SK279199B6 - N,n'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, a process of preparation and use thereof, pharmaceutical compositions containing the same - Google Patents

Abstract

N,N'-bis-(alkoxyalkyl)pyridine-2,4-dicarboxylic acid diamides of common formula (I), wherein R1 and R2' represent linear or branched C1-C4-alkylene, R2 and R2' represent unbranched C1-C4-alkyl or a hydrogen atom, n and n' are 1 or 2, wherein R1 a R1', R2 a R2', n and n' are identical or different, a method of preparation thereof, in reaction of halogenide pyridine-2,4-dicarboxylic acid with alkoxylalkylamine or hydroxyalkylamine. These compounds inhibit prolin hydroxylase and lysin hydroxylase and are suitable as fibrosuppressants and immunosuppressants. Pharmaceutical agents containing said compositions are also described.

Description

Technical field

The invention relates to novel N, N-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides, processes for their preparation and their use in medicaments.

However, the enteral resorbability of many of the compounds described in DE-A 37 03 959 is still unsatisfactory, so there is a need to provide compounds which, after oral administration, effectively inhibit proline hydroxylase and lysine hydroxylase even at low dosages.

BACKGROUND OF THE INVENTION

SUMMARY OF THE INVENTION

Compounds that inhibit proline hydroxylase and lysine hydroxylase prevent very selective collagen biosynthesis by affecting collagen-specific hydroxylation reactions. In the course of these, the proline bound to the protein or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is prevented by inhibitors, there will be a dysfunctional, inadequately hydroxylic collagen molecule, which can only be delivered to the extracellular space by cells in limited quantities. In addition, insufficiently hydroxylated collagen cannot be incorporated into the collagen matrix and is readily degraded proteolytically. As a result of this effect, the general amount of extracellular deposited collagen is reduced.

It is known that inhibition of proline hydroxylase by known inhibitors, such as α, and -dipyridyl, leads to inhibition of C1q - macrophage biosynthesis (W. Muller et al. FEBS Lett 90 (1978), 218; Immunbiology 155 (1978) 47). This leads to a loss of the classical path of complementary activation. Proline hydroxylase inhibitors also act as immunosuppressants, for example in immunocomplex diseases.

Proline hydroxylase is known to be effectively inhibited by pyridine-2,4-dicarboxylic acid and pyridine-2,5-dicarboxylic acid (K. Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). These compounds are only effective in inhibiting cell culture in very high concentrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).

DE-A 34 32 094 discloses pyridine-2,4-dicarboxylic acid diester and pyridine-2,5-dicarboxylic acid diester of 1 to 6 carbon atoms in the alkyl ester moiety as a medicament for inhibiting proline hydroxylase and lysine hydroxylase.

These low alkyl diesters, however, have the drawback that they cleave too rapidly into acids in the body and do not reach their site of action in the cell at a sufficiently high concentration, and thus are not suitable for administration as a medicament.

DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 describe in general form mixed esters / amides, higher alkylated diesters and pyridines of 2,4-dicarboxylic acid, which effectively inhibit collagen biosynthesis in animal model.

Thus, DE-A 37 03 959 describes, inter alia, the synthesis of N, N-bis- (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide III

It has now been found that N, N-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of formula (I)

CONH- (R 1) - (OR ² ) n

HOR) _n .

/ 1 / in which it means

R ¹ a linear or branched) - C ₄ - alkylene,

^R2 unbranched C] - C ₄ - alkyl, or hydrogen, n is 1 or 2 and

R ¹ ', R ² ' and n 'have the same meaning as R ¹ , R ² and n, wherein R ¹ and R ¹ ', R ² and R ² 'anan' are the same or different, except for the N, N-bis- (methoxyethyl) -pyridine-2,4-dicarboxylic acid and N, N-bis- (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid diamide and their physiologically acceptable salts meet the above requirements.

Preferred are the diamides of formula (f) in which R ¹ and R ¹ ', R ² and R ² ' and pin 'have the same meaning.

Also preferred are diamides of formula (I) wherein the substituents - (R ¹ ) - (OR ² ) on - (R ¹ ') - (OR ² ') n are different.

