CN102648208A - 微管蛋白抑制剂 - Google Patents
微管蛋白抑制剂 Download PDFInfo
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- CN102648208A CN102648208A CN201080055660XA CN201080055660A CN102648208A CN 102648208 A CN102648208 A CN 102648208A CN 201080055660X A CN201080055660X A CN 201080055660XA CN 201080055660 A CN201080055660 A CN 201080055660A CN 102648208 A CN102648208 A CN 102648208A
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- Prior art keywords
- alkyl
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- 239000003744 tubulin modulator Substances 0.000 title 1
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000002769 thiazolinyl group Chemical group 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 8
- 238000011282 treatment Methods 0.000 abstract description 5
- 102000004243 Tubulin Human genes 0.000 abstract description 2
- 108090000704 Tubulin Proteins 0.000 abstract description 2
- -1 CO-alkyl Chemical group 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 125000004432 carbon atom Chemical group C* 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 16
- 125000004404 heteroalkyl group Chemical group 0.000 description 16
- 125000003342 alkenyl group Chemical group 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 208000032839 leukemia Diseases 0.000 description 7
- 239000011593 sulfur Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 208000025113 myeloid leukemia Diseases 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 4
- 208000004736 B-Cell Leukemia Diseases 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 4
- 208000000389 T-cell leukemia Diseases 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 229910052711 selenium Inorganic materials 0.000 description 4
- 239000011669 selenium Substances 0.000 description 4
- 229910052710 silicon Inorganic materials 0.000 description 4
- 239000010703 silicon Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 3
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 206010024305 Leukaemia monocytic Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 230000001684 chronic effect Effects 0.000 description 2
