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US 2003/0229098 A1Published application
Polycyclic compounds exhibiting anti-tumor activities
AssigneeHoffman-La Roche Inc.
InventorsKenichi Kawasaki, Tatsuo Ohtsuka, Kiyoaki Sakata
Life of this patent
Estimating the term…
Abstract
This invention is concerned with novel polycyclic compounds of formula [I], 1 wherein ring A, ring B, R1, R2, R3, R4, R5, R6, X, Y, R1, R2′, R3′, R4′, R5′, R6′, ring A′, ring B′ and X′ are as defined hereinabove as well as pharmaceutically acceptable salts thereof. The compounds have anti-tumor activity and are useful for the treatment of cell proliferative disorders.
Claims32
A polycyclic compound of formula [I],
- 37
- wherein
- ring A is an unsubstituted nitrogen-containing 5 or 6 membered heteroaromatic ring or a substituted nitrogen-containing 5 or 6 membered heteroaromatic ring substituted by one or two groups independently selected from R1 and R2;
- ring A′ is an unsubstituted nitrogen-containing 5 or 6 membered heteroaromatic ring or a substituted nitrogen-containing 5 or 6 membered heteroaromatic ring substituted by one or two groups independently selected from R1′ and R2′;
- ring B is an unsubstituted benzene ring, or a substituted benzene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, an unsubstituted naphthalene ring, or a substituted naphthalene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, a benzene ring substituted with a (C1-C5) alkylenedioxy group, or a substituted benzene ring substituted with a (C1-C5) alkylenedioxy group further substituted by 1 to 3 groups independently selected from R3, R4 and R5;
- ring B′ is an unsubstituted benzene ring, or a substituted benzene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, an unsubstituted naphthalene ring, or a substituted naphthalene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, a benzene ring substituted with a (C1-C5)-alkylenedioxy group, or a substituted benzene ring substituted with a (C1-C5)-alkylenedioxy group further substituted by 1 to 3 groups independently selected from R3, R4 and R5;
- R1, R2, R1′ and R2″ are independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, (C1-C5)-alkyl, (C1-C5)-halogenalkyl, (C1-C5)-alkoxy, (C1-C5) halogenalkoxy, (C3-C5)-alkenyloxy, (C4-C7)-cycloalkyloxy, (C3-C7)-cyloalkyl(C1-C5) alkyloxy, aryl (C1-C5) alkyloxy, (C1-C5) alkylthio, (C1-C5)-alkylsulfinyl, (C1-C5)-alkylsulfonyl, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino;
- R3, R4, R5, R3′, R4′ and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, (C1-C5)-alkyl, (C3-C7)-cycloalkyl, (C1-C5)-halogenalkyl, (C1-C5)-alkoxy, (C1-C5) halogenalkoxy, (C3-C5)-alkenyloxy, (C4-C7)-cycloalkyloxy, (C3-C7)-cyloalkyl (C1-C5) alkyloxy, aryl (C1-C5) alkyloxy, (C1-C5) alkylthio, (C1-C5)-alkylsulfinyl, (C1-C5)-alkylsulfonyl, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino;
- X is ═O or ═N—O—R7, wherein R7 is a hydrogen, (C1-C5)-alkyl, (C3-C5)-alkenyl, (C4-C7)-cycloalkyl, (C3-C7)-cycloalkyl(C1-C5)-alkyl, aryl, or aryl(C1-C5)-alkyl;
- X′ is ═O or ═N—O—R7, wherein R7 is a hydrogen, (C1-C5)-alkyl, (C3-C5)-alkenyl, (C4-C7)-cycloalkyl, (C3-C7)-cycloalkyl(C1-C5)-alkyl, aryl, or aryl(C1-C5)-alkyl;
- R6 is hydrogen, unsubstituted (C1-C5)-alkyl or substituted (C1-C5)-alkyl substituted by 1 to 3 groups independently selected from hydroxy, amino or halogen;
- R6′ is hydrogen, unsubstituted (C1-C5)-alkyl or substituted (C1-C5) alkyl substituted by 1 to 3 groups independently selected from hydroxy, amino or halogen;
- Y is -[J-N(R8)]p-[K-N(R9)]q-L- or -J-M-L-, wherein J, K and L are the same or different unsubstituted (C2-C5)-alkylenes or substituted (C2-C5)-alkylenes substituted with 1 or 2 (C1-C5)-alkyl;
- M is an aliphatic ring having 2 nitrogen atoms;
- p and q are the same or different integers of 0 to 2;
- and R8 and R9 are independently hydrogen or (C1-C5)-alkyl, or a pharmaceutically acceptable salt thereof.
