IL98629A - 2,4- and 2,5-substituted pyridine-n-oxides processes for their preparation and their use - 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

2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, PROCESSES FOR THEI PREPARATION AND THEIR USE enn'e i wa:>n¾ ΪΙ Ο>Β ,ηηοηιο -s,2-i -4,2 nmamv- N -ιπη>ο HOECHST AKTIENGESELLSCHAFT HOE 90/F 192 Dr. Fi/PP Description 2,4- and 2 ,5-substituted pyridine-N-oxides, processes for their preparation and their use Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing collagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is suppressed by inhibitors, a non-functional, underhydroxylated collagen molecule is formed, which can be released into the extracellular space by the cells only to a small extent. In addition, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily degraded by proteolysis. As a result of these effects, the amount of collagen stored extracellularly is on the whole reduced.

Inhibitors of prolyl hydroxylase are therefore suitable substances in the treatment of disorders in which the storage of collagens contributes decisively to the symptoms. These include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and atherosclerosis.

It is known that the inhibition of proline hydroxylase by known inhibitors such as α , a '-dipyridyl leads to an inhibition of CI, biosynthesis by macrophages (W. Miiller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1978), 47). As a result, a failure of the classical route of complement activation occurs. Inhibitors of proline hydroxylase therefore also act as immunosuppressives, for example in immune complex diseases.

It is known that the enzyme proline hydroxylase is effectively inhibited by pyridine-2 , 4- and -2,5-dicarboxylic acid ( . Majamaa et al., - 2 - 98629/2 Eur. J. Biochem. 138 (1984) 239-245). However, these compounds are effective in cell culture as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 625-633).

DE-A 3, 32 , 094 describes pyridine-2, 4- and -2,5-dicar-boxylic acid diesters having 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for the inhibition of proline hydroxylase and lysine hydroxylase.

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

DE-A 3,703,959, corresponding to IL 85362, DE-A 3,703,962 corresponding to IL 85360 and DE-A 3,703,963, corresponding to IL 85361 describe in general form mixed ester/amides , igher alky lated diesters and diamides of pyridine-2, - and -2,5-dicarboxylic acid, which effectively inhibit, collagen biosynthesis in the animal model. Thus, DE-A 3,703,959, inter alia, describes the synthesis of N,N ' -bis ( 2-methoxyethyl )pyridine-2 , 4-dicarboxamide and N,N ' -bis ( 3-isopropoxypropyl )pyridine-2 , 4-dicarboxamide .

An improved process for the preparation of Ν,Ν' -bis ( 2-methoxyethyl )pyridine-2 , 4-dicarboxamide is proposed in German Patent Applications P 38 26 471.4 and p38 28 140.6 corresponding to IL 91185.

German Patent Application P 39 24 093.2 proposes novel N, N ' -bis ( alkoxyalkyl )pyridine-2 , 4-dicarboxamides .

German Patent Application P 40 01 002.3 describes the use of N,N'-(nitroxyalkyl)pyridine-2,4- and -2 , 5-dicarbox-amides for the preparation of pharmaceuticals inhibiting proline hydroxylase and lysine hydroxylase.

Both pyridine-2 , - and -2 , 5-dicarboxamide (Hirakata et al., J. pharm. Soc. Japan 77 (1957) 219 and HSring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and -2 ,5-dicarboxylic acid dihydrazide (Itai et al., Bl. nation, hyg. Labor. Tokyo, 74 (1956) 115, 117 and Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839) are already known as antituberculosis agents.

JP 53/28175 (78/28175) describes N,N'-bis(2-nitrooxy-ethyl)pyridine-2,4- and -2,5-dicarboxamides as substances having vasodilatory action.

Surprisingly, it has now been found that 2,4- and 2,5-substituted pyridine-N-oxides of the general formula I indicated below and the physiologically tolerable salts effectively inhibit lysine hydroxylase and proline hydroxylase in the animal model.

