LT3918B - 2,4- and 2,5- substituted pyridin-n-oxides, methods for the production thereof, pharmaceutical compositions and preparation the same - Google Patents

Abstract

2,4- and 2,5-substituted pyridine N-oxides which have fibrosuppressive and immunosuppressive activity are presented. The said compounds are likewise suitable for the treatment of disturbances of the metabolism of collagen and collagen-like substances and of the biosynthesis of C1q.

Description

The present invention relates to 2,4- or 2,5-substituted pyridine-N-oxides, processes for their preparation, as well as to pharmaceutical compositions containing these compounds and processes for their preparation.

The proposed compounds have valuable pharmacological properties.

Compounds that inhibit the activity of the enzymes proline and lysine carboxylases selectively inhibit collagen synthesis by acting on hydroxylation reactions. During these reactions, the protein-bound proline or lysine is hydroxylated with the aid of the enzyme proline or lysine hydroxylases. Inhibition of the reaction results in the formation of an incompletely hydroxylated collagen molecule that can be delivered in small quantities by the cells to the extracellular milieu. In addition, incompletely hydroxylated collagen cannot be incorporated into the collagen matrix and is very readily proteolytically cleaved. These processes reduce the total amount of collagen accumulated in the extracellular environment.

Therefore, agents suitable for the inhibition of proline hydroxylase are used in the treatment of diseases in which the disease predisposes to collagen accumulation. Such diseases include, but are not limited to, fibrosis of the lungs, liver and skin (scleroderma), as well as atherosclerosis.

Inhibitors that inhibit the action of proline hydroxylase, such as ip, Λ-dipyridyl, are known to inhibit the Clg biosynthesis of macrophages (W. Muller et al., FEBS Lett., 90, 218 (1978); Imir.unobiology, 158, 47). (1978)). This departs from the classical course of complement activation. For this reason, proline hydroxylase inhibitors work in the same way as immunodepressants, for example in immune complex disorders.

The action of proline hydroxylase is known to be effectively inhibited by pyridine-2,4- or -2,5-dicarboxylic acids (K. Majamaa et al., Eur. J. Biochem., 138, 239-245 (1984)). Incidentally, these compounds are effective inhibitors in cell culture only at very high concentrations (Tschank G. et al., Biochem.

J. 238: 625-633 (1987).

DE patent no. A 3432094 discloses pyridine-2,4- and -2,5-di-carboxylic acid esters having 1 to 6 C-atoms in the alkyl moiety as agents for inhibiting the action of proline and lysine hydroxylases.

However, these low C-atom esters have the disadvantage that they are very rapidly degraded to acids in the body, and higher concentrations are no longer available to the cells, making them unsuitable in some cases as a drug.

DE Pat. A 3703959, 3703962 and 3703963 jointly disclose mixed amidoesters, high C-numbered pyridine-2,4- or -2,5-dicarboxylic acid diesters and diamides which effectively inhibit collagen biosynthesis in animal experiments. For example, DE patent no. A 3703959 discloses, among other things, the synthesis of N, N'-bis- (2-methoxyethyl) diamide of pyridine-2,4-dicarboxylic acid and β, Ν'-bis (3-isopropoxypropyl) diamide of pyridine-2,4-dicarboxylic acid.

DE patent applications no. P 382 6471.4 and P 383 8140.6 propose an improved process for the preparation of pyridine-2,4-dicarboxylic acid N, N'-bis (2-methoxyethyl) diamide.

DE patent application no. Novel diamines of pyridine-2,4-dicarboxylic acid N, N'-bis (α1-coxyalkyl) are proposed in P 392 4093.2.

DE patent application no. P 4001002.3 describes the use of pyridine-2,4- and -2,5-dicarboxylic acid (nitroxyalkyl) amides for the preparation of medicaments that inhibit the action of proline and lysine hydroxylase.

