Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-05-13
2000-07-25
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 48, C07D49122, A61K 3147
Patent
active
060937211
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to amidino-camptothecin derivatives and, more particularly, it relates to 20(S)-7-ethyl-9- (N-methyl-N-phenyl) amidino-camptothecin and its pharmaceutically acceptable salts, to a process for their preparation and to pharmaceutical compositions comprising them.
Camptothecin and some of its analogous compounds such as, for instance, 9-amino-camptothecin, display potent antitumor activity by inhibiting topoisomerase I which is a monomeric enzyme involved in some important cellular functions and cells growth. For a general reference to camptothecin and its derivatives see, for instance, Wani et al., J. Med. Chem. 1987, 30, 1774; Hsiang et al., Cancer Res. 1989, 49, 4385 and Cancer res. 1989, 49, 1465. Our previous international patent application No. WO 95/22549 describes water-soluble camptothecin derivatives of formula ##STR1## wherein B is a group B' or B" ##STR2## wherein each of (x) and (y) is a single or double bond;
R.sub.1 and R.sub.2 are, each independently, hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl C.sub.1 -C.sub.6 alkyl or an optionally substituted phenyl ring;
R.sub.3 and R.sub.4 are
(a) each independently substituents having the same meaning of R.sub.1 and R.sub.2 or
(b) combined together with the nitrogen atom to which they are linked to form a 3-7 membered saturated optionally substituted heteromonocyclic ring, which may additionally contain another heteroatom selected among nitrogen, oxygen and sulphur; and
A.sup.- is a pharmaceutically acceptable anion of a pharmaceutically acceptable inorganic or organic acid; provided that,
(i) when (x) is a double bond, (y) is a single bond and when (y) is a double bond, (x) is a single bond, and
(ii) when B is a group B', then one of R.sub.2, R.sub.3 and R.sub.4 is absent;
R.sub.6 is hydrogen or a C.sub.1 -C.sub.6 alkyl; and
X is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 acyloxy, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloalkoxy, benzoyloxy, amino, hydroxy, nitro, a halogen atom or a methylenedioxy group linked to the positions 10 and 11 of the molecule.
The compounds therein described as well as the natural occurring camptothecin have a 20(S)-configuration. As set forth in the above reported formula (I), a dotted line () in position 20 indicates a substituent in the .alpha.-configuration, i.e. below the plane of the ring, whereas a wedged line () indicates a substituent in the .beta.-configuration, i.e. above the plane of the ring.
The compounds of formula (I) therein described are inhibitors of topoisomerase I and are thus effective in therapy as antitumor agents, for instance against leukaemia or other solid tumours such as colon and rectal tumours.
Because of their water-solubility, the compounds of formula (I) result to be extremely useful for preparing pharmaceutical formulations suitable, in particular, of being administered in aqueous media.
Besides being biologically active and endowed with chemico-physical characteristics which render them particularly advantageous (e.g. water-solubility) other parameters, mainly related to toxicity, result to be important when referring to the administration of drugs.
To this extent, it is worth noting that the use of a drug in therapy is significantly influenced by its therapeutic index (T.I.) value, as a lethal dose/effective dose ratio (DL.sub.10 /DE.sub.50), which often results to be a limiting factor.
Accordingly, it is an object of the present invention to provide compounds which, while displaying potent antitumor activity and excellent water-solubility, are also endowed with a favourable, i.e. high therapeutic index.
This is even more appreciated when referring, in particular, to drugs which have to be administered according to a prolonged schedule treatment.
It has now been surprisingly found that within the class of camptothecin derivatives of formula (I) described in the aforementioned application WO 95/22549, the compound 20(S)-7-ethyl-9-(N-methyl-N-phenyl)amidino-camptothecin (internal code PNU 166300
REFERENCES:
patent: 5602141 (1997-02-01), Bedeschi et al.
patent: 5614628 (1997-03-01), Cabri et al.
patent: 5840899 (1998-11-01), Bedeschi et al.
Bedeschi et al. (Bioorganic & Medicinal Chemistry Letters, vol. 6, No. 6, pp. 671-674 (1996).
Bedeschi Angelo
Cabri Walter
Candiani Ilaria
Capolongo Laura
Kifle Bruck
Pharmacia & Upjohn S.p.A.
Raymond Richard L.
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