CN103339141A - 作为hiv成熟抑制剂的c-3修饰的桦木酸衍生物的c-28胺 - Google Patents
作为hiv成熟抑制剂的c-3修饰的桦木酸衍生物的c-28胺 Download PDFInfo
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- CN103339141A CN103339141A CN2012800070200A CN201280007020A CN103339141A CN 103339141 A CN103339141 A CN 103339141A CN 2012800070200 A CN2012800070200 A CN 2012800070200A CN 201280007020 A CN201280007020 A CN 201280007020A CN 103339141 A CN103339141 A CN 103339141A
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- Prior art keywords
- alkyl
- methyl
- compound
- preparation
- pentamethyl
- Prior art date
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- 150000001412 amines Chemical class 0.000 title abstract description 243
- 239000003112 inhibitor Substances 0.000 title abstract description 24
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 title abstract description 12
- 230000035800 maturation Effects 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 302
- 238000000034 method Methods 0.000 claims abstract description 269
- 208000030507 AIDS Diseases 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 175
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000001475 halogen functional group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000003981 vehicle Substances 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 7
- 229940126154 HIV entry inhibitor Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 230000002924 anti-infective effect Effects 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000002955 immunomodulating agent Substances 0.000 claims description 5
- 229940121354 immunomodulator Drugs 0.000 claims description 5
- 230000002584 immunomodulator Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000012678 infectious agent Substances 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 402
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 240
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 203
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 173
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 163
- 239000000376 reactant Substances 0.000 description 150
- 239000000243 solution Substances 0.000 description 148
- 239000007787 solid Substances 0.000 description 147
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 127
- 239000000047 product Substances 0.000 description 125
- 238000005160 1H NMR spectroscopy Methods 0.000 description 119
- -1 sec.-propyl Chemical group 0.000 description 101
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 99
- 238000005481 NMR spectroscopy Methods 0.000 description 92
- 238000003756 stirring Methods 0.000 description 87
- 230000007062 hydrolysis Effects 0.000 description 77
- 238000006460 hydrolysis reaction Methods 0.000 description 77
- 239000002585 base Substances 0.000 description 76
- 238000001819 mass spectrum Methods 0.000 description 73
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 72
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
- 239000002904 solvent Substances 0.000 description 58
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 53
- 230000002829 reductive effect Effects 0.000 description 53
