DD300429A5 - N, N'-bis (alkoxy-alkyl) -pyridine-2,4-dicarboxylic acid diamides, process for their preparation and their use - Google Patents

Abstract

N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxylic acid diamides of the formula I <IMAGE> where R<1> is linear or branched C1-C4-alkanediyl, R<2> is unbranched C1-C4-alkyl or hydrogen and n is 1 or 2 and R<1'>, R<2'> and n' have the same meanings as R<1>, R<2> and n, where R<1> and R<1'>, R<2> and R<2'>, and n and n' are identical or different, and their physiologically acceptable salts with the exception of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)pyridine-2,4-dicarboxylic acid diamide. The compounds of the formula I inhibit prolin hydroxylase and lysin hydroxylase and are suitable as fibrosuppressants and immunosuppressants.

Description

CONH-CH ₂ -CH ₂ -OCH ₃

CONH- (CH ₂ ) ₃ -OCH ₃

and their physiologically acceptable salts are produced.

13. The method according to claim 1 or 2, characterized in that a compound of formula

CONK (CH ₂ J ₃ OCH ₃

CONH (CH ₂ J ₂ OCH ₃

and their physiologically acceptable salts are produced.

14. A pharmaceutical composition containing a compound of formula I, obtainable by a process according to any one of claims 1-13 and / oclor one of its physiologically acceptable salts with compatible pharmaceutical carriers.

15. Use of compounds of the formula I, obtainable by a process according to any one of claims 1-13 and / or their physiologically acceptable salts for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of C 1 _q .

16. Use of compounds of the formula I obtainable by a process according to any one of claims 1-13 and / or their physiologically acceptable salts for the treatment of disorders of the biosynthesis of collagen and kollagbnähnlichen substances or the biosynthesis of C 1 _q .

17. A process for the preparation of medicaments for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of C1 _q , which comprises introducing into the medicament a compound of the formula I obtainable by a process according to any one of claims 1 13 and / or a physiologically acceptable salt of this compound incorporated.

For this 2 pages drawings

N, N'-bis (alkoxy-alkyl) -pyridine-2,4-dicarboxylic acid diamides, process for their preparation and their use

Compounds which inhibit prolin and lysine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course of which protein-bound proline or lysine is hydroxylated by the enzymes proline or lysine hydroxylase. If this reaction is inhibited by inhibitors, a non-functional, underhydroxylated collagen molecule is formed, which can only be released by the cells into the extracellular space in small quantities. The underhydroxylated collagen also can not be incorporated into the collagen matrix and is very likely proteolytically degraded. As a result of these effects, the amount of extracellularly deposited collagen decreases overall.

It is known that the inhibition of proline hydroxylase by known inhibitors, such as α, α'-dipyridyl leads to an inhibition of C 1 _q biosynthesis of macrophages (W.Müller et al., FEBS Leu. 90 (1978), 218; Immunbiology 155 [1978] 47), leading to a failure of the classical pathway c '3r complement activation inhibitors of proline hydroxylase therefore also act as immunosuppressive agents, for example in immune complex diseases.

It is known that proline hydroxylase is effectively inhibited by pyridine-2,4- and -2,5-dicarboxylic acid (K.Maiamaa et al., Eur. J. Biochem., 138 (1984) 239-245) However, the cell culture is effective as inhibitors only in very high concentrations (Tschank, G. et al., Biochem., J. 238, 625-633, 1987).

DE-A 3432094 describes pyridine-2,4-and-2,5-dicarboxylic acid diesters having 1-6 C atoms in the alkyl ester part as a medicament for inhibiting proline and lysine hydroxylase.

However, these low-alkyl diesters have the disadvantage that they are cleaved too quickly in the organism to the acids and do not reach their site of action in a sufficiently high concentration in the cell and are therefore less suitable for a possible administration as medicaments.

DE-A 3703959, DE-A 3703962 and DE-A 3703963 describe in general terms mixed esters / amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid, which promote collagen biosynthesis in animal models inhibit. Thus, in DE-A 3703959, inter alia, the synthesis of N, N'-bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide (III)

CONH-CH ₂ -CH ₂ -O-CH ₃

(III) ↑ CONH-CH ₂ -CH ₂ -O-CH ₃

and N, N'-bis (3-isopropoxypropyl) -pyridine-2,4-dicarboxylic acid diamide (IV)

CH ₃ CONH- CH ₂ - CH ₂ - CH ₂ - CH 0-

^ CH ₃ CH ₃ (IV)

CONH-CH ₂ -CH ₂ -CH ₂ -O-CH ₂

described.

