 50 ml of pyridine at -30 to -20° C. The mixture is slowly allowed to warm to room temperature , is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed of solvent after drying and chromatographed over silica gel with ethyl acetate as eluent.

Melting point 190°C; yield 12.5 g.

17 . Pyridin- 2. 5- dicarboxylic acid- bis( 5- methyl- 2- oxo- l. 3-dioxol- 4-yl- methyl ester

6.3 g of pyridine-2,5-dicarboxylic acid sodium salt are reacted analogously to example 7 with 14.3 g of 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide and boiled in acetone for 2.5 hours during return run. After chromatography over silica gel with ethyl acetate as eluent, the product is recrystallized from ethyl acetate in a hot state.

Melting point 118°C; yield 0.23 g.

18. Pyridine-2.5-dicarboxylic acid di-(a-methoxycarbonylbenzyl ester) 10 g of pyridine-2,5-dicarboxylic acid is transferred analogously to example 1 to the acid chloride and reacted with 19.9 g (±)-mandelic acid methyl ester. The preparation takes place after the extraction by chromatography over silica gel with a mixture of toluene and ethyl acetate as eluent.

Melting point 125<*>C; yield 0.5 g

19. P. vr in din- 2- carbonamide- 5- carboxylic acid methyl ester

20 g of pyridine-2-carboxylic acid-5-carboxylic acid methyl ester are transferred as described in example 8 with 200 g of thionyl chloride to the acid chloride. The acid chloride is dissolved in chloroform, and with vigorous stirring, ammonia gas is passed over the suspension. The mixture is allowed to stand for three days, the product is suctioned off and washed with water.

Melting point 195-197°C; yield 15.6 g

20. Pyridine-2.5-dicarboxylic acid dibenzyl ester

20 g of pyridine-2,5-dicarboxylic acid is transferred analogously to example 1 with 160 ml of thionyl chloride to the acid chloride and reacted with 25.9 g of benzyl alcohol. The product is recrystallized from vinegar with the addition of activated charcoal.

Melting point 110°C; yield 20.4 g.

21. Pyridine-2-(3-isopropoxy-propyl)carboxylic acid amide-5-carboxylic acid benzyl ester 8 g of pyridine-2-carboxylic acid-5-benzyl ester are transferred analogously to example 8 with 90 ml of thionyl chloride to the acid chloride and reacted with 3-isopropyloxy-propylamine to amide . The product is chromatographed for purification over silica gel with a mixture of cyclohexane/acetic ester (1:1).

Melting point 41°C; yield 6.4 g.

22 . Pyridine-5-carboxylic acid-2-(3-isopropoxy-propyl)-carboxylic acid amide

5.3 g of pyridine-2-(3-isopropoxy-propyl)carboxylic acid amide-5-benzyl ester are hydrogenated for 5 hours in dioxane under normal pressure in the presence of a palladium-charcoal catalyst. After the end of the hydrogen absorption, the catalyst is sucked off and the solvent is drawn off.

Melting point 129°C; yield 2.4 g.

23. Pyr in din- 2-( 3- isopropoxy- propyl) carboxylic acid amide- 5-carboxylic acid benzyl ester

Corresponding to example 8, 1 g of pyridine-5-carboxylic acid-2-(3-isopropoxy-propyl)amide is transferred to the acid chloride (20 ml of thionyl chloride) and then reacted with 2 ml of benzyl alcohol to give the pyridine-2-isopropoxy-propylamide-5-benzyl ester. The product is chromatographed for purification over silica gel with a mixture of cyclohexane/acetic ester (1:1).

Melting point 41"C; yield 0.9 g.

24 . Pyridine-2. 5-di (5-methyl-2-nitrobenzyl) carboxylic acid ester 5 g of pyridine-2,5-dicarboxylic acid is transferred analogously to example 1 with 40 ml of thionyl chloride in 30 ml of methylene chloride to the acid chloride and reacted with 10 g of 5-methyl-2-nitro -benzyl alcohol in 50 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature and is then mixed with sodium bicarbonate solution, extracted with methylene chloride and the organic phase is dried. After removing the solvent, the residue is mixed with ethyl acetate, filtered off with suction and recrystallized twice from methylene chloride.

Melting point 182°C; yield 2.9 g.

25. Pyridine- 2. 5- dicarboxylic acid- bis( 2- ethoxyethyl) ester

10 g of pyridine-2,5-dicarboxylic acid is transferred analogously to example 1 with 80 ml of thionyl chloride in 60 ml of methylene chloride to the acid chloride and reacted with 10.78 g of ethylene glycol monomethyl ether in 100 ml of methylene chloride. Processing takes place by mixing with sodium bicarbonate solution, separating the organic phase and removing the solvent. The product is chromatographed twice over silica gel with acetic acid, dissolved in hot acetic acid, clarified with activated charcoal and freed from solvent. The product occurs as an oil.

