Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-12
2000-05-30
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 87, A01N 4340
Patent
active
060691506
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the use of derivatives of tetrahydro-beta-carbolines for the preparation of pharmaceutical compositions having antimetastatic properties.
The metastasizing tumor cells are capable to migrate from the primary tumor toward the target organs by means of a mechanism which encompasses the penetration through the blood vessel walls, the entrance of the tumor cells into the blood f low, followed-by the successive crossing of the vessel's walls to reach the target organ.
The penetration through the connective tissue of the vessels is accomplished by the degradation of the extracellular matrix by means of the metalloproteinases released by the resident connective tissue cells, which are activated by the tumor cells. Such a mechanism, which is shared also by the not tumor tissues, is usually in a dynamic equilibrium with the connective tissue regeneration, while it is expressed in an uncontrolled way in the invading cells such as the tumor or inflammatory cells and it is involved in several pathologies such as rheumatoid arthritis, osteoarthritis, septic arthritis, cornea's ulcerations, epidermic or gastric ulceration, coronary thrombosis, proteinuria (WO 95/13289).
In such processes three types of metallo-proteinases are involved: collagenases, gelatinases and stromelysins. In normal conditions their release and their activity are strictly controlled by endogenic proteinases-inhibitors, such as for example .alpha..sub.2 -macroglobulin.
Therefore, metallo-proteinase inhibitors may be useful in the treatment of the pathological conditions above described as well as of the pathological consequences of traumas or also as contraceptive agents, since the metallo-proteinases are involved in the ovulation process and in the successive implant of the ovule on the uterine wall. In particular, the inhibition of the tumor metastasis by means of metallo-proteinase inhibitors is described in Matrisian et al., PNAS USA, 83, 9413-7 (1986); Wilhelm et al., PNAS USA, 84, 6725-29 (1987); Werb et al., J. Cell Biol., 109, 872-89 (1989); Liotta et al., Lab. Invest., 49, 636-49 (1983).
Metallo-proteinase inhibitors are described in U.S. Pat. No. 4,511,504, U.S. Pat. No. 4,568,666, U.S. Pat. No. 4,771,037, WO 95/13289.
Beta-carboline derivatives are described to possess various pharmacological activities, such as for example antitumor activity [Anticancer Res., 13(6A), 2301-8 (1993); J. Antibiot., 46(11), 1672-7 (1993); EP 357.122], antiulcer activity [WO 92/04348 (19.03.92)], antimalarial activity [J. Nat. Prod., 54(5), 1360-7 (1991)] or are described as agents that enhance the absorption of antitumor drugs (JP 04275221).
None of such molecules is however described to have antimetastatic activity.
We have surprisingly found that the tetrahydro-beta-carbolines of formula (I) are endowed with a very high activity of inhibition of the metastatic process: ##STR1## wherein: R is selected in the group comprising hydrogen, linear or branched (C.sub.1 -C.sub.5)alkyl, phenyl (optionally substituted with a (C.sub.1 -C.sub.5)alkoxy group), --(CH.sub.2).sub.n --COOH, wherein n is an integer from 1 to 3; (C.sub.1 -C.sub.5)alkyl; bromine, fluorine or iodine), (C.sub.1 -C.sub.4)alkoxy, benzyloxy.
Object of the present invention is the use of the compounds of formula (I), as antimetastatic agents and as inhibitors of the tumor invasion process.
Also the enantiomers, the racemates and the diastereoisomers of the compounds of formula (I) are encompassed in the present invention, as well as their salts with pharmaceutically acceptable acids or bases.
Preferred examples of compounds of formula (I) are:
The compounds encompassed in the present invention are known compounds and are commercially available or can be obtained by extraction from plants or synthesized according to methods reported in literature (see for example WO 92/04348).
The compounds of the present invention have been tested in a pharmacological "in vitro" test of inhibition of MMP8 (human neutrophil collagenase). Said test provides for the determination via flu
REFERENCES:
patent: 4539407 (1985-09-01), Stack et al.
patent: 5010077 (1991-04-01), Braestrup et al.
patent: 5162336 (1992-11-01), Molino et al.
International Publication No. WO 92/04348 published Mar. 19, 1992.
International Publication No. WO 95/13289 published May 18, 1995.
AntiCancer Res., vol. 13, No. 6a, 1993, pp. 2301-2308, "PB-100: a potent and selective inhibitor of human BCNU resistant glioblastoma cell multiplication".
Drug Res., vol. 28, No. 1, 1978, pp. 42-46, "Major pharmacological effects of 6-methoxytetrahydro-beta carboline, a drug elevating the tissue 5-hydroxytryptamine level".
Krell Hans-Willi
Menta Ernesto
Spinelli Silvano
F. Hoffman-La Roche AG
Jones Dwayne C.
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