CA2063177A1 - Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds - Google Patents

Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds

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CA2063177A1
CA2063177A1 CA002063177A CA2063177A CA2063177A1 CA 2063177 A1 CA2063177 A1 CA 2063177A1 CA 002063177 A CA002063177 A CA 002063177A CA 2063177 A CA2063177 A CA 2063177A CA 2063177 A1 CA2063177 A1 CA 2063177A1
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Ekkehard Baader
Martin Bickel
Volkmar Gunzler-Pukall
Manfred Volz
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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
    • C07D213/60—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
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Abstract

Abstract of the disclosure Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds The invention relates to mixed pyridine-2,4- and -2,5-dicarboxamides where the carboxamide group in position 2 is a primary amide. The said compounds are suitable for the inhibition of proline hydroxylase and lysine hydroxylase and are used as fibrosuppressants and immunosuppressants.

Description

%~fi3177 HOECHST AKTIENGESELLSCH~FT HOE 91/F 079 Dr.FI/pl Description Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds Compounds which inhibit proline hydroxyla~e ~nd lysine hydroxyla~e effect a very selective inhibition of collagen biosynthesis due to influencing collagen-~pecific hydroxylation reactions. In the course thereof,protein-bound proline or lysine is hydroxylated by the enz~mes proline hydroxylase or lysine hydro~ylase respectively. If this reaction is snppre~sed by inhibitors, the resulting collagen molecule is unable to function, is insufficiently hydroxylated and can be released by the cells only in small ~mounts into the ex~racellular space. The insufficiently hydroxylated collagen cannot, moreover, be incorporated in the collagen matrix and i8 VQry easily broken down by ~0 proteolysis. The conseque~ce of these ef~ects i8 an overall reduction in the amount of collagen deposited in the extracellular ~pace.

It is known that inhibition of proline hydroxylase by known inhibitors such as ~ dipyridyl result~ in inhibition of Clg biosynthe~is by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 t1978), 47~. This results in the classical pathway of complement activation becG~ing inoperative. Hence inhibitors of proline hydroxylase act as immunosuppres-sants, for example in immune complex disea~es.

It is known that proline hydroxylase can be effectivelyinhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245).
However, in cell culture, these compounds are effective inhibitors only in very high concentrations (Tschank, G.
2~3~77 et al., ~iochem. J. 238 tl987) 625-633).

DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic disesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceutical~ for the inhibition of 5 proline hydroxylase ~nd ly~ins hydroxylasa.

These lower al~ylated die~ters have ~he disadvantage, however, that they are too rapidly clsaved in the body to the acid~ and do not reach their site of action in the cell in sufficiently high concentration and thus are less suitable for poqsible admini~tration a~ pharmaceuticals.

DE-~ 37 03 959, DE-A 37 03 362 and DE-A 37 03 963 describe in a general form mixed estexsJ~mides, higher alkylated dies~ers and diamides of pyridine-2,4- and -2,5-dicarbo~ylic acids which are effec~ive inhibitors of collagen biosynthesi~ in animal models.

Thus, DE-~ 37 03 959 describes, inter alia, the ~ynthesis of N~ N '-bis(2-methoxyeth~l~pyridine-2,4-dicarboxamideand N,N'-bi~3-isopropoxypropyl)pyridine-2,4-dicarboxamide.

German Patent Application~ P 38 26 471.4 and P 38 28 140.6 propose an improved process for preparing N,N'-bis~2-methoxyethyl)pyridine-2,4-dicarboxamide. Germa~ Patent Application P 39 24 093.2 proposes novel N,N'-bis(alkoxyalkyl)pyridine-2,4~dicarboxamides.

