VIDAL VIRGINIE (FR)
AYAD TAHAR (FR)
FAHY JACQUES (FR)
MAILLOS PHILIPPE (FR)
CENTRE NAT DE LA RECH SCIENT (CNRS) (FR)
ECOLE NAT SUPERIEURE DE CHIMIE DE PARIS (FR)
| WO2015051317A1 | 2015-04-09 | |||
| WO2015051284A2 | 2015-04-09 | |||
| WO2015051276A1 | 2015-04-09 |
YONG-HUI XIA ET AL: "L-Securinine induced the human colon cancer SW480 cell autophagy and its molecular mechanism", FITOTERAPIA, IDB HOLDING, MILAN, IT, vol. 82, no. 8, 20 August 2011 (2011-08-20), pages 1258 - 1264, XP028322591, ISSN: 0367-326X, [retrieved on 20110901], DOI: 10.1016/J.FITOTE.2011.08.015
BEUTLER ET AL., BRAIN RES., vol. 330, 1985, pages 135 - 40
XIA ET AL., FITOTERAPIA, vol. 82, 2011, pages 1258 - 1264
RANA ET AL., FASEB, vol. 24, 2010, pages 2126 - 2134
GUPTA ET AL., PLOS ONE, 2011, pages E21203
HOFFSTROM ET AL., NAT CHEM BIOL, vol. 6, 2010, pages 900 - 6
XU ET AL., DRUG DISC TODAY, vol. 19, 2014, pages 222 - 40
LI ET AL., TETRAHEDRON, vol. 68, 2012, pages 3972 - 79
| CLAIMS 1. A compound of the following formula (I): or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle- fused aryl group being optionally substituted. 2. The compound according to claim 1, wherein R1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle-fused aryl group being optionally substituted with one or several groups selected from: halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4, NR5R6, SR7, S(O)R8, SO2R9, SO2NR10R11, OCOR12, NR13COR14, NR15C(O)OR16, CONR17R18, OCO2R19, OCONR20R21, nitro (NO2) and cyano (CN), R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 andR22 being, independently of one another, H or a (C1-C6)alkyl, aryl or ary-l(C1-C6)alkyl group. 3. The compound according to any one of claims 1 and 2, wherein R1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle-fused aryl group being optionally substituted with one or several groups selected from: halo, (C1-C6)haloalkyl, (C1- C6)alkyl, OR2, COOR3, COR4, NR5R6, SR7, S(O)R8, SO2R9, SO2NR10R11, OCOR12, NR13COR14, NR15C(O)OR16, CONR17R18, OCO2R19 and OCONR20R21, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 and R22 being independently of one another, H or a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group. 4. The compound according to any one of claims 1 to 3, wherein R1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle-fused aryl group being optionally substituted with one or several groups selected from: halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4, NR5R6, SR7, S(O)R8, SO2R9, SO2NR10R11, NR13COR14 and NR15C(O)OR16, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R14, R15 andR16 being, independently of one another, H or a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group. 5. The compound according to any one of claims 1 to 4, wherein R1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle-fused aryl group being optionally substituted with one or several groups selected from: halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, R2, R3, R4, R5 and R6 being, independently of one another, H or a (C1-C6)alkyl, aryl or aryl-(C1- C6)alkyl group. 6. The compound according to any one of claims 1 to 5, wherein R1 is an aryl or fluorenyl group, optionally substituted with one or several groups selected from: halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4 and NR5R6, R2, R3, R4, R5 and R6 being, independently of one another, H or a (C1-C6)alkyl, aryl or aryl-(C1- C6)alkyl group. 7. The compound according to any one of claims 1 to 6, wherein R1 is a phenyl, naphtyl or fluorenyl group, optionally substituted with one or two groups selected from: halo, (C1- C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4 and NR5R6, R2, R3, R4, R5, and R6 being, independently of one another, H or a (C1-C6)alkyl, aryl or aryl-(C1- C6)alkyl group. 8. The compound according to claim 1, having the following formula (Ia): wherein Ra and Rb are, independently of one another, H, halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4, NR5R6, SR7, S(O)R8, SO2R9, SO2NR10R11, OCOR12, NR13COR14, NR15C(O)OR16, CONR17R18, OCO2R19, OCONR20R21, nitro (NO2) or cyano (CN), preferably halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4 or NR5R6, or Ra and Rb, when located on adjacent carbon atoms, formed together with the carbon atoms which carry them, a carbocycle, preferably an indane or a benzene, optionally substituted with one or several groups selected from: halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4, NR5R6, SR7, S(O)R8, SO2R9, SO2NR10R11, OCOR12, NR13COR14, NR15C(O)OR16, CONR17R18, OCO2R19 and OCONR20R21, advantageously halo, (C1-C6)haloalkyl, (C1-C6)alkyl, OR2, COOR3, COR4 a d NR5R6, ith R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 andR22 being, independently of one another, H or a (C1-C6)alkyl, aryl or aryl(C1-C6)alkyl group. 9. The compound according to claim 8, having the following formula (Ib): 10 10. The compound according to any one of claims 1 to 9, wherein it is selected from the following compounds: and the pharmaceutically acceptable salts and solvates thereof. 11. A compound according to any one of claims 1 to 10 for use as a drug. 12. A compound according to any one of claims 1 to 10 for use in the treatment of cancer. 13. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient. 14. The pharmaceutical composition according to claim 13, wherein it further comprises another active principle, such as an anticancer agent. 15. A process to prepare a compound according to any one of claims 1 to 10, comprising the following steps: a) reacting: - securinine of following formula (II): - a compound of following formula (III) R1-X (III) in which R1 is as defined in claim 1 and X is I, Br, Cl or OTf, preferably I, to give a compound of formula (I); and b) optionally salifying and/or solvating the compound of formula (I) to give a pharmaceutically acceptable salt and/or solvate thereof. |
Securinine is a major alkaloid of the following formula which is found in the plant leaves of Securinega suffruticosa, a sub-tropical semi-shrub that has been used in traditional Chinese folk medicine:
.
Securinine has been reported to have a wide range of pharmacological activities such as antagonist of γ-GABA A receptor (Beutler et al (1985) Brain Res. 330:135-40), therapeutic agent for the treatment of sequela of poliomyelitis, amyotrophic lateral sclerosis (ALS) and aplastic anemia, and macrophage activator against Coxiella burnetii, or an inhibitor of parasitic (Toxoplasma gondii) proliferation.
More recently, Securinine has been found to induce apoptosis in various human cancer cell lines including HL-60, SW480 (Xia et al. Fitoterapia 82 (2011) 1258–1264) and p53- deficient colon cancer cells (Rana et al. (2010) FASEB 24:2126–2134), and promote differentiation in several acute myeloid leukemia (AML) cells lines such as HL-60, THP-1 and OCI-AMLT3, as well as cells from primary leukemic patients (Gupta et al. (2011) Plos One e21203).