The invention accordingly relates to 2,4- and 2,5-sub-stituted pyridine-N-oxides of the general formula I -C(0)-X-R3, where is 0 or -N(R3' ) - and is hydrogen, Cj-Cjj-alkyl, C2-C12- alkynyl, non-benzo-fused or benzo-fused C5-C7- cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or more identical or different radicals R*, where is halogen, hydroxy!, cyano, nitro, nitroxy, amino, carboxyl, Cx-C^-alkoxy, -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub- stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C--C*- alkyl or where, in the case of polyeubstitution, the radicals are identical or different or R3, if X is -N(R3 ), is a radical -N(R5)(R6), in which R5 and R6 are identical or different and are hydrogen, Cx-CA-alkyl, C1-C3-alkylcarbonyl or phenyl and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II in which n is 1 to 3 and A is 0, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, Ci-Ce-alkyl, C2-C6-alkenyl or C2-C6-alkynyl/ where these mentioned alkyl, alkenyl or alkynyl radicals are unsubstituted or substituted by phenyl which phenyl is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different substituents selected from the groups comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl , or R7 designates: -N(R8)2, where R8 is hydrogen or C].-C3-alkyl; or-C00R8 or -CON (R$)2 or C0NHR7, where R9 has the meaning of R8 or where (R9)2 s a C4-Ce-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R8; or where R7 is C1-C^-alkoxycarbonyl or C3-C7-cycloalkyl and in which has the meaning of R1, where the radicals R1 and - O - ¾8629/2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position, excluding pyridine-2-carboxyl-4-octyl-carbox amide-N-oxide and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.

The invention furthermore relates to the use of compounds of the general formula I and the physiologically tolerable salts for the production of a pharmaceutical inhibiting proline hydroxylase and lysine hydroxylase.

Finally, the invention relates to the compounds of the general formula I for use as pharmaceuticals.

The invention relates in particular to the compounds of the formula I for use as fibrosuppressives and immunosuppressives and also for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clg.

All said alkyl radicals having more than 2 carbon atoms can be either straight-chain or branched.

The invention furthermore relates to a process for the preparation of compounds of the general formula I.

The compounds according to the invention are most simply prepared by adding oxidants such as, for example, hydrogen peroxide or peracids such as peracetic acid, per-fluoroacetic acid, perbenzoic acid or metachloroper-benzoic acid in solvents such as chlorinated hydrocarbons, such as, for example, methylene chloride, chloroform, tri- or tetrachloroethylene, benzene or toluene, to the pyridine compounds to be oxidized, which can likewise be dissolved in the abovementioned solvents, and stirring at a temperature between -30 and +40eC, preferably between 0 and +25°C, for between 30 minutes and 3 days. Completion of the reaction can be determined, for example, by means of thin layer chromatography. The compounds according to the invention can preferably be prepared by employing the pyridine derivative and the oxidant in eguimolar amounts or up to an about 5-fold excess of oxidant.

If appropriate, an excess of peracid can also be eliminated by introducing, for example, gaseous ammonia into the reaction solution and separating the resulting precipitate from the reaction solution by filtration.

If appropriate, the products can be worked up, for example, by extraction or by chromatography, for example by means of silica gel. The isolated product can be recrystallized.

A general procedure for this oxidation method is also described, for example, in "E. Lingsberg, Pyridine and its Derivatives, Interscience Publishers, New Tork, 1961, Part 2, 93".

Oxidation with hydrogen peroxide is described, for example, in "E. Ochiai, J. Org. Chem. 18, 534 (1953)".

The preparation of the different pyridine derivatives necessary for the oxidation described is set out in the Patent Applications already cited as prior art. Those which may be mentioned are German Patent Applications P 38 26 471.4, 38 28 140.6, 39 24 093.2, 40 01 002.3 and DE-A-3,703,959, 3,703,962 and 3,703,963.

The compounds of the formula I according to the invention have useful pharmacological properties and in particular show activity as inhibitors of proline hydroxylase and lysine hydroxylase, as a fibrosuppressive, immunosuppressive and antiatherosclerotic.

