NZ238701A

NZ238701A - 2,4- and 2,5-substituted pyridine-n-oxides and pharmaceutical compositions

Info

Publication number: NZ238701A
Application number: NZ238701A
Authority: NZ
Inventors: Ekkehard Baader; Martin Bickel; Volkmar Gunzler-Pukall
Original assignee: Hoechst Ag
Priority date: 1990-06-28
Filing date: 1991-06-26
Publication date: 1994-06-27
Also published as: CS195991A3; ES2061118T3; CA2045868A1; ZA914958B; IE65300B1; PT98108B; HRP940701A2; NO178026C; EP0463592A1; CN1057649A; FI101070B; HU912158D0; IE912253A1; IL98629A; CN1038585C; KR920000724A; NO178026B; AU636990B2; NO912541D0; CZ283782B6

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £38701 Henry Hughes Ltd 23870 1 Patents Form 5 Parity D:.t r'.J: n,— CcrijO&tzhtt, &/„*?,•, CQl/brtJ**; *3.$T. N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION 2.4- AND 2.5-SUBSTITUTED PYRIDINE-N-OXIDES. fl£°c.6SS£S PROCESS FOR THEIR PREPARATION AND THEIR USE We, HOECHST AKTIENGESELLSHAFT, a Corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of „ Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - -1 - (Followed by 1A) 23 87 01 -lA- 1 IIOECIIOT AKTIENGEGELLSCIIAFT IIOE DO/F 192 Dr. Fi/PP Description 2,4- and 2,5-substituted pyridine-N-oxides, processes for their preparation and their use 5 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 10 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 underhydroxy-15 lated 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 20 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 25 known inhibitors such as a,a'-dipyridyl leads to an inhibition of Clq 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 30 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 (K. Majamaa et al., 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). 5 US 4,717,727 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 disad-10 vantage 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 . 15 DE-A 3,703,959 corresponding to NZ Patent Specification 223433, DE-A 3,703,962 corresponding to NZ Patent Specification 223432 and EP 278,452 describe in general form mixed ester/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid, which effectively inhibit, collagen biosynthesis in the animal model. Thus, 20 NZ 223433, 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 N, N' -bis (2-methoxyethyl) pyridine-2,4-dicarboxamide is 25 proposed in the Patent Specification EP 353,668. \ v The Patent Specification EP 409,119 proposes novel I"* 13 JUL {993 N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxamides. \\ ^ A v ,N f ? £ « *T The Patent Specification EP 438,795 describes the use 30 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-2,4- and -2,5-dicarboxamide - 3 - (Hirakata et al./ 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 5 Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839) are already known as antituberculosis agents. 10 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. 15 The invention accordingly relates to 2,4- and 2,5-sub-stituted pyridine-N-oxides of the general formula I (I) R1 ,/«' -JL 13 JUL1993 A ' % <' in which ./^ ° R1 is -C(0)-X-R3, where 20 X is 0 or -N(R3')- and R3 is hydrogen, C1-C12-alkyl, Ca-C^-alkenyl, C^-C^- alkynyl, non-benzo-fused or benzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or 25 are substituted (with the exception of hydrogen) by one or more identical or different radicals R4, where ra is halogen, hydroxyl, cyano, nitro, H 4 v'- ' < f - 4 - nitroxy, amino, carboxyl, C1-CA-alkoxy/ Ca-C^-alkoxycarbonyl, C^-C^-alkyl- or di-CM-alkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub-stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, Ci-C,,-alkyl or Ci-C^-alkoxy, where, in the case of polysubstitution, the radicals are identical or different 10 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, Ci-C^-alkyl, Cx-Ca-alkylcarbonyl 15 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 20 they are bonded, are a radical of the formula II —J \ (") <CT2>n in which .. , . n is 1 to 3 and ^ ^ f 13 JUL 1993 "i 25 A is 0, S, CH2 or -N(R')-, where R7 is hydrogen, phenyl, C1-C6-alkyl, C2-C6-alkenyl ?V 701 fcra- '' or C2-C8-alkynyl, where these mentioned radicals are unsubstituted or substituted (with the exception of hydrogen) by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by 5 one or more identical or different sub- stituents selected from the group consisting of: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl 10 or -N(R8)2, where R8 is hydrogen or C1-C3-alkyl or -COOR8 15 or -CON (R9) 2 or CONHR8, 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 20 directly adjacent to the nitrogen atom is replaced by 0, S or N-R8 or where R7 is c,-C4-alkoxycarbonyl or Cj-CV-cycloalkyl and in which R^_ /VEN' r v 22 r ~ C n M 23 r / f j ^ - 6 - represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning of R1, wherein the radicals R1 and R2 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of. R1 and is only present at the 4-position of the pyridine moiety and one of the radicals R3 and R4, wherein R3 and R4 are as defined above, ).';d is present in the 5-position of the pyridine moiety, and the physiologically tolerable salts, where the 5 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 10 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 15 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. 20 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 25 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 hydro-carbons, such as, for example, methylene chloride, "■' 30 chloroform, tri- or tetrachloroethylene, benzene or v toluene, to the pyridine compounds to be oxidized, which "22 APR'9^ - 7 - *7 '"V: r"' ^ A !! can likewise be dissolved in the abovementioned solvents, and stirring at a temperature between -30 and +40°C, preferably between 0 and +25°C, for between 30 minutes and 3 days. Completion of the reaction can be determined, 5 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. 