Securinine has also been identified as an inhibitor of Protein Disulfide Isomerase, a molecular chaperone enzyme responsible for disulfide bond formation and reduction which has been proposed as a target in the cancer area (Hoffstrom et al. (2010) Nat Chem Biol 6:900-6, Xu et al. (2014) Drug Disc Today 19:222-40).
The present invention provides derivatives of securinine allowing improved anti- cancerous activity in comparison to securinine. The present invention relates thus to a compound of following formula (I):
(I) or a pharmaceutically acceptable salt and/or solvate thereof,
wherein R 1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle- fused aryl group further being optionally substituted. For the purpose of the invention, the term“pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non toxic, for a pharmaceutical use.
The term « pharmaceutically acceptable salt and/or solvate » is intended to mean, in the framework of the present invention, a salt and/or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
The pharmaceutically acceptable salts comprise:
(1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p- toluenesulfonic, trimethylacetic, or trifluoroacetic acid and the like, and
(2) salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvates made with water (these solvates are also called hydrates), methanol or ethanol. The term“(C 1 -C 6 )alkyl”, as used in the present invention, refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n- hexyl, and the like.
The term“halo”, as used in the present invention, refers to bromo (Br), chloro (Cl), iodo (I) or fluoro (F).
The term“(C 1 -C 6 )haloalkyl”, as used in the present invention, refers to a (C 1 -C 6 )alkyl group as defined above substituted by one or several halogen atoms, and preferably by one or several fluorine atoms. It can be in particular a trifluoromethyl group.
The term“aryl”, as used in the present invention, refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more fused rings, such as, for example, a phenyl or naphtyl group.
The term“aryl-(C 1 -C 6 )alkyl”, as used in the present invention, refers to an aryl group as defined above bound to the molecule via a (C 1 -C 6 )alkyl group as defined above. In particular, it is a benzyl group.
The term“(C 1 -C 6 )alkyl-aryl”, as used in the present invention, refers to a (C 1 -C 6 )alkyl group as defined above bound to the molecule via an aryl group as defined above. In particular, it can be a tolyl group (CH 3 Ph).
The term“carbocycle”, as used in the present invention, relates to a saturated or unsaturated hydrocarbon monocycle or bicycle, each cycle containing advanatgeously from 3 to 10, notably from 5 to 7, in particular 5 or 6, carbon atoms. In the case of a bicycle, the two cycles can be fused, bridged or have a spiro configuration. Preferably, they are fused. It can be in particular cyclopropane, cyclobutane, cyclopentane, cyclohexyane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, indane, indene and the like. Advantageously, the term“carbocycle”, as used in the present invention, refers to indane. Advantageously, R 1 is an aryl group optionally fused with a carbocycle, the said optionally carbocycle-fused aryl group being optionally substituted with one or several groups selected from: halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 , OCONR 20 R 21 , nitro (NO 2 ) and cyano (CN); advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 and OCONR 20 R 21 ; advantageously halo, (C 1 - C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 13 COR 14 and NR 15 C(O)OR 16 ; more advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 and NR 5 R 6 ,
R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 being, independently of one another, H or a (C 1 -C 6 )alkyl, aryl or aryl-(C 1 -C 6 )alkyl group, advantageously H or a (C 1 -C 6 )alkyl group, more advantageously H or a methyl. Notably, R 1 is an aryl or fluorenyl group, said group being optionally substituted with one or several groups selected from: halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 , OCONR 20 R 21 , nitro (NO 2 ) and cyano (CN); advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 and OCONR 20 R 21 ; advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 13 COR 14 and NR 15 C(O)OR 16 ; more advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 and NR 5 R 6 ,
R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 being, independently of one another, H or a (C 1 -C 6 )alkyl, aryl or aryl-(C 1 -C 6 )alkyl group, advantageously H or a (C 1 -C 6 )alkyl group, more advantageously H or a methyl. In a preferred embodiment, R 1 is a phenyl, naphtyl or fluorenyl group, said group being optionally substituted with one or several groups selected from: halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 , OCONR 20 R 21 , nitro (NO 2 ) and cyano (CN); advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 and OCONR 20 R 21 ; advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 13 COR 14 and NR 15 C(O)OR 16 ; more advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 and NR 5 R 6 ,
R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 being, independently of one another, H or a (C 1 -C 6 )alkyl, aryl or aryl-(C 1 -C 6 )alkyl group, advantageously H or a (C 1 -C 6 )alkyl group, more advantageously H or a methyl. In a particular embodiment of the invention, the compounds of the invention have the following formula (Ia), and notably the following formula (Ib):
(Ib) wherein R a and R b are, independently of one another, H, halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 , OCONR 20 R 21 , nitro (NO 2 ) and cyano (CN); advantageously H, halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 and OCONR 20 R 21 ; advantageously H, halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 13 COR 14 and NR 15 C(O)OR 16 ; more advantageously H, halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 and NR 5 R 6 , or R a and R b , when located on adjacent carbon atoms, formed together with the carbon atoms which carry them, an aryl or carbocycle, such as an indane or a benzene, optionally substituted with one or several groups selected from: halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 , OCONR 20 R 21 , nitro (NO 2 ) and cyano (CN); advantageously halo, (C 1 - C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , OCOR 12 , NR 13 COR 14 , NR 15 C(O)OR 16 , CONR 17 R 18 , OCO 2 R 19 and OCONR 20 R 21 ; advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl, OR 2 , COOR 3 , COR 4 , NR 5 R 6 , SR 7 , S(O)R 8 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 13 COR 14 and NR 15 C(O)OR 16 ; more advantageously halo, (C 1 -C 6 )haloalkyl, (C 1 - C 6 )alkyl, OR 2 , COOR 3 , COR 4 and NR 5 R 6 ,
with R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 being, independently of one another, H or a (C 1 -C 6 )alkyl, aryl or aryl-(C 1 -C 6 )alkyl group, advantageously H or a (C 1 -C 6 )alkyl group, more advantageously H or a methyl.
Preferably, R a is not H. In the above definitions of R 1 , R a and R b , the carbocycle will be more particularly an indane and the aryl will be more particularly a phenyl or naphtyl. The compound according to the present invention can be in particular selected from the compounds 1 to 18 of the examples below and the pharmaceutically acceptable salts and solvates thereof. The present invention also relates to a compound of formula (I) as defined previously for use as a drug, notably intended for the treatment of cancer.
The present invention also pertains to the use of a compound of formula (I) as defined previously for the manufacture of a drug, notably intended for the treatment of cancer.