- 239000012043 crude product Substances 0.000 description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 51
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 43
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 241000725303 Human immunodeficiency virus Species 0.000 description 37
- 239000012044 organic layer Substances 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 36
- 125000003368 amide group Chemical group 0.000 description 36
- 239000000463 material Substances 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000010936 titanium Substances 0.000 description 29
- 229910052719 titanium Inorganic materials 0.000 description 29
- 239000002253 acid Substances 0.000 description 28
- 239000000706 filtrate Substances 0.000 description 28
- 239000012141 concentrate Substances 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 25
- 239000011734 sodium Substances 0.000 description 24
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 24
- 150000001408 amides Chemical class 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 22
- 150000001299 aldehydes Chemical class 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- 229910052796 boron Inorganic materials 0.000 description 21
- 229910052760 oxygen Inorganic materials 0.000 description 21
- 239000001301 oxygen Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 19
- 238000010790 dilution Methods 0.000 description 19
- 239000012895 dilution Substances 0.000 description 19
- 150000004702 methyl esters Chemical class 0.000 description 19
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 18
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 17
- 239000000284 extract Substances 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000006260 foam Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 12
- 125000003700 epoxy group Chemical group 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 238000004293 19F NMR spectroscopy Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 238000005903 acid hydrolysis reaction Methods 0.000 description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 11
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 229960001866 silicon dioxide Drugs 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 11
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 10
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 10
- 239000005695 Ammonium acetate Substances 0.000 description 10
- 235000019257 ammonium acetate Nutrition 0.000 description 10
- 229940043376 ammonium acetate Drugs 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 241000700605 Viruses Species 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 8
- 0 CC([C@](CC1)[C@]2[C@@]1(COC(C)=O)CC[C@@]1(C)[C@](C)(CC[C@]3C(C)(C)C(OS(C(F)(F)F)(=O)=O)=C*3C)C(C)CCC21)C#C Chemical compound CC([C@](CC1)[C@]2[C@@]1(COC(C)=O)CC[C@@]1(C)[C@](C)(CC[C@]3C(C)(C)C(OS(C(F)(F)F)(=O)=O)=C*3C)C(C)CCC21)C#C 0.000 description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 238000006268 reductive amination reaction Methods 0.000 description 8
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 229960002555 zidovudine Drugs 0.000 description 8
