NZ627178B - New phosphate prodrugs of indolizine and pyrrole derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New phosphate prodrugs of indolizine and pyrrole derivatives, a process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- NZ627178B NZ627178B NZ627178A NZ62717814A NZ627178B NZ 627178 B NZ627178 B NZ 627178B NZ 627178 A NZ627178 A NZ 627178A NZ 62717814 A NZ62717814 A NZ 62717814A NZ 627178 B NZ627178 B NZ 627178B
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- carbonyl
- phenyl
- formula
- group
- Prior art date
Links
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 19
- 239000010452 phosphate Substances 0.000 title claims abstract description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 106
- 238000000034 method Methods 0.000 title claims description 66
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 19
- 230000008569 process Effects 0.000 title claims description 18
- 229940002612 prodrug Drugs 0.000 title claims description 18
- 239000000651 prodrug Substances 0.000 title claims description 18
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 title claims description 11
- 150000003233 pyrroles Chemical class 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 250
- -1 4-[{[3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizin-1-yl]carbonyl}(phenyl)amino]phenyl Chemical group 0.000 claims abstract description 99
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 41
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 229910000397 disodium phosphate Inorganic materials 0.000 claims abstract description 11
- 235000019800 disodium phosphate Nutrition 0.000 claims abstract description 11
- 239000001488 sodium phosphate Substances 0.000 claims abstract description 11
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 7
- 210000000987 immune system Anatomy 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 173
- 239000003814 drug Substances 0.000 claims description 89
- 125000000217 alkyl group Chemical group 0.000 claims description 76
- 125000003118 aryl group Chemical group 0.000 claims description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 62
- TYJOJLOWRIQYQM-UHFFFAOYSA-L disodium;phenyl phosphate Chemical compound [Na+].[Na+].[O-]P([O-])(=O)OC1=CC=CC=C1 TYJOJLOWRIQYQM-UHFFFAOYSA-L 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 56
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 150000001768 cations Chemical class 0.000 claims description 10
- 150000002148 esters Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000006684 polyhaloalkyl group Polymers 0.000 claims description 9
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 8
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 231100000024 genotoxic Toxicity 0.000 claims description 8
- 230000001738 genotoxic effect Effects 0.000 claims description 8
- 229940043355 kinase inhibitor Drugs 0.000 claims description 8
- 230000000394 mitotic effect Effects 0.000 claims description 8
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 8
- 239000002574 poison Substances 0.000 claims description 8
- 231100000614 poison Toxicity 0.000 claims description 8
- 239000003207 proteasome inhibitor Substances 0.000 claims description 8
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 230000000340 anti-metabolite Effects 0.000 claims description 7
- 229940100197 antimetabolite Drugs 0.000 claims description 7
- 239000002256 antimetabolite Substances 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 7
- 230000003211 malignant effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 6
- 210000000481 breast Anatomy 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 210000004185 liver Anatomy 0.000 claims description 6
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000003003 spiro group Chemical group 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 210000003932 urinary bladder Anatomy 0.000 claims description 6
- 210000004291 uterus Anatomy 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 4
- 230000000861 pro-apoptotic effect Effects 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000006091 1,3-dioxolane group Chemical group 0.000 claims description 2
- ZFFYPGZDXUPKNK-UHFFFAOYSA-N 2,3-dihydro-1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NCCC2=C1 ZFFYPGZDXUPKNK-UHFFFAOYSA-N 0.000 claims description 2
- QYASHELNMUPRKF-UHFFFAOYSA-N 5,6,7,8-tetrahydroindolizine Chemical compound C1CCCN2C=CC=C21 QYASHELNMUPRKF-UHFFFAOYSA-N 0.000 claims description 2
- 238000007341 Heck reaction Methods 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000005897 peptide coupling reaction Methods 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 125000003172 aldehyde group Chemical group 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 239000002207 metabolite Substances 0.000 claims 1
- 208000000649 small cell carcinoma Diseases 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 52
- 230000002424 anti-apoptotic effect Effects 0.000 abstract description 2
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 abstract 1
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 abstract 1
- 229940121649 protein inhibitor Drugs 0.000 abstract 1
- 239000012268 protein inhibitor Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- 239000000243 solution Substances 0.000 description 92
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 229940079593 drug Drugs 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- 239000000047 product Substances 0.000 description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 50
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000004587 chromatography analysis Methods 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 238000004896 high resolution mass spectrometry Methods 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 238000004452 microanalysis Methods 0.000 description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- ZBPHPBWGQALQCS-UHFFFAOYSA-N 1,2,3,5-tetrahydroindolizine Chemical compound C1C=CC=C2CCCN21 ZBPHPBWGQALQCS-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000009472 formulation Methods 0.000 description 18
- 150000002632 lipids Chemical class 0.000 description 18
- 238000001727 in vivo Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- HLCHESOMJVGDSJ-LOYHVIPDSA-N (3r)-n-[(2r)-3-(4-chlorophenyl)-1-[4-cyclohexyl-4-(1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-1-oxopropan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide Chemical compound C1=CC(Cl)=CC=C1C[C@H](C(=O)N1CCC(CN2N=CN=C2)(CC1)C1CCCCC1)NC(=O)[C@@H]1NCC2=CC=CC=C2C1 HLCHESOMJVGDSJ-LOYHVIPDSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 102000003952 Caspase 3 Human genes 0.000 description 14
- 108090000397 Caspase 3 Proteins 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 13
- 125000001931 aliphatic group Chemical group 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000003304 gavage Methods 0.000 description 12
- 239000013011 aqueous formulation Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000011002 quantification Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 8
- 230000036470 plasma concentration Effects 0.000 description 8
- 102000011727 Caspases Human genes 0.000 description 7
- 108010076667 Caspases Proteins 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 7
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 7
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000004811 liquid chromatography Methods 0.000 description 6
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- VEJPLARLFWIYNM-UHFFFAOYSA-N 2-bromo-3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Br VEJPLARLFWIYNM-UHFFFAOYSA-N 0.000 description 5
- 101800004419 Cleaved form Proteins 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 238000011579 SCID mouse model Methods 0.000 description 5
- 239000012736 aqueous medium Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- VEULIWWJVLYNEX-UHFFFAOYSA-N n-[dimethylamino(phenoxy)phosphoryl]-n-methylmethanamine Chemical compound CN(C)P(=O)(N(C)C)OC1=CC=CC=C1 VEULIWWJVLYNEX-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
Disclosed is phosphate containing anti-apoptotic Bcl-2 protein inhibitor compounds of general formula (I) wherein the substituents are as described in the specification. Additionally disclosed is the use of the compounds or compositions in the treatment of cancers, auto-immune disease and disease of the immune system. In one embodiment the compound is 4-[{[3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizin-1-yl]carbonyl}(phenyl)amino]phenyl disodium phosphate. In another embodiment the compound is 4-[{[5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrol-3-yl]carbonyl}(pyridin-4-yl)amino]phenyl disodium phosphate. In yet another embodiment the compound is 4-[(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl){[5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1Hpyrrol-3-yl]carbonyl}amino]phenyl disodium phosphate. the immune system. In one embodiment the compound is 4-[{[3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizin-1-yl]carbonyl}(phenyl)amino]phenyl disodium phosphate. In another embodiment the compound is 4-[{[5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrol-3-yl]carbonyl}(pyridin-4-yl)amino]phenyl disodium phosphate. In yet another embodiment the compound is 4-[(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl){[5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1Hpyrrol-3-yl]carbonyl}amino]phenyl disodium phosphate.
Description
N NE EW W P PH HO OS SP PH HA AT TE E P PR RO OD DR RU UG GS S O OF F I IN ND DO OL LI IZ ZI IN NE E A AN ND D P PY YR RR RO OL LE E
D DE ER RI IV VA AT TI IV VE ES S,,
A PROCESS FOR THEIR PREPARATION
A PROCESS FOR THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to new phosphate compounds, to a process for their
preparation and to pharmaceutical compositions containing them.
The compounds of the present invention are new and have very valuable pharmacological
and pharmacokinetic characteristics for use in the field of apoptosis and cancerology.
Apoptosis, or programmed cell death, is a physiological process that is crucial for
embryonic development and maintenance of tissue homeostasis.
Apoptotic-type cell death involves morphological changes such as condensation of the
nucleus, DNA fragmentation and also biochemical phenomena such as the activation of
caspases which cause damage to key structural components of the cell, so inducing its
disassembly and death. Regulation of the process of apoptosis is complex and involves the
activation or repression of several intracellular signalling pathways (Cory S. et al., Nature
Review Cancer, 2002, 2, 647-656).
Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is
associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's
disease and ischaemia. Conversely, deficits in the implementation of apoptosis play a
significant role in the development of cancers and their chemoresistance, in auto-immune
diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is
one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).
The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies.
The involvement of proteins of the Bcl-2 family is described in numerous types of cancer,
such as colorectal cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer,
bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia, follicular
lymphoma, myeloma, etc. Overexpression of the anti-apoptotic proteins of the Bcl-2
family is involved in tumorigenesis, in resistance to chemotherapy and in the clinical
prognosis of patients affected by cancer. There is, therefore, a therapeutic need for
compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.
In addition to being new, the compounds of the present invention have pharmacological
and pharmacokinetic properties making it possible to use them in pathologies involving a
defect in apoptosis, such as, for example, in the treatment of cancer, auto-immune diseases
and diseases of the immune system.
The present invention relates more especially to a phosphate compound of formula (I):
wherein:
♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they
may not simultaneously represent two carbons atoms or two nitrogen atoms,
♦ A and A , together with the atoms carrying them, form an optionally substituted,
aromatic or non-aromatic heterocycle Het composed of 5, 6 or 7 ring members
which may contain, in addition to the nitrogen represented by X or by Y, from one
to 3 hetero atoms selected independently from oxygen, sulphur and nitrogen, it
being understood that the nitrogen in question may be substituted by a group
representing a hydrogen atom, a linear or branched (C -C )alkyl group or a group
-C(O)-O-Alk wherein Alk is a linear or branched (C -C )alkyl group,
or A and A independently of one another represent a hydrogen atom, a linear or
branched (C -C )polyhaloalkyl, a linear or branched (C -C )alkyl group or a
1 6 1 6
cycloalkyl,
♦ T represents a hydrogen atom, a linear or branched (C -C )alkyl group optionally
substituted by from one to three halogen atoms, a group (C -C )alkyl-NR R , or a
1 4 1 2
group (C -C )alkyl-OR ,
1 4 6
♦ R and R independently of one another represent a hydrogen atom or a linear or
branched (C -C )alkyl group,
or R and R form with the nitrogen atom carrying them a heterocycloalkyl,
♦ R represents a linear or branched (C -C )alkyl group, a linear or branched
3 1 6
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a cycloalkyl
2 6 2 6
group, a (C -C )cycloalkyl-(C -C )alkyl group wherein the alkyl moiety is linear
3 10 1 6
or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being
understood that one or more of the carbon atoms of the preceding groups, or of
their possible substituents, may be deuterated,
♦ R represents a phenyl or a pyrimidinyl group both substituted in the para
position by one of the following phosphate groups: -OPO(OM)(OM'), -
- + - + - + - - 2+
OPO(OM)(O M ), -OPO(O M )(O M ), -OPO(O )(O )M ,-
1 1 2 3
- + 3
OPO(OM)(O[CH CH O] CH ), or -OPO(O M )(O[CH CH O] CH ), wherein M
2 2 n 3 1 2 2 n
and M' independently of one another represent a hydrogen atom, a linear or
branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or
1 6 2 6
branched (C -C )alkynyl group, a cycloalkyl or a heterocycloalkyl both composed
of 5 or 6 ring members, while M and M independently of one another represent
a pharmaceutically acceptable monovalent cation, and M represents a
pharmaceutically acceptable divalent cation and n is an integer from 1 to 5, it being
understood that one or more of the carbon atoms of the preceding groups, or of
their possible substituents, may be deuterated,
♦ R represents a hydrogen or halogen atom, a linear or branched (C -C )alkyl group,
1 6
or a linear or branched (C -C )alkoxy group,
♦ R represents a hydrogen atom or a linear or branched (C -C )alkyl group,
6 1 6
♦ R , R , R and R , each independently of the others, represent R , a halogen atom, a
a b c d 7
linear or branched (C -C )alkoxy group, a hydroxy group, a linear or
branched (C -C )polyhaloalkyl group, a trifluoromethoxy group,
-NR R ', nitro, R -CO-(C -C )alkyl-, R -CO-NH-(C -C )alkyl-,
7 7 7 0 6 7 0 6
NR R '-CO-(C -C )alkyl-, NR R '-CO-(C -C )alkyl-O-, R -SO -NH-(C -C )alkyl-,
7 7 0 6 7 7 0 6 7 2 0 6
R -NH-CO-NH-(C -C )alkyl-, R -O-CO-NH-(C -C )alkyl-, a heterocycloalkyl
7 0 6 7 0 6
group, or the substituents of one of the pairs (R ,R ), (R ,R ) or (R ,R ) form
a b b c c d
together with the carbon atoms carrying them a ring composed of from 5 to 7 ring
members, which may contain from one to 2 hetero atoms selected from oxygen and
sulphur, it also being understood that one or more carbon atoms of the ring defined
hereinbefore may be deuterated or substituted by from one to 3 groups selected
from halogen and linear or branched (C -C )alkyl,
♦ R and R ' independently of one another represent a hydrogen, a linear or branched
(C -C )alkyl, a linear or branched (C -C )alkenyl, a linear or branched
1 6 2 6
(C -C )alkynyl, an aryl or a heteroaryl, or R and R ' together with nitrogen atom
2 6 7 7
carrying them form a heterocycle composed of from 5 to 7 ring members,
it being understood that:
- "aryl" means a phenyl, naphthyl, biphenyl or indenyl group,
- "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at
least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur
and nitrogen (including quaternary nitrogens),
- "cycloalkyl" means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to
ring members,
- "heterocycloalkyl" means any mono- or bi-cyclic, non-aromatic, condensed or spiro group
composed of 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen,
sulphur, SO, SO and nitrogen,
it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined
and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups
selected from linear or branched (C -C )alkyl, (C -C )spiro, linear or branched, (C -
1 6 3 6 1
C )alkoxy, (C -C )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -
6 1 6
COOR', -OCOR', NR'R'', linear or branched (C -C )polyhaloalkyl, trifluoromethoxy, (C -
1 6 1
C )alkylsulphonyl, halogen, aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl
optionally substituted by one or more halogen atoms or alkyl groups, it being understood
that R' and R'' independently of one another represent a hydrogen atom or linear or
branched (C -C )alkyl group,
it being possible for the Het group defined in formula (I) to be substituted by from one to three groups
selected from linear or branched (C -C )alkyl, hydroxy, linear or branched (C -C )alkoxy, NR 'R " and
1 6 1 6 1 1
halogen, it being understood that R ' and R " are as defined for the groups R' and R'' mentioned hereinbefore,
to its enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid
or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying
any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid,
acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid,
glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid,
methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying
any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention include compounds of formula (I) wherein R represents phenyl
- + -
substituted in the para position by a group of formula -OPO(OM)(OM'), -OPO(OM)(O M ), -OPO(O
+ - + - - 2+ - +
M )(O M ), -OPO(O )(O )M , -OPO(OM)(O[CH CH O] CH ), or -OPO(O M )(O[CH CH O] CH ),
1 2 3 2 2 n 3 1 2 2 n 3
wherein M and M' independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl
group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a cycloalkyl or
2 6 2 6
a heterocycloalkyl both composed of 5 or 6 ring members, while M and M independently of one another
represent a pharmaceutically acceptable monovalent cation, and M represents a pharmaceutically
acceptable divalent cation and n is an integer from 1 to 5, it being understood that the phenyl group may
optionally be substituted by one or more halogen atoms.
Preference is given to compounds of formula (I) wherein R represents a phenyl or a pyrimidinyl group,
- + - +
both substituted in the para position by a group of formula -OPO(O M )(O M ), and even more especially
- + - +
by a group of formula -OPO(O Na )(O Na ).
Advantageously, X represents a carbon atom and Y represents a nitrogen atom. Even more advantageously,
the group:
represents a 5,6,7,8-tetrahydroindolizine, an indolizine or a dimethylated pyrrole.
T preferably represents a methyl, (morpholinyl)methyl or 3-(morpholinyl)propyl group.
In preferred compounds of the invention, R and R each represent a hydrogen atom and (R ,R ), together
a d b c
with the carbon atoms carrying them, form a 1,3-dioxolane group or a 1,4-dioxane group; or R , R and R
a c d
each represent a hydrogen atom and R represents a hydrogen or a halogen.
In another embodiment of the invention, R and R each represent a hydrogen atom, R represents a halogen
a d b
atom and R a methoxy group.
Alternatively, R , R and R each advantageously represent a hydrogen atom and R represents a group
a b d c
NR R '-CO-(C -C )alkyl-O-, and even more preferably R represents a 2-oxo(piperidinyl)ethoxy group.
7 7 0 6 c
Furthermore, R advantageously represents a group selected from phenyl, 1H-indole, 1H-pyrrolo[2,3-
b]pyridine, pyridine, 1H-pyrazole, 1H-pyrrole and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, those groups
optionally having one or more substituents selected from linear or branched (C -C )alkyl (more preferably
methyl), cyano and trideuteriomethyl.
Among the preferred compounds of the invention there may be mentioned:
- 4-[{[3-(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-
benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)amino]phenyl disodium
phosphate,
- 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(pyridin
yl)amino]phenyl disodium phosphate,
- 4-({[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}[1-(trideuteriomethyl)-
1H-pyrazolyl]amino)phenyl disodium phosphate,
- 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(5-cyano-1,2-dimethyl-
1H-pyrrolyl)amino]phenyl disodium phosphate,
- 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(5-cyanomethyl-1H-
pyrrolyl)amino]phenyl disodium phosphate,
- 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(1-methyl-1H-pyrazol-
4-yl)amino]phenyl disodium phosphate,
- 4-[(5-cyano-1,2-dimethyl-1H-pyrrolyl){[5-(5-fluoro{[(3S)(morpholin
ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-
pyrrolyl]carbonyl}amino]phenyl disodium phosphate,
- 4-[{[5-(5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(1-methyl-1H-pyrazol-
4-yl)amino]phenyl disodium phosphate,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically
acceptable acid or base.
Pharmacokinetic study of the phosphate compounds of formula (I) showed that they were
converted in vivo into compounds of formula (I') characterised in that the phosphate
function was metabolised into a hydroxy function. The compounds of formula (I)
accordingly behave as prodrugs of compounds of formula (I') having the following
formula:
R (I')
wherein:
♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they
may not simultaneously represent two carbons atoms or two nitrogen atoms,
♦ A and A , together with the atoms carrying them, form an optionally substituted,
aromatic or non-aromatic heterocycle Het composed of 5, 6 or 7 ring members
which may contain, in addition to the nitrogen represented by X or by Y, from one
to 3 hetero atoms selected independently from oxygen, sulphur and nitrogen, it
being understood that the nitrogen in question may be substituted by a group
representing a hydrogen atom, a linear or branched (C -C )alkyl group or a group
-C(O)-O-Alk wherein Alk is a linear or branched (C -C )alkyl group,
or A and A independently of one another represent a hydrogen atom, a linear or
branched (C -C )polyhaloalkyl, a linear or branched (C -C )alkyl group or a
1 6 1 6
cycloalkyl,
♦ T represents a hydrogen atom, a linear or branched (C -C )alkyl group optionally
substituted by from one to three halogen atoms, a group (C -C )alkyl-NR R , or a
1 4 1 2
group (C -C )alkyl-OR ,
1 4 6
♦ R and R independently of one another represent a hydrogen atom or a linear or
branched (C -C )alkyl group,
or R and R form with the nitrogen atom carrying them a heterocycloalkyl,
♦ R represents a linear or branched (C -C )alkyl group, a linear or branched
3 1 6
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a cycloalkyl
2 6 2 6
group, a (C -C )cycloalkyl-(C -C )alkyl group wherein the alkyl moiety is linear
3 10 1 6
or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being
understood that one or more of the carbon atoms of the preceding groups, or of
their possible substituents, may be deuterated,
♦ R represents a phenyl or a pyrimidinyl group both substituted in the para
position by one of the following phosphate groups: -OPO(OM)(OM'), -
- + - + - + - - 2+
OPO(OM)(O M ), -OPO(O M )(O M ), -OPO(O )(O )M ,-
1 1 2 3
- + 3
OPO(OM)(O[CH CH O] CH ), or -OPO(O M )(O[CH CH O] CH ), wherein M
2 2 n 3 1 2 2 n
and M' independently of one another represent a hydrogen atom, a linear or
branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or
1 6 2 6
branched (C -C )alkynyl group, a cycloalkyl or a heterocycloalkyl both composed
of 5 or 6 ring members, while M and M independently of one another represent
a pharmaceutically acceptable monovalent cation, and M represents a
pharmaceutically acceptable divalent cation and n is an integer from 1 to 5, it being
understood that one or more of the carbon atoms of the preceding groups, or of
their possible substituents, may be deuterated,
♦ R represents a hydrogen or halogen atom, a linear or branched (C -C )alkyl group,
1 6
or a linear or branched (C -C )alkoxy group,
♦ R represents a hydrogen atom or a linear or branched (C -C )alkyl group,
6 1 6
♦ R , R , R and R , each independently of the others, represent R , a halogen atom, a
a b c d 7
linear or branched (C -C )alkoxy group, a hydroxy group, a linear or
branched (C -C )polyhaloalkyl group, a trifluoromethoxy group,
-NR R ', nitro, R -CO-(C -C )alkyl-, R -CO-NH-(C -C )alkyl-,
7 7 7 0 6 7 0 6
NR R '-CO-(C -C )alkyl-, NR R '-CO-(C -C )alkyl-O-, R -SO -NH-(C -C )alkyl-,
7 7 0 6 7 7 0 6 7 2 0 6
R -NH-CO-NH-(C -C )alkyl-, R -O-CO-NH-(C -C )alkyl-, a heterocycloalkyl
7 0 6 7 0 6
group, or the substituents of one of the pairs (R ,R ), (R ,R ) or (R ,R ) form
a b b c c d
together with the carbon atoms carrying them a ring composed of from 5 to 7 ring
members, which may contain from one to 2 hetero atoms selected from oxygen and
sulphur, it also being understood that one or more carbon atoms of the ring defined
hereinbefore may be deuterated or substituted by from one to 3 groups selected
from halogen and linear or branched (C -C )alkyl,
♦ R and R ' independently of one another represent a hydrogen, a linear or branched
(C -C )alkyl, a linear or branched (C -C )alkenyl, a linear or branched
1 6 2 6
(C -C )alkynyl, an aryl or a heteroaryl, or R and R ' together with nitrogen atom
2 6 7 7
carrying them form a heterocycle composed of from 5 to 7 ring members,
it being understood that:
- "aryl" means a phenyl, naphthyl, biphenyl or indenyl group,
- "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at
least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur
and nitrogen (including quaternary nitrogens),
- "cycloalkyl" means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to
ring members,
- "heterocycloalkyl" means any mono- or bi-cyclic, non-aromatic, condensed or spiro group
composed of 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen,
sulphur, SO, SO and nitrogen,
it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined
and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups
selected from linear or branched (C -C )alkyl, (C -C )spiro, linear or branched, (C -
1 6 3 6 1
C )alkoxy, (C -C )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -
6 1 6
COOR', -OCOR', NR'R'', linear or branched (C -C )polyhaloalkyl, trifluoromethoxy, (C -
1 6 1
C )alkylsulphonyl, halogen, aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl
optionally substituted by one or more halogen atoms or alkyl groups, it being understood
that R' and R'' independently of one another represent a hydrogen atom or linear or
branched (C -C )alkyl group,
it being possible for the Het group defined in formula (I') to be substituted by from one to three groups
selected from linear or branched (C -C )alkyl, hydroxy, linear or branched (C -C )alkoxy, NR 'R " and
1 6 1 6 1 1
halogen, it being understood that R ' and R " are as defined for the groups R' and R'' mentioned hereinbefore,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or
base.
