IE67446B1 - Pyridine-2,4- and -2,5-dicarboxylic acid derivatives processes for their preparation the use thereof and medicaments based on these compounds - Google Patents

Pyridine-2,4- and -2,5-dicarboxylic acid derivatives processes for their preparation the use thereof and medicaments based on these compounds

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IE67446B1
IE67446B1 IE35088A IE35088A IE67446B1 IE 67446 B1 IE67446 B1 IE 67446B1 IE 35088 A IE35088 A IE 35088A IE 35088 A IE35088 A IE 35088A IE 67446 B1 IE67446 B1 IE 67446B1
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alkyl
denotes
formula
pyridine
phenyl
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IE35088A
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IE880350L (en
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Martin Bickel
Harald Burghard
Volkmar Guenzler
Dietrich Brocks
Hartmut Hanauske-Abel
Stephan Henke
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Hoechst Ag
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    • 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
    • C07D213/79—Acids; Esters
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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  • Immunology (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

Pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the formula I in which R<1>, R<2> and X have the meanings indicated, are used in particular for influencing the metabolism of collagen and collagen- like substances or the biosynthesis of C1q.

Description

Compounds which inhibit proline hydroxylase and lysine hydroxylase effect very selective inhibition of collagen biosynthesis by influencing collagen-specific hydroscylation reactions- In the course of these, protein-bonded # proline or lysine is hydroxylated by the enzymes proline hydroxylase and lysine hydroxylase. If this reaction is suppressed by inhibitors, a hypo-hydroxylated collagen molecule which is not capable of functioning and can he released by the cell into the extracellular space in only a small amount is formed. The hypo-hydroxylated collagen also cannot be incorporated into the collagen matrix and is very readily degraded proteolytreally. As a consequence of these effects, the total amount of extracellular ly deposited collagen is reduced.
It is known that inhibition of proline hydroxylase by known inhibitors, such as c,ot' -dipyridyl, leads to an inhibition of the Gl^-biosynthesis of macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Izemunbiology 155 (1978) 47) . There is thus a loss of the classical route of complement activation. Inhibitors of proline hydroxylase therefore also act as immunosuppressants, for example ia immunity complex diseases.
It is known that proline hydroxylase is inhibited effectively by pyridine-2,4- and -2,5-dicarboxylic acid (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245).
However, these compounds are active as inhibitors in the cell culture only in very high concentrations (V. Gunsler efc al. Collagen and Rel. Research 3, 71 1983) .
DB-A 3,432,094 describes pyridine-2,4- and -2,5-dicar30 boxylic acid diesters with 1-6 carbon atoms in the ester alkyl part as pharmaceuticals for inhibiting proline hydroxylase and lysine hydroxylase.
However, these lower alkyl diesters have the disadvantage that they are split too rapidly in the organism to gives the acids and do not arrive at their site, of action in. the cell -in a sufficiently high concentration, and therefore are not particularly suitable for possible administration as pharmaceuticals.
Surprisingly, it has now been found that the mixed 5 ester/amides of pyridine-2,4- and -2,5-dicarboxylic acid and likewise the higher alkylated diesters are excellent inhibitors of collagen biosynthesis in the animal model.
The actual active compound, the pyridine-2,4- or -2,5-dicarboxylic acid, is first formed in the cell by hydrolysis of the esters or ester/amides. On the basis of their higher lipophilieity and the fact that, surprisingly, they are hydrolyzed only very slowly during transportation, the asters and ester/amides can be transported into the cells. Only here is the actual active compound, pyridine-2,4- or -2,5-dicarboxylic acid, released.
The invention thus relates to: 1. Pyridine-2,4,- and -2,5-dicarboxylic acid derivatives of the formula I (I) C-X-R1 R ia which RJ denotes branched or unbranched C^-C^-alkyl which is monosubstifcuted or else, ia the case of the G,-C12-alkyl radicals, polysubs tx-tuted fay halogen, hydroxyl, cyano, carboacyl, alkoxy, alkoxycarboayl, alkylcarbonylosy or alkyl- or dialkylamiao, the alkyl radicals containing 1-4 carbon atoms and, in the case of the C3- and C,-alkyl radicals, it also being possible for them to be branched, phenyl, which is ia turn optionally mono-, di- or trisubstituted by halogen, nitro, C1-C4-alkyl or C^-C^-alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C3- and C4-alkyl radicals, for these to be branched, or R1 denotes saturated C5-C7-cycloalkyl, which is optionally benzo-fused, or R1 denotes phenyl, naphthyl or a 5~ or S-membered aromatic ring having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms, which in turn is optionally mono-, di- or trisubstituted by halogen, C^-C^-alkyl or Ch-C,-alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C3- and CA-alkyl radicals, for these to be branched, or R1 denotes 2-oxo-l,3-dioxolylmethyl, which is optionally also methyl-substituted, or R1, if I is nitrogen, denotes hydrogen, and R2 independently of R1 is hydrogen or R1, it also being possible for R2 to be identical to R1, and X denotes oxygen or R3-substituted nitrogen, in which R3 is hydrogen or C^-Cg-alkyl or optionally together with R1 forms a heterocyclic saturated 5-, 6- or 7-membered ring, it also being possible for the heterocyclic ring to include a second nitrogen atom, and it being possible for the heterocyclic ring in turn to be substituted by phenyl or phenyl-C^-C^-alkyl, and physiologically tolerated salts thereof for use as pfrarnaci&uticals.
The invention particularly relates to pyridine-2,4- and -2,5-dicarboxylic acid derivatives of formula I, ia which denotes branched or unbranched C^-C^-alkyl which is monosubstituted or else., in the case of the C3- and C4-alkyl radicals, polysubstituted by C^-C^-alkoxy and/or Cx-C3-alkoxycarbonyl, it also being possible for the C3-alkyl radicals to be branched, and/or phenyl, denotes C5~ or C6~cycloalkyl, which is optionally benzo-fused, or R1 denotes phenyl, which is optionally mono-, di- or trisufastituted by nitro, or R1 denotes 2-, 3- or 4-pyridyl, naphthyl, 2- or 3-thienyl, pyrazolyl, imidazolyl or thiazolyl, or R1 denotes 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl and independently of R1 is hydrogen or R1, it also being possible for R2 to be identical to R1, and denotes oxygen or R3-substituted nitrogen, in which R3 is hydrogen or Ci-C3-alkyl or optionally together with R1 forms a heterocyclic saturated 6-membered ring,'it also being possible for the heterocyclic 6-membered ring to include a second nitrogen atom and to be substituted in turn by phenyl or phenyl-C1-C3-alkyl, and physiologically tolerated salts thereof, for use as pharmaceuticals.