German patent applications P 3826471.4 and P 3828140.6 propose an improved process for the preparation of N, N'-bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide (III).

However, the enteral absorbability of many of the compounds described in DE-A 37 03959 is still unsatisfactory, so that there was a need to provide compounds which effectively inhibit proline and lysine hydroxylase after oral administration even at low dosages.

It has now been found that compounds of the formula I

CONH- (R ¹ J- (OR ² J _n

V 2 ' ^(l)

.CONH- (R ¹ J- (OR ^ J _n I,

R ^{1 is} linear or branched C ₎ -C ₄ alkanediyl,

R ^{2 is} unbranched C 1-10 alkyl or hydrogen

η is 1 or 2 and

R ¹ , R ² and n 'have the same meanings as R ¹ , R ² and η, wherein R ¹ and R ¹ ', and R ² and R ² 'and η and n' are identical or different, and their physiologically acceptable Salts other than N, N'-bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide and N, N'-bis (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid diamide meeting the above object.

In comparison to the compounds described in DE-A 37 03959 N, N'-bis (2-methoxyethyl) pyridine-2,4-dicarboxylic acid diamide and N, N'-bis (3-isopropoxypropyl) -pyridine-2,4 dicarboxylic acid diamide, the compounds of the formula I have both a better pharmacological activity and a better enteral absorbability.

Furthermore, the invention relates to a process for the preparation of N, N'-bis (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of the formula I.

CONH- (R ¹ J - ^ - (OR ² J _n CONH- (R ¹¹ J- (OR ²¹ J _n I

R ^{1 is} linear or branched C) -C ₄ alkanediyl,

R ^{2 is} unbranched C 1 -C ₄ -alkyl I or hydrogen

η is 1 or 2 and

R ', R ² and n' have the same meanings as R ¹ , P ² and η, wherein R ¹ and R ¹ , R ² and R ² and η and n 'are the same or different except N, N'-bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide and N, N'-bis (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid diamide, which is characterized in that pyridine-2,4-dicarbonsäurehalogenio with a Reacting alkoxyalkylamine or hydroxylalkylamine.

Dio invention also relates to a process for the preparation of N.N'-bis-ialkoxyalkyD-pyridine ^ Adicarbonsäurediamiden of formula I.

CONH- (R ¹ ) - (OR ² ) _n

CONH- (R ¹ ') - (0R ² ') _n i

(I)

R 'is linear or branched C 1 -C 4 -alkanediyl,

R ^{2 is} unbranched C ₁ -C ₄ -alkyl or hydrogen

η is 1 or 2 and

R ¹ , R ² and n 'have the same meanings as R ¹ , R ² and η, wherein R' and R ¹ ', R ² and R ² and η and n' are identical or different, which is characterized in that first

1. pyridine-2,4-dicarboxylic acid with at least two equivalents of a halogenating agent, and that

2. at least 2 equivalents of hydroxyalkylamine or alkoxyalkylamine of the formula II or II. ¹

H ₂ N- (R ¹ HOR ² J _n (II)

H ₂ N- (R ^r HOR ² ) _n · (H ')

R ¹ and R ^{1 are} linear or branched C) -C ₄ alkanediyl,

R ² and R ² 'unbranched C | -C ₄ alkyl or hydrogen and

η and n 'are 1 or 2 and

R ¹ and R ¹ ', R ² and R ² ' and η and n 'are identical or different, but where Il and ΙΓ are different, dissolves in a solvent and that then the solution prepared according to I. with the according to 2. brings the prepared solution to react, or that one

B) the thus obtained N, N'-bis (alkoxyalkyl) pyridine-2,4-dicarboxylic acid diamide converted into the bis (hydroxyalkyl) compound or that

C) the pyridine-2,4-dicarboxylic acid halide prepared according to A) is reacted with a substituted or unsubstituted benzyl alcohol to give the pyridine-2,4-dicarboxylic acid benzyl ester, the benzyl ester being saponified selectively in the 2-position of the pyridine, according to process variant A) 1. the free carboxylic acid in the 2-position again transferred to the acid halide and the resulting compound with a solution prepared according to A) 2nd solution using a compound of formula II ', wherein a pyridine ^ -carboxylic benzyl ester ^ -carboxamide is formed, and that subsequently the benzyl protecting group split off in the 4-position hydrogenolysis, the free carboxylic acid according to process variant A) 1 again transferred to the acid chloride, which is then mixed with a solution prepared according to A) 2 using a compound of formula II, wherein an unsymmetrically substituted compound of the formula I is formed and that, if appropriate, subsequently the VerLind obtained the formula I converted into its physiologically acceptable salt.

