Claims for Patent: 8,273,768

Summary for Patent: 8,273,768

Title:	Iso CA-4 and analogues thereof as potent cytotoxic agents inhibiting tubuline polymerization
Abstract:	The invention relates to a compound of the formula (I) in which: R.sub.1, R.sub.2 and R.sub.3 are independently a methoxy group optionally substituted by one or more fluorine atoms; R.sub.4 is a hydrogen atom; R.sub.5 and R.sub.6 are identical and each represent a hydrogen or fluorine atom; A is a cycle selected from the group including aryl and heteroaryl groups, wherein said groups can be substituted.
Inventor(s):	Alami; Mouad (Bussy Saint Georges, FR), Brion; Jean-Daniel (Saint Leu la Foret, FR), Provot; Olivier (Sartrouville, FR), Peyrat; Jean-Francois (Villebon sur Yvette, FR), Messaoudi; Samir (Palaiseau, FR), Hamze; Abdallah (Bourg la Reine, FR), Giraud; Anne (Le Perreux sur Marne, FR), Bignon; Jerome (Le Val Saint Germain, FR), Bakala; Joanna (Paris, FR), Liu; Jian-Miao (Paris, FR)
Assignee:	Centre National de la Recherche Scientifique (CNRS) (Paris, FR)
Application Number:	12/594,495
Patent Claims:	1. A compound of the following formula (I): ##STR00073## wherein: R.sub.1, R.sub.2 and R.sub.3 represent independently of each other a methoxy group optionally substituted with one or more fluorine atoms, R.sub.4 represents a hydrogen atom, R.sub.5 and R.sub.6 are identical and each represents a hydrogen or fluorine atom, A is a 1,3-benzodioxolyl, chromanyl or chromenyl group, said group being optionally substituted with one or more C.sub.1-C.sub.4 alkyl groups, or a phenyl or naphtyl group, said group being optionally substituted with one or more groups selected from halogens, --B(OH).sub.2 groups, C.sub.1-C.sub.4 alkyls, C.sub.2-C.sub.4 alkenyls, C.sub.2-C.sub.4 alkynyls, aryl, heteroaryl, --COOH, --NO.sub.2, methylenedioxy, --NR.sub.7R.sub.8, --NHCOR.sub.7, --CONR.sub.7R.sub.8, --NHCOOR.sub.9, --OSi(C.sub.1-C.sub.4 alkyl).sub.3, --NHSO.sub.2R.sub.9, C.sub.1-C.sub.4 alkoxy optionally substituted with one or more fluorine atoms, OCONR.sub.7R.sub.8, --OSO.sub.2CF.sub.3, --OSO.sub.2R.sub.9, --SO.sub.2R.sub.9, --OSO.sub.3H, --OPO(OR.sub.10).sub.2, --ONR.sub.7R.sub.8, --OR.sub.11, --SO.sub.2NR.sub.12R.sub.13, --SO.sub.2NHCOR.sub.14, --OCOR.sub.15, --OCOOR.sub.16, --SR.sub.17, OCO(CH.sub.2).sub.nC.sub.6H.sub.4N[(CH.sub.2).sub.mCl].sub.2 with n=1 to 4 and m=1 to 3, and a residue of a molecule with antitumoral activity, said molecule comprising a COOH function in order to bound said molecule to the phenyl or naphtyl group via an ester or amide bond, wherein: R.sub.7 and R.sub.8 represent independently of each other, a hydrogen atom or a C.sub.1-C.sub.4 alkyl, aryl or heteroaryl group, R.sub.9 represents a C.sub.1-C.sub.4 alkyl, aryl or heteroaryl group, R.sub.10 represents a hydrogen atom or a C.sub.1-C.sub.4 alkyl group or a benzyl group, R.sub.11 represents a hydrogen atom, an O-protective group, a sugar selected from glucose, mannose, arabinose or galactose, an aminosugar or an amino acid, the free OH and HN.sub.2 groups of sugars, aminosugars and amino acids may optionally be substituted with an O-protective and N-protective group, respectively, R.sub.12 and R.sub.13 represent independently of each other a hydrogen atom, a C.sub.1-C.sub.4 alkyl group, an aryl or heteroaryl group, --COR.sub.14 represents the remainder of an amino acid molecule bound to the --SO.sub.2NH-group, or R.sub.14 represents a C.sub.1-C.sub.4 alkyl group, R.sub.15 represents a hydrogen atom, a C.sub.1-C.sub.4 alkyl, aryl or heteroaryl group, or a (CH.sub.2).sub.mCO.sub.2H or --(CH.sub.2).sub.mNR.sub.7R.sub.8 group with m=1 to 3, R.sub.16 represents a C.sub.1-C.sub.4 alkyl, aryl or heteroaryl group or a --(CH.sub.2).sub.mCO.sub.2H or --(CH.sub.2).sub.mNR.sub.7R.sub.8 group with m=1 to 3, and R.sub.17 represents a hydrogen atom or a C.sub.1-C.sub.4 alkyl or aryl group, as well as its pharmaceutically acceptable salts, excluding the following compound: ##STR00074## 2. The compound