Both pyridine-2,4- or -2,5-dicarboxylic acid amides are known as anti-tuberculosis drugs (Hirakat et al.,

J. Pharm. Soc. Japan, ΊΊ, 219 (1957) and Haring et al., Helv. Chim. Acta, 37, 147-153 (1954)), as well as pyridine-2,4- and -2,5-dicarboxylic acid dihydrazides (Itai et al., BL.Nation. Hyg. Labor. Tokyo, 74, 115 (1957)). 117 and Shinohara et al., Chem. High Polymers Japan, 1958, 839).

Japanese patent no. 53/28175 (78/28175) discloses pyridine-2,4- or -2,5-dicarboxylic acid N, N'-bis (2-nitroxyethyl) diamides as substances having vasodilatory activity.

Unexpectedly, 2,4- or 2,5-substituted pyridine-N-oxides (their general formula I below), as well as their physiologically acceptable salts, were found to be effective in inhibiting lysine and proline hydroxylases in animal experiments.

The invention includes 2,4- or 2,5-substituted pyridine N-oxides of the general formula I, respectively:

And where:

3 '

R is -C (O) -XR a group where X is O or N (R) -gru3 PE, and R is hydrogen, C? -C? -Alkyl, ^C 2 ~ ^c ~ i2 ^{enllas al} ^, alkynyl, may also be benzanelated C 1 -C 4 -cycloalkyl, aryl, or heteroaryl, wherein the specified R moieties are unsubstituted or mono- or polysubstituted or substituted

R, and R is halogen, hydroxyl group, cyano, nitro, nitroksigrupė, amino, carboxyl, C 2 ^_ C ^ alkoxy, C₁-C₄ -aikoksikarbonilas, C₁-C₄ alkyl- or -dialkilaminogrupė, indolyl or phenyl wherein the indolyl and phenyl groups are unsubstituted or substituted by one, two or three substituents such as halogen, nitro, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, where they may be the same in the case of several substituents; different, or

R ^J , when X is -N (R ^J ) -, is a -N (R) (R) moiety, wherein R 4 and R 6 are the same or different and are hydrogen, C 1 -C 4 alkyl; C 1 -C 6 -alkylcarbonyl or phenyl, and

3 '3 33'

R is as R, wherein R and R are the same or

3 '. .

different, or R and R together with the nitrogen atom to which they are attached form a residue of formula II:

-N

A) ch /) (II) where n is from 1 to 3 and A is O, S, CH? or -N (R) - wherein R is hydrogen, phenyl, C₁-C₆-alkyl, C2-Cg alkenyl, or C2 ^- Cg alkynyl; in addition, these residues are unsubstituted or mono- or polysubstituted or selected from the group consisting of halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or

8th

-N (R) ₂ 'wherein R is hydrogen or C 1 -C 4 alkyl, or g

-COOR, or

-CON (R ⁹ ) 2 or CONHR ⁷ , wherein R ⁹ is the same as R ⁸ , or (R ⁹ ) 2 is a C ₄ -C ₆ alkylene chain unsubstituted in either CH ₂ group, or one CH ₂ group not present in g

adjacent to a nitrogen atom substituted with an O, S, or N-R residue, or

R ⁷ is C 1 -C 6 -alkoxycarbonyl or C 1 -C 4 -cycloalkyl, and wherein

112.

R is the same as R and the residues R and R are the same or different, -. . . or R is in the 4-position only and the 5-position is one

4

R or R;

the invention also encompasses physiologically acceptable salts1. Except for compounds of the general formula I in which R and R are the same or different and are a carboxyl group, its methyl or ethyl esters and also diamides.

The invention further encompasses the use of compounds of general formula I, as well as their physiologically acceptable salts, in the manufacture of a medicament for inhibiting proline and lysine hydroxylases.

The invention also encompasses the use of compounds of formula Z in medicaments; in particular, the invention encompasses the use of compounds of formula I as fibrosodepressants and immunodepressants, as well as as inhibitors of proline and lysine hydroxylases and as agents for the exchange of collagen and collagen-like substances, or for Clg biosynthesis.

All of the above alkyl residues having a C number greater than 2 can be both straight and branched chains.

The invention further provides a process for the preparation of compounds of general formula I.