Further preferred are the diamides of the formula (I) in which they are

R ^{1 is} linear or branched C ¹ -C ₃ -alkyl;

R ² unbranched C] - _C2 - alkyl group or a hydrogen atom.

Diamonds of the following formulas are particularly preferred:

CONH-CH-CHrCHj-O-CjHs

ABOUT.

CONH-CH-CH-CH-O-CjHs

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

CONH-CH 3 -CH 2 -CH 2 -O-CH 2 -

--COWŤ-CH, -CH, 'CH,' O-CH

CHo (IV),

O-CH)

O-CH

CONH-CH-CH

O-CH

CONH-CH2-CH2-CH2-OH

^M D-CONH-CH ohj-O-OH

CON-Foya OCHA

CONH- (CH 2) ₃ OCH 3 -;

Compared to N, N-bis- (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide and N, N-bis- (3-isopropoxypropyl) -pyridine-2,4-dicarboxylic acid diamide, which are disclosed in DE-A 37 03 959, the compounds of formula (I) show better pharmacological activity as well as improved resorbability.

The invention further relates to a process for the preparation of N, N-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of the general formula (I) in which R ¹ , R ² , R ¹ ', R ² ', nan ' The above-mentioned meaning is characterized in that the pyridine-2,4-dicarboxylic acid halide is reacted with an alkoxyalkylamine or a hydroxyalkylamine.

The invention further relates to a process for the preparation of N, N-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of the general formula (I) in which R ¹ , R ² , R ¹ ', R ² ', nan ' said meaning consisting in reacting a pyridine-2,4-dicarboxylic acid halide solution with a solution of at least 2 equivalents of hydroxyalkylamine or alkylamine of formula (II) or (II)

H ₂ N- (R *) - (OR ² ) n (II),

H ₂ N- (R ¹ ) - (OR ^{2 '} ) (I') in which it represents

R ¹ and R ^{1 are} linear or branched C ¹ -C 4 -alkylene R ² and R ^{2 are} unbranched C 1 -C 4 -alkyl or a hydrogen atom of number 1 or 2; and

R ¹ and R ¹ ', R ² and R ² ' as inan 'are the same or different, but the compounds of formula (II) and (II) are different, at a temperature between 90 ° C and 110 ° C, to form a compound of formula ( I) and optionally the obtained N, N-bis (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide is converted to a bis (hydroxyalkyl) compound or pyridine-2,4-dicarboxylic acid halide is reacted with asymmetric substitution with substituted or unsubstituted benzyl alcohol to pyridine-2,4-dicarboxylic acid benzyl ester, the benzyl ester is selectively saponified at the 2-position of pyridine, the free carboxylic acid at the 2-position is re-converted to the acid halide by reaction with a halogenating agent. of formula (II) to form pyridine-4-carboxylic acid benzyl ester amide, and then the benzyl protecting group at the 4-position, the free carboxylic acid, is hydrogenolytically cleaved. is converted with an halogenating agent to the acid halide, which is then mixed with a solution of the compound of formula (II) to form an unsymmetrically substituted compound of formula (I), and finally the optionally obtained compound of formula (I) is converted to a physiologically acceptable salt.

In the process of preparing compounds of formula (I), the pyridine-2,4-dicarboxylic acid, which can be as a starting material to purchase, suspended in a solvent such as toluene, and at room temperature is added to a halogenating agent, preferably chlorinating agent, such as SOC1 _second Based on the molar amounts of pyridine-2,4-dicarboxylic acid used, 2 to 3 equivalents of halogenating agent, preferably 2.5 equivalents, are used. The reaction mixture obtained is heated to 90 to 110 ° C, preferably to 100 ° C until no more gas evolution is observed and a clear solution is formed. Thereafter, 10% of the solution is preferably evaporated under high vacuum (up to about 1.33 Pa) and the resulting carboxylic acid halide is reacted.