The antifibrotic action can be determined in the carbon tetrachloride-induced liver fibrosis model. For this purpose, rats are treated twice weekly with CC14 (1 ml/kg) - dissolved in olive oil. The test substance is administered daily, if appropriate even twice daily, orally or intraperitoneally - dissolved in a suitable tolerable solvent. The extent of liver fibrosis is determined histologically and the proportion of collagen in the liver is analyzed by hydroxyproline determination - as described in Kivirikko et al. (Anal. Biochem. 19, 249 et seq. (1967)). The fibrogenesis activity can be determined by radioimmunological determination of collagen fragments and procollagen peptides in the serum. The compounds according to the invention are effective in this model in concentrations of 1 - 100 mg/kg.

The fibrogenesis activity can be determined by radioimmunological determination of the N-terminal propeptide of type III collagen or of the N- or C-terminal cross-linking domain of type IV collagen (7s collagen or type IV collagen-NCx) in the serum.

For this purpose, the hydroxyproline, procollagen III peptide, 7s-collagen and type IV collagen-NC^ concentrations in the liver of a) untreated rats (control) b) rats to which carbon tetrachloride was administered (CC14 control) c) rats to which first CC14 and then a compound according to the invention was administered were measured (this test method is described by Rouiller, C, experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pp. 335-476, New Tork, Academic Press, 1964).

Another model for the evaluation of antifibrotic action is bleomycin-induced lung fibrosis as described in Kelley et al. (J. Lab. Clin. Med. 96, 954, (1980)). The cotton pellet granuloma model, as described in Meier et al., Experientia 6, 469 (1950) can be used to evaluate the action of the compounds according to the invention in the granulation tissue.

The compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations which contain them, if appropriate together with tolerable pharmaceutical carriers. The compounds can be used as medicaments, for example in the form of pharmaceutical preparations, which contain these compounds in a mixture with a pharmaceutical organic or inorganic carrier suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, poly-alkylene glycols, petroleum jelly etc.

For this purpose, they can be administered orally in doses of 0.1 - 25 mg/kg/day, preferably 1 - 5 mg/kg/day or parenterally in doses of 0.01 - 5 mg/kg/day, pre-ferably 0.01 - 2.5 mg/kg/day, in particular 0.5 -1.0 mg/kg/day. In severe cases, the dosage can also be increased. In many cases, however, lower doses are also sufficient. This information relates to an adult weighing about 75 kg.

The invention furthermore includes the use of the compounds according to the invention in the production of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders.

The invention further relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or their physiologically tolerable salts .

The pharmaceuticals are prepared by processes which are known per se and which are familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds according to the invention are employed either as such or preferably in combination with suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the active compound content being up to about 95%, advantageously between 10 and 75%.

In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound carriers, suitable auxiliaries or excipients for the desired pharmaceutical formulation are also, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor correctants, preservatives, solubilizers or colorants.

The active compounds can be administered orally, paren-terally or rectally.

The active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents and brought into suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions, by the customary methods .

Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, preparation can be carried out both as dry and as moist granules. Possible oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired using the substances suitable for this such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, physiological saline solution or alcohols, for example ethanol, propanol or glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or, alterna-tively, a mixture of the various solvents mentioned.

The invention is illustrated in more detail below by Examples .

General procedure for the preparation of the compounds 1 equivalent of pyridine derivative (for preparation see description) is initially introduced in methylene chloride and 1 equivalent of metachloroperbenzoic acid (MCPBA) , dissolved in methylene chloride, is added dropwise at room temperature. The mixture is stirred at room temperature. After completion of the reaction, gaseous ammonia is blown into the solution with ice-cooling until a precipitate is no longer formed. The precipitate is filtered off, and the filtrate is dried with magnesium sulfate and concentrated.

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

The compounds mentioned in the following Examples are prepared according to this general procedure.

Example 1 N , N ' -Di- ( 2-methoxyethyl ) pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N,N'-di-(2-methoxyethyl)pyridine-2,4-dicarboxamide and 0.62 g of MCPBA.