The compounds of the invention are most readily obtained by the addition of oxidizing agents such as hydrogen peroxide or acid such as peracetic, perfluoroacetic, perbenzoic or metachloroperbenzoic acids in solvents such as chlorinated hydrocarbons such as methylene chloride, chloroform, tri- or tetrachloro to oxidizable pyridine compounds which may also be solubilized from the above solvents, and stirring the mixture at -30 ° C to +40 ° C, preferably 0 ° C to +20 ° C, at temperatures ranging from 30 minutes to 3 days. The end of the reaction can be determined, for example, by thin layer chromatography. The compounds of the invention are preferably synthesized using equimolar amounts of pyridine and oxidant, or up to about 5 times the excess oxidant.

The excess acid may be removed in some cases, for example by allowing gaseous ammonia in the reaction solution and separating the resulting precipitate by filtration.

In some cases, the product may be extracted or chromatographed, for example, silica gel chromatography. The isolated product can be recrystallized.

The general principles of this method are described, for example, in E. Lindsberg, Pyridine and its Derivatives, Interscience Publishers, New York, 1961, Part 2, p. 93.

A method of oxidation with hydrogen peroxide is described, for example, in E. Ochiai, J. Org. Chem., 18, 534 (1953).

The various pyridine derivatives required to carry out the described oxidation can be obtained from the claimed patents, which describe the achievements in the art. Reference is made to the following DE patent applications: P 3826471.4,

3828140.6, 3924093.2, 4001002.3, as well as DE Pat.

A 3703959, 3703962 and 3703963.

The compounds of the formula I according to the invention possess valuable pharmacological properties, namely they are effective inhibitors of proline and lysine hydroxylases, as well as fibrosodepressants, immunodepressants and anti-atherosclerotic agents.

The antifibrotic effect can be determined using a carbon tetrachloride-induced liver fibrosis model. For this purpose, rats are treated twice a week with CCl ^ il ml / kg) dissolved in olive oil. A solution of the test substance in a solvent suitable for the organism is administered throat or stomach twice daily. The degree of liver fibrosis is determined histologically and the amount of collagen in the liver is analyzed by oxyproline according to Kivirikko et al. Biochem., 19, 249f (1967). The activity of fibrogenesis can be controlled by detecting collagen fragments and procoaglagic peptides in serum by radioimmunoassay. The compounds of the present invention, when used in this model, are active at concentrations ranging from 1 to 100 mg / kg.

The activity of fibrogenesis can be controlled by radioimmunoassay of the N-terminal propeptide of type III collagen or the N- or C-terminal domains of type IV collagen cross-linked (7S-collagen or type IV-collagen-NC ^) in serum.

To this end, concentrations of oxyproline, proco-collagen-III-peptide, 7S-collagen and type IV-collagen-NC4 are measured.

(a) rats untreated with carbon tetrachloride (control),

(b) rats given carbon tetrachloride (CCl4-control),

c) rats which were initially exposed to CCl2 and subsequently to a liver compound of the invention. (This method of control is described by Rovililer, C., Experimental 'Toxic Injury of the Liver; In The Liver; C. Roviller, Vol. 2, p.

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

Another model for assessing antimicrobial activity is pulmonary fibrosis induced by bleomycin, according to Kelley et al., J. Lab. Clin. Med., 96, 954 (1986). A cotton swab granuloma model according to the method described by Meier et al., Experiment, 6, 469 (1950) may be used to determine the effect of the compounds of the invention on granulation tissue. The invention is further illustrated by the following examples.

The compounds of the formula I as pharmaceuticals may be used in the form of pharmaceutical preparations containing these compounds, if appropriate together with pharmaceutically acceptable carriers. These compounds may be used as medicaments, for example, in the form of pharmaceutical preparations containing these compounds, in admixture with pharmaceutical organic or inorganic excipients, in a form suitable for administration to the body, e.g., by stomach, transdermally, or parenterally, e.g. water, gum arabic, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycols, petroleum jelly, etc.

For this purpose, they may be administered orally at a dosage of 0.1 to 25 mg / kg / day, preferably 1 to 5 mg / kg / day, or non-gastrointestinal 0.01 to 5 mg / kg / day, preferably 0.01 to 2.5 mg / kg / day, in doses. In severe cases, the dose may be increased. However, in many cases lower doses are sufficient. These doses are for an adult weighing about 75 kg.

