AU636990B2 - 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

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: @*Priority 00.

0*0 0 :*.**Plelated Art 00 Name of Applicant e A~cldre~s of Applicant 00 0 Ptual Inventor :.Address for Service HOECHST AKTIENGESELLSCHAFT D-6230 Frankfurt/Main 80, Federal Republic of Germany EKKEHARD BAADER, MARTIN BICKEL and VOLKMAR GUNZLER-PUKALL WATERMARK PATENT TRADEMARK ATTORNEYS.

LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: 2,4- AND 2,5=SUBSTITUTED PYRIDINE-N-OXIDES, PROCESSES FOR THEIR PREPARATION AND THEIR USE The following statement is a full description of this invention, including the best method of performing it known to :-us 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, proteinbound 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 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.

9 99 99 9 9S *c 9 944 59 4 *9U 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 25 known inhibitors such as a,a'-dipyridyl leads to an inhibition of Clq biosynthesis by macrophages MUller 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 acid Majamaa et al., 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 3,432,094 describes pyridine-2,4- and 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.

n.

C

C

Ci a. S

C

a C. 0

C.

C

ease *6

C

C.

4*

C

ea 15 DE-A 3,703,959, DE-A 3,703,962 and DE-A 3,703,963 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, 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 N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide is proposed in German Patent Applications P 38 26 471.4 and P 38 28 140.6.

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 amides for the preparation of pharmaceuticals inhibiting proline hydroxylase and lysine hydroxylase.

Both pyridine-2,4- and I I -3 (Hirakata et al., J. pharn. Soc. Japan 77 (1957) 219 and Haring et al. Helv. 37 (1954) 147, 153) and pyridine- 2,4- and -2,5-dicarboxylic acid dihydrazide (Itai et al. Bi. 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-nitrooxyethyl) pyridine-2 and 5-dicarboxamides as substances having vasodilatory action.

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

ill 1 The invention accordingly relates to 2,4- and stituted pyridine-N-oxides of the general formula I Ve *R2_ 0:

R

0 is 00r-( n :ylakl ary or ineral whichtes difeen isicl RCO)X, 3 where R 4 is hdrogen, hydroxalyl, C 2 cy 2 alkn, nitro, -4 nitroxy, amino, carboxyl, Cl-C 4 -alkoxy,

CI-C

4 -alkoxycarbonyl, Cl-C-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C 1 alkyl or C,-C 4 -alkoxy, where, in the case of polysubstitution, the radicals are identical or different or

R

3 if X is -N(R 3 is a radical -N(R 5 in which R 5 and R 6 are identical or different and are hydrogen, Cl-C 4 -alkyl, Cl-C 3 -alkylcarbonyl or phenyl

S.

5 I~ 0*@e @5 0 kO *e 15 ft.'.

@6 50 0.

S

5.6 and .55556 56** 20 55 5 6

R

3 has the meaning of R where the radicals R 3 and R3'are identical or different or R 3 and R 3 together with the nitrogen atom to which they are bonded, are a radical of the formula II 5* S S S 5*

(CH

2 n (11) in which n is 1to 3and A is 0, S I CH 2 or -N (R where R is hydrogen, phenyl, C 1

-C

6 -alkyl, C 2

-C

6 ,-alkenyl I 0@ C C *0O* Re e Roe C SR CC C C 0 SCOt

OR

0* C 0O

C

0** or C 2 -CB-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 substituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -Ni(R 8 where Re is hydrogen or Cl-C 3 -alkyl or

-COOR'

or -CONW)2or CONHR where R9 has the meaning of Re or where (R'3) 2 is a C 4

-C

6 -alkylene chain in which no

CH

2 group or a CH 2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-Re or where R7 is Cl-C 4 -alkoxycarbonyl or C 3

-C

7 -CYCloalkyl

C

S.C. CS

C

0000 S C CC C

*C

C

00R4

CS

C..

