AU631285B2 - Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof - Google Patents

Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof Download PDF

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AU631285B2
AU631285B2 AU69366/91A AU6936691A AU631285B2 AU 631285 B2 AU631285 B2 AU 631285B2 AU 69366/91 A AU69366/91 A AU 69366/91A AU 6936691 A AU6936691 A AU 6936691A AU 631285 B2 AU631285 B2 AU 631285B2
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collagen
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Ekkehard Baader
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Description

31,128B Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION (OR IGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published.
Priority.
Related Art Name of Applicant Address of ApplIcant Actual Inrven tor A\dcreis for SeIrvice HOECHST AKTI ENGESELLSCVIAPN' 50 Bruningstrasse, d-62230 rFrarikfurt/Main 80, Federal Republic of Germany EKKEHARD BAADER WATERMARK PATENT MrAI)EMARK ATTIOHNEYS.
LO)CKE[) BAG NO). 5, HIAWT1HORN, VICTORIA 3122, AUSTR1ALIA Complete Spec'ification for the, invention entitled: DI(NITROX~~YL)N4IDES OF PYRIDINE-2,4- AND 2,5-DICARBOXYLIC ACIDS, A PROCESS FOR THE PREPA~RION THVEREOF, AMD TH1E USE THER M-F The following statement is a full description of this invention, including the best method of performing it known to us S' OECHST AKTIENGESELLSCHAFT HOE 90/F 010 Dr. SW/PP Description Di(nitroxyalkyl)amides of pyridine-2,4- and dicarboxylic acids, a process for the preparation thereof, and the use thereof Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase bring about a very selective inhibition of collagen biosynthesis by influencing the 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, the result is an insufficiently hydroxylated collagen molecule which is unable to function and can be released by the cells into the extracellular space only in a small amount.
Moreover, the insufficiently hydroxylated collagen cannot be incorporated in the collagen matrix and very readily undergoes proteolytic degradation. The consequence of these effects is an overall reduction in the amount of collagen deposited outside the cells.
It is known that the inhibition of proline hydroxylase by known inhibitors such as a,a'-dipyridyl results in inhibition of Clq biosynthesis by macrophages Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 (1978), 47). This leads to the classical pathway of complement activation becoming inoperative. Thus, inhibitors of proline hydroxylase also act as immunosuppressants, for example in immune complex diseases.
It is known that the enzyme proline hydroxylase is efficiently inhibited by pyridine-2,4- and oxylic acids Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). These compounds are, however, effective inhibitors in cell culture only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 625- 633).
I I sli- aar~sl~o~~aaarr;rt g 2 DE-A 34 32 094 gives a description of diesters of pyridine-2,4- and -2,5-dicarboxylic acids with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for inhibiting proline hydroxylase and lysine hydroxylase.
These lower alkyl diesters have the disadvantage, however, that in the body they are too rapidly cleaved to the acids and do not reach their site of action in the cell in sufficiently high concentration and thus are poorly suited for possible administration as pharmaceuticals.
DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 describe in a general form mixed ester/amides, higher alkyl diesters and diamides of pyridine-2,4- and boxylic acids, which are effective inhibitors of collagen biosynthesis in animal models.
Thus, DE-A 37 03 959 describes, inter alia, the synthesis of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide and N,N'-bis(3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
German Patent Applications P 38 26 471.4 and P 38 28 140.6 propose an improved process for the preparation of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide.
German Patent Application P 3924093.2 proposes new N,N'bis(alkoxyalkyl)pyridine-2,4-dicarboxamides.
Both pyridine-2,4- and -2,5-dicarboxamides (Hirakata et al., J. pharm. Soc. Japan 77 (1957) 219 and Haring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and (Itai et al., Bl. nation. hyg.
Labor. Tokyo, 74 (1956) 115, 117 and Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839) have already been disclosed as agents for tuberculosis.
JP 53/28175 (78/28175) describes N,N'-bis(2-nitroxyethyl)pyridine-2,4- and -2,5-dicarboxamides as substances with a vasodilator action.
I I L L I 3 It has now been found, surprisingly, that di(nitroxyalkyl)amides of pyridine-2,4- and acids, of the formula I 02NO- R- HNO -t x (I) N CONH-R-ONO 2 in which R is Ci-C 4 -alkanediyl, and the physiologically tolerated salts, effectively inhibit lysine hydroxylase and proline hydroxylase in animal models.
Accordingly, the invention relates to a) the use of compounds of the formula I 0 2
NO-R-HNOC..
N
CONH-R-ONO
2 in which R is Ci-C 4 -alkanediyl, and the physiologically tolerated salts, for the preparation of a pharmaceutical which inhibits proline hydroxylase and lysine hydroxylase.
The invention additionally relates to b) the compounds of the formula I in which R is methylene, propylene or butylene, and the physiologically tolerated salts, for use as pharmaceuticals.