The present invention also pertains to a method for treating cancer comprising the administration to a person in need thereof of an effective amount of a compound of formula (I) as defined previously. The cancer can be more particularly a colon cancer, breast cancer, kidney cancer, liver cancer, pancreas cancer, prostate cancer, lung cancer, ovarian cancer, head and neck cancer, glioblastoma, neuroblastoma, lymphoma, leukaemia, inflammatory myofibroblastic tumour, myelodysplastic syndrome, or myelofibrosis. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined previously and at least one pharmaceutically acceptable excipient.
The active principle can be administered in unitary dosage forms, in mixture with conventional pharmaceutical carriers, to animals and humans.
The pharmaceutical compositions according to the present invention are more particularly intended to be administered orally or parenterally (for ex. intravenously), notably to mammals including human beings.
Suitable unit forms for administration comprise the forms for oral administration, such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions.
When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.
A preparation in gelatin capsules can be obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of a syrup or an elixir may contain the active ingredient together with a sweetener, an antiseptic, a taste enhancer or a suitable coloring agent.
The water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents, wetting agents, or suspending agents, and with flavor correctors or sweeteners.
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents can be used.
The active principle may also be formulated in the form of microcapsules, optionally with one or more carrier additives.
The compounds of the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day. The daily administered dose is advantageously comprises between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art. The pharmaceutical compositions according to the present invention can further comprise at least another active principle, such as an anticancer agent.
The present invention also relates to a pharmaceutical composition comprising:
(i) at least one compound of formula (I) as defined previously, and (ii) at least another active principle, such as an anticancer agent, as a combination product for a simultaneous, separate or sequential use.
The present invention also relates to a pharmaceutical composition as defined previously for use in the treatment of cancer.
The present invention also relates to a method for treating cancer comprising the administration to a person in need thereof of an effective amount of a pharmaceutical composition according to the invention.
The cancer can be more particularly a colon cancer, breast cancer, kidney cancer, liver cancer, pancreas cancer, prostate cancer, lung cancer, ovarian cancer, head and neck cancer, glioblastoma, neuroblastoma, lymphoma, leukaemia, inflammatory myofibroblastic tumour, myelodysplastic syndrome, or myelofibrosis. The present invention concerns also a process to prepare a compound of formula (I) according to the present invention comprising the following steps:
a) reacting:
- securinine of following formula (II):
- a compound of following formula (III)
R 1 -X (III)
in which R 1 is as defined above and X is I, Br, Cl or OTf, preferably I,
to give a compound of formula (I) according to the invention; and
b) optionally salifying and/or solvating the compound of formula (I) to give a pharmaceutically acceptable salt and/or solvate thereof. Step a):
The coupling reaction of step a) can be carried out in the conditions of a Heck reaction well-known to the one skilled in the art.
Advantageously, this reaction is performed in the presence of a Pd0 catalyst. The Pd0 catalyst comprises a palladium atom at the oxidation state 0 complexed by several ligands. The ligand of the Pd0 catalyst is advantageously a phosphine-type ligand, such as PL 1 L 2 L 3 where L 1 , L 2 and L 3 notably are independently of one another (C 1 -C 6 )alkyl, aryl (e.g. phenyl), heteroaryl (e.g. furyl), aryl-(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl-aryl (e.g. tolyl), or a diphosphine-type ligand, such as L 1 L 2 P-A 1 -PL 3 L 4 where L 1 , L 2 , L 3 and L 4 notably are independently of one another (C 1 -C 6 )alkyl, aryl (e.g. phenyl), heteroaryl (e.g. furyl), aryl-(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl-aryl (e.g. tolyl) and A 1 notably is -(CH 2 ) n - with n comprised between 1 and 6 or binaphtyl. The ligand can be notably triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphtyle (BINAP), 1,3- bis(diphenylphosphino)propane (dppp), bis(diphenylphosphino)methane (dppm), 1,2- bis(diphenylphosphine)ethene (dppe), 1,1′-bis(diphenylphosphino)ferrocene (dppf) or 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos).
The Pd0 catalyst can be formed in situ in the presence of a PdII catalyst (e.g. Pd(OAc) 2 , Pd(TFA) 2 ) or a Pd0 catalyst (Pd 2 dba 3 ) and the ligand. In particular, the Pd0 catalyst can be prepared from Pd(OAc) 2 and dppp.
The reaction is advantageously performed in the presence of a base such as a secondary or tertiary amine (e.g. triethylamine, triethanolamine), K 2 CO 3 , Na 2 CO 3 , KHCO 3 , NaHCO 3 , KOAc, NaOAc or K 3 PO 4 , and in particular K 2 CO 3 .
The reaction is performed advantageously under heating, at a temperature notably between 80 and 200°C, notably between 100 and 150°C.
The coupling reaction can be carried out in a solvent such as toluene, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), or a mixture thereof. It can be notably toluene. Step b):
The salification and/or solvatation step can be carried out by methods well known to the one skilled in the art, in particular by reaction of the compound of formula (I) with a pharmaceutically acceptable acid (organic or inorganic acid), a pharmaceutically acceptable acid base (organic or inorganic base) or a solvent.
The solvent can be notably the solvent used in the last step of the preparation of the compound according to the invention, in particular the solvent used in step (a).
Thus steps (a) and (b) can be carried out in a single step, without isolating intermediate compounds. Further protection / deprotection steps or functionalization steps can be carried out in the process described above, such steps and their reaction conditions being well known to the one skilled in the art.
The compound obtained can be separated from the reaction medium by methods well known to the person skilled in the art, such as by extraction, evaporation of the solvent or by precipitation or crystallisation (followed by filtration). The compound can also be purified if necessary by methods well known to the person skilled in the art, such as by recrystallization, by distillation, by chromatography on a column of silica gel or by high performance liquid chromatography (HPLC). The present invention is illustrated by the following non-limitative examples. EXAMPLES: 1. Synthesis of the compounds according to the invention: The following abbreviations are used in the following examples: C = concentration
CI, NH 3 = chemical ionization in ammonia
d = doublet
g = gram
Hz = Hertz
J = coupling constant
m = multiplet
M = Molar
M+H+ = parent mass spectrum peak plus H+
mg = milligram
mL = milliliter
mM = millimolar
µM = micromolar
mmol = millimole
NMR = Nuclear Magnetic Resonance
ppm = part per million
R f = retention factor
TLC = thin-layer chromatography
°C = degree Celcius
%mol = percentage molaire General protocol for the synthesis of the compounds according to the invention
In a glass screw cap tube caped with a rubber septa, palladium acetate (Pd(OAc) 2 , 5 mg, 0.023 mmol), 1,3-bis(diphenylphosphino)propane (dppp, 9 mg, 0.023 mmol) are introduced under argon atmosphere. Then, 3 mL of freshly distilled toluene is added under argon. The mixture is stirred for 10 minutes to allow formation of the catalyst. Then securinine (100 mg, 0.46 mmol), potassium carbonate (K 2 CO 3 , 127 mg, 0.92 mmol) and iodoarene (0.92 mmol) are added. The septa is replaced by a screw cap, and the mixture is stirred at 130 °C, in an oil bath. After 24 h stirring, the reaction mixture is brought to room temperature and diluted with ethyl acetate (5 mL). The reaction mixture is filtered through a pad of Celite® eluting with AcOEt (20 mL). The organic layer is extracted with a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and brine (10 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification by flash chromatography on silica gel column eluted by pentane/ethyl acetate (50:50, 70:30 or 75:25) affords the coupling product.