The compounds of formula (I') have pro-apoptotic properties and as a result are of major therapeutic value in
the treatment of cancers, auto-immune diseases and diseases of the immune system. In the present invention
it has been shown that, by administering the phosphate compounds of formula (I), the in vivo exposure to the
compounds of formula (I') was optimised. The solubility of the compounds of formula (I) is in fact much
greater than that of the compounds of formula (I'). Consequently, using the compounds of formula (I) in the
manufacture of pharmaceutical compositions is especially advantageous from the galenic point of view.
The invention relates also to a process for the preparation of compounds of formula (I),
which process is characterised in that there is used as starting material the compound of
formula (II):
(II)
wherein R , R , R and R are as defined for formula (I'),
a b c d
which compound of formula (II) is subjected to a Heck reaction, in an aqueous or organic
medium, in the presence of a palladium catalyst, of a base, of a phosphine and of the
compound of formula (III):
(III)
wherein the groups A , A , X and Y are as defined for formula (I') and Alk represents a
linear or branched (C -C )alkyl,
to obtain the compound of formula (IV):
(IV)
wherein A , A , X, Y, R , R , R and R are as defined for formula (I') and Alk is as
1 2 a b c d
defined hereinbefore,
the aldehyde function of which compound of formula (IV) is oxidised to a carboxylic acid
to form the compound of formula (V):
wherein A , A , X, Y, R , R , R and R are as defined for formula (I') and Alk is as
1 2 a b c d
defined hereinbefore,
which compound of formula (V) is then subjected to peptide coupling with a compound of
formula (VI):
(VI)
wherein T and R are as defined for formula (I'),
to yield the compound of formula (VII):
(VII)
wherein A , A , X, Y, R , R , R , R , T and R are as defined for formula (I') and Alk is as defined
1 2 a b c d 5
hereinbefore,
the ester function of which compound of formula (VII) is hydrolysed to yield the
corresponding carboxylic acid or carboxylate, which may be converted into an acid
derivative such as the corresponding acyl chloride or anhydride before being coupled with
an amine NHR R wherein R and R have the same meanings as for formula (I'), before
3 4 3 4
being subjected to the action of a pyrophosphate, phosphonate or phosphoryl compound
under basic conditions, it being possible for the compound thereby obtained to be
optionally hydrolysed or hydrogenolysed to yield the compound of formula (I),
which compound of formula (I) may be purified according to a conventional separation technique, which is
converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is
optionally separated into its isomers according to a conventional separation technique,
it being understood that, at any time considered appropriate in the course of the above-described process,
certain groups (hydroxy, amino…) of the reagents or intermediates of synthesis may be protected and then
deprotected according to the requirements of synthesis.
The compounds of formulae (II), (III), (VI) and the amine NHR R are either commercially available or can
be obtained by the person skilled in the art using conventional chemical reactions described in the literature.
More specifically, the phosphate compounds of formula (I) according to the invention will be useful in the
treatment of chemo- or radio-resistant cancers and also in malignant haemopathies and small-cell lung
cancer.
Among the cancer treatments envisaged there may be mentioned, without implying any
limitation, cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias,
colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, non-
Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer,
non-small-cell lung cancer, prostate cancer and small-cell lung cancer. Among non-
Hodgkin lymphomas, there may be mentioned more preferably follicular lymphomas,
mantle cell lymphomas, diffuse large B-cell lymphomas, small lymphocytic lymphomas
and marginal zone B-cell lymphomas.
The present invention relates also to pharmaceutical compositions comprising at least one
compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable
acid or base in combination with one or more pharmaceutically acceptable excipients.
The invention also relates to a pharmaceutical composition comprising a compound of the
invention and an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-
metabolites, proteasome inhibitors, kinase inhibitors and antibodies, in combination with
one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention there may be
mentioned more especially those that are suitable for oral, parenteral, nasal, per- or
trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets
or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges,
suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the administration
route, the nature of the therapeutic indication, or of any associated treatments, and ranges
from 0.01 mg to 1 g per 24 hours in one or more administrations.
The invention also provides the use of a pharmaceutical composition of the invention in the
manufacture of a medicament for use as a pro-apoptotic agent.
The invention also provides the use of a pharmaceutical composition of the invention in the
manufacture of a medicament intended for the treatment of cancers, auto-immune diseases
and diseases of the immune system.
The invention also provides the use of a pharmaceutical composition in the manufacture of
a medicament intended for the treatment of cancers of the bladder, brain, breast and uterus,
chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver,
lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant
haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and
small-cell lung cancer.
The invention also provides the use of a compound of the invention and an anti-cancer
agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome
inhibitors, kinase inhibitors and antibodies in the manufacture of a medicament for use in
the treatment of cancers.
The invention also provides a use of a compound of the invention in the manufacture of a
medicament for sequential or simultaneous administration with an anti-cancer agent
selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors,
kinase inhibitors and antibodies.
Furthermore, the present invention relates also to the combination of a compound of
formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, anti-
metabolites, proteasome inhibitors, kinase inhibitors and antibodies, and also to
pharmaceutical compositions comprising that type of combination and their use in the
manufacture of medicaments for use in the treatment of cancer.
The compounds of the invention may also be used in association with radiotherapy in the
treatment of cancer.
The term 'comprising' as used in this specification and claims means 'consisting at least in
part of'. When interpreting statements in this specification and claims which include the
term 'comprising', other features besides the features prefaced by this term in each
statement can also be present. Related terms such as 'comprise' and 'comprised' are to be
interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of providing a
context for discussing the features of the invention. Unless specifically stated otherwise,
reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of
the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not
within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
The following Preparations and Examples illustrate the invention without limiting it in any
way.
Preparation 1: 6-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydroindolizinyl]-1,3-
Preparation 1: 6-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydroindolizinyl]-1,3-
b be en nz zo od diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c a ac ciid d
Step A: 1-Formylpiperidine-carboxylic acid
To a solution of 40 g of a racemic mixture of 2-piperidine-carboxylic acid (0.310 mmol) in
300 mL of formic acid placed at 0°C there are added, dropwise, 200 mL (2.15 mmol) of
acetic anhydride. The batch is then stirred at ambient temperature overnight. Then, the
reaction mixture is cooled to 0°C, hydrolysed by adding 250 mL of water, and stirred for
half an hour at 0°C before being concentrated to dryness. The oil thereby obtained is taken
up in 200 mL of methanol and then concentrated to dryness. The title product is obtained
in the form of an oil in a yield of 98 %. It is used directly, without being otherwise
purified, in the next Step.
H NMR: δ (400 MHz; dmso-d6; 300°K): 13.0 (m, 1H OH); 8.0-8.05 (2s, 1H aldehyde);
4.9-4.5 (2d, 1H α to the N and COOH) ; 4.1-2.6 (m, 2H α to the N); 2.2-1.2 (m, 6H
piperidine)
-1 -1
IR: ν: -OH: 2000-3000 cm acid; ν: >C=O 1703 cm wide band
Step B: Methyl 5,6,7,8-tetrahydroindolizine-carboxylate
To a solution of 10 g of the carboxylic acid obtained in Step A (63.6 mmol) in 65 mL of
dichloroethane there are successively added 13.4 g of tosyl chloride (70.4 mmol), 11.5 mL
of methyl 2-chloroacrylate (113.5 mmol) and then, dropwise, 17.8 mL of N,N,N-
triethylamine (127.2 mmol). The reaction mixture is then refluxed for 1 hour 30 minutes. It
is then placed at ambient temperature, and there are then added 5 mL of methyl 2-
chloroacrylate (48.9 mmol) and, dropwise, 9 mL of N,N,N-triethylamine (64 mmol). The
batch is refluxed overnight.
The reaction mixture is then diluted with methylene chloride, washed successively with
1M HCl solution, saturated aqueous NaHCO solution and then with brine until a neutral
pH is obtained. The organic phase is then dried over MgSO , filtered, concentrated to
dryness and purified by chromatography over silica gel (heptane/AcOEt gradient). The title
product is obtained in the form of an oil.
H NMR: δ (400 MHz; CDCl ; 300°K): 6.55-6.40 (d, 2H, tetrahydroindolizine); 3.91 (t,
3H methyl ester); 3.78 (s, 3H tetrahydroindolizine); 3.08 (t, 2H, tetrahydroindolizine);
1.95-1.85 (m, 4H, tetrahydroindolizine)
IR: ν:>C=O 1692 cm ester
Step C: Methyl 3-(6-formyl-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizine-
carboxylate
To a solution of 6.4 g of the ester obtained in Step B (35.7 mmol) in 12 mL of N,N-
dimethylacetamide, there are successively added 12.3 g of 6-bromo-1,3-benzodioxole
carbaldehyde (53.6 mmol) and 7 g of potassium acetate (71.4 mmol), and then the batch is
stirred under argon for 20 minutes. There are then added 1.3 g of palladium catalyst
dichlorobis(triphenylphosphine)palladium(II) (PdCl (PPh ) ) (1.8 mmol). The reaction
2 3 2
mixture is then heated at 130°C for one hour before adding 139 µL of H O thereto. Heating
is maintained at that same temperature overnight. The mixture is allowed to return to
ambient temperature and it is then diluted with AcOEt. Animal charcoal (25 g per g of
product) is added and the batch is stirred at ambient temperature for 1 hour and then
filtered. The organic phase is then washed with water, dried over magnesium sulphate and
concentrated to dryness. The crude product thereby obtained is purified by chromatography
over silica gel (heptane/AcOEt gradient). The title product is obtained in the form of an oil.
H NMR: δ:(400 MHz; dmso-d6; 353°K): 9.65 (s, 1H, H aldehyde); 7.3-7.15 (2s, 2H, aromatic Hs); 6.45 (s,
1H tetrahydroindolizine); 6.20 (s, 2H methylenedioxy); 3.70 (s, 3H methyl ester); 3.5-4.0 (m, 2H
tetrahydroindolizine); 3.05 (m, 2H tetrahydroindolizine); 1.85 (m, 4H tetrahydroindolizine)
-1 -1
IR: ν: >C=O 1695 cm ester; ν: >C=O 1674 cm
Step D: 6-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydroindolizinyl]-1,3-benzodioxole
carboxylic acid
A solution containing 3.37 g of the compound obtained in Step C (10.3 mmol) in 9.3 mL of
acetone and 8.8 mL (80.24 mmol) of 2-methylbutene is prepared and placed at 0°C.
There are added, dropwise, 9.3 mL of an aqueous solution containing a mixture of 3.3 g of
sodium chlorite (NaClO ) (36.05 mmol) and 3.6 g of sodium dihydrogen phosphate
monohydrate (NaH PO ) (25.75 mmol). The batch is then stirred at ambient temperature
for 7 hours. The reaction mixture is then concentrated in order to remove the acetone. The
solid then obtained is filtered off, washed with water and then dried at 40°C in vacuo
overnight. The title product is obtained in the form of a solid, which is subsequently used
without being otherwise purified.
H NMR: δ (400 MHz; dmso-d6; 300°K): 12.10 (m, 1H, H carboxylic acid); 7.40-6.88 (2s,
2H, aromatic Hs); 6.20 (s, 1H, H tetrahydroindolizine); 6.18 (s, 2H, H methylenedioxy);
3.70 (s, 3H, methyl ester); 3.55 (t, 2H tetrahydroindolizine); 3.00 (t, 2H
tetrahydroindolizine); 1.80 (m, 4H, H tetrahydroindolizine)
-1 -1
IR: ν: -OH: 3000-2000 cm acid; ν: >C=O 1686-1676 cm ester+acid; ν: >C=C<
1608 cm
P Pr re ep pa ar ra at tiio on n 2 2: : 2 2- -[ [1 1- -( (M Me et th ho ox xy yc ca ar rb bo on ny yll) )- -5 5,,6 6,,7 7,,8 8- -t te et tr ra ah hy yd dr ro o- -3 3- -iin nd do olliiz ziin ny yll] ]b be en nz zo oiic c a ac ciid d
The procedure is in accordance with the protocol described in Preparation 1, replacing the
6-bromo-1,3-benzodioxolecarbaldehyde used in Step C by 2-bromo-benzaldehyde.
P Pr re ep pa ar ra at tiio on n 3 3: : 6 6- -[ [1 1- -( (M Me et th ho ox xy yc ca ar rb bo on ny yll) )- -3 3- -iin nd do olliiz ziin ny yll] ]- -1 1,,3 3- -b be en nz zo od diio ox xo olle e- -5 5- -c ca ar rb bo ox xy ylliic c
acid
acid
Step A: 1-(Carboxymethyl)-1,2-dihydropyridinium bromide
To a solution of 16.2 mL of pyridine (200 mmol) in 120 mL of ethyl acetate there are
added, in portions, 27.8 g (200 mmoles) of bromoacetic acid. The batch is then stirred at
ambient temperature overnight. The precipitate thereby obtained is filtered off and then
washed with cold ethyl acetate. After drying, the title product is obtained in the form of a
powder which is used directly in the next Step.
H NMR: δ (400 MHz; dmso-d6; 300°K): 9.15 (d, 2H, aromatic Hs pyridine); 8.7 (t, 1H,
aromatic H); 8.25 (t, 2H, aromatic H); 5.65 (s, 2H, H CH COOH)
-1 -1
IR: ν: C=O: 1732 cm ; -OH acid: 2800 cm
Step B: Methyl 1-indolizinecarboxylate
To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30 mmol) in 240 mL
of toluene there are successively added 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of
triethylamine (30 mmol) and then, in portions, 20.9 g of MnO (240 mmol). The batch is
then heated at 90°C for 3 hours. After cooling, the reaction mixture is filtered over a cake
of Celite and concentrated to dryness. The title product is then isolated by purification over
silica gel (heptane / AcOEt gradient: 0-10%) in the form of an oil which crystallises in the
cold state.
H NMR: δ (300 MHz; dmso-d6; 300°K): 8.5 (d, 1H, H indolizine); 8.05 (d, 1H, H
indolizine); 7.6 (s, 1H, H indolizine); 7.15 (m, 2H, H indolizine); 6.85 (m, 1H, H
indolizine); 4.25 (q, 2H, -C(O)CH CH ); 1.35 (t, 3H, -C(O)CH CH )
2 3 2 3
-1 -1
IR: ν: C=O ester: 1675 cm ; aromatic C=C moieties: 1634 cm
Step C: 6-[1-(Methoxycarbonyl)indolizinyl]-1,3-benzodioxolecarboxylic acid
The procedure is in accordance with the protocol described in Steps C and D of
Preparation 1.
P Pr re ep pa ar ra at tiio on n 4 4: : 4 4- -C Ch hllo or ro o- -2 2- -[ [4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- -
benzoic acid
benzoic acid
Step A: Ethyl 1,2-dimethyl-1H-pyrrolecarboxylate
To a solution of 10 g of ethyl 2-methyl-1H-pyrrolecarboxylate (65.3 mmol) and
8.95 mL (130.6 mmol) of methyl iodide in 70 mL of dimethylformamide placed at 0°C
there are added, in three portions, 2.61 g (65.3 mmol) of sodium hydride 60 % . The batch
is then stirred at 0°C for 1 hour. Then, the reaction mixture is hydrolysed by the addition of
420 mL of ice-cold water. The reaction mixture is then diluted with ethyl acetate,
successively washed with 0.1M HCl solution, saturated aqueous LiCl solution and then
brine. The organic phase is then dried over MgSO , filtered, concentrated to dryness and
purified by chromatography over silica gel (petroleum ether/AcOEt gradient).
H NMR: δ (400 MHz; dmso-d6; 300K): 6.65 (d, 1H pyrrole); 6.3 (1d, 1H pyrrole); 4.1
(1q, 2H, OCH CH ); 3.5 (s, 3H N-pyrrole); 2.4 (s, 3H pyrrole); 1.5 (1t, 3H OCH CH )
2 3 2 3
-1 -1
IR: ν: >C=O: 1688 cm ; ν: C-O-C: 1172 cm
Step B: Ethyl 5-(5-chloroformylphenyl)-1,2-dimethyl-1H-pyrrolecarboxylate
To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-
dimethylacetamide there are successively added 15.2 g of 2-bromochlorobenzaldehyde
(69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under
argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdCl (PPh )
2 3 2
(3.14 mmol). The reaction mixture is then heated at 130°C overnight. The mixture is
allowed to return to ambient temperature and it is then diluted with dichloromethane.
Animal charcoal is added (30 g) and the batch is stirred at ambient temperature for 1 hour
and then filtered. The organic phase is then washed with water, dried over magnesium
sulphate and concentrated to dryness. The crude product thereby obtained is purified by
chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is
obtained in the form of a solid.
H NMR: δ (400 MHz; dmso-d6; 300K): 9.8 (s, 1H, formyl); 7.91-7.69-7.61 (d, 3H,
aromatic Hs); 6.5 (s, 1H pyrrole); 4.2 (q, 2H, OCH CH ); 3.4 (s, 3H, CH -N-pyrrole);
2 3 3
2.55 (s, 3H pyrrole); 1.28 (t, 3H, OCH CH )
Step C: 4-Chloro[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]benzoic acid
A solution is prepared containing 12.85 g of the compound obtained in Step B (42 mmol)
and 35.7 mL (336 mmol) of 2-methylbutene in a mixture containing 20 mL of acetone
and 20 mL of tetrahydrofuran. There are added, dropwise, 200 mL of an aqueous solution
containing a mixture of 13.3 g of sodium chlorite (NaClO ) (147 mmol) and 14.5 g of
sodium dihydrogen phosphate monohydrate (NaH PO H O) (105 mmol). The batch is
2 4 2
then vigorously stirred at ambient temperature for 7 hours. The reaction mixture is then
concentrated to remove the acetone. Ethyl acetate is added, and the organic phase is
washed with water and then concentrated to dryness. The residue is then taken up in a
minimum of ethyl ether. The solid then obtained is filtered off, washed with ether and then
dried in vacuo at 40°C overnight. The title product is obtained in the form of a solid, which
is subsequently used without being otherwise purified.
H NMR: δ (400 MHz; dmso-d6; 300K): 13 (m, 1H COOH); 7.85-7.6-7.41(d,dd, wd, 3H,
aromatic Hs); 6.3 (s, 1H, H pyrrole); 4.15 (q, 2H, OCH CH ); 3.25 (s, 3H, CH -N-
2 3 3
pyrrole); 2.5 (s, 3H, CH -pyrrole); 1.25 (t, 3H, OCH CH )
3 2 3
-1 -1
IR: ν: -OH: 3100-2500 cm acid; ν: >C=O: 1681 cm ester + acid
Preparation 5: 6-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]-1,3-benzodioxole-
Preparation 5: 6-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrolyl]-1,3-benzodioxole-
-carboxylic acid
-carboxylic acid
The procedure is in accordance with the process of Preparation 4, replacing the 2-bromo
chlorobenzaldehyde used in Step B by 6-bromo-1,3-benzodioxolecarbaldehyde.
P Pr re ep pa ar ra at tiio on n 6 6: : 4 4- -F Fllu uo or ro o- -3 3- -m me et th ho ox xy y- -2 2- -[ [4 4- -( (e et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -
p py yr rr ro oll- -2 2- -y yll] ]b be en nz zo oiic c a ac ciid d
The procedure is in accordance with the process of Preparation 4, replacing the 2-bromo
chlorobenzaldehyde used in Step B by 2-bromofluoromethoxybenzaldehyde.
Preparation 7: 4-Fluoro[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol
Preparation 7: 4-Fluoro[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol
yl]benzoic acid
yl]benzoic acid
The procedure is in accordance with the process of Preparation 4, replacing the 2-bromo
chlorobenzaldehyde used in Step B by 2-bromofluorobenzaldehyde.
P Pr re ep pa ar ra at tiio on n 8 8: : 7 7- -[ [4 4- -( (M Me et th ho ox xy yc ca ar rb bo on ny yll) )- -1 1,,5 5- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -2 2- -y yll] ]- -2 2,,3 3- -d diih hy yd dr ro o- -1 1,,4 4- -
b be en nz zo od diio ox xiin n- -6 6- -c ca ar rb bo ox xy ylliic c a ac ciid d
The procedure is in accordance with the process of Preparation 4, replacing the ethyl 2-
methyl-1H-pyrrolecarboxylate in Step A by methyl 2-methyl-1H-pyrrolecarboxylate
and the 2-bromochlorobenzaldehyde used in Step B by 7-bromo-2,3-dihydro-1,4-
benzodioxincarbaldehyde.
