LT3798B - Method for the preparation of n,n'-bis(alkoxyalkyl)-pyrimidine-2,4-dicarboxylic acids diamides and use thereof - 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

Compounds that inhibit proline and lysine hydroxylase highly selectively inhibit collagen synthesis by acting on specific collagen hydroxylation reactions. In these reactions, protein-bound proline or lysine is hydroxylated in the presence of the enzyme proline or lysine hydroxylase. Stopping these reactions with the help of inhibitors results in the formation of an inactive, incompletely (not completely) hydroxy-collagen molecule that can only be transferred from the cell to the extracellular domain in small amounts. Furthermore, insufficiently hydroxy-oxidized collagen is unable to incorporate into the collagen matrix and is very easily proteolytically degraded. This effect reduces the total amount of collagen present in the extracellular space.

Inhibition of proline hydroxylase by known inhibitors such as α, α'-dipyridyl is known to inhibit the Clg biosynthesis of macrophages (W. Mueller et al., FEBS Lett. 90 (1978), 218; Immunology, 155 (1978), 47). As a result, the classic re-activation paths are gone. Therefore, proline hydroxylase inhibitors also act as immunodepressants, for example in severe immune disorders.

Proline hydroxylase is known to be effectively inhibited by pyridine-2,4-dicarboxylic acid (K.Mayamao et al., Eur. I. Biochem. 138 (1984) 239-245). It is true that, in cell culture, these compounds act as inhibitors only at very high concentrations (Tschank G. et al. Biochem. 238,625-633,1987).

VFR application DE-A 3432 094 describes pyridine-2,4-dicarboxylic acid diester and pyridine-2,5-dicarboxylic acid diester having 1-6 carbon atoms in the alkyl portion of the ester group as drugs for inhibition of proline and lysine hydroxylase.

B

However, these esters with short alkyl chains have the disadvantage that they are rapidly degraded to acids and are not sufficiently high in the cellular site of action and, at the same time, have little potential for use as drugs.

VFR applications DE-A 37 03 959, DE-A 37 03 963 and DE-A 37 03 963 generally describe mixtures of pyridine-2,4- and-2,5-dicarboxylic acid esters / amides, long alkyl chain diesters and diamides which Actively inhibits (inhibits) collagen biosynthesis in animal models.

By the way, VFR application DE-A 3703-959 describes, inter alia, the synthesis of N, N '-bis- (2-methoxyethyl) diamide (III) pyridine-2,4-dicarboxylic acid,

CONH-CII2-CII2-OCI-I3

Synthesis of N-CONII I-CII2-CII2-OCH3 (III) Pyridine-2,4-Dicarboxylic Acid Ν, Ν'-bis (3-isopropoxypropyl) diamide (IV).

CH3

CONI-ICII-CH2-CH2-OCH

I ^x ch ₃

CONH-CH2-CH2-OCH ch ₃

-CII3

(IV)

German patent applications P 38 26 471.4 and P 38 28

140.6 proposes an improved process for the preparation of N, N'-bis- (2-methoxyethyl) -diamide (III) pyridine-2,4-dicarboxylic acid.

The enteric suction of many of the compounds described in VFR Application DE-A 37-03 959 is unsatisfactory and there is a need to provide compounds which, when administered orally at low doses, will effectively inhibit proline and lysine hydroxylase.

It has now been discovered that compounds of formula (1)

CONH (R ¹⁾ - (OR ²⁾ n ^ CONH (R ^r) - (OR ² ') n' d)

N wherein R ¹ is linear or branched C _x to C ₄ alkanediyl;

R is unsubstituted C _x to C ₄ alkyl or hydrogen;

n-i or 2;

R ¹ , R ² , n 'have the same meaning as R ¹ , R ² , n, with the exception that R ¹ 1' 2 2 'and R, R and R, n and n' are the same or different and also physiologically tolerable salts other than pyridine-2,4-dicarboxylic acid N, N'-bis- (2-methoxyethyl) diamide and pyridine-2,4-dicarboxylic acid N, N'-bis - (2-hydroxyethyl) -diamide satisfy the previously formulated task ·

Compared with the compounds described in German Patent Application DE-A 37 03 959, pyridine-2,4-dicarboxylic acid N, N'-bis4 (2-methoxyethyl) -diamide and pyridine-2,4-dicarboxylic acid N, N'-bis- (3 -isopropoxypropyl) -diamide, the compounds of formula 1 exhibit both improved pharmacological activity and better enteral absorption.