In the process for the preparation of the compounds of formula I, the commercially available as starting substance pyridine-2,4-dicarboxylic acid is suspended in a solvent such as toluene and at room temperature with a halogenating agent, preferably a chlorinating agent such as. B. SOCI ₂ , offset. Based on the molar amount of pyridine-2,4-dicarboxylic acid used, 2-3 equivalents of a halogenating agent are used, preferably 2.5 equivalents. The resulting reaction mixture is heated to 90-110 ° C, preferably to 100 ° C, until no gas evolution is observed and a clear solution is formed. Subsequently, the solution-preferably in a high vacuum (to about 10 ^-3 torr) -10% by evaporation, and the resulting carboxylic acid halide further reacted.

Based on the molar amount of pyridine-2,4-dicarboxylic acid used, the 2-4-fold molar amount of commercially available alkoxyalkylamine or hydroxyalkylamine is then dissolved in a solvent such as toluene and preferably the 2-4-fold molar amount of a base such as triethylamine is added. The carboxylic acid halide is reacted with the alkoxyalkylamine or the hydroxylalkylamine. This is preferably done by dripping the solution of said alkylamine to the dissolved pyridine-2,4-dicarboxylic acid halide. However, it is also possible to drip the solution of the carboxylic acid halide to the solution of the alkoxyalkylamine or hydroxyalkylamine. The addition takes place at a temperature of -5 to +5 ⁰ C, preferably at ⁰ ° C. The reaction mixture is then allowed to react by passing z. B. heated to room temperature and stirred for another 2-5 hours, preferably for 3 hours. The resulting product is then acidified to separate excess hydroxy or alkoxyalkylamine from the desired product. The acidification can be carried out, for example, with 0.2 molar citric acid. The organic phase is then separated and washed with water. Subsequently, the organic phase is dried-preferably over magnesium sulfate and finally freed from the solvent. Upon removal of the solvent, the product precipitates as a white solid or as an oil.

For the preparation of N, N'-bis (hydroxyalkyl) -pyridine-2,4-dicarboxylic diamides, it is best to provide a corresponding bis (alkoxyalkyl) diamide, preferably bis (methoxyalkyl) diamide, by literature methods, for example with Bortribromid, converted into the corresponding bis (hydroxyalkyl) diamide.

Unsymmetrically substituted compounds of the formula I can be synthesized, for example, by reacting a pyridine-2,4-dicarboxylic acid halide, preferably the chloride, with substituted or unsubstituted benzyl alcohol to give the pyridine-2,4-dicarboxylic acid benzyl ester, followed by selective saponification of the ester in the 2-position (eg in the presence of a copper catalyst, Acta HeIv., 44, 1963, p. 637), conversion of the free acid in the 2-position into the acid halide, reaction with a compound of the formula (ΙΓ) to give the pyridine -carboxylic acid benzyl ester. carboxamide,

hydrogenolytic cleavage of the remaining benzyl protecting group (eg with H ₂ / Pd, see Houben-Weyl Bd., IV / 1 c [1980], see 381-382) and subsequent transfer of the free acid in the 4 position of the pyridine ring in the acid halide. The acid halide can now be converted into the mixed diamide (I) with an amine II (see reaction scheme). Optionally, the workup of the products, for example, by extraction or by Chroma iographie, z. B. on silica gel. The isolated product can be recrystallized and optionally reacted with a suitable acid to give a physiologically acceptable salt. Examples of suitable acids are: mineral acids, such as hydrochloric and hydrobromic acid, and sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, and malic acids. , Tartaric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acid. The compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations, which they may contain together with compatible pharmaceutical carriers. The compounds can be used as a remedy, for. B. in the form of pharmaceutical preparations use, which compounds in admixture with a suitable for enteral, percutaneous or parenteral administration pharmaceutical, organic or inorganic carrier, wio z. As water, gum arabic, gelatin, lactose, starch, Marjnesiumstearat, talc, vegetable oils, polyalkylene glycols, vaseline, etc. included.