10 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 15 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 20 its Derivatives, Interscience Publishers, New York, 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 25 necessary for the oxidation described is set out in the Patent Specifications already cited as prior art. Those which may be mentioned are the Specifications EP 353,668, EP 409,119, EP 438,795, NZ 223433, NZ 223432 and EP 278,452. c 30 The compounds of the formula I according to the invention; have useful pharmacological properties and in particular 13 JULJ993 show activity as inhibitors of proline hydroxylase and 'Ve lysine hydroxylase, as a fibrosuppressive, 3 8 7 0 1 - 8 - 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) 5 - 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 10 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 15 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-20 linking domain of type IV collagen (7s collagen or type IV collagen-NCi) in the serum. For this purpose, the hydroxyproline, procollagen III peptide, 7s-collagen and type IV collagen-NC^ concentrations in the liver of 25 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 30 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 York, Academic Press, 1964). Another model for the evaluation of antifibrotic action 35 is bleomycin-induced lung fibrosis as described in 238701 - 9 - 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 5 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, 10 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, 15 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-20 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. 25 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 30 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 238701 -10- 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 5 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 10 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. 15 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 20 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 25 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 30 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 238701 - n - 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-5 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 10 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, 15 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 20 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 25 N-oxide From 1 g of N,N'-di-(2-methoxyethyl)pyridine-2,4-dicar-boxamide and 0.62 g of MCPBA. Yield: 620 mg (chromatography; ethyl acetate/methanol 5:1) 30 M.p.: 102 °C 238701 - 12 - Example 2 N, N'-Di-(3-methoxypropyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N'-di-(3-methoxypropyl)pyridine-2,4-dicarb-5 oxamide and 1.2 g of MCPBA. Yield: 0.58 g (recrystallization: ethanol) M.p.: 90°C Example 3 Pyridine-2,4-dicarboxamide N-oxide 10 From 1 g of pyridine-2,4-dicarboxamide and 1.2 g of MCPBA. Yield: 0.8 g (recrystallization: ethanol) M.p.: 260°C Example 4 15 N,N' -Di-(2-dimethoxyethyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N'-di-(2-dimethoxyethyl)pyridine-2,4-dicarboxamide and 1.1 g of MCPBA. Yield: 0.5 g (chromatography: ethyl acetate/methanol 5:1) 20 M.p.: 86°C 23870 1 - 13 - 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-dicarb-oxamide and 1.5 g of MCPBA. Yield: 0.34 g (chromatography: ethyl acetate/methanol 5:1) M.p.: 81°C Example 6 N, 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.: 137 °C 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 238701 - 14 - Example 8 N/N'-Diethylpyridine-2,5-dicarboxamide N-oxide From 1 g of N,N'-diethylpyridine-2,5-dicarboxamide and 1.8 g of MCPBA. Yield: 0.4 g (recrystallization: ethanol) M.p.: 128 °C 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-dicar-boxamide and 1.2 g of MCPBA. Yield: 0.3 g (recrystallization: diethyl ether/methano1) M.p.: 123 °C 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 238701 - 15 - Example 11 N,N '-Di- (4-hydroxybutyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N'-di-(4-hydroxybutyl)pyridine-2,4-dicarb-5 oxamide and 0.8 g of MCPBA. Yield: 0.82 g (ethanol) M.p.: 88°C Example 12 N,N'-Dicyclohexylpyridine-2,4-dicarboxamide N-oxide 10 From 1 g of N,N'-dicyclohexylpyridine-2,4-dicarboxamide and 0 g of MCPBA. Yields 0.59 g (ethanol) M.p.: 153°C Example 13 15 N,N ' -Di - ( 3-chlorobenzy 1)pyridine-2 ,4-dicarboxamide N-oxide From 1 g of N,N'-di-(3-chlorobenzyl)pyridine-2,4-dicarb-oxamide and 0.65 g of MCPBA. Yield: 0.76 g (toluene) 20 M.p.: 112 °C 23870 1 - 16 - Example 14 N,N ' -Di- (4-methylbenzyl) pyridine-2 ,4-dicarboxamide N-oxide From 1 g of N,N'-di-(4-methylbenzyl)pyridine-2,4-dicarb-oxamide and 1.2 g of MCPBA. Yield: 0.72 g (toluene) M.p.: 153°C Example 15 Di-(4-chlorobutyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di-(4-chlorobutyl) pyridine-2,4-dicarboxylate and 0.75 g of MCPBA. Yield: 0.83 g (ethanol) M.p.: 98°C Example 16 Dicyclohexyl pyridine-2,4-dicarboxylate N-oxide From 1 g of dicyclohexyl pyridine-2,4-dicarboxylate and 0.75 g of MCPBA. Yield: 0.87 g Oil, MS = 348 (M+H) molecular weight 347 c 6 3 7 0 1j - 17 - Example 17 Di-(methoxycarbonylmethyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di-(methoxycarbonylmethyl) pyridine-2,4-di-5 carboxylate and 1.1 g of MCPBA. Yield: 0.81 g Oil, MS = 328 (M+H) molecular weight 327 Example 18 Pharmacological activity 10 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 GT in the serum of a) untreated rats (control), 15 b) rats treated with CC1<,, 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, 20 C. Rouiller, Vol. 2, pages 335-476, New York, Academic Press 1964). The results are summarized in Table 1. </div>