The object to be achieved was thus to find compound which are suitable in a much improved manner than those hitherto disclosed for the inhibition of proline hydroxy-la~e and lysine hydroxylase. The ob~ect has been achieved by pyridine-2,g- and -2,5-dicarboxamides of the formula O
R -N-~- ~
Rl N tI) ~-N~2 2 ~

in whicA

Rl is Cl Cl2-alkyl, C2~C12~alkenyl or C2-Cl2-alkynyl, which are un~ubstituted or ~ubsti~uted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C12-alkynyls, al80 several times by halogen, hydroxyl, cyano, amino, carboxyl, alko~y, alkoxycarbonyl, alkylcarbonyloxy, alkyl-or dialkylam~no, where the alkyl radicals have 1-4 carbon atoms, or b~
indolyl or phenyl, which is unsubstituted or subs~ituted once, twice or three times by halo-gen, ni~ro, Cl-C4-alkyl or Cl-C4-alkoxy, it al~o baing possible in the case of multiple substitu-tions for the substituents to be independently different from one another, or R1 i~ saturated C5-C7-c~cloalkyl which i5 option-ally benzo-fused, : or R1 i8 aryl or heteroaryl, which i~ unsubstitu~ed or in turn 3ubstituted once, twice or three times by halo~en, nitro, cyano, C~-C4-alkyl or Cl-C4-alkoxy, it also being possible in the ca~e of multiple substitutions for the substituents to be independently dif~erent from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono- or disubstituted by Cl-C4-alkyl, phenyl or Cl-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and Rl are identical or different, :

20~3.~7~

or where the radicals Rl and R2 form, ~ogether with the nitrog~n atom~ a radical of the fonmula ~ R3 -N\ ~ X
(CH2)n in which n is 1 to 3 and X is 0, S, CH2 or N-R3, where R3 is ~ydrogen, phenyl or Cl-C6-alkyl, C2-C~-alkeIIyl or C2-C6-alkynyl, where these phenyl, alkyl, alkenyl and alkynyl radicals are unsubstitu~ed or sub~ti~uted one or more tlmes by:
phenyl which in turn i~ unsub~tituted or substituked one or more times by one or more substituents selected from: halogen, nitro, cyanot carboxyl, hydroxyl" methyl, ethyl, methoxy, e~hoxy and trifluoromethyl, or N(R4~2, where R4 is H or C1-C3-alkyl, or CoGR5, where R5 is H or C,-C3-alkyl, or CON ( R6 ) 2 or CONHR6, where R8 is H or Cl-C3 alkyll or where (R6)2 is a C4-C

~$~

alkylene chain in which zero or one CH2 group which is not directly ad;acent to the nitrogen atom is replaced by O, S or N-R4, or where R3 is C~-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts, which likewise effectively inhibit lysinP hydroxylase and prolin~
hydroxylase in animal models.

The invention particularly relates to pyridine-2,4- and -2,5-dicarboxamides of ~he formula I in which Rl is Cl-Cl2-alkyl which is unsubstituted or substitllted once or, in the case of the C2-Cl2-alkyls, 180 several times by phenyl, hydro~yl, alkoxy, amino, alkoxycarbonyl, lS alkyl- or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R2 is H, Rl is amino which i8 unsubstituted or mono~ubstituted ~y Cl-C3-alkyl, phenyl or Cl-C3 alkylcarbonyl, - and R2 i8 hydrogen, or where the radicals R1 and RZ form, together with the nitrogen atom, a radical of the formula r~
-N X

6 2~3~77 in which X is O, CH2 or N-R3, where R3 is hydrogen, or Cl-C3-alkyl, and the physiologically tolerated salts.

The meanings of halogen are fluorine, chlorine, bromine and iodine, those of aryl are, phenyl and naphthyl, and those of heteroaryl are 5- and 6-membered aromatic rings with l, 2 or 3 nitrogen and~or oxygen and/or sulfur atoms, which can also be benzo-fused where appropriate, the heteroaryl radicals are~ in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3~5-triazyl, pyrrolyl, pyrazolyl~ imidazolyl,~ tria 701yl ~ thienyl, oxazolyl and thiazolyl radicals and, where appropriate, the benzo-fused compounds thereof.