- 208000024207 chronic leukemia Diseases 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 235000019322 gelatine Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 201000006894 monocytic leukemia Diseases 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- JIDDDPVQQUHACU-YFKPBYRVSA-N (2s)-pyrrolidine-2-carbaldehyde Chemical group O=C[C@@H]1CCCN1 JIDDDPVQQUHACU-YFKPBYRVSA-N 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- MMZYCBHLNZVROM-UHFFFAOYSA-N 1-fluoro-2-methylbenzene Chemical compound CC1=CC=CC=C1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Abstract
本发明涉及式(I)的新微管蛋白结合分子以及它们用于治疗癌症和其他疾病的用途。
Description
技术领域
本发明涉及一类新的细胞毒性分子以及它们用于治疗癌症和其他疾病的用途。
发明内容
本发明的目的是提供具有高度有效的抗癌细胞系活性的新的细胞毒性分子。
本发明提供一种或多种式(I)的化合物或者其药理学可接受的盐、溶剂合物、水合物或药理学可接受的制剂：
其中
R为烷基、烯基、炔基、CO-烷基、杂烷基、芳烷基或杂芳烷基，所有上述基团均可以是任选地被取代的；
R’为OH、烷基、烯基、炔基、-O-CO-烷基或杂烷基，所有上述基团均可以是任选地被取代的；
R”为式CO2H、CO2R”’、CONHR”’或CONR2”’的基团，其中R”’独立地为烷基、芳基、芳烷基或杂烷基；
X为S或O；
Y独立地为任选地被取代的烷基、任选地被取代的杂烷基、卤素、CN、NO2或OH；
n为0、1、2、3、4或5。
表述烷基指饱和的直链或支化的烃基，其包含1-20个碳原子，优选1-12个碳原子，特别是1-6(例如1、2、3或4)个碳原子，例如甲基、乙基、丙基、异丙基、异丁基、正丁基、仲丁基、叔丁基、正戊基、2,2-二甲基丙基、2-甲基丁基、正己基、2,2-二甲基丁基或2,3-二甲基丁基。
表述烯基和炔基指至少部分不饱和的直链或支化的烃基，其包含2-20个碳原子，优选2-12个碳原子，特别是2-6(例如2、3或4)个碳原子，例如乙烯基、烯丙基、乙炔基、炔丙基、异戊烯基或己-2-烯基。优选地，烯基具有一个或两个(特别优选一个)双键，而炔基具有一个或两个(特别优选一个)三键。
此外，术语烷基、烯基和炔基指其中一个或多个氢原子(例如1、2或3个氢原子)被卤素原子(优选F或Cl)代替的基团，例如，2,2,2-三氯乙基或三氟甲基。
表述杂烷基指烷基、烯基或炔基，其中一个或多个(优选1、2或3个)碳原子被氧、氮、磷、硼、硒、硅或硫原子(优选被氧、硫或氮原子)代替。表述杂烷基还指羧酸或衍生自羧酸的基团，例如酰基(烷基-CO-)、酰基烷基、烷氧基羰基、酰氧基、酰氧基烷基、羧基烷基酰胺或烷氧基羰基氧基。
优选地，杂烷基包含1-12个碳原子以及1-4个选自氧、氮和硫(特别是氧和氮)的杂原子。特别优选地，杂烷基包含1-6(例如1、2、3或4)个碳原子以及1、2或3(特别是1或2)个选自氧、氮和硫(特别是氧和氮)的杂原子。
杂烷基的实例为下式的基团：Ra-O-Ya-、Ra-S-Ya-、Ra-N(Rb)-Ya-、Ra-CO-Ya-、Ra-O-CO-Ya-、Ra-CO-O-Ya-、Ra-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-Ya-、Ra-O-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-O-Ya-、Ra-N(Rb)-CO-N(Rc)-Ya-、Ra-O-CO-O-Ya-、Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-、Ra-CS-Ya-、Ra-O-CS-Ya-、Ra-CS-O-Ya-、Ra-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-Ya-、Ra-O-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-O-Ya-、Ra-N(Rb)-CS-N(Rc)-Ya-、Ra-O-CS-O-Ya-、Ra-S-CO-Ya-、Ra-CO-S-Ya-、Ra-S-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