CN113929727A - 阿比特龙酯类衍生物及其制备方法和应用 - Google Patents
阿比特龙酯类衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN113929727A CN113929727A CN202111143981.1A CN202111143981A CN113929727A CN 113929727 A CN113929727 A CN 113929727A CN 202111143981 A CN202111143981 A CN 202111143981A CN 113929727 A CN113929727 A CN 113929727A
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- abiraterone
- stereoisomer
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960000853 abiraterone Drugs 0.000 title abstract description 24
- -1 Abiraterone ester Chemical class 0.000 title abstract description 22
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008157 edible vegetable oil Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 13
- 238000004949 mass spectrometry Methods 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 229960004103 abiraterone acetate Drugs 0.000 description 7
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 5
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 5
- 210000001365 lymphatic vessel Anatomy 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 239000003098 androgen Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000004006 olive oil Substances 0.000 description 4
- 235000008390 olive oil Nutrition 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000001854 Steroid 17-alpha-Hydroxylase Human genes 0.000 description 3
- 108010015330 Steroid 17-alpha-Hydroxylase Proteins 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000010579 first pass effect Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229940124766 Cyp17 inhibitor Drugs 0.000 description 2
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 2
- 229960005471 androstenedione Drugs 0.000 description 2
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 229960002847 prasterone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical class OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical class NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical class OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 101100288143 Rattus norvegicus Klkb1 gene Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical class OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 125000005534 decanoate group Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及具有通式I的阿比特龙酯类衍生物、包含该化合物的药物组合物,以及该化合物和药物组合用于治疗和/或预防肿瘤的用途。式中基团定义详见说明书。
Description
技术领域
本发明属于医药领域,具体涉及一种阿比特龙酯类衍生物及其立体异构体或药学上可接受的盐,以及其在制备用于预防和治疗癌症相关药物中的用途。
背景技术
前列腺癌是男性常见的恶性致死性癌症。雄激素是前列腺癌症发生的关键因素。烯醇酮和孕酮依次经17α-羟化酶和C17,20-裂解酶催化形成脱氢表雄酮和雄烯二酮。脱氢表雄酮和雄烯二酮为睾酮的前体,后经多步催化转化为睾酮和二氢睾酮。CYP17为一种细胞色素P450酶,它能催化两种独立调节类固醇17α-羟化酶和C17,20裂解酶的活性,从而调节雄激素的合成。
醋酸阿比特龙为阿比特龙的前药,是一种CYP17抑制剂(阿比特龙与醋酸阿比特龙结构如下所示)。2011年,醋酸阿比特龙与泼尼松联用被美国食品药品监督管理局批准用于前列腺癌(CRPC)的治疗,推荐剂量为口服醋酸阿比特龙1000mg每天一次、泼尼松5mg每天2次。
目前有文献报道了多种阿比特龙酯类前药。由于醋酸阿比特龙的口服吸收差,口服生物利用度被认为不足10%,因此醋酸阿比特龙的口服剂量较大。
CN1024777061公开了吡啶雄甾体衍生物及其在制备预防和/或治疗前列腺癌药物中的用途,其中Rx选自多种酯类、碳酸酯类或胺类等前药基团,该文献设计的通式结构如下:
当Rx为CnH2n+1CO时,n为1~6。