P Pr re ep pa ar ra at tiio on n 9 9: : 5 5- -B Be en nz zy yllo ox xy y- -2 2- -( (1 1- -m me et th ho ox xy yc ca ar rb bo on ny yll- -5 5,,6 6,,7 7,,8 8- -t te et tr ra ah hy yd dr ro oiin nd do olliiz ziin n- -3 3- -
y yll) )b be en nz zo oiic c a ac ciid d
Step A: Methyl 3-(4-benzyloxyformyl-phenyl)-5,6,7,8-tetrahydroindolizine
carboxylate
-Benzyloxybromo-benzaldehyde (12.3 g, 42.2 mmol) is introduced into a flask in the
presence of potassium acetate (8.3 g; 84.2 mmol) and 120 mL of dimethylacetamide. After
degassing under argon, dichlorobis(triphenylphosphine)palladium (II) (1.04 g, 1.5 mmol)
is added and the mixture is then degassed under argon before being heated at 100°C for 16
hours. After returning to ambient temperature, the reaction mixture is poured into 200 mL
of ethyl acetate, filtered over Celite, and washed with water and then with brine. The
combined aqueous phases are extracted with ethyl acetate. The organic phases are dried
over sodium sulphate, filtered and concentrated under reduced pressure. The residue
obtained is purified by chromatography over silica gel in order to obtain the title product.
Step B: 5-Benzyloxy(1-methoxycarbonyl-5,6,7,8-tetrahydroindolizinyl)benzoic acid
To a solution of the compound obtained in Step B (4.63 g, 11.89 mmol) in 300 mL of
acetone there is added 2-methylbutene (6.31 mL, 59 mmol). A solution of sodium
dihydrogen phosphate monohydrate (6.56 g, 47.6 mmol) and sodium chlorite (2.69 g,
23.8 mmol) in 40 mL of water is then poured in dropwise whilst maintaining the
temperature below 20°C. After stirring for 30 minutes at ambient temperature, the mixture
is acidified with 2M HCl solution and then the phases are separated. The aqueous phase is
extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate,
filtered and evaporated to dryness to provide the expected compound.
P Pr re ep pa ar ra at tiio on n 1 1'': : ( (3 3S S) )- -3 3- -( (4 4- -M Mo or rp ph ho olliin ny yllm me et th hy yll) )- -1 1,,2 2,,3 3,,4 4- -t te et tr ra ah hy yd dr ro oiis so oq qu uiin no olliin ne e
Step A: Benzyl (3S)(4-morpholinylcarbonyl)-3,4-dihydro-2(1H)-isoquinoline-
carboxylate
To a solution of 5 g of (3S)[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro
isoquinolinecarboxylic acid (16 mmol) in 160 mL of dichloromethane there are added
1.5 mL of morpholine (17.6 mmol), then 9 mL of N,N,N-triethylamine (64 mmol), 3.3 g of
1-ethyl(3'-dimethylaminopropyl)-carbodiimide (EDC) (19.2 mmol) and 2.6 g of
hydroxybenzotriazole (HOBt) (19.2 mmol). The reaction mixture is stirred at ambient
temperature overnight; it is then poured into aqueous ammonium chloride solution and
extracted with ethyl acetate. The organic phase is then dried over magnesium sulphate, and
then filtered and evaporated to dryness. The crude product thereby obtained is then purified
by chromatography over silica gel (dichloromethane/methanol gradient). The product is
obtained in the form of a foam.
H NMR: δ (400 MHz; dmso-d6; 353K): 7.30 (m, 5H benzyl); 7.15 (m, 4H, aromatic Hs);
.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline); 4.75-4.5 (2d, 2H
dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine); 3.15-2.9 (2dd, 2H
dihydroisoquinoline)
IR: ν: >C=O: 1694;1650 cm
Step B: Benzyl (3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate
To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in 278 mL of
tetrahydrofuran there are added 14 mL of borane-dimethylsulphide complex (BH Me S)
(27.8 mmol) at ambient temperature. The batch is heated for 4 hours at 80°C. It is allowed
to return to ambient temperature and there are then added 7 mL (14 mmol) of BH Me S.
The reaction mixture is again heated at 80°C for 2 hours. The tetrahydrofuran is then
evaporated off and then there is slowly added methanol and then 5.6 mL of 5M
hydrochloric acid (27.8 mmol). The mixture is stirred at ambient temperature overnight,
and then at 80°C for 1 hour. Saturated aqueous NaHCO solution is then added to the
reaction mixture placed at 0°C until a pH of 8 is obtained, and extraction with ethyl acetate
is then carried out. The organic phase is then dried over magnesium sulphate, and then
filtered and evaporated to dryness. The title product is obtained in the form of an oil.
H NMR: δ (400 MHz; dmso-d6; 353K): 7.43-7.30 (unresolved peak, 5H benzyl); 7.19
(m, 4H, aromatic Hs); 5.16 (m, 2H, 2H benzyl); 4.79-4.29 (d, 2H dihydroisoquinoline);
4.58 (m, 1H dihydroisoquinoline); 3.50 (m, 4H morpholine); 3.02-2.80 (dd, 2H
dihydroisoquinoline); 2.42-2.28 (unresolved peak, 5H, 4H morpholine, 1H morpholine);
2.15 (dd, 1H morpholine)
-1 -1 -1
IR: ν: >CH: 2810 cm ; ν: >C=O: 1694 cm ; ν: >C-O-C<: 1114 cm ; ν: >CH-Ar: 751;
697 cm
Step C: (3S)(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline
To a solution of 4.9 g of the compound of Step B (13.4 mmol) in 67 mL of ethanol there is
added 0.980 g of palladium dihydroxide (20 % by weight) at ambient temperature. The
reaction mixture is placed under 1.2 bars of hydrogen at ambient temperature for 4 hours.
It is then passed through a Whatman filter and the palladium is then rinsed several times
with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form
of an oil.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.12-7.0 (unresolved peak, 4H, aromatic Hs); 3.92 (s, 2H
tetrahydroisoquinoline); 3.60 (t, 4H morpholine); 2.98 (m, 1H tetrahydroisoquinoline); 2.68 (dd, 1H
tetrahydroisoquinoline); 2.5-2.3 (unresolved peak, 8H, 1H tetrahydroisoquinoline, 6H morpholine, 1H NH)
-1; -1; -1
IR: ν: >NH: 3322 cm ν: >C-O-C<: 1115 cm ν: >CH-Ar: 742 cm
P Pr re ep pa ar ra at tiio on n 2 2'': : ( (3 3R R) )- -3 3- -M Me et th hy yll- -1 1,,2 2,,3 3,,4 4- -t te et tr ra ah hy yd dr ro oiis so oq qu uiin no olliin ne e h hy yd dr ro oc ch hllo or riid de e
Step A: {(3S)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolinyl}methyl
4-methylbenzenesulphonate
To a solution of 30.2 g of [(3S)-1,2,3,4-tetrahydroisoquinolinyl]methanol (185 mmol) in
750 mL of dichloromethane there are successively added 91.71 g of tosyl chloride
(481 mmol) and then, dropwise, 122.3 mL of N,N,N-triethylamine (740 mmol). The
reaction mixture is then stirred at ambient temperature for 20 hours. It is then diluted with
dichloromethane, washed successively with 1M HCl solution, saturated aqueous NaHCO
solution and then brine until neutral. The organic phase is then dried over MgSO , filtered
and concentrated to dryness. The solid obtained is then dissolved in a minimum volume of
dichloromethane and then cyclohexane is added until a precipitate is formed. This
precipitate is then filtered off and washed with cyclohexane. After drying, the title product
is obtained in the form of crystals.
H NMR: δ (400 MHz; dmso-d6; 300°K): 7.75 (d, 2H, aromatic Hs, ortho O-tosyl); 7.6 (d,
2H , aromatic Hs, ortho N-tosyl); 7.5 (d, 2H, aromatic Hs, meta O-tosyl); 7.3 (d, 2H,
aromatic Hs, meta N-tosyl); 7.15-6.9 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.4-
4.15 (dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 4.25 (m, 1H, aliphatic H,
tetrahydroisoquinoline); 4.0-3.8 (2dd, 2H, aliphatic Hs, CH -O-tosyl); 2.7 (2dd, 2H,
aliphatic Hs, tetrahydroisoquinoline); 2.45 (s, 3H, O-SO -Ph- CH ); 2.35 (s, 3H, N-SO -
2 3 2
Ph- CH )
IR: ν: -SO : 1339-1165 cm
Step B: (3R)Methyl[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinoline
To a suspension of 8.15 g (214.8 mmol) of LiAlH in 800 mL of methyl tert-butyl ether
(MTBE) there are added 101.2 g of the ditosyl compound obtained in Step A (214.8 mmol)
dissolved in 200 mL of MTBE. The batch is then heated at 50°C for 2 hours. It is allowed
to cool and placed at 0°C, and there are then added, dropwise, 12 mL of 5M NaOH
solution. The batch is stirred at ambient temperature for 45 minutes. The solid thereby
obtained is then filtered off and washed with MTBE and then with dichloromethane. The
filtrate is then concentrated to dryness. The title product is then obtained in the form of a
solid.
H NMR: δ (400 MHz; dmso-d6; 300°K): 7.70 (d, 2H, aromatic Hs, ortho N-tosyl); 7.38
(d, 2H, aromatic Hs, meta N-tosyl); 7.2-7.0 (m, 4H, aromatic Hs, tetrahydroisoquinoline);
4.4 (m, 2H, aliphatic Hs, tetrahydroisoquinoline); 4.3 (m, 1H, aliphatic H,
tetrahydroisoquinoline); 2.85-2.51 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.35 (s,
3H, N-SO -Ph- CH ); 0.90 (d, 3H, tetrahydroisoquinoline-CH )
2 3 3
IR : ν: -SO : 1332-1154 cm
Step C: (3R)Methyl-1,2,3,4-tetrahydroisoquinoline
To a solution of 31.15 g (103.15 mmol) of the monotosyl compound obtained in Step B in
500 mL of anhydrous methanol there are added, in portions, 3.92 g (161 mmol) of
magnesium turnings. The batch is stirred in the presence of ultrasound for 96 hours. The
reaction mixture is then filtered and the solid is washed several times with methanol. The
filtrate is then concentrated to dryness. After purification by chromatography over silica
gel (dichloromethane /EtOH /NH OH gradient), the title product is obtained in the form of
an oil.
H NMR: δ (400 MHz; dmso-d6; 300°K): 7.05 (m, 4H, aromatic Hs,
tetrahydroisoquinoline); 3.90 (m, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.85 (m, 1H,
aliphatic H, tetrahydroisoquinoline); 2.68-2.4 (2dd, 2H, aliphatic Hs, tetrahydro-
isoquinoline); 1.12 (d, 3H, tetrahydroisoquinoline-CH ); 2.9-2.3 (m, broad, 1H, HN
(tetrahydroisoquinoline))
IR: ν: -NH: 3248 cm
Step D: (3R)Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride
To a solution of 14.3 g (97.20 mmol) of the compound obtained in Step C in 20 mL of
anhydrous ethanol there are added, dropwise, 100 mL of a 1M solution of HCl in ether.
The batch is stirred at ambient temperature for 1 hour and then filtered. The crystals
thereby obtained are washed with ethyl ether. After drying, the title product is obtained in
the form of crystals.
H NMR: δ (400 MHz; dmso-d6; 300°K): 9.57 (m, broad, 2H, NH (tetrahydro-
isoquinoline); 7.22 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.27 (s, 2H, aliphatic Hs,
tetrahydroisoquinoline); 3.52 (m, 1H, aliphatic H, tetrahydroisoquinoline); 3.03--2.85 (2dd,
2H, aliphatic Hs, tetrahydroisoquinoline); 1.39 (d, 3H, tetrahydroisoquinoline-CH )
+ -1 -1
IR: ν: -NH : 3000-2300 cm ; ν: aromatic -CH: 766 cm
P Pr re ep pa ar ra at tiio on n 3 3'': : ( (3 3R R) )- -3 3- -[ [3 3- -( (M Mo or rp ph ho olliin n- -4 4- -y yll) )p pr ro op py yll] ]- -1 1,,2 2,,3 3,,4 4- -t te et tr ra ah hy yd dr ro oiis so oq qu uiin no olliin ne e
Step A: {(3S)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolinyl}methyl
4-methylbenzenesulphonate
The procedure is the same as that of Step A of Preparation 2'.
Step B: tert-Butyl 2-({(3R)[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin-
3-yl}methyl)(morpholinyl)oxopropanoate
To a suspension of 1 g of NaH (60 %) (25.08 mmol) in 30 mL of MTBE there are added,
dropwise, a solution of 5 g of tert-butyl 3-morpholinooxopropanoate (21.81 mmol) in
mL of anhydrous MTBE. This suspension is stirred at ambient temperature for 1 hour
and then the compound obtained in Step A is added in the form of a powder. The batch is
stirred at 60°C for 30 hours. 100 mL of saturated aqueous ammonium chloride solution are
added. The resulting solution is extracted with dichloromethane. The organic phase is then
dried over MgSO , filtered and concentrated to dryness. After purification by
chromatography over silica gel (dichloromethane/MeOH gradient), the expected product is
obtained in the form of an oil.
H NMR (500 MHz, dmso-d6) δ ppm: 7.63/7.59 (2d, 2 H), 7.3/7.26 (2d, 2 H), 7.13 (m,
2 H), 7.09/6.97 (2t, 2 H), 4.64/4.55/4.36/4.28 (2AB, 2 H), 4.25/4.11 (2m, 1 H), 3.81 (m,
1 H), 3.73-3.48 (m, 4 H), 3.57-3.32 (m, 4 H), 2.51 (m, 2 H), 2.32/2.31 (2s, 3 H), 1.88/1.79
(2m, 2 H), 1.39/1.38 (2s, 9 H)
IR (ATR) cm : ν: >C=O : 1731 (ester); ν: >C=O: 1644 (amide); ν: -SO2 : 1334-1156; ν:
>C-O-C<: 1115; γ : >CH-Ar: 815709
Step C: 2-({(3R)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin
yl}methyl)(morpholinyl)oxopropanoic acid
To a solution of 9.5 g (17.97 mmol) of the compound obtained in Step B in 40 mL of
dioxane there are added, dropwise, 20 mL of a 4M solution of HCl in dioxane. The batch is
stirred at ambient temperature for 48 hours and then the solution is concentrated to
dryness. After drying, the expected product is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 12.75 (m, 1 H), 7.6 (2*d, 2 H), 7.3 (2*d, 2 H),
7.1/6.95 (2*m, 4 H), 4.7-4.2 (d, 2 H), 4.25/4.12 (2*m, 1 H), 3.9-3.3 (m, 9 H), 2.55 (d, 2 H),
2.3 (2*s, 3 H), 1.8 (t, 2 H)
IR (ATR) cm : ν: -OH : 3500 to 2000; ν: >C=O : 1727 (acid); ν: >C=O: 1634 (amide); ν:
-SO2: 1330-1155
Step D: 3-{(3R)[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolinyl}
(morpholinyl)propanone
To a solution of 7.80 g (16.51 mmol) of the compound obtained in Step C in 100 mL of
DMSO there are added 1.16 g (19.83 mmol) of solid sodium chloride and then, dropwise,
mL of water. The batch is stirred at 130°C for 1 hour and then the solution is
concentrated to ¾. The reaction mixture is then diluted with dichloromethane and washed
successively with saturated aqueous lithium chloride solution and then with brine. The
organic phase is then dried over MgSO , filtered and concentrated to dryness. After
purification by chromatography over silica gel (cyclohexane/ethyl acetate gradient), the
expected product is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.65 (d, 2 H), 7.3 (d, 2 H), 7.15/7 (2 m, 4 H), 4.6 (d,
1 H), 4.25 (d, 1 H), 4.2 (m, 1 H), 3.5 (m, 4 H), 3.4 (2 m, 4 H), 2.6 (2 dd, 2 H), 2.35 (s, 3 H),
2.3 (m, 2 H), 1.5 (quad., 2 H)
IR (ATR) cm : ν: >C=O: 1639; ν: -SO2: 1331-1156; γ : >CH-Ar: 815-675
Step E: (3R)[(4-Methylphenyl)sulphonyl][3-(morpholinyl)propyl]-1,2,3,4-
tetrahydroisoquinoline
To a solution of 6.0 g (14.0 mmol) of the compound obtained in Step D in 60 mL of
MTBE and 14 mL of dichloromethane there are added 1.06 g (28 mmol) of LAH in
portions over 5 minutes. The batch is stirred at ambient temperature for 15 hours. There are
added, dropwise, 1.5 mL of water and stirring is carried out for 15 minutes. There are then
added, dropwise, 1.5 mL of 5M sodium hydroxide solution and stirring is carried out for
minutes. The reaction mixture is then diluted with MTBE and dichloromethane. The
suspension is then filtered and the precipitate is washed with MTBE and dichloromethane.
The organic phase is then dried over MgSO , filtered and concentrated to dryness. After
purification by chromatography over silica gel (dichloromethane/EtOH/NH OH gradient),
the expected product is obtained in the form of an oil.
H NMR (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2 H), 7.32 (d, 2 H), 7.1 (unresolved peak,
4 H), 4.65/4.23 (AB, 2 H), 4.2 (m, 1 H), 3.55 (t, 4 H), 2.7/2.6 (ABx, 2 H), 2.35 (s, 3 H),
2.25 (t, 4 H), 2.2 (t, 2 H), 1.4/1.3 (2m, 4 H).
IR (ATR) cm : ν: -SO2: 1333-1158
Step F: (3R)[3-(Morpholinyl)propyl]-1,2,3,4-tetrahydroisoquinoline
To a solution of 1.50 g (3.62 mmol) of the compound obtained in Step E in 20 mL of
anhydrous methanol there are added 2.0 g (82.3 mmol), in portions, of magnesium
turnings. The batch is stirred in the presence of ultrasound for 96 hours. The reaction
mixture is then filtered, the solid is washed several times with methanol, and the filtrate is
concentrated to dryness. After purification by chromatography over silica gel
(dichloromethane/EtOH/NH OH gradient), the expected product is obtained in the form of
an oil.
H NMR (400 MHz, dmso-d6) δ ppm : 7.3 (d, 2 H), 7.1 (t, 2 H), 7.1 (d+t, 3 H), 7 (d, 2 H),
3.9 (s, 2 H), 3.55 (t, 4 H), 2.75 (m, 1 H), 2.72/2.45 (dd, 2 H), 2.35 (t, 4 H), 2.25 (t, 2 H), 1.6
(m, 2 H), 1.45 (m, 2 H)
IR (ATR) cm : ν: >NH2+/NH+: 3500-2300; ν: >C-O-C<: 1115
High-resolution mass spectrometry (ESI+-/FIA/HR):
Empirical formula: C H N O
16 24 2
[M+H] calculated: 261.1961
[M+H] measured: 261.1959
Preparation 4': (3R)(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline
Preparation 4': (3R)(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline
The procedure is in accordance with the process of Preparation 1', replacing the (3S)
[(benzyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinolinecarboxylic acid used in Step A by
(3R)[(benzyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinolinecarboxylic acid.
P Pr re ep pa ar ra at tiio on n 1 1'''': : 4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }- -N N- -p ph he en ny ylla an niilliin ne e
To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL of acetonitrile there are added, at ambient
temperature, 6.7 g of imidazole (97.05 mmol) and 11.7 g of tert-butyl(chloro)dimethylsilane (77.64 mmol).
The batch is stirred at 70°C for 4 hours. The reaction mixture is then poured into water and extracted with
ether. The organic phase is then dried over magnesium sulphate, then filtered and evaporated to dryness. The
crude product thereby obtained is then purified by chromatography over silica gel (petroleum
ether/dichloromethane gradient). The title product is obtained in the form of a powder.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.84 (s, 1H NH); 7.17 (t, 2H aniline); 6.98 (d, 2H
phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2H phenoxy); 6.72 (t, 1H aniline); 0.95 (s, 9H tert-
butyl); 0.15 (s, 6H dimethyl)
-1 -1
IR: ν: >NH: 3403 cm ; ν:>Ar: 1597 cm
Preparation 2'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-indol
Preparation 2'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-indol
a am miin ne e
The procedure is in accordance with the process of Preparation 5'', replacing the 4-bromo-
1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-1H-indole.
Preparation 3'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-
Preparation 3'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-
pyrrolo[2,3-b]pyridinamine
pyrrolo[2,3-b]pyridinamine
The procedure is in accordance with the process of Preparation 5'', replacing the 4-bromo-
1-methyl-1H-pyrazole used in Step B by 5-bromomethyl-1H-pyrrolo[2,3-b]pyridine
(obtained in accordance with a protocol from the literature: Heterocycles, 60(4), 865,
2003).
-1 -1
IR: ν: -NH-: 3278 cm ; ν: aromatic -C=C- moieties: 1605 cm
P Pr re ep pa ar ra at tiio on n 4 4'''': N N- -( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )p py yr riid diin n- -4 4- -a am miin ne e
The procedure is in accordance with the process of Preparation 5'', replacing the 4-bromo-
1-methyl-1H-pyrazole used in Step B by 4-bromopyridine.
-1 -1 -1
IR: ν -NH-: 3200 and 2500 cm ; ν -Si-O-: 902 cm ; ν -Si-C-: 820 cm
Preparation 5'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-
Preparation 5'': N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methyl-1H-
p py yr ra az zo oll- -4 4- -a am miin ne e
Step A: 4-{[tert-Butyl(dimethyl)silyl]oxy}aniline
The title compound is obtained starting from 4-aminophenol in THF in the presence of
imidazole and tert-butyl(chloro)dimethylsilane in accordance with the protocol described
in the literature (S. Knaggs et al, Organic & Biomolecular Chemistry, 3(21), 4002-4010;
2005).