-S-Ya-、Ra-S-CO-O-Ya-、Ra-O-CO-S-Ya-、Ra-S-CO-S-Ya-、Ra-S-CS-Ya-、Ra-CS-S-Ya-、Ra-S-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-S-Ya-、Ra-S-CS-O-Ya-、Ra-O-CS-S-Ya-，其中Ra为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基，Rb为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基，Rc为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基，Rd为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基，并且Ya为直接的键、C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基，其中每个杂烷基包含至少一个碳原子，并且一个或多个氢原子可以被卤素(例如氟或氯)原子代替。
杂烷基的具体实例为甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、甲氧基甲基、乙氧基甲基、-CH2CH2OH、-CH2OH、-CH2CH2SH、-CH2SH、-CH2CH2SSCH2CH2NH2、-CH2CH2SSCH2CH2COOH、甲氧基乙基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、异丙基乙基氨基、甲基氨基甲基、乙基氨基甲基、二异丙基氨基乙基、烯醇醚、二甲基氨基甲基、二甲基氨基乙基、乙酰基、丙酰基、丁酰氧基、乙酰氧基、甲氧基羰基、乙氧基羰基、N-乙基-N-甲基氨基甲酰基或N-甲基氨基甲酰基。杂烷基的其他实例为腈、异腈、氰酸酯、硫氰酸酯、异氰酸酯、异硫氰酸酯以及烷基腈基团。
表述环烷基指饱和或部分不饱和(例如，环烯基)的环状基团，其包含一个或多个环(优选1或2个)，并且包含3-14个环碳原子，优选3-10(特别是3、4、5、6或7)个环碳原子。表述环烷基还指其中一个或多个氢原子被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH、N3或NO2基团代替的基团，因此，例如环酮，如环己酮、2-环己烯酮或环戊酮。环烷基的其他具体实例为环丙基、环丁基、环戊基、螺[4,5]癸基、降龙脑基(norbornyl)、环己基、环戊烯基、环己二烯基、萘烷基、二环[4.3.0]壬基、四氢化萘、环戊基环己基、氟环己基或环己-2-烯基。
表述杂环烷基指如上文所定义的环烷基，其中一个或多个(优选1、2或3个)环碳原子各自独立地被氧、氮、硅、硒、磷或硫原子(优选被氧、硫或氮原子)代替。杂环烷基优选具有1或2个包含3-10(特别是3、4、5、6或7)个环原子(优选选自C、O、N和S)的环。表述杂环烷基还指其中一个或多个氢原子被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH、N3或NO2基团代替的基团。实例为哌啶基、脯氨酰基(prolinyl)、咪唑烷基、哌嗪基、吗啉基、乌洛托品基(urotropinyl)、吡咯烷基、四氢噻吩基(tetrahydrothiophenyl)、四氢吡喃基、四氢呋喃基或2-吡唑啉基，以及内酰胺、内酯、环状亚胺和环酐。
表述烷基环烷基指包含根据上文定义的环烷基以及烷基、烯基或炔基的基团，例如烷基环烷基、环烷基烷基、烷基环烯基、烯基环烷基和炔基环烷基。烷基环烷基优选包含环烷基以及一个或两个烷基、烯基或炔基，所述环烷基包含一个或两个具有3-10(特别是3、4、5、6或7)个环碳原子的环系统，所述烷基、烯基或炔基具有1或2至6个碳原子。
表述杂烷基环烷基指如上文所定义的烷基环烷基，其中一个或多个(优选1、2或3个)碳原子各自独立地被氧、氮、硅、硒、磷或硫原子(优选被氧、硫或氮原子)代替。杂烷基环烷基优选包含1或2个具有3-10(特别是3、4、5、6或7)个环原子的环系统，以及一个或两个具有1或2至6个碳原子的烷基、烯基、炔基或杂烷基。这类基团的实例为烷基杂环烷基、烷基杂环烯基、烯基杂环烷基、炔基杂环烷基、杂烷基环烷基、杂烷基杂环烷基以及杂烷基杂环烯基，所述环状基团是饱和的或者单、双或三不饱和的。
表述芳基或Ar指芳香基团，其包含一个或多个包含6-14个环碳原子、优选6-10(特别是6)个环碳原子的环。表述芳基(或分别的Ar)还指其中一个或多个氢原子被氟、氯、溴或碘原子或者被OH、SH、NH2、N3或NO2基团代替的基团。实例为苯基、萘基、联苯基、2-氟苯基、苯胺基、3-硝基苯基或4-羟基苯基。