Based on the molar amount of pyridine-2,4-carboxylic acid used, a 2 to 4-fold molar amount of a commercial alkoxyalkylamine or hydroxylamine is now dissolved in a solvent such as toluene and preferably a 2 to 4-fold molar amount of a base such as triethylamine is added. The carboxylic acid halide is reacted with an alkoxyalkylamine or a hydroxyalkylamine. This is preferably done by dropwise adding the solution of said alkylamine to the dissolved pyridine-2,4-dicarboxylic acid halide. However, it is also possible to add dropwise the carboxylic acid halide solution to the alkoxyalkylamine or hydroxyalkylamine solution. The addition is carried out at a temperature of -5 to +5 ° C, preferably at 0 ° C. The reaction mixture is then allowed to react by, for example, warming to room temperature and stirring for a further 2 to 5 hours, preferably 3 hours. The product obtained is then acidified in order to separate the excess hydroxyalkylamine 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. Finally, the organic phase is dried - preferably over magnesium sulphate - and finally freed from the solvent. After removal of the solvent, the product precipitated as a white precipitate or precipitated as an oil.

For the preparation of N, N-bis- (hydroxyalkyl) -pyridine-2,4-dicarboxylic acid diamides, it is best to carry out the corresponding bis (alkoxyalkyl) diamide, preferably bis (methoxyalkyl) diamide, in a manner known from the literature, for example borontribromide. , to the corresponding bis (hydroxyalkyl) diamide.

Unsymmetrically substituted compounds of formula (I) may be substituted, for example, as follows:

by reacting pyridine-2,4-dicarboxylic acid halide, preferably pyridine-2,4-dicarboxylic acid chloride, with substituted or unsubstituted benzyl alcohol, to pyridine-2,4-dicarboxylic acid benzyl ester, followed by selective saponification of the ester at the 2-position (e.g. in the presence of a catalyst) copper (Acta Helv. 44, 1963, p. 637), converting the free acid at the 2-position to the acid halide, by reaction with a compound of formula (II) to pyridine-4-carboxylic acid amide-benzyl ester-2-carboxylic acid, by hydrogenolytic cleavage of the remaining benzyl protecting groups (e.g., with H ₂ Pd, see Houben-Weyl vol. IV (1c (1980), pp. 381-82)) and subsequent conversion of the free acid at the 4-position of the pyridine ring to the acid halide.

The acid halide can now be converted to the mixed diamide (I) with amine II (see reaction scheme).

Optionally, the products can be worked up, for example, by extraction or chromatography, for example on silica gel. The isolated product may be recrystallized and optionally reacted with a suitable acid to form a physiologically tolerable salt. Suitable acids are, for example:

inorganic acids such as hydrochloric acid and hydrobromic acid as well as sulfuric acid, phosphoric acid, nitric acid 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, fiimaric acid, phenylacetic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, oxalic acid, 4-aminobenzoic acid, naphthalene-1,5-disulfonic acid or ascorbic acid.

The compounds of formula (I) may be used as medicaments in the form of pharmaceutical preparations containing them optionally together with compatible pharmaceutical carriers. The compounds may be used as medicaments, for example in the form of pharmaceutical preparations containing the compounds in admixture with an organic or inorganic carrier suitable for pharmaceutical enteral, percutaneous or parenteral administration, such as water, gum arabicum, gelatin, milk sugar, starch, stearate magnesium, talc, vegetable oils, polyalkyl glycols, petrolatum, etc.

The pharmaceutical preparations may be available in solid form, for example, as tablets, dragees, suppositories, or capsules; in semi-solid form, for example as an ointment or in liquid form, for example as a solution, suspension or emulsion. They are optionally sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may contain other therapeutically active substances.

The compounds of formula (1) have been found to exhibit extremely good enteral resorbability. Resorbability was tested in Wistar rats to which the compounds of the invention were administered intragastrally. Serum levels decreased in the first hours after dosing and reached only a slightly decreasing level after about 5 hours. From the serum level, which was initially very high, a good resorbability of the substances can be judged after administration of the substances.

DETAILED DESCRIPTION OF THE INVENTION

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

Example 1 Pyridine-2,4-dicarboxylic acid bis-Ν, Ν - (methoxypropyl) amide g of pyridine-2,4-dicarboxylic acid was dissolved in 50 ml of toluene and 1 ml of dimethylformamide (DMF) and 2.7 ml was added dropwise. thionyl chloride. Warm up until no more gas evolution (approx

2.5 hours). It was cooled, 5 ml of toluene was distilled off and 4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine were added dropwise. After stirring the solution at the stirring temperature for 4 hours, the solution was evaporated, the residue was taken up in water and extracted four times with methylene chloride. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The crude product was chromatographed on silica gel (solvent ethyl acetate).

