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
Antitumour 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.
Claims92
A compound of the formula:
- wherein:
- R′ is selected from the group consisting of —CH2—N(Ra)2 and —CH2—ORa,
- where Ra is selected from the group consisting of H;
- alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkyl-CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- alkeny;
- 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—;
- and cycloalkylalkyl—CO—;
- and
- R21 is —OH;
- or a pharmaceutically acceptable salt thereof.
A compound of a formula selected from the following general structures I, II and III:
- 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
- COCH2CH2CH3
- 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
- COOCH2CCl3
- COCH2Ph
- COCH2CH2Ph
- COCH═CHCH3
- COCH═CHPh
- COCH═CHArCF3
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(CH3)NHCOCF3
- CO—(R)—CH(CH3)NHCOCF3
- CO—(S)—CH(NHCbz)CH(CH3)2
- Boc
- CSNHPh
- or a pharmaceutically acceptable salt thereof.
A compound which is selected from the following formulae:
- or a pharmaceutically acceptable salt thereof.
A compound of the formula:
- or a pharmaceutically acceptable salt thereof.
A compound of the formula:
- 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—N(Ra)2 and —CH2—ORa,
- where Ra is selected from the group consisting of H;
- alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O-CO—;
- arylalkyl-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—;
- and cycloalkylalkyl-CO—;
- and
- R21 is —OH;
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutical acceptable carrier.
A composition comprising a compound of a formula selected from the following general structures I, II and III:
- 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
- COCH2CH2CH3
- 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
- COOCH2CCl3
- COCH2Ph
- COCH2CH2Ph
- COCH═CHCH3
- COCH═CHPh
- COCH═CHArCF3
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(CH3)NHCOCF3
- CO—(R)—CH(CH3)NHCOCF3
- CO—(S)—CH(NHCbz)CH(CH3)2
- Boc
- CSNHPh
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutically acceptable carrier.
A composition comprising a compound which is selected from the following formulae:
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutically acceptable carrier.
A composition comprising a compound of the formula
- together with a pharmaceutically acceptable carrier;
- or a pharmaceutically acceptable salt thereof.
A composition comprising a compound of the formula:
- together with a pharmaceutically acceptable carrier;
- or a pharmaceutically acceptable salt thereof.
A method of treating a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula:
- wherein:
- R1 selected from the group consisting of —CH2—N(Ra)2 and —CH2—ORa,
- where Ra is selected from the group consisting of H;
- alkyl-CO—;
- haloalkyl-CO—;
- cycloalkylalkyl-CO—;
- haloalkyl-O—CO—;
- arylalkyl-CO—;
- arylalkenyl-CO—;
- heteroaryl-CO—;
- alkenyl-CO—;
- alkeny;
- 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—;
- and cycloalkylalkyl-CO—;
- R21 is —OH;
- or a pharmaceutically acceptable salt thereof.
A method of treating a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound selected from the following general structures I, II and III:
- 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
- COCH2CH2CH3
- 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
- COOCH2CCl3
- COCH2Ph
- COCH2CH2Ph
- COCH═CHCH3
- COCH═CHPh
- COCH═CHArCF3
- COCH(CH3)NHCOCH2CH2Ph
- CO—(S)—CH(CH3)NHCOCF3
- CO—(R)—CH(CH3)NHCOCF3
- CO—(S)—CH(NHCbz)CH(CH3)2
- Boc
- CSNHPh
- or a pharmaceutically acceptable salt thereof.
A method of treating a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound which is selected from the following formulae:
- or a pharmaceutically acceptable salt thereof.
A method of treating a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
A method of treatment a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
A compound of a formula selected from the following general structures I, II and III:
- wherein R′, X2, R1 and R6 are each independently selected from the groups defined below:
- R′
- X2
- R1
- R6
- COCH2CH2CH3
- OH
- OH
- OH
- COCH═CHPh
- OAc
- OAc
- COCH═CHArCF3
- OCH2CH═CH2
- OMOM
- CO—(S)—CH(CH3)NHCOCF3
- OCOOCH2CH═CH2
- OCOCH2C6H11
- OCOCF3
- OCOCH2CH2C6H11
- OCOCH2Cl
- OCOCH2CH2CH3
- OCOCH2CH2Cl
- OCO(CH2)4CH3
- OCOCF2CF2CF3
- OCO(CH2)8CH3
- OCO(CH2)16CH3
- or a pharmaceutically acceptable salt thereof.
A compound which is selected from the following formulae:
- or a pharmaceutically acceptable salt thereof.
A composition comprising a compound of a formula selected from the following general structures I, II and III:
- wherein R′, X2, R1 and R6 are each independently selected from the groups defined below:
- R′
- X2
- R1
- R6
- COCH2CH2CH3
- OH
- OH
- OH
- COCH═CHPh
- OAc
- OAc
- COCH═CHArCF3
- OCH2CH═CH2
- OMOM
- CO—(S)—CH(CH3)NHCOCF3
- OCOOCH2CH═CH2
- OCOCH2C6H11
- OCOCF3
- OCOCH2CH2C6H11
- OCOCH2Cl
- OCOCH2CH2CH3
- OCOCH2CH2Cl
- OCO(CH2)4CH3
- OCOCF2CF2CF3
- OCO(CH2)8CH3
- OCO(CH2)16CH3
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutically acceptable carrier.
A composition comprising a compound which is selected from the following formulae:
- or a pharmaceutically acceptable salt thereof;
- together with a pharmaceutically acceptable carrier.
A method of treating a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound selected from the following general structures I, II and III:
- wherein R′, X2, R1 and R6 are each independently selected from the groups defined below;
- R′
- X2
- R1
- R6
- COCH2CH2CH3
- OH
- OH
- OH
- COCH═CHPh
- OAc
- OAc
- COCH═CHArCF3
- OCH2CH═CH2
- OMOM
- CO—(S)—CH(CH3)NHCOCF3
- OCOOCH2CH═CH2
- OCOCH2C6H11
- OCOCF3
- OCOCH2CH2C6H11
- OCOCH2Cl
- OCOCH2CH2CH3
- OCOCH2CH2Cl
- OCO(CH2)4CH3
- OCOCF2CF2CF3
- OCO(CH2)8CH3
- OCO(CH2)16CH3
- or a pharmaceutically acceptable salt thereof.
A method of treating a mammal affected by bladdar cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering to the affected mammal a therapeutically effective amount of a compound which is selected from the following formulae:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.