Patent EA-001400-B1 (EA)
Title: Method for preparing camptothecin derivatives
Inventor: FANG FRANCIS G
IPC: C07D491/22
Filed: 1996-11-01
Abstract: 1. A method of preparing a compound of Formula (I)    which comprises dihydroxylating a compound of Formula (II), wherein: R1 and R2, which may be the same or different, are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, or  (-CH2NR7R8), wherein:  i) R7 and R8, which may be the same or different, are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl; or ii) R7 represents hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, and R8 represents -COR9, wherein: R9 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, (C3-7)cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C1-8) alkenyl hydroxy (C1-8) alkyl, (C1-8) alkoxy, (C1-8) alkoxy (C1-8) alkyl; or iii) R7 represents hydrogen or (C1-8) alkyl; and R8 represents diphenyl-methyl or -(CH2)tAr wherein: t is 0 to 5 and Ar represents phenyl, furyl, pyridyl, Nmethylpyrrolyl, imidazolyl optionally substituted with one or more substituents selected from hydroxy, methyl, halogen, and amino; or iv) R7 and R8 taken together with the linking nitrogen form a staturated 3 to 7 atom heterocyclic group of formula (IA)   wherein: Y represents O, S, SO, SO2, CH2 or NR10, wherein: R10 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, aryl, aryl substituted with one or more substituents selected from (C1-8) alkyl, (C1-8) alkoxy, halogen, nitro, amino, (C1-8) alkylamino, perhalo-(C1-8) alkyl, hydroxy (C1-8) alkyl, (C1-8) alkoxy (C1-8) alkyl groups or -COR11 wherein: R11 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, (C1-8) alkoxy, aryl, aryl substituted with one or more substituents selected from (C1-8) alkyl, perhalo-(C1-8) alkyl, hydroxy (C1-8) alkyl, (C1-8) alkoxy (C1-8) alkyl groups; or R3 and R4 are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalky1, (C3-7) cycloalky1-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl; or R3 and R4 taken together form a saturated 5 to 6 atom heterocyclic group of formula (IB)    wherein,  n represents the integer 1 or 2; or  R3 represents -OCONR12R13,  wherein, R12 and R13, which may be the same or different, areindependently selected from hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R12 and R13 are substituted or unsubstituted alkyl groups, they may b e combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with -O-, -S- and/or >N-R14 in which R14 is hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl and  R5 represents hydrogen or (C1-8) alkyl, and  R6 represents hydrogen or (C1-8) alkyl, and pharmaceutically acceptable salts thereof. 2. A compound of Formula (II)    wherein R1 and R2, which may be the same or different, are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, or  (-CH2NR7R8), wherein:  i) R7 and R8, which may be the same or different, are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl; or ii) R7 represents hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, and R8 represents -COR9, wherein: R9 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, (C3-7)cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C1-8) alkenyl hydroxy (C1-8) alkyl, (C1-8) alkoxy, (C1-8) alkoxy (C1-8) alkyl; or iii) R7 represents hydrogen or (C1-8) alkyl; and R8 represents diphenyl-methyl or -(CH2)tAr wherein: t is 0 to 5 and Ar represents phenyl, furyl, pyridyl, Nmethylpyrrolyl, imidazolyl optionally substituted with one or more substituents selected from hydroxy, methyl, halogen, and amino; or iv) R7 and R8 taken together with the linking nitrogen form a staturated 3 to 7 atom heterocyclic group of formula (IA)   wherein: Y represents O, S, SO, SO2, CH2 or NR10, wherein: R10 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, aryl, aryl substituted with one or more substituents selected from (C1-8) alkyl, (C1-8) alkoxy, halogen, nitro, amino, (C1-8) alkylamino, perhalo-(C1-8) alkyl, hydroxy (C1-8) alkyl, (C1-8) alkoxy (C1-8) alkyl groups or -COR11 wherein: R11 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, (C1-8) alkoxy, aryl, aryl substituted with one or more substituents selected from (C1-8) alkyl, perhalo-(C1-8) alkyl, hydroxy (C1-8) alkyl, (C1-8) alkoxy (C1-8) alkyl groups; or R3 and R4 are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalky1, (C3-7) cycloalky1-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl; or R3 and R4 taken together form a saturated 5 to 6 atom heterocyclic group of formula (IB)    wherein,  n represents the integer 1 or 2; or  R3 represents -OCONR12R13,  wherein, R12 and R13, which may be the same or different, areindependently selected from hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R12 and R13 are substituted or unsubstituted alkyl groups, they may b e combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with -O-, -S- and/or >N-R14 in which R14 is hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl and  R5 represents hydrogen or (C1-8) alkyl, and  R6 represents hydrogen or (A compund according tp claim 4, wherein said compound is C1-8) alkyl, and pharmaceutically acceptable salts thereof. 3. A compound according to claim 1, wherein said compound is 11H-1,4-Dioxino[2,3-g]pyrano[3'4':6,7]indolizino[1,2-b]quinoline-12(14H)-one,8-ethyl-2,3-dihydro-15-[(4-methyl-1-piperazinyl)methyl]. 4. A compound of formula (III)   R1 and R2, which may be the same or different, are independently selected from (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, or  (-CH2NR7R8), wherein:  i) R7 and R8, which may be the same or different, are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl; or ii) R7 represents hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, and R8 represents -COR9, wherein: R9 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, (C3-7)cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C1-8) alkenyl hydroxy (C1-8) alkyl, (C1-8) alkoxy, (C1-8) alkoxy (C1-8) alkyl; or iii) R7 represents hydrogen or (C1-8) alkyl; and R8 represents diphenyl-methyl or -(CH2)tAr wherein: t is 0 to 5 and Ar represents phenyl, furyl, pyridyl, Nmethylpyrrolyl, imidazolyl optionally substituted with one or more substituents selected from hydroxy, methyl, halogen, and amino; or iv) R7 and R8 taken together with the linking nitrogen form a staturated 3 to 7 atom heterocyclic group of formula (IA)   wherein: Y represents O, S, SO, SO2, CH2 or NR10, wherein: R10 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, aryl, aryl substituted with one or more substituents selected from (C1-8) alkyl, (C1-8) alkoxy, halogen, nitro, amino, (C1-8) alkylamino, perhalo-(C1-8) alkyl, hydroxy (C1-8) alkyl, (C1-8) alkoxy (C1-8) alkyl groups or -COR11 wherein: R11 represents hydrogen, (C1-8) alkyl, perhalo-(C1-8) alkyl, (C1-8) alkoxy, aryl, aryl substituted with one or more substituents selected from (C1-8) alkyl, perhalo-(C1-8) alkyl, hydroxy (C1-8) alkyl, (C1-8) alkoxy (C1-8) alkyl groups; and R2 can be also hydrogen  R3 and R4 are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalky1, (C3-7) cycloalky1-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl; or R3 and R4 taken together form a saturated 5 to 6 atom heterocyclic group of formula (IB)    wherein,  n represents the integer 1 or 2; or  R3 represents -OCONR12R13,  wherein, R12 and R13, which may be the same or different, areindependently selected from hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R12 and R13 are substituted or unsubstituted alkyl groups, they may b e combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with -O-, -S- and/or >N-R14 in which R14 is hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl and  R5 represents hydrogen or (C1-8) alkyl, and  R6 represents hydrogen or (C1-8) alkyl, and pharmaceutically acceptable salts thereof. 5. A compound according to claim 4, wherein said compound is 11H-1,4-Dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-12(8H,14H)-one,8-ethyl-2,3-dihydro-8,9-dihydroxy-15-[(4-methyl-1-piperazinyl)methyl]-(9R-cis). 6. A compound of formula (IV)   R1 and R2, which may be the same or different, are independently selected from hydrogen, (C1-8) alkyl, (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-8) alkyl, (C2-8) alkenyl, hydroxy (C1-8) alkyl, or (C1-8) alkoxy (C1-8) alkyl, or  (-CH2NR7R8), wherein:  i) R7 and R8, which may be the same or different, are independently selected