Yield: 4.3 g; oil (1 H-NMR (CDCl 3)): δ = 1.6 to 2.3 (4H, m); 3.2 to 3.8 (14H, m);

7.8 to 8.0 to 8.0 (1H, m); 8.3 to 8.5 (14H, m);

8.6 to 8.8 (1H-m).

Example 2

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

See Example 1 for a prescription; amine components 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 to 8.0 (1H, m);

8.4 to 8.5 (1H, m); 8.5 to 8.8 (1H, m).

Example 3

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

See Example 1 for a prescription; amine component 2-dimethoxyethylamine.

Yield: 1.6 g, (from 3 g pyridine-2,4-dicarboxylic acid), oil 1 H-NMR (CDCl ₃ ):

δ = 3.4 (12H, s); 3.7 (4 H, m); 4.5 (2 H, m);

7.9 to 8.0 (1H, m); 8.4 to 8.5 (1H, m);

8.7 to 8.8 (1H, m).

Example 4

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

See Example 1 for a prescription; amine component 2-methoxyisopropylamine

Yield: 3.3g, (from 3g 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 (2 H, m); 7.9 to 8.0 (1H, m);

8.4 to 8.5 (1H, m); 8.7 to 8.8 (1H, m).

Example 5

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

See Example 1 for a prescription; amine component ethoxyethylamine

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

Mp: 42-44 ° C 1 H-NMR (CDCl ₃ ): δ = 1.2 (3H, tr); 3.3-3.8 (12H, qu. Am);

7.9 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m).

Example 6

Pyridine-2,4-dicarboxylic acid bis-Ν, Ν - (3-hydroxyethyl) amide

Pyridine-2,4-dicarboxylic acid bis-Ν, Ν - (3-methoxyethyl) amide (0.5 g) was dissolved in dichloromethane (10 ml) and boron tribromide (1 ml, 1 molar solution in dichloromethane) was added dropwise at -78 ° C. ). After the addition was complete, it was allowed to warm to room temperature and stirred for an additional 3 hours. Pour onto 100 mL of saturated bicarbonate solution and extract 3x with ethyl acetate. The combined organic solvents were dried (MgSO 4) and evaporated. The crude product is chromatographed on silica gel.

Yield: 0.45 g, oil. H-NMR (CDC1 _3): δ = 1.5- 2.2 (4H, m); 3.4 (4H, m); 3.6 (4 H, m);

7.9 to 8.0 (1H, m); 8.4-8.5 (1H, m);

8.7 to 8.8 (1H, m).

Example 7a

Pyridine-2,4-dicarboxylic acid dibenzyl ester

30 g of pyridine-2,4-dicarboxylic acid are converted in analogy to Example 1 with 30 ml of thionyl chloride into the acid chloride and reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether. Yield: 42.1 g. Melting point 63-65 ° C.

Example 7b

Pyridine-2-carboxylic acid 4-carboxylic acid benzyl ester g of pyridine-2,4-dicarboxylic acid dibenzyl ester from Example 7a is added to a suspension of 27.8 g of copper nitrate in 700 ml of methanol. It is boiled under reflux for one hour and, after cooling, is filtered off from the copper complex. The complex is suspended in dioxane and carbon disulfide is introduced. The precipitated copper sulphide is filtered off and mixed with petroleum ether.

Yield: 25.3 g. Melting point 113-115 ° C.

Example 7c

Pyridine-2- (3-methoxypropyl) -carboxylic acid amide-4-carboxylic acid benzyl ester

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

Yield: 4.3 g, oil.

Example 7d

Pyridine-4-carboxylic acid 2- (3-methoxypropyl) -carboxylic acid amide

4.3 g of the compound of Example 7c are dissolved in 100 ml of dioxane and hydrogenated with 500 mg of palladium carbonate catalyst (10%) at normal pressure for 4 hours. After the hydrogen uptake is complete, it is filtered off with suction from the catalyst and the solvent is distilled off.