"Substituted several times~ means hereinbefore andhPreinafter that at least 2~ not more than 4, hydrogen atoms present in the alkyl, alkenyl, alk~nyl, het roaryl and aryl radicals are replaced by the ~ubstituents mentloned. In the case of multiple substitutions the substituents can also be independently different from one another.

All alkyl and alkenyl radicals mentioned with more than 2 carbon atoms and all alkynyl radicals with more than 3 carbon atoms can be ~oth ~traight-chain and branched.

~he invention further relates to the compounds of the formula I for use as pharmaceuticals. The invention additional~.y relates to the compounds of the formula I
for use as fibrosuppressants and immunosuppressant~ and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of 2 ~ s7 7 collagen and collagen-like substances and the biosynthesis of Clq. Inhibitors cE proline hydroxylase are sui~able tools in the therapy of diseases in which the deposition of collagens makes a crucial contribution to the clinical picture. The~e include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and ~therosclerosis.

The pyridine-2,4- and -2,5-dicarboxamides o~ the formula I which are substituted exclusively in position ~ or S in the amide group show a considarable and surpri~ing improved activity in inhibiting proline hydroxylase and lysina hydroxylase in animal experiments comparad with the pyridine-2,4-dicarboxamides substituted in position 5 also by carboxamide groups from ~E-A-3 707 429 and compared with the pyridine-2,4- and -2,5-dicarbo~clmides substituted in both amide groups of DE-A 37 039 59.

The invention furthsr relates to a process for the preparation of compounds of tha formula I, which com-prises reacting ~0 a compound of the formula II' \ c5~
(II') with a compound of the formula III
~,1 H-N (III) where R1 and R~ have the meanings indicated for formula I, and Y is halogen, especially chloriney and subsequently converting the resulting compound of the formula IV

2~$317~

C - N RlR2 (IV) 1, ll ~l with ~H3 into a compound of the formula I

- N RlR2 N ~1 - NH2 followed, where appxopriate, by co~ersion into its ph~siologically tolera~ed salts.

The following reaction diagram shows the preparation : route ~tages 5 and 6), including the synthesi~ of the precursors (1 to 4) 2~63 ~ 7rl Reaction diagram Stage 2 C02CH2~ C02CH2~

;; NC2CH3 N CO2H

:~ Staye 4 C02H CONRlR2 Stage 5 : . ¦ (II) ~ ¦ (IV) - ~ ~ C02CH3 H~Rl NC2CH3 N~3/
MeOH Stage 6 ~ ~ .
CONRlR2 ( I

2 ~ 7 7 In ~tage 1, commerclally availabls pyridine-2,4-dicarboxylic acid is converted into its dicarbonyl dihalide, preferably its dichlorid~, and reaoted with an optionally ~ubstituted benzyl alcohol to give dibenzyl pyridine-2,4-dicarboxylate.

In stage 2, the diester is ~electlvely hydrolyzed in position 2, for example in the presence of a copper salt as described by Delaxge, J.: Phar. Acta. Helv. ~4 ~10), 637 (1969).

The free acid functionality in position 2 i~ subseguently converted in stage 3 into the corresponding acid chloride and reacted with an alcohol such as, for example, methyl or ethyl alcohol to give the corre~ponding 2-carboxylic e~ter.

The remaining benzyl protective group in position 4 is elLminated by hydrogenolysiR in stage 4 tor example with H2/Pd, Houben-Weyl- Vol. IV/lc (1980), pp. 381 ~ 82).

The free acid in position 4 (foxmula II) is converted into its acid halide, preferably chloride. ~he acid chloride can now be convQrted with the amine of the foxmula (III) into the mixed pyridine-4-carboxamide-2-carboxylic ester (IV).

The mixed diamide of the formula (I) is prepaxed from the 2-carboxylic ester (IV) with alcoholic ammonia ~olution (for example in methanol).

The said process, which has been described in the reac-tion diagram for the compounds substituted in position 4, also applies to the compounds correspondingly sub~tituted in position S.