CN104017045公开了CYP17抑制剂的新型药物前体,为碳酸酯前药。所述前提药物可用于治疗泌尿生殖系统、雄激素相关的癌症,该文献设计的结构如下:
WO2014111815公开了阿比特龙类似物及其在预防和/治疗前列腺癌药物中的用途,其中R选自C1~6直链烷基、C3-C7环烷基、氨基等,该文献涉及的结构如下:
Xenobiotica.2013,43(4):379-89文献报道,当健康受试者口服C14标记的醋酸阿比特龙后,血浆中阿比特龙放射当量的Cmax与AUC0-t皆为阿比特龙实测量的300倍,提示醋酸阿比特龙具有较强的首过效应。
淋巴管吸收是脂肪、脂溶性维生素和胆固醇的主要吸收方式,也是环孢素、普罗布考和美雄烷的主要吸收方式。药物口服通过淋巴管吸收,可有效避免肝脏的受过效应,从而提升生物利用度,降低给药剂量。药物通过淋巴管吸收需具备:高脂溶性(LogP>5,甘油三酯中高溶解度);含长链脂肪酸(脂肪酸链碳数大于10时,分子倾向于淋巴管吸收)。
因此,本发明意外地发现,高脂肪酸酯前药化的阿比特龙可以改变吸收方式,提高口服生物利用度,降低给药剂量。
发明内容
发明目的:本发明的目的是为了提供一类可提高口服生物利用度、降低口服剂量的阿比特龙衍生物及其立体异构体或药学上可接受的盐,以及其在制备用于预防和治疗癌症相关药物中的用途。
具体地,本发明涉及具有通式具有通式(I)所示化合物及其立体异构体或药学上可接受的盐:
其中:R任选自C7-17饱和或不饱和直链烷基,所述的烷基可进一步C1~6烷基取代。
作为本发明优选方案,具有通式(I)所示的化合物及其立体异构体或药学上可接受的盐,其中该化合物选自如下结构之一:
本发明还提供一种药物组合物,所述药物组合物含有治疗有效剂量的本发明化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
在一种实施方式中,所述药物组合物含有治疗有效剂量的本发明化合物或其立体异构体或药学上可接受的盐和药学上可接受的食用油,如大豆油,蓖麻油,橄榄油等。优选地,所述食用油为橄榄油。
进一步,本发明还提供本发明所述的化合物或其立体异构体或药学上可接受的盐,以及本发明化合物的组合物在制备治疗与癌症相关疾病药物中的用途。优选地,所述药物为口服药物。
本发明优选方案,其中所述的癌症为前列腺癌。
本发明还提供一种治疗与癌症相关疾病的方法,所述方法包括给药本发明所述的化合物或其立体异构体或药学上可接受的盐,或本发明所述的组合物。
根据本发明所述的方法,其中所述的癌症为前列腺癌。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,其中碳的同位素包括12C、13C和14C,请的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),样的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,修的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团。
“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料、着色剂、矫昧剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“药学上可接受的盐”包括药学上可接受的酸加成盐。“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2.2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、荼二磺酸盐等。这些盐可通过本专业己知的方法制备。
“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergβmon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。
“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
有益效果:本发明提出的阿比特龙酯类衍生物脂溶性高,改变原有的吸收方式为经淋巴管吸收,避免胃肠道吸收的肝脏首过效应,提升口服Cmax和AUCo-t,提升口服生物利用度,从而降低口服剂量,特别是本申请意外的发现,用正葵酸和正十一酸对阿比特龙进行修饰后,不论脂溶性还是药代动力学都有显著的提高。
具体实施方式
下面结合具体实施例对本发明名做进一步详细说明。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400)核磁仪,测定溶剂为氘代氯仿(CDCl3),内标为四甲基硅烷(TMS)。MS的测定用(Agilent 6120B)
薄层层西硅胶板使用烟台黄海HSGF254或青岛海洋GF254硅胶板,薄层色谱法(TLC)使用的硅胶规格是0.15~0.20mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的已知起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海毕得、韶远化学科技、百灵威科技等公司。
实施例1
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]辛酸酯(化合物1)的合成
25mL单口瓶中加入2.16g正辛酸,10g N,N-二甲基甲酰胺,搅拌溶解后,加入1.9g二异丙基碳二亚胺,搅拌10min,得到活性酯溶液。另取100mL三口瓶,加入20g N,N-二甲基甲酰胺,搅拌下加入3.5g阿比特龙,得到的悬浊液中滴加入前述活性酯溶液,滴加完毕后,加入1.84g对二甲氨基吡啶,室温搅拌。反应完毕后,将反应液倒入200mL水中,乙酸乙酯萃取3次。合并有机相,有机相用饱和氯化钠水溶液洗涤3次后,用无水硫酸钠干燥有机相。减压浓缩后所得粗品经柱层析纯化得1.8g化合物1,收率38%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=1.9Hz,1H),8.48(dd,J=4.8,1.5Hz,1H),7.67(dt,J=7.9,1.9Hz,1H),7.24(dd,J=7.9,4.8Hz,1H),6.01(dd,J=3.1,1.7Hz,1H),5.44(d,J=5.0Hz,1H),4.71–4.57(m,1H),2.43–2.33(m,2H),2.33–2.24(m,3H),2.16–2.01(m,3H),1.95–1.84(m,2H),1.84–1.45(m,10H),1.40–1.24(m,8H),1.24–1.09(m,5H),1.07(s,3H),0.98–0.83(m,3H).