Further, the invention includes pyridine-2,4-dicarboxylic acid N, N'-bis (alkoxyalkyl) -diamide of formula 1:

CONH- (R ¹ ) - (OR ² ) n

(1) wherein R is linear or branched C _x -C ₄ alkanediyl;

R is unsubstituted C ₂ -C ₄ alkyl or hydrogen n-1 or 2;

R ¹ , R ² , n 'have the same meanings as R', R ² , n, 1 1 '2 2', and R and R, R and R, n and n 'are the same or different except for pyridine. 2,4-Dicarboxylic acid N, N'-bis- (2-methoxyethyl) -diamide and pyridine-2,4-dicarboxylic acid N, N'-bis (2-hydroxyethyl) -diamide, characterized in that pyridine-2 , 4-Carboxylic acid halide anhydride reacts with alkoxyalkylamine or hydroxyalkylamine.

The invention also includes pyridine-2,4-dicarboxylic acid N, N'-bis (alkoxyalkyl) diamide of formula 1

CONH- (R ¹ ) - (OR ² ) n

J ^ CONH- (R ^r ) - (OR ² ') n' (1)

wherein R ¹ is linear or branched C ₄ alkanediyl;

R ² is unsubstituted C _x -C ₄ alkyl or hydrogen;

n is 1 or 2;

1/2 '12 R, R, n' have the same meanings as R, R, n; in addition, R ¹ and R ¹ , R ² and R ² , n and n 'are the same or different;

a method of obtaining which, in particular,

a)

a. Pyridine-2,4-dicarboxylic acid is mixed with at least two equivalents of a halogenating agent; and that

a. At least 2 equivalents of hydroxyalkylamine or alkoxyalkylamine of formula II or II '

H ₂ N - (R ¹ ) - (OR ² ) n (II)

H ₂ N - (R ¹ ') - (OR ² ') n '(II *),

1 'wherein R and R are linear or branched C _x to C ₄ alkanediyl;

2 '

R and R are unbranched C ₄ - C ₄ alkyl or hydrogen, n and n '- 1 or 2, i' 2 2 '

R and R, R and R, as well as n and n 'being the same or different, while II and II' being different, dissolve in a solvent; and that the solution prepared according to (1 a) is then reacted with a solution prepared according to 2 a. way, or that

b) The N, N'-bis (alkoxyalkyl) -diamide of the pyridine-2,4-dicarboxylic acid thus obtained is converted into the bis (hydroxyalkyl) - compound; or that

c) Obtained according to 1 a. the method of reacting the pyridine-2,4-dicarboxylic acid halide anhydride with a substituted or unsubstituted benzyl alcohol to give a benzyl ester of pyridine-2,4-dicarboxylic acid; the benzyl ester is selectively hydrolyzed at the 2-position of the pyridine; free carboxylic acid at position 2 according to 1 a. converting the process again to the acid halide anhydride and mixing the resulting compound in the presence of a compound of formula II 'with a solution prepared according to 2a. way; formation of the pyridine-2,4-dicarboxylic acid 2-amido-4-benzyl ester; and that the benzyl protecting group is then cleaved at the 4-position; free carboxylic acid according to 1 a. the process is again converted to the acid anhydride, which is then, in the presence of a compound of formula II, mixed with a solution prepared according to 2a. way; forming an unsymmetrically named compound of formula I; and converting the final compound of formula I to a physiologically tolerated salt thereof.