r 4 I 4 I The invention additionally relates to c) the compounds of the formula I in which R is methylene, propylene or butylene, and the physiologically tolerated salts thereof.
The invention particularly relates to the compounds of the formula I defined in b) and c) for use as fibrosuppressants and immunosuppressants and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagenlike substances and the biosynthesis of Clq.
All the said alkyl radicals with more than 2 carbon atoms can be both straight-chain and branched.
"'he invention additionally relates to a process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II
O
Y-C--
N C-Y
(II)
with a compound of the formula III
H
2 N-R-ON0 2
(III)
where R has the meaning specified for formula I, and Y is halogen, hydroxyl or C 1
-C
4 -alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises nitrating a compound of the formula IV 1 L I 5
HO-R-HNOC-
I
(IV)
N CONH-R-OH in which R is as defined above, and subsequently converting the reaction products where appropriate into their physiologically tolerated salts.
The preparation of compounds of the formula I and the preparation of those starting substances required for this which cannot be bought is described in detail hereinafter.
The compounds according to the invention are prepared most straightforwardly by the two components, the pyridine derivative of the formula (II) and the amine of the formula (III), being mixed in equimolar amounts or with an up to about 5-fold excess of III and reacted at temperatures between -30 and 150*C, preferably at 20 to 100"C, until the reaction is complete. The completion of the reaction can be determined, for example, by thinlayer chromatography. One variant of this process comprises using a suitable solvent such as diethyl ether or dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, tri- or tetrachloroethylene, benzene, toluene or else polar solvents such as dimethylformamide, acetone, alcohols such as methanol or ethanol or dimethyl sulfoxide. It is also possible in this case to use an excess of amine of the formula (III), which can be up to about amounts. The temperatures for this reaction are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature to 130°C being particularly preferred.
The reaction can likewise be carried out via a mixed
I
6anhydride such as ethyl chloroformate or via an activated ester such as paranitrophenyl ester CICH 2 -COO or
NO
2
-C
6 Appropriate methods are described in the literature.
It is also possible, where appropriate, for the reaction to be carried out in the presence of bases. Examples of suitable additional bases are carbonates or bicarbonates such as sodium or potassium carbonate or sodium or potassium bicarbonate, or tertiary amines such as triethylamine, tributylamine, ethyldiisopropylamine or heterocyclic amines such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.
One variant for the preparation of the compounds of the formula I comprises nitration of the corresponding hydroxyalkyldiamides of pyridine-2,4- or carboxylic acid This entails adding concentrated nitric acid to the corresponding hydroxyalkyldiamides at reaction temperatures from -20°C to +10 0 C, preferably at to 5C. The reaction time in this case is 10-240 min, preferably 20-90 min. The reaction product is subsequently neutralized where appropriate.
Where appropriate the products can be worked up, for example, by extraction or by chromatography, for example on silica gel. The isolated product can be recrystallized and, where appropriate, reacted with a suitable acid to give a physiologically tolerated salt. Examples of suitable acids are: mineral acids such as hydrochloric and hydrobromic acid, and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, auccinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-, onic or ascorbic acid.
7 Those starting compounds of the formula (III) which cannot be bought can be synthesized by processes known from the literature.
The starting Compounds of the formula (II) are obtained, for example, by converting pyridine-2,4- or oxylic acid into the corresponding pyridine-2,4- or dicarbonyl halide, preferably chloride (by processes known from the literature), preferably in the presence of a catalyst such as dimethylformamide. This acid halide can then be reacted, for example, either with a suitable alcohol, for example paranitrobenzyl alcohol, to give the corresponding active ester, or else with lower alcohols such as methanol or ethanol to give the corresponding esters. It is likewise also possible for the pyridine- 2,4- or -2,5-dicarboxylic acid initially to be converted by addition of a suitable carboxylic acid or of a carboxylic ester such as ethyl chloroformate into a mixed anhydride which is then reacted with the amines (III) to give the products according to the invention. An appropriate method is likewise described in the literature.
The starting compounds of the formula (IV) are obtained, for example, by reacting corresponding N,N'-bis(alkoxyalkyl)pyridine-2,4- or -2,5-dicarboxamides, preferably the bis(methoxyalkyl)diamide by processes known from the literature, for example with boron tribromide. The preparation of the bis(alkoxyalkyl)diamides is known and described, for example, in DE-A 3,703,959. This entails reacting a reactive pyridinedicarboxylic acid derivative, for example the pyridinedicarbonyl chloride, with an alkoxyalkylamine.