Example 1: (6S,11aR,11bS)-5-phenyl-9,10,11,11a-tetrahydro-8H-6,11b-meth anofuro[2,3- c]pyrido[1,2-a]azepin-2(6H)-one
Compound 1 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being iodobenzene.
Chemical formula: C 19 H 19 NO 2
Molecular weight: 293.37g.mol-1
Mass spectrometry CI/NH 3 : m/z = 294.18 (M+H+)
Compound: 94 mg (70%) amorphous solid orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 75/25, R f = 0.30
1H NMR (300 MHz, CDCl 3 ) δ = 7.58– 7.48 (m, 2H), 7.44– 7.31 (m, 3H), 6.82 (d, J = 1.4 Hz, 1H), 5.59 (s, 1H), 4.38 (d, J = 4.4 Hz, 1H), 2.90 (dt, J = 10.5, 3.6 Hz, 1H), 2.65 (dd, J = 9.3, 4.3 Hz, 1H), 2.31 (td, J = 10.3, 4.3 Hz, 1H), 2.22 (dd, J = 11.3, 2.5 Hz, 1H), 1.96– 1.81 (m, 2H), 1.72– 1.48 (m, 4H), 1.28– 1.14 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.94, 170.48, 150.25, 138.37, 129.49, 128.89 (2C), 126.29 (2C), 115.33, 104.52, 89.12, 63.17, 61.68, 48.86, 42.02, 27.44, 25.78, 24.20. Example 2: (6S,11aR,11bS)-5-(p-tolyl)-9,10,11,11a-tetrahydro-8H-6,11b-m ethanofuro[2,3- c]pyrido[1,2-a]azepin-2(6H)-one
Compound 2 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 4-iodotoluene.
Chemical formula: C 20 H 21 NO 2
Molecular weight: 307.39g.mol-1
Mass spectrometry CI/NH 3 : m/z = 308.18(M+H+)
Compound: 91 mg (70%) amorphous solid yellow orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.40
1H NMR (300 MHz, CDCl 3 ) δ = 7.42 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 6.79 (d, J = 1.3 Hz, 1H), 5.55 (s, 1H), 4.38 (d, J = 4.3 Hz, 1H), 2.98– 2.80 (m, 1H), 2.62 (dd, J = 9.3, 4.3 Hz, 1H), 2.37 (s, 3H), 2.32– 2.14 (m, 2H), 1.94– 1.79 (m, 2H), 1.72– 1.41 (m, 4H), 1.28– 1.13 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 174.01, 170.70, 149.93, 139.83, 135.30, 129.57 (2C), 126.15 (2C), 114.30, 103.91, 89.01, 63.20, 61.33, 48.78, 41.91, 27.43, 25.75, 24.22, 21.18. Example 3: (6S,11aR,11bS)-5-(3-methoxyphenyl)-9,10,11,11a-tetrahydro-8H -6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 3 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3-iodoanisol.
Chemical formula: C 20 H 21 NO 3
Molecular weight: 323.39g.mol-1
Mass spectrometry CI/NH 3 : m/z = 324.15 (M+H+)
Compound: 100mg (74%) thick oil yellow orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.34
1H NMR (300 MHz, CDCl 3 ) δ = 7.31 (t, J = 8.0 Hz, 1H), 7.09 (dd, J = 6.3, 0.8 Hz, 1H), 7.03– 6.98 (m, 1H), 6.94– 6.88 (m, 1H), 6.80 (d, J = 1.3 Hz, 1H), 5.57 (s, 1H), 4.34 (d, J = 4.2 Hz, 1H), 3.82 (s, 3H), 2.90 (dt, J = 10.4, 3.8 Hz, 1H), 2.62 (dd, J = 9.3, 4.3 Hz, 1H), 2.30 (td, J = 10.3, 4.5 Hz, 1H), 2.19 (dd, J = 11.2, 2.5 Hz, 1H), 1.94– 1.79 (m, 2H), 1.70– 1.46 (m, 4H), 1.28 – 1.13 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.85, 170.36, 159.75, 150.01, 139.70, 129.82, 118.70, 115.42, 114.60, 112.08, 104.49, 89.03, 63.04, 61.63, 55.22, 48.76, 41.95, 27.38, 25.72, 24.15. Example 4: (6S,11aR,11bS)-5-(3-chlorophenyl)-9,10,11,11a-tetrahydro-8H- 6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 4 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 1-chloro-3-iodobenzene.
Chemical formula: C 19 H 18 ClNO 2
Molecular weight: 327.80g.mol-1
Mass spectrometry CI/NH 3 : m/z = 328.10 (M+H+)
Compound: 117mg (85%) thick oil orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.45
1H NMR (300 MHz, CDCl 3 ) δ = 7.47 (s, 1H), 7.43– 7.27 (m, 3H), 6.80 (d, J = 1.3 Hz, 1H), 5.60 (s, 1H), 4.29 (d, J = 4.2 Hz, 1H), 2.88 (dt, J = 10.4, 3.8 Hz, 1H), 2.62 (dd, J = 9.3, 4.3 Hz, 1H), 2.29 (td, J = 10.3, 4.7 Hz, 1H), 2.19 (dd, J = 11.2, 2.5 Hz, 1H), 1.93– 1.78 (m, 2H), 1.69– 1.46 (m, 4H), 1.28– 1.11 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.59, 169.79, 148.68, 140.18, 134.83, 130.08, 129.28, 126.32, 124.37, 116.30, 105.24, 88.95, 62.92, 61.57, 48.71, 41.81, 27.30, 25.66, 24.05. Example 5: methyl 4-((6S,11aR,11bS)-2-oxo-2,6,9,10,11,11a-hexahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-5-yl)benzoate
Compound 5 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being methyl 4-iodobenzoate.
