Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1998-01-29
1999-01-05
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
552208, 552222, A01N 3712
Patent
active
058563580
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. National Stage Application of PCT/EP96/02597 filed Jun. 17, 1996 now WO/97/00875 published Jan. 9, 1997.
The present invention relates to compounds useful for the treatment of the pathologies in which the erosion of the cartilaginous and bone matrix occurs in the most advanced steps of the disease, such as osteoarthrosis and rheumatoid arthritis, and to pharmaceutical compositions containing them. Furthermore, the invention relates to novel anthraquinone derivatives and to the process for the preparation thereof.
Osteoarthrosis are known to be treated mainly using substances acting on the pain and exerting their symptomatic effect thanks to their antiinflammatory activity. Said medicaments are usually referred to as non steroidal antiinflammatory drugs (NSAID) such as for example indomethacin and steroidal ones, such as hydrocortisone and bethametasone.
Other used compounds comprise copper chelating agents, such as penicillamine, and those compounds which interfere with collagene synthesis, with DNA or with synovial membranes, such as cyclophosphamide.
Among the most recent substances used in the above mentioned pathologies there are diacetylrhein, a pro-drug of rhein, which exerts its therapeutical activity being a copper chelating agent, moreover it inhibits the formation of ceruloplasmin during the acute phase of arthritis inflammation and it is also a calcium chelating agent, forming soluble complexes with calcium thanks to the solubilizing COOH group present in its structure. Such a characteristic of forming soluble complexes with calcium is likely to be of paramount importance, since it avoids the formation and precipitation of microcrystals at the articulation sites, thereby preventing inflammatory reactions from occurring or from going on (Friedman, U.S. Pat. No. 4,244,968 del 13, Jan. 1981). Furthermore, rhein inhibits the formation and release of the superoxide anion from NADPH-dependent biological systems (Mian M. et al. J. Pharm. Pharmacol. 1987; 39: 845-847) and the activity of serine proteases, such as elastase and cathepsin G from man (Raimondi I. et al. Pharmacol. Res. Comm. 1982; 14 (2): 103-112), Zembower D E. et al. J. Med. Chem. 1992; 35: 1597-1605 1992).
Further pharmacological and clinical studies described in literature proved that, in addition to the above mentioned mechanisms, other pathogenetic mechanisms act in the diseases affecting articulations, causing the erosion of the cartilaginous and bone matrix.
Among such mechanisms, the increase in some enzyme activities or an unbalance among the latter and the inhibitors thereof should be stressed. As recently proved by some researchers, cysteine proteases, such as cathepsin B and L, are enzymes strictly connected with the degradation of the cartilage and therefore with the related pathologies. It has widely been reported in literature, that cysteine proteases, cathepsins B and L, are capable of inducing directly or indirectly (by activation of proenzymes), the degradation of the main components of the cartilaginous and bone extracellular matrix (Roughley P J. et al. Biochem. J. 1977; 167; 639-637; Sakamoto S. et al. MOL. Aspects Med. 1988; 10; 299-428; Nguyen P j. et al. Biochem. J. 1991 Aug. 15; 278 (pt 1): 143-7; Maciewiez R A. et al. Biomed. Biochim. Acta 1991; 50 (4-6): 561-4; Buttle D J. Arthritis Rheum. 1993; 36 (12); 1709-17; Pelletier J P. et al. Osteoarthritis 1993; 19 (3); 545-568).
Moreover, the interest in these enzyme activities, has been confirmed by studies carried out on laboratory animals (rats) in which rheumatoid arthritis had been induced. In said animals, the effect of the inhibitors of cysteine proteases, such as fluoromethylketones, on the development of the disease was evaluated particularly on the cartilaginous and bone articular lesions.
The results of said studies showed that the enzyme inhibitors can be clinically valuable in the treatment of arthritis (Ahmed N K. et al. Biochem. Pharmacol. 1992; 44 (6); 1201-7; Meijers M, Billingham M. et al. Agents actions 1993; 39 (1); 219-21; Esser R
REFERENCES:
J. Med. Chem., vol. 17, No. 8, 1974, pp.890-893, XP000608424, J. M. Grisar et al, "Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents."
Aloisi Ruggero
Benetti Dino
Guainai Giuseppe
Rosini Sergio
Boonville Limited
Geist Gary
Padmanabhan Sreeni
LandOfFree
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