according to claim 1, wherein the molecule with an antitumoral activity is selected from methotrexate, raltitrexed, melphalan, chlorambucil, L-asparaginase, (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol- -3-yl]-propionic acid, 4-((9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidol(5,4-d)(2)benzazepin-2-yl- )amino)benzoic acid, 5,6-dimethylxanthenone-4-acetic acid and 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid. 3. The compound according to claim 1, wherein A is a ring selected from phenyl and naphtyl groups, and said ring may be substituted with one or more groups selected from -Me, --OH, --OMe, --OCF.sub.3, --NH.sub.2, --NO.sub.2, --COOH, --B(OH).sub.2, --OSitBuMe.sub.2, --OCOMe, --OCOtBu, methylenedioxy, --OCONEt2, --OCO(CH.sub.2).sub.2COOH, --OCOCH.sub.2NMe.sub.2, --OSO.sub.3H, --OSO.sub.2CF.sub.3, --OP(O)(OH).sub.2, --OP(O)(OEt).sub.2, OPO(OCH.sub.2Ph).sub.2, --Br, --F, --OCO(CH.sub.2).sub.3C.sub.6H.sub.4N[(CH.sub.2).sub.2Cl].sub.2, --OCO(C.sub.5H.sub.4N), ##STR00075## 4. The compound according to claim 1, wherein it fits the following formula (II): ##STR00076## wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are as defined in claim 1, Ra represents a hydrogen or halogen atom, or a group --B(OH).sub.2, C.sub.1-C.sub.4 alkyls, C.sub.2-C.sub.4 alkenyls, C.sub.2-C.sub.4 alkynyls, aryl, heteroaryl, --COOH, --NO.sub.2, methylenedioxy, --NR.sub.7R.sub.8, --NHCOR.sub.7, --CONR.sub.7R.sub.8, --NHCOOR.sub.9, --OSi(C.sub.1-C.sub.4 alkyl).sub.3, --NHSO.sub.2R.sub.9, C.sub.1-C.sub.4 alkoxy optionally substituted with one or more fluorine atoms, --OCONR.sub.7R.sub.8, --OSO.sub.2CF.sub.3, --OSO.sub.2R.sub.9, SO.sub.2R.sub.9, --OSO.sub.3H, --OPO(OR.sub.10).sub.2, --ONR.sub.7R.sub.9, --OR.sub.11, --SO.sub.2NR.sub.12R.sub.13, --SO.sub.2NHCOR.sub.14, --OCOR.sub.15, --OCOOR.sub.16, --SR.sub.17, or --OCO(CH.sub.2).sub.nC.sub.6H.sub.4N[(CH.sub.2).sub.mCl].sub.2 with n=1 to 4 and m=1 to 3, R.sub.a advantageously representing a hydrogen atom, and Rb represents a halogen atom, a --OR.sub.11, --OCOR.sub.15, --OCOOR.sub.15, --OCONR.sub.7R.sub.9, --OSO.sub.2R.sub.9, --OSO.sub.2CF.sub.3, --OSO.sub.3H, --OPO(OR.sub.10).sub.2, --NH.sub.2, --NHCOR.sub.7, --NHCOOR.sub.9, --NHSO.sub.2R.sub.9 group, or a residue of a molecule with antitumoral activity, said molecule comprising a COOH function in order to bound said molecule to the phenyl or naphtyl group via an ester or amide bond, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16 and R.sub.17 being as defined in claim 1. 5. The compound according to claim 1 wherein it is selected from: ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## 6. A method for preparing a compound of formula (I) as defined in claim 1, wherein said method comprises the following successive steps: reacting a compound of the following formula (II): ##STR00083## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined in claim 1, with an organometallic compound of formula A-M wherein A is as defined in claim 1 and M represents an alkaline metal or an earth alkaline metal substituted with a halogen, in order to form a compound of the following formula (III): ##STR00084## reacting the compound of formula (III) with an acid in order to form a compound of formula (I). 7. A method for inhibiting polymerization of tubulin comprising the administration to a person in need thereof of an effective amount of a compound according to claim 1 or a compound of the following formula: ##STR00085## or a pharmaceutically acceptable salt thereof. 8. A method for treating or a proliferative disease comprising the administration to a person in need thereof of an effective amount of a compound according to claim 1 or a compound of the following formula: ##STR00086## or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition, comprising at least one compound according to claim 1 or a compound of the following formula: ##STR00087## or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients. 