SK357690A3 - N,n'-bis-/alkoxyalkyl/-pyridine-2,4-dicarboxylic acid diamides, process for their preparation, their use and pharmaceutical composition containing the same - 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

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.

BACKGROUND 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, a dysfunctional, inadequate hydroxyl molecule of collagen is formed 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 the inhibition of proline hydroxylase by known inhibitors such as α, and -dipyridylom results in inhibition of Cl _q - biosynthesis of macrophages (W. Muller et al., FEBS Lett 90 (1978), 218, 155 Immunbiology (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 as inhibitory substances in cell culture at 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 poorly suited for administration as a medicament.

DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 disclose in general form mixed esters / amides, higher alkylated diesters and pyridines of pyridine-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

CONH-CH ₂ -CH ₂ -O-CH ₃

CONH-CH2-CH2-O-CH3 and N, N ^, -bis- (3-isopropoxypropyl) -pyridine-2,4-dicarboxylic acid diamide of formula IV

/ In /,

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

SUMMARY OF THE INVENTION

It has now been found that dicarboxylic acid diamides of the formula I

N, N ^, -bis- (alkoxyalkyl) -pyridine-2,4CONH- (R ') - (OR ² ) n 2'

CONH- (F 'HOR) (1) in which is

R ¹ a linear or branched (-04- ^ alkylene,

^R2 unbranched - 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,

While R ¹ and R ¹ ', R ² and R ² ' anan 'are the same or different, except for N, N'-bis- (methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide and diamide i

N, N-bis- (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid, and physiologically acceptable salts thereof, meet the above requirements.

Preferred diamides of the formula I, wherein R ¹ and R ¹ ', R ² and R ^2' Anan 'are the same.

Also preferred are diamides of formula (I) wherein the substituents - (R ¹ ) - (OR ² ) on - (R ^{1 -} 7) / OR ² 7n · are different.

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

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

R ² branched C 1 - C 2 alkyl or hydrogen.

Diamonds of the following formulas are particularly preferred:

CONH-CH ₂ -CH ₂ -CH 2 -O-CH 3

CONH-CH ₂ 'CH ₂ -CH ₂ -O-CH 3

C0NH-CH ₂ CH ₂ CH ₂ ~ ~ O 'C ₂ H ₅

CONH-C ^ -CH-Cl - ^ - O-CGHS

O-CH.

CONH-CH2-CH \

O-CH.

^N CONH-CH 2 -CH _x

O-CH

CONH-CH-CH ₂ OCH ₃

_{CONH-CH2-CH2-O-C2H5} No

CONH-CH-CH₂-O-C ^ Hs

_{CONH-CH2-CH2--ΌΗ2} ΟΗ

_CONH-CH2 -CH2 "CH-OH

CONH ^- CH 2 ^- CH 2 OCH ₃ ^_

To CONH-ICHah-OCHa

CONH- (CH 2) ₃ OCH 3 s

CONH (ΟΗ ₂ ) ₂ ΟΟΗ ₂

Compared to the acid diamide N, N ^/ bis / 2-methoxyethyl / 2,4dikarboxylovej pyridine-acetic acid diamide and N, N-bis ^{of the} / 3-isopropoxypropyl / 2,4dikarboxylovej pyridine ester, which are as described in DE-A 37 03 959, the compounds of the formula I show better pharmacological activity as well as better resorbability.

The invention furthermore 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 ', nano 'are as defined above. characterized in that the pyridine-2,4-dicarboxylic acid halide is reacted with an alkoxyalkylamine or a hydroxyalkylamine.

The invention furthermore 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 ', nano ' meaning that the pyridine-2,4-dicarboxylic acid halide solution is reacted with a solution of at least 2 equivalents of hydroxyalkylamine or alkylamine of formula II or II

H ₂ N- (R ') - (OR 1' (II)

H ₂ N- (R ') - (OR ² ') n '(III') in which is

R ¹ and R ¹ 'linear or branched - C ₄ - alkylene

R ² and R ² 'branched C - C 4 - alkyl, or hydrogen, and

n and n 'the number 1 or 2 a

R ¹ and R ¹ ', R ² and R ² ' as inan 'are the same or different, but the compounds of formula (IIa) are different,

Ί at a temperature in the range of 90 to 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 asymmetric substitution reacts pyridine-2,4-dicarboxylic acid halide with substituted or unsubstituted benzyl alcohol to pyridine-2,4-dicarboxylic acid benzyl ester, benzyl ester selectively saponifies at position 2 of pyridine, free carboxylic acid at position 2 is converted to acid halide again by reaction with a halogenating agent and the compound thus obtained is mixed with a solution of the compound of formula II to give the pyridyl-4-carboxylic acid benzyl ester amide and then hydrogenolytically cleaving the benzyl protecting group at the 4-position; which is then mixed with a solution of the compound of formula II to form an unsymmetrically substituted compound of formula I and finally converting the optionally obtained compound of formula I to a physiologically acceptable salt.