The invention also relates to pyridine-2,4- and -2,5dicarboxylic acid derivatives of the formula I' 9» II r -o-c— C - X’ - R (X’) denotes branched or unbranched C^-Cj^-alkyl which IS or R1' or R1' or Ror R~ , and R2' and is- monosubstituted or else, in the ease of C2-C12-alkyl, polysubstituted by halogen, hydroxyl, cyano, carboscyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy or alkyl- or dialkylamino, the alkyl radicals containing 1-4 carbon atoms and it also being possible, in the case of the C3- and C4-alkyl radicals, for these to be branched, phenyl, which is in turn optionally mono-, di- or trisubstituted by halogen, Cx-C4" alkoxy or C^-C^-alkyl, it also being possible for the C3- and C^-alkyl radicals mentioned to be branched and it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another, denotes saturated C5-C7-cycloalkyl, which is optionally benso-fused, denotes phenyl, naphthyl or a 5- or 6-membered aromatic ring having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms, which is in turn optionally mono-, di- or trisubstituted by halogen, nitro, Cx-C4-alkyl or C^-C^-alkoxy, it also being possible, ia the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C3- and C4~alkyl radicals, for these to be branched, denotes 2-oxo-l, 3-dioxolyImethyl, which is optionally methyl-substituted, if X/ is nitrogen, denotes hydrogen, independently of R1’ is hydrogen or R1', it also being possible for R2' to be identical to R1', denotes oxygen or R3'-substituted nitrogen, in which R3' is hydrogen or Cj^-Cg-alkyl or, optionally together with R1’, forms a heterocyclic, saturated 5-, 6- or 7-membered ring, it also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible for the heterocyclic ring in turn to be substituted by phenyl or phenyl-Cx-C3-alkyl, and physiologically tolerated salts thereof, excluding the compounds in which X' denotes oxygen and R1' and R2' are methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl, and di (4-methoxyphenyl) pyridine-2,5-diearboxylate.
Preferred pyridine-2,4- and -2,5-dicarboxylic acid derivatives of formula I* ar© those in which R1' denotes branched or unbranched C1-C4-alkyl, which is monosubstituted or else, in the case of the C2-C4-alkyl radicals, polysubstituted by alkoxy or alkoxyearbonyl, the alkyl radicals containing 1-3 carbon atoms and if also being possible, in the case of the C3--alkyl compounds, for these to be branched, or phenyl or R1' denotes cyclopentyl or cyclohexyl, which are optionally benro-fused, or R1' denotes phenyl, which is optionally substituted by 1, 2 or 3 nitro groups, or naphthyl, or R1# denotes 2-, 3- or 4-pyridyl, 3-thienyl, pyrazolyl, imidazolyl or thiazolyl, or R1' denotes 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl and R2' independently or R1' is hydrogen or R1’, it also being possible for R2* to be identical to R1’, and X' denotes oxygen or R3'-substituted nitrogen, in which R3' is hydrogen or Cx-C3-alkyl or optionally together with R1' forms a heterocyclic, saturated S-membered ring, it also being possible for the heterocyclic 6-membered ring to include a second nitrogen atom and in cum to be substituted by phenyl or phenyl-Cj-Cg-alkyl, and physiologically tolerated salts thereof, - 7 excluding -the compounds in which X' denotes oxygen and R1' and R2' are methyl or ethyl which, is substituted by chlorine, hydroxyl or phenyl,, and di (4-methoxyphenyl) pyridine-2,5-dicarboxylate.
Particularly preferred pyridine-2,4- and -2,5dicarboxylie acid derivatives of the formula 1' are those in which R1' is branched or unbranched C1-C4-alkyl, which is substituted by alkoxycarbonyl, the alkyl radicals containing 1-3 carbon atoms and it also being possible, in the case of the C3-alkyl radicals, for these to be branched, and R2’ independently of R1' is hydrogen or R1', it also being possible for R2’ to be identical to R1', and X' denotes oxygen, and physiologically tolerated salts thereof.
These compounds have, inter alia, a particular activity on oral administration, as do the especially preferred pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the formula I' in which R1' and R2' ar© 1-isopropoxycarbonylethyl groups and Γ denotes oxygen (such as, for example, bis(1-isopropoxycarbonylethyl) pyridine-2,5dicarboxylate (Example 3) or bis(lisopropoxycarbonylethyl) pyridine-2,4-dicarboxylate (Example 30)), and physiologically tolerated salts thereof.
By halogen there are understood fluorine, chlorine, bromine and iodine, by aryl there are understood phenyl and naphthyl and by heteroaryl there are understood 5and 6-membered aromatic rings having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms and can' optionally also be benzo-fused? the heteroaryl radicals- are, in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3,5-fcriazyl, pyrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl, oxazolyl and thiazolyl radicals and where appropriate benzo-fused compounds thereof» "Polysubstitutedm above and below means that at least 2 and at most all of the hydrogen atoms present in the alkyl radicals are replaced by the substituents mentioned. It is preferably a matter hare of one substituent per methyl or methylene group.
In the case of polysuhstitutioti, th© substituents can also differ independently of one another.
The invention furthermore relates to a process for the preparation of compounds of the formula Ip, which comprises a) reacting a compound of the formula II II with a compound of the formula III ΞΧ' -R1' (III) in which R1’, R2' and X' have the meanings given in the case of formula I' and ¥ is halogen or hydroxyl, or b) reacting a compound of the formula IV (IV) I! with a compound of the formula V ΞΟ-R2' (V) in which R1', R2' and have the meanings given in the ease of formula I* and 2 is halogen, or c) reacting a compound of the formula VI CVI) with, an alcohol ΒΌ-R2' or an alcohol of the formula VII ΞΟ-R1' (VII) in which R1' and R2' have the meanings given in the case of formula I and Z is halogen, or d) reacting an alkali metal salt of pyridine-2,4- or -2,5-dicarboxylic acid with a halide of the formula VIII ΚΧ'-Ζ (VIII) in which R1' has the meanings given in the case of formula I' and Z is halogen, and, if appropriate, converting the reaction products into their physiologically tolerated salts.
