University of Pittsburgh

Other

Bom David

Dennis Patrick Curran

Hubert B Josien

Thomas G Burke

A method of inhibiting topoisomerase I mediated DNA cleavage including administering a pharmaceutically effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof: wherein Rand Rare independently the same or different and are hydrogen, an alkyl group, an aminoalkyl group, an alkylaminoalkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, &#x2014;C(O)R, an amino group, an alkylamino group, a dialkylamino group, &#x2014;SR, or Rand Rtogether form a group of the formula &#x2014;O(CH)O&#x2014; wherein n represents the integer 1 or 2; Ris H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or Rand R3 together form &#x2014;O(CH)O&#x2014; (n=1 or 2); Ris H, F, a Calkyl group, a Calkenyl group, a Calkynyl group, or a Calkoxyl group; Ris a Calkyl group, or a propargyl group.

Camptothecin analogs and methods of preparation thereof

A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form; wherein X is a radical precursor; Ris a Calkyl group, an alkenyl group, an alkynyl group, or a benzyl group; Ris an alkyl group, &#x2014;Si(RRR) or &#x2014;(R)Si(RRR), wherein Ris an alkylene group, an alkenylene group, or an alkynylene group; and R, Rand Rare independently a Calkyl group, a Calkenyl group, a Calkynyl group, an aryl group or a &#x2014;(CH)Rgroup, wherein N is an integer within the range of 1 through 10 and Ris a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, &#x2014;SRor a nitro group; and Ris H, F or &#x2014;CH.

Intermediates in the preparation of homocamptothecin analogs

The present invention provides generally a compound having the following general formula (1): wherein Rand Rare independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a carbonyloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, &#x2014;SR, wherein, Ris hydrogen, an acyl group, an alkyl group, or an aryl group, or Rand Rtogether form a group of the formula &#x2014;O(CH)O&#x2014; wherein n represents the integer 1 or 2; Ris H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or Rand Rtogether form a group of the formula &#x2014;O(CH)O&#x2014; wherein n represents the integer 1 or 2; Ris H, F, a Calkyl group, a Calkenyl group, a Calkynyl group, or a Calkoxyl group; Ris a Calkyl group, or a propargyl group; and R, Rand Rare independently a Calkyl group, a Calkenyl group, a Calkynyl group, an aryl group or a &#x2014;(CH)Rgroup, wherein N is an integer within the range of 1 through 10 and Ris a hydroxyl group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and pharmaceutically acceptable salts thereof.

A compound has the formula in racemic form, enantiomerically enriched form or enantiomerically pure form. Ris preferably &#x2014;Si(RRR) or &#x2014;(R)Si(RRR), wherein Ris an alkylene group, an alkenylene group, or an alkynylene group; and R, Rand Rare independently a Calkyl group, a Calkenyl group, a Calkynyl group, an aryl group or a &#x2014;(CH)Rgroup, wherein N is an integer within the range of 1 through 10 and Ris a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, &#x2014;SRor a nitro group. Rcan be broadly substituted. Ris preferably a Calkyl group, an alkenyl group, an alkynyl group, or a benzyl group. Ris preferably H, F or &#x2014;CH. Ris Ris &#x2014;C(O)Ror H. The E-ring (the lactone ring) may be opened. A method of synthesis of compound (1) and intermediates in the synthesis thereof are provided.

The present invention provides generally a compound having the following general formula (1): ##STR1## wherein R.sup.1 and R.sup.2 are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a OC(O)OR.sup.d group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, --SR.sup.c, wherein, R.sup.c is hydrogen, an acyl group, an alkyl group, or an aryl group, or R.sup.1 and R.sup.2 together form a group of the formula --O(CH.sub.2).sub.n O-- wherein n represents the integer 1 or 2; R.sup.3 is H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano id group; or R.sup.2 and R.sup.3 together form a group of the formula --O(CH.sub.2).sub.n O-- wherein n represents the integer 1 or 2; R.sup.4 is H, F, a C.sub.1-3 alkyl group, a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, or a C.sub.1-3 alkoxyl group; R.sup.5 is a C.sub.1-10 alkyl group, or a propargyl group; and R.sup.6, R.sup.7 and R.sup.8 are independently a C.sub.1-10 alkyl group, a C.sub.2-l0 alkenyl group, a C.sub.2-10 alkynyl group, an aryl group or a --(CH.sub.2).sub.N R.sup.9 group, wherein N is an integer within the range of 1 through 10 and R.sup.9 is a hydroxyl group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and pharmaceutically acceptable salts thereof.

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Pittsburgh, PA, United States of America

Bom David