MS(ESI)m/z=476.5[M+H]+
实施例2
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]壬酸酯(化合物2)的合成
参照实施例1的合成方法,使用正壬酸与阿比特龙反应,制备得到化合物2,收率37%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=2.0Hz,1H),8.48(dd,J=4.8,1.5Hz,1H),7.66(dt,J=7.9,1.9Hz,1H),7.24(dd,J=7.9,4.8Hz,1H),6.01(dd,J=3.0,1.7Hz,1H),5.44(d,J=5.1Hz,1H),4.65(tdd,J=10.4,6.0,4.2Hz,1H),2.42–2.33(m,2H),2.33–2.25(m,3H),2.14–2.02(m,3H),1.94–1.42(m,12H),1.41–1.24(m,10H),1.24–1.09(m,5H),1.07(s,3H),0.90(t,J=6.8Hz,3H).
MS(ESI)m/z=490.6[M+H]+
实施例3
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]葵酸酯(化合物3)的合成
参照实施例1的合成方法,使用正葵酸与阿比特龙反应,制备得到化合物3,收率48%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=1.9Hz,1H),8.48(dd,J=4.8,1.4Hz,1H),7.67(dt,J=7.9,1.8Hz,1H),7.24(dd,J=7.9,4.8Hz,1H),6.01(dd,J=3.0,1.7Hz,1H),5.44(d,J=5.0Hz,1H),4.71–4.59(m,1H),2.39–2.33(m,2H),2.33–2.25(m,3H),2.14–2.02(m,3H),1.94–1.85(m,2H),1.84–1.42(m,11H),1.40–1.24(m,12H),1.24–1.09(m,5H),1.07(s,3H),0.90(t,J=6.8Hz,3H).
MS(ESI)m/z=504.6[M+H]+
实施例4
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十一酸酯(化合物4)的合成
参照实施例1的合成方法,使用正十一酸与阿比特龙反应,制备得到化合物4,收率33%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=1.6Hz,1H),8.48(dd,1H),7.67(dt,J=7.9,2.0Hz,1H),7.24(dd,J=7.9,4.8Hz,1H),6.02(dd,J=3.3,1.7Hz,1H),5.44(d,J=4.9Hz,1H),4.70–4.59(m,1H),2.41–2.33(m,2H),2.33–2.25(m,3H),2.14–2.02(m,3H),1.94–1.85(m,2H),1.82–1.46(m,12H),1.39–1.23(m,13H),1.23–1.09(m,5H),1.07(s,3H),0.90(t,J=6.7Hz,3H).
MS(ESI)m/z=518.5[M+H]+
实施例5
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十二酸酯(化合物5)的合成
参照实施例1的合成方法,使用正十二酸与阿比特龙反应,制备得到化合物5,收率69%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=1.9Hz,1H),8.48(dd,J=4.8,1.5Hz,1H),7.67(dt,J=7.9,1.9Hz,1H),7.24(dd,J=7.9,4.8Hz,1H),6.01(dd,J=3.1,1.7Hz,1H),5.44(d,J=5.1Hz,1H),4.72–4.59(m,1H),2.41–2.33(m,2H),2.33–2.24(m,3H),2.16–2.01(m,3H),1.90–1.86(m,2H),1.81–1.46(m,10H),1.39–1.23(m,15H),1.23–1.09(m,5H),1.07(s,3H),0.90(t,J=6.8Hz,3H).