It is possible where appropriate for the products to be worked up, for example, by extraction or by chromato-graphy, for example on silica gel. The isolated products can be recry~tallized and, wher~ appropriate, reacted with a suitable acid ~o give a physiologically tolerated salt. Examplas of ~uitable acids are:
mineral acids such as hydrochloric and hydrobromic acid 5 and sulfuric, pho~phoric, nitric or perchloric acid or organic acids such as formic, acetic, prop~onic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phe~ylacetic, benzoic, methane~ulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ~scorbic acid.

The starting compounds of the formula ~III) which cannotbe bought can be synthesized s~raightforwardly (for example Organikum, Organisch Chemisches Grundpra~tikum, 15th edition, VEB Deutscher Verlag der Wi~senschaften, 1976; a summary of the various possibilities is to be found in the me~hods index, p. 822).

The compounds of the formula I according to the invention have valuable pharmacological properties and, in parti-cular, display activity as inhibitors of proline hydroxy-lase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.

The activity of the fibrogenase can be determined by ; radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or C-terminal crossl~nking domain of collagen type IV (7s collagen or type IV collagen NCl) in ~erum.

For this purpose, the hydroxyproline, procollagen III
peptide, 7s collagen and type IV collagen NC
concentrations were measured ln the liver of a) untreated rats (control) b) rats given tetrachloromethane (CCl4 control) c) rats given first CCl4 and then a compound according to the invention (this test method is described by Rouiller, C., 3~ experimental toxic injury of the liver; in The '7 7 Liver, C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Pre~s, 1964).

By reason of these pha~macological propertie~ the compounds according to the invention are suitable for the treatment of di~orders of the metabolism of collagen and collagen-like substances and for ~he trea~ment of dis-orders of the biosynthesis of Clg.

The invention therefore further relates to the use of the compounds of the formula I according to the in~ention, and of the physiologically tolerated salts thereof, for the treatment of the abovementioned metabolic disorders.

The compounds can be used a~ pharmaceuticals either alone or mixed with physiologically tolera~ed auxiliari~s or vahicles. They can be administered for this purpose orally in doses of 0.01 ~ 25.0 mg/kg~day, preferably 0.01 - 5.0 mgfkg/day or parenterally in dose~ of 0.001 - 5 mg/kg/day/ preferably 0.001 - 2.5 mg/kg/day, especially to 0.005 - 1.0 mg/kg/day. It is also possible ~o increase the dosage in severe cases. However, lower do~es al~o suffice in many cases. These data relate to an adult weighing about 75 kg.

The invention also embraces the use of the compounds according to the invention for preparing pharmaceutical~
which are employed for the ~reatment and prophylaxis of the abovementioned metabolic disorders.

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

The pharmaceuticals are producing by processes known per se and familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds (= active substance) according to the invention are 2 ~ 7 ~

employed either as ~uch or, preferably, in combination with suitable pharmaceutical auxiliaries or vehicles in the f Qrm of tabletR, coated tablets, capsule~, suppositories, emulsions, suspensions or solutions, where S the content of active substance is up to 95 %
advantageou~ly between 10 to 7S ~.

Suitable auxiliaries and vehicle~ for the required pharmaceutical formulation are, for example, besides solvents, gel formers, suppo~itory bases, tableting auxiliaries and other active ~ubstancQ vehicles, also antioxidant6, ~ispersants,` emulsifiers, foxm suppressants, f~avorings, preservatives, solubili2ers or colorants.

The active substances can be administered orally, parenterally or rectslly.

~ha active compounds are mixed with tha additives suitable for this, such as vehicles, ~abilizers or lner diluents, and converted by the usual methods into suitable ~osage forms such as tablets, coa~ed tablets, hard gelatin capsules, aqueous alcoholic or oily suspen~ions or aqueous or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or ~tarch, especially corn starchn The preparation can be carried out either as dry or as wet granules. Examples o~ suitable oily vehicles or solvents are vegetable or animal oils, such as ~unflower oil or fish liver oil.

For subcutaneous or intravenous administxation, the active compounds are, if required, converted into a solution, suspension or emulsion 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, propanol, glycerol, as well as sugar ~ v ~ ~ ~

solutions ~uch a~ glucose or mannitol ~olution~, or el3e a mixture oP the various solvent mentioned.