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 7
- 150000003512 tertiary amines Chemical class 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- XTYSXGHMTNTKFH-BDEHJDMKSA-N (2s)-1-[(2s,4r)-4-benzyl-2-hydroxy-5-[[(1s,2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]amino]-5-oxopentyl]-n-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide;hydrate Chemical compound O.C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 XTYSXGHMTNTKFH-BDEHJDMKSA-N 0.000 description 6
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 6
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 6
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 125000004104 aryloxy group Chemical group 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 6
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- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 6
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- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 5
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- JYDNKGUBLIKNAM-UHFFFAOYSA-N Oxyallobutulin Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(CO)CCC(C(=C)C)C5C4CCC3C21C JYDNKGUBLIKNAM-UHFFFAOYSA-N 0.000 description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000001311 chemical methods and process Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
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- 239000004030 hiv protease inhibitor Substances 0.000 description 5
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
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- HJORCZCMNWLHMB-UHFFFAOYSA-N 1-(3-aminopropyl)pyrrolidin-2-one Chemical compound NCCCN1CCCC1=O HJORCZCMNWLHMB-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 4
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 4
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Oncology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本文提出具有药物和生物-作用特性的化合物,它们的药用组合物和使用方法。特别是,提供具有独特抗病毒活性的C-3修饰的桦木酸衍生物的C-28胺作为HIV成熟抑制剂。这些化合物用于治疗HIV和AIDS。特别是,本文提供以下化合物,包括其药学上可接受的盐:
Description
相关申请的交叉参照
本非临时性申请要求2011年1月31日提交的美国临时申请系列号61/437,870的权益。
发明领域
本发明涉及对抗HIV的有用的新化合物,且更特别是涉及用作HIV成熟抑制剂的衍生自桦木酸的化合物和其它结构上相关的化合物,并且涉及含有相同化合物的药用组合物,以及涉及它们的制备方法。
发明背景
HIV-1(人免疫缺陷病毒-1)感染仍然是一个主要的医学问题,估计在2007年末全世界有45,000,000人感染。HIV和AID(获得性免疫缺陷综合征)的病例数已快速增加。在2005年,报告有约5.000,000个新感染者,并且3,100,00人死于AIDS。目前可利用的治疗HIV的药物包括核苷逆转录酶(RT)抑制剂或已批准的单一丸剂组合:齐多夫定(或AZT或)、去羟肌苷(或)、司他夫定(或)、拉米夫定(或3TC或)、扎西他滨(或DDC或)、琥珀酸阿巴卡韦(或)、富马酸替诺福韦盐(或)、恩曲他滨(或)、(含-3TC加AZT)、(含阿巴卡、拉米夫定和齐多夫定)、(含阿巴卡韦和拉米夫定)、(含和);非-核苷逆转录酶抑制剂:奈韦拉平(或)、地拉韦啶(或)和依法韦仑(或)、和依曲韦林,以及拟肽蛋白酶抑制剂或批准的制剂:沙奎那韦、茚地那韦、利托那韦、奈非那韦、氨普那韦、洛匹那韦、(洛匹那韦和利托那韦)、达卢那韦、阿扎那韦和替拉那韦和整合酶抑制剂如雷特格韦(raltegravir)以及进入抑制剂如恩夫韦肽(T-20)和马拉韦罗
这些药物中的每一个如果单独使用,仅可短暂地抑制病毒的复制。然而,当组合使用时,这些药物对病毒血症和疾病进展具有显著的效果。事实上,由于广泛应用联合疗法,AIDS患者中死亡率的显著减少最近已得到证明。然而,尽管有这些印象深刻的结果,30-50%的患者可能最终对组合药物疗法无效。不充分的药物效力、非-依从性、有限的组织渗透和在某些细胞类型中的药物-特异性限制(如大多数核苷类似物在休眠细胞中不能被磷酸化)可能是不完全抑制敏感病毒的原因。此外,HIV-1的高复制率和快速的代谢回转结合突变的频繁插入,导致耐药变异体的出现和治疗失败(当次优药物浓度存在时)。因此,新的抗-HIV药物显示出不同的耐药性模式,并且需要有利的药代动力学和安全性特征以提供更多的治疗选项。改进的HIV融合抑制剂和HIV进入共同受体拮抗剂是许多研究人员进一步研究的新型抗-HIV药物的两个实例。
HIV附着抑制剂是抗病毒化合物的另外的亚类,其结合于HIV表面糖蛋白gp120,并干扰表面蛋白gp120和宿主细胞受体CD4之间的相互作用。因此,它们阻止HIV附着于人CD4T-细胞,并在HIV生命周期的第一阶段阻断HIV复制。已努力改进HIV附着抑制剂的特性,以获得作为抗病毒剂的具有最大效用和效果的化合物。特别是,US7,354,924和US2005/0209246说明了HIV附着抑制剂。