C. C C C c~ and in which R 2 has the meaning of R1, where the radicals R 1 and R 2 6 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the and the physiologically tolerable salts, where the compounds of the general formula I in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides are excluded.

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 fLr influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq.

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

The invention also relates to a process for the preparation of compounds of the formula I which comprises 20 a) reacting a compound of the formula III 2

.R

2

RO

.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 as previously defined, or 25 b) reacting a compound of the formula V 0 \r K

R

1 S

(V)

in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula VI H X- RI

(VI

in which X and R3 have the meanings as previously defined, 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.

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, perfluoroacetic acid, perbenzoic acid or metachloroperbenzoic 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 oee O 0 *0 *a w 7 can likewise be dissolved in the abovementioned solvents, and stirring at a temperature between -30 and +40 0

C,

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 equimolar amounts or up to an about 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.

a 15 a a.

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 *5SO A general procedure for this oxidation method is also described, for example, in Lingsberg, Pyridine and itp Derivatives, Interscience Publishers, New York, 1961, Part 2, 93".

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

25 o I* 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 xibrosuppressive, 8 immunosuppressive and antiatherosclerotic.

0*

S

The antifibrotic action can be determined in the carbon tetrachloride-induced liver fibrosis model. For this purpose, rats are treated twice weekly with CC1 4 (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 %iodel 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 crosslinking domain of type IV collagen (7s collagen or type IV collagen-NC 1 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 (CClI control) c) rats to which first CC1 4 and then a compound according to the invention was administered were measured (this test method is described by Rouiller, 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 is bleomycin-induced lung fibrosis as described in

S

S

S

55 9 Kelley et al. Lab. Clin. Med. 96, 954, (1980)). The cotton pellet graruloma 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, 15 starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly etc.

S

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, preferably 0.01 2.5 mg/kg/day, in particular 0.5 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 S 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 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 tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the active compound content being up to about 95%, advantageously between and 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.

15 The active compounds can be administered orally, paren- 6* terally or rectally.

6 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 suspen- "sions or aqueous or oily solutions, by the customary S* 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 bc--h 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 11 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, alternatively, 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 S. dropwisi at room temperature. The mixture is stirred at S room temperature. After completion of the reaction, gaseous ammonia is blown into the solution with icecooling 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 S 20 of thin layer chromatography.

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

Example 1 09* 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) 102°C 12 Example 2 N, N -Di- (3-methoxypropyl )pyridine-2 ,4-d.carboxamide N-oxide From 1 g of N,N' 3-methoxypropyl)pyridine-2, 4-dicarboxamide and 1.2 g of MCPBA.

Yield: 0.58 g (recrystallization: ethanol) 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) 260-C Example 4 to 0 15 N,N'-Di-(2-dimethoxyethyl)pyridine-2,4-dicarboxamide '06:06 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 /me-thanol 5:1) ~20 86 0

C

13 Example 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.

Yield: 0. 34 g (chromatography: ethyl acetate /methanol 5:1) Bloc Example 6 N,N'-Di-(2-methcoxyethyl)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.

0 too Yield: 0.4 g (recrystallization: ethanol) 137 0

C

Example 7 Di- (2-methoxyethyl) pyridine-2, 4-dicarboxylate N-oxide From 1 g of di-(2-methoxyethyl) pyridine-2,4-dicarboxylate and 1.3 g of MCPBA.

2. :0 Yield: 0.2 g (chromatography: ethyl acetate) oil 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 MCPHA.

Yield: 0.4 g (recrystallization: ethanol) 128 0

C

Example 9 N,N' -Di- (3-methoxypropyl)pyridine-2, 5-dicarboxamide Noxide From 1 g of il,N-di-(3-methoxypropyl)pyridine-2,5-dicarboxamide and 1.2 g of MCPBA.