Chemical formula: C 21 H 21 NO 4
Molecular weight: 351.40g.mol-1
Mass spectrometry CI/NH 3 : m/z = 352.14 (M+H+)
Compound: 88 mg (60%) thick oil orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.29 1H NMR (300 MHz, CDCl 3 ) δ = 8.04 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 1.3 Hz, 1H), 5.63 (s, 1H), 4.35 (d, J = 4.2 Hz, 1H), 3.91 (s, 3H), 2.88 (dt, J = 10.3, 3.9 Hz, 1H), 2.64 (dd, J = 9.3, 4.3 Hz, 1H), 2.29 (td, J = 10.2, 4.4 Hz, 1H), 2.20 (dd, J = 11.2, 2.4 Hz, 1H), 1.95– 1.78 (m, 2H), 1.69– 1.46 (m, 4H), 1.28– 1.12 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.58, 169.75, 166.25, 149.01, 142.60, 130.61, 130.02 (2C), 126.22 (2C), 117.00, 105.55, 89.00, 62.95, 61.59, 52.21, 48.74, 41.85, 27.33, 25.67, 24.06. Example 6: (6S,11aR,11bS)-5-(4-fluorophenyl)-9,10,11,11a-tetrahydro-8H- 6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 6 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 1-fluoro-4-iodobenzene.
Chemical formula: C 19 H 18 FNO 2
Molecular weight: 311.35g.mol-1
Mass spectrometry CI/NH 3 : m/z = 312.15 (M+H+)
Compound: 97 mg (75%) amorphous solid red orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.46
1H NMR (300 MHz, CDCl 3 ) δ = 7.50 (dd, J = 8.9, 5.3 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.76 (d, J = 1.3 Hz, 1H), 5.57 (s, 1H), 4.32 (d, J = 4.3 Hz, 1H), 2.87 (dt, J = 10.4, 3.9 Hz, 1H), 2.62 (dd, J = 9.3, 4.3 Hz, 1H), 2.28 (td, J = 10.2, 4.5 Hz, 1H), 2.19 (dd, J = 11.2, 2.5 Hz, 1H), 1.94– 1.78 (m, 2H), 1.70– 1.46 (m, 4H), 1.26– 1.11 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.81, 170.23, 163.34 (d, J1C-F = 251.0 Hz), 149.00, 134.49 (d, J4C-F = 3.0 Hz), 128.19 (d, J3C-F = 8.3 Hz), 115.91 (d, J2C-F = 21.7 Hz), 115.10, 104.53, 88.97, 63.05, 61.67, 48.75, 41.80, 27.33, 25.67, 24.08. Example 7: (6S,11aR,11bS)-5-(m-tolyl)-9,10,11,11a-tetrahydro-8H-6,11b-m ethanofuro[2,3- c]pyrido[1,2-a]azepin-2(6H)-one
Compound 7 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3-iodotoluene.
Chemical formula: C 20 H 21 NO 2
Molecular weight: 307.39g.mol-1
Mass spectrometry CI/NH 3 : m/z = 308.17 (M+H+)
Compound: 87 mg (67%) thick oil orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.46
1H NMR (300 MHz, CDCl 3 ) δ = 7.38– 7.25 (m, 3H), 7.25– 7.11 (m, 1H), 6.80 (d, J = 1.3 Hz, 1H), 5.57 (s, 1H), 4.37 (d, J = 4.3 Hz, 1H), 2.90 (dt, J = 10.3, 3.9 Hz, 1H), 2.63 (dd, J = 9.2, 4.1 Hz, 1H), 2.38 (s, 3H), 2.30 (td, J = 10.3, 4.1 Hz, 1H), 2.20 (dd, J = 11.2, 2.5 Hz, 1H), 1.89 (d, J = 9.2 Hz, 1H), 1.86– 1.80 (m, 1H), 1.70– 1.46 (m, 4H), 1.29– 1.14 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.92, 170.55, 150.33, 138.44, 138.25, 130.25, 128.68, 126.88, 123.39, 115.06, 104.20, 89.03, 63.09, 61.54, 48.76, 41.93, 27.38, 25.72, 24.16, 21.39. Example 8: (6S,11aR,11bS)-5-(4-methoxyphenyl)-9,10,11,11a-tetrahydro-8H -6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 8 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 4-iodoanisole.
Chemical formula: C 20 H 21 NO 3
Molecular weight: 323.39g.mol-1
Mass spectrometry CI/NH 3 : m/z = 324.17 (M+H+)
Compound: 91 mg (67%) thick oil orange TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.29
1H NMR (300 MHz, CDCl 3 ) δ = 7.48 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.74 (d, J = 1.3 Hz, 1H), 5.52 (s, 1H), 4.37 (d, J = 4.3 Hz, 1H), 3.82 (s, 3H), 2.96– 2.78 (m, 1H), 2.60 (dd, J = 9.3, 4.3 Hz, 1H), 2.25 (td, J = 10.3, 4.2 Hz, 1H), 2.17 (dd, J = 11.3, 2.4 Hz, 1H), 1.92– 1.78 (m, 2H), 1.70– 1.46 (m, 4H), 1.25– 1.13 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 174.12, 170.89, 160.74, 149.41, 130.42, 127.72 (2C), 114.24 (2C), 113.18, 103.38, 88.96, 63.29, 61.17, 55.27, 48.74, 41.80, 27.41, 25.73, 24.19. Example 9: (6S,11aR,11bS)-5-(3,4-dichlorophenyl)-9,10,11,11a-tetrahydro -8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 9 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3,4-dichloro-1-iodobenzene. Chemical formula: C 19 H 17 Cl 2 NO 2
Molecular weight: 362.25g.mol-1
Mass spectrometry CI/NH 3 : m/z = 362.08(M+H+)
Compound: 102 mg (68%) thick oil orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.36
1H NMR (300 MHz, CDCl 3 ) δ = 7.58 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.5, 2.2 Hz, 1H), 6.81 (d, J = 1.3 Hz, 1H), 5.62 (s, 1H), 4.27 (d, J = 4.3 Hz, 1H), 2.87 (dt, J = 10.4, 3.9 Hz, 1H), 2.63 (dd, J = 9.4, 4.3 Hz, 1H), 2.28 (td, J = 10.2, 4.9 Hz, 1H), 2.18 (dd, J = 11.2, 2.5 Hz, 1H), 1.91– 1.80 (m, 2H), 1.69– 1.46 (m, 4H), 1.27– 1.11 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.52, 169.51, 147.57, 138.34, 133.51, 133.16, 130.79, 128.08, 125.44, 116.53, 105.59, 88.90, 62.90, 61.47, 48.73, 41.72, 27.29, 25.65, 24.04. Example 10: (6S,11aR,11bS)-5-(4-(dimethylamino)phenyl)-9,10,11,11a-tetra hydro-8H- 6,11b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 10 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 4-iodo-N,N-dimethylaniline. Chemical formula: C 21 H 24 N 2 O 2
Molecular weight: 336,44g.mol-1
Mass spectrometry CI/NH 3 : m/z = 337.23(M+H+)
Compound: 56 mg (36%) thick oil bright yellow
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 75/25, Rf= 0.19
1H NMR (300 MHz, CDCl 3 ) δ = 7.48 (d, J = 9.1 Hz, 2H), 6.75– 6.63 (m, 3H), 5.45 (s, 1H), 4.44 (d, J = 4.3 Hz, 1H), 3.02 (s, 6H), 2.95– 2.87 (m, 1H), 2.60 (dd, J = 9.2, 4.3 Hz, 1H), 2.26 (td, J = 10.4, 3.9 Hz, 1H), 2.17 (dd, J = 11.3, 2.4 Hz, 1H), 1.93– 1.78 (m, 2H), 1.67– 1.47 (m, 4H), 1.31 – 1.08 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 174.53, 171.71, 151.18, 149.67, 127.55 (2C), 124.91, 111.87 (2C), 110.51, 101.84, 88.99, 63.79, 60.61, 48.82, 41.85, 40.01 (2C), 27.59, 25.88, 24.37. E l 11 (6S 11 R 11bS) 5 (9H fl 3 l) 9101111 t t h d 8H 611b
Compound 11 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3-iodoflurorene.