The pharmaceutical preparations can be in solid form, for. As tablets, dragees, suppositories or capsules; in semi-solid form, e.g. B. salves, or ir liquid form, z. As solutions, suspensions or emulsions are present. Optionally, they are sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically active substances. It has been found that the compounds of formula I have exceptionally good enteral absorbabilities. The resorbent barocco was examined on Wistar rats to which the compounds according to the invention were administered intragastrically. The serum level decreased in the first hours after administration of the substance and reached a plateau only slightly after about 5 hours. From the initially very high serum level directly after administration of the substances can be concluded on the good Absorbierbarkoit of the substances

 In the following the invention is explained in more detail by way of examples.

example 1

Pyridine-2,4-dicarboxylic acid bis-N, N '- (methoxypropyl) amide

3 g of pyridine-2,4-dicarboxylic acid are placed in 50 ml of toluene and 1 ml of DMF and added dropwise to the solution 2.7 ml of thionyl chloride. It is heated until no gas evolution is observed (about 2.5 hours). It is cooled, distilled off 5 ml of toluene and added dropwise to the solution of 4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine. After stirring the solution at room temperature for 4 h is evaporated, the residue taken up in water and extracted 4 χ with methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated. The crude product is chromatographed with silica gel (solvent ethyl acetate).

Yield: 4.3 g; oil

¹ H-NMR (CDCl ₃ ): δ = 1.6-2.3 (4 H, m); 3.2-3.8 (14H, m); 7.8-8.0 (1H, m); 8.3-8.5 (1H, m); 8.6-8.8 (1H, m).

Example 2

Pyridine-2,4-dicarboxylic acid bis-N, N '- (ethoxypropyl) amide

Regulation see Example 1; amine component

ethoxypropylamine,

Yield: 4.5 g, mp. 46-48 ° C.

¹ H-NMR (CDCl ₃ ): δ = 1.3 (6H, tr); 1.7-2.1 (4H, m); 3.3-3.8 (12H, m); 7.8-8.0 (1H, m); 8.4-8.5 (1H, m); 8.5-8.8 (1H, m);

Example 3

Pyridine-2,4-dicarboxylic acid bis-N, N '- (2-dimethoxyethyl) amide

For instructions see Example 1, amine component 2-dimethoxyethylamine,

Yield: 1.6 g (from 3 g of pyridine-2,4-dicarboxylic acid), oil

¹ H-NMR (CDCl ₃ ): δ = 3.4 (12 H, s); 3.7 (4H, m); 4.5 (2H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Example 4

Pyridine-2,4-dicarboxylic acid bis-N, N '- (2-methoxyisopropyl) amide

Regulation see Example 1; Amine component 2-methoxyisopropylamine;

Yield: 3.3 g (from 3 g of pyridine-2,4-dicarboxylic acid), oil

¹ H NMR (CDCl ₃ ): δ = 1.3 (6H, d); 3.2 (6H, s); 3.5 (4H, d); 4.4 (2H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Example 5

Pyridine-2,4-dicarboxylic acid bis-N, N '- (2-ethoxyethyl) amide

Regulation see Example 1; Amine component ethoxyethylamine,

Yield: 7.8 g (from 10 g of pyridine-2,4-dicarboxylic acid),

Mp .: 42-44 ⁰ C

¹ H-NMR (CDCl ₃ ): δ = 1.2 (3 H, tr); 3.3-3.8 (12H, qu, and m); 7.9 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Examples

Pyridine-2,4-dicarboxylic acid bis-N, N '- (3-hydroxy-ethyl) amide

0.5 g of pyridine-2,4-dicarboxylic acid bis-N, N '- (3-methoxyethyl) amide are dissolved in 10 ml of dichloromethane and added dropwise at -78 ⁰ C boron tribromide (11 ml, 1 molar solution in dichloromethane). After complete addition, allow to come to room temperature and stir for 3 hours. Add 100 ml of saturated bicarbonate solution and extract 3 χ with ethyl acetate. The

combined organic solvent are dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel.