In the process for the preparation of compounds of formula I, the starting material is pyridine-2,4-dicarboxylic acid, which is commercially available, suspended in a solvent such as toluene and mixed at room temperature with a halogenating compound, usually chlorinating agent; such as SOC1 ₂ . Depending on the molar amount of pyridine-2, 4-dicarboxylic acid used, 2 to 3 equivalents of chlorinating agent are used, usually

2.5 eq. The resulting reaction mixture is heated to 90-110 ° C, usually 100 ° C, until gas evolution is observed and a clear solution is formed. Subsequently, 10% of the solution is evaporated, preferably under high vacuum (up to about 10 ³ Tor), and the resulting carboxylic acid anhydride is subjected to further reactions.

Depending on the molar amount of pyridine-2,4-dicarboxylic acid used, 2-4 equivalents of alkoxyalkylamine or hydroxyalkylamine (commercially available) are dissolved in a solvent such as toluene and added preferably.

2-4 times as many moles of alkali as triethylamine. The carboxylic anhydride reacts with alkoxyalkylamine or hydroxyalkylamine. The reaction is usually carried out by adding a solution of the indicated -alkylamine to the dissolved pyridine-2,4-dicarboxylic acid halide anhydride. Alternatively, a solution of the carboxylic acid halide anhydride may be added to the alkoxyalkylamine or hydroxyalkylamine solution. The drip is carried out at -5 ° C to 4-5 ° C, preferably at 0 ° C. Allows the reaction to proceed to completion; while the reaction mixture is warmed to room temperature and stirred for a further 2 to 5 hours, preferably 3 hours. The resulting product is then acidified to separate the unreacted hydroxy or alkoxyalkylamine from the final product. Acidification can be done, for example, with 0.2M citric acid. The organic layer is then separated and washed with water, then dried, preferably with magnesium sulfate, and finally the solvent is evaporated. Upon evaporation of the solvent, the product is precipitated as a white solid or an oil.

In order to obtain the N, N'-bis (hydroxyalkyl) diamides of pyridine-2,4-dicarboxylic acid, the corresponding bis (alkoxyalkyl) diamide, preferably bis (methoxyalkyl), is converted to the corresponding bis (hydroxyalkyl) diamide by methods known in the art, e.g. using boron tribromide.

The unsymmetrically substituted compounds of formula I may be synthesized, for example, by reaction of a pyridine-2,4-dicarboxylic acid halide anhydride, preferably chloro anhydride, with a substituted or unsubstituted benzyl alcohol to form a pyridine-2,4-dicarboxylic acid benzyl ester; followed by selective hydrolysis of the ester at the 2-position (using, for example, a copper catalyst, Acta Helv., 44, 1963,637), conversion of the free acid at the 2-position to a halide, by reaction with a compound of formula 11 'to give pyridine-2. , 4-dicarboxylic acid for 2-amide-4-benzyl ester, hydrolytic cleavage of the benzyl protecting group (e.g., using H ₂ / Pd, HoubenWeyl., Vol / vol (1980), 381-82) and the pyridine ring 4 of the free acid. conversion to the acid halide anhydride.

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

In this case the product can be purified by extraction or chromatography (eg silica gel). The isolated product can be recrystallized and converted into a physiologically tolerated salt using a suitable acid. Suitable acids include, for example, mineral acids, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, or organic - formic, acetic, propane, succinic, glycolic, lactic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, acidic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acids.

The compounds of Formula I may be used as active ingredients in pharmaceutical compositions where they are combined with a suitable pharmaceutical excipient (base). These compounds can be used in the preparation of pharmaceutical compositions in admixture with suitable organic or inorganic excipients for enteral, subcutaneous or parenteral administration such as water, gum arabic, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols. , petroleum jelly, etc

The pharmaceutical preparations may be in solid dosage form such as tablets, dragees, suppositories or capsules; in semi-solid form, eg in the form of lubricants; or in liquid form, such as in the form of solution suspensions or emulsions. In this case, they must be sterilized and / or contain auxiliaries such as preservatives, stabilizers, humectants or emulsifiers, salts for maintaining osmotic pressure or a buffer. They may also contain other substances with a therapeutic effect.