Yield: 620 mg (chromatography: ethyl acetate/methanol 5:1) M.p.: 102eC Example 2 , N ' -Di- ( 3-methoxypropyl )pyridine-2 , 4-dicarboxamide N-oxide From 1 g of Ν,Ν'-di-( 3-methoxypropyl)pyridine-2 ,4-dicarb-oxamide and 1.2 g of MCPBA.

Yield: 0.58 g (recrystallization: ethanol) M.p.: 90eC Example 3 Pyridine-2, 4-dicarboxamide N-oxide From 1 g of pyridine-2, 4-dicarboxamide and 1.2 g of MCPBA.

Yield: 0.8 g (recrystallization: ethanol) M.p.: 260eC Example 4 N,N ' -Di- ( 2-dimethoxyethyl )pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N, ' -di- (2-dimethoxyethyl)pyridine-2 ,4-dicarboxamide and 1.1 g of MCPBA.

Yield: 0.5 g (chromatography: ethyl acetate/methanol 5:1) M.p.: 86eC Example 5 N , N ' -Di- ( 3-ethoxypropyl ) pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N,N'-di-(3-ethoxypropyl)pyridine-2,4-dicarboxamide and 1.5 g of MCPBA.

Tield: 0.34 g (chromatographyt ethyl acetate/methanol 5.1) M.p.: 81eC Example 6 , N ' -Di- ( 2-methoxyethyl ) pyridine-2 , 5-dicarboxamide N-oxide From 1 g of N,N'-di-( 2-methoxyethyl)pyridine- 2 ,4-dicarboxamide and 1.3 g of MCPBA.

Yield: 0.4 g (recrystallization: ethanol) M.p.: 137eC Example 7 Di-( 2-methoxyethyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di-(2-methoxyethyl) pyridine-2,4-dicarboxy-late and 1.3 g of MCPBA.

Yield: 0.2 g (chromatography: ethyl acetate) M.p.: oil From 1 g of N,N'-diethylpyridine-2,5-dicarboxamide and 1.8 g of MCPBA.

Yield: 0.4 g (recrystallization: ethanol) M.p.: 128eC Example 9 N,N ' -Di- ( 3-methoxypropyl)pyridine-2 ,5-dicarboxamide N- oxide From 1 g of N,N'-di-(3-methoxypropyl)pyridine-2,5-dicarboxamide and 1.2 g of MCPBA.

Yield: 0.3 g (recrystallization: diethyl ether/methanol) M.p.: 123eC Example 10 2,4-Di-[ (morpholin-l-yl)carbonyl]pyridine N-oxide From 1 g of 2 , 4-di-[ (morpholin-l-yl)carbonyl]pyridine and 1,2 g of MCPBA.

Yield: 0.5 g (chromatography: ethyl acetate/methanol 5/1) M.p.: oil Example 11 Μ,Ν' -Di- (4-hydroxybutyl ) pyridine-2 , 4-dicarboxamide N-oxide Prom 1 g of Ν,Ν' -di-(4-hydroxybutyl)pyridine-2,4-dicarb-oxamide and 0.8 g of MCPBA.

Yield: 0.82 g (ethanol) M.p.: 88eC Example 12 Ν,Ν' -Dicyclohexylpyridine-2,4-dicarboxamide N-oxide From 1 g of Ν,Ν' -dicyclohexylpyridine-2,4-dicarboxamide and 0 g of MCPBA.

Yield: 0.59 g (ethanol) M.p.: 153eC Example 13 , ' -Di- ( 3-chlorobenzyl ) pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N,N'-di-( 3-chlorobenzyl)pyridine-2,4-dicarboxamide and 0.65 g of MCPBA.

Yield: 0.76 g (toluene) M.p.: 112eC Example 17 Di- (methoxycarbonylmethyl) pyridine-2 ,4-dicarboxylate N-oxide From 1 g of di-(methoxycarbonylmethyl) pyridine-2,4-di-carboxylate and 1.1 g of MCPBA.