另一类新出现的HIV治疗化合物被称为HIV成熟抑制剂。成熟是HIV复制或HIV生命周期中最后的多达10个或10个以上的阶段,其中HIV由于几个HIV蛋白酶-介导的gag蛋白(其最终导致壳体(CA)蛋白的释放)中的裂解事件而变得具有感染性。成熟抑制剂阻止HIV壳体正确的装配和成熟,防止形成保护性外壳,或阻止从人细胞中排出。作为替代,产生非-感染性病毒,防止随后的HIV感染周期。
现在,已显示某些桦木酸的衍生物作为HIV成熟抑制剂表现出有效的抗-HIV活性。例如,US7,365,221公开了单乙酰化桦木醇和二氢桦木醇衍生物,和它们作为抗-HIV药物的用途。如在‘221参考文献中所讨论的,用某些取代的酰基,如3′,3′-二甲基戊二酰基和3′,3′-二甲基琥珀酰基酯化桦木酸(1)产生具有增强的活性的衍生物(Kashiwada,Y.,et al.,J.Med.Chem.39:1016-1017(1996))。为有效的抗-HIV药物的酰化桦木酸和二氢桦木酸衍生物也描述于美国专利号5,679,828中。桦木醇的3位碳中的羟基与琥珀酸的酯化也产生能够抑制HIV-1活性的化合物(Pokrovskii,A.G.,et al.,Gos.Nauchnyi Tsentr Virusol.Biotekhnol.″Vector″9:485-491(2001))。
其它的涉及使用衍生自桦木酸的化合物治疗HIV感染的参考文献包括US2005/0239748和US2008/0207573,以及WO2006/053255、WO2009/100532和WO2011/007230。
一种正在开发中的HIV成熟化合物已被鉴定为贝韦立马(Bevirimat)或PA-457,其具有化学式C36H56O6和3β-(3-羧基-3-甲基-丁酰基氧基)羽扇豆-20(29)-烯-28-酸(lup-20(29)-en-28-oic acid)的IUPAC命名。
本文也参照由Bristol-Myers Squibb于2011年6月2日提交的题目为“作为HIV成熟抑制剂的修饰的C-3桦木酸衍生物”USSN13/151,706和2011年6月2日提交的“C-28AMIDES OF作为HIV成熟抑制剂的修饰的C-3桦木酸衍生物的C-28酰胺”USSN13/151,722的申请。
本领域现在需要的是用作HIV成熟抑制剂的新化合物,以及含有这些化合物的新的药用组合物。
发明简述
本发明提供下式I、II和III化合物,包括其药学上可接受的盐,它们的药物制剂,以及它们在患有或易患病毒如HIV的患者中的用途。式I-III化合物是有效的抗病毒剂,特别是作为HIV的抑制剂。它们对治疗HIV和AIDS是有用的。
本发明的一个实施方案涉及化合物,包括其药学上可接受的盐,其选自:
式I化合物
式II化合物
式III化合物
其中R1为异丙烯基或异丙基;
J和E独立地为-H或-CH3和当存在双键时,E不存在;
X为被A取代的苯基或杂芳基环,其中A为选自以下基团的至少一个成员:-H、-卤代、-羟基、-C1-6烷基、-C1-6烷氧基和-COOR2;
R2为-H、-C1-6烷基、-烷基取代的C1-6烷基或-芳基取代的C1-6烷基;
Y选自-COOR2、-C(O)NR2SO2R3、-C(O)NHSO2NR2R2、-NR2SO2R2、-SO2NR2R2、-C3-6环烷基-COOR2、-C1-6烯基-COOR2、-C1-6炔基-COOR2、-C1-6烷基-COOR2、-NHC(O)(CH2)n-COOR2、-SO2NR2C(O)R2、-四唑和-CONHOH,其中n=1-6;
R3为-C1-6烷基或烷基取代的C1-6烷基;
R4选自H、-C1-6烷基、-C3-6环烷基、-C1-6取代的烷基、-C1-6烷基-杂芳基、-C1-6烷基-取代的杂芳基、-C1-6烷基-NR6R7、-C1-6烷基-CONR8R9、-C3-6环烷基-CONR8R9、-C3-6环烷基-(CH2)1-3-NR6R7、-(CH2)1-3-C3-6环烷基-NR6R7、-(CH2)1-3-C3-6环烷基-(CH2)1-3-NR6R7;-C1-6烷基-Q1、C3-6环烷基-Q1、-COR10,-SO2R3和-SO2NR2R2;Q1=-羟基、-COOR2、-卤代、-SO2Ra;
Rb=-H、-C1-6烷基、-COR3、-SO2R3、-SONR3R3;
R4也可选自:
R5选自-H、-C1-6烷基、-C3-6环烷基、-C1-6烷基取代的烷基、-COR10,-SO2R3和-SO2NR2R2;
前提是R4或R5只有一个可选自-COR10、-SO2R3和-SO2NR2R2;
或者R4和R5与邻近的N结合在一起形成环如
R10选自-H、-C1-6烷基、-C1-6烷基-NR6R7、-NR11R12、-OR13、-C1-6烷基-Q2、-C3-6环烷基-Q2、芳基-Q2,其中n=1-6,
其中Q2=羟基、-COOR2、-卤代、SO2Ra、-CONHSO2R3、-CONHSO2NR2R2;
R10也可选自:
R6和R7独立地选自-H、-C1-6烷基、-C1-6取代的烷基、芳基、杂芳基、取代的芳基、取代的杂芳基,和-C1-6烷基-Q1,
或者R6和R7与邻近的N结合在一起形成选自以下的环
Rc=C1-6烷基、NR2R2、-COOR3;
R8和R9独立地选自-H、-C1-6烷基、-C3-6环烷基、-C1-6取代的烷基、-C1-6烷基-杂芳基、-C1-6烷基-取代的杂芳基、-C1-6烷基-NR2R2、-C1-6烷基-CONR2R2、-C1-6烷基-Q1、C3-6环烷基-Q1,
或者R8和R9也可独立地选自
或R8和R9与邻近的N结合在一起形成选自以下的环:
以及R11和R12独立地选自-H、-C1-6烷基、-C3-6环烷基,和-C1-6烷基取代的烷基;
或者R11和R12与邻近的N结合在一起形成选自以下的环
R13选自-H、-C1-6烷基、-C1-6烷基取代的烷基,和-C1-6烷基NR14R15,其中
R14和R15独立地选自-H、-C1-6烷基和-C1-6烷基取代的烷基,或R14和R15与邻近的N结合在一起形成选自以下的环
在进一步的实施方案中,在此提供用于治疗感染病毒(尤其是其中所述病毒为HIV)的哺乳动物的方法,其包括给予所述哺乳动物抗病毒有效量的化合物,所述化合物选自以上的式I、II、III化合物,以及一种或多种药学上可接受的载体、赋形剂或稀释剂。任选地,式I、II和/或III化合物可以与抗病毒有效量的选自以下的另一种-AIDS治疗剂联合给予:(a)AIDS抗病毒剂;(b)抗-感染剂;(c)免疫调节剂;和(d)其它的HIV进入抑制剂。
本发明的另一个实施方案为药用组合物,其包含抗病毒有效量的化合物,所述化合物选自式I、II和III化合物,以及一种或多种药学上可接受的载体、赋形剂和稀释剂;并且任选地与抗病毒有效量的另一种选自以下的AIDS治疗剂组合:(a)AIDS抗病毒剂;(b)抗-感染剂;(c)免疫调节剂;和(d)其它的HIV进入抑制剂。在本发明的另一个实施方案中,提供一种或多种制备式I、II和III化合物的方法。本文也提供用于制备式I、II和III化合物的中间体化合物。
本发明涉及在下文描述的这些以及其它重要的目标。
实施方案的详述
由于本发明的化合物可具有不对称中心,因此可作为非对映体和对映体的混合物存在,本公开包括式I、II和III化合物的各个非对映异构体的和对映异构体的形式以及它们的混合物。
