Naphthyridine derivatives as alpha V beta 6 integrin antagonists for the treatment of E.G. fibrotic diseases

{
  "publication_number": "US10513517B2",
  "country": "US",
  "kind": "B2",
  "title": "Naphthyridine derivatives as alpha V beta 6 integrin antagonists for the treatment of E.G. fibrotic diseases",
  "abstract": "A compound of formula (I) or a salt thereof: wherein R 1 represents a five-membered aromatic heterocycle selected from a N- or a C-linked mono- or di-substituted pyrazole, an N- or a C-linked optionally mono- or di-substituted triazole or an N- or a C-linked optionally mono- or di-substituted imidazole, which five-membered aromatic heterocycle may be substituted by one or two of the groups selected from a hydrogen atom, a methyl group, an ethyl group, a fluorine atom, a hydroxymethyl group, a 2-hydroxypropan-2-yl group, a trifluoromethyl group, a difluoromethyl group or a fluoromethyl group, except that when R 1 represents an N-linked mono- or di-substituted pyrazole, R 1 does not represent 3,5-Dimethyl-1H-pyrazol-1-yl, 5-Methyl-1H-pyrazol-1-yl, 5-Ethyl-3-methyl-1H-pyrazol-1-yl, 3,5-Diethyl-1H-pyrazol-1-yl, 4-Fluoro-3,5-dimethyl-1H-pyrazol-1-yl, 3-Methyl-1H-pyrazol-1-yl or 1H-pyrazol-1-yl.",
  "claims": [
    "1. A compound which is 3-(3-(1,4-dimethyl-1H-imidazol-2-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid or pharmaceutically acceptable salt thereof.",
    "2. A compound which is (S)-3-(3-(1,4-dimethyl-1H-imidazol-2-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid or pharmaceutically acceptable salt thereof.",
    "3. A compound which is (R)-3-(3-(1,4-dimethyl-1H-imidazol-2-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid or pharmaceutically acceptable salt thereof."
  ],
  "description_excerpt": "The present invention relates to pyrrolidine compounds being α v β 6 integrin antagonists, pharmaceutical compositions comprising such compounds and to their use in therapy, especially in the treatment of conditions for which an α v β 6 integrin antagonist is indicated, for the use of a compound in the manufacture of a medicament for the treatment of conditions in which an antagonist of α v β 6 integrin is indicated and a method for the treatment or prophylaxis of disorders in which antagonism of α v β 6 integrin is indicated in a human.\n\nIntegrin superfamily proteins are heterodimeric cell surface receptors, composed of an alpha and beta subunit. At least 18 alpha and 8 beta subunits have been reported, which have been demonstrated to form 24 distinct alpha/beta heterodimers. Each chain comprises a large extracellular domain (>640 amino acids for the beta subunit, >940 amino acids for the alpha subunit), with a transmembrane spanning region of around 20 amino acids per chain, and generally a short cytoplasmic tail of 30-50 amino acids per chain. Different integrins have been shown to participate in a plethora of cellular biologies, including cell adhesion to the extracellular matrix, cell-cell interactions, and effects on cell migration, proliferation, differentiation and survival (Barczyk et al, Cell and Tissue Research, 2010, 339, 269).\n\nIntegrin receptors interact with binding proteins via short protein-protein binding interfaces. The integrin family can be grouped into sub-families that share similar binding recognition motifs in such ligands.",
  "cpc": [
    "C07D 471/04",
    "A61K 31/4375",
    "A61P 11/00",
    "A61P 43/00",
    "C07B 2200/05",
    "C07B 59/002"
  ],
  "ipc": [
    "C07B 59/00",
    "C07D 471/04"
  ],
  "assignees": [
    "GlaxoSmithKline Intellectual Property Development Ltd"
  ],
  "inventors": [
    "Niall Andrew Anderson",
    "Ian Baxter Campbell",
    "Matthew Howard James CAMPBELL-CRAWFORD",
    "Ashley Paul Hancock",
    "Seble LEMMA",
    "Simon John Fawcett Macdonald",
    "John Martin Pritchard",
    "Panayiotis Alexandrou Procopiou"
  ],
  "filing_date": "2018-10-19",
  "publication_date": "2019-12-24",
  "grant_date": "2019-12-24",
  "priority_date": "2014-09-26",
  "application_number": "US-201816165506-A",
  "family_id": "51901231",
  "cited_by_count": 11,
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