Yield: 0.45g; oil

¹ H-NMR (COCl ₃ ) δ = 1.5-2.2 (4 H, m); 3.4 (4H, m); 3.6 (4H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Example 7a

Pyridine-2,4-dicarboxylic acid dibenzyl ester

30 g of pyridine-2,4-dicarboxylic acid are converted into the acid chloride analogously to Example 1 using 30 ml of thionyl chloride and reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether.

Yield: 42.1 g of melting point 63-65 ⁰ C

Example 7b

Pyridine carboxylic acid ^ ^ -carboxylate

40g of pyridine-2,4-dicarboxylic acid dibenzyl ester of Example 7a are added to a suspension of 27.8g of cupric nitrate in 700ml of methanol. It is refluxed for one hour and filtered off after cooling from the copper complex. The complex is suspended in dioxane and carbon disulfide introduced. The precipitated copper sulfide is filtered off and the organic phase is concentrated. The product is stirred with petroleum ether.

Yield: 25,3g melting point 113-115 ⁰ C.

Example 7c

Pyridine ^ -beta-methoxypropyU-carboxamide ^ -carboxylate

3.9 g of pyridine-2: arbonsäure-4-carboxylic acid benzyl ester from Example 7 b are converted analogously to Example 1 with 1.2 ml of thionyl chloride in the acid chloride and reacted with 3-methoxypropylamine to the amide. The product is chromatographed on silica gel with a mixture of cyclohexane / ethyl acetate (1: 1).

Yield: 4.3 g; oil

Example 7d

Pyridine carboxylic acid ^ ^ -beta-methoxypropyD-carboxylic acid amide

4.3 g of compound from Example 7c are dissolved in 100 ml of dioxane and hydrogenated with 500 mg of palladium / carbon (10%) catalyst under normal pressure for 4 hours. After completion of the hydrogen uptake is sucked from the catalyst and removed from the solvent.

Yield: 3.5 g Melting point 124-126 ⁰ C.

Example 7e

Pyridine-4-carboxylic acid- (2-methoxyethyl) -2-carboxylic acid- (3-methoxypropyl) -diamide According to Example 1, 1.8 g of the compound from Example 7d are converted with 0.6 ml of thionyl chloride into the acid chloride and then reacted with 2-methoxyethylamine , The product is chromatographed on silica gel with a mixture of dichloromethane / methanol (20: 1)

 Yield: 1.0g; oil

¹ H-NMR (CDCl ₃ ): δ = 1.9-2.0 (2H, qui); 3,4 (6H, s); 3.5-3.7 (8H, m); 6.9 (1H, s, br); 8.0 (1H, dd); 8.4 (1H, s, br); 8.5 (1H, s); 8.7 (1H, d);

Example 8

Pyridine-2-carboxylic acid- (2-methoxyethyl) -4-carboxylic acid- (3-methoxypropyl) -diamide Analogously to Examples 7 ae, the compound according to Example 8 is prepared by reacting in the reaction step Example 7c 2-methoxyethylamine and in the reaction step Example 7e 3-methoxypropylamine is used. Melting point: 69-72 ⁰ C

'H-NMR (CDCl ₃ ): δ = 1.9-2.0 (2 H.qui); 3.4 (3H, s); 3.45 (3H, s); 3.6-3.7 (8H, m); 7.4 (1H, br); 7.9 (1H, dd); 8.3 (1H, br); 8.4 (1H, d); 8.7 (1H, d);

Example 9

Enteral absorbability

Female Wistar rats of about 150 g body weight receive 50 mg / kg of the substance to be examined by intragastric gavage. It will be after 5; 10; 15; 30; 60; 120; 4 rats were anesthetized for 180 and 240 minutes and bled over the vena cava. The blood is immediately centrifuged and the administered compound extracted with ether from the serum.

After evaporation of the ether, the residue is taken up in 100 ml of superplasticizer. The eluent consists of 0.05 M phosphoric acid and acetonitrile (4: 1).

From this sample 50μΙ are injected in an HPLC column. Detection takes place at UV 200 nm and a retention time of 2.2 min. The results are documented in Table 1.

Table 1: Serum levels of the compounds according to the invention from Examples 1-3 after administration of 50 mg / kg p.o.