The compounds of formula I have been found to exhibit particularly good enteral absorption. Absorption capacity was studied in rats, which were administered intragastrically (via the gastrointestinal tract) by the compounds of the invention. Serum counts (serum mirror) fall within the first hours after administration and after approximately 5 hours. since the introduction of the compounds reaches only a slightly variable plateau. Very high serum levels at baseline suggest good absorption.

The invention is further illustrated by the following examples.

Example 1.

Pyridine-2,4-dicarboxylic acid bis-N, N '- (methoxypropyl) amide Dissolve g of pyridine-2,4-dicarboxylic acid in 50 ml of toluene and 1 ml of DMF and add 2.7 ml of thionyl chloride to the solution. The mixture is heated until no gas evolution is observed (about 2.5 hours). The mixture is then cooled, distilled with 5 ml of toluene and added dropwise

4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine. After stirring at room temperature for 4 hours, the solvent was evaporated and the residue was poured into water and extracted with methylene chloride several times. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated. The crude product is chromatographed on silica gel (solvent-ethyl acetate).

Yield 4.3 g; oil.

¹ H-NMR (CDCl ₃ ): δ, m. d = 1.6 - 2.3 (4H, m); 3.2-3.8 (14 H, 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-Ν, Ν - (ethoxypropyl) amide

See synthesis progress. In Example 1; amino-component acetoxypropylamine.

Yield: 4.5 g; melting point: 46-48 ° C;

¹ H-NMR (CDCl ₃ ): δ, md = 1.3 (6H, t); 1.7-2.1 (4 H, m); 3.33.8 (12 H, 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

See synthesis progress. In Example 1; amino component2-dimethoxyethylamine;

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

¹ H-NMR (CDCl ₃ ): δ, md = 3.4 (12H, s); 3.7 (4 H, m); 4.5 (2 H, m);

7.8-8.0 (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-methoxy-isopropyl) -amide

See synthesis progress. In Example 1; amino component2-methoxyisopropylamine.

Yield: 3.3 g (of pyridine-2,4-dicarboxylic acid);

oil.

¹ H-NMR (CDCl ₃ ):, md = 1.3 (6H, d); 3.2 (6H, s); 3.5 (4H, d);

4.4 (2 H, 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

See synthesis progress. In Example 1; amino-component acetoxyethylamine.

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

Melting point: 42-44 ° C.

¹ H-NMR (CDCl ₃ ): δ, md = 1.2 (3H, t); 3, 3-3.8 (12H, pd and m);

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, (3-hydroxyethyl) amide

Yield: 0.5 g of pyridine-2,4-dicarboxylic acid bis-Ν, (3-methoxyethyl) amide are dissolved in 10 ml of dichloromethane and boron tribromide (11 ml, 1M in dichloromethane) is added dropwise. After boron tribromide is added, the solution is allowed to warm to room temperature for 3 hours. stirring. The reaction mixture is then poured into 100 ml of a saturated bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated. The crude product is chromatographed on silica gel.

Yield: 0.45 g; oil.

¹ H-NMR (CDCl ₃ ): δ, m.'d = 1.5 - 2.2 (4H, m); 3.4 (4 H, m);

3.6 (4 H, m); 7.9-8.0 (1H, m); 8.4 - 8.5 (1H, m); 8.7-8.8 (1H, m).

Example 7a

The dibenzyl ester of pyridine-2,4-dicarboxylic acid is converted into g of pyridine-2,4-dicarboxylic acid with 30 ml of thionyl chloride in a manner analogous to that described in Example 1 to the acid halide, which is further reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl alcohol.

Yield: 42.1 g.

Melting point: 63-65 ° C.

Example 7b

Pyridine-2,4-dicarboxylic acid 4-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 (II) nitrate in 700 ml of methanol. Blend for 1 hour. refluxing; upon cooling, the copper complex is filtered off. The complex is suspended in dioxane and carbon disulfide is added. The precipitated copper sulphide is filtered off and the organic solvent is evaporated. The product is mixed with petroleum ether.

Yield: 2.53 g.

Melting point: 113-115 ° C.