Yield: 3.5 g. Mp 124-126 ° C.

Example 7e (3-Methoxypropyl) -diamide-pyridine-4-carboxylic acid (2-methoxyethyl) -2-carboxylic acid

In accordance with Example 1, 1.8 g of the compound of Example 7d was converted with 0.6 ml of thionyl chloride into the acid chloride and then reacted with 2-methoxyethylamine. For purification, the product is chromatographed on silica gel with dichloromethane / methanol (20: 1).

Yield: 1.0 g, oil, 1 H-NMR (CDCl ₃ ): δ = 1.9 to 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 (2-Methoxyethyl) -4-carboxylic acid (3-methoxypropyl) -diamide-pyridine-3-carboxylic acid

Analogously to Examples 7a-e, the compound of Example 8 was prepared by using 2-methoxyethylamine in the reaction step of Example 7c and 3-methoxypropylamine in the reaction step of Example 7e.

Melting point: 69-72 ° C. H-NMRÍCDCIj):

δ = 1.9 to 2.0 (2H, mqui), 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 resorbability

Female Wistar rats, weighing about 150 g, received 50 mg / kg of the test substance, which was administered intragastrally via a pectoral probe. Po 5; 10; 15; 30; 60; 120; At 180 and 240 minutes, 4 rats were each anesthetized and bled via the vena cava. The blood was immediately centrifuged and the drug was extracted from the serum with ether. After evaporation of the ether, the residue is taken up in 100 ml of liquid. The liquid consists of 0.05 M phosphoric acid and acetonitrile (4: 1).

Inject a 50 μΐ syringe onto the HPLC column from this sample. Detection is performed at UV 200 nm and a retention time of 2.2 min. The results are shown in the table

First

Table 1

Serum levels of the compounds of Examples 1 to 3 following a 50 mg / kg p-o dose.

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

X = average of 4 measurements

SD = standard deviation <NWG = from the detection limit

Example 10

Pharmacological efficacy

To demonstrate effective inhibition of proline hydroxylase and lysine hydroxylase by the compounds of the invention, hydroxyproline concentrations were measured in the liver and serum 7s- (IV) -collagen concentrations were measured.

(a) untreated rats (control),

(b) rats treated with carbon tetrachloride (CC1 ₄ - control),

c) rats were first administered CC1 ₄ and then the compound of the invention (the test method described Rouiller, C., experimental toxic injury of the liver; in The Liver C. Rouiller, Vol. 2, pp. 335-476, New York, Acadcmic Press, 1964).

The intensity of action of the compounds was determined as the percent inhibition of hydroxyproline in liver and 7S- (IV) -kolagénu levels after oral administration as compared to the control animals, who received only the carbon tetrachloride (CC1 ₄ - control). The results are shown in Table 2. The compounds of Examples 2 and 3 of DE-A-37 03 959 (N, N-bis-) 3-isopropoxypropyl) -pyridine-2,4-dicarboxylic acid diamide are also shown as reference substances. . Surprisingly, even when administered orally, the compounds of the invention show better efficacy than the ip-administered compound of Example 2 DE-A-37 03 959.

Table 2

hydroxy 7S- (IV). podá- Fabric from pr. a dosing proline collagen tion tion in liver (% in serum (%) inhibition) inhibition) 1 2x2 mg 62 28 after. 2x10 mg 90 67 after. 2 2x2 mg 25 2 after. 2x10 mg 60 35 after. 2 (from DE- 2x25 mg 55 48 ip A3703959) 3 (from DE- 2x25 mg 49 11 after. A3703959)

Claims (2)