定义
除非在本申请中的其它地方另外特别指出,本文可使用一或多个以下术语,并且应具有以下含义:
“H”指氢,包括其同位素,如氘。
术语″C1-6烷基″用于本文和权利要求书中时(除非另外指明)意指直链或支链烷基如甲基、乙基、丙基、异丙基、丁基、异丁基、叔-丁基、戊基、己基等。
″C1-C4氟代烷基”指F-取代的C1-C4烷基,其中至少一个H原子被F原子取代,和每一个H原子可独立地被F原子取代;
“卤素”指氯、溴、碘或氟。
“芳基”或“Ar”基团指具有完全共轭的π(pi)-电子系统的所有碳单环或稠环多环
(即,共享邻近的碳原子对的环)基团。芳基的实例(不限于)为苯基、萘基和蒽基。芳基可以是取代的或未取代的。当被取代时,所述取代的基团优选为一或多个选自以下的基团:烷基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳基氧基、杂芳基氧基、杂脂环氧基、氢硫基、硫代芳基氧基、硫代杂芳基氧基、硫代杂脂环氧基、氰基、卤素、硝基、羰基、O-氨基甲酰基、N-氨基甲酰基、C-酰胺基、N-酰胺基、C-羧基、O-羧基、亚硫酰基、磺酰基、亚磺酰氨基、三卤代甲基、脲基、氨基和-NRxRy,其中Rx和Ry独立地选自氢、烷基、环烷基、芳基、羰基、C-羧基、磺酰基、三卤代甲基,以及合并为5-或6-元杂脂环族环。
如本文所用的,“杂芳基”基团指单环或稠合的环(即,共享邻近的原子对的环)基团,其在环上具有一或多个选自氮、氧和硫的原子并且另外还具有完全共轭的π(pi)-电子系统。除非另外指明,杂芳基可连接于杂芳基中的或者碳或者氮原子。应该注意到,术语杂芳基意欲包括母体杂芳基的N-氧化物,如果这样的N-氧化物是化学上可行的,如本领域已知的。杂芳基的实例(不限于)为呋喃基、噻吩基、苯并噻吩基、噻唑基、咪唑基、噁唑基、噁二唑基、噻二唑基、苯并噻唑基、三唑基、四唑基、异噁唑基、异噻唑基、吡咯基、吡喃基、四氢吡喃基、吡唑基、吡啶基、嘧啶基、喹啉基、异喹啉基、嘌呤基、咔唑基、苯并噁唑基、苯并咪唑基、吲哚基、异吲哚基、吡嗪基、二嗪基、吡嗪、三嗪基、四嗪基和四唑基。当被取代时,取代的基团优选为一或多个选自以下的基团:烷基、环烷基、芳基、杂芳基、杂脂环基、羟基,烷氧基、芳基氧基、杂芳基氧基、杂脂环氧基、硫代烷氧基、氢硫基、硫代芳基氧基、硫代杂芳基氧基、硫代杂脂环氧基、氰基、卤素、硝基、羰基、O-氨基甲酰基、N-氨基甲酰基、C-酰胺基、N-酰胺基、C-羧基、O-羧基、亚硫酰基、磺酰基、亚磺酰氨基、三卤代甲基、脲基、氨基,和-NRxRy,其中Rx和Ry如上所定义。
如本文所用的,“杂脂环族”基团指单环或稠环基团,其在环上具有一或多个选自氮、氧和硫的原子。所述环选自提供健的稳定排列的那些环并且不打算包括将不存在的系统。环也可具有一或多个双键。然而,环不具有完全共轭的π(pi)-电子系统。杂脂环族基团的实例(不限于)为氮杂环丁烷基、哌啶基、哌嗪基、咪唑啉基、噻唑烷基、3-吡咯烷-1-基、吗啉基、硫吗啉基和四氢吡喃基。当被取代时,所述取代的基团优选为一或多个选自以下的基团:烷基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳基氧基、杂芳基氧基、杂脂环氧基、氢硫基、硫代烷氧基、硫代芳基氧基、硫代杂芳基氧基、硫代杂脂环氧基、氰基、卤素、硝基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰胺基、C-硫代酰胺基、N-酰胺基、C-羧基、O-羧基、亚硫酰基、磺酰基、亚磺酰氨基、三卤代甲烷亚磺酰氨基、三卤代甲烷磺酰基、甲硅烷基、脒基、胍基、脲基、膦酰基(phosphonyl)、氨基和-NRxRy,其中Rx和Ry如上所定义。
“烷基”基团指饱和的脂族烃,包括直链和支链基团。优选地,烷基含有1-20个碳原子(只要本文提及数字范围;例如,“1-20”,其意指在这种情况下的基团,烷基可含有1个碳原子、2个碳原子、3个碳原子等,至多包括20个碳原子)。更优选地,其为具有1-10个碳原子的中等大小的烷基。最优选地,其为具有1-4个碳原子的低级烷基。烷基可以是取代的或未取代的。当被取代时,所述取代基优选为一或多个独立地选自以下的取代基:三卤代烷基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳基氧基、杂芳基氧基、杂脂环氧基、氢硫基、硫代烷氧基、硫代芳基氧基、硫代杂芳基氧基、硫代杂脂环氧基、氰基、卤代、硝基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰胺基、C-硫代酰胺基、N-酰胺基、C-羧基、O-羧基、亚硫酰基、磺酰基、亚磺酰氨基、三卤代甲烷亚磺酰氨基、三卤代甲烷磺酰基,以及结合成5-或6-元杂脂环族环。
“环烷基”基团指所有的碳单环或稠合的环(即,共享邻近的碳原子对的环)基团,其中一或多个环不具有完全共轭的π(pi)-电子系统。环烷基的实例(不限于)为环丙烷,环丁烷、环戊烷、环戊烯、环己烷、环己烯、环庚烷、环庚烯和金刚烷。环烷基可以被取代或未被取代。当被取代时,所述取代基优选为一或多个独立地选自以下的取代基:烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳基氧基、杂芳基氧基、杂脂环氧基、氢硫基、硫代烷氧基、硫代芳基氧基、硫代杂芳基氧基、硫代杂脂环氧基、氰基、卤代、硝基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰胺基、C-硫代酰胺基、N-酰胺基、C-羧基、O-羧基、亚硫酰基、磺酰基、亚磺酰氨基、三卤代-甲烷亚磺酰氨基、三卤代甲烷磺酰基、甲硅烷基、脒基、胍基、脲基、膦酰基、氨基和-NRxRy,其中Rx和Ry如上所定义。
“烯基”基团,如本文定义的,指具有至少两个碳原子和至少一个碳-碳双键的烷基。
“炔基”基团,如本文定义的,指具有至少两个碳原子和至少一个碳-碳三健的烷基。“羟基”基团指-OH基团。
“烷氧基”基团指如本文所定义的-O-烷基和-O-环烷基两者。
“芳基氧基”基团指如本文所定义的-O-芳基和-O-杂芳基两者。
“杂芳基氧基”基团指具有如本文所定义的杂芳基-O-基团。
“杂脂环氧基”指具有如本文所定义的杂脂环基的杂脂环基-O-基团。
“氢硫基”指-SH基团。
“硫代烷氧基”基团指如本文所定义的S-烷基和-S-环烷基两者。
“硫代芳基氧基”基团指如本文所定义的-S-芳基和-S-杂芳基两者。
“硫代杂芳基氧基”基团指具有如本文所定义的杂芳基的杂芳基-S-基团。
“硫代杂脂环氧基”基团指如本文所定义的杂脂环基的杂脂环基-S-基团。
“羰基”基团指-C(=O)-R”基团,其中R”选自氢、烷基、烯基、炔基、环烷基、芳基、杂芳基(通过环碳键结)和杂脂环基(通过环碳键结),各自如本文所定义。
“醛”基团指其中R”为氢的羰基。
“硫代羰基”基团指如本文所定义的-C(=S)-R”基团,其中R”如本文所定义。
“酮基”基团指-CC(=O)C-基团,其中C=O的任何一侧或者两侧上的碳可以是烷基、环烷基、芳基或杂芳基或杂脂环族基团的碳。
“三卤代甲烷羰基”基团指Z3CC(=O)-基团,其中所述Z是卤素。
“C-羧基”基团指-C(=O)O-R”基团,其中R”如本文所定义。
“O-羧基”基团指R”C(-O)O-基团,其中R”如本文所定义。