Time (min). Substance off SD Substance off SD Substance off 8.9 SD example 1 ± 15.4 Example 2 ± 11.2 Example 3 11.5 ± 3.1 X ± 3.6 X ± 4.0 X 14.7 +0.6. 5 45.3 ± 11.0 51.4 ± 6.7 10.7 ± 1.9 10 49.8 ± 3.2 39.2 ± 5.6 11.3 ± 1.9 15 39.9 ± 5.5 29.4 ± 1.0 5.5 ± 1.5 30 28.1 ± 0.3 15.2 2.9 ± 0.9 60 9.4 1.4 1.7 ± 0.5 120 0.3 <NWG ± 0.4 180 <NWG <NWG 240 <NWG <NWG

χ = average of 4 measurements

SD = standard deviation <NWG = below the detection limit e

Example 10

Pharmacological efficacy

To demonstrate the effective inhibition of the pro and lysine hydroxylase by the compounds according to the invention, the hydroxyproline concentrations in the liver and the 7s (IV) collagen concentrations in the serum of

a) untreated rats (control)

b) rats given carbon tetrachloride (CCU control)

(c) Rats given first CCI ₄ and then a compound of the invention (this test method is described by Rouiller, C, Experimental Toxic Injury to the liver, in The Liver, C. Rouiller, Vol.

Pp. 335-476, New York, Academic Press, 1964).

The potency of the compounds according to the invention was determined as a percent inhibition of liver hydroxyproline and serum 7 s (IV) collagen synthesis after oral administration in comparison to control animals administered only carbon tetrachloride (CCU control). The results are listed in Tabtlle 2. As comparison substances are olfi compounds from Examples 2 and 3 of DE-A 3703959 (N, N'-bis (2-methoxyethyl) pyridine-2,4-dicarboxylic acid diamide and N, N'-bis (3-isopropoxypropyl) -pyridine -2,4-dicarboxylic acid diamide) also listed. Surprisingly, even after oral administration, the compounds according to the invention show better efficacy than the i.p. administered compound from Example 2 of DE-A 3703959.

Table 2

substance dosage Liver- 7 S (IV) - administration out hydroxy Serum- example proline collagen (%Inhibition) (% Inhibition) 1 2 χ 2mg 62 28 p.o. 2 x 10mg 90 67 p.o. 2 2 x 2mg 25 2 p.o. 2 χ 10mg 60 35 p.o. 2 (off 2 x 25 mg 55 48 i.p. DE-A 3703959) 3 (off 2 χ 25 mg 49 11 p.o. DE-A 3703959)

scheme

OH

NH ₂ (CH ₂ I ₂ OCH ₃

Ho / Pd

0. M

NH ₂ (CH ₂ J ₃ OCH ₃

HN

NH ₂ (CH ₂ I ₃ OCH ₃

HN 0

NH ₂ (CH ₂ I ₂ OCH ₃ T

HN. 0

Soo te 9

NH ₂ (CHj) ₂ OCH

H, / Pd

NK ₂ (CH ₂ J ₃ OCH ₃

NH ₂ (CHj) ₃ OCH ₃

1 H ₂ / Pd

NH ₂ (CH ₂ J ₂ OCH ₃

Claims (12)