Yield: 0.3 g (recrystallization: diethyl ether/methanol) M4.P.: 123'C ego* Example 2,4-Di-E (morpholin-1-yl)carbonyl~pyridine N-oxide From 1 g of 2,4-di-( (morpholin-1-yl)carbonyl]pyridine and 1,2 g of MCPBA.

00 Yield: 0.5 g (chromatography: ethyl acetate /methanol 5/1) oil o ego .64 0 es 15 Example 11 N,N'-Di-(4-hydroxybutyl)py-ridine-2,4-dicarboxamide N-oxide From 1 g of N,N' -di-(4-hydroxybutyl)pyridine-2 ,4-dicarboxainide and 0.8 g of !4CPBA.

Yield: 0.82 g (ethanol) B6*C Example 12 N, N '-Dicyclohexylpyridine-2 ,4-dicurboxamide N-oxide From 1 g of N,N! -dicyclohexylpyridine-2,4-dicarboxamide 16. and 0 g of MCPBA.

Yield: 0.59 g (ethanol) 6 153 0

C

Example 13 N,N'-Di-(3-chlorobenzyl)pyridine-2,4-dicarboxamide 0 N-oxide 5. From 1 g of N,N'-di-(3-chlorobenzyl)pyridine-2,4-dicarboxamide and 0.65 g of MCPBA.

Yield: 0.76 g (tolnene) 112 0

C

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-dicarboxaniide and 1.2 g of MCPBA.

Yield: 0.72 g (toluene) 1-93 0

C

Example Di- (4-chiorobutyl) pyridine-2, 4-dicarboxylate N-oxide From 1 g of di-(4-chlorobutyl) pyridine-2,4-dicarboxylate and 0.75 g of MCPBA.

e.Yield: 0.8, g (ethanol) 96'C Example 16 Dicyclohexyl pyridine-2,4-dicarbc'xylate N-oxide From 1 g of dicyclohexyl pyridine-2,4-dicarboxylate and g of MCPBA.

Yield: 0.87 g~ MS 348 molecular weight 347 17 Example 17 Di-(methoxycarbonylmethyl) N-oxide pyridine-2,4-dicarboxylate From 1 g of di-(methoxycarbonylmethyl) pyridine-2,4-dicarboxylate and 1.1 g of MCPBA.

Yield: 0.81 g Oil, MS 328 molecular weight 327 Example 18 Pharmacological activity i0 00* 0 *0 0 20 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), b) rats treated with CC1 4 c) rats to which first CClI 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.

**0 18 Table 1: Action of prolyl hydroxylase inhibitors on CCl 4 -induced liver fibrosis iii rats Treatm~ent Control CCl4 Example 1 Example 2

D

Owe Biflrubin ifkc N "iM 5 1.76 0.27 22 4.98 1.06 20 12 6.30 t 5.4 (0) 20 11 2.90 0.94* Bile acids 26 6.8 81 8.7 97 76 (0) 71 42 (18) Gm Gr 5.3 ±1.4 4,3 ±3.1 (27) 3.3 2.2* (59) *0 0 1 00 0 :000 0 a g The results are mean values standard deviation, *P <0.05 for CCd 4 treatment, values in brackets ar~e the percentage improvement compared to an exclusive CCd 4 treatment.

a: total daily oral dose.

0 00 00 0 0 00 00

Claims (3)

1. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I N N 0 in which R is where 99 9* 0 *900 09 9 00 0 9 0 00*e 0 S *9 9 *9 0 *00909 0009 9* 09 00 9 0 909* X is 0 or -N (R 3 and R 3 is hydrogen, C-C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 alkynyl, non-benzo-fused or benzo-fused C5-C 7 cycloalkylf aryl or hetproary, where these radicals mentioned for R 3 are unsubstitutid or are substituted by one or more identical or different radicals R 4 where R 4 is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, Cl-C 4 -alkoxy, Cl-C 4 -alkoxycarbonyl, Cl-C-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub- stituted or mono subs tituted, disubstituted or trisubstituted by halogen, nitro, CI-C 4 alkyl or Cl-C 4 -alkoxy, where, in the case of polysubstitution, the radicals are identical or different or R 3 if X is -N(R 3 is a radical -N(R 5 )(R 6 in which