Claims

23 8 7 0 - 18 - Table Is Action of prolyl hydroxylase inhibitors on CCl^-induced liver fibrosis in rats Treatment Dose" Bilirubin Bile acids Garnm GF 5 ma/kcr N m U/L Control - 5 1.76 ± 0.27 26 ± 6.8 2 ± 0 CC1< - 22 4.98 i 1.06 81 ± 8.7 5.3 ± 1.4 Example 1 20 12 6.30 ± 5.4 97 i 76 4.3 ± 3.1 (0) (0) (27) 10 Example 2 20 11 2.90 ± 0.94* 71 ± 42 3.3 ± 2.2* (65) (18) (59) The results are mean values i standard deviation, *p <0.05 for CC14 treatment, values in brackets are the percentage improvement com-15 pared to an exclusive CC1* treatment. as total daily oral dose. - 19 - WHAT;WE CLAIM IS:

1. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I (I) 5 in which R1 is -C(0) -X-R3, where X is 0 or -N(R3') - and R3 is hydrogen, Ci-C^-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, non-benzo-fused or benzo-fused C5-C7-10 cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted (with the exception of hydrogen) by one or more identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, nitro, 15 nitroxy, amino, carboxyl, C^C^-alkoxy, Cx^-alkoxycarbonyl, Ci-C^-alkyl- or di-CM-alkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsubstituted or monosubstituted, disubstituted 20 or trisubstituted by halogen, nitro, Ci-C*- alkyl or Ci-C^-alkoxy, where, in the case of polysubstitution, the radicals are identical or different si or 13 JUL1993 ; r 25 R3, if X is -N(R3'), is a radical -N(R5)(R6), in F , m which L ; " 1 - 20 - R5 and R5 are identical or different and are hydrogen, Ci-C^-alkyl, Ci-Ca-alkylcarbonyl or phenyl 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 A is 0, S, CH2 or -N (R7) -, where R7 is hydrogen, phenyl, Cj-Cg-alkyl, C2-C6-al3cenyl or C2-C6-alkynyl, where these radicals are unsubstituted or substituted (with the exception of hydrogen) by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub- and in which n is 1 to 3 and stituents selected from the group consisting of: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or < •N(Ra)2, where /13 JUU953 t - 21 - 9 * ~ 7 0 R8 is hydrogen or C1-C3-alkyl or -COOR8 or -C0N(R9)2 or CONKR1, where R8 . has the meaning of R* or where (R°)2 is a C4-C8-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 C,rC4-alkoxycarbonyl or C^-Cj-cycloalkyl and in which represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning of R1, wherein the radicals R1 and R2 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of R1 and is only present at the 4-position of the pyridine moiety and one of the radicals R3 and R4, wherein R3 and R4 are as defined above, ■ is present in the 5-position of the pyridine moiety, and the physiologically tolerable salts thereof, 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.

2. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I V 11 APR'994 - 22 - r4 y: ' ■ - n 4 'J I (I) 4 0 in which 5 10 15 and R3' is -C (0) -X-R3, where X is 0 or -N(R3')- and R3 is hydrogen, Ci-Cs-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted (with the exception of hydrogen) by one or two identical or different radicals R4, where Ra is halogen, hydroxyl, cyano, amino, carboxyl, Cj-C^-alkoxy, Cj-C^-alkoxy-carbonyl, Ci-C^-alkyl- or di-CM-alkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, C1-C2-alkyl or Ci-Cz-alkoxy, has the meaning of R3, where the radicals R3 and R3' are identical or different or i R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II (II) - 23 - in which n is 1 to 3 and A is 0, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or Cx-Cg-alkyl, where these mentioned radicals are unsubstituted or substituted (with the exception of hydrogen) by phenyl which, for its part, is unsubstituted, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or R7 is C,-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning ofR1, wherein the radicals R1 and R7 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of R' and is only present at the 4-position of the pyridine moiety and one of the radicals R* and R\ wherein R3 and R4 are as defined above, is present in the 5-position of the pyridine moiety, and the physiologically tolerable salts thereof, 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 or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group consisting, of: halogen, nitro, cyano, carboxyl, R2. (I) 0 •=2 2APtffl* - 23a in which R1 is -C(0)-X-R3, where X is 0 or -N(R3')- and 701 R3 is hydrogen, Cj-Cj-alkyl, Ca-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted (with the exception of hydrogen) by one or two identical radicals R4, where R4 is hydroxyl, amino, carboxyl, Ci-C^-alkoxy, C1-C4-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 / \ — N A (Wn in which n is 2 and A is 0 or CH2, and in which R2 represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning of R1, wherein the radicals R1 and R2 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of R1 and is only present at the 4-position of the pyridine moiety and one of the radicals R3 and R\ wherein R3 and R4 are as defined above, is present in the 5-position of the pyridine moiety, and the physiologically tolerable salts thereof, wfiere the \ t a r compounds of the general formula I are excluded in whicdf<t " T2 2 APR 1994; 23 8701 - 25 - 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 (III) in which Y is halogen, hydroxyl or alkoxy, and R2 is as defined in claim 1; 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 •/\ '£ N C A \' \\ (V) - 5 NOV 1993 ' , ° / r \ \ in which Y is halogen, hydroxyl or alkoxy, and R1 is as defined in claim 1; 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 '0 - 26 - 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 10 R3 is hydrogen, Cj-C^-alkyl, Cz-C^-alkenyl, Cj-C^- alkynyl, non-benzo-fused or benzo-fused Cs-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted (with the exception of hydrogen) by one or more 15 identical or different radicals R4, where Ra is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, Cx-C^-alkoxy, C1-C4-alkoxycarbonyl, Ci-C^-alkyl- or di-C^-alkylamino, indolyl or phenyl, where 20 the indolyl or phenyl radical is unsub stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, Cj-C*-alkyl or Ci-C^-alkoxy, where, in the case of polysubstitution, the radicals are 25 identical or different or 4. «« > '■> V 13 JUL 1993 A ' '*c e P3.-- * 238701 R3, if X is -N(R3'), is a radical -N(R5) (R6) , in which R5 and R6 are identical or different and are hydrogen, Cj.-C^-alkyl, Cx-03-alkylcarbonyl or phenyl and R 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 10 they are bonded, are a radical of the formula II — N A (H) (CH2)n in which n is 1 to 3 and 15 A is O, S, CH2 or -N(R7)-, where R7 is hydrogen,- phenyl, Cj-Cg-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these radicals are unsubstituted or substituted (with the exception of hydrogen) by phenyl which, for its part, is unsubstituted, 20 or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group consisting of: halogen, nitro, cyano, carboxyl, V * hydroxyl, methyl, ethyl, methoxy, ethoxy 25 and trifluoromethyl Y ^13 JUL 1993 or ^E!v' - 28 - •N(Ra)2, where ?'701 Ra is hydrogen or Ci-Ca-alkyI or -COOR8 or -CON(R9)2 or CONHR8, where R9 has the meaning of R8 or where (R8)2 is a CA-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 C,-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning of R1, wherein the radicals R1 and R2 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of R1 and is only present at the 4-position of the pyridine moiety and one of the radicals R3 and R4, wherein R3 and R4 are as defined above, is present in the 5-position of the pyridine moiety, (with the proviso that compounds of formula 1 are excluded when R1 is -C(0)-X-R3 wherein at the same time X is 0 and R3 is hydrogen) and the physiologically tolerable salts thereof for use as medicaments.