MS(ESI)m/z=532.7[M+H]+
实施例6
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十四酸酯(化合物6)的合成
参照实施例1的合成方法,使用正十四酸与阿比特龙反应,制备得到化合物6,收率71%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=2.0Hz,1H),8.48(dd,J=4.8,1.4Hz,1H),7.66(dt,J=7.9,1.9Hz,1H),7.23(dd,J=7.9,4.8Hz,1H),6.01(dd,J=3.0,1.7Hz,1H),5.44(d,J=5.0Hz,1H),4.71–4.57(m,1H),2.41–2.33(m,2H),2.33–2.24(m,3H),2.16–2.00(m,3H),1.95–1.84(m,2H),1.84–1.46(m,10H),1.40–1.23(m,20H),1.23–1.08(m,5H),1.06(s,3H),0.90(t,J=6.8Hz,3H).
MS(ESI)m/z=560.7[M+H]+
实施例7
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十六酸酯(化合物7)的合成
参照实施例1的合成方法,使用正十六酸与阿比特龙反应,制备得到化合物7,收率41%。
1H NMR(400MHz,Chloroform-d)δ8.64(d,J=1.9Hz,1H),8.48(dd,J=4.7,1.3Hz,1H),7.66(dt,J=7.9,1.8Hz,1H),7.24(dd,J=7.9,4.8Hz,1H),6.07–5.96(m,1H),5.44(d,J=5.0Hz,1H),4.72–4.57(m,1H),2.42–2.33(m,2H),2.33–2.24(m,3H),2.15–2.02(m,3H),1.95–1.84(m,2H),1.84–1.46(m,10H),1.39–1.23(m,24H),1.23–1.08(m,5H),1.07(s,3H),0.90(t,J=6.8Hz,3H).
MS(ESI)m/z=588.7[M+H]+
实施例8
[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]十八酸酯(化合物8)的合成
参照实施例1的合成方法,使用正十八酸与阿比特龙反应,制备得到化合物8,收率49.2%。
MS(ESI)m/z=616.8[M+H]+
本发明制备的阿比特龙酯类衍生物具有更好的生物利用度,脂溶性提高,药物经淋巴管吸收,降低首过效应,降低口服剂量。
实施例9阿比特龙酯类衍生物溶解度的测定。
将过量的待测化合物加入到装有5mL橄榄油的离心管中,置于25℃条件下震荡24h。悬浮液离心(8000rpm)后,取上清液经适当稀释后,HPLC检测,计算待测化合物浓度,结果如表1所示。
表1.橄榄油溶解度
实施例 | 溶解度 |
1 | 97.3mg/mL |
2 | 104mg/mL |
3 | 137mg/mL |
4 | 152mg/mL |
5 | 144mg/mL |
6 | 162mg/mL |
7 | 154mg/mL |
8 | 167mg/mL |
实施例10阿比特龙酯类衍生物的大鼠PK测定。
雄性SD大鼠180-220g,禁食给水过夜,6只大鼠口服灌胃100mg/kg(以阿比特龙原形药物计)。于给药前及给药后30min,1h,2h,4h,6h,8h,12h,24h眼眶取血0.3ml,肝素抗凝,4℃3000rpm离心10分钟后分离血浆,于-80℃保存。取各时间点大鼠血浆30μΙ加入内标含维拉帕米7.5ng/的乙腈溶液混合后,涡旋混合1.5分钟,13000转/分钟离心10分钟,取上清液进行LC-MS/MS检测。主要药代动力学参数用WinNonlin6.3软件非房室模型分析。结果见表2。
表2.大鼠药代动力学参数结果
Claims (7)
4.一种药物组合物,其特征在于,所述药物组合物含有治疗有效剂量的权利要求1~3中任意一项所述的化合物或其立体异构体或药学上可接受的盐、以及药学上可接受的载体和赋形剂。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物包括治疗有效剂量的权利要求1~3中任意一项所述的化合物或其立体异构体或药学上可接受的盐和药学上可接受的食用油。
6.权利要求1~3任意一项所述的化合物或其立体异构体或药学上可接受的盐,以及权利要求4所述的组合物在制备治疗与癌症相关疾病药物中的用途。
7.根据权利要求6所述的用途,其中所述的癌症为前列腺癌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2020110397003 | 2020-09-28 | ||
CN202011039700 | 2020-09-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113929727A true CN113929727A (zh) | 2022-01-14 |
Family
ID=79277273
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111143981.1A Pending CN113929727A (zh) | 2020-09-28 | 2021-09-28 | 阿比特龙酯类衍生物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113929727A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023038933A1 (en) * | 2021-09-08 | 2023-03-16 | Propella Therapeutics, Inc. | Oral abiraterone formulations |