The preparation of compounds according to formula I and the preparation of the starting substances required for this - where they are not commercially available - are described in more detail below.
The compounds according to the invention are most easily prepared by mixing the two components, the pyridine derivative according to formula (II), (IV) or (VI) and. the amine or alcohol according fo formula (III), (V) or (VII), in equimolar amounts or with up to an approximately 5-fold excess of III, V or VII, and reacting them at temperatures between -30 to 150 °C, preferably at 20 to 100°C, until the reaction has ended. The end of the reaction can be determined by means of thin layer chromatography (TLC control) . Ona variant of this process comprises carrying out the reaction in a suitable · solvent, such as diethyl ether or dimethoxyethane or t@trahydrofure.zx, chlorinated hydrocarbons, such as methylene chloride, chloroform or trior tetrachloroethylene, benzene, toluene or polar solvents, such as dimethylformamide or acetone or dimethyl sulfoxide. An excess of amine/alcohol according to formula (III) , (V) or (VII) , which can be up to 5 times the amounts, can also be used here. The reaction temperatures here are between room temperature and the boiling point of the solvent, temperatures in the range from room temperature to 130°C being particularly preferred.
If appropriate, the reaction can also be carried out in the presence of bases. Possible additional bases are inorganic acid-trapping agents, such as carbonates or bicarbonates, for example sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or organic acid-trapping agents, such as tertiary amines, such as triethylamine, fcributvlamine or ethyl diisopropylamine, or heterocyclic amines, such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.
The reaction of the compounds according to formula (II) with alcohols according to formula (III) (X'= 0) is preferably carried out with the addition of a dehydrating agent, such as a dialkylcarbodiimide, the alkyl radicals containing 1 to 8 carbon atoms and it also being possible, in the case of the C3-C8-compounds, for these to be branched or cyclic; dicyclohexylcarbodiimide is preferably used. A corresponding method is described in Houben-Weyl, Volume XV/2, pages 103-111', Methoden der Organischen Chemie (Methods of Organic Chemistry) , 4th edition, Georg Thieme Verlag, Stuttgart, 1974If appropriate, the products can be worked up, for example by extraction or by chromatography, for example over silica gel. The isolated products can be recrystallized and if appropriate reacted with a suitable acid to give a physiologically tolerated salt. Examples of possible suitable acids are: mineral acids, such as hydrochloric and hydrobromic acid, as well as sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphchaiene-1,5-disulfonic or ascorbic acid.
The starting compounds of the formula (III) , (V) and (VII), where they are not commercially available, can be synthesized in a simple manner (for example Organikum, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry) , 15th edition, VEB Deutsehar Verlag der Wissenschaften, 1976; a review of the various possibilities is to be found in the method register; Alcoholss page 821, Amines: page 822).
The starting compounds of the formula (II) are obtained, for ..example, by converting pyridine-2,4- or -2,5dicarboxylic acid into the corresponding pyridine-2,4- or -2,5-dicarboxylic acid halide (VI), preferably the chloride (by processes which are known from the literature, for example Organikum, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry), 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976, page 595 et seq.), which is then reacted with an alcohol of the formula R,2'-QH (V) to give the corresponding 2,4or 2,5-diester. Selective hydrolysis of the ester in the 2-position of the pyridine derivative (for example by a copper complex, see Pharm. Acta Eelv. 44 1969, page 637) or partial alkaline hydrolysis (see J. Org. Chem. 39 (8) 1974, page 1158) gives the pyridine-4- or -5-carboxylic acid ester-2-carboxylic acid, which is either used directly (II, T=QB) or can be converted into the acid halide (II, Y»C1, Br or I), preferably the acid chloride.
The starting compounds of the formula (IV) can be synthesised, for example, as follows; Reaction of the pyridine-2„4- or -2,5-dicarboxylic acid halide, preferably the chloride, with benzyl alcohol to give pyridine-2,4- or -2,5-dicarboxylic acid benzyl ester; subsequent selective hydrolysis of the ester in the 2-position (for example in the presence of a copper catalyst, Loc.cit.Pharm. Acta Helv.), conversion of the free acid in the 2-position into the acid halide, reaction with a compound of the formula HX* -R1' (III) to give the pyridine-4- or 5-carhoxylic acid benzyl ester-2 carboxylic acid (R1) ester or -amide, hydrogen©lytic splitting off of the benzyl protective group which remains (for example with H2/Pt, see Houben-Weyl Volume IV/Ic (1980), pages 381-82) and subsequent conversion of the free acid in the 4- or 5-position of the pyridine ring into the acid halide (XV)θ The pyridine-2,4- or -2,5-dicarboxylic acid halide according to formula VI can be obtained by known methods, for example by reaction of pyridine-2,4- or -2,5dicarboxylic acid with a phosphorus trihalide (see, for example, Organikum, Organ!sch Chemisches Grundpraktikum (Basie Practical Organic Chemistry),, ISfch edition, VBB Deutscher Verlag der Wissenschaftea, 1976, pages 527 and 595 et seq.) .
The reaction of alkali metal salts of the pyridine-2,4or -2„5-dicarboxylic acid, with a halide of the formula VIII is carried out by processes which are known from the literature (se®, for example, Organikum, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry), 15th edition, VE3 Deutscher Verlag der Wissenschaften, 1976, page 255 et seq.).
The compounds of the formula I and If according to the. invention have useful pharmacological properties, and in particular show an activity as inhibitors of proline hydroxylase and lysine hydroxylase and as fibrosuppressasts and immunosuppressants.
The activity of the £ibrogenase can be determined by radioimmunological assay of the N~terminal propeptide of collagen type III or the N- or C-terminal crosslinking domains of collagen type IV (7s-collagen or type IV coIlagen-NC^^) in the serum.