9. 9 090 20 09 20 R 5 and R 6 are identical or different and are hydrogen, Cl-C 4 -alkyl, C,-C 3 -alkylcarbonyl or phenyl and R 3 has the meaning of R 3 where the radicals R 3 and R3'are identical or different or R 3 and R 3 together with the nitrogen atom to which they are bonded, are a. radical of the formula II *o 10 0 0 i.. 0 Os 0 9 *0s S 00 00 0 0 0 0.9. 0 0 09 0 00 0 000 (CM 2 (11) in which n isl1to 3and A is 0, S, CH 2 or -N(R 7 where C se* at 00 0 000* R7 is hydrogen, phenyl., Cl-C 6 -alkyl, C.-C-alkenyl (7r C 2 -C-alkynyl, where these mentioned radicals are unsublstituted or substituted by phenyl which, foL its part, is unsubstituted, or monosubstituted ox polysubstituted by one or more identical or different sub- stituents selected from the group compri- sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl -N (R 8 )21 where

21. R 8 is hydrogen or C 1 -C 3 -alkyl or -COOR' or -CON or CONHR 7 where R 9 has the meaning of R8 or where (R 9 2 is a C 4 -C 6 -alkylene chain in which no CH 2 group or a CH. group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R 8 10 C. C C el's Ce C C Ca. C. C or where a a R 7 is Cl-C-alkoxycarbonyl or C 3 -C 7 -CyCloalkyl and in which R 2 has the meaning of R 1 where the radicals R1 and R 2 are identical or different or R 2 is nly present in the 4-position, and one of the radicals R 3 or R 4 is in the memo*: 15 to.* C. a 5*5 5* 5 a CC and the physiologically tolerable salts, where the compounds of the general formula I awe oxeluded in which 20 R 1 and R 2 are identical or different and are carboxyl, its methyl or ethyl esters anid its diethylamides creXi~ 2. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I 22 in which R 1 is -C(O)-X-R 3 where X is 0 or -N(R 3 and S 0 *4ee 0* S 0 0eS S S. *t 0 0 U ee S. SW S.. R 3 is hydrogen, Cl-C-alkyl, C 2 -C-alkenyl, C 2 -Cr 6 r- alkynyll C 5 -C 7 cycloalkyl 1 aryl or hetoroe1ryl, where tI~ese radicals mentioned for R 3 are unsubstituted or are substituted by one or two identical or different radicals where R4 is halogen, hydroxyl, cyano, amino, carboxyl, Cl-C-alkoxy, Cl-C 4 -alkoxy- carbonyl, C-C 4 -alkyl- or -dialkylaniino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, Cl-C 2 ,-alkyl or Cl-C 2 -alkoxy, and R -has the meaning of R3, where the radicals R 3 and R 3 are identical or different or R 3 and together with the nitrogen atom to which they are bonded, are a radical of the formula II S *05 S. 15 S. SW S 55 55 5545 SO S. .5 S 5* (C8 2 (II) 23 in which n is 1 to 3 and A is 0, CH 2 or -N(R 7 where R 7 is hydrogen, phenyl or Cl-C.-alkyl, where these mentioned radicals are unsubstituted or sub- stituted 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 compri- sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl *7 R is C 1 -C 4 -alkoxycarbonyl or C 3 -C7-cycloalkyl and in which a R 2 has the meaning of R 1 where the radicals R 1 and R 2 are identical or different or R 2 is only present in the 4-position, and one of the radicals R 3 or R 4 is in the and the physiologically tolerable salts, where the compounds of the general formula I aro e- ludcd in which R 1 and R 2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides cra ec\oAe.. 3. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I R 2 N R 4 0 '0 C) 23a in which 3 is where X is 0 or -N(R 3 and a. a a a. a a a a. a a a S a Se S a. a S *a a a a a S. S a. a S a. a. S* S.. a a S 24 R3 is hydrogen, CI-C 5 -alkyl, C 6 -cycloalkyl, phenyl or pyridyl, where these radica>F mentioned for R 3 are unsubstituted or are subi'tituted by one or two identical radicals R 4 where R 4 is hydroxyl, am-ino, carboxyl, Cl-C 4 -alkoxy, C.'