Pyridine-2,4-and -2,5-dicarboxylic acid amides and medicaments based on these compounds

{
  "publication_number": "US5037839A",
  "country": "US",
  "kind": "A",
  "title": "Pyridine-2,4-and -2,5-dicarboxylic acid amides and medicaments based on these compounds",
  "abstract": "The invention relates to pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the formula I (I) in which R1, R2, R3, R4 and X have the meanings given, a process for the preparation of these compounds and their use, in particular in medicaments for influencing the metabolism of collagen and collagne-like substances or the biosynthesis of Clq.",
  "claims": [
    "1. A pyridine-2,4- or -2,5-dicarboxylic acid amide of the formula I' ##STR8## in which R 1' denotes branched or unbranched C 1 -C 4 -alkyl, which is substituted by C 1 -C 3 -alkoxy, it being possible for the C 3 -alkyl moiety of the C 3 -alkoxy group to be branched, and R 2', independently of R 1', is hydrogen or has one of the meanings described for R 1', it also being possible for R 2' to be identical to R 1' and R 3', independently of R 1', is hydrogen or has one of the meanings described for R 1', it also being possible for R 3' to be identical to R 1' and/or R 2', and R 4' independently of R 1', R 2' and R 3' is hydrogen or has one of the meanings described for R 1', it also being possible for R 4' to be identical to R 1' and/or R 2' and/or R 3' or a physiologically tolerated salt thereof.",
    "2. A pyridine-2,4- or -2,5-dicarboxylic acid amide of the formula I' ##STR9## in which R 1' denotes a 3-isopropoxypropyl group; R 2' denotes hydrogen; R 3' denotes a 3-isopropoxypropyl group; and R 4' denotes hydrogen; or a physiologically tolerated salt thereof.",
    "3. A pyridine-2,4- or -2,5-dicarboxylic acid amide of the formula I' ##STR10## in which R 1' denotes a 2-methoxyethyl group; R 2' denotes hydrogen; R 3' denotes a 2-methoxyethyl group; and R 4' denotes hydrogen; or a physiologically tolerated salt thereof.",
    "4. A method for inhibiting proline hydroxylase and lysine hydroxylase in a mammal comprising administering a pharmaceutically effective amount of a compound of the formula I' as claimed in claim 1.",
    "5. A method for fibrosuppression and immunosuppression in a mammal comprising administering a pharmaceutically effective amount of a compound of the formula I' as claimed in claim 1.",
    "6. A method for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq in a mammal comprising administering a pharmaceutically effective amount of a compound of the formula I' as claimed in claim 1.",
    "7. A method for treating a disturbance of the metabolism of collagen and collagen-like substances or the biosynthesis of Clq in a mammal comprising administering a pharmaceutically effective amount of a compound of the formula I' as claimed in claim 1.",
    "8. A pharmaceutical composition for the inhibition of proline and lysine hydroxylase in a mammal which comprises an effective amount for said inhibition of a compound of the formula I' as claimed in claim 17 together with a pharmaceutically tolerated vehicle."
  ],
  "description_excerpt": "This is a continuation of application Ser. No. 07/153,087, filed Feb. 8, 1988 now abandoned.\n\nCompounds which inhibit proline hydroxylase and lysine hydroxylase effect very selective inhibition of collagen biosynthesis by influencing collagen-specific hydroxylation reactions. In the course of these, protein-bonded proline or lysine is hydrolyzed 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 be 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 proteolytically. As a consequence of these effects, the total amount of extracellularly deposited collagen is reduced.\n\nIt is known that inhibition of proline hydroxylase by known inhibitors, such as α,α'-dipyridyl, leads to an inhibition of the Cl q -biosynthesis of macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1978) 47). This results in a loss of the classical route of complement activation. Inhibitors of proline hydroxylase therefore also act as immunosuppressants, for example in immunity complex diseases.\n\nIt 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 effective as inhibitors in cell culture only in very high concentrations (V. Gunsler et al. Collagen and Rel. Research 3, 71 1983).",
  "cpc": [
    "C07D 213/81",
    "A61P 3/00",
    "A61P 37/06",
    "A61P 43/00",
    "C07D 213/82",
    "C07D 401/14",
    "C07D 409/14",
    "C07D 417/14"
  ],
  "ipc": [
    "A61K 31/44",
    "A61K 31/4402",
    "A61K 31/455",
    "A61P 3/00",
    "A61P 37/06",
    "A61P 43/00",
    "C07D 213/81",
    "C07D 213/82",
    "C07D 401/12",
    "C07D 401/14",
    "C07D 409/12",
    "C07D 409/14",
    "C07D 417/12",
    "C07D 417/14"
  ],
  "assignees": [
    "Hoechst AG"
  ],
  "inventors": [
    "Martin Bickel",
    "Dietrich Brocks",
    "Harald Burghard",
    "Volkmar Gunzler",
    "Stephan Henke",
    "Hartmut Hanauske-Abel",
    "Jurgen Mohr",
    "Georg Tschank"
  ],
  "filing_date": "1989-11-13",
  "publication_date": "1991-08-06",
  "grant_date": "1991-08-06",
  "priority_date": "1987-02-10",
  "application_number": "US-43440289-A",
  "family_id": "6320590",
  "cited_by_count": 15,
  "citations": [
    "US2852519A",
    "DE2803592A1",
    "EP0057797A2",
    "EP0198202A2",
    "EP0278908A2"
  ]
}