For this purpose, the hydroxyproline, procollagen III, peptide, 7s-collagen and type IV collagan-HCX concentrations ia the liver of a) untreated rats (control) b) rats to which carbon tetrachloride had been administered (CC14 control) c) rats to which first CC1. and then a compound according to the invention had been administered were measured (this test method is described by Rouiller, G„, experimental toxic injury of the liver; in The Liver, C. Rouiller, Volume 2, pages 335-476, New York, Academic Press, 1964) .
The pharmacological activity of the substances according to the invention has been investigated in a series of experiments (see Table 1) . A. clear inhibition of proline hydroxylase and lysine hydroxylase was thereby found.
Table 1 Substance frosa JSitnsapl® XJoaasgo Hydrossy- proliae lig/sng of lives Srocollaggs III peptide ag/sal 73-collffigeE ug/al Typo XV coilfcgEin-KCl ng/sal 4 2 X 0.482 37.2 121.4 100.8 CC14 control 23 ssg 0.773 73.S 308. 168.4 control 0.289 11.1 22.8 23.5 The compounds of the formula I and If can be used as medicaments in the form of pharmaceutical preparations which contain them, if appropriate together with tolerated pharmaceutical excipients. The compounds can, be used as medicines, for example in the form of pharmaceutical preparations which contain these compounds as a mixture with a pharmaceutical organic or inorganic excipient suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline and the like.
The pharmaceutical preparations can be in the solid form. for example as tablets, coated tablets, suppositories or capsules; in the semi-solid form, for example as ointments, or in the liquid form, for example as solutions, suspensions or emulsions. If appropriate, they are sterilized and/or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for modifying the osmotic pressure or buffers. They can furthermore also contain other therapeutically active substances.
The invention is illustrated in more detail with the aid of examples belows Examples 1. Bis(1-methoxycarbonylethyl) pyridine-2,5-dicarboxylate g of pyridine-2,5-dicarboxylic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dime thyl formamide are added- The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 12.5 g of methyl lactate, dissolved in methylene chloride, is added dropwise to the reaction mixture at -30 to -20°C. The mixture is allowed to warm slowly to room -temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is recrystallized from isopropanol.
Melting point 78°C; yield 7.2 g 2. Bis(1-ethoxycarbonylethyl) pyridine-2,5-dicarboxylate g of pyridine-2,5-dicarboxylic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 14.1 g of ethyl lactate, dissolved in 1 1 of methylene chloride, is added dropwise to the reaction mixture at -30 to -20°C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oil.
Yield 16.S g 3. Bis (1-isopropoxycarbonylethyl) pyridine-2,5 dicarboxylate g of pyridine-2,5-dicarboxylic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled under- reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 15.8 g of isopropyl lactate, dissolved in 100 ml of methylene chloride, is added dropwise to the reaction mixture at -30 to -20 °C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and stirred with diisopropyl ether. The monoester is separated off and the mother liquor is chromatographed over silica gel with a mixture of four parts of toluene and one part of ethyl acetate as the mobile phase. The oily product slowly crystallizes completely.
Melting point 52 - 53°C Yield 13.5 g Bis (2-methoxycarbonyl-2,2-dimethylethyl) pyridine2,5-dicarboxylate g of pyridine-2,5-dicarboxylic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thi onyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled under reflux for three hours, the excess thi onyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 15.8 g of methyl 2,2-dimethyl-3-hydroxypropxonate, dissolved in 100 ml of methylene chloride, is added to the reaction mixture at -30 to -20°C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and the product is recrystallised from Isopropanol.
Melting point 114-5eC Yield 18.6 g . Bis(2-methoxycarbonyl-2,2-dimethylethyl) pyridine2,4-dicarboxylate 7.5 g of pyridine-2,4-di carboxy lie acid are taken In 5 45 ml of dry methylene chloride, and 60 ml of freshly distilled thionyl chloride and 2 ml of dry dimethyl formamide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 11.9 g of methyl 2,2-dimethyl-3-hydroxypropionate, dissolved in 100 ml of methylene chloride, is added to the reaction mixture at -30 to -20 °C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, th® organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oil. Yield 6,7 g. 6. Bis(1-ethoxycarbonylethyl) pyridine-2,4-dicarboxylate 7.5 g of pyridine-2,4-dicarboxylic acid are taken in 45 ml of dry methylene chloride, and 60 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are. added. The mixture is boiled for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 10.6 g of ethyl lactate, dissolved in 100 ml of methylene chloride, is added dropwise to the reaction mixture at -30 to -20 °C. The mixture is allowed to warm slowly to room tern35 perature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oil, which slowly crystallizes completely.
Melting point 59 - 60°C Yield 3.7 g. 7. Bis (5-mathyi-2-G3EO"X, 3-dioxol-4-ylmethyl) pvridine2,4-dicarhoxylate 6.3 g of pyridine-2,4-dicarboxylic acid sodium salt are boiled under reflux with 14.3 g of 5-aethyl-2oxo-1,3-dioxol-4-yl-methyl bromide and 4.5 g of potassium carbonate in 125 ml of dry acetone for 40 hours. The carbonate is filtered off and the solution is chromatographed over silica gel with a 4:1 mixture of toluene and ethyl acetate.
Melting point 113°C Yield 2.5 g 8. Methyl 2-(4-(2-phenylethyl)piperazinocarbonyl)pyridine-5-carboxylate 1.5 g of methyl pyridine-2-(carboxylic acid)-5carboxylate are heated under reflux with, 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 3.15 g of 1-(2-phenylethyl)-piperazine in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol, with the addition of a little active charcoal. The product is obtained as the hydrochloride.
Melting point 201 - 203°C Yield 2.6 g 9. Methyl 2-banzylaminocarbonyl-pyridine-5-carboxylate 1.5 g of methyl pyridine-2-(carboxylic acid)-5carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 1.15 g of benzylamine in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol, with the addition of a .little active charcoal.