-C,-alkoxycarbonyl or phenyl, w~here the phenyl radical is unsubstituted or mono- substituted by methyl or methoxy and R 3 hats the meaning of R 3 where the radicals R 3 and R 3 are identical or different or R' and R 3 together with the nitrogen atom to which they are bonded, are a radical of the formula II 6 *600 S. S S S 9@p* SO S. S S. 055 -N .eA (CH 2 n (II) S 55 a *5 a *5 55 0 in which n is 2and A is 0or CH 2 and in which S. S .5* 4* S a SI R2 has the meaning of where the radicals R1 are identical or different and R 2 or R 2 is only present in the 4-position, and one of the radicals R 3 or R 4 is in the and the physiologically tolerable salts, where the compounds of the general formula I -avo oMcludo-d in which '0Nr Of, 25 R 1 and R 2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides Ckre excjluckeA. 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 R 2 I X (III) N Y 0 in which Y is halogen, hydroxyl or alkoxy, I- with a compound of the formula IV H-X-R 3 (IV) S 10 in which X and R 3 have the meanings indicated in claim 1, or b) reacting a compound of the formula V in which Y is halogen, hydroxyl or alkoxy, S 15 with a compound of the formula V H-X-R 3 (VI) in which X and R 3 have the meanings indicated in claim 1, if desired introducing a further substituent into the side chain R 3 and then converting the compound thus obtained into the N-oxide and if desired then converting the compound thus obtained into a physiologicailly tolerable salt. A pharmaceutical composition comprising a compound of the formula I e e* 26 obtained ±nb Hie N-~ii and if desired then convert -ng- the compound thus obtained into a phys~qogrd-a'1y tolerable salt. A 2,4- ,5-BubStituted pyridine-N-oxide of the f9 T RI 0 in which 00 0S *ee. 00 S 0* 0 II 0SeS 0. 0* S 10 S *~0SS. 0 15 Ri is -C where X is 0 or -N(R 3 and 00 5000 0S 000 00 S S S 0* R 3 is h~ydrogen, Cl-C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -r.1 2 alkynyl, non-benzo-fused or benzo-fused C 5 -C7- cycloalkyl, aryl or heteroaryl, where thes~e radicals mentioned for R' are unsubstituted or are substituted by one or more identical or different radicals R 4 where R4 is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, C,-C 4 -alkoxy, Cl-C-akoxycarbonyl, Cl-C-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub- stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C 1 alkyl or CI-C4-alkoxy, where, in the case of polysubstitution, the radicals are identical or different 27 R 3 if X is -N(R 3 is a radical -N(R 5 )(R 6 in whI c h R 5 and R 6 are identical or different and are hydrogen, C.-C 4 -alkyl, Cl-C 3 -alkylcarbonyl or phenyl and R' has the meaning of R where the radicals R 3 and R 3 are identical ~rdifferent or R' and RV', together with the nitrogen atom to which they are bonded, are a radical of~ the *.*formula II to: S N i ,C2o whr inny whicho tspr, sunusittd ist0,l,,ethylorm-N(Rx)-,ewhere an rfurmty -N(R8) 2 where R8 is hydrogen or C1-C 3 -alkyl or -COOR8 or -CON(R9) 2 or CONHR7, where R9 has the meaning of R8 or where (R9) 2 is a C 4 -C 6 -alkylene chain in which no CH 2 group or a CH 2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R8 or where R7 is Cl-C 4 -alkoxycarbonyl or Cs-Cy-cycloalkyl and in which R2 has the meaning of R1, where the radicals Ri 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 in adjunct with pharmaceutically acceptable carriers or excipients. 