Example 7c

Pyridine-2,4-dicarboxylic acid 2- (3-methoxypropyl) amido-4-benzyl ester

3.9 g of 4-benzyl ester of pyridine-2,4-dicarboxylic acid from Example 7b with 1.2 ml of thionium chloride as described in Example 1 are converted into the acid chloro-anhydride, followed by reaction with 3-methoxypropylamine to give the amide. The product is purified by chromatography on silica gel; solvent-cyclohexane-ethyl acetate (1: 1).

Yield: 4.3 g; oil.

Example 7d

Pyridine-2,4-dicarboxylic acid 2- (3-methoxypropyl) amide

4.3 g of the compound from Example 7c are dissolved in 100 ml of dioxane and hydrogenated with 500 mg of 10% Pd / C catalyst for 4 hours at normal pressure. When hydrogen ceases to adsorb, the mixture is removed from the catalyst and the solvent is evaporated.

Yield: 3.5g.

Melting point: 124-126 ° C.

Example 7e

Pyridine-2,4-dicarboxylic acid 2- (3-methoxypropyl) -4 (2-methoxyethyl) diamide

1.8 g of the compound from Example 7d with 0.6 ml of thionyl chloride is converted into the acid chloro anhydride (as described in Example 1), which is further reacted with 2-methoxyethylamine. The product is purified by chromatography on silica gel; solvent-dichloromethane-methanol mixture 20: 1.

Yield: 1.0 g; oil.

¹ H-NMR (CDCl ₃ ): δ, md = 1.90 - 2.0 (2H, pd); 3.4 (6H, s); 3.53.7 (8 H, m); 6.9 (1H, ps); 8.0 (1H, dd); 8.4 (1H, ps);

8.55 (1H, s); 8.7 (1H, d).

Example 8

Pyridine-2,4-dicarboxylic acid 2- (2-methoxyethyl) -4- (3-methoxypropyl) diamide

As in Examples 7a-e, Example 8c gives 2-methoxyethylamine in Example 7c and 3-methoxypropylamine in Example 7e.

Melting point: 69-72 ° C.

¹ H-NMR (CDCl ₃ ): δ, m. d = 1.9 - 2.0 (2H, pd); 3.4 (3H, s);

3.45 (3 H, s); 3. 6-3.7 (8H, m); 7.4 (1H, ps); 7.9 (1H, dd);

8.3 (1H, ps); 8.4 (1H, d); 8.7 (1H, d).

Example 9

Enteral intake

Female rats weighing approximately 150 g are intraperitoneally injected with 50 mg / k g of the test substance. After 5, 10, 15, 30, 60, 120, 180, 240 minutes, 4 rats are euthanized and blood is drawn from a vein (Vena Cava). The blood is immediately centrifuged and the administered compound is extracted from the serum with ether. After evaporation of the ether, the residue is dissolved in 100 ml of a liquid (carrier liquid) which is a mixture of 0.05 M phosphoric acid and acetonitrile (4: 1). From this purity, 50 μΐ is applied to an HPLC column. Detection occurs in the UV region at 200 nm with persistence

2.2 min.

The results are shown in Table I.

Table I

The serum ro-

dicks, way) after administration of 50 mg / kg dose (introduction by oral route Time Material from 1 example Material from Example 2 Material from Example 3 I II III IV X ± SD X ± SD X ± SD 5 45.3 ± 15.4 51.4 ± 11.2 8.9 ± 3.1 10th 49.8 ± 3.6 59.2 ± 4.0 11.5 ± 0.6 15th 39.9 ± 11.0 29.4 ± 6.7 14.7 ± 1.9 30th 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 <NR 3.5 ± 0.9 180 <NR <NR 2.9 ± 0.5 240 <NR <NR 1.7 ± 0.4

In Table I:

I - time, min.

II - Material from Example 1

III - Material from Example 2

IV - Material from Example 3

X is the average of 4 measurements

SD - standard deviation <NR - below detection limit

Example 10

Pharmacological efficacy

In order to demonstrate that the compounds of the invention were effective in inhibiting the action of proline and lysine hydroxylases, the liver hydroxyproline and serum γ- (IV) -collagen concentrations were measured as follows:

(a) rats which did not receive test compounds (controls);

(b) rats given carbon tetrachloride (CC1 ₄ - control);

c) the rats were first brought to CC1 ₄ and then the compounds of the invention;

(These research methods are described in Ruiler: Rouiller C., Experimental Toxic Injury of the Liver: In The Liver, C. Rouiller, Vol. 2, pp. 935-976, New Yourk, Akademic Press, 1964).