H NMR: δ (400 MHz; dmso-d6; 300K): 6.45-6.55 (dd, 4H, aromatic Hs); 4.60 (m, 2H,
NH -Ph); 0.90 (s, 9H, Si (CH ) CH(CH ) ); 0.10 (s, 6H, Si (CH ) CH(CH ) )
2 2 2 3 2 2 2 3 2
+ -1
IR: ν: -NH : 3300-3400 cm
Step B: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]methyl-pyrazolamine
To a solution of 30.8 g (0.137 mol) of the compound of Step A in 525 mL of anhydrous
toluene there are successively added 29.8 g of sodium tert-butylate (0.310 mol), 4.55 g of
Pd (dba) (also referred to as tris(dibenzylideneacetone)dipalladium(0)) (4.96 mmol),
4.81 g of 2-di-tert-butylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (9.91 mmol) and
12.8 mL of 4-bromomethyl-1H-pyrazole (0.124 mol). The batch is degassed under
argon for 30 minutes and then refluxed for 3 hours. It is allowed to cool. The reaction
mixture is concentrated to dryness and then taken up in dichloromethane, filtered over
Celite and then concentrated to dryness again. The residue is then purified by
chromatography over silica gel (gradient CH Cl /AcOEt) to provide the expected product
in the form of a solid.
H NMR: δ (400 MHz; dmso-d6; 300K): 7.55 (s, 1H, pyrazole); 7.23 (s, 1H, pyrazole);
7.18 (broad s, 1H, NH -Ph); 6.64 (m, 4H, aromatic Hs); 3.77 (s, 3H, CH -pyrazole); 0.90
(s, 9H, Si (CH ) CH(CH ) ); 0.12 (s, 6H, Si (CH ) CH(CH ) )
2 2 3 2 2 2 3 2
+ -1 -1 -1
IR: ν -NH : 3275 cm ; ν Ar and C=N: 1577 and 1502 cm ; ν -Si-C-: 1236 cm ;
-1 -1
ν -Si-O-: 898 cm ; ν -Si-C-: 828, 774 cm
Preparation 6'': N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}trideuteriomethyl-1H-
pyrazolamine
Step A: 4-Bromotrideuteriomethyl-1H-pyrazole
4-Bromo-1H-pyrazole (9.05 g, 61.6 mmol) is added in portions to a suspension of sodium
hydride (60 % in oil) (2.83 g, 70.8 mmol) in tetrahydrofuran (90 mL) cooled in an ice bath.
After having taken away the ice bath, the solution is stirred at ambient temperature for
0.5 hours. It is again cooled in an ice bath and iodomethane-d (5.0 mL, 80.3 mmol) is
added. The solution is stirred at ambient temperature for 19 hours. The suspension is then
concentrated. The evaporation residue is triturated with tert-butyl methyl ether (90 mL)
and filtered. The filtrate is concentrated in vacuo to obtain the expected compound in the
form of an oil.
H NMR (400 MHz, CDCl ) δ ppm: 7.37 (s, 1 H), 7.43 (s, 1 H)
Step B: N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}trideuteriomethyl-1H-pyrazol
amine
4-Bromotrideuteriomethyl-1H-pyrazole (9.6 g, 58.5 mmol), 4-[(tert-butyldimethyl-
silyl)oxy]aniline (14.4 g, 64.6 mmol) and toluene (150 mL) are added to a 500-ml three-
necked flask. The solution is degassed with nitrogen for 15 minutes, and then sodium tert-
butylate (11.4 g, 0.12 mol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.77 g,
1.81 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.64 g, 1.79 mmol) are
successively added. The suspension is heated at 85°C for 1.5 hours. The reaction mixture is
then cooled to ambient temperature and water (270 mL) is added. The mixture is stirred for
minutes. Celite (30 g) is then added and the suspension is filtered on a bed of Celite.
The phases of the filtrate are separated and the aqueous phase is extracted with ethyl
acetate (3 x 200 mL). The combined organic phases are dried over sodium sulphate and
filtered. The product is purified by chromatography over silica gel (ethyl acetate/heptane
gradient). The product obtained is recrystallized from heptane (80 mL) to obtain the
expected compound.
H NMR (400 MHz, CDCl ) δ ppm: 0.16 (s, 6 H), 0.97 (s, 9 H), 4.92 (s, 1 H), 6.61 – 6.73
(m, 4 H), 7.25 (s, 1 H), 7.36 (s, 1 H)
13 1
C NMR (100 MHz, CDCl ) δ ppm: -4.37, 18.28, 25.86, 38.67 (sept., J = 21.0 Hz),
3 C-D
115.12, 120.73, 123.76, 126.52, 134.74, 141.07, 148.43
MS (ESI): [M+H] 307.08
Preparation 7'': 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-
Preparation 7'': 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-
1 1H H- -p py yr rr ro olle e- -2 2- -c ca ar rb bo on niit tr riille e
Step A: 4-Bromo-1,5-dimethyl-1H-pyrrolecarbonitrile
A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) is added dropwise, with the aid of a
dropping funnel, to a solution of 1,5-dimethyl-1H-pyrrolecarbonitrile (15.0 g, 0.12 mol) in acetic acid
(300 mL). The batch is stirred at ambient temperature for 24 hours. The reaction mixture is then poured into a
beaker containing 300 mL of water. The solid formed is filtered off and rinsed with water. It is then dissolved
in dichloromethane (300 mL) and the organic phase is washed with brine, dried over sodium sulphate,
filtered and concentrated in vacuo to yield the expected product in the form of a solid.
H NMR (CDCl ) δ ppm: 2.25 (s, 3 H), 3.67 (s, 3 H), 6.74 (s, 1 H)
Step B: 4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H-pyrrole
carbonitrile
A solution of the compound of the above Step (1.5 g, 7.53 mmol), 4-[(tert-
butyldimethylsilyl)oxy]aniline (2.02 g, 9.04 mmol), sodium tert-butylate (1.45 g,
.06 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.13 g,
0.30 mmol) in toluene (20 mL) is purged with nitrogen. Tris(dibenzylideneacetone)-
dipalladium(0) (0.28 g, 0.30 mmol) is added, and then the reaction mixture is heated at
90˚C until the reaction is complete (monitored by TLC). Heating is stopped and the
mixture is allowed to return to ambient temperature. Water (75 mL) is added and the
mixture is extracted with ethyl acetate (3 x 75 mL). The combined organic phases are
washed with brine and then concentrated. The crude product is purified by flash
chromatography over silica gel (ethyl acetate/heptane gradient). The product thereby
obtained is dissolved in heptane in the warm state and is allowed to precipitate, with
stirring, at ambient temperature, and then at 0˚C. The solid is filtered off and the operation
is repeated on the filtrate to yield the expected compound in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 0.15 (s, 6 H), 0.97 (s, 9 H), 2.13 (s, 3 H), 3.66 (s,
3 H), 4.68 (br. s, 1 H), 6.49 (d, J = 8.5 Hz, 2 H), 6.64 (s, 1 H), 6.66 (d, J = 8.7 Hz, 2 H)
C NMR (100 MHz, CDCl ) δ ppm: 4.34, 9.72, 18.30, 25.88, 32.94, 101.27, 114.37,
114.70, 116.41, 120.73, 124.52, 131.23, 141.54, 148.27
MS (ESI+): [M+H] measured: 342.3
P Pr re ep pa ar ra at tiio on n 8 8'''': : 4 4- -[ [( (4 4- -{ {[ [tte er rtt- -B Bu ut ty yll( (d diim me et th hy yll) )s siilly yll] ]o ox xy y} }p ph he en ny yll) )a am miin no o] ]- -1 1- -m me et th hy yll- -1 1H H- -
p py yr rr ro olle e- -2 2- -c ca ar rb bo on niit tr riille e
Step A: 1-Methyl-1H-pyrrolecarbonitrile
N,N-Dimethylformamide (3 mL) and 1,4-diazabicyclo[2.2.2]octane (0.49 g, 4.3 mmol) are
added to a solution of pyrrolecarbonitrile (4 g, 43.4 mmol) in dimethyl carbonate
(56 mL). The solution is stirred at 90°C for 15 hours, and is then heated at 110°C for
8 hours. The mixture is cooled to ambient temperature, and then ethyl acetate (80 mL) is
added. The phases are separated and the organic phase is washed with water (2 x 80 mL)
and 1M aqueous hydrochloric acid solution (1 x 80 mL). The combined aqueous phases are
extracted again with ethyl acetate (1 x 80 mL). The combined organic phases are washed
with brine (1 x 80 mL), dried over magnesium sulphate, filtered and concentrated in vacuo
to obtain the expected product in the form of a liquid.
H NMR (400 MHz, CDCl ) δ ppm: 3.78 (m, 2 H), 6.12 - 6.18 (m, 1 H), 6.74 - 6.82 (m,
1 H)
Step B: 4-Bromomethyl-1H-pyrrolecarbonitrile
N-Bromosuccinimide (6.2 g, 34.9 mmol) is added to a solution of 1-methyl-1H-pyrrole
carbonitrile (3.7 g, 34.9 mmol) in N,N-dimethylformamide (150 mL). The solution is
stirred for 15 hours at ambient temperature. Another amount of N-bromosuccinimide
(2.0 g, 11 mmol) is added and the mixture is stirred for 3 hours. The product is purified by
chromatography over silica gel (ethyl acetate/heptane gradient) to obtain the expected
product in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 3.77 (s, 3 H), 6.75 (d, J = 1.7 Hz, 1 H), 6.80 (d, J =
1.7 Hz, 1 H)
Step C: 4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)methyl-1H-pyrrole
carbonitrile
Nitrogen is bubbled through a solution of 4-bromomethyl-1H-pyrrolecarbonitrile
(2.82 g, 15.2 mmol) and 4-[(tert-butyldimethylsilyl)oxy]aniline (4.08 g, 18.3 mmol) in
toluene (55 mL) for 5 minutes. Sodium tert-butylate (2.92 g, 30.4 mmol),
tris(dibenzylideneacetone)dipalladium(0) (556 mg, 0.6 mmol) and 2-di-tert-
butylphosphino-2′,4′,6′-triisopropylbiphenyl (255 mg, 0.6 mmol) are then added to the
reaction mixture. The mixture is stirred for 1 hour at 80 C under nitrogen. The suspension
is then cooled to ambient temperature and filtered over Celite. The Celite cake is then
rinsed with ethyl acetate. The filtrate is washed with water and then with brine. The
organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The
product is purified twice by chromatography over silica gel (AcOEt/heptane gradient), and
then by trituration in heptane to obtain the expected product in the form of a solid.
H NMR (400 MHz, CDCl ) δ ppm: 0.16 (s, 6 H), 0.97 (s, 9 H), 3.73 (s, 3 H), 6.57 (d, J =
1.9 Hz, 1 H), 6.64 - 6.66 (m, 1 H), 6.70 (s, 4 H); NMR
C NMR (100 MHz, CDCl ) δ ppm: -4.48, 18.17, 25.72, 35.46, 103.01, 113.56, 113.69,
115.92, 119.55, 120.67, 129.04, 139.94, 148.85
MS (ESI+): [M+H] 328.25
The amines NHR R wherein R and R , each independently of the other, represent an aryl
3 4 3 4
or heteroaryl group are obtained in accordance with processes described in the literature
(Surry D.S. et al., Chemical Science, 2011, 2, 27-50, Charles M.D. et al., Organic Letters,
2005, 7, 3965-3968). The reaction protecting the hydroxy function of the 4-anilinophenol
described in Preparation 1" can be applied to various secondary amines NHR R (as
defined hereinbefore) having one or more hydroxy functions, when they are available
commercially. Alternatively, the secondary amines having at least one hydroxy substituent
may be synthesised directly in a protected form, i.e. starting from reagents whose hydroxy
function has been protected beforehand. Among the protecting groups, tert-
butyl(dimethyl)silyloxy and benzyloxy are especially preferred.
Among the amines NHR R having a hydroxy substituent that are used for synthesising the
compounds of the invention there may be mentioned: 4-(4-toluidino)phenol, 4-(4-
chloroanilino)phenol, 4-(3-fluoromethylanilino)phenol, 4-[4-(trifluoromethoxy)anilino]-
phenol, 4-[4-hydroxyanilino]phenol, {4-[(1-methyl-1H-indolyl)amino]phenyl}-
methanol, 4-(2,3-dihydro-1H-indolylamino)phenol, 4-[(1-methyl-2,3-dihydro-1H-indol-
6-yl)amino]phenol, 4-[(1-methyl-1H-indolyl)amino]phenol, 4-[(1-methyl-1H-indol
yl)amino]cyclohexanol, 4-[(1-methyl-1,2,3,4-tetrahydroquinolinyl)amino]phenol, 4-[(4-
methyl-3,4-dihydro-2H-1,4-benzoxazinyl)amino]phenol, 4-[4-(diethylamino)anilino]-
phenol, 4-(2,3-dihydro-1H-indenylamino)phenol, 4-[(1-methyl-1H-indazolyl)amino]-
phenol, 4-[(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-5'-yl)amino]phenol, 4-
[(1,3,3-trimethyl-2,3-dihydro-1H-indolyl)amino]phenol, 4-[4-methoxy(trifluoro-
methyl)anilino]phenol, 4-[4-(methylsulphanyl)(trifluoromethyl)anilino]phenol, 2-
fluoro[(1-methyl-1H-indolyl)amino]phenol, 4-[(1-ethyl-1H-indolyl)amino]phenol,
4-[(1-ethyl-2,3-dihydro-1H-indolyl)amino]phenol, 4-[(1-isopropyl-2,3-dihydro-1H-
indolyl)amino]phenol, 4-(butylamino)phenol, 3-[(1-methyl-1H-indolyl)amino]
propanol, 4-[(1-methyl-1H-indolyl)amino]butanol, 4-[(3-fluoromethylphenyl)-
amino]phenol, 4-[(3-chloromethylphenyl)amino]phenol, 4-[(4-fluorophenyl)amino]-
phenol, 4-[(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]phenol, 4-[(4-fluorophenyl)-
amino]phenol, 4-[(2-fluorophenyl)amino]phenol, 4-[(3-fluorophenyl)amino]phenol, 4-
[(2,4-difluorophenyl)amino]phenol, 4-[(3,4-difluorophenyl)amino]phenol, 3-[(4-hydroxy-
phenyl)amino]benzonitrile, 4-[(3-methoxyphenyl)amino]phenol, 4-[(3,5-difluorophenyl)-
amino]phenol, 4-[(3-methylphenyl)amino]phenol, 4-[(4-hydroxyphenyl)amino]benzo-
nitrile, 4-[(3-chlorophenyl)amino]phenol, 4-(pyrimidinylamino)phenol, 4-[(cyclobutyl-
methyl)amino]phenol, 2-[(4-hydroxyphenyl)amino]benzonitrile, 4-{[(1-methyl-1H-
pyrazolyl)methyl]amino}phenol, 4-[(cyclopropylmethyl)amino]phenol, 4-{[(1-methyl-
1H-pyrazolyl)methyl]amino}phenol, 4-(butynylamino)phenol, 4-(pyrazinyl-
amino)phenol, 4-(pyridinylamino)phenol, 4-(pyridazinylamino)phenol, 4-(pyrimidin-
-ylamino)phenol, 4-(pyridinylamino)phenol, 4-[(3,5-difluoromethoxyphenyl)-
amino]phenol, 4-(pyridinylamino)phenol, 4-[(3-fluoromethoxyphenyl)amino]phenol,
2-(phenylamino)pyrimidinol, 5-[(4-hydroxyphenyl)amino]methoxybenzonitrile and
4-{[3-(trifluoromethyl)phenyl]amino}phenol.
The hydroxy function(s) of the secondary amines listed above is (are) protected beforehand
by a suitable protecting group prior to any coupling to an acid derivative of the compound
of formula (VII) as defined in the preceding general process.
Example 1. 4-[{[3-(6-{[(3S)(Morpholinylmethyl)-3,4-dihydroisoquinolin-
Example 1.
2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizin
yl]carbonyl}(phenyl)amino]phenyl disodium phosphate
Step A: Methyl 3-{6-[((3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-
carbonyl]-1,3-benzodioxolyl}-5,6,7,8-tetrahydroindolizine-carboxylate
To a solution of 2 g of the compound of Preparation 1 (5.83 mmol) in 20 mL of
dichloromethane there are added, at ambient temperature, 5.5 mL of N,N,N-triethylamine
(6.96 mmol), 2.12 g of the compound of Preparation 1' (6.96 mmol), and then 0.94 g of
hydroxybenzotriazole (HOBT) and 1.34 g of 1-ethyl(3'-dimethylaminopropyl)-
carbodiimide (EDC) (6.96 mmol). The reaction mixture is then stirred at ambient
temperature overnight and then it is poured into saturated aqueous ammonium chloride
solution and extracted with ethyl acetate. The organic phase is then dried over magnesium
sulphate and then filtered and evaporated to dryness. The crude product thereby obtained is
then purified by chromatography over silica gel (heptane/AcOEt gradient). The title
product is obtained in the form of an oil.
H NMR: δ (500 MHz; dmso-d6; 300°K): 7.2-6.9 (m, 4H, aromatic Hs); 7.04-7.03-7.00 (m, 1H, aromatic
H); 6.85 (m, 1H, aromatic H); 6.35-6.26-6.06 (m, 1H, H tetrahydroindolizine); 6.15-6.12 (m, 2H, H
methylenedioxy); 5.06-4.84 (m, 1H, H dihydroisoquinoline); 4.86-4.17 (m, 2H, H dihydroisoquinoline);
3.65-3.6-3.55 (m, 3H, H methyl ester); 3.43-4.26 (m, 2H, H tetrahydroindolizine); 3.58-3.5 (m, 4H, H
morpholine); 2.37-3.05 (m, 4H, 2H dihydroisoquinoline, 2H tetrahydroindolizine); 1.68-2.56 (m, 4H, H
morpholine); 1.4-2.0 (m, 4H, H tetrahydroindolizine)
-1 -1 -1
IR: ν: >C=O 1695 cm ester; ν: >C=O 1625 cm amide; ν: >C-O-C< 12141115 cm ; >CH-Ar 772-
744 cm
Step B: Lithium 3-[6-[(3S)(morpholinomethyl)-3,4-dihydro-1H-isoquinoline
carbonyl]-1,3-benzodioxolyl]-5,6,7,8-tetrahydroindolizine-carboxylate
To a solution of 4.6 g of the compound of Step A (8.26 mmol) in 24 mL of dioxane there is
added a solution of lithium hydroxide (675 mg, 16.1 mmol). The batch is placed in a
microwave oven at 140W, 100°C for a period of 2 hours 30 minutes. The reaction mixture
is then filtered and evaporated. The solid thereby obtained is dried at 40°C in an oven in
the presence of P O .
H NMR: δ (400 MHz; dmso-d6; 353°K): 6.7-7.15 (unresolved peak, 6H, aromatic Hs);
6.21 (s, 1H, aromatic H); 6.03 (s, 2H, H methylenedioxy); 4.0-5.0 (unresolved peak, 3H
dihydroisoquinoline); 3.4-3.6 (unresolved peak, 3H tetrahydroindolizine, 3H morpholine);
2.5-3.1 (unresolved peak, 4H, 2H tetrahydroindolizine, 2H morpholine); 1.5-2.4
(unresolved peak, 10H morpholine)
-1 -1
IR : ν :>C=O broad 1567 cm acetate ; ν : 1236 cm
Step C: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl){6-[((3S)(4-morpholinyl-
methyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-
,6,7,8-tetrahydroindolizine carboxamide
To a solution of 2.6 g of the compound of Step B (4.73 mmol) in 47 mL of dichloromethane there are added,
dropwise, 1.2 mL of oxalyl chloride (14.2 mmol) at 0°C. The reaction mixture is stirred at ambient
temperature for 11 hours and then co-evaporated several times with dichloromethane. The product thereby
obtained is suspended in 37 mL of dichloromethane, and is then added to a solution of 2.1 g of the compound
obtained in Preparation 1'' (7.1 mmol) in 10 mL of dichloromethane in the presence of 0.6 mL of pyridine
(7.1 mmol). The batch is stirred at ambient temperature overnight.
The reaction mixture is concentrated and purified by chromatography over silica gel
(dichloromethane/methanol gradient). The title product is obtained in the form of a foam.
H NMR: δ (500MHz; dmso-d6; 300°K): 6.9-7.3 (9H, aromatic Hs); 6.88 (2H, aromatic Hs); 6.72-6.87 (2H,
aromatic Hs); 6.64 (2H, aromatic Hs); 6.13 (2H methylenedioxy); 5.05-4.74 (1H dihydroisoquinoline); 4.25-
4.13 (2H dihydroisoquinoline); 3.44-3.7 (4H morpholine); 3.62-3.52 (2H tetrahydroindolizine); 3.0-2.6 (4H,
2H tetrahydroindolizine, 2H dihydroisoquinoline); 2.54-1.94 (6H morpholine); 1.91-1.53 (4H
tetrahydroindolizine); 0.92 (9H tert-butyl); 0.17 (6H dimethyl)
-1 -1 -1 -1
IR: ν:>C=O: 1632 cm ; ν: >C-O-C< : 1237 cm ; ν: -Si-O-C-: 1035 cm ; -Si-C-: 910 cm ; >CH-Ar: 806
Step D: N-(4-Hydroxyphenyl){6-[((3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-
isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-5,6,7,8-tetrahydroindolizine
carboxamide hydrochloride
To a solution of 1.9 g of the compound obtained in Step C (2.3 mmol) in 4 mL of methanol there is added
0.646 g (11.5 mmol) of potassium hydroxide dissolved in 8 mL of methanol. The batch is stirred at ambient
temperature for 30 minutes. The reaction mixture is then diluted with dichloromethane and washed
successively with 1M HCl solution, saturated aqueous NaHCO solution and then brine until a neutral pH is
reached. The organic phase is then dried over magnesium sulphate, filtered and evaporated. The crude
product thereby obtained is purified by chromatography over silica gel (dichloromethane/methanol gradient).
The solid is then dissolved in dichloromethane, and 2 mL of 1M ethereal HCl are added. The batch is stirred
for 1 hour and then evaporated to dryness. The hydrochloride thereby obtained is dissolved in a mixture of
water/acetonitrile until dissolution is complete, and is then lyophilised.
