Antitumoral analogs of ET-743
AssigneePharma Mar, S.A.
InventorsIgnacio Manzanares, Carmen Cuevas, Marta Perez, Maria Jesus Martin, Alberto Rodriguez, Simon Munt
Life of this patent
Estimating the term…
Abstract
Antitumor compounds have the five membered fused ring ecteinascidin structure of the formula (XIV). The present compounds lack a 1,4-bridging group as found in the ecteinascidins. They have at the C-1 position a substituent selected from an optionally protected or derivatised aminomethylene group or an optionally protected or derivatised hydroxymethylene group.
Claims74
A compound of the following formula or a pharmaceutically acceptable salt thereof:
- wherein:
- R1 is —CH2—N(Ra)2 or —CH2—ORa, where Ra is H;
- alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkyl-CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- alkenyl;
- amino acid acyl;
- or a protecting group;
- R5 is OR″, where R″ is H;
- alkyl-CO—;
- cycloalkyl-CO—;
- haloalkyl-CO—;
- or a protecting group;
- R18 is —OR, where R is H;
- alkyl-CO—;
- cycloalkylalkyl-CO—;
- or a protecting group;
- and
- R21 is —OH;
- provided that
- where an amino group is protected, the amino group together with the protecting group forms:
- (a) a carbamate selected from the group consisting of alkyl, arylalkyl, sulpho- or halo-arylalkyl, alkylsilylalkyl, arylalkyl, cycloalkylalkyl, alkylarylalkyl, heterocyclylalkyl, nitroarylalkyl, acylaminoalkyl, nitroaryldithioarylalkyl, dicycloalkylcarboxamidoalkyl, cycloalkyl, alkenyl, arylalkenyl, nitroarylalkenyl, heterocyclylalkenyl, heterocyclyl, hydroxyheterocyclyl, alkyldithio, alkoxy- or halo- or alkylsulphinyl arylalkyl, and heterocyclylacyl carbamate;
- (b) an aroyl, arylaroyl, haloaroyl, or nitroaroyl amide;
- or (c) alkylamino, alkylsilylalkoxyalkylamino, alkoxyalkylamino, cyanoalkylamino, heterocyclylamino, alkoxyarylalkylamino, cycloalkylamino, nitroarylamino, arylalkylamino, or alkoxy- or hydroxy-arylalkylamino;
- and where a hydroxy group is protected, the hydroxyl group together with the protecting group forms:
- (a) an ether selected from the group consisting of alkyl, alkoxyalkyl, aryloxyalkyl, alkoxyalkoxyalkyl, alkylsilylalkoxyalkyl, alkylthioalkyl, arylthioalkyl, azidoalkyl, cyanoalkyl, chloroalkyl, heterocyclic, cycloalkylalkyl, alkenyl, cycloalkyl, alkylarylalkyl, alkoxyarylalkyl, nitroarylalkyl, haloarylalkyl, alkylaminocarbonylarylalkyl, alkylsulfinylarylalkyl and alkylsilyl ether;
- or (b) arylacyloxy, aryl alkyl carbonate, aliphatic carbonate, alkylsulfinylarylalkyl carbonate, alkyl carbonate, aryl haloalkyl carbonate, aryl alkenyl carbonate, arylcarbamate, alkylphosphinyl, alkylphosphinothioyl, arylphosphinothioyl, or alkyl sulphonate.
A compound with the following general structure (I) or a pharmaceutically acceptable salt thereof:
- wherein R′ is selected from CH2NHRa, CH2ORa, and CH2—NH—CO—CHCH3—NHRa;
- and Ra, R5, R18 and R21 are each independently selected from the groups defined below:
- Ra
- R5
- R18
- R21
- H
- OH
- OH
- OH
- COCH2CH2CH3
- OAc
- COCH2Ph
- COCH2CH2Ph
- COCH═CHPh
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(CH3)NHCOCF3
- CO—(R)—CH(CH3)NHCOCF3
- CO—(S)—CH(NHCbz)CH(CH3)2
- Boc
- CSNHPh
- .
A compound with the following general structure (II) or a pharmaceutically acceptable salt thereof:
- wherein R1 is selected from CH2NHRa, CH2ORa, and CH2—NH—CO—CHCH3—NHRa;
- and Ra, R5, R18 and R21 are each independently selected from the groups defined below:
- Ra
- R5
- R18
- R21
- H
- OH
- OH
- OH
- COCH2CH2CH3
- OAc
- COCH2Ph
- COCH2CH2Ph
- COCH═CHPh
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(CH3)NHCOCF3
- CO—(R)—CH(CH3)NHCOCF3
- CO—(S)—CH(NHCbz)CH(CH3)2
- Boc
- CSNHPh
- .
A compound with the following general structure (III), (IV) or (V) or a pharmaceutically acceptable salt thereof:
- wherein R′, X2, R1 and R6 are each independently selected from the groups defined below:
- R
- X2
- R1
- R6
- H
- OH
- OH
- OH
- CH2CH═CH2
- OAc
- OAc
- COCH2CH3
- OCH2CH═CH2
- OMOM
- OCOOCH2CH═CH2
- OCOCH2C6H11
- CO(CH2)4CH3
- OCOCF3
- OCOCH2CH2C6H11
- CO(CH2)12CH3
- OCOCH2Cl
- OCOCH2CH2CH3
- CO(CH2)16CH3
- OCOCH2CH2Cl
- OCO(CH2)4CH3
- COCH2C6H11
- OCOCF2CF2CF3
- OCO(CH2)8CH3
- COCH2CH2C6H11
- OCO(CH2)16CH3
- COCH2Ph
- COCH2CH2Ph
- COCH═CHCH3
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(NHCbz)CH(CH3)2
- Boc
- CSNHPh
- .
A compound of the following formula or a pharmaceutically acceptable salt thereof:
A compound of the following formula or a pharmaceutically acceptable salt thereof:
A compound of the following formula or a pharmaceutically acceptable salt thereof:
Dependencies are inferred from the claim text.