The compounds of the formula I according to the invention have valuable pharmacological properties and display, in particular, activity as inhibitors of proline hydroxylase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.
Because of these pharmacological properties, the compounds according to the invention are suitable for the treatment of disturbances of the metabolism of collagen and collagen-like substances and for the treatment of disturbances of the biosynthesis of Clq.
Hence the invention furthermore relates to the use of the compounds of the formula I according to the invention and of the physiologically tolerated salts thereof for the treatment of the abovementioned metabolic disorders.
The compounds can be used as pharmaceuticals either alone or mixed with physiologically tolerated auxiliaries or excipients. They can be administered for this purpose orally in doses of 0.01 25.0 mg/kg/day, preferably 0.01 5.0 mg/kg/day or parenterally in doses of 0.001 5 mg/ kg/day, preferably 0.001 2.5 mg/kg/day, in particular 0.005 1.0 mg/kg/day. The dose can also be increased in severe cases. However, in many cases, lower doses are also sufficient. These data relate to adults weighing about 75 kg.
The invention additionally embraces the use of the compounds according to the invention for the preparation of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders.
The invention furthermore relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or the physiologically tolerated salts thereof.
The pharmaceuticals are prepared by processes which are known per se and familiar to those skilled in the art.
The pharmacologically active compounds active substance) according to the invention are employed as pharmaceuticals either as such preferably, in combination with suitable pharmaceutical auxiliaries or 9 excipients in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, in which the content of active substance is up to about 95%, advantageously between 10 and Examples of suitable auxiliaries or excipients for the desired pharmaceutical formulation are, besides solvents, gel-formers, suppository bases, tablet auxiliaries and other active substance vehicles, also antioxidants, dispersing agents, emulsifiers, antifoam agents, flavor correctives, preservatives, solubilizers and colorants.
The active substances can be administered orally, parenterally or rectally.
The active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions.
Examples of inert excipients which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose ot starch, especially corn starch. This preparation can be carried out both as dry and as wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are converted into solution, suspension or emulsion, if desired with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example ethanol, propano, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
10 The invention is explained in detail hereinafter by means of examples.
Precursor 1: bis-N,N'-(Methoxyethyl)amideof pyridine-2,4-dicarboxylic acid CONH-h 2-CH 2 OCH3 N
CONH-CH
2 -CH2-OCH 3 3 g of pyridine-2,4-dicarboxylic acid are introduced into ml of toluene and 1 ml of DMF, and 2.7 ml of thionyl chloride are added dropwise to the solution. The mixture is heated until no further evolution of gas is evident (about 2.5 The mixture is cooled, 5 ml of toluene are distilled out, and 4.6 ml of 2-methoxyethylamine and 5 ml of triethylamine are added dropwise to the solution. The solution is stirred at room temperature for 4 h and then evaporated, the residue is taken up in water and extracted 4 x with methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated.
The crude product is chromategraphed on silica gel (solvent ethyl acetate).
Melting points 42 44"C 1 H-NMR (CDCl 3 6S 1.2 (3H, tr); 3.3-3.8 (12H, qu. and m) 7.9 (1H, 8.4-8.5 (1H, m); 8.7-8.8 (1H, m); Precursor 2: bis-NN'-(2-Hydroxyethyl)amide of pyridine-2,4dicarboxylic acid CONH-CH2-CH2
OH
b" CONH-CH2-H 2
-OH
g of bis-(N,N'-(2-methoxyethyl)anide of pyridine-214dicarboxylic acid (precursor 1) is dissolved in 10 ml of dichioromethane and, at -780C, boron tribromide (11 ml, 1 molar solution in dichioromethane) is added dropwise.
After addition is complete, allow to reach room temperature and then stir for 3 hours. Pour- into 100 ml of saturated bicarbonate solution and extract 3 x with ethyl acetate. The combined organic solvents are dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel.
1 11NMR (CDCl 3 6 -1.5-2.2 (4H, in); 3.4 (4H1, mn); 3.6 (4H1, in); 7.9-8.0 (1H1, in); 8.4-8.5 (1H, in); 8.7-8.8 (111, in) Example 1 N,N I'-Di 2-nitroxyethyl amide of pyridine-21,4-dicarboxylic acid CONH-CH2-CH2 0N0 2 C CONH- CH~ 1 q of di(2-hydroxyethyl)anide of pyridine-2*4-dicarboxylic acid (precursor 2) is added at -IO0C to -SOC 12 of concentrated nitric acid. The mixture is allowed to warm to 2*C and then stirred for 40 minutes. It is poured into ice/water and neutralized with sodium carbonate. The solution is extracted three times with dichloromethane, and the organic phases are dried over magnesium sulfate and evaporated. The residue crystallizes from ether.
Yield: 750 mg Melting point: 85 88°C