Elemental microanalysis: (%, theoretical:measured)
%C=69.11:68.95; %H=5.8:5.46; %N=7.5:7.51; %Cl-=4.74:4.48
Optical rotation: (α) = + 50.8° (c = 9 mg/mL, MeOH)
Step E: 4-[{[3-(6-{[(3S)(Morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-
carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)-
amino]phenyl dibenzyl phosphate
To a suspension of 82 mg of sodium hydride (2.06 mmol) in 10 mL of anhydrous THF
there are added, in portions and at 0°C, 700 mg of the compound of Step D. After stirring
for 30 minutes at 0°C and for 30 minutes at ambient temperature, tetrabenzyl
pyrophosphate is added at 0°C and the reaction mixture is stirred overnight at ambient
temperature. After evaporating off the solvent, the crude reaction product is diluted with
dichloromethane (30 mL), washed with saturated aqueous NaHCO solution and then with
brine. The organic phase is then dried over MgSO , filtered, concentrated to dryness and
purified by chromatography over silica gel (gradient CH Cl /MeOH). The title product is
then obtained in the form of a solid.
H NMR: δ (500 MHz; DMSO-d6; 300K): 7.34 (m, 10H, phenyl); 7.30-6.71 (m, 15H,
aryl); 6.06 (s, 1H, methylenedioxy); 5.30-4.97 (m, 1H, pyrrole); 5.11 (m, 4H, benzyl):
.03-3.64 (m, 1H, tertiary C THIQ); 4.91-4.09 (m, 2H, secondary C THIQ); 3.99-3.48 (m,
2H, secondary C THIQ); 3.54-3.44 (m, 4H, morpholine); 2.89-2.65 (m, 3H, secondary C
THIQ); 2.51-1.87 (m, 4H, secondary C THID); 2.36-1.85 (m, 2H, secondary C THIQ);
1.91-1.45 (m, 4H, secondary C THID)
Step F: 4-[{[3-(6-{[(3S)(Morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-
carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)-
amino]phenyl disodium phosphate
50 mg of Pd(OH) are added to a solution of the product obtained in Step E (505 mg;
0.52 mmol) in methanol (10 mL), and then the reaction mixture is placed under a hydrogen
atmosphere (1 bar) for 5 hours. After filtering off the catalyst and concentrating to dryness,
the crude reaction product is dissolved in methanol (5 mL) and treated with 0.95 mL of 1M
sodium hydroxide solution. The solvents are then evaporated off and the crude reaction
product is purified by chromatography over an OASIS® phase (acetonitrile/H O gradient)
to obtain a white solid.
Elemental microanalysis:
%C %H %N %Na
Calculated 61.87 4.95 6.71 5.51
Found 61.45 4.46 6.61 5.38
-1 -1 -1 -1 -1
IR: ν: -C=O: 1628 cm ; ν: C-O-C: 1234 cm ; ν: P=O: 115 cm ; ν: P-O: 985 cm ; ν: CH-Ar: 876 cm
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N Na O P
43 41 4 2 9
[M+H]+ calculated: 835.2479
[M+H]+ measured: 835.2467
Example 2. 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-
Example 2.
1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)amino]-
phenyl disodium phosphate
Step A: N-(4-Hydroxyphenyl)(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}-1,3-benzodioxolyl)-N-phenyl-5,6,7,8-tetrahydroindolizinecarboxamide
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing the product of Preparation 1' in Step A by that of Preparation 2', it
being understood that the product thereby obtained is not subjected to a step of conversion
into salt form in the presence of HCl in ether.
Elemental microanalysis: (%, theoretical:measured)
%C=74.86:74.88; %H=5.64:5.31; %N=6.72:6.78
Step B : 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-
benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)amino]phenyl
disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps E
and F of Example 1.
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N O P
39 36 3 8
[M+H] calculated: 706.2313
[M+H]+ measured: 706.2324
E Ex xa am mp plle e 3 3.. 4-[(1-Methyl-1H-indolyl){[3-(2-{[(3S)(morpholinylmethyl)-3,4-
dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizinyl]-
carbonyl}amino]phenyl disodium phosphate
Step A: 3-{5-Chloro[((3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-
carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indolyl)-5,6,7,8-tetrahydro
indolizine carboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 2 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 2''.
Elemental microanalysis:
%C %H %N %Cl
Calculated 68.04 5.72 8.82 4.91
Found 67.84 5.46 8.64 5.21
Optical rotation: (α) = + 55.9° (c = 7 mg/mL, MeOH)
Step B : 4-[(1-Methyl-1H-indolyl){[3-(2-{[(3S)(morpholinylmethyl)-3,4-
dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizinyl]-
carbonyl}amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps E
and F of Example 1.
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N Na O P
45 44 5 2 7
[M-2Na+3H] calculated: 800.3208
[M-2Na+3H]+ measured: 800.3211
E Ex xa am mp plle e 4 4.. 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-
1,3-benzodioxolyl)indolizinyl]carbonyl}(1-methyl-1H-pyrrolo[2,3-b]pyridin
yl)amino]phenyl disodium phosphate
Step A: N-(4-Hydroxyphenyl)(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}-1,3-benzodioxolyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-
indolizinecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compounds of Preparations 1 and 1' used in
Step A by the compounds of Preparations 3 and 2' and, on the other hand, the compound of
Preparation 1'' used in Step C by that of Preparation 3''.
Elemental microanalysis: (%, theoretical:measured)
%C=69.14:70.09; %H=4.81:4.55; %N=9.83:10.09; %Cl-=4.98:3.26
Step B: 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-
benzodioxolyl)indolizinyl]carbonyl}(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-
amino]phenyl diethyl phosphate
To a suspension of the compound obtained in Step A (1.5 mmol) in 10 mL of anhydrous
CH Cl there are added triethylamine (0.42 mL; 3 mmol), and then diethyl
cyanophosphonate (0.24 mL; 1.65 mmol) dropwise at ambient temperature. After stirring
overnight at ambient temperature, the reaction mixture is diluted with CH Cl , washed with
saturated aqueous NaHCO solution and then with brine. The organic phase is then dried
over MgSO , filtered, concentrated to dryness and purified by chromatography over silica
gel (CH Cl /MeOH gradient). The title product is then obtained in the form of a solid.
Step C: 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzo-
dioxolyl)indolizinyl]carbonyl}(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]-
phenyl disodium phosphate
0.4 mL of trimethylsilyl bromide (3 mmol) is added dropwise at ambient temperature to a
solution of the product obtained in Step B (0.78 mmol) in CH Cl (12 mL). The reaction
mixture is stirred for 5 hours, and then a solution of Na CO (580 mg) in water (4 mL) is
slowly added at 0°C. After stirring for 30 minutes, the reaction mixture is concentrated to
dryness, diluted with anhydrous methanol (25 mL) and microfiltered. The filtrate is dried
and purified by chromatography over an OASIS® phase (acetonitrile/H O gradient).
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N Na O P
45 44 5 2 7
[M-2Na+3H] calculated: 800.3211
[M-2Na+3H]+ measured: 800.3201
E Ex xa am mp plle e 5 5.. 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-
1,3-benzodioxolyl)indolizinyl]carbonyl}(pyridinyl)amino]phenyl disodium
phosphate
Step A: N-(4-Hydroxyphenyl)(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]-
carbonyl}-1,3-benzodioxolyl)-N-(pyridinyl)indolizinecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compounds of Preparations 1 and 1' used in
Step A by the compounds of Preparations 3 and 2' and, on the other hand, the compound of
Preparation 1'' used in Step C by that of Preparation 4''.
Elemental microanalysis: (%, theoretical:measured)
%C=69.24:69.12; %H=4.74:4.23; %N=8.5:8.45; %Cl-=5.38:5.2
Step B: 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzo-
dioxolyl)indolizinyl]carbonyl}(pyridinyl)amino]phenyl diethyl phosphate
To a suspension of 950 mg of the compound obtained in Step A (1.5 mmol) in 10 mL of
anhydrous CH Cl there are added triethylamine (0.42 mL; 3 mmol), and then diethyl
cyanophosphonate (0.24 mL; 1,65 mmol) dropwise at ambient temperature. After stirring
overnight at ambient temperature, the reaction mixture is diluted with CH Cl , washed with
saturated aqueous NaHCO solution and then with brine. The organic phase is then dried
over MgSO , filtered, concentrated to dryness and purified by chromatography over silica
gel (CH Cl /MeOH gradient). The title product is then obtained in the form of a solid.
H NMR: δ (500 MHz; DMSO-d6; 300K): 8.5-8. 0 (m, 5H); 7.2-7.1 (m, 1H); 6.85-6.65
(m, 1H); 7.3-6.8 (m, 10H); 6.25-6.10 (bs, 1H); 6.2 (bs, 2H); 5.1-3.7 (6d, 2H); 4.7-3.8
(m,1H); 4.15 (m, 4H); 3.0-1.7 (m,2H); 1.25 (m, 6H); 0.85-0.24 (m,3H)
Step C: 4-[{[3-(6-{[(3R)Methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzo-
dioxolyl)indolizinyl]carbonyl}(pyridinyl)amino]phenyl disodium phosphate
0.4 mL of trimethylsilyl bromide (3 mmol) is added dropwise at ambient temperature to a
solution of the product obtained in Step B (591 mg; 0.78 mmol) in CH Cl (12 mL). The
reaction mixture is stirred for 5 hours, and then a solution of Na CO (580 mg) in water
(4 mL) is slowly added at 0°C. After stirring for 30 minutes, the reaction mixture is
concentrated to dryness, diluted with anhydrous methanol (25 mL) and microfiltered. The
filtrate is dried and purified by chromatography over an OASIS® phase (acetonitrile/H O
gradient).
H NMR: δ (500 MHz; D O; 300K): 8.23-7.98 (m, 2H, pyridyl); 7.01-6.97 (m, 2H,
pyridyl); 7.88-7.80 (m, 1H, indolizine); 7.18-6.57 (m, 13H, aromatic Hs
THIQ+aryl+indolizine+phenol); 6.17-6.15 (m, 1H, indolizine): 5.96 (m, 2H,
methylenedioxy); 4.61-3.76 (m, 1H, ternary C THIQ); 4.16 (m, 2H, secondary C THIQ);
2.86-2.31 (m, 2H, secondary C THIQ); 0.94-0.76 (m, 3H, primary C THIQ)
-1 -1 -1 -1 -1
IR: ν: -C=O: 1620 cm ; ν: C-O-C: 1218 cm ; ν: P=O: 1107 cm ν: P-O: 981 cm ν: CH-Ar: 881-741 cm
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N Na O P
38 29 4 2 8
[M-2Na+3H] calculated: 703.1952
[M-2Na+3H]+ measured: 703.1951
Example 6. 4-[{[3-(6-{[(3S)(Morpholinylmethyl)-3,4-dihydroisoquinolin-
Example 6.
2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizin
yl]carbonyl}(phenyl) amino]phenyl dibenzyl phosphate
The procedure is in accordance with the protocol described in Steps A-E of Example 1.
H NMR: δ (500 MHz; DMSO-d6; 300K): 7.34 (m, 10H, phenyl); 7.30-6.71 (m, 15H,
aryl); 6.06 (s, 1H, methylenedioxy); 5.30-4.97 (m, 1H, pyrrole); 5.11 (m, 4H, benzyl):
.03-3.64 (m, 1H, tertiary C THIQ); 4.91-4.09 (m, 2H, secondary C THIQ); 3.99-3.48 (m,
2H, secondary C THIQ); 3.54-3.44 (m, 4H, morpholine); 2.89-2.65 (m, 3H, secondary C
THIQ); 2.51-1.87 (m, 4H, secondary C THID); 2.36-1.85 (m, 2H, secondary C THIQ);
1.91-1.45 (m, 4H, secondary C THID)
Example 7. Diethyl 4-[{[3-(6-{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]-
Example 7.
carbonyl}-1,3-benzodioxolyl)indolizinyl]carbonyl}(pyridinyl)amino]phenyl
phosphate
The procedure is in accordance with the protocol described in Steps A and B of Example 5.
H NMR: δ (500 MHz; DMSO-d6; 300K): 8.5-8. 0 (m, 5H); 7.2-7.1 (m, 1H); 6.85-6.65
(m, 1H); 7.3-6.8 (m, 10H); 6.25-6.10 (bs, 1H); 6.2 (bs, 2H); 5.1-3.7 (6d, 2H); 4.7-3.8 (m,
1H); 4.15 (m, 4H); 3.0-1.7 (m,2H); 1.25 (m, 6H); 0.85-0.24 (m, 3H)
E Ex xa am mp plle e 8 8.. 4-[{[3-(6-{[(3S)(Morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}-
(phenyl)amino]phenyl dihydrogen phosphate hydrochloride
100 mg of Pd(OH) are added to a solution of the product obtained in Step E of Example 1
(500 mg; 0.51 mmol) in methanol (10 mL), and then the reaction mixture is placed under a
hydrogen atmosphere (1 bar) for 5 hours. After filtering off the catalyst and concentrating
to dryness, the crude reaction product is immediately purified by chromatography over a
C18 phase (acetonitrile/H O +0.2% HCl gradient) to obtain a solid.
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N O P
43 43 4 9
[M+H] calculated: 791.2846
[M+H] measured: 791.2852
E Ex xa am mp plle e 9 9.. 4-[{[5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]-
carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(pyridinyl)amino]phenyl
disodium phosphate
Step A: 5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-
phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H-pyrrolecarboxamide
hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compounds of Preparations 1 and 1' used in
Step A by the compounds of Preparations 4 and 2' and, on the other hand, the compound of
Preparation 1'' used in Step C by that of Preparation 4''.
Elemental microanalysis: (%, theoretical:measured)
%C=66.99:66.88; %H=5.14:5.28; %N=8.93:8.87; %Cl-=5.65:4.98
High-resolution mass spectrometry (ESI+):
Empirical formula: C H ClN O
32 4 3
[M+H] calculated: 591.2157
[M+H] measured: 591.2178
Step B: 4-[{[5-(5-Chloro{[(3R)methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-
phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(pyridinyl)amino]phenyl disodium
phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 4.
E Ex xa am mp plle e 1 10 0.. 4-[{[1,2-Dimethyl(6-{[(3S)(morpholinylmethyl)-3,4-dihydroiso-
quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolyl]carbonyl}(1-
methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]phenyl disodium phosphate
Step A: N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-
5-(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-
benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 5 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 3''.
Elemental microanalysis : (%, measured(theoretical))
%C=66.41(66.62);%H=5.08(5.59);%N=10.85(10.84);%Cl-=4.68(4.57)
Step B: 4-[{[1,2-Dimethyl(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolyl]carbonyl}(1-methyl-1H-
pyrrolo[2,3-b]pyridinyl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 4.
Example 11. 4-[{[1,2-Dimethyl(6-{[(3S)(morpholinylmethyl)-3,4-
Example 11.
dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrol
yl]carbonyl}(1-methyl-1H-pyrazolyl)amino]phenyl disodium phosphate
Step A: N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(6-{[(3S)
(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol
yl)-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 5 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 5''.
Elemental microanalysis : (%, measured(theoretical))
%C=64.25(64.59);%H=5.4(5.7);%N=11.41(11.59);%Cl-=4.93(4.89)
Step B: 4-[{[1,2-Dimethyl(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolyl]carbonyl}(1-methyl-1H-
pyrazolyl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps E
and F of Example 1.
IR (cm ): ν: C=O: 1628; ν: (phosphate; ether): 1238, 1143,1113, 985; γ: >CH Ar: 740
Elemental microanalysis:
%C %H %N
Calculated 57.64 4.84 10.34
Found 56.62 4.54 10.14
High-resolution mass spectrometry (ESI+-/FIA/HR):
Empirical formula: C H ClN Na O P
39 39 6 2 9
[M-Na+H] calculated: 791.2565
[M-Na+H] measured: 791.2564
E Ex xa am mp plle e 1 12 2.. 4-[{[1,2-Dimethyl(6-{[(3R)[3-(morpholinyl)propyl]-3,4-dihydro-
isoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolyl]carbonyl}(1-
methyl-1H-pyrrolo[2,3-b]pyridinyl)amino]phenyl disodium phosphate
Step A: N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridinyl)-
-(6-{[(3R)[3-(morpholinyl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-
benzodioxolyl)-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compounds of Preparations 1 and 1' used in
Step A by the compounds of Preparations 5 and 3' and, on the other hand, the compound of
Preparation 1'' used in Step C by that of Preparation 3''.
Elemental microanalysis: (%, measured(theoretical))
%C=67.63(68.06);%H=5.27(5.95);%N=10.08(10.13);%Cl-=4.53(4.27)
High-resolution mass spectrometry (ESI+):
Empirical formula: C H ClN O
32 4 3
[M+H] calculated: 793.3708
[M+H] measured: 793.3704
Step B: 4-[{[1,2-Dimethyl(6-{[(3R)[3-(morpholinyl)propyl]-3,4-dihydroiso-
quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-1H-pyrrolyl]carbonyl}(1-methyl-
1H-pyrrolo[2,3-b]pyridinyl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps E
and F of Example 1.
Unless otherwise mentioned, the compounds of the following Examples are
synthesised in accordance with the process of Example 1 using: (i) the appropriate
acid obtained according to one of Preparations 1 to 9 and (ii) the appropriate
tetrahydroisoquinoline compound obtained according to one of Preparations 1' to 4'
and, in Step C: (iii) the suitable NHR R amine (a non-exhaustive list is proposed in
Preparations 1'' to 8'').
Example 13. 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroiso-
Example 13. 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroiso-
q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll] ]c ca ar rb bo on ny yll} }( (p py yr riid diin n- -
4 4- -y yll) )a am miin no o] ]p ph he en ny yll d diis so od diiu um m p ph ho os sp ph ha at te e
Step A: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridinyl)-1H-pyrrole
carboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 4 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 4''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of 1M HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
High-resolution mass spectrometry (ESI+):
Empirical formula: C H ClN O
39 38 5 4
[M+H] calculated: 676.2685
[M+H] measured: 676.2684
Step B : 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(pyridinyl)amino]-
phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (500 MHz, D O) δ ppm: -0.05
IR (cm ): ν: C=O: 1631; ν: (phosphate; ether): 1243, 1136, 1112, 982; γ: >CH Ar: 883,
Elemental microanalysis:
%C %H %N
Calculated 58.54 4.66 8.75
Found 58.23 4.51 8.76
High-resolution mass spectrometry (ESI+):
Empirical formula: C H ClN Na O P
39 37 5 2 7
[M-Na+2H] calculated: 778.2168
[M-Na+2H] measured: 778.2169
E Ex xa am mp plle e 1 14 4.. 4 4- -[ [{ {[ [5 5- -( (5 5- -F Fllu uo or ro o- -4 4- -m me et th ho ox xy y- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -
dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]-
dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]-
c ca ar rb bo on ny yll} }( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )a am miin no o] ]p ph he en ny yll d diis so od diiu um m p ph ho os sp ph ha at te e
E Ex xa am mp plle e 1 15 5.. 4 4- -[ [{ {[ [5 5- -( (5 5- -F Fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so o- -
q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll] ]c ca ar rb bo on ny yll} }( (1 1- -m me et th hy yll- -
1H-pyrazolyl)amino]phenyl disodium phosphate
1H-pyrazolyl)amino]phenyl disodium phosphate
Step A: 5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-
1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 7 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 5''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, measured (theoretical))
%C=65.69(65.28);%H=5.38(5.77);%N=11.18(12.02);%Cl-=5.61(5.07)
Step B: 4-[{[5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(1-methyl-1H-pyrazol-
4-yl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (400/500 MHz, CD OD) δ ppm: -0.5
IR (cm ): ν: C=O: 1628; ν: (phosphate; ether): 1238, 1114, 983
Elemental microanalysis:
%C %H %N
Calculated 58.02 4.87 10.68
Found 59.03 4.98 10.14
High-resolution mass spectrometry (ESI+):
Empirical formula: C H FN Na O P
38 38 6 2 7
[M-2Na+3H] calculated: 743.2752
[M-2Na+3H] measured: 743.2760
Example 16. 4-[{[1,2-Dimethyl(7-{[(3S)(morpholinylmethyl)-3,4-
Example 16. 4-[{[1,2-Dimethyl(7-{[(3S)(morpholinylmethyl)-3,4-
dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxinyl)-1H-pyrrol-
dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxinyl)-1H-pyrrol-
3 3- -y yll] ]c ca ar rb bo on ny yll} }( (1 1- -m me et th hy yll- -1 1H H- -p py yr ra az zo oll- -4 4- -y yll) )a am miin no o] ]p ph he en ny yll d diis so od diiu um m p ph ho os sp ph ha at te e
Step A: N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)(7-{[(3S)
(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-
benzodioxinyl)-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 8 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 5''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of 1M HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured)
%C=64.99:64.67; %H=5.86:5.67; %N=11.37:11.27; %Cl-=4.8:4.71
High-resolution mass spectrometry (ESI+) :
Empirical formula: C H N O
40 43 6 6
[M+H] calculated: 703.3236
[M+H] measured: 703.3239
Step B: 4-[{[1,2-Dimethyl(7-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxinyl)-1H-pyrrolyl]carbonyl}(1-
methyl-1H-pyrazolyl)amino]phenyl N,N,N',N'-tetramethylphosphorodiamidate
To a solution of 125 mg of the compound of Step A (0.18 mmol) in dichloromethane
(6 mL) there are added 55 µL of diazabicyclo[5.4.0]undecene (DBU; 0,36 mmol), and
then 33 µL of bisdimethylaminophosphoryl chloride (0.19 mmol) and 2 mg of
dimethylaminopyridine (0.02 mmol). The reaction mixture is stirred for 15 hours,
diluted with dichloromethane and then with saturated aqueous sodium carbonate solution.
The aqueous phase is extracted with dichloromethane; the organic phases are then
combined, washed with water and with brine and dried over magnesium sulphate. After
evaporating off the solvents, the crude reaction product is used directly in the next Step.
Step C: 4-[{[1,2-Dimethyl(7-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxinyl)-1H-pyrrolyl]carbonyl}(1-
methyl-1H-pyrazolyl)amino]phenyl disodium phosphate
4 mL of trifluoroacetic acid are added dropwise to a solution of 125 mg of the compound
of Step B (0.15 mmol) in a 1:1 mixture of acetonitrile and water (5 mL). After stirring for
hours at ambient temperature, the reaction mixture is evaporated to dryness, keeping the
temperature of the water bath below 40°C, and then the residue is treated with a solution of
sodium carbonate (95 mg; 0.9 mmol) in water (4 mL). After stirring for 2 hours at ambient
temperature, the reaction mixture is evaporated to dryness and then 6 mL of anhydrous
ethanol are added. The solid is filtered off, and the filtrate is concentrated to dryness, and
then purified over an OASIS® phase (acetonitrile/water gradient).