The present invention further encompasses the use of the present compounds in the manufacture of a medicament for the treatment and prevention of the aforementioned metabolic disorders.

Another object of the invention are pharmaceutical compositions comprising one or more compounds of formula I and / or their physiologically acceptable salts.

Methods well known to those skilled in the art are used for the preparation of the medicaments. The drugs used are either the pharmacologically active compounds themselves (active ingredient) or, preferably, these compounds together with pharmaceutically acceptable excipients or excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions containing up to 95% of the active ingredients. 10 to 75%.

Suitable excipients or excipients for the desired formulation, in addition to solvents, gel-forming agents, suppository bases, tablet excipients and other excipients, together with the active ingredients are, for example, antioxidants, dispersants, emulsifiers, anti-foaming agents, flavoring agents, preservatives. , dissolving additives or paints.

The active ingredients may be administered orally, bypassing the digestive tract or directly into the intestine.

The active ingredient is admixed with suitable additives such as fillers, stabilizers or inert diluents, and the usual forms are prepared in the form of tablets, dragees, capsules, suspensions in a water-alcohol mixture or in oil or in solutions in water or oil.

Inert excipients include, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular maize starch. Mixtures can be prepared by both dry and wet granulation. Oil-type fillers or solvents may be, for example, vegetable or animal oils, such as sunflower oil or fish oil.

The active ingredient for subcutaneous or intravenous injection may, if desired, be mixed with suitable excipients such as solvents, emulsifiers or other excipients to form a solution, suspension or emulsion. Solvents may be, for example, saline or alcohols, such as ethanol, propanol, glycerol, as well as solutions of sugars, such as glucose or mannitol, or mixtures of the various solvents mentioned.

The invention is further illustrated by the following examples.

General methodology for compound synthesis

One equivalent of the pyridine derivative (see description) is dissolved in methylene chloride and one equivalent of m-chloroperbenzoic acid (MCPBR) dissolved in methylene chloride is added dropwise at room temperature. Stir at room temperature for some time; when the reaction is complete, gaseous ammonia is added to the mixture under ice-cooling until the precipitate ceases to settle. The precipitate is filtered off, the filtrate is dried over magnesium sulfate and the solvent is evaporated.

The crude product is recrystallized or purified by thin layer chromatography.

The following compounds were prepared according to the following general procedure.

Example Pyridine-2,4-dicarboxylic acid di-N, N '- (2-methoxyethyl) amide N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid N, N '- (2-methoxyethyl) amide and 0.62 g of MCPBR (procedure described above).

Yield: 620 mg (chromatography: ethyl acetate / methanol)

5 / i).

Lyd. mp: 102 ° C.

example

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

N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid di-N, N '- (3-methoxypropyl) amide and 1.2 g of MCPBR.

Yield: 0.58 g (recrystallization: ethanol)

Lyd. mp: 90 ° C.

example

Pyridine-2,4-dicarboxylic acid diamide N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid diamide and 1.2 g

MCPBR.

yield: 0.8 g (recrystallization: ethanol).

Mp: 260 ° C.

example

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

N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid N, N '- (2-dimethoxyethyl) amide and 1.1 g of MCPBR.

Yield: 0.5 g (chromatography: ethyl acetate / methanol 5/1). Lyd. mp: 86 ° C.

example

Pyridine-2,4-dicarboxylic acid di-N, N '- (3-ethoxypropyl) amide

N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid di-N, N '- (3-ethoxypropyl) amide and 1.5 g of MCPBR.

Yield: 0.34 g (chromatography: ethyl acetate / methanol 5/1) m.p. mp: 81 ° C.

example

Pyridine-2,5-dicarboxylic acid di-N, N '- (2-methoxyethyl) amide

N-oxide

From 1 g of pyridine-2,5-dicarboxylic acid di-N, N '- (2-methoxyethyl) amide and 1.3 g of MCPBR.

Yield: 0.4 g (recrystallization: ethanol).