Chemical formula: C 26 H 23 NO 2
Molecular weight: 381,48 g.mol-1
Mass spectrometry CI/NH 3 : m/z = 382.28 (M+H+)
Compound: 85 mg (48%) amorphous solid yellow TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 75/25, Rf= 0.33
1H NMR (300 MHz, CDCl 3 ) δ = 7.84– 7.77 (m, 2H), 7.72 (br s, 1H), 7.60– 7.52 (m, 2H), 7.44– 7.29 (m, 2H), 6.87 (d, J = 1.2 Hz, 1H), 5.59 (s, 1H), 4.47 (d, J = 4.3 Hz, 1H), 3.93 (s, 2H), 3.03– 2.86 (m, 1H), 2.67 (dd, J = 9.3, 4.3 Hz, 1H), 2.34 (td, J = 10.3, 4.0 Hz, 1H), 2.25 (dd, J = 11.2, 2.5 Hz, 1H), 1.97– 1.83 (m, 2H), 1.75– 1.51 (m, 4H), 1.27– 1.15 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.99, 170.67, 150.46, 143.81, 143.63, 143.22, 140.65, 136.72, 127.44, 126.95, 125.33, 125.08, 122.86, 120.26, 120.10, 114.70, 104.07, 89.10, 63.27, 61.70, 48.82, 41.90, 36.85, 27.44, 25.77, 24.17. Example 12: (6S,11aR,11bS)-5-(4-acetylphenyl)-9,10,11,11a-tetrahydro-8H- 6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 12 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 4-iodoacetophenone.
Chemical formula: C 21 H 21 NO 3
Molecular weight: 335,40 g.mol-1
Mass spectrometry CI/NH3 : m/z = 336.23 (M+H+)
Compound: 98 mg (64%) gum yellow
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 50/50, Rf= 0.37
1H NMR (300 MHz, CDCl 3 ) δ = 7.96 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 1.3 Hz, 1H), 5.63 (s, 1H), 4.36 (d, J = 4.3 Hz, 1H), 2.92– 2.78 (m, 1H), 2.63 (dd, J = 9.4, 4.3 Hz, 1H), 2.59 (s, 3H), 2.28 (td, J = 10.2, 4.3 Hz, 1H), 2.20 (dd, J = 11.2, 2.5 Hz, 1H), 1.93– 1.77 (m, 2H), 1.69– 1.46 (m, 4H), 1.25– 1.12 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 197.05, 173.49, 169.68, 148.90, 142.66, 137.23, 128.75 (2C), 126.43 (2C), 117.05, 105.59, 88.97, 62.92, 61.53, 48.72, 41.82, 27.32, 26.52, 25.66, 24.04. Example 13: (6S,11aR,11bS)-5-(3-acetylphenyl)-9,10,11,11a-tetrahydro-8H- 6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 13 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3-iodoacetophenone.
Chemical formula: C 21 H 21 NO 3
Molecular weight: 335,40 g.mol-1
Mass spectrometry CI/NH 3 : m/z = 336.21 (M+H+)
Compound: 107 mg (69%) thick oil orange
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 50/50, Rf= 0.37
1H NMR (300 MHz, CDCl 3 ) δ = 8.09 (t, J = 1.6 Hz, 1H), 7.97– 7.85 (m, 1H), 7.69 (ddd, J = 7.9, 1.6, 1.1 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 5.59 (s, 1H), 4.36 (d, J = 4.3 Hz, 1H), 2.88 (dt, J = 10.4, 3.9 Hz, 1H), 2.66– 2.57 (m, 4H), 2.28 (td, J = 10.2, 4.3 Hz, 1H), 2.19 (dd, J = 11.2, 2.6 Hz, 1H), 1.91– 1.77 (m, 2H), 1.67– 1.45 (m, 4H), 1.24– 1.10 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 197.27, 173.56, 169.87, 149.18, 138.90, 137.50, 130.49, 129.16 (2C), 125.77, 116.27, 105.13, 88.96, 62.93, 61.63, 48.72, 41.84, 27.31, 26.55, 25.67, 24.04. Example 14: methyl 3-((6S,11aR,11bS)-2-oxo-2,6,9,10,11,11a-hexahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-5-yl)benzoate
Compound 14 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being methyl 3-iodobenzoate. Chemical formula: C 21 H 21 NO 4
Molecular weight: 351.40g.mol-1
Mass spectrometry CI/NH 3 : m/z = 352.20 (M+H+)
Compound: 108 mg (67%) thick oil orange TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.32
1H NMR (300 MHz, CDCl3) δ = 8.18 (t, J = 1.6 Hz, 1H), 8.02 (dt, J = 7.7, 1.3 Hz, 1H), 7.76– 7.64 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 5.61 (s, 1H), 4.43– 4.33 (m, 1H), 3.92 (s, 3H), 2.94– 2.83 (m, 1H), 2.64 (dd, J = 9.3, 4.2 Hz, 1H), 2.28 (td, J = 10.2, 4.3 Hz, 1H), 2.20 (dd, J = 11.2, 2.5 Hz, 1H), 1.93– 1.80 (m, 2H), 1.70– 1.45 (m, 4H), 1.25– 1.12 (m, 1H). 13C NMR (75 MHz, CDCl 3 ) δ = 173.63, 169.94, 166.33, 149.10, 138.72, 130.85, 130.40, 130.23, 129.03, 127.40, 116.21, 105.16, 89.01, 63.03, 61.62, 52.27, 48.77, 41.89, 27.38, 25.75, 24.13. Example 15: (6S,11aR,11bS)-5-(3-fluorophenyl)-9,10,11,11a-tetrahydro-8H- 6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 15 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 1-fluoro-3-iodobenzene. Chemical formula: C 19 H 18 FNO 2
Molecular weight: 311.35g.mol-1
Mass spectrometry CI/NH3: m/z = 312.22 (M+H+)
Compound: 84 mg (59%) thick oil yellow
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 80/20, Rf= 0.26
1H NMR (300 MHz, CDCl 3 ) δ = 7.40– 7.28 (m, 1H), 7.28– 7.20 (m, 1H), 7.20– 7.09 (m, 1H), 7.03 (tdd, J = 8.2, 2.5, 1.0 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 5.57 (s, 1H), 4.26 (d, J = 4.2 Hz, 1H), 2.86 (dt, J = 10.4, 3.8 Hz, 1H), 2.60 (dd, J = 9.3, 4.3 Hz, 1H), 2.26 (td, J = 10.2, 4.6 Hz, 1H), 2.16 (dd, J = 11.2, 2.5 Hz, 1H), 1.91– 1.76 (m, 2H), 1.67– 1.45 (m, 4H), 1.23– 1.07 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.62, 169.86, 162.91 (d, J = 247.1 Hz) 148.85, 140.64 (d, J = 7.3 Hz), 130.45 (d, J = 8.3 Hz), 128.87, 126.28, 121.99, 116.28 (d, J = 21.2 Hz), 116.13, 113.19 (d, J = 22.4 Hz), 105.28, 89.04, 63.01, 61.69, 48.78, 41.89, 27.37, 25.72, 24.11. Example 16: (6S,11aR,11bS)-5-(3-trifluoromethyl-phenyl)-9,10,11,11a-tetr ahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 16 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 1-trifluoromethyl-3- iodobenzene.