表述杂芳基指芳香基团，其包含一个或多个包含5-14个环原子、优选5-10(特别是5或6)个环原子的环，并且包含一个或多个(优选1、2、3或4个)氧、氮、磷或硫环原子(优选O、S或N)。表述杂芳基还指其中一个或多个氢原子被氟、氯、溴或碘原子或者被OH、SH、N3、NH2或NO2基团代替的基团。实例为吡啶基(例如4-吡啶基)、咪唑基(例如2-咪唑基)、苯基吡咯基(例如3-苯基吡咯基)、噻唑基、异噻唑基、1,2,3-三唑基、1,2,4-三唑基、噁二唑基、噻二唑基、吲哚基、吲唑基、四唑基、吡嗪基、嘧啶基(pyrimidinyl)、哒嗪基、噁唑基、异噁唑基、三唑基、四唑基、异噁唑基、吲唑基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、哒嗪基、喹啉基、异喹啉基、吡咯基、嘌呤基、咔唑基、吖啶基、嘧啶基(pyrimidyl)、2,3′-二呋喃基、吡唑基(例如3-吡唑基)以及异喹啉基。
表述芳烷基指包含按照上文定义的芳基以及烷基、烯基、炔基和/或环烷基的基团，例如，芳基烷基、芳基烯基、芳基炔基、芳基环烷基、芳基环烯基、烷基芳基环烷基以及烷基芳基环烯基。芳烷基的具体实例为甲苯、二甲苯、均三甲苯(mesitylene)、苯乙烯、苄基氯、邻氟甲苯、1H-茚、四氢化萘、二氢萘、2,3-二氢-1-茚酮、苯基环戊基、枯烯、环己基苯基、芴以及1,2-二氢化茚。芳烷基优选包含一个或两个芳香环系统(1或2个环)以及一个或两个烷基、烯基和/或炔基，和/或环烷基，所述芳香环系统包含6-10个碳原子，所述烷基、烯基和/或炔基包含1或2至6个碳原子，所述环烷基包含5或6个环碳原子。
表述杂芳烷基指如上文所定义的芳烷基，其中一个或多个(优选1、2、3或4个)碳原子各自独立地被氧、氮、硅、硒、磷、硼或硫原子(优选氧、硫或氮)代替，即指分别包含按照上文定义的芳基或杂芳基，以及烷基、烯基、炔基和/或杂烷基和/或环烷基和/或杂环烷基的基团。杂芳烷基优选包含一个或两个芳香环系统(1或2个环)以及一个或两个烷基、烯基和/或炔基，和/或环烷基，所述芳香环系统包含5或6至10个环碳原子，所述烷基、烯基和/或炔基包含1或2至6个碳原子，所述环烷基包含5或6个环碳原子，其中这些碳原子中的1、2、3或4个被氧、硫或氮原子代替。
实例为芳基杂烷基、芳基杂环烷基、芳基杂环烯基、芳基烷基杂环烷基、芳基烯基杂环烷基、芳基炔基杂环烷基、芳基烷基杂环烯基、杂芳基烷基、杂芳基烯基、杂芳基炔基、杂芳基杂烷基、杂芳基环烷基、杂芳基环烯基、杂芳基杂环烷基、杂芳基杂环烯基、杂芳基烷基环烷基、杂芳基烷基杂环烯基、杂芳基杂烷基环烷基、杂芳基杂烷基环烯基以及杂芳基杂烷基杂环烷基，所述环状基团是饱和的或者单、双或三不饱和的。具体实例为四氢异喹啉基、苯甲酰基、2-或3-乙基吲哚基、4-甲基吡啶并、2-,3-或4-甲氧基苯基、4-乙氧基苯基、2-,3-或4-羧基苯基烷基。
术语“任选地被取代”涉及这样的基团，其中一个或多个氢原子被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH或NO2基团代替。该术语还涉及这样的基团，其可以唯一或额外地被未取代的C1-C6烷基、C2-C6烯基、C2-C6炔基(alkinyl)或C1-C6杂烷基取代。
保护基团是本领域技术人员已知的，并且例如P.J.Kocienski,ProtectingGroups,Georg Thieme Verlag,Stuttgart,1994和T.W.Greene,P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,New York,1999所述。常见的氨基保护基团例如叔丁氧基羰基(Boc)、叔丁基二甲基甲硅烷基(TBS)、苄氧基羰基(Cbz,Z)、苄基(Bn)、苯甲酰基(Bz)、芴基甲氧基羰基(Fmoc)、烯丙氧基羰基(Alloc)、三乙基甲硅烷基(TES)、三氯乙氧基羰基(Troc)、乙酰基或三氟乙酰基。
式(I)的化合物可以包含几个手性中心，这取决于它们的取代模式。本发明涉及所有定义的对映异构体和非对映异构体以及它们的所有比例的混合物。此外，本发明涉及通式(I)的化合物的所有顺式/反式异构体以及它们的混合物。此外，本发明涉及通式(I)的化合物的所有互变异构形式。
优选地，R为C1-C6烷基；特别是甲基、乙基、丙基、丁基、异丙基、异丁基、正戊基或正己基。
优选地，R’为-O-CO-烷基、烷基或杂烷基(例如-O-烷基、-O-烷基-O-烷基)，特别是O-乙酰基(OAc,OCOCH3)、-O-丙基或-OCH2OCH3。
优选地，R”为式CO2H或CO2R”’的基团，其中R”’优选为烷基。
优选地，X为S。
优选地，Y独立地为任选地被取代的烷基、卤素(例如F或Cl)或OH。
优选地，n为0、1、2或3，特别是0或1。
特别优选式(I)的化合物，其中：
R为C1-C6烷基，特别是-CH3、乙基、丙基或丁基；
R’为-O-CO-烷基或杂烷基，特别是-O-CO-CH3、-O-丙基或-OCH2OCH3；
R”为-CO2H或-CO2R”’，其中R”’为烷基；
X为S；
Y独立地为任选地被取代的烷基、卤素(例如F或Cl)或OH；并且
