Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-20
1998-07-07
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514313, A61K 3147
Patent
active
057769478
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the use of quinoline-3-carboxamide compounds, in particular roquinimex (Linomide.RTM.), or a pharmaceutically acceptable salt thereof for inhibiting the production of tumour necrosis factor (TNF) and/or for the treatment of septic shock.
BACKGROUND OF THE INVENTION
Septic shock is a highly lethal disease which is induced by polyclonal stimulators produced by bacteria, namely lipopolysaccharide (LPS, an endotoxin that stimulates B cells and macrophages) and superantigens implies a critical clinical condition for which thus far no effective syndrome due to a hyperacute activation of inflammatory cells in response
In addition to septic shock there are a number of serious diseases related to the production of TNF, i. a. disease, antibodies for prevention of graft rejection,
Antibodies directed against TNF prevent the detrimental effect of (CENTO-COR INC.) discloses a high-affinity mouse monoclonal antibody, a chimeric antibody and an anti-TNF antibody, all of which can be used for treatment of for example sepsis syndrome.
Application of cytokines that inhibits TNF secretion reduces the toxicity multivalent immunoglobulin used to treat or prevent diseases associated with elevated cytokine levels, for example sepsis.
Quinoline-3-carboxamide compounds have been suggested as pharmaceuticals. The compounds have comprised the structure given in formula I below, optionally with substituents for the hydrogen atoms shown (H.sup.1-9, where H.sup.9 is part of X.sub.1 or X.sub.2 as shown in (b) below) and, where appropriate, salts of the compounds: ##STR1##
This formula is a collective formula for the tautomeric structures II-IV. ##STR2##
In formula I-IV: the atoms comprised by the dashed line (only formula I). NH.sup.9 group that is possibly substituted, said X.sub.1 and X.sub.2 being bound by a single bond to the ring when attached to H.sup.7 or H.sup.8 and by a double bond when not bound to H.sup.7 or H.sup.8. present when at least one of X.sub.1 and X.sub.2 is the NH.sup.9 group. selected among X.sub.1, X.sub.2 and the nitrogen atom in the quinoline ring said X.sub.1 and X.sub.2 being bound by a single bond to the ring when attached to H.sup.7 or H.sup.8 and by a double bond when not bound to H.sup.7 or H.sup.8.
The substituents that are to replace H.sup.1-9 may, according to the prior art, comprise any substituent that gives compounds that can be isolated. See for instance Indian Journal of Chemistry Vol 17B (1979) 488-90 (anti-inflammatory properties), U.S. Pat. No. 3,960,868 (=GB 1,467,061, analgesic, anticonceptive, anti-inflammatory and anti-allergic properties), U.S. Pat. Nos. 4,547,511 and 4,738,971 (enhancing cell-mediated immunity), WO 9015052 (=U.S. Ser.No. 651,234, filed May 31, 1990) (immunomodulator), U.S. Pat. No.4,107,310 (analgetics) and JP 68023948 (bacteriocides). U.S. patents and patent applications given above are hereby incorporated by reference. In general it can be stated that many of the compounds comprising structure I are classified as immune modulators with individual effects spanning the spectra from suppression to stimulation of the immune system. The specific effect achieved depends on the substituents.
One of the most important compounds with formula I is the 1,2-dihydro-hydroquinoline-3-carboxamides, particularly N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxa mide roquinimex (Linomide.RTM.), i.e. structures I and II with a substituent for H.sup.1 that equals phenyl, for H.sup.2 that equals methyl, for H.sup.8 that equals methyl (attached to the nitrogen atom of the quinoline ring), with no substituents for H.sup.3-7, with H.sup.7 attached to X.sub.1, and with each of X.sub.1 and X.sub.2 equalling an oxygen atom. The compound has double bonds between positions 3 and 4 and between positions 2 and X.sub.2.
The scientific experimentation with roquinimex has shown that roquinimex has multiple immunological activities. It has thus been found that roquinimex increases the proliferative response to T- and B-cell mitogens 31!. Moreove
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Alonso Carlos Martinez
Gonzalo Jose-Angel
Kalland Terje
Kroemer Guido Peter
Goldberg Jerome D.
Pharmacia AB
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