9,10 disubstituted camptothecin derivatives with antitumor activ

Details 9,10 disubstituted camptothecin derivatives with antitumor activ 9,10 disubstituted camptothecin derivatives with antitumor activ

1997-09-29

1999-12-07

Shah, Mukund J.

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

059984260

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to 9,10 disubstituted camptothecin derivatives, to a process for their preparation, to a pharmaceutically composition comprising them and to their use as antitumor agents.
Our previous International Patent Application WO 95/09169 discloses a general class of disubstituted camptothecin derivatives.
It has now been found that certain 9,10 disubstituted camptothecin derivatives, not specifically disclosed in WO 95/09169, possess excellent antitumor activity.
Accordingly, the present invention provides a 9,10 disubstiluted camptolhecin derivative of formula (Ia) ##STR1## namely: 9-amino-10-(1-naphthylsulfonyloxy)-20(S)-camptothecin; a 9,10 disubstituted camptothecin derivative of formula (Ib) ##STR2## namely: 9-amino-10-phenylsulfonyloxy-20(S)-camptothecin; a 9,10 disubstituted camptothecin derivative of formula (Ic) ##STR3## namely: 7-ethyl-9-amino-10-(p-toluensulfonyloxy)-20(S)-camplothecin; and the pharmaceutically acceptable salts thereof.
The pharmaceutically acceptable salts of the above compounds include salts with pharmaceutically acceptable acids, either inorganic acids, such as e.g., hydrochloric, hydrobromic, nitric, or sulphuric acid or organic acids, such as e.g., citric, tartaric, maleic, fumaric, methanesulfonic or ethanesulfonic acid.
The above compounds may be prepared by a process which comprises: ##STR4## wherein R.sub.1 is hydrogen or ethyl, to obtain a compound of formula (III): ##STR5## wherein R.sub.1 is as defined above; (2) converting the compound of formula (III) into a compound of formula (V): ##STR6## wherein R is 1-naphthyl, phenyl or p-methylphenyl and R.sub.1 is as defined above; (Ia), (Ib) or (Ic); and, if desired, pharmaceutically acceptable salt thereof.
A starting compound of formula (II) has a 20(S)-configuration which is retained throughout the process. A compound of formula (II) is typically free of the corresponding 20(R)-isomer. However, the present invention may be applied to a racemic mixture of a compound of formula (II) or to the corresponding 20(R)-isomer. In that case, a racemic mixture of derivatives of 20(S)-camptothecin or 20(R)-camptothecin of formula (Ia), (Ib) or (Ic) is obtained. 10-Hydroxy-20(S)camptothecin may be obtained by known methodologies from 20(S)-camptothecin; see, for instance, JP-A59-51288, JP-A-59-51299; J. Med. Chem. 34, 98, 1991; and Chem. Pharm. Bull. 1991, 39, 3183, 1991.
9-amino-10-(1-naphthylsulfonyloxy)-20(S)-camptothecin (compound (1a)) in pure form or substantially free of 9-amino-10-(1-naphthylsulfonyloxy)-20(R)-camptothecin, 9-amino-10-phenylsulfonyloxy-20(S)-camptothecin (compound (1b)) in pure form or substantially free of 9-amino-10-phenylsulfonyloxy-20(R)-camptothecin and 7-ethyl-9-amino-10-(p-toluenesulfonyloxy)-20(S)-camptothecin (compound (1c)) in pure form or substantially free of 7-ethyl-9-amino-10-(p-toluenesulfonyloxy)-20(R)-camptothecin may be prepared by means of the above process, using as a starting material a compound of formula (II) in pure form or substantially free from the corresponding 20(R) isomer. Alternatively the above compounds of formula (1a), (1b) and (1c) which have a 20 (S) configuration may be isolated from a corresponding racemic mixture by known techniques.
The nitration described as step (1) may be carried out with a nitrating agent such as, e.g., nitric acid, a mixture of nitric and sulfuric acid, potassium nitrate or nitric acid and a boron trifluoride such as boron trifluoride monohydrate (see, for instance, Olah, G. A., et al. Synthesis 1085, 1992), nitric acid and trifluoromethansulfonic anhydride (ibid., 1087, 1992). Typically the reaction temperature is from about -20.degree. C. to about 100.degree. C. Typically, the reaction time may vary from a few minutes to several days such as from 5 minutes to 3 days,for example from 4 hours to 24 hours.
The conversion described as step (2) may be carried out, for example, by reacting a compound of formula (III) with a sulfonylating agent of formula (IV) halogen atom, an imidazolyl group, a --OSO.sub.2 R or a --N(C.sub.6 H.s

REFERENCES:
patent: 5614628 (1997-03-01), Cabri et al.
Hsiang et al, Cancer Res. vol 49 pp. 4385-4389 (1989).
Wani et al, J. Med, Chem, vol 29 pp. 2358-2363 (1986).
Kingsbury et al. J. Med. Chem vol 34 pp. 98-100 (1991).

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