10. The pharmaceutical composition according to claim 9, further compromising at least one other active ingredient. 11. The pharmaceutical composition according to claim 10, wherein the active ingredient is selected from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocine, carboplatine, cisplatine, oxaliplatine, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifene, octreotide, lanreotide, (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol- -3-yl]-propionic acid, 4-((9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidol(5,4-d) (2)benzazepin-2-yl)amino)benzoic acid, 5,6-dimethylxanthenone-4-acetic acid and 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid. 12. A pharmaceutical composition comprising: (i) at least one compound according to claim 1 or a compound of the following formula: ##STR00088## or a pharmaceutically acceptable salt thereof, (ii) at least one other active ingredient, as combination products for simultaneous, separate use, or use spread out over time. 13. The composition according to claim 12, wherein the active ingredient(s) is(are) selected from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocine, carboplatine, cisplatine, oxaliplatine, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifene, octreotide, lanreotide, (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol- -3-yl]-propionic acid, 4-((9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidol(5,4-d) (2)benzazepin-2-yl)amino)benzoic acid, 5,6-dimethylxanthenone-4-acetic acid and 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid. 14. The compound according to claim 1, wherein R.sub.1, R.sub.2 and R.sub.3 each represents a methoxy group. 15. The compound according to claim 1, wherein R.sub.5 and R.sub.6 each represents a hydrogen atom. 16. The compound according to claim 1, wherein R.sub.7 and R.sub.8 represent a hydrogen atom or a C.sub.1-C.sub.4 alkyl group. 17. The compound according to claim 1, wherein R.sub.9 represents a C.sub.1-C.sub.4 alkyl group. 18. The compound according to claim 1, wherein A is: a 1,3-benzodioxolyl, chromanyl or chromenyl group, said group being optionally substituted with one or more C.sub.1-C.sub.4 alkyl groups, a phenyl group optionally substituted with one or more groups selected from halogens, --B(OH).sub.2 groups, C.sub.1-C.sub.4 alkyls, C.sub.2-C.sub.4 alkenyls, C.sub.2-C.sub.4 alkynyls, aryl, heteroaryl, --COOH, --NO.sub.2, methylenedioxy, --NR.sub.7R.sub.8, --NHCOR.sub.7, --CONR.sub.7R.sub.8, --NHCOOR.sub.9, --OSi(C.sub.1-C.sub.4 alkyl).sub.3, --NHSO.sub.2R.sub.9, C.sub.1-C.sub.4 alkoxy optionally substituted with one or more fluorine atoms, --OCONR.sub.7R.sub.8, --OSO.sub.2CF.sub.3, --OSO.sub.2R.sub.9, --SO.sub.2R.sub.9, --OSO.sub.3H, --OPO(OR.sub.10).sub.2, --ONR.sub.2R.sub.8, --OR.sub.11, --SO.sub.2NR.sub.12R.sub.13, SO.sub.2NHCOR.sub.14, --OCOR.sub.15, --OCOOR.sub.16, --SR.sub.17, --OCO(CH.sub.2).sub.nC.sub.6H.sub.4N[(CH.sub.2).sub.mCl].sub.2 with n=1 to 4 and m=1 to 3, and a residue of a molecule with antitumoral activity, said molecule comprising a COOH function in order to bound said molecule to the phenyl or naphtyl group via an ester or amide bond, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17 being as defined in claim 1. 19. The compound according to claim 3, wherein A is a phenyl ring, wherein said ring may be substituted with one or more groups selected from -Me, --OH, --OMe, --OCF.sub.3, --NH.sub.2, --NO.sub.2, --COOH, --B(OH).sub.2, OSitBuMe.sub.2, --OCOMe, --OCOtBu, methylenedioxy, --OCONEt.sub.2, --OCO(CH.sub.2).sub.2COOH, --OCOCH.sub.2NMe.sub.2, --OSO.sub.3H, --OSO.sub.2CF.sub.3, --OP(O)(OH).sub.2, --OP(O)(OEt).sub.2, --OPO(OCH.sub.2Ph).sub.2, --Br, --F, --OCO(CH.sub.2).sub.3C.sub.6H.sub.4N[(CH.sub.2).sub.2Cl].sub.2, --OCO(C.sub.5H.sub.4N), ##STR00089## 20. The method according to claim 8, wherein the proliferative disease is cancer, psoriasis or fibrosis.

Details for Patent 8,273,768

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2027-04-04