“羧酸”基团指C-羧基,其中R”是氢。
“三卤代甲基”基团指-CZ3基团,其中Z为如本文所定义的卤素基团。
“三卤代甲烷磺酰基”基团指Z3CS(=O)2-基团,其中Z如上所定义。
“三卤代甲烷亚磺酰氨基”基团指Z3CS(=O)2NRx-基团,其中Z如上所定义和Rx为H或(C1-6)烷基。
“亚硫酰基”基团指-S(=O)-R”基团,其中R”为(C1-6)烷基。
“磺酰基”基团指-S(=O)2R”基团,其中R”为(C1-6)烷基。
“S-亚磺酰氨基”基团指-S(=O)2NRXRY,其中RX和RY独立地为H或(C1-6)烷基。
“N-亚磺酰氨基”基团指R”S(=O)2NRX-基团,其中Rx为H或(C1-6)烷基。
“O-氨基甲酰基”基团指-OC(=O)NRxRy基团,其中RX和RY独立地为H或(C1-6)烷基。
“N-氨基甲酰基”基团指RxOC(=O)NRy基团,其中Rx和Ry独立地为H或(C1-6)烷基。
“O-硫代氨基甲酰基”基团指-OC(=S)NRxRy基团,其中Rx和Ry独立地为H或(C1-6)烷基。
“N-硫代氨基甲酰基”基团指RxOC(=S)NRy-基团,其中Rx和Ry独立地为H或(C1-6)烷基。
“氨基”指-NH2基团。
“C-酰胺基”基团指-C(=O)NRxRy基团,其中Rx和Ry独立地为H或(C1-6)烷基。
“C-硫代酰胺基”基团指-C(=S)NRxRy基团,其中Rx和Ry独立地为H或(C1-6)烷基。
“N-酰胺基”基团指RxC(=O)NRy-基团,其中Rx和Ry独立地为H或(C1-6)烷基。
“脲基”基团指-NRxC(=O)NRyRy2基团,其中Rx、Ry和Ry2独立地为H或(C1-6)烷基。
“胍基”基团指-RxNC(=N)NRyRy2基团,其中Rx、Ry和Ry2独立地为H或(C1-6)烷基。
“脒基”基团指RxRyNC(=N)-基团,其中Rx和Ry独立地为H或(C1-6)烷基。“氰基”基团指-CN基团。
“甲硅烷基”基团指-Si(R”)3,其中R”是(C1-6)烷基或苯基。
“膦酰基”基团指P(=O)(ORx)2,其中Rx是(C1-6)烷基。
“肼基”基团指-NRxNRyRy2基团,其中Rx、Ry和Ry2独立地为H或(C1-6)烷基。
任何两个相邻的R基团可结合形成另外的稠合于最初携带那些R基团的环的芳基、环烷基、杂芳基或杂环。
本领域已知杂芳基系统中的氮原子可“参与构建杂芳基环双键”,并且这指包含5-元环杂芳基的两个互变异构结构中的双键的形式。这如本领域化学家所充分理解的,规定了氮是否可被取代。本公开的内容和权利要求基于化学键合的已知的一般原理。应该理解,权利要求书不包括已知不稳定的结构或者基于文献不能存在的结构。
本文公开的化合物的药学上可接受的盐和前药均在本发明的范围内。术语“药学上可接受的盐”用于本文和权利要求书中时意欲包括无毒的碱加成盐。合适的盐包括衍生自有机和无机酸的那些盐,如,不限于氢氯酸、氢溴酸、磷酸、硫酸、甲烷磺酸、乙酸、酒石酸、乳酸、亚磺酸、柠檬酸、马来酸、富马酸、山梨酸、乌头酸、水杨酸、酞酸等。如本文所用的术语″药学上可接受的盐″也意欲包括酸性基团,如羧酸根,与这样的抗衡离子所成的盐,如铵盐、碱金属盐,特别是钠或钾,碱土金属盐,特别是钙或镁,以及与合适的有机碱如低级烷基胺(甲基胺、乙基胺、环己基胺等)或与取代的低级烷基胺(如羟基-取代的烷基胺如二乙醇胺、三乙醇胺或三(羟基甲基)-氨基甲烷),或与碱如哌啶或吗啉所成的盐。
如上所述的,本发明的化合物也包括“前药”。如本文所用的术语“前药”包括术语“前药酯”和术语“前药醚”两者。如本文所用的术语“前药酯”包括采用本领域技术人员已知的生成乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯、氨基酸酯、磷酸酯、半酸酯(half acid esters)如丙二酸酯、琥珀酸酯或戊二酸酯等的程序,通过使式I化合物的一个或多个羟基与或者烷基、烷氧基,或者芳基取代的酰化基或磷酸化剂反应所形成的酯和碳酸酯。在某些实施方案中,氨基酸酯可能是特别优选的。
这样的前药酯的实例包括
术语“前药醚”包括磷酸酯缩醛(phosphate acetals)和O-葡糖苷二者。这样的前药醚的代表性实施例包括
如上所提出的,本发明涉及化合物,包括其药学上可接受的盐,所述化合物选自:
式I化合物
式II化合物
式III化合物
其中R1为异丙烯基或异丙基;
J和E独立地为-H或-CH3和当存在双键时,E不存在;
X为被A取代的苯基或杂芳基环,其中A为选自以下基团的至少一个成员:-H、-卤代、-羟基、-C1-6烷基、-C1-6烷氧基和-COOR2;
R2为-H、-C1-6烷基或-烷基取代的C1-6烷基或-芳基取代的C1-6烷基;
Y选自-COOR2,-C(O)NR2SO2R3、-C(O)NHSO2NR2R2、-NR2SO2R2、-SO2NR2R2、-C3-6环烷基-COOR2、-C1-6烯基-COOR2、-C1-6炔基-COOR2、-C1-6烷基-COOR2、-NHC(O)(CH2)n-COOR2、-SO2NR2C(O)R2、-四唑和-CONHOH,其中n=1-6;
R3为-C1-6烷基或烷基取代的C1-6烷基;
R4选自H、-C1-6烷基、-C3-6环烷基、-C1-6取代的烷基、-C1-6烷基-杂芳基、-C1-6烷基-取代的杂芳基、-C1-6烷基-NR6R7、-C1-6烷基-CONR8R9、-C3-6环烷基-CONR8R9、-C3-6环烷基-(CH2)1-3-NR6R7、-(CH2)1-3-C3-6环烷基-NR6R7、-(CH2)1-3-C3-6环烷基-(CH2)1-3-NR6R7、-C1-6烷基-Q1、C3-6环烷基-Q1、-COR10、-SO2R3和-SO2NR2R2;
Q1=-羟基、-COOR2、-卤代、-SO2Ra;
Rb=-H、-C1-6烷基、-COR3、-SO2R3、-SONR3R3;
R4也可选自:
R5选自-H、-C1-6烷基、-C3-6环烷基、-C1-6烷基取代的烷基、-COR10,-SO2R3和-SO2NR2R2;
前提是R4或R5只有一个可选自-COR10、-SO2R3和-SO2NR2R2;
或者R4和R5与邻近的N结合在一起形成环如
R10选自-H、-C1-6烷基、-C1-6烷基-NR6R7、-NR11R12、-OR13、-C1-6烷基-Q2、-C3-6环烷基-Q2、芳基-Q2,其中n=1-6,
其中Q2=羟基、-COOR2、-卤代、SO2Ra、-CONHSO2R3、-CONHSO2NR2R2;
R10也可选自:
R6和R7独立地选自-H、-C1-6烷基、-C1-6取代的烷基、芳基、杂芳基、取代的芳基、取代的杂芳基,和-C1-6烷基-Q1,
或者R6和R7与邻近的N结合在一起形成选自以下的环
Rc=C1-6烷基、NR2R2、-COOR3;
R8和R9独立地选自-H、-C1-6烷基、-C3-6环烷基、-C1-6取代的烷基、-C1-6烷基-杂芳基、-C1-6烷基-取代的杂芳基、-C1-6烷基-NR2R2、-C1-6烷基-CONR2R2、-C1-6烷基-Q1、C3-6环烷基-Q1,
或者R8和R9也可独立地选自
或R8和R9与邻近的N结合在一起形成选自以下的环:
以及R11和R12独立地选自-H、-C1-6烷基、-C3-6环烷基和-C1-6烷基取代的烷基;
或者R11和R12与邻近的N结合在一起形成选自以下的环
R13选自-H、-C1-6烷基、-C1-6烷基取代的烷基,和-C1-6烷基NR14R15,其中