1. pyridine-2,4-dicarboxylic acid with at least two equivalents of a halogenating agent, and that 1. A process for the preparation of N, N'-bis (alkoxy <k \, pyridine-2,4-dicarboxylic acid diamides of the formula I. CONH- (R ¹ ) - (OR ² ) _n / CONH- (R ¹¹ J R ¹ linear or branched Ci-CrAlkandiyl,
R ^{2 is} unbranched C ₁ -C ₄ -alkyl or hydrogen
η is 1 or 2 and R ¹ , R ² and n 'have the same meanings as R', R ² and η, wherein R ¹ and R ¹ , R ² and R ² and η and n 'are the same or different except N, N'-bis (2-methoxyethyl) pyridine-2,4-dicarboxylic acid diamide and N, N'-bis (2-hydroxyethyl) pyridine-2,4-dicarboxylic acid diamide, characterized in that pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or Reacting hydroxylalkylamine. 2. at least 2 equivalents of hydroxyalkylamine or alkoxyalkylamine of the formula II or ΙΓ H ₂ N- (R ¹ MOR ² I _n (II) H ₂ N- (R ¹ V (OR ² V (II ') R ¹ and R ¹ 'are linear or branched C 1 -C 4 alkanediyl, R ² and R ^{2 are} unbranched C 1 -C ₄ -alkyl or hydrogen and η and n 'are 1 or 2 and R ¹ and R ¹ ', R ² and R ² and η and n' are identical or different, but where Il and II 'are different, dissolved in a solvent and that then brings the solution prepared according to 1 with the solution prepared according to the 2nd reaction, or that one B) the thus obtained N, N'-bis (alkoxyalkyl) pyridine-2,4-dicarboxylic acid diamide converted into the bis (hydroxyalkyl) compound or the man C) the pyridine-2,4-dicarboxylic acid halide prepared according to A) is reacted with a substituted or unsubstituted benzyl alcohol to give pyridine-2,4-dicarboxylic acid benzyl ester, the benzyl ester is saponified selectively in the 2-position of the pyridines, according to Verfalirensvariante A) 1. the free carboxylic acid in the 2-position again transferred to the acid halide and d ^: e thus obtained compound with a solution prepared according to A) 2nd using a compound of formula II ', wherein a pyridine-4-carboxylic acid benzylestercarbonsäureamid formed, and in that the benzyl protecting group is then removed by hydrogenolysis in the 4-position, the free carboxylic acid is again converted into the acid chloride according to Variant A), which is then mixed with a solution prepared according to A) 2 using a compound of the formula II, wherein a unsymmetrically substituted compound of formula I is formed and that, if appropriate, then the resulting compound of formula I is converted into its physiologically acceptable salt. 2. A process for the preparation of N, N'-bis (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of the formula I. CONH- (R ¹ ) - (OR ² J _n X. CONH- (R ¹ ') - (OR ² ') _n .
N R ^{1 is} linear or branched C 1 -C 4 -alkanediyl, R ^{2 is} unbranched C ₁ -C ₄ -alkyl or hydrogen η is 1 or 2 and R ¹ ', R ² ' and n 'have the same meanings as R ¹ , R ² and η, wherein R ¹ and R ¹ ', R ² and R ² 'and η and n' are identical or different, characterized in that you 3. The method according to claim 1 or 2, characterized in that in formula I each R ¹ and R ¹ , R ² and R ² and η and n 'have the same meaning. 4. The method according to claim 1 or 2, characterized in that in the formula I, the substituents - (R ¹ HOR ² I _n and- (R ¹ V (OR ² I _n .) Are different. 5. The method according to claim 1 or 2, characterized in that R ^{1 is} linear or branched Ci-C3-alkyl and R ^{2 is} unbranched C, -C ₂ alkyl or hydrogen. 6. The method according to claim 1 or 2, characterized in that a compound of formula CONHCH ₉ -CH ₇ -CH ₉ -O-CHO IΔ Δ Δ ύ ο. CONH-CH ₂ -CH ₂ -CH ₂ -O-CH ₃ and their physiologically acceptable salts are produced. 7. The method according to claim 1 or 2, characterized in that a compound of formula CONH-CH ₉ -CH ₉ -CH ₉ -OC ₉ Ht- and their physiologically acceptable salts are produced. 8. The method according to claim 1 or 2, characterized in that a compound of formula 0-CH ₃
CONH-CH ₂ -CH <$ O- C ¹ H CONH-CH ₉ -CH - ^ ³ N ^l ^ 0 -CH ₃ and their physiologically acceptable salts are produced. 9. The method according to claim 1 or 2, characterized in that a compound of formula ^CH 3
CONH-CH-CH ₉ -OCHO N \ CONh-CH-CH ₂ -OCH ₃ CH ₃ and their physiologically acceptable salts are produced. 10. The method according to claim 1 or 2, characterized in that a compound of formula CONH-CH ₂ -CH ₂ -OC ₂ H ₅ ST-A. CONH-CH ₂ -CH ₂ -OC ₂ H ₅ and their physiologically acceptable salts. 11. The method according to claim 1 or 2, characterized in that a compound of the formula CONH-CH ₂ -CH ₂ -CH ₂ -OH CONh-CH ₉ -CH ₉ -CH ₉ -OH _N Δ Δ Δ and their physiologically acceptable salts are produced. 12. The method according to claim 1 or 2, characterized in that a compound of formula