n为0或1。
式(I)的化合物的药理学可接受的盐的实例是生理上可接受的无机酸的盐，例如盐酸、硫酸和磷酸；或者有机酸的盐，例如甲磺酸、对甲苯磺酸、乳酸、甲酸、乙酸、三氟乙酸、柠檬酸、琥珀酸、富马酸、马来酸和水杨酸。式(I)的化合物的药理学可接受的盐的其他实例是碱金属和碱土金属盐，例如钠、钾、锂、钙或镁盐；铵盐或者有机碱的盐，例如甲胺、二甲胺、三乙胺、哌啶、乙二胺、赖氨酸、氢氧化胆碱(choline hydroxide)、甲基葡胺、吗啉或精氨酸盐。式(I)的化合物可以是溶剂化的，特别是水合的。水合可以发生在例如制备过程中，或者由于式(I)的初始无水化合物的吸湿性。溶剂合物和/或水合物可以例如以固体或液体形式存在。
式(I)的化合物，它们各自的药理学可接受的盐、溶剂合物和水合物，以及制剂和药物组合物的治疗用途也在本发明的范围内。
本发明的药物组合物包含至少一种式(I)的化合物作为活性成分，以及任选存在的载体物质和/或佐剂。
式(I)化合物在制备用于治疗和/或预防癌症或其他疾病的药物中的用途也是本发明的目的。此外，本发明的化合物可用于预防和/或治疗肿瘤疾病。
可以由本发明的组合物和方法治疗或预防的癌症包括但不限于人肉瘤和癌，例如纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎瘤、维耳姆斯瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜细胞瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑素瘤、神经母细胞瘤、视网膜母细胞瘤；白血病，例如急性淋巴细胞白血病和急性粒细胞白血病(原始粒细胞、早幼粒细胞、粒-单核细胞、单核细胞和红白血病)；慢性白血病(慢性粒细胞(粒细胞)白血病和慢性淋巴细胞白血病)，以及真性红细胞增多症、淋巴瘤(霍奇金病和非霍奇金病)、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症和重链病。
白血病的其他实例包括急性和/或慢性白血病，例如淋巴细胞白血病(例如，如p388(小鼠)细胞系所示例)、大颗粒淋巴细胞白血病和原始淋巴细胞白血病；T-细胞白血病，例如T-细胞白血病(例如，如CEM、Jurkat和HSB-2(急性)，YAC 1(小鼠)细胞系所示例)、T-淋巴细胞白血病和T-原始淋巴细胞白血病；B细胞白血病(例如，如SB(急性)细胞系所实例)，和B-淋巴细胞白血病；混合型细胞白血病(mixed cellieukaemia)，例如B和T细胞白血病以及B和T淋巴细胞白血病；髓性白血病，例如粒细胞白血病、髓细胞白血病(例如，如HL-60(早幼粒细胞)细胞系所示例)和髓细胞性白血病(例如，如K562(慢性)细胞系所示例)；中性粒细胞白血病；嗜酸性粒细胞白血病；单核细胞白血病(例如，如THP-1(急性)细胞系所示例)；粒-单核细胞白血病；内格利型髓性白血病；以及非淋巴细胞白血病。白血病的其他实例描述于The Chemotherapy Sourcebook,Michael C.Perry Ed.,Williams &Williams(1992)的第60章和Holland Frie Cancer Medicine 5th Ed.,Bast et al.Eds.,B.C.Decker Inc.(2000)的第36节。前述参考文献整体援引加入本文。
一般来说，式(I)的化合物可以作为单一治疗或作为综合治疗单独或与任意治疗物质联合根据已知并接受的模式给药，或者作为连续治疗给药，其中有效成分可以包埋在基质中，例如可植入的水凝胶。本发明的组合物可以以下方式之一给药：口服，包括糖锭剂、包衣片剂、丸剂、半固体、软胶囊剂或硬胶囊剂、溶液剂、乳剂或者混悬剂；肠胃外，包括可注射的溶液剂；直肠，如栓剂；通过吸入，包括粉末制剂或者如喷雾剂、透皮或鼻内。为了制备这类片剂、丸剂、半固体、包衣片剂、糖锭剂和硬明胶胶囊剂，将治疗用产物与药理学惰性的无机或有机载体混合，例如与乳糖、蔗糖、葡萄糖、明胶、麦芽糖、硅胶、淀粉或它们的衍生物、滑石、硬脂酸或其盐、脱脂奶粉等混合。为了制备软胶囊剂，可以使用载体，如植物油、石油、动物油或合成油、蜡、脂肪、多元醇。为了制备液体溶液剂和糖浆剂，可以使用载体，例如水、醇、盐水溶液、葡萄糖水溶液、多元醇、甘油、植物油、石油、动物油或合成油。为了制备栓剂，可以使用赋形剂，例如植物油、石油、动物油或合成油、蜡、脂肪以及多元醇。对于气溶胶制剂，可以使用适合这个目的的压缩气体，例如氧气、氮气、稀有气体和二氧化碳。药学有用的物质还可以包含用于保存、稳定的添加剂，例如UV稳定剂、乳化剂、甜味剂、芳化剂、改变渗透压的盐、缓冲剂、包衣添加剂以及抗氧化剂。
与其他治疗剂的组合可以包括常用来治疗上文所提到的疾病，特别是肿瘤疾病的其他物质。
令人惊讶地发现，本发明的化合物表现出与已知的Tubulysins(参见例如WO 9813375;F.Sasse,H.Steinmetz,G.