The inventien i8 explained in more detail hereinafter by means of example~.

General procedure for the preparation of the compounds 1 mmol of methyl pyridine-4~carboxam1de-2-carboxylate (IV) is di~solved in 30 ml of sa~urated methanolic ammonia solution and tirred at room temperature for 2 hours. The solution is concentrated and the residue i5 stirred with diisopropyl ether and filtered off with suction.

Example 1 4-N-Ethylpyridine-2-carboxamide-4-carboxamide ~elting point: 197C

Exampl~ 2 4-Norpholinocarbonylpyridine 2-carbox~mide Melting point: 12BC

Example 3 4-N,N-Diethylpyridine-2-carboxamide-4-carboxamide Oil, MS = 222 ~M + H+) molecular mass C11~15N302 (221) Example 4 4-N-(2-methoxypropyl)pyridine-2-carboxamide-4-carboxamids ~elting point: 116 - 120C

- 15 - ~ 7~
Example 5 4-N-~3-methoxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 14~C

~xampl~ 6 4-N-(3-hydroxypropyl)pyridine-2-carbox~mide-4-~arboxamide ~eltin~ point~ 154 - 156C

Example 7 4-N-alanylp~idine-2-carboxamide-4-carboxamide Melting point: 124 - 125C

Example 8 4-N-(O-benzylalanyl~pyridine-2-carboxamide-4-carboxamide Melting point: 138 - 140C

Claims (11)

1. A pyridine-2,4- or -2,5-dicarboxamide of the formula I

(I) in which R1 is C1-C12-alkyl, C2-C12-alkenyl or C2-C12-alkynyl, which are unsubstituted or substituted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C12-alkynyls, also several times by halogen, hydroxyl, cyano, amino, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyl-ox dialkylamino, where the alkyl radicals have 1-4 carbon atoms, or by indolyl or phenyl, which is unsubstituted or substituted once, twice or three times by halo-gen, nitro, C1-C4-alkyl or C1-C4-alkoxy, it also being possible in the case of multiple substitu-tions for the substituents to be independently different from one another, or R1 is saturated C5-C7-cycloalkyl which is option-ally benzo-fused, or R1 is aryl or heteroaryl, which is unsubstituted or in turn substituted once, twice or three times by halogen, nitro, cyano, C1-C4-alkyl or C1-C4-alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono° or disubstituted by C1-C4-alkyl, phenyl or C1-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and R1 are identical or different, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which n is 1 to 3 and X is O, S, CH2 or N-R3, where R3 is hydrogen, phenyl or C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where the phenyl, alkyl, alkenyl and alkynyl radicals are unsubstituted or substituted one or more times by:
phenyl which in turn is unsubstituted or substituted one or more times by one or more substituents selected from: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or N(R4)2, where R4 is H or C1-C3-alkyl, or COOR5, where R5 is H or C1-C3-alkyl, or CON(R6)2 or CONHR6, where R6 is H or C1-C3-alkyl, or where (R6)2 is a C4-C6-alkylene chain in which zero or one CH2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R4, or where R3 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts.
2. A pyridine-2,4- or -2,5-dicarboxamide of the formula I as claimed in claim 1, in which R1 is C1-C12-alkyl which is unsubstituted or substituted once or, in the case of the C2-C12-alkyls, also several times by phenyl, hydroxyl, alkoxy, alkoxycarbonyl, or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R2 is H, R1 is amino which is unsubstituted or monosubstituted by C1-C3-alkyl, phenyl or C1-C3-alkylcarbonyl, and R2 is hydrogen, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which X is O, CH2 or N-R3, where R3 is hydrogen, or C1-C3-alkyl, and the physiologically tolerated salts.
3. A pyridine-2,4- or -2,5-dicarboxamide of the formula I as claimed in claim 1, in which R1 is C1-C12-alkyl which is unsubstituted or substituted once or, in the case of the C2-C12-alkyls, also several times by phenyl, hydroxyl, alkoxy, alkoxycarbonyl, or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl, or, provided that R2 is H, R1 is amino which is unsubstituted or monosubstituted by methyl-carbonyl, and R2 is hydrogen, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which X is O, CH2 or N-R3, where R3 is hydrogen, or methyl, and the physiologically tolerated salts.
4. A process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II' (II') with a compound of the formula III
(III) where R1 and R2 have the meanings indicated for formula I, and Y is halogen, especially chlorine, and subsequently converting the resulting compound of the formula IV