The invention provides efficacy of the compounds described hydroxyproline synthesis in the liver and 7S- (IV) -kolageno fusion serum braking percentage introduction of these compounds orally, as compared to control animals which introduced only of carbon tetrachloride (CC1 ₄ controls). The results are shown in Table 2. The table also shows the compounds of Example 2 and 3 of the German Patent Application DE-A 37 03 959 for comparison, N, N'-bis (2-methoxyethyl) -diamide and N, N'-bis-pyridine-2,4-dicarboxylic acid. (3-isopropoxypropyl) diamide. The compounds of the present invention unexpectedly showed greater efficacy even when administered orally than the compound of Example 2 of DE-A 37 03 959, VFR.

Introduced subcutaneously.

table

Material from e.g. The dose Liver Hydroxyproline (Stopping)% Serum 7S- (IV) Collagen (stop)% Introduction I II III IV V 1 2x2mg 62 28th oral 2x10mg 90 67 Tl 2 2x2mg 25th 2 H 2x10mg 60 35 H 2 2x25mg 55 48 under the skin (FROM DE-A 37 03 959) 3 2x25mg 49 11th under the skin

(from DE-A 37 03 959)

Claims (17)

DEFINITION OF INVENTION 1. N, N-bis- (alkoxyalkyl) diamides of pyridine-2,4-dicarboxylic acid of formula I CONH- (R ^x ) - (OR ^z ) n wherein R ¹ is linear or branched C ₁ -C ₄ alkyl; R ² is unbranched C 1 -C 6 alkyl or hydrogen; n is 1 or 2; R ¹ ', R ² , n' have the same meanings as R ¹ , R ² , n, in addition R ¹ and R ¹ , R ² and R ² , n and n 'are the same or different except for pyridine A process for the preparation of -2,4-dicarboxylic acid N, N '- (2-methoxyethyl) diamide and pyridine-2,4-dicarboxylic acid N, N'-bis (2-hydroxyethyl) diamine, wherein pyridine-2,4 halogen anhydride of dicarboxylic acid reacts with alkoxyalkylamine or hydroxyalkylamine. 2. Pyridine-2,4-dicarboxylic acid N, N'-bis (alkoxyalkyl) diamides of formula I CONH- (R ¹ ) - (OR ² ) n (I) wherein R ¹ is linear or branched C 1 -C 4 alkyl; R ² is unbranched C 1 -C ₄ alkyl or hydrogen; n is 1 or 2; R ¹ , R ² , n 'have the same meanings as R ¹ , R ² , n, 1 1' 2 2 ', and R and R, R and R, n and n' are the same or different. a way that differs in that a) la. pyridine-2,4-dicarboxylic acid is mixed with at least two equivalents of the halogenating compound, and 2a. at least 2 equivalents of hydroxylamine or alkoxyalkylamine of formula II or II ' H ₂ N - (R ¹ ) - (OR ² ) n (II) H ₂ N- (R ¹ ') - (OR ² ') n '(II') wherein R ¹ and R ¹ are linear or branched C ₁ -C ₄ alkanediyl; 2 2 ' R and R are unsubstituted C ₁ -C ₄ alkyl or hydrogen; n and n 'are 1 or 2, 1 1 '2 · 2' R and R, R and R, n and n 'are the same or different, but compounds II and II' are different, are dissolved in a solvent and the solution prepared according to la is reacted with the solution prepared according to 2a or b) converting the N, N'-bis (alkoxyalkyl) diamide of the pyridine-2,4-dicarboxylic acid thus obtained into a bis (hydroxyalkyl) compound, or c) reacting the pyridine-2,4-dicarboxylic acid halide anhydride obtained with method la with benzyl alcohol, substituted or unsubstituted, to form the benzyl ester of pyridine-2,4-dicarboxylic acid; the benzyl ester is selectively hydrolyzed at the 2-position of the pyridine ring; according to method la, the free carboxyl group at the 2-position is converted again into the acid halide anhydride and the resulting compound, after addition of a compound of formula II ', mixed with the solution prepared according to method 2a to give pyridine-2,4-dicarboxylic acid 