H.Reichenbach,J.Antibiot.2000,53,879-885;A.W.Patterson et al,Chem.Eur.J.2007,13,9534-9541)相同或非常相似的生物学活性，虽然“Tup”单元已被苯丙氨酸衍生物代替，但是苯丙氨酸衍生物是更简单的结构单元，其合成简单得多。用天然氨基酸代替“Tup”单元使得整个化合物更肽样(peptide-like)，这提高化合物在体内的生物降解性。而且，这种代替导致所得的化合物的总分子量(overallweight)减少，这导致提高的生物利用度。此外，新化合物表现出增强的对微管蛋白的结合。
具体实施方式
根据本文所公开的构件(building block)的合成方法，利用本领域技术人员已知的常见的肽偶联方法合成式(I)的化合物。
在制备时式(I)的化合物具有以下残基：
R：H、甲基、丙基；
R’：O乙酰基、-OCH2OCH3；
R”：-CO2H、-CO2CH3、-CONHCH2CH2OH；
X：S；
Y：H、F、OH；
n：0、1。
特别优选这些化合物。
合成方法
用于制备式(I)的化合物的各构件的合成根据PCT/EP2008/003762(WO2008/138561)所述的方法来进行。本专利所述的所有化合物均通过1H-NMR、13C-NMR和质谱分析来表征。纯度通过HPLC来鉴定。
RD325
向二肽(150mg,0.35mmol)在DMF(5mL)中的溶液加入HOAt(57mg,0.42mmol)、HATU(160mg,0.42mmol)和Et3N(107μL,0.77mmol)。搅拌5min后，加入盐酸盐形式的苯丙氨酸甲酯(84mg,0.39mmol)。将反应混合物搅拌2h，将反应用H2O(10mL)稀释，并且用Et2O萃取(1x10mL)。将有机相用1N HCl水溶液(1x15mL)、饱和的NaHCO3水溶液(1x15mL)和盐水(2x15mL)洗涤。用无水Na2SO4干燥并过滤后，在真空中去除溶剂以提供176mg白色泡沫状的纯RD325(86%收率)。
RD327
向RD325(166mg,0.28mmol)在MeOH(5mL)中的溶液加入Pd/C。将反应混合物在氢气气氛下搅拌18h。将反应通过硅藻土过滤，并且将滤液在减压下浓缩以提供157mg白色泡沫状的纯RD327(定量收率)。
RD329
向Mep(44mg,0.31mmol)在DCM(5mL)中的悬浮液加入HOAt(46mg,0.34mmol)、HATU(129mg,0.34mmol)、Et3N(86μL,0.62mmol)和RD327(157mg,0.28mmol)。将反应混合物搅拌4h。将反应用H2O(10mL)、饱和的NaHCO3水溶液(1x15mL)和盐水(1x15mL)洗涤。用无水Na2SO4干燥并过滤后，在真空中去除溶剂。将粗产物通过FC (DCM:MeOH 95:5)纯化以提供178mg白色泡沫状的RD329(92%收率)。
RD331
向RD329(168mg,0.24mmol)在THF(5mL)中的溶液加入1N LiOH水溶液(720μL,0.72mmol)。将反应搅拌18h，然后用TFA酸化直至达到pH1-2。将所得的混合物用H2O(5mL)洗涤，并且用AcOEt(10mL)萃取。将有机相用无水Na2SO4干燥，过滤，并且在真空中去除溶剂。将残余物通过FC(DCM/MeOH 9:1)纯化，提供169mg白色泡沫状的RD331(90%收率)。
RD333
向RD331(157mg,0.20mmol)在吡啶(4mL)中的溶液加入Ac2O(2mL)，并且将溶液搅拌过夜。在真空中去除溶剂，并且将粗产物通过FC(DCM:MeOH 98:2,9:1)和反相HPLC纯化以提供25mg的RD333(16%收率)。