(IV) with NH3 into a compound of the formula I and into its physiologically tolerated salts.
5. A compound as claimed in one or more of claims 1 to 3 for use as pharmaceuticals.
6. A compound as claimed in one or more of claims 1 to 3 for the inhibition of proline hydroxylase and lysine hydroxylase.
7. A compound as claimed in one or more of claims 1 to 3 for use as fibrosuppressant and immunosuppressant.
8. A pharmaceutical containing a compound of the formula I with compatible pharmaceutical vehicles.
9. The use of compound of the formula I for influenc-ing the metabolism of collagen and collagen-like substan-ces and the biosynthesis of Clq.
10. The use of compounds of the formula I for the treatment of disorders of the metabolism of collagen and collagen-like substances and of the biosynthesis of Clq.
11. A process for the production of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq, which comprises incorporating a compound of the formula I in the pharma-ceutical.
CA002063177A 1991-03-18 1992-03-17 Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds Abandoned CA2063177A1 (en)

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DE4108824 1991-03-18

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DE3703959A1 (en) * 1987-02-10 1988-08-18 Hoechst Ag PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS
EP0353668B1 (en) * 1988-08-04 1994-10-19 Hoechst Aktiengesellschaft Process for the preparation of N,N-bis(alkoxyalkyl) diamides of pyridine-2,4-dicarboxylic acid
DE3924093A1 (en) * 1989-07-20 1991-02-07 Hoechst Ag N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF
DE3928144A1 (en) * 1989-08-25 1991-02-28 Hoechst Ag CYCLIC PYRIDINE-2,4- AND -2,5-DICARBONIC ACIDEDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF
DE3938805A1 (en) * 1989-11-23 1991-05-29 Hoechst Ag PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF
DE4030999A1 (en) * 1990-10-01 1992-04-09 Hoechst Ag 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT

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NZ241968A (en) 1994-04-27
TW199147B (en) 1993-02-01
ATE154929T1 (en) 1997-07-15
HUT62565A (en) 1993-05-28
IL101257A (en) 1998-03-10
AU1296792A (en) 1992-09-24
DE59208651D1 (en) 1997-08-07
HRP940835A2 (en) 1997-06-30
FI101701B (en) 1998-08-14
JPH0586032A (en) 1993-04-06
CS80392A3 (en) 1992-10-14
NO178859C (en) 1996-06-19
ES2104758T3 (en) 1997-10-16
ZA921945B (en) 1992-11-25
EP0504799A1 (en) 1992-09-23
AU645668B2 (en) 1994-01-20
HU217809B (en) 2000-04-28
IL101257A0 (en) 1992-11-15
HU9200891D0 (en) 1992-05-28
NO178859B (en) 1996-03-11
DK0504799T3 (en) 1998-02-02
JP3121428B2 (en) 2000-12-25
GR3024309T3 (en) 1997-10-31
KR920018051A (en) 1992-10-21
FI921119L (en) 1992-09-19
KR100243959B1 (en) 2000-03-02
EP0504799B1 (en) 1997-07-02
CZ282298B6 (en) 1997-06-11
YU48156B (en) 1997-05-28
FI921119A0 (en) 1992-03-16
MX9201156A (en) 1992-10-01
IE920843A1 (en) 1992-09-23
NO921025L (en) 1992-09-21
YU24692A (en) 1994-06-24
FI101701B1 (en) 1998-08-14
NO921025D0 (en) 1992-03-17

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