Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-27
1999-01-05
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514279, 546 41, 546 48, C07D49122, A61K 31435
Patent
active
058563334
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new substituted camptothecin derivatives possessing antitumor activity, to a process for their preparation, and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Camptothecin and some of its analogs display potent antitumor activity by the inhibition of Topoisomerase I, that is an enzyme involved in some important cellular functions and cellular growth (see, for instance, Wani et al., J. Med. Chem. 1987, 30, 1774; Hsiang et al., Cancer Res. 1989, 49, 4385; Cancer Res. 1989, 49, 1465).
Anticancer activity of Camptothecin both in vitro and in vivo is significantly greater for the lactone versus the carboxylate form (as disclosed, for instance, by W. J. Slichenmyer et al., in "The Current Status of Camptothecin Analogues as Antitumor Agents", J. Natl. Cancer Inst. 1993, 85, 271-291, and reference therein), since a closed a-hydroxy lactone ring is an important structural requirement for both passive diffusion of drug into cancer cells, as well as for successful drug interaction with the pharmacological target. It has recently been pointed out that, in the presence of biologically relevant levels of human albumin, the biologically active form of camptothecin has a very short half-life (about 12 min.), and 2 hours after drug addition to human plasma, a percentage greater than 99% of the drug has converted to camptothecin carboxylate, the biologically inactive and potentially toxic form of the drug (see Burke, G. T.; Mi, Z. "The Structural Basis of Camptothecin Interactions with Human Serum Albumin: Impact on Drug Stability", J. Med. Chem. 1994, 37, 40-46). The same authors disclose also the importance of the substitution in 9 and 7 positions on the camptothecin nucleus in order to improve drug stability in the presence of albumin.
There is therefore a need to find new camptothecin derivatives that have high intrinsic potency, and may gain, at the same time, stability in the presence of serum albumin.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to substituted camptothecin derivatives of formula (I) ##STR2## wherein the symbol - - - - represents a single or double bond; -C.sub.6 alkyl or benzyl and the other is hydrogen C.sub.1 -C.sub.6 alkanoyl, an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl, an optionally substituted benzoyl, phenyl C.sub.1 -C.sub.6 alkanoyl, an optionally substituted phenoxycarbonyl or phenyl C.sub.1 -C.sub.6 alkoxycarbonyl, or R.sub.5 and R.sub.6, combined together with the nitrogen atom to which they are linked, form a 4-7 membered saturated, optionally substituted, heteromonocyclic ring residue, represented by a group (G) ##STR3## wherein W is --C.dbd.O, R.sub.7 is hydrogen or C.sub.1 -C.sub.6 alkyl and n is an integer of 2 to 5; -C.sub.7 cycloalkyl or phenyl C.sub.1 -C.sub.6 alkyl; or cycloalkyl, phenyl C.sub.1 -C.sub.6 alkyl, an optionally substituted phenyl ring or NR.sub.10 R.sub.11 wherein R.sub.10 and R.sub.11 are, each independently, hydrogen or C.sub.1 -C.sub.6 alkyl; and phenyl ring; or substituted, carbomonocyclic ring; and phenyl C.sub.1 -C.sub.6 alkyl; -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkoxy, C.sub.1 -C.sub.6 alkanoyloxy, benzoyloxy, amino, hydroxy, nitro, halogen or it is a methylenedioxy group linked to the positions 10 and 11 of the molecule, and the pharmaceutically acceptable salts thereof.
In the formulae of the present specification, a dotted line (- - -) indicates a substituent below the plane of the ring; a wedged line () indicates a substituent above the plane of the ring.
When in a compound of formula (I) the symbol - - - - means a double bond, both Z and E isomers and a mixture of Z and E isomers are included into the scope of the present invention. Pharmaceutically acceptable salts according the invention are the salts with pharmaceutically acceptable acids, both inorganic acids such as, e.g. hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid, and organic acids such as, e.g., citric, fumaric, maleic, malic, ascorbic, succinic, tartar
REFERENCES:
patent: 5004758 (1991-04-01), Boehm et al.
patent: 5122606 (1992-06-01), Wani et al.
patent: 5340817 (1994-08-01), Wall et al.
patent: 5401747 (1995-03-01), Wall et al.
patent: 5602141 (1997-02-01), Bedeschi et al.
patent: 5614628 (1997-03-01), Cabri et al.
Kingsbury, J. Med. Chem. vol. 34 pp. 98-107 (1991).
Bedeschi Angelo
Cabri Walter
Candiani Ilaria
Penco Sergio
Zarini Franco
Daus Donald G.
Pharmacia & Upjohn S.p.A.
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