Chemical formula: C 20 H 18 F 3 NO 2
Molecular weight: 361,36g.mol-1
Mass spectrometry CI/NH3: m/z = 362.22 (M+H+)
Compound: 86 mg (52%) oil red
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 80/20, Rf= 0.22
1H NMR (300 MHz, CDCl 3 ) δ = 7.75 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 1.3 Hz, 1H), 5.65 (s, 1H), 4.35 (d, J = 4.3 Hz, 1H), 2.90 (dt, J = 10.3, 3.9 Hz, 1H), 2.67 (dd, J = 9.3, 4.3 Hz, 1H), 2.32 (td, J = 10.2, 4.6 Hz, 1H), 2.23 (dd, J = 11.2, 2.6 Hz, 1H), 1.95– 1.81 (m, 2H), 1.73– 1.47 (m, 4H), 1.28– 1.12 (m, 1H).
13C NMR (75 MHz, CDCl3) δ = 173.55, 169.65, 148.72, 139.32, 131.41 (q, J = 32.2 Hz), 129.50 (2C), 125.93, 123.75 (q, J = 272.7 Hz),123.01, 116.81, 105.67, 89.05, 77.42, 77.00, 76.58, 62.99, 61.80, 48.80, 41.91, 27.37, 25.74, 24.07. Example 17: : (6S,11aR,11bS)-5-(3-(dimethylamino)phenyl)-9,10,11,11a-tetra hydro-8H- 6,11b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 17 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3-iodo-N,N-dimethylaniline. Chemical formula: C 21 H 24 N 2 O 2
Molecular weight: 336,44g.mol-1
Mass spectrometry CI/NH3: m/z = 337.27 (M+H+)
Compound: 150 mg (97%) oil yellow
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 70/30, Rf= 0.38
1H NMR (300 MHz, CDCl 3 ) δ = 7.26 (t, J = 7.9 Hz, 1H), 6.91– 6.82 (m, 1H), 6.82– 6.70 (m, 3H), 5.57 (s, 1H), 4.38 (d, J = 4.3 Hz, 1H), 2.99 (s, 6H), 2.98– 2.83 (m, 1H), 2.63 (dd, J = 9.2, 4.3 Hz, 1H), 2.35 (td, J = 10.3, 4.5 Hz, 1H), 2.22 (dd, J = 11.2, 2.4 Hz, 1H), 1.96– 1.80 (m, 2H), 1.68– 1.47 (m, 4H), 1.33– 1.19 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.99, 170.77, 151.40, 150.64, 139.24, 129.40, 114.90, 114.60, 113.63, 109.85, 104.00, 89.12, 63.16, 61.88, 48.88, 42.15, 40.43, 27.49, 25.84, 24.25. Example 18: : (6S,11aR,11bS)-5-(2-naphtyl)-9,10,11,11a-tetrahydro-8H-6,11b - methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 18 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the iodoarene being 3-iodo-N,N-dimethylaniline. Chemical formula: C 23 H 21 NO 2
Molecular weight: 343,43g.mol-1
Mass spectrometry CI/NH3: m/z = 344.18 (M+H+)
Compound: 100 mg (63%) orange yellow oil
TLC data: silica gel 60 F 254 Merck, petroleum ether/ ethyl acetate 30/70, Rf= 0.30
1H NMR (300 MHz, CDCl 3 ) δ = 7.99 (d, J = 1.4 Hz, 1H), 7.95– 7.71 (m, 3H), 7.64 (dd, J = 8.7, 1.9 Hz, 1H), 7.59– 7.48 (m, 2H), 6.96 (d, J = 1.3 Hz, 1H), 5.63 (s, 1H), 4.57 (d, J = 4.3 Hz, 1H), 3.03– 2.84 (m, 1H), 2.70 (dd, J = 9.3, 4.3 Hz, 1H), 2.42– 2.18 (m, 2H), 2.02– 1.82 (m, 2H), 1.75– 1.46 (m, 4H), 1.34– 1.17 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.94, 170.48, 149.87, 135.50, 133.55, 133.13, 128.73, 128.56, 127.61, 127.18, 126.79, 126.23, 123.49, 115.59, 104.57, 89.13, 63.30, 61.48, 48.90, 41.96, 27.50, 25.83, 24.25. 2. Biological activity of the compounds according to the invention: The antiproliferative activity of compounds was measured using the ATPlite assay (Perkin Elmer). HCT-116 cells (human colon cancer) were seeded in 96-well plates, incubated for 24 h and treated with 0.4 µM, 1 µM and 10 µM solution of test compounds. Cells were then incubated for 72 h at 37 °C under 5% CO 2 . At the end of the experiment, cell viability was evaluated by determining the level of ATP released by viable cells. Results are expressed in percentage of growth inhibition compared to non-treated cells. The results are presented in Tables 1 and 2 below. Table 1. Antiproliferatives activities of the tested compounds on HCT 116 cells.