RD370
向在0°C下冷却的乙醇胺(0.603mL,10mmol)在DCM(5mL)中的溶液加入TBDPCl(2607μL,1mmol)。使反应混合物升温至r.t.，搅拌过夜并用水(5mL)终止。将层分离，将有机相用无水Na2SO4干燥，过滤，并且在真空中去除溶剂。将残余物通过FC(DCM/MeOH 9:1)纯化，提供154mg无色油状的RD370(51%收率)。
RD373
向被保护的苯丙氨酸(183mg,0.61mmol)在DMF(5mL)中的溶液加入HOBt(89mg,0.66mmol)、EDC HCl(126mg,0.66mmol)和Et3N(163μL,1.17mmol)。搅拌5min后，加入RD370(154mg,0.51mmol)。将反应混合物搅拌2h。将反应用H2O(10mL)稀释，并且用Et2O萃取(1x10mL)。将有机相用饱和的NaHCO3水溶液(1x15mL)和盐水(2x15mL)洗涤。用无水Na2SO4干燥并过滤后，在真空中去除溶剂。将残余物通过FC(Hex/AcOEt75:25)纯化以提供258mg白色泡沫状的RD373(87%收率)。
RD375
向RD373(248mg,0.43mmol)在MeOH(5mL)中的溶液加入Pd/C。将反应混合物在氢气气氛下搅拌18h。将反应通过硅藻土过滤，并且将滤液在减压下浓缩以提供178mg无色油状的胺(93%收率)。向二肽(65mg,0.15mmol)在DMF(5mL)中的悬浮液加入HOAt(25mg,0.18mmol)、HATU(68mg,0.18mmol)、Et3N(46μL,0.33mmol)和胺(80mg,0.18mmol)。将反应混合物搅拌4h，并且加入20mL Et2O。将反应用H2O(10mL)、饱和的NaHCO3水溶液(1x15mL)和盐水(1x15mL)洗涤。用无水Na2SO4干燥并过滤后，在真空中去除溶剂以提供127mg白色泡沫状的纯RD375(定量收率)。
RD378
向RD375(120mg,0.14mmol)在DCM(10mL)中的溶液加入Ac2O(57μL,0.7mmol)、吡啶(33μL,0.35mmol)和催化量的DMAP。将反应混合物搅拌3h，并且在真空中去除溶剂。将残余物通过FC(Hex/AcOEt 6:4)纯化以提供111mg白色泡沫状的RD378(88%收率)。
RD381
向RD378(105mg,0.12mmol)在MeOH(5mL)中的溶液加入Pd/C。将反应混合物在氢气气氛下搅拌18h。将反应通过硅藻土过滤，并且将滤液在减压下浓缩以提供96mg白色泡沫状的纯RD381(92%收率)。
RD382
向Mep(19mg,0.13mmol)在DCM(5mL)中的悬浮液加入HOAt(19mg,0.14mmol)、HATU(55mg,0.14mmol)、Et3N(37μL,0.26mmol)和RD381(95mg,0.11mmol)。将反应混合物搅拌4h。将反应用H2O(10mL)、饱和的NaHCO3水溶液(1x15mL)和盐水(1x15mL)洗涤。用无水Na2SO4干燥并过滤后，在真空中去除溶剂。将粗产物通过FC(DCM:MeOH 97:3)纯化以提供74mg白色泡沫状的RD382(67%收率)。
RD387
向RD382(69mg,0.07mmol)在THF(3mL)中的溶液加入Bu4NF在THF中的1M溶液(140μL,0.14mmol)。将反应混合物搅拌30min，并且用水(5mL)洗涤。将水相用AcOEt萃取(1X10mL)。将收集的有机相用无水Na2SO4干燥，过滤，并且在真空中去除溶剂。将粗产物通过FC(DCM:MeOH97:3,9:1)纯化以提供36mg白色泡沫状的RD387(68%收率)。
用于制备式(I)的化合物的各种构件的合成
