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US 5,705,508 AGranted
Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment
AssigneesThe Research Foundation of State University of New York, Indena SpA of Viale Ortles
InventorsIwao Ojima, Ezio Bombardelli
Life of this patent
Estimating the term…
Abstract
The present invention is directed to novel taxanes useful as chemotherapeutic agents or their precursors. Processes for preparing the novel taxanes include coupling reactions, in the presence of a base, of baccatin of formula (III) or (IV) ##STR1## with .beta.-lactams of formula (V). ##STR2## The invention also provides pharmaceutical compositions including the novel taxanes and methods for treatment of certain cancers with these new compounds.
Claims30
A compound of the formula (I) ##STR15## wherein R.sup.1 is an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl radical, a substituted aryl or heteroaryl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical;
- R.sup.2 is an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl radical;
- or R.sup.2 is an RO--, RS-- or RR'N-- wherein R is an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl radical;
- R' is a hydrogen or R as defined above;
- R and R' can be connected to form a cyclic structure;
- R.sup.3 is a hydrogen or an acyl or an alkyl or an alkenyl or an alkynyl or an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, or an unsubstituted or substituted aryl or heteroaryl radical or a hydroxyl protecting group;
- R.sup.4 is a hydrogen or an acyl radical or a carbamoyl radical or an alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, an unsubstituted or substituted aryl or heteroaryl radical, or a hydroxyl protecting group;
- R.sup.5 is a hydrogen or an acyl radical or an alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, an unsubstituted or substituted aryl or heteroaryl radical, or a hydroxyl protecting group;
- R.sup.6 is a hydrogen or an acyl radical or an alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, an unsubstituted or substituted aryl or heteroaryl radical, or a hydroxyl protecting group;
- R.sup.5 and R.sup.6 can be connected to form a cyclic structure;
- R.sup.7 is an acyl group;
- R.sup.8 is an hydrogen or a hydroxyl protecting group.
8 more elements
A process for the synthesis of a compound of the formula (I) ##STR16## wherein R.sup.1 is an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, an unsubstituted or substituted aryl or heteroaryl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical;
- R.sup.2 is an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl;
- or R.sup.2 is an RO--, RS-- or RR'N-- wherein R is an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl;
- R' is a hydrogen or R as defined above;
- R and R' can be connected to form a cyclic structure;
- R.sup.3 is a hydrogen or an acyl or an alkyl or an alkenyl or an alkynyl or an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, or an unsubstituted or substituted aryl or heteroaryl radical or a hydroxyl protecting group;
- R.sup.4 is a hydrogen or an acyl radical or a carbamoyl radical, or an alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, an unsubstituted or substituted aryl or heteroaryl radical, or a hydroxyl protecting group;
- R.sup.5 is a hydrogen or an acyl radical or an alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, an unsubstituted or substituted aryl or heteroaryl radical, or a hydroxyl protecting group;
- R.sup.6 is a hydrogen or an acyi radical or an alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, an unsubstituted or substituted aryl or heteroaryl radical, or a hydroxyl protecting group;
- R.sup.5 and R.sup.6 can be connected to form a cyclic structure;
- R.sup.7 is an acyl group;
- R.sup.8 is an hydrogen or a hydroxyl protecting group;
- which comprises:
- (a) reacting, in the presence of a base, baccatin of the formula (III) ##STR17## wherein G.sub.1, G.sub.2, G.sub.3, or G.sub.4 is independently an acyl or a carbamoyl or an alkyl or an alkenyl or an alkynyl or an unsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, or an unsubstituted or substituted aryl or heteroaryl radical or a hydroxyl protecting group selected from the group consisting of methoxylmethyl, methoxyethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxyl)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxylcarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trichloroethoxymethyl, trimethylsilyl, triethylsilyl, tripropylsilyl, dimethylethylsilyl, dimethyl(t-butyl)silyl, diethylmethylsilyl, dimethylphenylsilyl and diphenylmethylsilyl;
- said acyl radical selected from the group consisting of acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, cyclohexanecarbonyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl, phenylacetyl, methoxycabonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, crotonoyl and methyl crotonoyl;
- G.sub.3 and G can be connected to form a cyclic structure;
- R.sup.7 is as defined hereinabove;
- with the .beta.-lactams of the formula (V) ##STR18## wherein G is a hydroxyl protecting group selected from the group consisting of methoxylmethyl, methoxyethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxyl)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxylcarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxymethyl, trimethylsilyl, triethylsilyl, tripropylsilyl, dimethylethylsilyl, dimethyl(t-butyl)silyl, diethylmethylsilyl, dimethylphenylsilyl, diphenylmethylsilyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl;
- and R.sup.1 and R.sup.2 are as defined above;
- and
- (b) deprotecting of said hydroxyl protecting groups.
17 more elements
Dependencies are inferred from the claim text.