In the process for the preparation of compounds of formula I, pyridine 2,4-dicarboxylic acid, which can be purchased as starting material, is suspended in a solvent such as toluene and is supplemented at room temperature with a halogenating agent, preferably a chlorinating agent such as SOCl ₂ . 2 to 3 equivalents of halogenating agent, preferably 2.5 equivalents, are used, based on the molar amounts of pyridine-2,4I-dicarboxylic acid used. The reaction mixture obtained is heated to 90 to 110 ° C, preferably to 100 ° C until no further evolution of gas is observed and a clear solution is formed. Thereafter, preferably 10% of the solution is evaporated from the solution under high vacuum (up to about 0.1 mmHg) and the resulting carboxylic acid halide is reacted.

Based on the molar amount of pyridine-2,4-carboxylic acid used, the 2-4-fold molar amount of the alkoxyalkylamine or hydroxylamine is now dissolved in a solvent such as toluene and preferably 2% SCKC2 is added.

up to 4 times the molar amount of triethylamine. The carboxylic acid halide is reacted with an alkoxyalkylamine or a hydroxyalkylamine. This is preferably done by dropwise adding a 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 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 free of 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, e.g. 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, preferably chlorine-pyrrine-ganine. dicartraxylic acid _from substituted or unsubstituted benzyl alcohol to pyridyl-2,4-dicarboxylic acid benzyl ester, fh, followed by selective saponification of the ester at the 2-position (e.g. in the presence of a copper catalyst, Acta Helv. 44, 1963, page 637, by conversion of the free acid in the 2-position into the acid halide by reaction with a compound of formula II in the amide-pyridin-4-carboxylic acid benzyl ester-2-carboxylic acid, hydrogenolytic removal of the remaining benzyl protecting group (e.g., β H ₂ Pd, see Houben-Weyl, Vol. IV / 1c (1980), pp. 381-82), followed by 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 the aid of 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, 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 acid or ascorbic acid.

The compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations which optionally contain them 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, magnesium stearate, talc, vegetable oils, polyalkyl glycols, petrolatum, etc.

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

The compounds of formula I 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 of thionyl chloride was added dropwise. It was heated until no further gas evolution was observed (about 2.5 hours). It was cooled, 5 ml of toluene were distilled off and the solution was added dropwise

4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine. 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 (ethyl acetate solvent).

Yield: 4.3 g; oil ^{@ 1} H-NMR (CDCl3) .delta. = 1.6-2.3 (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

5i

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

See Example 1 for a prescription; amine components ethoxypropylamine,

Yield: 4.5 g, mp: 46-48 ° C.

^{@ 1} H-NMR (CDCl3): .delta. = 1.3 (6H, tr); 1.7-2.1 (4H, m);

3.3 to 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 / 4H, mZ; 4.5 (2H, m);

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

8.7 to 8.8 (1H, m);

Example 4 ^e ?

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 (CDCl3): .delta. = 1.3 (6H, d); 3.2 (6H, s); 3.5 (4H, d);

4.4 / 2H, 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 (1 H, m); 8.7-8.8 (1 H, m);

Example 6 e J

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

0.5 g of pyridine-2,4-dicarboxylic acid bis-Ν, Ν - [3-methoxyethyl] amide was dissolved in 10 ml of dichloromethane and borontribromide (11 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.

^{@ 1} H-NMR (CDCl3): .delta. = 1.5-2.2 (4H, m); 3.4 (4H, m); 3.6 (4H, 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 ^e J

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. Boil under reflux for one hour and, after cooling, filter out 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. For purification, 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 a palladium / carbon 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 (2-Methoxyethyl) -2-carboxylic acid (3-methoxypropyl) -diamidopyridine-4-carboxylic acid

In accordance with Example 1, 1.8 g of the compound of Example 7d is converted with 0.6 ml of thionyl chloride to 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

In analogy 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.

^{@ 1} H-NMR (CDCl3): .delta. = 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 (1 H, 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 the esophagus probe. Po 5; 10; 15 ^ 60; 120; 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 μΙ 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 Table 1.

Table 1

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

Time (min) the substance of Example 1 Example compound Example compound 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 = below 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 (CCI ₄ - control)

c) rats first administered CCI ₄ and then a compound of the invention (these test methods are described by Rouiller C., experimental toxic injury of the liver; in The Liver C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Press, 1964).