R14和R15独立地选自-H、-C1-6烷基和-C1-6烷基取代的烷基,或R14和R15与邻近的N结合在一起形成选自以下的环
更优选的化合物包括由式I涵盖的那些化合物。在这些化合物中,其中X为苯基环的那些化合物甚至为更优选的。甚至更优选其中X为苯基环和Y在对位的式I化合物。
也优选其中A为选自以下基团的至少一个成员的式I化合物:-H、-OH、-卤代、-C1-3烷基和-C1-3烷氧基,其中-卤代选自-Cl、-F和-Br,其中-F为更优选的。
也优选这样的式I化合物,其中Y为-COOR2,且更优选为-COOH。
在另一个优选的实施方案中,提供以下的式Ia化合物,其中X为苯基环和Y为对位的-COOH::
在这种实施方案中,也优选A为选自以下基团的至少一个成员:-H、-卤代、-OH、-C1-3烷基和-C1-3烷氧基。特别优选A为选自以下基团的至少一个成员:-H、-氟代、-氯代、-OH、-甲基和-甲氧基。
优选作为本发明的一部分的其它化合物包括以下化合物:
甚至更优选的化合物包括以下化合物:
本发明的化合物,根据下述所有各种实施方案,可以经口服、胃肠外(包括皮下注射、静脉内、肌内、胸骨内注射或输注技术)、经吸入喷雾,或直肠和经其它方式,以含有本领域技术人员可获得的非-毒性药学上可接受的载体、赋形剂和稀释剂的剂量单位制剂给予。也可包括一种或多种辅助剂。
因此,依据本发明,进一步提供用于治疗病毒感染如HIV感染和AIDS的治疗方法和药用组合物。所述治疗涉及给予需要这种治疗的患者含有与一种或多种药学上可接受的载体、赋形剂或稀释剂一起的抗病毒有效量的一种或多种式I、II和/或III化合物的药用组合物。如本文所用的,术语″抗病毒有效量″意指所述组合物和方法中足以显示出有意义的患者益处(即,抑制、改善,或治愈特征为抑制HIV感染的急性病症)的各个活性成分的总量。当应用于单独给予的各个活性成分时,该术语指单一的成分。当应用于组合时,该术语指产生治疗效果的各活性成分的合并量,无论是否组合、连续或同时给予。术语″治疗、处理、医治″用于本文和权利要求书中时,意指预防、改善或治愈与HIV感染相关的疾病。
本发明的药用组合物可以呈现为可口服给予的混悬液或片剂的形式;以及鼻喷雾剂、无菌可注射制剂,例如,作为无菌可注射水性或油性混悬液或栓剂。药学上可接受的载体、赋形剂或稀释剂可用于药用组合物中,并且为药物制剂领域中所用的那些。
当作为混悬剂口服给予时,这些组合物依据药物制剂领域通常已知的技术制备,并且可包含用于赋予体积的微晶纤维素、作为助悬剂的藻酸或藻酸钠、作为粘度增强剂的甲基纤维素,以及本领域已知的甜味剂/矫味剂。作为立即释放片剂,这些组合物可含有微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和乳糖和/或本领域已知的其它赋形剂、粘合剂、填充剂、崩解剂、稀释剂和润滑剂。
可注射溶液或混悬液可依据已知的技术,使用合适的非-毒性的胃肠外可接受的稀释剂或溶剂(如甘露醇、1,3-丁二醇、水、Ringer’s溶液或等渗氯化钠溶液),或合适的分散剂或湿润剂和助悬剂(如无菌的、温和的固定油,包括合成的单-或二甘油酯),以及脂肪酸(包括油酸)来配制。
本文提出的化合物可以约1-100mg/kg体重的剂量范围分多个分剂量口服给予人,通常持续一个延长的时间段,如数天、数周、数月或甚至数年。一个优选的剂量范围为约1-10mg/kg体重,分成几个分剂量口服。另一个优选的剂量范围为约1-20mg/kg体重,分成几个分剂量。然而,应该理解,对于任何具体的患者,特定的剂量水平和给药频率可以变化并将取决于多个因素,包括所用的具体化合物的活性、化合物的代谢稳定性和作用的持续时间、年龄、体重、一般健康状况、性别、食谱、给药方式和次数、排泄速率、联合用药情况、具体病症的严重性,以及宿主经历的治疗。
本文提出的式I、II和/或III化合物与一种或多种其它用于治疗AIDS的药物在一起的组合也包括在本文中。例如,本公开的化合物可有效地(无论是在暴露前和/或暴露后期间)与有效量的AIDS抗病毒剂、免疫调节剂、抗感染剂,或疫苗,如以下的非-限制性表中的那些药物联合给予:
此外,本文提出的本公开的化合物可以与HIV进入抑制剂联合使用。这样的HIV进入抑制剂的实例在未来的药物(DRUGS OF THE FUTURE)1999,24(12),pp.1355-1362;CELL,Vol.9,pp.243-246,Oct.29,1999;和今日的药物开发(DRUGDISCOVERY TODAY),Vol.5,No.5,May2000,pp.183-194和HIV进入宿主细胞的抑制剂(Inhibitors of the entry of HIV into host cells).Meanwell,Nicholas A.;Kadow,John F.药物发现和开发的当前看法(Current Opinion in Drug Discovery&Development(2003),6(4),451-461中讨论。特别地,所述化合物可与附着抑制剂、融合抑制剂,以及针对或者CCR5或者CXCR4共同受体的趋化因子受体拮抗剂联合使用。HIV附着抑制剂描述于US7,354,924和US2005/0209246中。
应该理解,本申请的化合物与AIDS抗病毒剂、免疫调节剂、抗-感染剂、HIV进入抑制剂或疫苗的组合的范围不限于上面表中的罗列,但大体上包括与用于治疗AIDS的任何药用组合物的任何组合。
优选的组合为用本公开的化合物和HIV蛋白酶抑制剂和/或HIV逆转录酶的非-核苷抑制剂同时或交替治疗。所述组合中的任选的四种组分为HIV逆转录酶的核苷抑制剂,如AZT、3TC、ddC或ddI。优选的HIV蛋白酶抑制剂为(活性成分阿扎那韦)。典型地,一天一次给予300-600mg的剂量。这可以与低剂量的利托那韦(50-500mgs)共同给予。另一个优选的HIV蛋白酶抑制剂为、另一个有用的HIV蛋白酶抑制剂为茚地那韦,其为N-(2(R)-羟基-1-(S)-茚满基)-2(R)-苯基甲基-4-(S)-羟基-5-(1-(4-(3-吡啶基-甲基)-2(S)-N′-(叔-丁基甲酰胺基)-哌嗪基))-戊酰胺乙醇化物的硫酸盐,并可依据U.S.5,413,999合成。茚地那韦通常以800mg的剂量,一天3次给予。其它优选的蛋白酶抑制剂为奈非那韦和利托那韦。另一个优选的HIV蛋白酶抑制剂为沙奎那韦,其以600或1200mg的剂量给予(tid)。优选的HIV逆转录酶的非-核苷抑制剂包括依法韦仑。这些组合对限制HIV感染的传播和程度可具有意外的效果。优选的组合包括具有以下药物的那些组合:(1)茚地那韦与依法韦仑,并且任选地,AZT和/或3TC和/或ddI和/或ddC;(2)茚地那韦和AZT和/或ddI和/或ddC和/或3TC的任何一种,特别是,茚地那韦和AZT和3TC;(3)司他夫定和3TC和/或齐多夫定;(4)富马酸替诺福韦酯盐和恩曲他滨。
在这样的组合中,本发明的化合物和其它活性剂可分开给予或组合给予。此外,一种成分可在给予其它药物之前、同时或之后给予。
通用化学(合成方法)
本发明包括式I、II和III化合物,它们的药物制剂,以及它们在患有或易感HIV感染的患者中的用途。式I、II和III化合物也包括其药学上可接受的盐。构建结构式I、II和III化合物和用于合成它们的中间体的通用程序描述于以下流程(缩写词之后)中。
缩写词