Melting point 215 - 216°C Yield 1.9 g . Methyl 2- (M-benzyl-N-methylaminocarbonyl) -pyridine5-carboxylate 1.5 g of methyl pyridine-2-(carboxylic acid)-5carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 2.0 g of N-aethylbenzylamine in 8 ml of methylene chloride. and the components ar© subsequently stirred at x'ooxa temperature for five minutes and freed from the solvent. The-residue is chromatographed over silica gel with a mixture of 7 parts of methylene chloride and 3 parts of acetone. The product is obtained as an oil. 11. Methyl S-banzyloxyearbonylpyridine-S-carboxylate 1.5 g of methyl pyridine-2-(carboxylic acid)-5carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed» The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely» The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 1.79 g of benzylalcohol in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol, with the addition of a little active charcoal.
Melting point 104°C Yield 1.5 g 12. Methyl 2-phenylaminocarbonylpyridine-5-carboxylate 1.5 g of methyl pyridine-2-(carboxylic acid)-5carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 1.54 g of .aniline in S ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol, with the addition of a little active charcoal.
Melting point 167°C Yield 1.5 g . Methyl 2-(2,2 -diphenylethylamino) carbonylpyridins-5 carboxylate 1.5 g of methyl pyridine-2-(carboxylic acid)-5carboxylate are heated under "eflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 3.27 g of diphenyl ethyl amine in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallised from isopropanol, with the addition of a little active charcoal.
Melting point 147°C Yield 1.8 g 14. Methyl 2-(N-methyl -N-phenylamino) carbony lpyr idine-5carboxylate .5 g of methyl pyridine-2~(carboxylic acid)-5carboxylate are heated under reflux with 380 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred, st room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 250 ml of dry methylene chloride, the mixture is added dropwise co a solution of 30 g of K-methylaniline in ISO ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallised from isopropanol, with the addition of a little active charcoal.
Melting point 123°G Yield 30 g . Methyl 2-N-propylamino-earbonylpyridine-5-carboxylate g of methyl pyridine-2 -(carboxylic acid)-5carboxylate are heated under reflux with 225 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride Is distilled off completely. The residue is taken up in 70 ml of dry methylene chloride, the mixture is added dropwise to a solution of 13.7 g of propylamine in 150 al of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is chromatographed over silica gel with a mixture of 7 parts of methylene chloride and 3 parts of acetone as the mobile phase. Melting point 88°C Yield 12.6 g 16. Di(4-nitro-phenyl) pyridine-2,5-carboxylate 16.7 g of pyridine-2,5-dicarboxylic acid are taken In 100 ml of dry methylene chloride, and 135 ml of freshly distilled thionyl chloride and 3 ml of dry dime thy If ormamide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 27.8 g of 4-nitrophenol In 50 ml of pyridine Is added dropwise to the reaction.mixture at -30 co -20’C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase.
Melting point 190°C Yield 12.5 g 17. Bis (5-methyl-2-oxo-· 1,3-dioxol-4-vl -methyl) pyridine2,5-dicarboxylate Analogously to Example 7, 6 »3 g of pyridine-2,5di carboxylic acid sodium salt are reacted with 14.3 g of 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide aad the mixture is boiled under x'eflux in acetone for 2.5 hours. After chromatography over silica gel with ethyl acetate as the mobile phase, the product is recrystallized from hot ethyl acetate.
Melting point 118°C ’field 0.23 g 18. Di -(e-methoxycarbonylbeazyl) pyridine-2,5dicarboxylate Analogously to Example 1, 10 g of pyridine-2,5dicarboxylic acid are converted into the acid chloride and this is reacted with 19.9 g of methyl (i)-mandelate. After extraction, working up is carried out by chromatography over silica gel with a mixture of toluene and ethyl acetate as the mobile phase.
Melting point 125°C yield 0.5 g 19. Methyl pyridine-2-carboxamide-5-carboxylate g of methyl pyridine-2-(carboxylic acid)-5carboxylate ara converted into the acid chloride with 200 g of thionyl chloride as described in Example 8. The acid chloride is dissolved in chloroform, and ammonia gas is passed over 'the suspension, with vigorous stirring. The mixture is left to stand for two days and the product is filtered off with suction and washed with water.
Melting point 195-197°C Yield 15.6 g . Dibenzyl pyridine-2,5-dicarboxylate Analogously to Example 1, 20 g of pyridine-2,5dicarboxylic acid are converted into the acid chloride with ISO ml of thionyl chloride and thics is reacted with 25.9 g of benzyl alcohol. The product Is recrystallized from ethyl acetate, with the addition of active charcoal.
Melting point 110°C Yield 20.4 g 21. Benzyl pyridine-2-(carboxylic acid)-5-carboxylate g of dibenzyl pyridine-2,5-dicarboxylate are suspended in methanol and the suspension is added to a suspension of 12.1 g of copper(XX) nitrate. The mixture is boiled under reflux for one hour and, after cooling, the copper complex is filtered off. The complex is suspended in dioxane, and hydrogen sulfide Is passed In up to a weight Increase of 4 g. The copper sulfide is separated off and the organic phase is concentrated. The product is reerystallized from toluene.
Melting point 132°C Yield 10.2 g . Benzyl pyridine-2- (3-isopropoxy-propyl) carboxamide5-carboxy late Analogously to Example 8, 8 g of 5-benzyl pyridine2-carboxylate are converted info the acid chloride with 90 ml of thionyl chloride and this is reacted with 3-isopropoxy-propyl amine to give the amide. For purification, the product is 'chromatographed over silica gel with a mixture of cyclohexane/ethyl acetate (1:1).
Melting point 41°C Yield 6.4 g 23. Pyridine-5-carboxylic acid 2-(3-isopropoxy-propyl)» carboxamide .3 g o£ pvridine-2-(3-isopropoxy~propyl)-amide 5-benzyl ester are hydrogenated in dioxane under normal pressure in the presence of a palladium-onchareoal catalyst for five hours. When the uptake of hydrogen has ended, the catalyst is filtered off with suction and the solvent is stripped off. Melting point 129°C Yield 2.4 g 24. Benzyl pyridine-2-(3-isopropoxy-propyl)carboxamide5-carboxylate In accordance with Example 8, 1 g of pyridine-5earboxylic acid 2-(3-isopropoxy-propyl)amide are converted into the acid chloride (20 ml of thionyl chloride) and this is then reacted with 2 ml of benzyl alcohol to give the pyridine-2 -(isopropoxypropyl) amide 5-benzyl ester. For purification, the product is chromatographed over silica .gel with a mixture of cyclohexane/ethyl acetate (1:1).