Table 2. Comparison of antiproliferatives activities on HCT 116 cells of compounds according to the invention having a meta or para substitution of the aromatic ring
Introduction of an aromatic substituent in the 15-position leads to derivatives which have an inhibitory activity similar to or higher than that of the securinine (see tbale 1). Moreover, unexpectedly, when the aromatic ring is itself substituted in the meta position, the cytotoxic activity is greatly increased (see Table 2). To complete the characterization of the antitumor potential of the compound according to the invention, antiproliferative properties were evaluated on a panel of other tumor cell lines of human origin:
A375: malignant melanoma
A549: epithelial carcinoma of the lung
HCT 116: epithelial colon carcinoma
HL-60: acute promyelocytic leukemia The activities reported in Table 3 are expressed as IC 50 which is the concentration of the tested compound leading to 50% proliferation inhibition of the considered cell lines. Table 3. Cytotoxic properties of the tested compounds
The potency of the compounds of the invention is increased very significantly, by a factor greater than 70, relative to securinine. 3. Comparative example: Synthesis of securinine derivatives substituted at the -14 position: In order to confirm further the interest of the 15-substituted-derivatives of securinine according to the invention, a series of compounds substituted at the -14 position have been synthesized and evaluated in comparison to the 15-substituted derivatives. Such 14-substituted compounds are prepared in two steps from securinine through the 14-iodosecurinine as intermediate derivative. 14-iodosecurinine was prepared from securinine in the presence of N- iodosuccinimide according to the procedure described by Li et al (2012) in Tetrahedron 68:3972-79 General protocol for the synthesis of the compounds substituted at the -14 position
In a glass screw cap tube caped with a rubber septa, 14-iodosecurinine (100 mg, 0.29 mmol) are introduced under argon atmosphere. Then, 1 mL of water and 1 mL of 1,2-dimethoxyethane are added under argon. Then boronic acid (0.6 mmol), Na 2 CO 3 (117 mg, 0.6 mmol) and palladium on activated charcoal 10 % wt Pd (3 mg, 0.003 mmol) are added. The septa is replaced by a screw cap, and the mixture is stirred at 85 °C, in an oil bath. After the iodosecurinine has been consumed (as indicated by TLC), the reaction mixture is filtered through a pad of Celite® eluting with AcOEt (10 mL). The organic layer is extracted with a 1M aqueous solution of sodium hydroxide (10 mL) and brine (10 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification by flash chromatography on silica gel (pentane-ethyl acetate) affords the coupling product. Comparative example 19: (6S,11aR,11bS)-4-phenyl-9,10,11,11a-tetrahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 19 has been synthesized using the above recited general protocol for the synthesis of the compounds substituted at the -14 position, the boronic acid being phenyl boronic acid. Chemical formula: C 19 H 19 NO 2
Molecular weight: 293.36 g.mol-1
Mass spectrometry CI/NH 3 : m/z = 294.24 (M+H+)
Compound: 73 mg (85%) thick yellow oil
1H NMR (300 MHz, CDCl 3 ) δ = 7.45– 7.33 (m, 5H), 6.45 (d, J = 5.4 Hz, 1H), 5.67 (s, 1H), 3.96 – 3.85 (t, J = 4.7 Hz, 1H), 3.01 (dt, J = 10.5, 3.8 Hz, 1H), 2.56 (dd, J = 9.3, 4.1 Hz, 1H), 2.51– 2.35 (m, 1H), 2.24 (dd, J = 11.2, 2.2 Hz, 1H), 1.96– 1.85 (m, 2H), 1.76– 1.54 (m, 4H), 1.29– 1.15 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.35, 170.34, 136.49(2C), 135.30, 128.75 (2C), 128.62, 127.39 (2C), 106.18, 89.82, 62.97, 58.53, 48.83, 42.11, 27.30, 25.87, 24.53. Comparative example 20: (6S,11aR,11bS)-4-(p-tolyl)-9,10,11,11a-tetrahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 20 has been synthesized using the above recited general protocol for the synthesis of the compounds substituted at the -14 position, the boronic acid being p-tolyl boronic acid. Chemical formula: C 20 H 21 NO 2
Molecular weight: 307.39 g.mol-1
Mass spectrometry CI/NH 3 : m/z = 308.20(M+H+)
Compound: 74 mg (83%) yellow solid.
Mp : 174-176°C
1H NMR (300 MHz, CDCl 3 ) δ = 8.05 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.52 (d, J = 5.4 Hz, 1H), 5.63 (s, 1H), 3.91 (s, 4H), 3.00 (dt, J = 10.4, 3.6 Hz, 1H), 2.56 (dd, J = 9.3, 4.0 Hz, 1H), 2.50– 2.39 (m, 1H), 2.23 (dd, J = 11.2, 2.4 Hz, 1H), 1.87 (d, J = 9.2 Hz, 2H), 1.72– 1.48 (m, 4H), 1.32– 1.14 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 172.98, 169.49, 166.40, 140.82, 137.92, 134.38, 129.99 (2C), 127.36 (2C), 106.29, 89.71, 62.85, 58.42, 52.18, 48.74, 41.89, 27.25, 25.81, 24.41. Comparative example 21: (6S,11aR,11bS)-4-(m-tolyl)-9,10,11,11a-tetrahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one
Compound 21 has been synthesized using the above recited general protocol for the synthesis of the compounds substituted at the -14 position, the boronic acid being m-tolyl boronic acid. Chemical formula: C 20 H 21 NO 2
Molecular weight: 307.39 g.mol-1
Mass spectrometry CI/NH 3 : m/z = 308.21(M+H+)
Compound: 45 mg (50%) pale beige solid.
Mp : 98-100°C
1H NMR (300 MHz, CDCl 3 ) δ = 7.41– 7.33 (m, 1H), 7.30– 7.20 (m, 3H), 6.52 (d, J = 5.4 Hz, 1H), 5.74 (s, 1H), 3.98 (t, J = 4.6 Hz, 1H), 3.08 (dt, J = 10.4, 3.7 Hz, 1H), 2.63 (dd, J = 9.2, 4.1 Hz, 1H), 2.58– 2.47 (m, 1H), 2.46 (s, 3H), 2.30 (dd, J = 11.2, 2.4 Hz, 1H), 2.03– 1.89 (m, 2H), 1.84– 1.58 (m, 4H), 1.42– 1.26 (m, 1H).
13C NMR (75 MHz, CDCl 3 ) δ = 173.38, 170.44, 138.44, 136.40, 136.25, 135.30, 129.31, 128.62, 128.05, 124.44, 106.11, 89.78, 62.94, 58.47, 48.80, 42.14, 27.31, 25.88, 24.56, 21.35. 4. Comparative example: Biological activity of selected compounds according to the invention in comparison to compounds substituted at the -14 position: In Table 3 are reported the antiproliferative activities of 3 securinine derivatives synthesized according to the invention (Example 1, Example 2 and Example 7) in comparison to compounds substituted at the -14 position bearing the same substituent (Example 19, Example 20 and Example 21, respectively). Table 3. Antiproliferatives activities on HCT 116 cells of selected compounds according to the invention in comparison to compounds substituted at the -14 position
From the values reported in Table 3, it appears clearly that compounds substituted at the -15 position prepared according to the invention exhibit higher activities in terms of cytotoxic potency compared to compounds substituted at the -14 position.
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