Patent EA-003206-B1 (EA)
Title: New derivatives of analogues of camptothecin, their preparation method and the pharmaceutical compositions containing them
Inventor: LAVIELLE GILBERT
IPC: C07D471/14
Filed: 2000-11-17
Abstract: 1. A compound of formula (I): wherein: n is 0, 1 or 2, R1, R2, R3, R4 and R5 are selected each independently of the others from hydrogen, halogen, alkyl, alkoxy, and the groups (CH2)p -NRaRb wherein p is an integer from 0 to 6, and Ra and Rb together with the nitrogen atom carrying them, a pyrrolyl, piperidinyl or piperazinyl group, it being possible for each cyclic group to be optionally substituted, or two adjacent groups R2, R3, R4 and R5 form together with the carbon atoms carrying them a group -O-(CH2)t -O, t being an integer from 1 to 3 inclusive, R60, R70, R80 and R90, each independently of the others, represents hydrogen, hydroxy, alkoxy groups. R61, R71n, R81, and R91, each independently of the others, represents hydrogen, alkyl, or two geminal groups selected from R60 and R61, R70n and R71n, R80 and R81, and R90 and R91 form oxo or -O-(CH2)t -O, t being an integer from 1 to 3 inclusive, with the proviso that R60, R61, R70n, R71n, R80, R81, R90 and R91 do not all represent a hydrogen atom, an enantiomer, diastereoisomer, or addition salt thereof with a pharmaceutically acceptable acid or base, it being understood that: -the term "alkyl" denotes a linear or branched chain having from 1 to 6 carbon atoms, -the term "alkenyl" denotes a linear or branched chain having from 2 to 6 carbon atoms and containing form 1 to 3 double bonds, -the term "alkynyl" denotes a linear or branched chain having from 2 to 6 carbon atoms and containing from 1 to 3 triple bonds, -the term "alkoxy" denotes a linear or branched alkyl-oxy radical containing from 1 to 6 carbon atoms, -the term "acyl" denotes a linear or branched alkyl-carbonyl radical containing from 1 to 6 carbon atoms, -the term "aryl" represents phenyl or naphthyl, -the expression "substituted", when used in relation to aryl or arylalkyl groups, means that the groups in question are substituted by one or more of halogen and/or alkyl, alkoxy, hydroxy, cyano, nitro, and/or amino (optionally substituted by one or two alkyl group), -the expression "substituted", when used in relation to pyrrolyl, piperidinyl or piperazinyl groups, means that the substituted groups in question are substituted by one or more alkyl, alkoxy, aryl, arylalkyl, aryloxy, and aryloxyalkyl. 2. A compound of formula (I) by claim 1 wherein n is 0, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 3. A compound of formula (I) by claim 1 wherein n is 1, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 4. A compound of formula (I) by claim 1 wherein n is 2, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 5. A compound of formula (I) by claim 1 wherein R60 represents hydroxy and R61 represent alkyl, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 6. A compound of formula (I) by claim 1 wherein R80 and R81 together form an oxo group, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 7. A compound of formula (I) by claim 1 wherein R90 and R91 together form an oxo group, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 8. A compound of formula (I) by claim 1 wherein R80 with R81 and R90 and R91 form two oxo groups, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 9. A compound of formula (I) by claim 1 wherein R1 represents hydrogen, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 10. A compound of formula (I) by claim 1 wherein R2, R3, R4 and R5 are selected from hydrogen, halogen, alkyl and alkoxy, or R2, R3, R4 and R5, together form methylenedioxy or ethylenedioxy, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 11. A compound of formula (I) by claim 1 wherein each of R1, R2, and R5 represents hydrogen, R3, and R4 are selected from hydrogen, halogen, alkyl and alkoxy, or together form methylenedioxy, R60, R70n, R80, and R90, each independently of the others, represents hydrogen, hydroxy, or alkoxy, and R61, R71n, R81, and R91, each independently of the others, represents hydrogen or alkyl or, taken in pairs on adjacent carbon atoms, together form a bond or oxirane or two geminal groups selected from R60 and R61, R70n and R71n, R80 and R81, and R90 and R91 form an oxo group, their enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base. 12. A compound of formula (I) by claim 1 which is 3-chloro-7-ethyl-7-hydroxy-2-methyl-9,12-dihydro-7H-cyclopenta[6,7]indolizino-[1,2-b]quinolin-8,10-one. 13. A compound of formula (I) by claim 1 which is 2,3-difluoro-7-ethyl-7-hydroxy-9, 12-dihydro-7H-cyclopenta[6,7]indolizino-[1,2-b]quinooline-8,10-dione. 14. A method of obtaining of compounds of formula (I), wherein the compound of formula (I) is used as a starting material: wherein R60, R61, R70n, R71n, R80, R81, R90, R91 and Hal - are such as defined for formula (I), which is condensing in alkaline medium with a compound of formula (III) wherein R1, R2, R3, R4, and R5, are such as defined for formula (I) and Hal' and Hal each independently one from other represents a halogen atom, or with a compound of formula (III') wherein R1, R2, R3, R4, R5, and Hal are such as defined over with obtaining of compound of formula (IV) wherein R1, R2, R3, R4, and R5, R60, R61, R70n, R71n, R80, R81, R90 and R91 are such as defined over, which (compound (IV)) is subjected to reaction of intermolecular cyclization, catalized with palladium compound, with obtaining of a compound of formula (I), with proviso that in order to simplify over shown process, reactive groups, presenting in R60, R61, R70n, R71n, R80, R81, R90 and R91, can be protected by simple protective groups and in convenient moment liberate from protection, that hydroxy groups in the same positions can be oxidize by traditional protective methods until oxo groups, and vise versa oxo groups in the same positions can be reduced by traditional reducing agent in any convenient moment of synthesis and, that when 2 of said particles form together bond, the last can be entered in any moment, that the specialist of that domain of chemistry will consider convenient for facilitation of synthesis, where compounds of formula (I): - can be upon the necessity purged according to traditional methods of purging. - can be upon the necessity devised to the isomers according to traditional methods. - can be upon the necessity reformed to addition salts thereof with a pharmaceutically acceptable acid or base. 15. A method of preparation by claim 14 wherein substance of formula (II') is used: wherein n, R60, R61, R70n, R71n, R80, R81, R90, and R91- are such as defined for formula (I), and * means, that carbonic atom, carrying the groups R60, R61 has a fixed configuration (R) and (S), to obtain a compound of formula (I'): wherein R1, R2, R3, R4, R5, R60, R61, R70n, R71n, R80, R81, R90 and R91 are such as defined for formula (I), and * means that configuration of carbonic atom is fixed. 16. A pharmaceutical composition, containing as an active component, at least, one compound according to any of claims 1-13 separately or in combination with one or more inert non-toxic pharmaceutically acceptable stuff and carrier. 17. A pharmaceutical composition according to claim 16 containing at least one active component according to any of claims 1-13, for using in manufacture of drugs for treatment of cancer diseases.