Melting point 41°C Yield 0.9 g . Di (5-methyl-2-nitro-benzyl) pyridine - 2,5-carboxylate Analogously to Example. 1, 5 g of pyridine-2,5dicarboxylic acid are converted into the acid chloride with 40 ml of thionyl chloride in 30 ml of methylene chloride and this is reacted with 10 g of 5-methyl-2-nitro-benzyl alcohol in 50 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, sodium bicarbonate solution is then added, the mixture is extracted with methylene chloride and the organic phase is dried. After the solvent has been stripped off, the residue is stirred with ethyl acetate, filtered off with suction and recrystallized twice from methylene chloride.
Melting point 182°C Yield 2.9 g 26. Bis(2-ethoxy-ethyl) pyridine-2,5-dicarboxylate Analogously to Example 1, 10 g of pyridine-2,5dicarboxylic acid are converted info the acid chloride with 80 ml of thionyl chloride in 60 ml of methylene chloride and this is reacted with 10.78 g of ethylene glycol monomethyl ether in 100 ml of methylene chloride. Working up is by adding sodium bicarbonate solution, separating off the organic phase and stripping off the solvent. The product is chromatographed twice over silica gel with ethyl acetate and dissolved in hot ethyl acetate, and the solution is clarified with active charcoal and freed from the solvent. The product is obtained as an oil.
Yield 7.2 g 27. Bis(2-methoxy-ethyl) pyridine-2,5-dicarboxylate Analogously to Example 26, 10 g of pyridine-2,5dicarboxylic acid are converted into the acid chloride and this is reacted with 9.1 g of ethylene glycol monomethyl ether. Working up is carried out in accordance with Example 26. The product is obtained as an oil.
Yield 6.5 g 28. Bis(2-ethoxy-ethyl) pyridine-2,4-dicarboxylate As described in Example 25, 10 g of pyridine-2,4dicarboxylic acid are reacted with ethylene glycol monoethyl ether via the acid chloride. The reaction mixture is worked up analogously to Example 26. The product is obtained as an oil.
Yield 7.2 g 29. 2-Methoxycarbonyl-2-methyl-propyl pyridine-5carboxylate-2-N-(3-isopropoxy-propyl)carboxamide g of pyridine-5-carboxylic acid 2-(3isopropoxypropyl) amide are boiled under reflux in 20 ml of thionyl chloride until a solution is obtained. The solution is left to stand at room temperature for one hour, the thionyl chloride is distilled off, the residue is dissolved in 10 ml of dry methylene chloride and a solution of 0.5 g of methyl 2,2-dimethyl-3-hydroxypropionate in 20 ml of dry methylene chloride is added dropwise. When the reaction has ended, the solvent is stripped off and the product is chromatographed over silica gel with ethyl acetate.
Yield 0.15 g . Bis(1-isopropoxycarbonylethyl) pyridine-2,4 dicarboxylate g of pyridine-2,4-dicarboxylic acid are taken in SO ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 15,,8 g of isopropyl lactate dissolved in 100 ml of methylene chloride is added dropwise to the reaction mixture at -30 to -20 °C. The mixture is allowed to warm slowly co room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and stirred with diisopropyl ether. The monoester is separated off and the mother liquor is chromatographed over silica gel with a mixture of four parts of toluene and one part of ethyl acetate as the mobile Yield: phase. The product is obtained as 11.2 g an oil.

Claims (7)

1. PATENT CLAIMS 1. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula I in which R 1 denotes branched or uhbranched C 1 -C 12 -alkyl which is monosubstituted or else, in the ease of the C 2 -C 12 -alkyl radicals, polysubstituted by halogen, hydroxyl, cyano, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy or alkyl- or dialkylamino, th© alkyl radicals containing 14 carbos, atoms and, in the case of the C 3 - and C^-alkyl radicals, it also being possible for them to be branched, phenyl, which is in turn optionally mono-, di- or trisubstituted by halogen, nitro, C^-C^-alkyl or Ci-C 4 “ alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C 3 - and C A -alkyl radicals, for these to be branched, or R 1 denotes saturated C s -C 7 -cycloalkyl, which is optionally bento-fused, or R 3, denotes phenyl, naphthyl or a 5- or 6membered aromatic ring having lj 2 or 3 nitrogen and/or oxygen and/or sulfur atoms, which in turn are optionally mono-, di- or trisubstituted by halogen, C^-C^-alkyl or alkoxy, it also being possible, in the ease of polysubscitution, for th® substituents to differ independently of one another and it - also being possible, in the case of the C 3 and C 4 -alkyl radicals, for these to be branched, or R 1 denotes 2-oxo-l,3-dioxolylmethyl, which is optionally also methyl-substituted, or R x ,if X is nitrogen, denotes hydrogen, and R 2 independently of R 1 is hydrogen or R 1 , it also being possible for R 2 to be identical to R 1 , and X denotes oxygen or R 3 -substituted nitrogen, in which R 3 is hydrogen or Cj^-Cg-alkyl or optionally together with R 1 forms a heterocyclic saturated 5-, S- or 7-membered ring, it also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible foi' the heterocyclic ring in turn to be substituted by phenyl or phenyl-Cj-C 3 alkyl, or a physiologically tolerated salt thereof for use as a pharmaceutical.
2. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of formula X as claimed in claim 1, in which R 1 denotes branched or unbranched C·,-C 4 -alkyl which is monosubstituted or else, in the case of th© C 3 - and -alkyl radicals, polysubstituted by C-j-C 3 -alkoxy and/or -C 3 -alkoxy carbonyl, it also being possible for the C 3 alkyl radicals to be branched, and/or phenyl, or R 1 denotes C s - or C 6 -cycloalkyl, which is optionally benzo-fused, or R 1 denotes phenyl, which is optionally mono-, di- or trisubstituted by nitro, or R 1 denotes 2-, 3- or 4-pyridyl, naphthyl, 2» or 3-thienyl, pyrazolyl, imidazolyl or thiazolyl, or R 1 denotes 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl and R 2 Independently of R 1 is hydrogen or R 1 , it aiso being possible for R 2 to be identical to R 1 , and X denotes oxygen or R 3 -substituted nitrogen, in which R 3 is hydrogen or Ci-G 3 -alkyl or optionally together with R 1 forms a heterocyclic saturated 6-membered ring, it also being possible for the heterocyclic 6 -membered ring to Include a second nitrogen atom and to be substituted In turn by phenyl or phenylC^-Cj-alkyl, or a physiologically tolerated salt thereof, for use as a pharmaceutical. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula I e
3. « II R -o-c->o. (I’> Q W 'X 1 ’ 1 C - X’ - R II 0 in which r 1 ' denotes branched or unhranched C 1 -C 12 -alkyl which Is monosubstituted or else, in the case of C 2 -C 12 -alkyl, polysubstituted by halogen, hydroxyl, cyano, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy or alkyl- or dialkylamino, the alkyl radicals containing 1-
4. Carbon atoms and it also being possible, in the case of the C 3 - and C s -alkyl radicals, for these to be branched, phenyl, which is in turn, optionally mono-, di- or trisubstituted by halogen, C^-C^-alkoxy or Cj.-C^-alkyl, it also being possible for the C 3 - and C^-alkyl radicals mentioned to be branched and it also •being possible, in the case of polysubstitution, for the substituents to differ independently of one another, or R 1 'denotes saturated C 5 -C 7 -cycloalkyl, which is optionally benzo-fused, or R 1 ' denotes phenyl, naphthyl or a 5- or 5membered aromatic ring having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms, which is in turn optionally mono-, di- or trisubstituted by halogen, nitro, C x -C 4 -alkyl or -alkoxy, it also being possible, in the case of polysubstitution, for the substituents to differ independently of one another and it also being possible, in the case of the C 3 - and C 4 -alkyl radicals, for these to be branched, or R 1 ' denotes 2-oxo-l, 3-dioxolylmethyl, which is op t ional ly me thy 1 - sub s ti tut ed, or R 1 ', if X' is nitrogen, denotes hydrogen, and R 2 ' independently of R 1 ' is hydrogen or R 1 ', if also being possible for R 2 * to be identical to R 1 ', and 2/ denotes oxygen or R 3 '-substituted nitrogen, in which R 3 ' is hydrogen or ^-Cg-alkyl or, optionally together with R 1 ', forms a heterocyclic, saturated 5-, 6- or 7-membered ring, if also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible for the heterocyclic ring in turn to be substituted by phenyl or phenyl-C-j^-Cg-alkyl, or a physiologically tolerated salt thereof, excluding the compounds in which 3£' ? denotes oxygen and R 1 ' and R 2 ' are methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl, and di (4mefhoxyphenyl) pyridine-2,5-dicarboxylate. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of formula I* as claimed in claim 3, ia which R 1 ' denotes branched or unbranched C 1 -C 4 -alkyl, which is monosubstituted or els®, in the case of the C 2 -C A -alkyl radicals, polysubs ti tuted by alkoxy or alkoxycarbonyl, the alkyl radicals containing 1-3 carbon atoms and it also being possible, in the case of the C 3 ~ alkyl compounds, for these to be branched, or phenyl or R 1 ' denotes cyclopentyl or cyclohexyi, which are optionally benzo-fused, or R 1 ' denotes phenyl, which is optionally substituted by 1, 2 or 3 nitro groups, or naphthyl, or R 1# denotes 2-, 3- or 4-pyridyl, 3-thienyl, pyrazolyl, imidazolyl or thiazolyl, or R 1 ' denotes 5-methyl-2-oxo-l,3-dxoxol-4-ylmethyl and R 2 ' independently of R 1 ' is hydrogen or R 1 ', it also being possible for R 2 ' to be identical to R 1 *, and X f denotes oxygen or R 3 '-substituted nitrogen, in «2» f which R is hydrogen or C x -C 3 - alkyl or optionally together with R 1 ' forms a heterocyclic, saturated 6-membered ring, it also being possible for the heterocyclic 6-membered ring to include a second nitrogen atom and in turn fo b® substituted by pheavl or phenylC x -C 3 - alkyl, or a physiologically tolerated salt thereof, excluding the compounds in which 3C ? denotes oxygen and R 1 ’ and R 2 ” are methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl, and di- (4methoxyphenyl) pyridine-2,5-dicarboxylate. A process fox' the preparation of a compound of the formula I' as claimed in claim 3, which comprises a) reacting a compound of the formula II II (IT) with a compound of the formula III HX’-R 1 ’ (III) in which R 1 ', R 2 ’ and 2' have the meanings given in the case of formula I' and Y is halogen or hydroxyl, or b) reacting a compound of the formula IV II (IV) with a compound of the formula V ΞΟ-R 2 ' (V) in which R 1 ', R 2 ' and 2E' have the case of formula I and Z c) reacting a compound of the meanings given in is halogen, or the formula VI TO) c-z II with an alcohol HO-S, 2 ' or an alcohol of the formula VII HO-R 1 ' (VII) in which R 1 ' and R 2 ' have the meanings, given in the 5 case of formula I e and Z is halogen, or d) reacting an alkali metal salt of pyridine-2,4- or -2,5-dicarboxylic acid with a halide of the formula VIII R v -Z (VIII) 10 in which R 1 ' has the meanings given in the ease of formula 1' and Z is halogen, and, if appropriate, converting the reaction product into one of its physiologically tolerated salts. 6. The process as claimed in claim 5, wherein, in 15 process variant a), the reaction is carried out with simultaneous addition of a dialkylcarbodiimide, the dialkyl radicals containing 1 to 8 carbon atoms and it also being possible, in the case of the C 3 -C 8 compounds, for these to be branched or cyclic. 20 7. A compound as claimed in one of claims 1 to 4 for inhibiting proline hydroxylase and lysine hydroxylase. 8. A compound as claimed in claim 1 to 4 for use as a fibrosuppressant and immunosuppressant. 25 9. A pharmaceutical containing a compound of the formula I or I as claimed in claim 1 or 3 with tolerated pharmaceutical excipients. 10. A process for the preparation of a pharmaceutical for influencing the metabolism of collagen and 30 collagen-like substances or the biosynthesis of CX^, which comprises incorporating a compound of the formula I or I* as claimed ia claim 1 or 3 into the pharmaceutical. 3o 11. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula I' as claimed in claim 3, ia which R 1 ' is branched or unhranehed C 1 -C 4 -alkyl, which is substituted by aXkojcycarboayl, the alkyl radicals
5. Containing 1-3 carbon atoms and it also being possible, in the ease of the C 3 -alkyl radicals, for these to be branched, and R 2 ’ independently of H 1 * is hydrogen or R 1 ', it also being possible for R 2 ’ to be identical to , and XT denotes oxygen, 1© or a physiologically tolerated salt thereof. 12. A pyr idine-2,4- or -2,5-dicarboxylic acid derivative of the formula I fJ as claimed in claim 3, in which R 1 ' and R 2 ’ are 1-isopropoxycarbonylethyl groups and X' denotes oxygen, or a physiologically tolerated 15 salt thereof. 13. A compound as claimed in claim 3, substantially as hereinbefore described and exemplified. 14. A process for the preparation of a compound as claimed in claim 3, substantially as hereinbefore described and exemplified. 15. A compound as claimed in claim 3, whenever prepared by a process claimed in any one of claims 5, 6 or 14. 1
6. A pharmaceutical as claimed in claim 9, substantially as hereinbefore described and exemplified. 30 1
7. A process for the preparation of a pharmaceutical as claimed in claim 9, substantially as hereinbefore described and exemplified. A pharmaceutical as claimed in claim 9, whenever prepared by a process claimed in claim 10 or 17.