Lyd. 137 ° C.

example

Pyridine-2,4-dicarboxylic acid di- (2-methoxyethyl) ester N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid di- (2-methoxyethyl) ester and 1.3 g of MCPBR.

Yield: 0.2 g (chromatography: ethyl acetate).

Lyd. temp .: oil.

example

Pyridine-2,5-dicarboxylic acid di-N, N'-ethylamide N-oxide

From 1 g of pyridine-2,5-dicarboxylic acid N, N'-diethylamide and

1.8 g MCPBR.

Yield: 0.4 g (recrystallization: ethanol).

Lyd. mp: 128 ° C.

example

Pyridine-2,5-dicarboxylic acid di-N, N '- (3-methoxypropyl) amide

N-oxide

From 1 g of pyridine-2,5-dicarboxylic acid N, N '- (3-methoxypropyl) amide and 1.2 g of MCPBR.

Yield: 0.3 g (recrystallization: diethyl ether / methanol). Lyd. mp: 128 ° C.

example

2,4-Di / (morpholin-1-yl) carbonyl / pyridine N-oxide

From 1 g of 2,4-di / (morpholin-1-yl) carbonyl / pyridine and 1.2 g

MCPBR.

Yield: 0.5 g (chromatography: ethyl acetate / methanol 5/1) m.p. temp .: oil.

example

Pyridine-2,4-dicarboxylic acid di-N, N '- (4-hydroxybutyl) amide

N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid di-N, N '- (4-hydroxybutyl) amide and 0.8 g of MCPBR.

Yield: 0.82 g recrystallization: ethanol)

Lyd. mp: 88 ° C.

example

Pyridine-2,4-dicarboxylic acid dicyclohexylamide N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid dicyclohexylamide and 0.75 g of MCPBR.

Yield: 0.59 g (ethanol).

Lyd. mp: 153 ° C.

example

Pyridine-2,4-dicarboxylic acid di- (3-chlorobenzyl) amide N-oxide From 1 g of pyridine-2,4-dicarboxylic acid di- (3-chlorobenzyl) amide and 0.65 g of MCPBR.

Yield: 0.75 g (toluene).

Melting point: 112 ° C.

example

Pyridine-2,4-dicarboxylic acid di- (4-methylbenzyl) amide N-oxide From 1 g of pyridine-2,4-dicarboxylic acid di- (4-methylbenzyl) amide and 1.2 g of MCPBR.

Yield: 0.72 g (toluene).

Lyd. mp: 153 ° C.

example

Pyridine-2,4-dicarboxylic acid di- (4-chlorobutyl) ester N-oxide 1 g of pyridine-2,4-dicarboxylic acid di- (4-chlorobutyl) ester and 0.75 g of MCPBR.

Yield: 0.83 g (ethanol).

Lyd. mp: 98 ° C.

example

Pyridine-2,4-dicarboxylic acid dicyclohexylester N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid dicyclohexylester and 0.75 g of MCPBR.

Yield: 0.87 g.

Oil, MS = 348 (M + H), molecular weight 347.

example

Pyridine-2,4-dicarboxylic acid di- (methoxycarbonylmethyl) ester

N-oxide

From 1 g of pyridine-2,4-dicarboxylic acid di- (methoxycarbonyl15 methyl) ester and 1.1 g of MCPBR.

Yield: 0.81 g.

Oil, MS = 328 (M + H), MW 327.

example

Pharmacological effects

To demonstrate that the compounds of the invention effectively inhibit the action of proline and lysine hydroxylases, concentrations of bilirubin, bile acids and gamma QT were measured.

(a) unaffected rats (control),

(b) rats exposed to CCl ^, and

c) in the serum of rats to which CCl4 was first administered and then the compound of the invention. (This method is described in Roviller, C., Experimental Toxic Injury of the Liver; In The Liver, C. Roviller, vol.2, pp. 335-476, New York, Academic Press, 1964).