6. A 2,4- or 2,5-substituted pyridine-N-oxide of ■* f n2. formula I 22 mWH ' - 29 - 2 3 P 7 01 r (i) N 4 0 in which R1 is -C (O) -X-R3, where X is 0 or -N(R3')- and R3 is hydrogen, Ci-Cg-alkyI, C2-C6-alkenyl, C2-C6-alkynyl, C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted (with the exception of hydrogen) by one or two identical or different radicals R*, where R* is halogen, hydroxyl, cyano, amino, carboxyl, Cx-C4-alkoxy, C1-C4-alkoxy-carbonyl, Ci-C^-alkyl- or di-CM-aIkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, Ci-C^-alkyl or C1-C2-alkoxy, 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 and (II) N A \ / (CH2)n - 30 in which n is 1 to 3 and A is 0/ CH2 or -N(R7) - / where R7 is hydrogen, phenyl or C1-Cs-alkyl/ where these mentioned radicals are unsubstituted or substituted (with the exception of hydrogen) 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 consisting of: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or R7 is Cj-C4-alkoxycarbonyl or Cj-Cy-cycloalkyl and in which represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning of R1, wherein the radicals Rl and R2 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of R1 and is only present at the 4-position of the pyridine moiety and one of the radicals R3 and R4, wherein R3 and R4 are as defined above, is present in the 5-position of the pyridine moiety, (with the proviso that compounds of formula I are excluded when R1 is -C(0)-X-R3 wherein at the same time X is 0 and R3 is hydrogen) and the physiologically tolerable salts thereof, for the inhibition of proline hydroxylase and lysine hydroxylase.

7. A 2,4- or 2,S-substituted pyridine-N-oxide of the formula I r2_ N R1 O P. * 701 (i) V 12 AW94, - 30a - 23 8 7 0 1 in which R1 is -C(O)-X-R3, where X is 0 or -N (R3') - and R3 is hydrogen, Ci-Cj-alkyl, C6-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted (with the exception of hydrogen) by one or two identical radicals R*, where R* is hydroxyl, amino, carboxyl, Ci-C^-alkoxy, Ci-C*-alkoxy carbonyl 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 -T\ (II) (CH2)n in which n is 2 and A is 0 or CH2, and in which R2— represents the moieties present at the 4- and 5- positions of the pyridine moiety, wherein either R2 has the meaning of Rl, wherein the radicals R1 and R2 are identical or different, at either the 4-position or 5-position and at the other position is a hydrogen atom or R2 has the meaning of Rl and is only present at the 4-position of the pyridine moiety and one of the radicals R3 and R\ wherein R3 and R4 are as defined above, is present in the 5-position of the pyridine moiety, (with the proviso that compounds of formula I are excluded when Rl is -C(0)-X-RJ wherein- at the same time X is 0 and R3 is hydrogen) and the physiologically tolerable salts thereof, for use as fibrosuppressives and ^ E K < immunosuppressives. / '<? ? 7 (\po-Q94

8. A pharmaceutical composition containing a compound of the formula I as claimed in claim 1 and a pharmaceutically tolerable carrier.

9. The use of compounds of the formula I as claimed in claim 5 for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq; with the proviso that a method of medical treatment of the human body is excluded.

10. The use of compounds of the formula I as claimed in claim 5 for the treatment of disorders of the metabolism of collagen and collagen-like substances or the biosynthesis of Clq; with the proviso that a method of medical treatment of the human body is excluded.

11. 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.

12. A compound according to any one of claims 1, 2, 3, 5, 6, and 7 substantially as herein, idescribed or^exemplified.

13. A process according to claim 4 substantially as herein described or exemplified.

14. A pharmaceutical composition according to claim 8 substantially as herein described or exemplified.

15. A process according to claim 11 substantially as herein described or exemplified. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES Per: £ N 13 JUL 1993