P NMR (500 MHz, D O) δ ppm: 0.9
IR (cm ): ν: C=O: 1623; ν: (phosphate; ether): 1235, 1162,1115, 1065, 985; γ: >CH
Ar:745
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N Na O P
40 41 6 2 9
[M-2Na+3H] calculated: 783.2902
[M-2Na+3H] measured: 783.2907
Example 17. 5-[{[5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-
Example 17. 5-[{[5-(5-Fluoro{[(3S)(morpholinylmethyl)-3,4-
d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -
yl]carbonyl}(pyridinyl)amino]pyrimidinyl disodium phosphate
yl]carbonyl}(pyridinyl)amino]pyrimidinyl disodium phosphate
E Ex xa am mp plle e 1 18 8.. 5 5- -[ [{ {[ [5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -
d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -
yl]carbonyl}(pyridinyl)amino]pyrimidinyl disodium phosphate
yl]carbonyl}(pyridinyl)amino]pyrimidinyl disodium phosphate
E Ex xa am mp plle e 1 19 9.. 4 4- -( ({ {[ [5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so o- -
quinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}[1-
quinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}[1-
(trideuteriomethyl)-1H-pyrazolyl]amino)phenyl disodium phosphate
(trideuteriomethyl)-1H-pyrazolyl]amino)phenyl disodium phosphate
Step A: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-1H-
pyrazolyl]-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 4 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 6''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of 1M HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured)
%C=63.51:63.41; %H=5.63:5.42; %N=11.69:11.61; %Cl =4.93:4.85
High-resolution mass spectrometry (ESI+-/FIA/HR, ESI-/FIA):
Empirical formula: C H Cl D N O
38 36 3 6 4
[M+H] calculated: 682.2982
[M+H] measured: 682.2986
Step B: 4-({[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}[1-(trideuteriomethyl)-
1H-pyrazolyl]amino)phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (500 MHz, D O) δ ppm: 4.8
IR (cm ): ν: C=O: 1626; ν: (phosphate; ether): 1243, 1141,1115, 982; γ: >CH Ar :880,
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):
Empirical formula: C H Cl D N Na O P
38 35 3 6 2 7
[M+H] calculated: 806.2285
[M+H] measured: 806.2280
Example 20. 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroiso-
Example 20. 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroiso-
q qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll] ]c ca ar rb bo on ny yll} }( (5 5- -c cy ya an no o- -
1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )a am miin no o] ]p ph he en ny yll d diis so od diiu um m p ph ho os sp ph ha at te e
Step A: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-
dimethyl-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 4 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 7''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of 1M HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
H NMR (500 MHz, dmso-d6) δ ppm: 11.2 (bs, 1H), 9.39 (bs,1H), 7.83 (d, 1 H), 7.54 (d,
1 H), 7.33 (s, 1 H), 7.14 (m, 2 H), 7 (m, 2 H), 6.8 (d, 2 H), 6.62 (d, 2 H), 6.57 (bs, 1 H),
.26 (s, 1 H), 5.26 (m, 1 H), 4.64/4.03 (AB, 2 H), 4.01/3.92 (2m, 4 H), 3.75/3.43/3.15/3.02
(4m, 4 H), 3.59 (s, 3 H), 3.3/3.15 (2m, 2 H), 2.97 (s, 3 H), 2.69/2.52 (dd+d, 2 H), 2.06 (s,
3 H), 1.91 (s, 3 H)
Elemental microanalysis: (%, theoretical:measured)
%C=65.34:65.50; %H=5.62:5.15; %N=11.15:10.84 %Cl-=4.70:4.44
High-resolution mass spectrometry (ESI+):
Empirical formula: C H Cl N O
41 41 6 4
[M+H] calculated: 717.2952
[M+H] measured: 717.2951
Step B: 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(5-cyano-1,2-dimethyl-
1H-pyrrolyl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (500 MHz, dmso-d6) δ ppm: 3.7
-1 -1
IR (cm ): ν: -CN: 2210 cm ; ν: C=O: 1623; ν: (phosphate; ether): 1227, 1133, 1110, 982;
γ: >CH Ar:884-741
Elemental microanalysis:
%C %H %N
Calculated 58.54 4.79 9.99
Found 58.75 4.71 10.18
High-resolution mass spectrometry (ESI+-/FIA/HR):
Empirical formula: C H Cl N Na O P
41 40 6 2 7
[M-2Na+H] calculated: 797.2614
[M-2Na+H] measured: 797.2618
E Ex xa am mp plle e 2 21 1.. 4 4- -[ [{ {[ [5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -
d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -
yl]carbonyl}(5-cyanomethyl-1H-pyrrolyl)amino]phenyl disodium phosphate
yl]carbonyl}(5-cyanomethyl-1H-pyrrolyl)amino]phenyl disodium phosphate
Step A: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-N-(5-cyanomethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-
dimethyl-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 4 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 8''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of 1M HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured)
%C=64.95:65.09; %H=5.45:5.20; %N=11.36:11.26; %Cl-=4.79:4.62
High-resolution mass spectrometry (ESI/+):
Empirical formula: C H Cl N O
40 39 6 4
[M+H] calculated: 703.2794
[M+H] measured: 703.2789
Step B : 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(5-cyanomethyl-1H-
pyrrolyl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (500 MHz, dmso-d6) δ ppm: 4.5
-1 -1
IR (cm ): ν: -CN: 2215 cm ; ν: C=O 1626; ν: (Phosphate; ether): 1227, 1141, 1112, 982;
γ >CH Ar: 826-742
High-resolution mass spectrometry (ESI+-/FIA/HR):
Empirical formula: C H Cl N Na O P
40 38 6 2 7
[M-2Na+3H] calculated: 783.2457
[M-2Na+3H] measured: 783.2462
E Ex xa am mp plle e 2 22 2.. 4 4- -[ [{ {[ [3 3- -( (6 6- -{ {[ [( (3 3R R) )- -3 3- -( (M Mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -
2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -1 1,,3 3- -b be en nz zo od diio ox xo oll- -5 5- -y yll) )- -5 5,,6 6,,7 7,,8 8- -t te et tr ra ah hy yd dr ro oiin nd do olliiz ziin n- -1 1- -
yl]carbonyl}(phenyl)amino]phenyl disodium phosphate
yl]carbonyl}(phenyl)amino]phenyl disodium phosphate
Step A: N-(4-Hydroxyphenyl){6-[((3R)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-
isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-5,6,7,8-tetrahydroindolizine
carboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing the compound of Preparation 1' used in Step A by the compound of
Preparation 4'. The solid is then dissolved in dichloromethane, and 2 mL of 1M HCl in
ether are added. The batch is stirred for 1 hour and then evaporated to dryness. The
hydrochloride thereby obtained is dissolved in a mixture of water/acetonitrile until
dissolution is complete, and then lyophilised.
Elemental microanalysis:
%C %H %N %Cl
Calculated 69.11 5.80 7.50 4.74
Found 68.89 5.23 7.41 4.62
Optical rotation: (α) = - 45.1° (c = 9 mg/mL, MeOH)
Step B: 4-[{[3-(6-{[(3R)(Morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)-
amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (400/500 MHz, dmso-d6) δ ppm: 2.6
Elemental microanalysis:
%C %H %N
Calculated 61.87 4.95 6.71
Found 61.33 4.93 7.14
High-resolution mass spectrometry (ESI+-/FIA/HR):
Empirical formula: C H N Na O P
43 41 4 2 9
[M-2Na+H] calculated: 791.2840
[M-2Na+H] measured: 791.2845
E Ex xa am mp plle e 2 23 3.. 4 4- -[ [( (1 1- -M Me et th hy yll- -2 2,,3 3- -d diih hy yd dr ro o- -1 1H H- -p py yr rr ro ollo o[ [2 2,,3 3- -b b] ]p py yr riid diin n- -5 5- -y yll) ){ {[ [3 3- -( (2 2- -{ {[ [( (3 3S S) )- -3 3- -
( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }- -4 4- -[ [2 2- -o ox xo o- -2 2- -
(piperidinyl)ethoxy]phenyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}amino]-
(piperidinyl)ethoxy]phenyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}amino]-
p ph he en ny yll d diis so od diiu um m p ph ho os sp ph ha at te e
Step A: Methyl 3-[4-benzyloxy[(3S)(morpholinomethyl)-3,4-dihydro-1H-
isoquinolinecarbonyl]phenyl]-5,6,7,8-tetrahydroindolizinecarboxylate
To a solution of 14.19 g (35.0 mmol) of the compound obtained in Preparation 9 in
200 mL of dimethylformamide there are successively added 4-[[(3S)-1,2,3,4-
tetrahydroisoquinolinyl]methyl]morpholine (Preparation 1'; 8.13 g; 35.0 mmol),
hydroxybenzotriazole (6.15 g; 45,5 mmol), 1-ethyl(3'-dimethylaminopropyl)-
carbodiimide hydrochloride (6.70 g; 45.5 mmol) and triethylamine (21.95 mL; 0.16 mol).
The batch is then stirred overnight at ambient temperature. The reaction mixture is then
poured into 400 mL of ethyl acetate and then successively washed with saturated aqueous
NaHCO solution, water and brine. The combined aqueous phases are extracted with ethyl
acetate. The resulting organic phases are dried over sodium sulphate, filtered and
concentrated under reduced pressure. The product obtained is purified by chromatography
over silica gel to provide the title compound.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 7.5-7.3 (m, 5 H), 7.38 (d, 1 H), 7.2-6.9 (m,
4 H), 7.15 (dd, 1 H), 6.9 (d, 1 H), 6.35/6.25/6.08 (3*s, 1 H), 5.21/5.12 (3*s, 2 H),
.09/4.85/3.7 (3*m, 1 H), 4.9-3.8 (8*d, 2 H), 4.2-3.4 (m, 2 H), 3.65/3.6/3.55 (3*s, 3 H),
3.6-3.4 (m, 4 H), 3-2.4 (m, 2 H), 2.9-1.8 (6*dd, 2 H), 2.5-1.95 (4*m, 4 H), 2.35-1.7 (6*m,
2 H), 2-1.45 (6*m, 4 H)
Step B: 3-[4-Benzyloxy[(3S)(morpholinomethyl)-3,4-dihydro-1H-isoquinoline
carbonyl]phenyl]-5,6,7,8-tetrahydroindolizinecarboxylic acid
40.1 mL of 1M aqueous LiOH solution are added to a solution of 12.7 g (20 mmol) of the
compound obtained in the Step above in 40 mL of dioxane. The batch is heated at 100°C
overnight. The reaction mixture is poured into water and then extracted with ethyl ether.
The ethereal phase is extracted once more with water. The combined aqueous phases are
acidified to pH 4 by adding powdered citric acid, and then extracted with dichloromethane.
The dichloromethane phase is washed with brine, dried over sodium sulphate, filtered and
concentrated to dryness. The title product is obtained in the form of a meringue.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 11.35 (bs, 1 H), 7.5-7.3 (m, 5 H), 7.38 (m,
1 H), 7.2-6.9 (m, 4 H), 7.15 (m, 1 H), 6.9 (m, 1 H), 6.31/6.25/6.1 (3*s, 1 H), 5.22/5.2/5.15
(3*s, 2 H), 5.1/4.82/3.7 (3*m, 1 H), 4.85-3.8 (8*d, 2 H), 4.2-3.4 (m, 2 H), 3.6-3.45 (m,
4 H), 3-2.3 (m, 2 H), 2.9-1.8 (m, 2 H), 2.5-1.9 (6*m, 4 H), 2.35-1.8 (6*m, 2 H), 1.9-1.3 (m,
4 H)
Step C: 3-[4-Benzyloxy[(3S)(morpholinomethyl)-3,4-dihydro-1H-isoquinoline
carbonyl]phenyl]-N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-N-(1-methylpyrrolo[2,3-b]-
pyridinyl)-5,6,7,8-tetrahydroindolizinecarboxamide
The acid obtained in Step B (9 g, 11.8 mmol) is dissolved in 90 mL of 1,2-dichloroethane.
1.9 mL of 1-chloro-N,N,2-trimethylpropenylamine (14 mmol) are added thereto. After
stirring for 3 hours at ambient temperature, 90 mL of toluene and 4.62 g of N-[4-[tert-
butyl(dimethyl)silyl]oxyphenyl]methyl-1H-pyrrolo[2,3-b]pyridinamine
(Preparation 3'', 13 mmol) are added. The reaction mixture is heated at 110°C for 20 hours.
After returning to ambient temperature, the reaction mixture is washed with brine, dried
over Na SO , filtered and concentrated to dryness. The residue obtained is purified by
chromatography over silica gel (dichloromethane/ethanol gradient) to yield the expected
product.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 7.95/7.8/7.75 (3*d, 1 H), 7.68/7.65/7.4 (3*d,
1 H), 7.4/7.3 (2*d, 1 H), 7.25-6.8 (m, 9 H), 7.05/6.9 (2*m, 1 H), 7-6.6 (3*bd, 2 H), 6.9 (m,
1 H), 6.75-6.45 (3*bd, 2 H), 6.7 (m, 1 H), 6.3 (2*d, 1 H), 5.15-4.95 (m, 2 H), 5.15/5.1/4.8
(3*s, 1 H), 4.95/4.6/3.5 (3*m, 1 H), 4.9-3.7 (8*d, 2 H), 3.8-3.3 (3*m, 2 H), 3.75/3.7/3.5
(3*s, 3 H), 3.45/3.3 (2*m, 4 H), 3-2.5 (3*m, 2 H), 3-2.3 (m, 2 H), 2.4-1.75 (5*m, 4 H),
2.25-1.7 (6*m, 2 H), 1.75-1.3 (m, 4 H), 0.7 (bs, 9 H), 0.1 (m, 6 H)
Step D: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl][4-hydroxy[(3S)(morpholino-
methyl)-3,4-dihydro-1H-isoquinolinecarbonyl]phenyl]-N-(1-methylpyrrolo[2,3-b]-
pyridinyl)-5,6,7,8-tetrahydroindolizinecarboxamide
0.9 g of Pd/C 10 % is added to a solution, in 100 mL of ethanol, of 8.88 g (8.4 mmol) of
the compound obtained in Step C, whilst bubbling through argon. The reaction mixture is
placed under 1.2 bars of hydrogen at ambient temperature for 15 hours. The catalyst is
filtered off and the solvent is evaporated off under reduced pressure to provide the title
compound.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 8.06/7.92/7.87 (3*d, 1 H), 7.75/7.5/7.39
(3*d, 1 H), 7.5 (m, 1 H), 7.28-6.9 (m, 5 H), 6.87/6.7 (2*m, 2 H), 6.76 (m, 1 H),
6.75/6.67/6.62 (3*m, 2 H), 6.67/6.46 (m, 1 H), 6.4/6.36 (2*m, 1 H), 5.19/5.13/4.9 (3*bs,
1 H), 5.06/4.7/3.6 (3*m, 1 H), 4.97/4.2/4.15/4.07 (4*m, 2 H), 4.87/4.81 (bs, 1H),
3.86/3.56/3.39 (3*m, 2 H), 3.78/3.57 (2*m, 3 H), 3.59/3.44 (2*m, 4 H), 2.96-2.61 (2*m,
2 H), 2.88/2.6 (2*m, 2 H), 2.59-1.81 (m, 6 H), 1.87-1.42 (m, 4 H), 0.89 (s, 9 H), 0.12 (m,
6 H)
Step E: N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-N-(1-methylpyrrolo[2,3-b]pyridin
yl)[2-[(3S)(morpholinomethyl)-3,4-dihydro-1H-isoquinolinecarbonyl][2-oxo-
2-(1-piperidyl)ethoxy]phenyl]-5,6,7,8-tetrahydroindolizinecarboxamide
The compound of Step D (3.0 g, 2.9 mmol) is dissolved in 100 mL of toluene. 1.53 g
(5.8 mmol) of triphenylphosphine and 0.62 g (4.3 mmol) of 2-hydroxy(1-
piperidyl)ethanone are added thereto. The mixture is heated to 50°C, and then 1.01 g
(4.3 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is stirred at
50°C for 1 hour and is then allowed to return to ambient temperature before adding 1 mL
of trifluoroacetic acid. After stirring overnight at ambient temperature, the mixture is
successively washed with water, saturated NaHCO and brine solution. The combined
aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried
over sodium sulphate, filtered and concentrated under reduced pressure. The crude product
obtained is purified by chromatography over silica gel (dichloromethane/ethanol 98/2) to
yield the expected compound.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 8.06/7.92/7.87 (3*d, 1 H), 7.75/7.51/7.4
(3*d, 1 H), 7.49 (2*d, 1 H), 7.29-6.89 (m, 5 H), 6.93 (m, 1 H), 6.88/6.7 (m, 2 H), 6.75/6.67
(m, 1 H), 6.75/6.68/6.59 (3*m, 2 H), 6.4/6.36 (2*m, 1 H), 5.2/5.16/4.92 (3*m, 1 H),
5.06/4.69/3.58 (3*m, 1 H), 4.97/4.25/4.16/4.03 (4*d, 2 H), 4.89/4.81 (2*m, 2 H), 3.79/3.59
(2*m, 3 H), 3.59/3.43/3.4 (3*m, 6 H), 3.58/3.43 (2*m, 4 H), 3.03-2.61 (m, 2 H), 2.97-2.65
(m, 2 H), 2.57-1.74 (m, 6 H), 1.89-1.3 (m, 10 H), 0.89 (2bs, 9 H), 0.11 (m, 6 H)
Step F: N-(4-Hydroxyphenyl)-N-(1-methylpyrrolo[2,3-b]pyridinyl)[2-[(3S)
(morpholinomethyl)-3,4-dihydro-1H-isoquinolinecarbonyl][2-oxo(1-
piperidyl)ethoxy]phenyl]-5,6,7,8-tetrahydroindolizinecarboxamide
A 1M solution of tetrabutylammonium fluoride (3.14 mL, 3 mmol) in tetrahydrofuran is
added at ambient temperature to a solution, in 30 mL of tetrahydrofuran, of the compound
obtained in Step E (2.92 g, 2.9 mmol). After stirring for 5 minutes, the reaction mixture is
poured into a 50/50 mixture of ethyl acetate and saturated aqueous NaHCO solution. The
separated organic phase is washed with water and then with brine. The combined aqueous
phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium
sulphate, filtered and concentrated under reduced pressure. The crude product obtained is
purified by chromatography over silica gel (dichloromethane/ethanol/ammonia gradient) to
yield the title compound.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 9.4 (m, OH), 8.1-7.8 (3*d, 1 H), 7.7-7.3
(2*m, 1 H), 7.5/7.4 (2*m, 1 H), 7.3-6.9 (m, 4 H), 7.2 (m, 1 H), 6.9 (m, 1 H), 6.8-6.5 (m,
2 H), 6.7-6.5 (m, 2 H), 6.7 (m, 1 H), 6.4 (m, 1 H), 5.3-5 (m, 1 H), 5.1/4.7/3.6 (3*m, 1 H),
-3.6 (m, 2 H), 5-3.6 (m, 2 H), 4.8 (m, 2 H), 3.8-3.6 (m, 3 H), 3.6/3.4 (m, 2 H), 3.4 (m,
6 H), 3.1-2.5 (m, 2 H), 2.9-1.9 (m, 2 H), 2.5-1.7 (m, 4 H), 1.8-1.4 (m, 6 H), 1.6-1.3 (m,
4 H)
Step G: N-(4-Hydroxyphenyl)-N-(1-methyl-2,3-dihydropyrrolo[2,3-b]pyridinyl)[2-
[(3S)(morpholinomethyl)-3,4-dihydro-1H-isoquinolinecarbonyl][2-oxo(1-
piperidyl)ethoxy]phenyl]-5,6,7,8-tetrahydroindolizinecarboxamide
0.71 g (11 mmol) of sodium cyanoborohydride is added to a solution, in 20 mL of acetic
acid, of the compound obtained in Step F (2.0 g, 2.2 mmol). After stirring for 14 hours at
ambient temperature, 0.36 g (5.5 mmol) of sodium cyanoborohydride is again added, and
then the reaction mixture is heated at 50°C for 3 hours before a second addition of 0.1 eq.
of sodium cyanoborohydride to complete the reaction in 30 minutes at 50°C. The acetic
acid is evaporated off under reduced pressure, and then the residue is taken up in
dichloromethane and washed with saturated aqueous NaHCO solution, water and brine.
The combined aqueous phases are extracted with dichloromethane. The resulting organic
phases are dried over sodium sulphate, filtered and concentrated under reduced pressure.
The crude product obtained is purified by chromatography over silica gel
(dichloromethane/ethanol/ammonia gradient) to yield the title compound in the form of a
meringue.
H NMR (500 MHz, dmso-d6, 300K) δ ppm: 9.3 (bs, 1 H), 7.5/7.4/7.3 (3*m, 1 H), 7.2/6.7
(2*m, 1 H), 7.2 (m, 1 H), 7.1-6.8 (m, 4 H), 6.9/6.7 (m, 1 H), 6.9 (m, 1 H), 6.8-6.5 (m, 2 H),
6.7-6.5 (m, 2 H), 5.3-5.1 (2*d, 1 H), 5.1/4.7/3.6 (3*m, 1 H), 4.9/4.2-3.5 (2*m, 1 H),
4.9/4.2-3.5 (2*, 1 H), 4.9-4.8 (m, 2 H), 3.6/3.4 (2*m, 4 H), 3.4/3.3 (m, 2 H), 3.4 (m, 6 H),
3.1-2.5 (m, 4 H), 3-2.4 (m, 2 H), 2.8/2.6 (m, 3 H), 2.6-1.7 (m, 6 H), 1.9-1.3 (m, 10 H)
Step H: N-(4-Hydroxyphenyl)-N-(1-methyl-2,3-dihydropyrrolo[2,3-b]pyridinyl)[2-
[(3S)(morpholinomethyl)-3,4-dihydro-1H-isoquinolinecarbonyl][2-oxo(1-
piperidyl)ethoxy]phenyl]-5,6,7,8-tetrahydroindolizinecarboxamide hydrochloride
The base obtained in Step G (0.60 g, 0.69 mmol) is dissolved in acetonitrile and then
converted into salt form using 0.7 mL (0.7 mmol) of 1N HCl solution. The solution is
filtered, frozen and then lyophilised to provide the title compound in the form of a powder.