The results are given in Table 1.

table

Effect of Proline Hydroxylase Inhibitors on CCl ^ -induced Rat Liver Fibrosis

Processing the feeling - · Dose in mg / kg N Bilirubin Bile acids / <M Gamma — QT V / L control - 5 1.76 + 0.27 26 ± 6.8 2 ± 0.5 CC1 ₄ - 22nd 4.98 + 1.06 81 to 8.7 5.3 ± 1.4 Figure 1 20th 12th 6.30 + 5.4 97 + 76 4.3 + 3.1 (0) (0) (27) Figure 2 20th 11th 2.90 + 0.94 * 71 + 42 3.3 + 2.2 (65) (18) (59)

The results in the table are: mean + standard deviation; * p <0.05 compared with CCl ^ treated animals. The numbers in parentheses show a percentage improvement over CCl ^ treated animals.

daily dose, administered through the throat.

summed up

Claims (9)

definition of the invention A 2,4- or 2,5-substituted pyridine N-oxide of formula I (I) wherein: R ^x is a group -C (O) -XR wherein 3 ' X is O or -N (R), and 3 R is hydrogen, C? -C - ^ - alkyl, C ₂ -C ^ ₂ alkenyl, C ₂ ~ ₂ C ^ -alkynyl, can also be benzanelintas C₁-cycloalkyl, 3. . aryl, or heteroaryl; the aforesaid R radicals are unsubstituted or have one or more identical or different R substituents ₍ where R is halogen, hydroxy, cyano, nitro, nitro, amino, carboxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkyl or -dialkylamino, indolyl or phenyl wherein it may be one, two or three substituents, such as halogen, nitro, C 1 -C 4 -C 4 alkyl or -alkoxy, where they may be the same or different in the presence of several substituents, or R 'in case X is present 3 of -N {R ;, is a residue -N (R ⁵ ) (R ⁶ ) in which R ⁸ and R ⁸ are the same or different and are hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyl or phenyl, and 3 ' R is the same, different, or 3 3 ' R and R together form a residue which 3 3 3 'as R and R and R are the same or the nitrogen atom to which they are attached has the formula II: / - \ (II); -NA) cH ₂ ^Z ) _n wherein n is from 1 to 3, and A is O, S, CH ₂ or -N (R) -, wherein 7 R is hydrogen, phenyl, C 1 -C 6 alkyl, C 1 -C 8 alkenyl or C 1 -C 8 alkynyl, said substituents being unsubstituted or substituted by phenyl which may in turn be substituted by one or more substituents such as halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or -N (R ⁸ ) ₂ where θ R is hydrogen or C 1 -C 6 -alkyl, or -COOR ⁸ or -CON (R ⁹ ) ₂ or CONHR ⁷ , where 9 8 9 R is the same as R, or (R) ₂ is a C 1 -C 6 -cyclic chain which is unsubstituted in any CH ₂ group or one CH ₂ group which is not adjacent to a nitrogen atom is substituted with 0, S or -NR ⁸ residue, or R? is C 1-4 C 1-4 alkoxycarbonyl or C 1-4 C 1-4 cycloalkyl, and wherein 9 112 R is the same as R and the residues R and R are the same or different, 2 3 or R is present only at the 4-position and 5-position is one of the residues R or R and their physiologically acceptable salts, except for compounds of the formula I in which R and R are the same or different and are carboxyl, methyl and ethyl ester as well as its diethylamides, the process of which is carried out by carrying out an exchange reaction between (a) for a compound of formula III: And wherein Y is a halogen, a hydroxyl group or an alkoxy group, and a compound of formula IV: H-X-R ³ (IV), 3 - -. .v wherein X and R have the meanings given above or carry out an exchange reaction between (b) for a compound of formula V: O Y (V) wherein Y is halogen, a hydroxyl group or an alkoxy group, and a compound of formula VI: HXR ³ (VI) wherein X and R have the meanings indicated above, optionally introducing another substituent on the side chain R and converting the compounds so obtained into N-oxides and, if necessary, converting the resulting compound into a physiologically acceptable salt thereof. 2. 