The potency of the compounds of the invention was determined as a percentage inhibition of the synthesis of hydroxyproline in the liver and 7s- (IV) -collagen in the serum following an oral dose compared to control animals receiving only carbon tetrachloride (CCI ₄ - control). The results are shown in the table

2. As a reference substance at the same time are also the compounds of Examples 2 and 3 of DE-A-37 03 959 diamide / N, N-bis / 3-isopropoxypropyl / pyridine 2,4-dicarboxylic ^e J ^ acid. 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

Fabric from pr. batching hydroxyproline in the liver (% inhibition) 7S- / IV / - collagen in serum (% inhibition) feed 1 2x2 mg 62 28 after. 2x10 mg 90 67 P-θ · 2 2x2 mg 25 2 after. 2 (from DE-A 2x10 mg 60 35 after. 3703959) 3 (from DE-A 2x25 mg 55 48 ip 3703959) 2x25 mg 49 11 after.

TL A O

Claims (16)

PATENT CLAIMS Diamides 1. N, ^N'-bis / alkoxyalkyl / pyridine-2,4-dicarboxylic acids of formula I CONH- (R ¹ ) - (OR ² ) _n \ _n ^ -CONH- (B ¹ ') - (OR) _n , in which ^R1 straight or branched, - C ₄ - alkylene, ^R2 unbranched Ci - C ₄ - alkyl, or hydrogen, n is 1 or 2 and R ¹ ', R ² ' and n 'have the same meanings 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 diamide 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. The diamides according to claim 1 of the general formula I, in which R ¹ and R ¹ ', R ² and R ² ' anan 'have the same meaning. The diamides of claim 1, wherein the substituents (R ¹ ) - (OR ² ) on - (R ¹ 7-) OR ² 7n- are different. The diamides according to claim 1 of the general formula I, in which is R ^{1 is} linear or branched C 1 -C 3 -alkylene a ^R2 unbranched Ci-C ₂ alkyl or hydrogen. 5. A compound according to claim 1, which is a compound of the formula C0NH-CH ₂ -CH ₂ -CH ₂ ^- H ^_ CH ₃ CONH-CH 2 ^N-CH ₂ -CH ₂ -O-CH 3, and physiologically acceptable salts thereof. 6. A compound according to claim 1, which is a compound of formula CONH-CH 2 -CH 3 -CH 3 O-C 1 H 5 CONH-CH ₂ -CH ₂ ^_ CH 2 ^- O-C2H5, as well as physiologically acceptable salts thereof. 7. A compound of the formula I as well as its physiologically acceptable salts. A compound according to claim 1, which is a compound of the formula and physiologically acceptable salts thereof. A compound according to claim 1, which is a compound of the formula CONH-CH ₂ -CH 2 -OC ₂ H ₅ N CONH ^- CH 2 ^_ CH 2 -OC ₂ H _5, as well as physiologically acceptable salts thereof. 10. The diamide according to claim 1 of formula I which is a compound of formula _{-CONH-CH2 CH2} ^_ -ΌΒ2-0Η CONH-CH2-CH2-CH2-OH as well as its physiologically acceptable salts. 11. A compound according to claim 1, which is a compound of the formula CONH-CH-CHjj-OCH CONH- (CH 2) ₃ -OCH 3 as well as physiologically acceptable salts thereof. 12. A compound according to claim 1, which is a compound of the formula CONH- (CH 2) ₃ OCH 3 CONH- (CH ₂ ) ₂ OCH ₃ as well as its physiologically acceptable salts. A process for the preparation of N, N-bis-alkoxyalkyl-2-pyridine-2,4-dicarboxylic acid diamides of the general formula I, in which R and R ', R and R' anan 'are as defined above, according to any one of claims 1 to 12, characterized The method of claim 1, wherein at least 2 equivalents of hydroxylamine or alkylamine of formula (II) or (II) are reacted with a solution of pyridine-2,4-dicarboxylic acid halide, preferably in toluene. H ₂ N- (R ¹ ) - (OR ² ) _n (II) H ₂ N- (R ¹ 7-) OR ² '( _n ) (II)' in which it represents R ¹ and R ¹ 'linear or branched - C ₄ - alkylene R ² and R ² 'straight - C ₄ - alkyl or hydrogen and 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 (IIIa ') are different at a temperature between 90 ° C and 110 ° C to form the compound of formula I and optionally 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 substituted or unsubstituted benzyl alcohol to give pyridine- benzyl ester for asymmetric substitution. 2,4-dicarboxylic acid, the benzyl ester is selectively saponified at the 2-position of pyridine, the free carboxylic acid at the 2-position is converted to the acid halide again by treatment with a halogenating agent, and the compound thus obtained is mixed with a solution of the compound of formula II to form the pyridyl benzyl ester 4-carboxylic acid, and then the benzyl protecting group at the 4-position is hydrogenolytically cleaved, the free carboxylic acid by means of a halogenating agent, it is converted again to an 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 I / 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.