MSRD356
向二肽(200mg,0.44mmol)在氯仿/甲醛缩二甲醇的1:1混合物(2mL)中的溶液分批加入P2O5(626mg,4.4mmol)。将反应混合物倒入饱和的NaHCO3水溶液(25mL)，并且用AcOEt萃取(1x10mL)。在真空中去除溶剂，并且将粗产物通过快速色谱(己烷:AcOEt 7:3)纯化以提供154mg无色油状的MSRD356(70%收率)。
MSRD357
向MSRD356(144mg,0.29mmol)在THF/H2O 4:1混合物(5mL)中的溶液加入LiOH.H2O(19mg,0.43mmol)。将反应搅拌5h，然后加入H2O(10mL)和AcOEt(10mL)。将层分离，并且将1M的HCl溶液加入水相直至达到pH 1-2。将所得的混合物用AcOEt萃取。将有机相用无水Na2SO4干燥，过滤，并且在真空中去除溶剂以提供119mg白色固体状的纯MSRD357(87%收率)。
使用适当的起始原料根据类似方法合成化合物RD343、RD358、RD410和RD483。
测定抗各种癌细胞系的IC-50浓度
在体外利用基于荧光刃天青的测定来确定本发明的一些代表性实例化合物的抗增殖活性。如Strotmann,U.J.,et al.,The dehydrogenase assay withresazurin:Practical performance as a monitoring system and pH-dependenttoxicity of phenolic compounds.Ecotox.Environ.Safety 25,79-89,(1993)所述，根据通过代谢活跃细胞的非荧光刃天青还原为荧光染料试卤灵来定量癌细胞的增殖和成活力。
结果如表1所示。
表1
总的来说，本发明的新分子表现出0.1-400 nM的抗几种癌细胞系的活性。
Claims (12)
1.式(I)的化合物或者其药理学可接受的盐、溶剂合物、水合物或药理学可接受的制剂：
其中
R为H、烷基、烯基、炔基、CO-烷基、杂烷基、芳烷基或杂芳烷基，所有上述基团均可以是任选地被取代的；
R’为OH、烷基、烯基、炔基、-O-CO-烷基或杂烷基，所有上述基团均可以是任选地被取代的；
R”为式CO2H、CO2R”’、CONHR”’、CONR2”’的基团，其中R”’独立地为烷基、芳基、芳烷基或杂烷基；
X为S或O；
Y独立地为任选地被取代的烷基、任选地被取代的杂烷基、卤素、CN、NO2或OH；
n为0、1、2、3、4或5。
2.如权利要求1所述的化合物，其中R为C1-C6烷基。
3.如权利要求1或2所述的化合物，其中R’为-O-CO-烷基、烷基或杂烷基。
4.如权利要求1-3中任一项所述的化合物，其中R”为CO2H。
5.如权利要求1-3中任一项所述的化合物，其中R”为式CO2R”’、CONHR”’或CONR2”’的基团，其中R”’为烷基、芳基、芳烷基或杂烷基。
6.如权利要求1-5中任一项所述的化合物，其中X为S。
7.如权利要求1-6中任一项所述的化合物，其中Y独立地为任选地被取代的烷基、卤素或OH，并且n为1。
8.如权利要求1-6中任一项所述的化合物，其中n为0。
9.如权利要求1所述的化合物，其中R为丙基，R’为O-乙酰基，X为S，n为0并且R”为CO2H。
10.药物组合物，其包含权利要求1-9中任一项所述的化合物以及任选存在的一种或多种载体和/或佐剂。
11.如权利要求1-10中任一项所述的化合物或药物组合物，其用作治疗和/或预防癌症疾病的药物。
12.权利要求1-10中任一项所述的化合物或药物组合物用于治疗癌症疾病的用途。
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