2,4- or 2,5-substituted Pyridine N-oxides of Formula I: R ² (D> k V- * ¹ Kuriojeο where: 1 3 R is a -C (O) -X-R group in which the 3 ' X is O or N (R), while R is hydrogen, C₁-C₆-alkyl, C2-Cg alkenyl, ^ 2 ~ ^C 6 ^_ -alkynyl, C 1 -C 4 -cycloalkyl, aryl or heteroaryl, wherein the 3 R residues indicated are unsubstituted or one or two 4 identical or different substituents R R is halogen, hydroxy, cyano, amino, carboxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkyl or -dialkylamino or unsubstituted phenyl a substituent such as halogen, C 1 -C 2 -alkyl or C 1 -C 2 -alkoxy, and 3 '3 3 3' R is the same as R and R and R are the same or different, or R ro and Ii ekan together with the nitrogen atom of formula II: to which they are attached a suda (II) wherein n is from 1 to 3, and A is O, CH ₂ or N (R) wherein R ^{4 * * 7} are hydrogen, phenyl, C 1 -C 8 -alkyl, and the aforesaid residues are unsubstituted or substituted by phenyl, which in turn may be substituted by one or more identical or different substituents such as halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and triflic acid, R ⁷ is C 1 -C 6 -alkoxycarbonyl or C 1 -C 4 -cycloalkyl, and wherein 2 11.2. R is the same as R and the residues R and R are the same or different, or 2 3 R is in the 4-position only and the 5-position is one of the residues R or R and the physiologically acceptable salts thereof, with the exception of the compounds of formula I wherein R and R are the same or different and are carboxyl, its methyl or ethyl esters as well as their diamides, the process according to claim 1. 3. 2,4- or 2,5-substituted Pyridine N-oxides of Formula I: - R '(I) in which 1 3. . R is a -C (O) -X-R group with 3 ' X is O or -N (R) -, o R is hydrogen, C 1 -C 6 alkyl, C 8 -cycloalkyl, phenyl or pyridyl, wherein the radicals R mentioned are unsubstituted or mono- or di-substituted with R 4 ... R is a hydroxyl group, an amino group, a carboxyl group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy carbonyl or phenyl, which may be a single methyl or methoxy group, and 3 '333' R is the same as R and R and R are the same or different or 3 3 ' R and R together with the nitrogen atom to which they are attached form a residue of formula II: (II) wherein n is 2 and A is O or CH ₂ and wherein 2112 R is the same as R and R and R are the same or different; or 2. ..., R is only in the 4-position and 5-position is one of them 3 4 A process for the preparation of R or R residues as well as their physiologically acceptable salts, except for the compounds of formula I for which R and R are the same or different and are carboxyl, its methyl or ethyl esters and its diamides. . 4. 2,4- or 2,5-substituted Pyridine N-oxides of Formula I: Oh where 1 3 R is a -C (O) -X-R group in which the 3 ' X is O or -N (R) -, o R ¹ is hydrogen, C1 ~ C32 alkyl, ^C2-C ₃₂ alkenyl, ^C 2 ~ ^c g2 alkynyl may also be benzanelintas C₁-cycloalkyl, 'three aryl or heteroaryl, wherein the R moiety is not specified or alternatively, there is one or more identical or different substituents R o 4 ..... R is halogen, hydroxy, cyano, nitro, nitro, amino, carboxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkyl or -diacylamino, indolyl or phenyl wherein the indolyl or phenyl moieties may have one, two or three substituents such as halogen, nitro, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and may be the same or different when multiple substituents are present. or R ^{8 in} the case X is -N (R ⁸ ) - is a residue -N (R ⁸ ) (R ⁸ ) wherein r ⁸ or R * ² is the same or different and is hydrogen, C 1 -C 6; -alkyl, C 1 -C 3 -alkylcarbonyl or phenyl and 3 '3 3' 3 R is the same as R and the residues R and R are the same or different, or 33 '.... R and R together with the nitrogen atom to which they are attached form a residue of formula II: / S (II), -N A ') cH?) Λ n where n is from 1 to 3, o A is O, S, CH _2, or -N (R) - in which 7 R is