2-amido 4-benzyl ester; and that the benzyl protecting group is then cleaved at the 4-position by hydrogenation; converting the free carboxyl group according to Method la into an acid chloro anhydride which is then mixed with the solution prepared according to Method 2a after the addition of a compound of formula II; the asymmetrically substituted compound of formula I is formed and, if necessary, converted to its physiologically acceptable salt. 3. A process according to claim 1 or 2, wherein in formula I, R and R, R and R, n and n 'have the same meanings, depending on the circumstances. 4. Process according to claim 1 or 2, characterized in that in formula I the substituents - (R ¹ ) - (OR ² ) n and - (R ¹ ) - (OR ² ) n 'are different. 5. A process according to claim 1 or 2, wherein R ¹ represents straight-chain or branched C ₁ -C ₂ alkyl or hydrogen. 6. A process according to claim 1 or 2, wherein the compound is of formula CONH-CH ₂ -CH ₂ -O-CH ₃ CONH-CH2-CH2-CH2-OCH3 as well as physiologically acceptable salts of this compound. 7. The process according to claim 1 or claim 2, characterized in that a compound of the formula -CONH-CH ₂ - CH ₂ -CH ₂ -O-C ₂ H ₅ CONH-CH2- CIT ₂ -CII2 -O-C2H5 as well as its physiologically acceptable salts. 8. The process of claim 1 or 2, wherein the compound is of formula 0-CII3 co-nh-ch ₂ -ch ₂ ^ -. O-cii ₃ ^ o-ch ₃ -ęO-NII-CIL-CH n '^ -O-CH _3, as well as the following compound, physiologically acceptable salts thereof. 9. The process of claim 1 or 2 wherein the compound is of formula CH ₃ I CONH-CH-CH ₂ -OCH ₃ conh-ch-ch ₂ -o ch ₃ ch ₃ as well as physiologically acceptable salts of this compound. 10. A process according to claim 1 or 2, wherein the compound is of formula CONH-CH ₂ -CH ₂ -OC ₂ H ₅ ^ CONII-CH ₂ -CH ₂ -OC ₂ H ₅ 11. A process according to claim 1 or 2, wherein the compound is of formula 0CONH- CH ₂ - CH ₂ CH ₂ OH / CH ₂ CONH - CH ₂ - CH ₂ -OH, N as well as the following compound, physiologically acceptable salts thereof. 12. The process of claim 1 or 2, wherein the compound is of formula CONH-CHz -ch ₂ -och ₃ CONH- (CH ₂ ) ₃ -OCII ₃ as well as physiologically acceptable salts of this compound. 13. The process of claim 1 or 2, wherein the compound is of formula CONH (R ^l) - (OR ²⁾ n ^ ll ^ J -CONH- (R ^r) - (OR ² ') n' n as well as the following compound, physiologically acceptable salts thereof. Pharmaceutical composition, characterized in that it comprises a compound of formula I, which can be obtained according to one of claims 1 to 13 and / or one of the physiologically acceptable salts of this compound with a pharmaceutically acceptable excipient. Compounds of formula I, which may be obtained according to one of claims 1 to 13 and / or one of their physiologically acceptable salts, for use in affecting the biosynthesis of collagen and similar substances or proline hydroxylase. Compounds of formula I, which may be obtained according to one of claims 1 to 13 and / or one of their physiologically acceptable salts, for use in the prevention of disorders of collagen and similar substances or lysine hydroxylase biosynthesis. 17. A process for the preparation of a medicament for the biosynthesis of collagen and similar substances, which comprises mixing a compound of formula I which can be obtained according to one of claims 113 and / or a physiologically acceptable salt thereof with pharmaceutically acceptable organic or inorganic fillers.