Pharmachemie B.v.

Johan W Scheeren

Dick De Vos

Dirk De Vos

Eric Wilhelmus Damen

Ruben G Leenders

Hidde J Haisma

Joannes F De Bie

Duncan Sperling

Eric W P Damen

Peter H G Wiegerinck

Joannes F Martinus De Bie

Dirk DeVos

Hendricus B De Bont

Pieter H Houba

Lesly Braamer

Joannes F DeBie

Marcel Van Der Rijst

The invention relates to water soluble antitumor analogs of paclitaxel of formula (I) wherein R &equals;C(O)CH CH(OH)COOX, R &equals;H, C(O)CH CH(OH)COOX, X&equals;H, Li, Na or any other pharmaceutically acceptable counterion, as well as to a pharmaceutical composition comprising an antineoplastically effective amount of such analogs as an active ingredient.

Water soluble analogs and prodrugs of paclitaxel

10-Deacetylbaccatin III is selectively acylated to baccatin III and derivatives thereof in high yield with anhydrides (e.g. acetic anhydride), catalysed by Lewis acids. Extremely effective catalysts in this reaction are compounds of the formula ML.sub.x wherein M is a rare earth metal and L is a anion, preferably a strong electron withdrawing counterion such as triflate.

Method for the preparation of baccatin III and derivatives thereof from

This invention relates to a novel method for the chemical preparation of epirubicin or acid addition salts thereof, in particular the HCl salt, from daunorubicin. This process avoids the disadvantages of the prior art. First daunorubicin is methanolized to obtain daunomycinone and daunosamine methyl ether in very high yields. Daunomycinone is converted to 14-acetoxy daunomycinone by bromination and acetoxylation, while daunosamine methyl ether is converted into an N-protected 4'-epi daunosamine. The choice of the protecting group of the amino group of the daunosamine methyl ether is important because it has to be removed after coupling the sugar with the aglycone without causing side reactions of the aglycone. Two protecting groups were selected: the trifluoroacetyl group and the allyloxycarbonyl group. After coupling the 14-acetoxy daunomycinone with the N-protected 4'-epi daunosamine, the obtained compound was converted to epirubicin; for the latter conversion two routes were developed, depending on the amino-protecting group.

Process for preparing epirubicin or acid addition salts thereof from

A paclitaxel prodrug has a paclitaxel portion coupled to a cleavable N-(aliphatic or aromatic)-O-glycosyl carbamate spacer group, and can be administered orally, topically or by injection to provide an anti-tumor effect, the prodrug being activated by a hydrolizing enzyme, an endogeneous enzyme or an exogeneous enzyme.

Paclitaxel prodrugs, method for preparation as well as their use in

Anthracycline derivatives are disclosed which are coupled to an enzymatically cleavable N-phenyl-O-glycosyl carbamate spacer group, which derivatives are represented by the formula ##STR1## as well as the acid addition salts thereof. Further the synthesis of these derivatives and their use, alone or in combination with enzymes or antibody enzyme conjugates are disclosed.

Anthracycline prodrugs, method for preparation as well as their use in

This invention provides novel anti-tumour compounds of the formula ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen or together form an alkyl-, alkoxy- or OH-substituted aromatic group, which optionally contains an N atom as a hetero-atom; R is --COCH.sub.3 or --C.tbd.C--R.sub.4 and R.sub.4 is H or trimethylsilyl; and R.sub.3 is H or --COCF.sub.3 ; and acid addition salts thereof; as well as compositions containing these compounds.

Anthracycline compounds and intermediates

The invention provides novel cyclic triketone compounds of the formulae ##STR1## wherein S is H, alkyl or alkoxy and R* is a group of the formule ##STR2## wherein R.sup.1 is methyl and R.sub.2 is an alkyl group containing at least 2 carbon atoms or R.sup.1 is an alkyl group having 1-4 carbon atoms and R.sup.2 is an aryl group, a hetero aryl group, a --CH.sub.2 OR' group, a --CH.sub.2 N&lt;group, a --CH.sub.2 SR' group or a --CH.sub.2 CH.dbd.CH.sub.2 group, wherein R' and R' are alkyl groups having 1-4 carbon atoms. These compounds can be used for preparing daunomycinone and derivatives thereof. Daunomycinone is used for preparing daunomycin and adriamycin. By introducing chirality at C-1 of ring A in the preparation of said novel compounds by using a novel diene of formula (1) in a Diels-Alder reaction for said preparation, the chirality of C-3 is established in the subsequent reaction with LiC.tbd.CSi(CH.sub.3).sub.3 in the synthesis of daunomycinone and deriviatives thereof. ##STR3## This last reaction leads to the desired compound wherein OH at C-3 and OR at C-1 are in the cis-position with respect to each other.

Cyclic triketone compounds and trimethylsilyoxy butadiene compounds and

The invention provides novel cyclic triketone compounds of the formulae ##STR1## wherein S is H, alkyl or alkoxy and R* is a group of the formule ##STR2## wherein R.sup.1 is methyl and R.sub.2 is an alkyl group containing at least 2 carbon atoms or R.sup.1 is an alkyl group having 1-4 carbon atoms and R.sup.2 is an aryl group, a hetero aryl group, a --CH.sub.2 OR' group, a --CH.sub.2 N&lt; group, a --CH.sub.2 SR' group or a --CH.sub.2 CH.dbd.CH.sub.2 group, wherein R' and R' are alkyl groups having 1-4 carbon atoms. These compounds can be used for preparing daunomycinone and derivatives thereof. Daunomycinone is used for preparing daunomycin and adriamycin. by introducing chirality at C-1 of ring A in the preparation of said novel compounds by using a novel diene of formula (1) in a Diels-Alder reaction for said preparation, the chirality of C-3 is established in the subsequent reaction with LiC.tbd.CSi(CH.sub.3).sub.3 in the synthesis of daunomycinone and derivatives thereof. ##STR3## This last reaction leads to the desired compound wherein OH at C-3 and OR at C-1 are in the cis-position with respect to each other.

Cyclic triketone compounds and trimethylsilyloxy butadiene compounds and

The invention relates to novel compounds of the formulae ##STR1## wherein S is H, alkyl or alkoxy and R is a good leaving group, and to the preparation of these compounds in a stereospecific manner to obtain a configuration wherein OH at C-3 and OR at C-1 are in the cis-position, which compounds can be used for the synthesis of daunomycinone and derivatives thereof. Daunomycinone can be used for the preparation of daunomycin and adriamycin.

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Malden, Netherlands

Johan W Scheeren