hydrogen, phenyl, C₁-C₆ _alkyl, C2-C₆-alkenyl or C_-C _r -alkynyl, and these residues are the D BoardSports PAZ or contains a phenyl substituent which may be mono- or polysubstituted by identical or different, such as halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or -N (R ⁸ ) ₂ where R ⁸ is hydrogen or C 1 -C 6 -alkyl, or -COOR ⁸ or -CON (R ⁹ ) ₂ or CONHR ⁷ where o 8 9 R is the same as for R, or (R) ₂ is a C 0 -C 8 alkylene chain in which neither group is unsubstituted or one CH ₂ group not adjacent to the nitrogen atom is replaced by O, S β or an N-R residue, or R is C 1 -C 6 -alkoxycarbonyl or C 1 -C 4 -cycloalkyl, and wherein 2 11.2. R is the same as R and the residues R and R are the same or different, or 2 3 R is present only at the 4-position, and at the 5-position is one of the residues R or R, as well as their physiologically acceptable salts with biological activity. 2,4- or 2,5-substituted pyridine-N-oxides of formula I wherein 1 3 R is a -C (O) -XR group in which 3 ^Z X is O or -N (R) and is hydrogen, C 1 -C 6 alkyl, C 1 -C 8 alkenyl, C 1 -C 4 alkynyl, C ₅ -C ₇ cycloalkyl, aryl or heteroaryl, wherein the specified R residues are unsubstituted or have one or more 4 identical or different R substituents, o 4 ..... R is halogen, hydroxy, cyano, amino, carboxyl, C 1 -C 4 -alkoxy, C ¹ -C 4 -alkoxycarbonyl, C ¹ -C ¹ -C ¹ -alkyl or -dialkylamino or phenyl which may be unsubstituted, or be one halogen, C ₁ ~ C ₂ alkyl or C ± ~ ^C 2 ~ -alkoxy, and 3 '.33.3 ^{4 * * 7} R is the same as R and R and R are either different or 33 '.... R and R together with the nitrogen atom to which they are leaving a residue of formula II: the residues are the same (are connected) (s), where n is from 1 to 3, o A is O, CH ₂ or -N (R 6) - where 7 R is hydrogen, phenyl, (C 1 -C 8) -alkyl, wherein the said moieties are unsubstituted, or are phenyl substituted with one or more identical or different substituents such as halogen, nitro, cyano, carboxyl, hydroxy, methyl, ethyl , methoxy, ethoxy and trifluoromethyl, R is C 1 -C 6 -alkoxycarbonyl or C 1 -C 4 -cycloalkyl, and wherein 2 .11.2 R is the same as R and R and R are the same or different, 2 3 or R is present only at the 4-position and 5-position is one of the residues R or R as well as their physiologically acceptable salts which inhibit proline and lysine hydroxylase. 2,4- and 2,5-substituted pyridine-N-oxides of formula I i Oh where 1 3 R is a -C (O) -XR group in which 3 ^Z X is O or -N (R) -, and 3 ... R is hydrogen, C 1 -C 6 -alkyl, C 1 -C 4 -cycloalkyl, phenyl 3, or pyridyl, wherein in the foregoing moiety R may be one to four or two identical substituents R R is hydroxy, amino, carboxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl or phenyl, unsubstituted or mono- or methoxy, and 3 <3 3. 3 ^Z R is the same as R and R and S are the same or different, or 33 '... R is. R, together with the nitrogen atom to which they are attached, forms a residue of formula II: (II) wherein n is 2 and A is O, Ct ^, and wherein 2. 1 R is the same as R different, or R ² is in position 4 only and position 5 is one of R ^x and R ^z are the same or 3 4 R or R residues, as well as their physiologically acceptable salts with fibrosodepressive and immunodepressant effects. 7. A pharmaceutical composition comprising the active ingredient and the necessary additives, wherein the active ingredient is a compound of formula I as claimed in any one of claims 4 to 6. 8. A process for the preparation of a pharmaceutical dosage form, which comprises converting the compounds of the formula I according to any of claims 4 to 6 and pharmaceutically acceptable excipients into a suitable dosage form. A pharmaceutical composition according to claim 7 for use in the manufacture of a medicament for treating metabolic disorders.