Elemental microanalysis: (%, theoretical:measured)
%C=68.02:68.06; %H=6.49:6.21; %N=10.89:10.87; %Cl=4.14:3.94
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N O
51 57 7 6
[M+H] calculated: 864.4445
[M+H] measured: 864.4443
Step I: 4-[(1-Methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl){[3-(2-{[(3S)
(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}[2-oxo
(piperidinyl)ethoxy]phenyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}amino]phenyl
disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
IR (cm ): ν: C=O: 1625; ν: (phosphate; ether): 1229, 1138, 1115, 982; γ: >CH Ar: 880-
748-745
Elemental microanalysis:
%C %H %N
Calculated 62.00 5.71 9.92
Found 61.45 5.53 9.96
High-resolution mass spectrometry (ESI+):
Empirical formula: C H N Na O P
51 56 7 2 9
[M-2Na+3H] calculated: 944.4106
[M-2Na+3H] measured: 944.4116
E Ex xa am mp plle e 2 24 4.. 4 4- -[ [{ {[ [5 5- -( (5 5- -C Ch hllo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -
d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -
yl]carbonyl}(1-methyl-1H-pyrazolyl)amino]phenyl disodium phosphate
yl]carbonyl}(1-methyl-1H-pyrazolyl)amino]phenyl disodium phosphate
Step A: 5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-
yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolyl)-
1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 4 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 5''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
Elemental microanalysis: (%, theoretical:measured)
%C=63.77:62.83; %H=5.63:5.83; %N=11.74:11.29; %Cl-=4.95:5.42
Step B : 4-[{[5-(5-Chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(1-methyl-1H-pyrazol-
4-yl)amino]phenyl disodium phosphate
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
IR (cm ): ν: C=O: 1625; ν: (phosphate; ether): 1241, 1146, 1112, 983
Elemental microanalysis:
%C %H %N
Calculated 56.83 4.77 10.46
Found 56.82 4.58 10.43
High-resolution mass spectrometry (ESI+):
Empirical formula : C H Cl N Na O P
38 38 6 2 7
[M-2Na+3H] calculated: 759.2457
[M-2Na+3H] measured: 759.2465
E Ex xa am mp plle e 2 25 5.. 4 4- -[ [( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) ){ {[ [5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -
( (m mo or rp ph ho olliin n- -4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -
dimethyl-1H-pyrrolyl]carbonyl}amino]phenyl disodium phosphate
dimethyl-1H-pyrrolyl]carbonyl}amino]phenyl disodium phosphate
Step A: N N- -( (5 5- -C Cy ya an no o- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -p py yr rr ro oll- -3 3- -y yll) )- -5 5- -( (5 5- -f fllu uo or ro o- -2 2- -{ {[ [( (3 3S S) )- -3 3- -( (m mo or rp ph ho olliin n- -
4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-
4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-
1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride
1,2-dimethyl-1H-pyrrolecarboxamide hydrochloride
The procedure is in accordance with a protocol analogous to that described in Steps A-D of
Example 1 replacing, on the one hand, the compound of Preparation 1 used in Step A by
the compound of Preparation 7 and, on the other hand, the compound of Preparation 1''
used in Step C by that of Preparation 7''. The product obtained is finally subjected to a step
of conversion into salt form in the presence of HCl in ether. After filtration and
lyophilisation in a mixture of acetonitrile/water, the expected compound is obtained.
High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):
Empirical formula: C H F N O
41 41 6 4
[M+H] calculated: 701.3246
[M+H] measured: 701.3282
Step B: 4-[(5-Cyano-1,2-dimethyl-1H-pyrrolyl){[5-(5-fluoro{[(3S)(morpholin-
4-[(5-Cyano-1,2-dimethyl-1H-pyrrolyl){[5-(5-fluoro{[(3S)(morpholin-
4 4- -y yllm me et th hy yll) )- -3 3,,4 4- -d diih hy yd dr ro oiis so oq qu uiin no olliin n- -2 2( (1 1H H) )- -y yll] ]c ca ar rb bo on ny yll} }p ph he en ny yll) )- -1 1,,2 2- -d diim me et th hy yll- -1 1H H- -
p py yr rr ro oll- -3 3- -y yll] ]c ca ar rb bo on ny yll} }a am miin no o] ]p ph he en ny yll d diis so od diiu um m p ph ho os sp ph ha at te e
The procedure is in accordance with a protocol analogous to that described in Steps B
and C of Example 16.
P NMR (400/500 MHz, CD OD) δ ppm: -0.5
-1 -1
IR (cm ): ν: -CN: 2211 cm ; ν: C=O: 1629; ν: (phosphate; ether): 1236, 1114, 984
Elemental microanalysis:
%C %H %N
Calculated 59.71 4.89 10.19
Found 60.09 4.95 9.88
High-resolution mass spectrometry (ESI+):
Empirical formula: C H F N Na O P
41 40 6 2 7
[M-2Na+3H] calculated: 781.2909
[M-2Na+3H] measured: 781.2898
PHARMACOLOGICAL AND PHARMACOKINETIC STUDIES
PHARMACOLOGICAL AND PHARMACOKINETIC STUDIES
For clarification purposes, and in anything which follows, compounds of formula (I’) will
be referred to as “drug of Example x” from which they have been derived. As for an
example, N-(4-hydroxyphenyl){6-[((3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-
isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-5,6,7,8-tetrahydroindolizine
carboxamide will be referred to as the “drug from Example 1”.
EXAMPLE A1: Induction of caspase activity in vivo by compounds of formula (I')
EXAMPLE A1: Induction of caspase activity in vivo by compounds of formula (I')
The ability of the compounds of formula (I') to activate caspase 3 is evaluated in a xenograft model of
RS4;11 leukaemia cells.
1x10 RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days
after the graft, the animals are treated orally with the various compounds. Sixteen hours after treatment, the
tumour masses are recovered and lysed, and the caspase 3 activity is measured in the tumour lysates.
This enzymatic measurement is carried out by assaying the appearance of a fluorigenic cleavage product
(DEVDase activity, Promega). It is expressed in the form of an activation factor corresponding to the ratio
between the two caspase activities: the activity for the treated mice divided by the activity for the control
mice.
N-(4-Hydroxyphenyl){6-[((3S)(4-morpholinylmethyl)-3,4-dihydro-2(1H)-
isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-5,6,7,8-tetrahydroindolizine
carboxamide (also referred to as the drug from Example 1) was tested. At a dose of
100 mg/kg p.o., the in vivo caspase activation factor is 29.3.
The results obtained show that the compounds of formula (I') are capable of inducing apoptosis in RS4;11
tumour cells in vivo.
EXAMPLE A2: Quantification of the cleaved form of caspase 3 in vivo brought
EXAMPLE A2: Quantification of the cleaved form of caspase 3 in vivo brought
a ab bo ou ut t b by y c co om mp po ou un nd ds s o of f f fo or rm mu ulla a ( (I I'') )..
The ability of the compounds of formula (I') to activate caspase 3 is evaluated in a xenograft model of
RS4;11 leukaemia cells.
1x10 RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days
after the graft, the animals are treated orally with the various compounds. After treatment, the tumour masses
are recovered and lysed, and the cleaved (activated) form of caspase 3 is quantified in the tumour lysates.
The quantification is carried out using the "Meso Scale Discovery (MSD) ELISA platform" test, which
specifically assays the cleaved form of caspase 3. It is expressed in the form of an activation factor
corresponding to the ratio between the quantity of cleaved caspase 3 in the treated mice divided by the
quantity of cleaved caspase 3 in the control mice.
The results show that the compounds of formula (I') are capable of inducing apoptosis in RS4;11 tumour cells
in vivo.
Table 1: Caspase activation factors (cleaved caspase 3 MSD test in the tumours of
treated mice versus control mice) in vivo, after treatment by the oral route
Compound tested Dose (mg/kg) Sampling Activation factor +/-
time S.E.M.
Drug from Example 13 12.5 2 hours 24.5 +/- 7.5
Drug from Example 19 12.5 2 hours 13.5 +/- 1.2
Drug from Example 20 12.5 2 hours 52.0 +/- 8.6
Drug from Example 21 12.5 2 hours 22.6 +/- 2.4
Drug from Example 24 25 2 hours 45.7 +/- 2.0
Drug from Example 25 12.5 2 hours 38.7 +/- 10.7
Drug from Example 15 25 2 hours 29.8 +/- 4.0
EXAMPLE A3: Quantification of the cleaved form of caspase 3 in vivo brought about
EXAMPLE A3: Quantification of the cleaved form of caspase 3 in vivo brought about
b by y c co om mp po ou un nd ds s o of f f fo or rm mu ulla a ( (I I) )..
The ability of the compounds of formula (I) to activate caspase 3 is evaluated in a xenograft model of RS4;11
leukaemia cells in accordance with the protocol given in Example A2.
Table 2: Caspase activation factors (cleaved caspase 3 MSD test in the tumours of
treated mice versus control mice) in vivo, after treatment by the oral route
Compound Dose (mg/kg) Sampling time Activation factor +/- S.E.M.
tested
Example 13 12.5 2 hours 58.6 +/- 4.6
Example 1 50 2 hours 21.2 +/- 1.3
Example 19 12.5 2 hours 27.5 +/- 3.5
Example 20 12.5 2 hours 62.1 +/- 3.4
Example 21 25 2 hours 55.2 +/- 6.2
Example 24 25 2 hours 60.5 +/- 4.5
Example 25 12.5 2 hours 61.8 +/- 8.9
Example 15 25 2 hours 12.1 +/-1.1
EXAMPLE B: Solubility of compounds of formula (I)
EXAMPLE B: Solubility of compounds of formula (I)
The solubility of compounds of formula (I) in water was measured and compared with that
of compounds of formula (I').
More specifically, 4-[{[3-(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-
2(1H)-yl]carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}-
(phenyl)amino]phenyl disodium phosphate (also referred to as the compound of
Example 1) was tested and compared to N-(4-hydroxyphenyl){6-[((3S)(4-
morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-
phenyl-5,6,7,8-tetrahydroindolizine carboxamide (also referred to as the drug from
Example 1).
The solubility of the compound of Example 1 in water is greater than or equal to
mg/mL (12.6mM) whereas that of the associated drug is only 40 µg/mL (56.2µM). The
solubilities of the compounds were also measured in a medium buffered to physiological
pH (cf. Table 3).
Table 3: Solubilities in aqueous medium (buffer solution: phosphate 0.33M, pH=7.4)
of compounds of formula (I) and the associated compounds of formula (I'), measured
at four concentrations: 10μ μ μ μM, 20μ μ μ μM, 50μ μ μ μM and 100μ μ μ μM
Compound tested Solubility at Solubility at Solubility at Solubility at
10µM 20µM 50 µM 100 µM
Example 19
Soluble Soluble Soluble Soluble
Drug from Example 19
Soluble Soluble Soluble Insoluble
Example 20
Soluble Soluble Soluble Soluble
Drug from Example 20
Soluble Insoluble Insoluble Insoluble
Example 25
Soluble Soluble Soluble Soluble
Drug from Example 25
Soluble Soluble Insoluble Insoluble
Example 1
Soluble Soluble Soluble Soluble
Drug from Example 1
Insoluble Insoluble Insoluble Insoluble
The results show that the compounds of formula (I) are much more soluble than the
compounds of formula (I'). Only compounds of formula (I) exhibit solubilities greater than
or equal to 100μM.
E EX XA AM MP PL LE E C C: : I In n v viiv vo o c co on nv ve er rs siio on n o of f c co om mp po ou un nd ds s o of f f fo or rm mu ulla a ( (I I) )
The pharmacokinetic profile of the phosphate compounds of formula (I) is evaluated in a
lipid formulation and in aqueous solution in female SCID mice. This is compared to the
pharmacokinetic profile of compounds of formula (I') in a lipid formulation. More
specifically, 4-[{[3-(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-
carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)-
amino]phenyl disodium phosphate (also referred to as the compound of Example 1) was
tested and compared to N-(4-hydroxyphenyl){6-[((3S)(4-morpholinylmethyl)-3,4-
dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-5,6,7,8-
tetrahydroindolizine carboxamide (also referred to as the drug from Example 1).
Lipid formulation of the compound of Example 1
The compound of Example 1 is prepared in a mixture of anhydrous ethanol/polyethylene
glycol 300/water (10/40/50, v/v/v) intended for administration by the p.o. route. The study
is carried out in 2 groups of SCID mice to which the compound of Example 1 is
administered under the following conditions:
- Group 1: 3 mg/kg p.o. (gavage, 10 mL/kg),
- Group 2: 25 mg/kg p.o. (gavage, 10 mL/kg).
Blood samples are taken at the following points in time (3 samples per animal and 3
animals for each point in time): 0.25 hr, 0.5 hr, 1 hr, 2 hrs, 6 hrs and 24 hrs after oral
administration.
Aqueous formulation of the compound of Example 1
The compound of Example 1 is also administered by the oral route in an aqueous medium
to SCID mice, under the following conditions:
- Group 1: 30 mg/kg p.o. dissolved in 1mM sodium carbonate solution (gavage,
mL/kg),
- Group 2: 100 mg/kg p.o. in water (gavage, 10 mL/kg).
Blood samples are taken at the following points in time (3 animals for each point in time
and 1 sample per animal): 0.25 hr, 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs and 24 hrs after oral
administration.
For all formulations of the compound of Example 1, the blood thereby collected is
centrifuged and the plasma is transferred to tubes containing 1M hydrochloric acid. The
plasma concentrations of the phosphate compound (prodrug) and its hydroxylated
homologue (drug) are determined simultaneously using a method of liquid chromatography
coupled with mass spectrometric detection (TFC-LC-MS/MS). The limit of detection for
both entities is 0.5 ng/mL.
Lipid formulation of the drug from the compound of Example 1
The drug from Example 1 is prepared in a mixture of anhydrous ethanol/polyethylene
glycol 300/water (10/40/50, v/v/v) intended for administration by the p.o. route. The study
is carried out in several groups of SCID mice to which the drug from Example 1 is
administered under the following conditions:
- Group 1: 3 mg/kg p.o. (gavage, 10 mL/kg),
- Group 2: 30 mg/kg p.o. (gavage, 10 mL/kg),
- Group 3: 25 mg/kg p.o. (gavage, 10 mL/kg),
- Group 4: 100 mg/kg p.o. (gavage, 10 mL/kg).
Blood samples are taken at the following points in time (3 animals for each point in time
and 3 samples per animal for Groups 1-2 and 1 sample per animal for Groups 3 and 4):
- p.o.: before administration and then 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,
16 hrs and 24 hrs after oral administration at 3 and 30 mg/kg,
- p.o.: 0.5 hr, 2 hrs, 6 hrs, 16 hrs and 24 hrs after oral administration at 25 mg/kg and
0.5 hr, 1 hr, 2 hrs, 6 hrs, 16 hrs, 30 hrs and 48 hrs after oral administration at 100 mg/kg.
The plasma from the blood samples collected after administration of the lipid formulations
of the drug from the compound of Example 1 are analysed by liquid chromatography
coupled with mass spectrometric detection. The limit of quantification of the drug from the
compound of Example 1 is less than or equal to 0.5 ng/mL.
Non-compartmental pharmacokinetic analysis is carried out on the mean values of the
plasma concentrations of the compounds tested. The results are shown in Tables 4 and 5
hereinbelow.
The results show that, whatever the dose (from 3 to 100 mg/kg) and the carrier (lipid or
aqueous formulation), the major part of the prodrug of formula (I) is rapidly converted in
vivo into the corresponding drug of formula (I') (see Table 4). Plasma exposure of the
prodrug (C , AUC) is low in comparison to that of the corresponding drug. The results
also show that the plasma concentration of the drug so measured (after administration of
the prodrug) is equivalent to or even greater than that measured after direct administration
of the drug by the oral route (see Table 5).
Table 4
Compound administered Compound measured
Example 1 Drug from Example 1
C (ng/mL) = 16 C (ng/mL) = 342
max max
Example 1, 3 mg/kg p.o.
T (h)= 0.25 T (h)= 0.25
max max
Lipid formulation
AUC (ng.h/mL) = 5 AUC (ng.h/mL) = 314
C (ng/mL) = 244 C (ng/mL) = 6204
max max
Example 1, 25 mg/kg p.o.
T (h)= 0.25 T (h)= 0.5
max max
Lipid formulation
AUC (ng.h/mL) = 92 AUC (ng.h/mL) = 20952
C (ng/mL) = 391 C (ng/mL) = 11967
max max
Example 1, 30 mg/kg p.o.
T (h)= 1.0 T (h)= 0.5
max max
Aqueous formulation
AUC (ng.h/mL) = 879 AUC (ng.h/mL) = 49416
C (ng/mL) = 359 C (ng/mL) = 28066
max max
Example 1, 100 mg/kg p.o.
T (h)= 2.0 T (h)= 2.0
max max
Aqueous formulation
AUC (ng.h/mL) = 797 AUC (ng.h/mL) = 168478
Table 5
Compound administered Compound measured
Drug from Example 1
C (ng/mL) = 295
Drug from Example 1, 3 mg/kg p.o.
T (h)= 0.25
Lipid formulation
AUC (ng.h/mL) = 225
C (ng/mL) = 5070
Drug from Example 1, 25 mg/kg p.o.
T (h)= 2.0
Lipid formulation
AUC (ng.h/mL) = 20400
C (ng/mL) = 8580
Drug from Example 1, 30 mg/kg p.o.
T (h)= 1.0
Lipid formulation
AUC (ng.h/mL) = 24200
C (ng/mL) = 25878
Drug from Example 1, 100 mg/kg p.o.
T (h)= 0.5
Lipid formulation
AUC (ng.h/mL) = 148046
More specifically, p.o. administration of the prodrug in an aqueous carrier makes it
possible to obtain plasma concentrations of the drug which are equivalent to or even
greater than those obtained after direct p.o. administration of the drug in a lipid carrier. The
prodrug therefore offers the benefit of ease of formulation compared to the corresponding
drug, especially in an aqueous medium, which is very advantageous with a view to clinical
development. Indeed, as Example D shows, the drug from Example 1 is difficult to
formulate in an aqueous medium.
Aqueous formulation of the compounds of Examples 20 and 25
The compounds of Examples 20 and 25 are administered by the oral route in an aqueous
medium to SCID mice, under the following conditions:
- Group 1: 3 mg/kg p.o. in solution in 1M sodium carbonate (gavage, 10 mL/kg),
- Group 2: 25 mg/kg p.o. in solution in 1M sodium carbonate (gavage, 10 mL/kg).
Blood samples are taken at the following points in time (3 animals for each point in time):
0.25 hr, 0.5 hr, 1 hr, 2 hrs, 6 hrs and 24 hrs after oral administration.
The blood thereby collected is centrifuged and the plasma is transferred to tubes containing
1M hydrochloric acid. The plasma concentrations of the phosphate compound (prodrug)
and its hydroxylated homologue (drug) are determined simultaneously using a method of
liquid chromatography coupled with mass spectrometric detection (TFC-LC-MS/MS). The
limit of detection for both entities is 0.5 ng/mL.
Lipid formulation of the drug from the compounds of Examples 20 and 25
The drugs from Examples 20 and 25 are prepared in a mixture of polyethylene glycol
300/ethanol/Phosal 50PG (30/10/60, v/v/v) intended for administration by the p.o. route to
SCID mice, under the following conditions:
- Group 1: 3 mg/kg p.o. (gavage, 10 mL/kg),
- Group 2: 25 mg/kg p.o. (gavage, 10 mL/kg).
Blood samples are taken at the following points in time (3 animals for each point in time):
0.25 hr, 0.5 hr, 1 hr, 2 hrs, 6 hrs and 24 hrs after oral administration.
The blood thereby collected is centrifuged and the plasma is transferred to tubes containing
1M hydrochloric acid. The plasma concentrations of the drug are determined using a
method of liquid chromatography coupled with mass spectrometric detection (TFC-LC-
MS/MS). The limit of quantification is 0.5 ng/mL.
Non-compartmental pharmacokinetic analysis is carried out. The mean results are shown in
Tables 6, 7, 8 and 9 hereinbelow.
Table 6, Example 20
Compound administered Compounds measured
Example 20 Drug from Example 20
C (ng/mL) = BLQ C (ng/mL) = 56
max max
Example 20, 3 mg/kg p.o.
T (h)= ND T (h)= 1.0
max max
Aqueous formulation
AUC (ng.h/mL) = ND AUC (ng.h/mL) = 51
C (ng/mL) = 127 C (ng/mL) = 3701
max max
Example 20, 25 mg/kg p.o.
T (h)= 0.25 T (h)= 1.0
max max
Aqueous formulation
AUC (ng.h/mL) = 106 AUC (ng.h/mL) = 8724
ND: not determined
BLQ: below the limit of quantification
Table 7, Example 20
Compound administered Compound measured
Drug from Example 20
C (ng/mL) = 39
Drug from Example 20, 3 mg/kg p.o.
Lipid formulation T (h)= 1.0
AUC (ng.h/mL) = 55
Drug from Example 20, 25 mg/kg p.o. C (ng/mL) = 5524
Lipid formulation T (h)= 2.0
AUC (ng.h/mL) = 10172
Table 8, Example 25
Compound administered Compounds measured
Example 25 Drug from Example 25
C (ng/mL) = 17 C (ng/mL) = 29
max max
Example 25, 3 mg/kg p.o.
T (h)= 1.0 T (h)= 1.0
max max
Aqueous formulation
AUC (ng.h/mL) = 14 AUC (ng.h/mL) = 31
C (ng/mL) = 106 C (ng/mL) = 2232
max max
Example 25, 25 mg/kg p.o.
T (h)= 1.0 T (h)= 1.0
max max
Aqueous formulation
AUC (ng.h/mL) = 114 AUC (ng.h/mL) = 3965
Table 9, Example 25
Compound administered Compound measured
Drug from Example 25
C (ng/mL) = 33
Drug from Example 25, 3 mg/kg p.o.