Yield: 0.81 g Oil, MS = 328 (M+H) molecular weight 327 Example 18 Pharmacological activity In order to show the efficient inhibition of proline hydroxylase and lysine hydroxylase by the compounds according to the invention, the concentrations of bilirubin, bile acids and gamma 6T in the serum of a) untreated rats (control ) , b) rats treated with CC14, c) rats to which first CC1 and then a compound according to the invention have been given, are measured. (The method is described by Rouiller, C, Experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pages 335-476, New York, Academic Press 1964).

The results are summarized in Table 1.

Table I t Action of prolyl hydroxylase inhibitors on CCl -induced liver fibrosis in rats Treatment Dose* Bilirubin Bile acids fl-wrtmw GT Control 5 1.76 ± 0.27 26 ± 6.8 2 ± 0 CC1, - 22 4.98 ± 1.06 81 ± 8.7 5.3 ± 1.4 Example 1 20 12 6.30 1 5.4 97 ± 76 4.3 i 3.1 (0) (0) (27) Example 2 20 11 2.90 ± 0.94* 71 ± 42 3.3 ± 2.2* (65) ( 18) (59) The results are mean values ± standard deviation, *p <0 . 05 for CC1A treatment , values in brackets are the percentage improvement compared to an exclusive CCl* treatment , a : total daily oral dose .

Claims (10)

- 19 - HOE 90/F 192 Patent claims:

1. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I C(0)-X-R3, where is 0 or -N(R3' )- and is hydrogen, Cj-Cig-elkyl, ^-C^—alkenyl , C2~C12— alkynyl, non-benzo-fused or benzo-fused C5-C7- cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or more identical or different radicals R*, where R* is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C^-C^- alkyl or where, in the case of polysubstitution, the radicals are identical or different or if X is -N(R3'), is a radical -N(R3)(R6), which R5 and R6 are identical or different and are hydrogen, Cx-C^-alkyl, Cx-Ca-alkylcarbonyl or phenyl and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II in which n is 1 to 3 and A is 0, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, Cx-Ce-alkyl, C2-Ce-alkenyl or C2-C6-alkynyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub- stituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoro ethyl or -N(R8)2, where - 21 - 98629/2 R8 is hydrogen or Ci-Ca-alJc l or -COOR8 or -CON(Re)2 or CONHR7, where Re has the meaning of R8 or where (R9)2 is a C«-C6-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R8 or where R7 is or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position, excluding pyridine-2-carboxyl-4-octyl-carbox amide-N-oxide and the physiologically tolerable salts, were the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.

2. A 2/4- or 2, 5-substituted pyridine-N-oxide of the formula I in which R1 is -C(0)-X-R3, where X is 0 or -N(R3' )- and R3 is hydrogen, Cj-Ce-alkyl, C2-Ce-alkenyl, C2-C6- alkynyl, C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R*, where R* is halogen, hydroxy1, cyano, amino, carboxyl, Cj-C^-alkoxy, Cj-C^-alkoxy- carbonyl, or -dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, C1-C2-alkyl or C1-C2-alkoxy, and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II (II) 98629/2 in which n is 1 to 3 and A is 0, CH2 or -N ( R7 ) - where R7 is hydrogen, phenyl or Ci-Ce-alkyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub- stituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, raethoxy, ethoxy and trifluoromethyl R7 is or C3-C7-cycloalkyl and in which R2 has the meaning of Rl, where the radicals R1 and R2 are identical or different where R2 is either in the 4- or 5-position, and if R2 is in position 4, one of the substituents R3 or R4 may be a substituent on the moiety on the pyridine ring in position 5, resulting in a triple substituted pyridine moeity in positions 2, 4 (R1 or R2), and 5 (R3 or R4) . and the physiologicail'y tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.

