Antitumoral analogs of ET-743
AssigneePharma Mar, S.A.
InventorsIgnacio Manzanares, María Jesús Martin, Alberto Rodriguez, Simon Munt, Carmen Cuevas, Marta Perez
Life of this patent
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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
Claims66
A compound of the formula:
- wherein:
- R1 is selected from the group consisting of —CH2—NHRa and —CH2—ORa, where Ra is selected from the group consisting of alkyl-CO—;
- haloalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- and amino acid acyl;
- R5 is —OR″, where R″ is selected from the group consisting of H and C1-C4 alkyl-CO—;
- R18 is —OH;
- and
- R21is —CN;
- or a pharmaceutically acceptable salt thereof.
A compound of general structure:
- wherein R21 is —CN, and Ra, R5, R18, and R1, and are each independently selected from the groups defined below:
- Ra
- X5
- R18
- R1
- OH
- OH
- CH2NHRa
- OAc
- CH2ORa
- COCH2CH2CH3
- COCH═CHPh
- COCH═CHArCF3
- COCH(CH3)NHCOCH2CH2Ph
- CO-(S)-CH(CH3)NHCOCF3
- CO-(R)-CH(CH3)NHCOCF3
- CO-(S)-CH(NHCbz)CH(CH3)2
- CSNHPh
- or a pharmaceutically acceptable salt thereof.
A compound of general structure I:
- wherein Rb, R5, R1, R18, and R21 are each independently selected from the groups defined below:
- R1 is —CH2—NH—CO—CHCH3—NHRb
- Rb
- R5
- R18
- R21
- H
- OH
- OH
- CN
- OAc
- COCH2CH2CH3
- COCH2Ph
- COCH2CH2Ph
- COCH═CHPh
- Boc
- CSNHPh;
- or a pharmaceutically acceptable salt thereof.
A compound selected from the following formulae:
- or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound of the formula:
- wherein:
- R1 is selected from the group consisting of —CH2—NHRa and —CH2—ORa, where Ra is selected from the group consisting of alkyl-CO—;
- haloalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- and amino acid acyl;
- R5 is —OR″, where R″ is selected from the group consisting of H and C1-C4 alkyl-CO—;
- R18 is —OH;
- and
- R21 is —CN;
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutical acceptable carrier.
A method of treating a mammal affected by lung cancer, colon cancer, kidney cancer, prostate cancer, melanoma or leukemia which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula:
- wherein:
- R1 is selected from the group consisting of —CH2—NHRa and —CH2—ORa, where Ra is selected from the group consisting of alkyl-CO—;
- haloalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- and amino acid acyl;
- R5 is —OR″, where R″ is selected from the group consisting of H and C1-C4 alkyl-CO—;
- R18 —OH;
- and
- R21 is —CN;
- or a pharmaceutically acceptable salt thereof.
A compound having the formula
- or a pharmaceutically acceptable salt thereof.
A compound of general structure (II):
- wherein Ra, R5, R18, R1, and R21 are each independently selected from the groups defined below:
- Ra
- R5
- R18
- R1
- R21
- COCH2CH2CH3
- OH
- OH
- CH2NHRa
- CN
- OAc
- CH2ORa
- COCH═CHPh
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(CH3)NHCOCF3
- CO—(R)—CH(CH3)NHCOCF3
- CO—(S)—CH(NHCbz)CH(CH3)2
- CSNHPh
- or a pharmaceutically acceptable salt thereof.
A compound of general structure II:
- wherein Rb, R5, R1, R18 and R21 are each independently selected from the groups defined below:
- R1 is —CH2—NH—CO—CHCH3—NHRb
- Rb
- R5
- R18
- R21
- H
- OH
- OH
- CN
- COCH2CH2CH3
- OAc
- COCH2Ph
- COCH2CH2Ph
- COCH═CHPh
- Boc
- CSNHPh;
- or a pharmaceutically acceptable salt thereof.
A compound of a formula selected from the following general structures (III) and (IV):
- wherein R′, X2, R1, and R6 are each independently selected from the groups defined below:
- R′
- X2
- R1
- R6
- CH2CH═CH2
- OH
- OH
- CN
- COCH2CH3
- OAc
- OAc
- CO(CH2)4CH3
- OCOOCH2CH═CH2
- OCOCH2C6H11
- CO(CH2)12CH3
- OCOCF3
- OCOCH2CH2C6H11
- CO(CH2)16CH3
- OCOCH2Cl
- OCOCH2CH2CH3
- COCH2C6H11
- OCOCH2CH2Cl
- OCO(CH2)4CH3
- COCH2CH2C6H11
- OCOCF2CF2CF3
- OCO(CH2)8CH3
- COCH═CHCH3
- OCO(CH2)16CH3
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(NHCbz)CH(CH3)2
- or a pharmaceutically acceptable salt thereof.
A compound of general structure V:
- wherein X2, R1, R6, and R are each independently selected from the groups defined below:
- R′
- X2
- R1
- R6
- OH
- OH
- CN
- CH2CH═CH2
- OAc
- OAc
- COCH2CH3
- OCOOCH2CH═CH2
- OCOCH2C6H11
- CO(CH2)4CH3
- OCOCF3
- OCOCH2CH2C6H11
- CO(CH2)12CH3
- OCOCH2Cl
- OCOCH2CH2CH3
- CO(CH2)16CH3
- OCOCH2CH2Cl
- OCO(CH2)4CH3
- COCH2CH2C6H11
- OCOCF2CF2CF3
- OCO(CH2)8CH3
- COCH2CH2C6H11
- OCO(CH2)16CH3
- COCH2Ph
- COCH2CH2Ph
- COCH═CHCH3
- COCH(CH3)NHCOCH2CH2Ph
- CO-(S)-CH(CH3)NHCOCF3
- CO-(R)-CH(CH3)NHCOCF3
- CO-(S)-CH(NHCbz)CH(CH3)2
- Boc
- or a pharmaceutically acceptable salt thereof.
A compound selected from the following formulae:
- or a pharmaceutically acceptable salt thereof.
A compound of the formula:
- wherein:
- R1 is —CH2—ORa,
- where Ra is selected from the group consisting of alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- alkenyl;
- and amino acid acyl;
- R5 is —OR″, where R″ is selected from the group consisting of H;
- alkyl-CO—;
- cycloalkyl-CO—;
- and haloalkyl-CO—;
- R18 is —OR, where R is selected from the group consisting of H, alkyl-CO—;
- cycloalkylalkyl-CO—;
- and
- R21 is —CN;
- or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound of the formula:
- wherein:
- R1 is —CH2—ORa,
- where Ra is selected from the group consisting of alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- alkenyl;
- and amino acid acyl;
- R5 is —OR″, where R″ is selected from the group consisting of H;
- alkyl-CO—;
- cycloalkyl-CO—;
- and haloalkyl-CO—;
- R18 is —OR, where R is selected from the group consisting of H, alkyl-CO—;
- cycloalkylalkyl-CO—;
- and
- R21 R is —CN;
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutically acceptable carrier.
A method of treating a mammal affected by lung cancer, colon cancer, kidney cancer, prostate cancer, melanoma or leukemia which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula:
- wherein:
- R1 is —CH2—ORa,
- where Ra is selected from the group consisting of alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- alkenyl;
- and amino acid acyl;
- R5 is —OR″, where R″ is selected from the group consisting of H;
- alkyl-CO—;
- cycloalkyl-CO—;
- and haloalkyl-CO—;
- R18 is —OR, where R is selected from the group consisting of H, alkyl-CO—;
- cycloalkylalkyl-CO—;
- and
- R21 is —CN;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.