7-Substituted camptothecin derivatives and methods for inhibitin

Details 7-Substituted camptothecin derivatives and methods for inhibitin 7-Substituted camptothecin derivatives and methods for inhibitin

1998-08-20

2000-10-10

Rothman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546 51, 546 48, A61K 314761, C07D47114, C07D47116

Patent

active

061302279

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to derivatives of camptothecin, to a process for their preparation, to their use as active ingredients for the preparation of medicament useful in the treatment of tumors, and to pharmaceutical preparations containing them.
The antitumoral agent 20S-camptothecin, of formula ##STR1## where R.sub.1, R.sub.2 and R.sub.3 are hydrogen, discovered in 1966 by M. E. Wall et al. (J. Amer. Chem. Soc. 88, 3888-90 (1966), after a preliminary clinical evaluation was withdrawn as a therapeutic agent because of its toxicity for man and of its low solubility, which made difficult its administration in suitable pharmaceutical preparations. The attention of academic and industrial researchers was then devoted to the synthesis of camptothecin analogues with improved therapeutic profile. Two out of the numerous analogues described by the above drawn formula, namely Topotecan, where R.sub.1 is hydrogen, R.sub.2 is the --CH.sub.2 --NH(CH.sub.3).sub.2 group, R.sub.3 is OH, and CPT-11, where R.sub.1 is ethyl, R.sub.2 is hydrogen, and R.sub.3 is ##STR2## have recently become available to the oncologist for the treatment of some tumors (J. of Clinical Oncology, 10, 1775-80 (1992); J. of the National Cancer Inst. 85, 271 (1993). Other derivatives presently in clinical trials are 9-aminocamptothecin and the analogue of formula: ##STR3##
(Cancer Treatment Reviews 20, 73-96 (1994)).
Most synthetic efforts have been devoted to the introduction of suitable substituents to overcome the problem of the scarce water solubility that characterizes this class of compounds, and that can lead to difficulties in their formulation and to unpredictable plasma levels of the drug. Moreover, the persistence of the lactone ring in closed form is an important factor for the antitumor efficacy.
The relevance of this class of compounds is also due to their peculiar mechanism of action: in fact they display their antitumoral effects by inhibiting topoisomerase I, an enzyme that regulates DNA topology and therefore plays a critical role in essential cellular pathways such as DNA replication, transcription, recombination and repair (C. Capranico and F. Zunino, Current Pharm. Design, 1, 1-14 (1995). The need for new drugs effective against colorectal, non small cell lung carcinoma, ovarian tumors and prostatic carcinoma, still little responsive to chemiotherapeutic treatment, makes rewarding the search for new camptothecin derivatives with improved pharmacological properties.
It has now been found that derivatives of camptothecin and of 10-hydroxycamptothecin carrying substituents at carbon C-7 exhibit antitumor activity and possess favourable physico-chemical properties that allow their formulation in suitable pharmaceutical compositions.
The present invention comprises compounds of formula (I), ##STR4## wherein: R.sub.1 is --CN, --CH(CN)--R.sub.4, --CH.dbd.C(CN)--R.sub.4, --CH.sub.2 --CH(CN)--R.sub.4, --C(.dbd.NOH)--NH.sub.2, --C(.dbd.NH)--NH.sub.2, --CH.dbd.C(NO.sub.2)--R.sub.4, --CH(CN)--R.sub.5, --CH(CH.sub.2 NO.sub.2)--R.sub.5 ; 5-tetrazolyl, 2-(4,5-dihydrooxazolyl), 1,2,4-oxadiazolin-3-yl-5-one; COOR.sub.7 ; -C.sub.12) aryl (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkoxy (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkyl (C.sub.6 -C.sub.12) aryl, (C.sub.6 -C.sub.12) aryl (C.sub.2 -C.sub.4) acyl, (C.sub.2 -C.sub.4) acyl, amino (C.sub.1 -C.sub.4) alkyl, amino (C.sub.2 -C.sub.4) acyl, glycosyl; -C.sub.12) aryl (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkoxy (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkyl (C.sub.6 -C.sub.12) aryl; mixtures thereof, as well as their metabolites, in particular active metabolites.
The present invention includes also the pharmaceutically acceptable salts.
The present invention includes the use of compounds of formula (I) as active ingredients for the preparation of medicaments, in particular medicaments useful for the treatment of tumors.
The present invention includes pharmaceutical compositions containing compounds of formula (I) as active ingredients.
The present invention includes a

REFERENCES:
patent: 4399282 (1983-08-01), Hausheer et al.
patent: 5859023 (1999-01-01), Hausheer et al.
patent: 5910491 (1999-06-01), Hausheer et al.

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