13 more elements
A method for treating a cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula [I],
- 39
- wherein
- ring A is an unsubstituted nitrogen-containing 5 or 6 membered heteroaromatic ring or a substituted nitrogen-containing 5 or 6 membered heteroaromatic ring substituted by one or two groups independently selected from R1 and R2;
- ring A′ is an unsubstituted nitrogen-containing 5 or 6 membered heteroaromatic ring or a substituted nitrogen-containing 5 or 6 membered heteroaromatic ring substituted by one or two groups independently selected from R1′ and R2′;
- ring B is an unsubstituted benzene ring, or a substituted benzene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, an unsubstituted naphthalene ring, or a substituted naphthalene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, a benzene ring substituted with a (C1-C5) alkylenedioxy group, or a substituted benzene ring substituted with a (C1-C5) alkylenedioxy group further substituted by 1 to 3 groups independently selected from R3, R4 and R5;
- ring B′ is an unsubstituted benzene ring, or a substituted benzene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, an unsubstituted naphthalene ring, or a substituted naphthalene ring substituted by 1 to 3 groups independently selected from R3,
- R4 and R5, a benzene ring substituted with a (C1-C5)-alkylenedioxy group, or a substituted benzene ring substituted with a (C1-C5)-alkylenedioxy group further substituted by 1 to 3 groups independently selected from R3, R4 and R5;
- R1, R2, R1′ and R2″ are independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, (C1-C5)-alkyl, (C1-C5)-halogenalkyl, (C1-C5)-alkoxy, (C1-C5) halogenalkoxy, (C3-C5)-alkenyloxy, (C4-C7)-cycloalkyloxy, (C3-C7)-cyloalkyl(C1-C5) alkyloxy, aryl (C1-C5) alkyloxy, (C1-C5) alkylthio, (C1-C5)-alkylsulfinyl, (C1-C5)-alkylsulfonyl, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino;
- R3, R4, R5, R3′, R4′ and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, (C1-C5)-alkyl, (C3-C7)-cycloalkyl, (C1-C5)-halogenalkyl, (C1-C5)-alkoxy, (C1-C5) halogenalkoxy, (C3-C5)-alkenyloxy, (C4-C7)cycloalkyloxy, (C3-C7)-cyloalkyl (C1-C5) alkyloxy, aryl (C1-C5) alkyloxy, (C1-C5) alkylthio, (C1-C5)-alkylsulfinyl, (C1-C5)-alkylsulfonyl, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino;
- X is ═O or ═N—O—R7, wherein R7 is a hydrogen, (C1-C5)-alkyl, (C3-C5)-alkenyl, (C4-C7)-cycloalkyl, (C3-C7)-cycloalkyl(C1-C5)-alkyl, aryl, or aryl(C1-C5)-alkyl;
- X′ is ═O or ═N—O—R7, wherein R7 is a hydrogen, (C1-C5)-alkyl, (C3-C5)-alkenyl, (C4-C7)-cycloalkyl, (C3-C7)-cycloalkyl(C1-C5)-alkyl, aryl, or aryl(C1-C5)-alkyl;
- R6 is hydrogen, unsubstituted (C1-C5)-alkyl or substituted (C1-C5)-alkyl substituted by 1 to 3 groups independently selected from hydroxy, amino or halogen;
- R6 is hydrogen, unsubstituted (C1-C5)-alkyl or substituted (C1-C5) alkyl substituted by 1 to 3 groups independently selected from hydroxy, amino or halogen;
- Y is -[J-N(R8)]p-[K-N(R9)]q-L- or -J-M-L-, wherein J, K and L are the same or different unsubstituted (C2-C5)-alkylenes or substituted (C2-C5)-alkylenes substituted with 1 or 2 (C1-C5)-alkyl;
- M is an aliphatic ring having 2 nitrogen atoms;
- p and q are the same or different integers of 0 to 2;
- and R8 and R9 are independently hydrogen or (C1-C5)-alkyl, or a pharmaceutically acceptable salt thereof.