US11957696B2 (en) | 2021-02-15 | 2024-04-16 | Propella Therapeutics, Inc. | Abiraterone prodrugs |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016082792A1 (zh) * | 2014-11-28 | 2016-06-02 | 四川海思科制药有限公司 | 一种阿比特龙衍生物及其制备方法和医药用途 |
WO2020180942A1 (en) * | 2019-03-06 | 2020-09-10 | Propella Therapeutics, Inc. | Abiraterone prodrugs |
-
2021
- 2021-09-28 CN CN202111143981.1A patent/CN113929727A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016082792A1 (zh) * | 2014-11-28 | 2016-06-02 | 四川海思科制药有限公司 | 一种阿比特龙衍生物及其制备方法和医药用途 |
CN105646637A (zh) * | 2014-11-28 | 2016-06-08 | 四川海思科制药有限公司 | 一种阿比特龙衍生物及其制备方法和医药用途 |
WO2020180942A1 (en) * | 2019-03-06 | 2020-09-10 | Propella Therapeutics, Inc. | Abiraterone prodrugs |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11957696B2 (en) | 2021-02-15 | 2024-04-16 | Propella Therapeutics, Inc. | Abiraterone prodrugs |
WO2023038933A1 (en) * | 2021-09-08 | 2023-03-16 | Propella Therapeutics, Inc. | Oral abiraterone formulations |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113929727A (zh) | 阿比特龙酯类衍生物及其制备方法和应用 | |
ES2964818T3 (es) | Profármacos de abiraterona | |
WO2012116290A2 (en) | Neuroactive 17(20)-z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same | |
TW201511755A (zh) | 苯並吡喃化合物之組合,其組成物及用途 | |
JP2009522239A (ja) | トリテルペンキノンおよびトリテルペンフェノール誘導体、ならびに腫瘍および寄生生物性疾患の治療のためのそれらの適用 | |
AU2014248928B2 (en) | Onapristone polymorphic forms and methods of use | |
JP6842474B2 (ja) | ステロイド系化合物、当該化合物を含む組成物及びその使用 | |
CN106243180A (zh) | 炔雌醇新晶型 | |
WO2012134446A1 (en) | Epiandrosterone and/or androsterone derivatives and method of use thereof | |
EP2987799B1 (en) | Ester derivative of 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17beta-diol having antitumour activity and preparation method thereof | |
JPWO2020180942A5 (zh) | ||
CN109651377B (zh) | 一种治疗癌症的化合物及其用途 | |
EP2556082B1 (en) | Substituted androst-4-ene diones | |
CN112851741B (zh) | 一种取代的甾体类化合物及其应用 | |
CN113200966B (zh) | 一种呋喹替尼衍生物、药物组合物和用途 | |
WO2020098516A1 (zh) | 4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途 | |
KR20230114274A (ko) | 5α-하이드록시-6β-[2-(1H-이미다졸-4-일)에틸아미노]콜레스탄-3β-올의전구약물 및 암 치료에 사용하기 위한 이를 포함하는 약제학적 조성물 | |
ES2254924T3 (es) | 19-nor-17alfa-pregna-1,3,5(10)-trien-17beta-oles con un anillo de 21,16alfa-lactona, sustituidos en la posicion 11beta con un radical de cadena larga. | |
WO2016095248A1 (zh) | 20(R)-人参皂苷Rg3衍生物、制备方法及其应用 | |
US20060160895A1 (en) | Anti-cancer agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220114 |