Claims (7)

1. The use of di(nitroxyalkyl)amides of pyridj-e-2,4- and acids, of the formula I 0 2 NO-R-HNOC-- (I) N CONH-R-ONO 2 in which R is linear or branched Cl-C-alkanediyl, and the physiologically tolerated salts, for the prepar- ation of pharmaceuticals which inhibit proline hydroxyl- ase and lysine hydroxylase.
2. The use as claimed in claim 1, wherein R is ethylene or propylene.
3. A compound of the formula I 0 2 NO-R-HNOC-. C- (I) N CONH-R-ONO 2 in which R is methylene, propylene or butylene, and the physiologically tolerated salts.
4. A compound of the formula I as claimed in claim 3, wherein R is methylene or n-propylene. 54==Asmpound=s= am- ed--n c-aam--4-, for use as a A process for the preparation of compounds of the A process for the preparation of compounds of the r V r^ i~iri~~(ao~-- formula I as claimed in claim 3, which comprises reacting a compound of the formula II 0 O with a compound of the formula III H 2 N-R-ON0 2 (III) where R has the meanings specified in claim 3, and Y is halogen, hydroxyl or C,-C4- alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises nitrating a compound of the formula IV HO-R-HNOC--- I (IV) N CONH-R-OH In which R is defined In claim 3, and subsequently converting the reaction products where appropriate Into their physiologically tolerated salts.
6. A method of Inhibiting proline hydroxylase and lyslne hydroxylase comprising administering to a patient requiring such treatment an effective amount of a compound as claimed in claim 3 or 4.
7. A method of fibrosuppression and Immunosuppresslon comprising administering to a patient requiring such treatment an effective amount of a compound as claimed in any one of claims 1-4,
8. A pharmaceutical containing a compound of the formula I as claimed in claim 3 or 4 with tolerated pharmaceutical vehicles, AU0g000I.WPC(DO. 21)1 bEMiK r i The use of compounds of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq. The use of compounds of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 for the treatment of disturbances of the metabolism of collagen and collagen-like substances and of the bio- synthesis of Clq. 2l9. A process for the preparation of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq, which comprises adding a compound of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 to the pharmaceutical. DATED this 14th day of January 1991. HOECHST AKTIENGESELLSCHAFT WA.E'tLRMARK PATENT TRADEMARK ATTORNEYS "THE ATRIUM" 290 BURWOOD ROAD HAWTHORN. VIC. 3122.
AU69366/91A 1990-01-16 1991-01-15 Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof Ceased AU631285B2 (en)

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Application Number Priority Date Filing Date Title
DE4001002A DE4001002A1 (en) 1990-01-16 1990-01-16 N'N'-di:(nitroxyalkyl) pyridine-2,4- and -2,5-di:carboxamide derivs. - used as proline and lysine hydroxylase inhibitors for use a immuno:suppressive, fibro-suppressive and collagen biosynthesis inhibitors
DE4001002 1990-01-16

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AU631285B2 true AU631285B2 (en) 1992-11-19

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BR (1) BR9100159A (en)
CA (1) CA2034206A1 (en)
CS (1) CS7591A2 (en)
DE (1) DE4001002A1 (en)
FI (1) FI910177A (en)
HU (1) HUT59102A (en)
IE (1) IE910126A1 (en)
IL (1) IL96941A0 (en)
MA (1) MA22041A1 (en)
MX (1) MX24143A (en)
NO (1) NO910163L (en)
NZ (1) NZ236766A (en)
PT (1) PT96493A (en)
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DE4020570A1 (en) 1990-06-28 1992-01-02 Hoechst Ag 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF
YU9492A (en) * 1991-02-05 1995-03-27 Hoechst Ag. 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation
EP0533130A1 (en) * 1991-09-19 1993-03-24 Hoechst Aktiengesellschaft 2-Hydroxymethylpyridines, the corresponding pyridine-N-oxides and derivatives thereof, process for their preparation and their use
EP0541042A1 (en) * 1991-11-05 1993-05-12 Hoechst Aktiengesellschaft 2,4- and 2,5-pyridine-dicarboxylic acid derivatives, process for their preparation and their use

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FI910177A (en) 1991-07-17
KR910014352A (en) 1991-08-31
HU910109D0 (en) 1991-08-28
CN1053606A (en) 1991-08-07
NO910163D0 (en) 1991-01-15
HUT59102A (en) 1992-04-28
AU6936691A (en) 1991-07-18
PT96493A (en) 1991-10-15
JPH04330060A (en) 1992-11-18
EP0438795A1 (en) 1991-07-31
CS7591A2 (en) 1991-09-15
BR9100159A (en) 1991-10-22
NZ236766A (en) 1993-08-26
IL96941A0 (en) 1992-03-29
FI910177A0 (en) 1991-01-14
ZA91291B (en) 1991-09-25
DE4001002A1 (en) 1991-07-18

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