PATENT CLAIMS The diamides according to claim 1 of the general formula (I) in which the substituents - (R 1) - (OR ² ) on - (R ¹ ) - (OR ² ') n · are different. The diamides according to claim 1 of the general formula (I), in which they are R ^{1 is} linear or branched C 1 -C 4 -alkylene a R ² -C ₂ straight chain alkyl or hydrogen. The diamide of claim 1 of formula (I), which is a compound of formula CONH-C1-CH2-CH2-O-CHa COFH-CH 1 -CH 3 -CH 3 -O-CH, and physiologically acceptable salts thereof. The diamide of claim 1, which is a compound of formula (I) as well as physiologically acceptable salts thereof. The diamide of claim 1 of formula (I), which is a compound of formula ^, O-CH, O-CH O-CH COHt-CH2-CH as well as physiologically acceptable salts thereof. A diamide according to claim 1 of the general formula (I), which is a compound of the formula as well as physiologically acceptable salts thereof. The diamide of claim 1 of formula (I), which is a compound of formula N, N-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of general formula (I) ONHrlR’YtORX / 1 / which means R ¹ a linear or branched C] - C 4 - alkylene, ^R2 unbranched C | - C4 - alkyl or hydrogen atom n 1 or 2 and R ¹ ', R ² ' and n 'have the same meaning as R ¹ , R ² and n, wherein R ¹ and R ¹ R ² and R ² ' anan 'are the same or different, except for the N, N-bis- (methoxyethyl) diamide 1-pyridine-2,4-dicarboxylic acid and N, N-bis- (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid diamide, and their physiologically acceptable salts. The diamides according to claim 1 of the general formula (I) in which R ¹ and R ¹ ', R ² and R ² ' and pin 'have the same meaning. as well as its physiologically acceptable salts. The diamide of claim 1 of formula (I), which is a compound of formula CONH-OrCH, -CH3-OH CONH-CH 2 CH 3 -CH 3 -OH as well as physiologically acceptable salts thereof. The diamide of claim 1 of formula (I), which is a compound of formula CONH-CH 3 -CH 3 -OCH 2, ΟΟΝΗ- (ΟΗ * -ΟΟΗ), and physiologically acceptable salts thereof. The diamide of claim 1 of formula (I), which is a compound of the formula as well as physiologically acceptable salts thereof. A process for the preparation of N, N-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamides of formula (I) wherein R ¹ and R ¹ ', R ² and R ² ' and n 'are as defined above, according to any one of claims 1 to 12, characterized in that the solution of pyridine-2,4-dicarboxylic acid halide is reacted with the solution preferably in toluene with at least 2 equivalents of hydroxylamine or alkylamine of formula (II) or (II) H ₂ N- (R 1) - (OR ² ) _n (II), H ₂ N- (R ¹ ) - (OR ² ) _n · (II) in which ch is R ¹ and R ¹ 'linear or branched C 1 -C 4 -alkylene, R ² and R ² ' unbranched C 1 -C 4 -alkyl or hydrogen atom n 1 or 2; and R ¹ and R ¹ ', R ² and R ² ' as well as n '' are the same or different, but the compounds of formula (II) and (II) are different at a temperature between 90 ° C and 110 ° C to form a compound of formula (I) and optionally the obtained N, N-bis (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide is converted to a bis (hydroxyalkyl) compound or pyridine-2,4-dicarboxylic acid halide is reacted for asymmetric substitution acid with substituted or unsubstituted benzyl alcohol to pyridine-2,4-dicarboxylic acid benzyl ester, benzyl ester selectively saponified at the 2-position of pyridine, the free carboxylic acid at the 2-position is converted to the acid halide by reaction with a halogenating agent, and the compound thus obtained is mixed with the solution of the compound of formula (II) to form pyridine-4-carboxylic acid benzyl ester amide, and then the benzyl protecting group at the 4-position, the free carboxylic acid, is removed by hydrogenolysis The eline is converted with a halogenating agent to the acid halide, which is then mixed with a solution of the compound of formula (II) to form an unsymmetrically substituted compound of formula (I), and finally the optionally obtained compound of formula (I) is converted to a physiologically acceptable salt. 14. A pharmaceutical composition for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of C _q, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 12 and / or a physiologically acceptable salt thereof in acceptable pharmaceutical carrier . 15. The diamides of formula (I) according to any one of claims 1 to 12 and / or physiologically acceptable salts thereof for the manufacture of a medicament for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of C _q. 16. The diamides of formula (I) according to any one of claims 1 to 12 and / or physiologically acceptable salts thereof for the manufacture of a medicament for the treatment of disorders of the biosynthesis of collagen and collagen-like substances or the biosynthesis of C _q.