14 more elements
A process for producing polycyclic compounds of the formula [I],
- 40
- wherein ring A is an unsubstituted nitrogen-containing 5 or 6 membered heteroaromatic ring or a substituted nitrogen-containing 5 or 6 membered heteroaromatic ring substituted by one or two groups independently selected from R1 and R2;
- ring A′ is an unsubstituted nitrogen-containing 5 or 6 membered heteroaromatic ring or a substituted nitrogen-containing 5 or 6 membered heteroaromatic ring substituted by one or two groups independently selected from R1′ and R2′;
- ring B is an unsubstituted benzene ring, or a substituted benzene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, an unsubstituted naphthalene ring, or a substituted naphthalene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, a benzene ring substituted with a (C1-C5) alkylenedioxy group, or a substituted benzene ring substituted with a (C1-C5) alkylenedioxy group further substituted by 1 to 3 groups independently selected from R3, R4 and R5;
- ring B′ is an unsubstituted benzene ring, or a substituted benzene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, an unsubstituted naphthalene ring, or a substituted naphthalene ring substituted by 1 to 3 groups independently selected from R3, R4 and R5, a benzene ring substituted with a (C1-C5)-alkylenedioxy group, or a substituted benzene ring substituted with a (C1-C5)-alkylenedioxy group further substituted by 1 to 3 groups independently selected from R3, R4 and R5;
- R1, R2, R1′ and R2″ are independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, (C1-C5)-alkyl, (C1-C5)-halogenalkyl, (C1-C5)-alkoxy, (C1-C5) halogenalkoxy, (C3-C5)-alkenyloxy, (C4-C7)-cycloalkyloxy, (C3-C7)-cyloalkyl(C1-C5) alkyloxy, aryl (C1-C5) alkyloxy, (C1-C5) alkylthio, (C1-C5)-alkylsulfinyl, (C1-C5)-alkylsulfonyl, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino;
- R3, R4, R5, R3′, R4′ and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, (C1-C5)-alkyl, (C3-C7)-cycloalkyl, (C1-C5)-halogenalkyl, (C1-C5)-alkoxy, (C1-C5) halogenalkoxy, (C3-C5)-alkenyloxy, (C4-C7)-cycloalkyloxy, (C3-C7)-cyloalkyl (C1-C5) alkyloxy, aryl (C1-C5) alkyloxy, (C1-C5) alkylthio, (C1-C5)-alkylsulfinyl, (C1-C5)-alkylsulfonyl, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino;
- R6 is hydrogen, unsubstituted (C1-C5)-alkyl or substituted (C1-C5)-alkyl substituted by 1 to 3 groups independently selected from hydroxy, amino or halogen;
- R6′ is hydrogen, unsubstituted (C1-C5)-alkyl or substituted (C1-C5) alkyl substituted by 1 to 3 groups independently selected from hydroxy, amino or halogen;
- Y is -[J-N(R8)]p-[K-N(R9)]q-L- or -J-M-L-, wherein J, K and L are the same or different unsubstituted (C2-C5)-alkylenes or substituted (C2-C5)-alkylenes substituted with 1 or 2 (C1-C5)-alkyl;
- M is an aliphatic ring having 2 nitrogen atoms;
- p and q are the same or different integers of 0 to 2;
- and R8 and R9 are independently hydrogen or (C1-C5)-alkyl, and X and X′ are O,
- which comprises reacting either two compounds of the formulae [VI], [VI′], [VII] or [VII′],
- 41
- wherein ring A, ring B, R1, R2, R3, R4, R5, ring A′, ring B′, R1′, R2′, R3′, R4′ and R5′ are the same as defined above;
- Hal and Hal′ are the same or different halogen atoms;
- and R12 and R12′ are independently (C1-C5)-alkyl, (C1-C5)-halogenalkyl or aryl, with a compound of the formula [VIII],
- 42
- wherein R6, Y and R6′ are the same as defined above.
17 more elements
Dependencies are inferred from the claim text.