3. A 2,4- or 2 , 5-substituted pyridine-N-oxide of the formula I 0 is -C(0)-X-R3, where X is 0 or -N(R3' ) - and R3 is hydrogen, Cj-Cs-alkyl, Ce-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R*, where R* is hydroxyl, amino, carboxyl, C1-C4-alkoxy, Cj-C^-alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or mono- substituted by methyl or methoxy and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II / \ -\ (ID <∞2>η in which n is 2 and A is 0 or CH2, and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R* is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides. .

4. A process for the preparation of compounds of the formula I as claimed in claim 1, which comprises a) reacting a compound of the formula III in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula IV H-X-R3 ( IV) in which X and R3 have the meanings indicated in claim 1, or b) reacting a compound of the formula V in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula VI H-X-R3 (VI) in which X and R3 have the meanings indicated in claim 1, if desired introducing a further substituent into the side chain R3 and then converting the compound thus obtained into the N-oxide and if desired then converting the compound thus obtained into a physiologically tolerable salt.

5. A 2,4- or 2 , 5-substituted pyridine-N-oxide of the formula I in which R1 is -C(0)-X-R3, where X is 0 or -N(R3')- and R3 is hydrogen, Ci-Cxa-alkyl, C2-C12-alkenyl, C2-C12- alkynyl, non-benzo-fused or benzo-fused C3-C7- cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or more identical or different radicals RA, where R* is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, Ci-C^-alkoxycarbonyl, Cj-C^-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, Cx-C^- alkyl or Cx-Ct-alko y, where, in the case of polysubstitution, the radicals are identical or different or R3, if X is -N(R3' ) , is a radical -N(R5)(Re), in which Rs and R6 are identical or different and are hydrogen, d-C^-alkyl, C1-Ca-alkylcarbonyl or phenyl and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II (CH2)n in which n is 1 to 3 and A is 0, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, Cx-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstltuted or polysubstituted by one or more identical or different sub- stituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -N(R8)2, where R8 is hydrogen or Ci-Ca-alkyl or -COOR8 or -CON(R9)2 or CONHR7, where R9 has the meaning of R8 or where (R9)2 is a C4-C6-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R8 or where R7 is Cj-Ci.-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of Rl, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R* is in the 5-position and the physiologically tolerable salts for use as medicaments .

6. A 2,4- or 2 ,5-substituted pyridine-N-oxide of the formula I in which R1 is -C(0)-X-R3, where X is 0 or -N(R3')- and R3 is hydrogen, Cx-Ce-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R, where R* is halogen, hydroxyl, cyano, amino, carboxyl, C1-C4-alkoxy- carbonyl, dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, Ci-Ca-alkyl or Ci-Ca-alko , and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II — in which n is 1 to 3 and A is 0, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or Ci-Ce-alkyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub- stituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is Cj-C^-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals Rl and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R* is in the 5-position and the physiologically tolerable salts, for the inhibition of proline hydroxylase and lysine hydroxylase.

7. A 2,4- or 2 , 5-substituted pyridine-N-oxide of the formula I is -C(0)-X-R3, where X is 0 or -N(R3' ) - and R3 is hydrogen, Cj-Cj-alkyl, C8-cycloalkyl, phenyl - 31 - or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R*, where R* is hydroxyl, amino, carboxyl, or phenyl, where the phenyl radical is unsubstituted or mono- substituted by methyl or methoxy and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II in which n is 2 and A is 0 or CH2, and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R* is in the 5-position and the physiologically tolerable salts, for use as fibrosuppressives and immunosuppressives. 98629/3 -32- 98629/2

8. A pharmaceutical composition containing a compound of the formula I as claimed in claim 5 and a pharmaceutically tolerable carrier.

9. The use of compounds of the formula I as claimed in Claim 5 in the preparation of a medicament for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq., as hereinbefore described.

10. The use of compounds of the formula I as claimed in claim 5 in the preparation of a medicament for the treatment of disorders of the metabolism of collagen and collagenlike, substances or the bio synthesis of Clq., as hereinbefore described. 1 1. A process for the production of a pharmaceutical composition as claimed in claim 8, which comprises converting a compound of the formula I as claimed in claim 1 and a pharmaceutically tolerable carrier into a suitable administration form.