T (h)= 1.0
Lipid formulation
AUC (ng.h/mL) = 37
C (ng/mL) = 3004
Drug from Example 25, 25 mg/kg p.o.
T (h)= 1.0
Lipid formulation
AUC (ng.h/mL) = 5704
The results show that, whatever the dose (3 or 25 mg/kg), the major part of the prodrugs of
formula (I) is rapidly converted in vivo into the corresponding drugs of formula (I') (see
Tables 6, 7, 8 and 9). Plasma exposures of the prodrugs (C , AUC) are low in
comparison to exposures of the corresponding drugs. The results also show that the plasma
concentrations of the drugs so measured (after administration of the prodrugs) are
equivalent to those measured after direct administration of the drugs by the oral route (see
Tables 7 and 9).
E EX XA AM MP PL LE E D D: : I In n v viiv vo o p ph ha ar rm ma ac co ok kiin ne et tiic c p pr ro of fiille e o of f t th he e c co om mp po ou un nd ds s o of f f fo or rm mu ulla a ( (I I'') )
The pharmacokinetic profile of N-(4-hydroxyphenyl){6-[((3S)(4-morpholinyl-
methyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxolyl}-N-phenyl-
,6,7,8-tetrahydroindolizine carboxamide (also referred to as the drug from Example 1)
is also evaluated in a lipid and aqueous formulation in the Wistar rat.
The drug from Example 1 is prepared in an aqueous suspension in hydroxyethylcellulose
1 % (w/v) in water and compared to a lipid formulation composed of a mixture of
anhydrous ethanol/polyethylene glycol 400/Phosal 50PG (10/30/60, v/v/v). The two
formulations are administered by the oral route to male Wistar rats (3 rats per formulation)
at a dose of 100 mg/kg p.o. (gavage, 10 mL/kg).
Blood samples are taken at the following points in time from each animal (3 animals/point
in time): 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hrs, 4 hrs, 8 hrs and 24 hrs after oral
administration.
The plasma concentrations of the tested compound are determined after extraction
followed by liquid chromatography coupled with mass spectrometric detection. The limit
of quantification is 0.1 ng/mL. The results are presented in the Table hereinbelow:
Table 10
Compound administered Compound measured
Drug from Example 1
C (ng/mL) = 816
Drug from Example 1, 100 mg/kg p.o.
Aqueous formulation AUC (ng.h/mL) = 3480
Drug from Example 1, 100 mg/kg p.o. C (ng/mL) = 5070
Lipid formulation AUC (ng.h/mL) = 42900
The results show that the lipid formulation makes possible much better plasma exposure of
the drug from Example 1 than the aqueous formulation.
E EX XA AM MP PL LE E E E: : I In n v viittr ro o t te es st t o on n h hu um ma an n C Ca ac co o- -2 2 c ce elllls s..
The cellular transport from A to B (Apical to Basolateral) of the phosphate compounds of
formula (I) and the compounds of formula (I') (corresponding drugs) is studied in human
Caco-2 cells. Each compound is deposited apically at 1 or 3 µM (in duplicate) and then
incubated for 120 minutes.
Several samples are taken during the experiment;
- apically: immediately after deposition (t=0) and at 120 minutes
- basolaterally: at the end of the experiment (120 minutes)
The concentrations of the phosphate compound (prodrug) and/or of its hydroxylated
homologue (drug) are determined by liquid chromatography coupled with mass
spectrometric detection (LC-MS/MS). The limit of quantification for both entities is
2 ng/mL.
The apparent permeability (P ) and the predicted absorbed fraction (F ) in humans are
app abs
calculated for the prodrug, for the drug after incubation of the prodrug and for the drug
after incubation of the drug (Hubatsch et al, Nat Protoc. 2007; 2(9), 2111-2119).
The experiment yield, which corresponds to the ratio (in percent) of the total amount of
compound found at the end of the experiment versus that incubated, is also calculated.
The results have been collated in Table 11. They show that the prodrugs of the compounds
of formula (I) are markedly decomposed in the course of the experiment (experiment
yields of < 1.5 %), thereby bringing about the formation of the associated drugs in
substantial amounts.
At the end, the predicted absorbed fraction in humans for the drugs formed after incubation
of the prodrugs is similar to that obtained after incubation of the drugs.
Table 11
Compound administered Compounds measured
Example 1 Drug from Example 1
-6 -6
P (10 cm/s) = 0.01 P (10 cm/s) =0.83
app app
Example 1 F (%) = ND F (%) = 71
abs abs
Yield (%) =0 Yield (%)=42
P (10 cm/s) = 0.65
F (%) = 67
Drug from Example 1
Yield (%) =37
Example 4 Drug from Example 4
-6 -6
P (10 cm/s) = 0.33 P (10 cm/s) = 0.43
app app
Example 4 F (%) = ND F (%) =69
abs abs
Yield (%)=1.3 Yield (%)=38
P (10 cm/s) = 0.21
Drug from Example 4 F (%) =46
Yield (%)=20
Example 5 Drug from Example 5
-6 -6
P (10 cm/s) = 0.26 P (10 cm/s) = 2.3
app app
Example 5 F (%) = ND F (%) = 86
abs abs
Yield (%) =1.2 Yield (%) =78
P (10 cm/s) = 0.7
Drug from Example 5 F (%) = 68
Yield (%)=34
Example 20 Drug from Example 20
-6 -6
P (10 cm/s) = 0 P (10 cm/s) = 0.16
app app
F (%) = ND F (%) = 16
Example 20
abs abs
Yield (%) = 0.94 Yield (%) = 100
P (10 cm/s) = 0.29
Drug from Example 20 F (%) = 25
Yield (%)= 91
Example 21 Drug from Example 21
-6 -6
P (10 cm/s) = 0 P (10 cm/s) = 0.21
app app
Example 21 F (%) = ND F (%) = 19
abs abs
Yield (%) = 0.83 Yield (%) = 100
P (10 cm/s) = 0.27
F (%) = 24
Drug from Example 21
Yield (%)= 82
Example 25 Drug from Example 25
-6 -6
P (10 cm/s) = 0 P (10 cm/s) = 0.22
Example 25
app app
F (%) = ND F (%) = 20
abs abs
Yield (%)= 33 Yield (%) = 48
P (10 cm/s) = 0.49
Drug from Example 25 F (%) = 40
Yield (%)= 100
ND: not determined
EXAMPLE F: Anti-tumour activity in vivo.
EXAMPLE F: Anti-tumour activity in vivo.
The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of RS4;11
leukaemia cells.
1x10 RS4;11 cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 25 to 30 days
after the graft, when the tumour mass has reached about 150 mm , the mice are treated orally with the various
compounds in two different regimes (daily treatment for five days per week for two weeks, or two treatments
per week for two weeks). The tumour mass is measured twice a week from the start of treatment.
The compounds of the invention have antitumour activity, via the oral route, in the RS4;11 leukaemia model
(acute lymphoblastic leukaemia). The results obtained show that the compounds of the invention are capable
of inducing significant tumour regression.
EXAMPLE G: Pharmaceutical composition: Tablets
1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 25 5 g
Wheat starch ................................................................................................. 20 g
Maize starch ............................................................................................................. 20 g
Lactose ..................................................................................................................... 30 g
Magnesium stearate ................................................................................................. 2 g
Silica ........................................................................................................................ 1 g
Hydroxypropylcellulose .......................................................................................... 2 g
Claims (40)
1. Phosphate compound of formula (I): R (I) wherein: 5 ♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they may not simultaneously represent two carbons atoms or two nitrogen atoms, ♦ A and A , together with the atoms carrying them, form an optionally substituted, aromatic or non-aromatic heterocycle Het composed of 5, 6 or 7 ring members which may contain, in addition to the nitrogen represented by X or by Y, from one 10 to 3 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (C -C )alkyl group or a group -C(O)-O-Alk wherein Alk is a linear or branched (C -C )alkyl group, or A and A independently of one another represent a hydrogen atom, a linear or 15 branched (C -C )polyhaloalkyl, a linear or branched (C -C )alkyl group or a 1 6 1 6 cycloalkyl, ♦ T represents a hydrogen atom, a linear or branched (C -C )alkyl group optionally substituted by from one to three halogen atoms, a group (C -C )alkyl-NR R , or a 1 4 1 2 group (C -C )alkyl-OR , 1 4 6 ♦ R and R independently of one another represent a hydrogen atom or a linear or 5 branched (C -C )alkyl group, or R and R form with the nitrogen atom carrying them a heterocycloalkyl, ♦ R represents a linear or branched (C -C )alkyl group, a linear or branched 3 1 6 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a cycloalkyl 2 6 2 6 group, a (C -C )cycloalkyl-(C -C )alkyl group wherein the alkyl moiety is linear 3 10 1 6 10 or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated, ♦ R represents a phenyl or a pyrimidinyl group both substituted in the para position by one of the following phosphate groups: -OPO(OM)(OM'), - - + - + - + - - 2+ 15 OPO(OM)(O M ), -OPO(O M )(O M ), -OPO(O )(O )M ,- 1 1 2 3 - + 3 OPO(OM)(O[CH CH O] CH ), or -OPO(O M )(O[CH CH O] CH ), wherein M 2 2 n 3 1 2 2 n and M' independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or 1 6 2 6 branched (C -C )alkynyl group, a cycloalkyl or a heterocycloalkyl both composed 20 of 5 or 6 ring members, while M and M independently of one another represent a pharmaceutically acceptable monovalent cation, and M represents a pharmaceutically acceptable divalent cation and n is an integer from 1 to 5, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated, 25 ♦ R represents a hydrogen or halogen atom, a linear or branched (C -C )alkyl group, 5 1 6 or a linear or branched (C -C )alkoxy group, ♦ R represents a hydrogen atom or a linear or branched (C -C )alkyl group, 6 1 6 ♦ R , R , R and R , each independently of the others, represent R , a halogen atom, a a b c d 7 linear or branched (C -C )alkoxy group, a hydroxy group, a linear or 30 branched (C -C )polyhaloalkyl group, a trifluoromethoxy group, -NR R ', nitro, R -CO-(C -C )alkyl-, R -CO-NH-(C -C )alkyl-, 7 7 7 0 6 7 0 6 NR R '-CO-(C -C )alkyl-, NR R '-CO-(C -C )alkyl-O-, R -SO -NH-(C -C )alkyl-, 7 7 0 6 7 7 0 6 7 2 0 6 R -NH-CO-NH-(C -C )alkyl-, R -O-CO-NH-(C -C )alkyl-, a heterocycloalkyl 7 0 6 7 0 6 group, or the substituents of one of the pairs (R ,R ), (R ,R ) or (R ,R ) form a b b c c d together with the carbon atoms carrying them a ring composed of from 5 to 7 ring members, which may contain from one to 2 hetero atoms selected from oxygen and 5 sulphur, it also being understood that one or more carbon atoms of the ring defined hereinbefore may be deuterated or substituted by from one to 3 groups selected from halogen and linear or branched (C -C )alkyl, ♦ R and R ' independently of one another represent a hydrogen, a linear or branched (C -C )alkyl, a linear or branched (C -C )alkenyl, a linear or branched 1 6 2 6 10 (C -C )alkynyl, an aryl or a heteroaryl, or R and R ' together with nitrogen atom 2 6 7 7 carrying them form a heterocycle composed of from 5 to 7 ring members, it being understood that: - "aryl" means a phenyl, naphthyl, biphenyl or indenyl group, - "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring 15 members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quaternary nitrogens), - "cycloalkyl" means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 10 ring members, - "heterocycloalkyl" means any mono- or bi-cyclic, non-aromatic, condensed or spiro 20 group composed of 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO and nitrogen, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups selected from linear or branched (C -C )alkyl, (C -C )spiro, linear or branched (C - 1 6 3 6 1 25 C )alkoxy, (C -C )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, - 6 1 6 COOR', -OCOR', NR'R'', linear or branched (C -C )polyhaloalkyl, trifluoromethoxy, (C - 1 6 1 C )alkylsulphonyl, halogen, aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, it being understood that R' and R'' independently of one another represent a hydrogen atom or linear or 30 branched (C -C )alkyl group, it being possible for the Het group defined in formula (I) to be substituted by from one to three groups selected from linear or branched (C -C )alkyl, hydroxy, linear or branched (C -C )alkoxy, NR 'R " and halogen, it being understood that R ' and R " are as defined 1 6 1 1 1 1 for the groups R' and R'' mentioned hereinbefore, 5 its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
2. Compound of formula (I) according to claim 1, wherein R represents phenyl substituted in the para position by a group of formula -OPO(OM)(OM'), - + - + - + - - 2+ -OPO(OM)(O M ), -OPO(O M )(O M ), -OPO(O )(O )M , 1 1 2 3 10 -OPO(OM)(O[CH CH O] CH ), or -OPO(O M )(O[CH CH O] CH ), wherein M and M' 2 2 n 3 1 2 2 n 3 independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl 2 6 2 6 group, a cycloalkyl or a heterocycloalkyl both composed of 5 or 6 ring members, while M and M independently of one another represent a pharmaceutically acceptable 15 monovalent cation, and M represents a pharmaceutically acceptable divalent cation and n is an integer from 1 to 5, it being understood that the phenyl group may optionally be substituted by one or more halogen atoms.
3. Compound of formula (I) according to claim 1, wherein R represents phenyl - + - + substituted in the para position by a group of formula -OPO(O Na )(O Na ). 20
4. Compound of formula (I) according to one of claims 1 to 3, wherein X represents a carbon atom and Y represents a nitrogen atom.
5. Compound of formula (I) according to one of claims 1 to 3, wherein the group: represents a 5,6,7,8-tetrahydroindolizine, an indolizine or a dimethylated pyrrole.
6. Compound of formula (I) according to one of claims 1 to 5, wherein T represents a methyl, (morpholinyl)methyl or 3-(morpholinyl)propyl group. 5
7. Compound of formula (I) according to one of claims 1 to 6, wherein R and R each represent a hydrogen atom and (R ,R ), together with the carbon atoms carrying them, form a 1,3-dioxolane group or a 1,4-dioxane group; or R , R and R each represent a a c d hydrogen atom and R represents a hydrogen or a halogen.
8. Compound of formula (I) according to one of claims 1 to 6, wherein R and R each 10 represent a hydrogen atom, R represents a halogen atom and R a methoxy group.
9. Compound of formula (I) according to one of claims 1 to 6, wherein R , R and R a b d each advantageously represent a hydrogen atom and R represents a group NR R '-CO-(C -C )alkyl-O-. 7 7 0 6
10. Compound of formula (I) according to one of claims 1 to 9, wherein R 15 advantageously represents a group selected from phenyl, 1H-indole, 1H-pyrrolo[2,3-b]- pyridine, pyridine, 1H-pyrazole, 1H-pyrrole and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, those groups optionally having one or more substituents selected from linear or branched (C -C )alkyl, cyano and trideuteriomethyl.
11. Compound of formula (I) according to claim 1, selected from the following list: - 4-[{[3-(6-{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1,3-benzodioxolyl)-5,6,7,8-tetrahydroindolizin yl]carbonyl}(phenyl)amino]phenyl disodium phosphate, - 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- 5 yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(pyridin yl)amino]phenyl disodium phosphate, - 4-({[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}[1-(trideuteriomethyl)- 1H-pyrazolyl]amino)phenyl disodium phosphate, 10 - 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(5-cyano-1,2-dimethyl- 1H-pyrrolyl)amino]phenyl disodium phosphate, - 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(5-cyanomethyl-1H- 15 pyrrolyl)amino]phenyl disodium phosphate, - 4-[{[5-(5-chloro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}(1-methyl-1H-pyrazol- 4-yl)amino]phenyl disodium phosphate, - 4-[(5-cyano-1,2-dimethyl-1H-pyrrolyl){[5-(5-fluoro{[(3S)(morpholin 20 ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H- pyrrolyl]carbonyl}amino]phenyl disodium phosphate, - 4-[{[5-(5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl} (1-methyl-1H- pyrazolyl)amino]phenyl disodium phosphate, 25 their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
12. Compound of formula (I) according to claim 1 which is 4-[{[3-(6-{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol yl)-5,6,7,8-tetrahydroindolizinyl]carbonyl}(phenyl)amino]phenyl disodium phosphate. 5
13. Compound of formula (I) according to claim 1 which is 4-[{[5-(5-chloro{[(3S)- 3-(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-1H-pyrrolyl]carbonyl}(pyridinyl)amino]phenyl disodium phosphate.
14. Compound of formula (I) according to claim 1 which is 4-({[5-(5-chloro{[(3S)- 10 3-(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-1H-pyrrolyl]carbonyl}[1-(trideuteriomethyl)-1H-pyrazolyl]amino)phenyl disodium phosphate.
15. Compound of formula (I) according to claim 1 which is 4-[{[5-(5-chloro{[(3S)- 15 3-(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-1H-pyrrolyl]carbonyl}(5-cyano-1,2-dimethyl-1H-pyrrolyl)amino]phenyl disodium phosphate.
16. Compound of formula (I) according to claim 1 which is 4-[{[5-(5-chloro{[(3S)- 20 3-(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-1H-pyrrolyl]carbonyl}(5-cyanomethyl-1H-pyrrolyl)amino]phenyl disodium phosphate.
17. Compound of formula (I) according to claim 1 which is 4-[{[5-(5-chloro{[(3S)- 25 3-(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-1H-pyrrolyl]carbonyl}(1-methyl-1H-pyrazolyl)amino]phenyl disodium phosphate.
18. Compound of formula (I) according to claim 1 which is 4-[(5-cyano-1,2-dimethyl- 30 1H-pyrrolyl){[5-(5-fluoro{[(3S)(morpholinylmethyl)-3,4-dihydroisoquinolin- 2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrolyl]carbonyl}amino] phenyl disodium phosphate.
19. Compound of formula (I) according to claim 1 which is 4-[{[5-(5-fluoro{[(3S)- 3-(morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2- dimethyl-1H-pyrrolyl]carbonyl} (1-methyl-1H-pyrazolyl)amino]phenyl disodium 5 phosphate.
20. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material the compound of formula (II): (II) 10 wherein R , R , R and R are as defined in claim 1, a b c d which compound of formula (II) is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, of a base, of a phosphine and of the compound of formula (III): (III) 15 wherein A , A , X and Y are as defined in claim 1 and Alk represents a linear or branched (C -C )alkyl group, to obtain the compound of formula (IV): (IV) wherein A , A , X, Y, R , R , R and R are as defined in claim 1 and Alk is as defined 1 2 a b c d hereinbefore, the aldehyde function of which compound of formula (IV) is oxidised to a carboxylic acid 5 to form the compound of formula (V): wherein A , A , X, Y, R , R , R and R are as defined in claim 1 and Alk is as defined 1 2 a b c d hereinbefore, which compound of formula (V) is then subjected to peptide coupling with a compound of formula (VI): (VI) wherein T and R are as defined in claim 1, 5 to yield the compound of formula (VII): (VII) wherein A , A , X, Y, R , R , R , R , T and R are as defined in claim 1 and Alk is as 1 2 a b c d 5 defined hereinbefore, the ester function of which compound of formula (VII) is hydrolysed to yield the 10 corresponding carboxylic acid or carboxylate, which may be converted into an acid derivative such as the corresponding acyl chloride or anhydride before being coupled with an amine NHR R wherein R and R have the same meanings as in claim 1, before being 3 4 3 4 subjected to the action of a pyrophosphate, phosphonate or phosphoryl compound under basic conditions, it being possible for the compound thereby obtained to be optionally 15 hydrolysed or hydrogenolysed to yield the compound of formula (I), which compound of formula (I) may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, 5 it being understood that, at any time considered appropriate in the course of the above- described process, certain groups (hydroxy, amino…) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.
21. Pharmaceutical composition comprising a compound of formula (I) according to 10 any one of claims 1 to 19 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.
22. Pharmaceutical composition according to claim 21 for use as a prodrug of a pro-apoptotic agent.
23. Pharmaceutical composition according to claim 21 for use in the treatment of 15 cancers, auto-immune diseases and diseases of the immune system.
24. Pharmaceutical composition according to claim 23 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- 20 cell lung cancer, prostate cancer and small-cell lung cancer.
25. Use of a pharmaceutical composition according to claim 21 in the manufacture of a medicament for use as a pro-apoptotic agent.
26. Use of a pharmaceutical composition according to claim 21 in the manufacture of a medicament intended for the treatment of cancers, auto-immune diseases and diseases of the immune system.
27. Use, according to claim 26, of a pharmaceutical composition in the manufacture of 5 a medicament intended for the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer. 10
28. Compound of formula (I) according to one of claims 1 to 19, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung 15 cancer, prostate cancer and small-cell lung cancer.
29. Use of a compound of formula (I) according to one of claims 1 to 19, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of a medicament intended for the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, 20 lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
30. Combination of a compound of formula (I) according to any one of claims 1 to 19 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti- 25 metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
31. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-19 and an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies, in combination with one or more pharmaceutically acceptable excipients. 5
32. Combination according to claim 30 for use in the treatment of cancers.
33. Use of a compound of formula (I) according to any one of claims 1 to 19 and an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies in the manufacture of a medicament for use in the treatment of cancers. 10
34. Use of a compound of formula (I) according to any one of claims 1-19 in the manufacture of a medicament for use in the treatment of cancers wherein the medicament is for sequential or simultaneous administration with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
35. Compound of formula (I) according to any one of claims 1 to 19 for use in association with radiotherapy in the treatment of cancers.
36. A compound of claim 1, substantially as herein described with reference to any 20 example thereof.
37. A process of claim 20, substantially as herein described with reference to any example thereof. 25
38. A pharmaceutical composition of claims 21 and 31, substantially as herein described with reference to any example thereof.
39. A use of any one of claims 25, 26, 33 and 34, substantially as herein described with reference to any example thereof.
40. A combination of claim 30, substantially as herein described with reference to any 5 example thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1357259A FR3008979B1 (en) | 2013-07-23 | 2013-07-23 | NOVEL PHOSPHATE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
FR13/57259 | 2013-07-23 |
Publications (2)
Publication Number | Publication Date |
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NZ627178A NZ627178A (en) | 2016-01-29 |
NZ627178B true NZ627178B (en) | 2016-05-03 |
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