IE35088A 1987-02-10 1988-02-09 Pyridine-2,4- and -2,5-dicarboxylic acid derivatives processes for their preparation the use thereof and medicaments based on these compounds IE67446B1 (en)

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DE19873703963 DE3703963A1 (en) 1987-02-10 1987-02-10 PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS

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DE (2) DE3703963A1 (en)
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Families Citing this family (12)

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DE3707429A1 (en) * 1987-03-07 1988-09-15 Hoechst Ag SUBSTITUTED PYRIDINE-2,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS
HU202516B (en) * 1987-10-02 1991-03-28 Egyt Gyogyszervegyeszeti Gyar Process for producing (2-thenyl)-thiourea derivatives and yield increasing agents comprising such compounds
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
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
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
US5260323A (en) * 1990-06-28 1993-11-09 Hoechst Aktiengesellschaft 2,4- and 2,5-substituted pyridine-N-oxides, processes for their preparation and their use
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
YU9492A (en) * 1991-02-05 1995-03-27 Hoechst Ag. 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation
CA2085954A1 (en) * 1991-12-24 1993-06-25 Klaus Weidmann Substituted pyridine n-oxides, processes for their preparation, and their use
DE4233124A1 (en) * 1992-10-02 1994-04-07 Hoechst Ag Acylsulfonamido and sulfonamidopyridine-2-carboxylic acid esters and their pyridine N-oxides, processes for their preparation and their use as medicaments
ATE255581T1 (en) * 1997-10-24 2003-12-15 Fibrogen Inc PHENANTHROLINE DERIVATIVES
KR100579792B1 (en) * 1998-05-13 2006-05-12 동화약품공업주식회사 Novel 2,5-pyridinedicarboxylic acid derivatives

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093622A (en) * 1975-05-19 1978-06-06 Zoecon Corporation Pyridine esters of cyclopropane-carboxylic acid
EP0123700A1 (en) * 1983-04-27 1984-11-07 Byk Gulden Lomberg Chemische Fabrik GmbH Substituted picolinic acids, processes for their preparation, their use, and pharmaceutical preparations containing them
DE3432094A1 (en) * 1984-08-31 1986-03-06 Hoechst Ag, 6230 Frankfurt ESTER OF PYRIDINE-2,4- AND -2,5-DICARBONIC ACID AS A MEDICINAL PRODUCT FOR INHIBITING PROLIN AND LYSINE HYDROXYLASE
US4757071A (en) * 1984-12-14 1988-07-12 Nisshin Flour Milling Co., Ltd. 1,4-dihydropyridine derivatives, and pharmaceutical compositions containing same, useful for treating cardiovascular diseases
US4691018A (en) * 1985-05-23 1987-09-01 Chugai Seiyaku Kabushiki Kaisha Pyridine derivatives and their use as anti-allergic agents
GB8702890D0 (en) * 1987-02-10 1987-03-18 Zyma Sa Heterocyclic compounds
ATE113036T1 (en) * 1988-08-04 1994-11-15 Hoechst Ag IMPROVED PROCESS FOR THE PRODUCTION OF N,N-BIS(ALKOXYALKYL)-PYRIDINE-2,4-DICARBONIC DIAMIDES.

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FI880554A0 (en) 1988-02-08
DE3703963A1 (en) 1988-08-18
AU1145088A (en) 1988-08-11
IE880350L (en) 1988-08-10
NO173184C (en) 1993-11-10
FI91524B (en) 1994-03-31
PT86734B (en) 1992-05-29
FI91524C (en) 1994-07-11
DE3853839D1 (en) 1995-06-29
KR880009935A (en) 1988-10-05
NO173184B (en) 1993-08-02
EP0278452A2 (en) 1988-08-17
KR960011371B1 (en) 1996-08-22
HUT47249A (en) 1989-02-28
DK66088D0 (en) 1988-02-09
DK90992D0 (en) 1992-07-10
IL85361A (en) 1993-01-31
NZ223431A (en) 1990-07-26
AU600084B2 (en) 1990-08-02
ATE123022T1 (en) 1995-06-15
HU207295B (en) 1993-03-29
DK66088A (en) 1988-08-11
AR247816A1 (en) 1995-04-28
IL85361A0 (en) 1988-07-31
NO880556D0 (en) 1988-02-09
DK170245B1 (en) 1995-07-17
DK168379B1 (en) 1994-03-21
ES2073393T3 (en) 1995-08-16
NO880556L (en) 1988-08-11
FI880554A (en) 1988-08-11
JPS63216870A (en) 1988-09-09
DK90992A (en) 1992-07-10
ZA88897B (en) 1988-08-09
EP0278452A3 (en) 1989-10-18
PT86734A (en) 1988-03-01
EP0278452B1 (en) 1995-05-24

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