6. A process for the production of a pharmaceutical composition as claimed in claim 5, which comprises converting a compound of the formula I as defined in claim 5 and a pharmaceutically tolerable carrier into a suitable administration form. 7. A method of inhibiting proline hydroxylase and lysine hydroxylase comprising administering to a patient requiring such an effective amount of a compound of the formula I 0* S S* S S S S S. S S. S S 29 in which R1 is -C(O)-X-R 3 where X is 0 or -N(R 3 and S 9 S. IS S 555 S 55 9 5 S *S55 0* S. *9 Sgj R 3 is hydrogen, C,-C-alkyl, C 2 -C-alkenyl, C 2 -C 6 alkynyl, C-C 7 -cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R 3 are unsubstituted or are substituted by one or two identical or different radicals R 4 where R 4 is halogen, hydroxyl, cyano, amino, carboxyl, cl-C-alkoxy, CI-C 4 -aJlkoxy- carbonyl, Cl-C-alkyl- or -dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted, by halogen, Cl-C 2 -alkyl Or C 1 -C 2 -alkoxy, and has the nipaning of R where the radicals R 3 and R 3 are identical or different or R' and R 3 together with the nitrogen atom to which they are bonded, are a radical of the formula II 0 555559 S *ee. 15 S. 9* a S. S S So. a. S 9. *5 NA (CH 2 n IX) in which n is 1 to 3 and A is O, CH 2 or where R7 is hydrogen, phenyl or Ci-Cs-alkyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstiluted or polysubstituted by one or more identical or different substituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is Ci-C 4 -alkoxycarbonyl or C 3 -C 7 -cycloalkyl and in which R2 has the meaning of Ri, 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 8. A method of fibrosuppression and immunosuppression comprising administering to a patient requiring such an effective amount of a compound of the formula I R 2 'R (I) 0 S *ooo: Jf 30a in which Rl is where X is 0 or -N(R 3 and R 3 is hydrogen, Cl-C 5 -a2.kyl, C.-cycloalkyi, phenyl 6 GeV O k I I v 31 or pyridyl, where these radicals mentioned for R 3 are unsubstituted or are substituted by one or two identical radicals where R 4 hydroxyl, amino, carboxyl, C 1 -C 4 -alkoxy, Ci-C 4 -alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or mono- substituted by methyl or methoxy and R 3 has the meaning of R 3 where the radicals R 3 and R 3 are identical or different or R 3 and R 3 together with the nitrogen atom to which they are bonded, are a radical of the formula II (CH 2 )n in which n is 2 and A is 0 or CH 2 and in which R 2 has the meaning of R 1 where the radicals R 1 and R 2 20 are identical or different or R 2 is only present in the 4-position, and one of the radicals R 3 or R' is in the -and the phy iologically tolerab-le alts, fo--as a T' *Z^)4 9. A method of influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq comprising administering to a patient requiring such an effective amount of compound I as defined in claim A method of treating disorders of the metabolism of collagen and collagen-like substances or the biosynthesis of Clq comprising administering to a patient requiring such an effective amount of compound I as defined in claim DATED this 24th day of February, 1993. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA SDBM/CJH/ML DOC 030 AU7935691.WPC i 9 *9 ABSTRACT 2,4 and 2,5-Substituted pyridine-n-oxides of the formula I R 2 RR 0 are prepared by oxidising pyridine compounds which are appropriately 0e substituted and then, if necessary, converting the compound to a physiologically tolerated salt. The compounds are useful for the •inhibition of lysine hydroxylase and proline hydroxylase and in a Sb pharmarceutical form as fibrosuppressors and immunosuppressives and for infuencing the metalbolism of collagen and collagen like substantes as well as the biosynthesis of Cl q b S S *3