Yield 7.2 g.

26. Pyridine-2.5-dicarboxylic acid-bis(2-methoxyethyl ester) 10 g of pyridine-2,5-dicarboxylic acid is transferred analogously to example 25 to acid chloride and reacted with 9.1 g of ethylene glycol monomethyl ether. The work-up takes place according to example 25. The product occurs as an oil.

Yield 6.5 g.

27. Pyridine- 2. 4- dicarboxylic acid- bis( 2- ethoxyethyl ester

10 g of pyridine-2,4-dicarboxylic acid is reacted as described in example 25 over the acid chloride with ethylene glycol monoethyl ether. The reaction mixture is worked up analogously to example 25. The product occurs as an oil.

Yield 7.2 g.

28. Pyridine-5-(2-methoxycarbonyl-2-methylpropyl)-carboxylic acid reester-2-N-(3- isopropoxypropyl)carboxylic acid amide 1 g of pyridine-5-carboxylic acid-2-(3-isopropoxypropyl)amide is boiled in 20 ml thionyl chloride under reflux until dissolution. The mixture is allowed to stand for 1 hour at room temperature, the thionyl chloride is distilled off, the residue is dissolved in 10 ml of dry methylene chloride and a solution of 0.5 g of 2,2-dimethyl-3-hydroxypropionic acid methyl ester in 20 ml of dry methylene chloride is added dropwise. After completion of the reaction, the solvent is removed, and the product is chromatographed over silica gel with acetic acid.

Yield 0.15 g.

29. Pyridine-2.4-dicarboxylsvre-bis(1-isopropoxycarbonylethyl)-ester 10 g of pyridine-2,4-dicarboxylic acid are placed in 60 ml of dry methylene chloride and mixed with 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is boiled for 3 hours under reflux and then the excess thionyl chloride and methylene chloride are distilled off, and the residue is evaporated once with dry toluene. A solution of 15.8 g of lactic acid isopropyl ester dissolved in 100 ml of methylene chloride at -30 to -20°C is added dropwise to the reaction mixture. The mixture is slowly warmed to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed from solvent after drying and stirred with diisopropyl ether. It is separated from the monoester and the mother liquor is chromatographed over silica gel with a mixture of four parts toluene and one part acetate as eluent. The product occurs as an oil.

Yield: 11.2 g.

Claims (1)

Analogous process for the preparation of therapeutically active pyridine-2,4- and -2,5-dicarboxylic acid derivatives of formula (I'): in which R<1>' is branched or unbranched C₁-C₂-alkyl, which is optionally monosubstituted, or in the case of C₂-C₂-alkyl also polysubstituted, with alkoxy, alkoxycarbonyl, whereby the alkyl residues have 1-4 C atoms, and whereby in the case of C3- and C4-alkyls these can also be branched, or phenyl, whereby the substituents in the case of multiple substitutions can also be different from each other or R<*>' stands for phenyl which is optionally single- or double-substituted with nitro, C1-C4-alkyl, whereby the substituents in the case of multiple substitutions can also be different from each other and whereby in the case of C3- and C4-alkyl these can also be branched, or R<1>' stands for 2-oxo-1,3-dioxolylmethyl which is optionally methyl substituted, or R<1>' stands for hydrogen when X' is nitrogen, and R<2>' stands, independently of R<1>', for hydrogen or R<1>', whereby R<2>' can also be identical to R<*>', and X' stands for oxygen or with R<3>' substituted nitrogen, whereby R<3>' is hydrogen or C^-C^-alkyl and optionally together with R^' forms a piperazine ring, whereby the heterocyclic ring again may be substituted with phenyl or phenyl-C1-C3-alkyl, as well as physiologically tolerable salts thereof, except for those compounds in which X' stands for oxygen and R<1>' and R<2>' are simultaneously unsubstituted C^-C^-alkyl, characterized by a) reacting a compound of formula (II): with a compound of formula (III): whereby R<1>', R<2>' and X' have the meanings indicated by formula (I') and Y is halogen or hydroxy or b) reacts a compound of formula (IV ): with a compound of formula (V): whereby R<1>', R<2>' and X' have the meanings indicated by formula (I') and Z is halogen or c) reacts with a compound of formula (VI): with an alcohol HO-R<2>' or an alcohol of formula (VII): whereby R<1>' and R<2>' have the meanings indicated by formula (I') and Z is halogen or d) reacts a alkali salt of pyridine-2,4- or -2,5-dicarboxylic acid with a halide of formula (VIII): whereby R<1>' has the meaning given by formula (I') and Z is halogen, possibly hydrogenating in the process obtained diester of formula (I') to a monoester of formula (I'), and optionally transfers the reaction products to their physiologically tolerable salts.