一或多个以下的缩写词,其大多数是本领域技术人员熟知的常规缩写词,可以在本公开的描述和实施例中通篇使用:
Bz2O=苯甲酸酐
TBTU=O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓四氟硼酸盐
HATU=2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐
孔雀绿磷钨钼酸盐(methanaminium)
DCE=二氟乙烷
DCM=二氟甲烷
CDI=羰基二咪唑
prep.HPLC=制备型高效液相层析法
rt=室温
DIPEA=二异丙基乙胺
DMAP=4-二甲基氨基吡啶
DMSO=二甲基亚砜
THF=四氢呋喃
KHMDS=双(三甲基甲硅烷基)氨化钾
min=分钟
h=小时
sat.=饱和的
TEA=三乙胺
EtOAc=乙酸乙酯
TFA=三氟乙酸
PCC=氯代铬酸吡啶鎓
TLC=薄层层析
Tf2NPh=(三氟甲基磺酰基)甲烷磺酰胺
二氧六环=1,4-二氧六环
PG=保护基团
atm=大气
mol=摩尔
mmol=毫摩尔
mg=毫克
μg=微克
μl=微升
μm=微米
mm=毫米
HOAc=乙酸
MeOH=甲醇
DMF=N,N-二甲基甲酰胺
TBAF=四丁基氟化铵
术语“C-3”和“C-28”指依据IUPAC规则(以下关于示例性三萜烯:桦木醇描述的位置)编号的三萜烯核心的某些位置:
当在流程和方法的一般说明中提及化合物系列时,保持相同的编号。
式I、II和III化合物的制备通用化学流程:
式I、II和III化合物的制备通用化学流程:
式I化合物可通过以下流程中描述的化学方法,由市售可获得的(Aldrich,其它)桦木酸和桦木醇制备。式II和III化合物在下文描述。
通用反应流程如下所示:
流程1
桦木醇的C-28位中的羟基可用合适的羟基-保护基团进行保护。C-3羟基的标准氧化(即PCC,Dess-Martin)产生C-3酮,然后采用本领域技术人员已知的条件将其转化为三氟甲磺酸酯。钯催化的与硼酸的交叉偶联(也可采用使用锡烷的Stille偶合),得到相应的C-3修饰的桦木醇衍生物。C-28位羟基的去保护,随后经标准的条件(即PCC)下的氧化,得到相应的醛。这种醛与胺使用三乙酰氧基硼氢化钠(也可使用氰基硼氢化钠)的标准还原性胺化,随后使羧酸去保护,得到要求的C-28胺。
流程2
作为选择,某些C-28叔胺可如流程2中所述制备:首先,用伯胺还原性胺化C-28醛生成C-28仲胺。使羧酸去保护,随后,用二烷基缩醛的醛在标准条件下使C-28仲胺还原性胺化,得到要求的C-28叔胺。
流程3
作为选择,C-28胺可通过用羟胺在标准条件下处理,将C-28醛转化为相应的肟来制备。使用氰基硼氢化钠在三氯化钛的存在下还原羟基胺,得到C-28伯胺,其可使用本领域技术人员已知的方法进一步衍生化,提供要求的最终产物。
流程4
某些C-28胺可如流程4中所述制备:在标准条件下,在2,2-二乙氧基乙胺的存在下,使C-28醛还原性胺化,随后经缩酮水解,生成携带醛的C-28胺,其也可在标准条件下经受还原性胺化。使羧酸去保护,产生要求的C-28胺。
取代基R4、R5、R6和R7可含有可用本领域技术人员已知的方法进一步修饰的官能团(即COOH、COOR、OH、NHR)。所述修饰可在实施最终的羧酸去保护之前或之后进行,这取决于官能团的性质。
作为选择,当R4、R5、R6和/或R7为H时,相应的胺可通过本领域技术人员已知的方法被进一步修饰(例如经烷基化、酰化、迈克尔加成(Michael addition),等)。异丙烯基的饱和可通过在标准条件下氢化最终产物而实现。
流程5
苯甲酸可通过本领域技术人员已知的方法被进一步修饰。这样的修饰的实例示于流程5中。在标准条件下安置合适的保护基团以掩蔽C-28位中的游离的NH。然后,在偶合剂和碱的存在下,使用相应的亲核试剂,例如磺酰胺或脲处理羧酸,随后除去C-28胺保护基团,得到要求的最终产物。
其中C-3位的修饰不是苯甲酸的式I化合物可通过在示于流程1(流程6)的钯交叉偶联步骤中选择相应的硼酸,然后使用描述于以上流程中的化学方法进行制备。
流程6
作为选择,式I化合物可采用下面流程7中描述的方法制备。C-28伯胺可在碱和1,2-二取代的乙烷(其中的取代基为两个离去基团(即,甲苯磺酸基、甲磺酸基、Br、Cl、I))的存在下被处理,形成C-28氮杂环丙烷。用亲核试剂使氮杂环丙烷开环可在加热或不加热的情况下实现,产生相应的C-28仲胺,其可被进一步修饰。
流程7
式II化合物可使用以上对式I化合物描述的化学方法,用由如示于下面流程8的双键饱和构成的一个额外步骤进行制备:
流程8
式III化合物可以以上面对式I和II化合物描述的相同方法,使用齐墩果酸(oleanoic acid)或乌索酸作为起始原料代替桦木醇来制备。
实施例
以下实施例说明了如上一般描述的式I、II和III化合物的典型合成。这些实施例仅仅是示例性的并不打算以任何方式限制本公开。试剂和起始原料对于本领域普通技术人员而言都是容易地获得的。
化学
选择的实施例的典型程序和特征鉴定:
除非另外说明,溶剂和试剂以从商业来源获得的原样使用,以及反应在氮气气氛下进行。快速层析在硅胶(Silica gel)60(0.040-0.063粒度;EM Sciencesupply)上进行。1H NMR谱在Bruker DRX-500f上以500MHz(或如所述的在Bruker AV 400 MHz,Bruker DPX-300B或Varian Gemini300上以300MHz)记录。化学位移在相对于δTMS=0的δ标度上,以ppm报告。对以下溶剂中的残留质子采用以下内部参考标准:CDCl3(δH7.26)、CD3OD(δH3.30)、Acetic-d4(乙酸d4)(δH11.6,2.07)、DMSO混合物或DMSO-D6_CDCl3((H2.50和8.25)(比例75%∶25%),和DMSO-D6(δH2.50)。标准的首字母简略词被用于描述峰裂数模式:s(单峰),br.s(寛单峰),d(双峰),t(三重峰),q(四重峰),m(多重峰),b(宽峰),app(明显的)。偶合常数(J)以赫兹(Hertz)表示。所有的液相层析(LC)数据在ShimadzuLC-10AS液相层析仪上,使用SPD-10AV UV-Vis检测器记录,质谱(MS)数据使用用于LC的Micromass平台(Micromass Platform),以电喷雾模式确定。
LC/MS方法
方法1
起始%B=20,最终%B=100,经1分钟梯度
流速=4ml/min
波长=254
溶剂A=10%MeOH-90%水-0.1%TFA
溶剂B=90%MeOH-10%水-0.1%TFA
柱3=Xbridge Phenyl4.6x50mm S5
方法2
起始%B=30,最终%B=100,经1分钟梯度
流速=0.8ml/min
波长=220
溶剂A=10%甲醇/90%水/0.1%TFA
溶剂B=90%甲醇/10%水/0.1%TFA
柱3=Xbridge Phenyl2.1x50mm2.5μm
方法3
起始%B=20,最终%B=100,经2分钟梯度
流速=0.8ml/min
波长=254
溶剂A=10%甲醇/90%水/0.1%TFA
溶剂B=90%甲醇/10%水/0.1%TFA
柱3=Xbridge Phenyl2.1x50mm2.5μm
方法4
起始%B=0,最终%B=100,经2分钟梯度
流速=4ml/min
波长=220
溶剂A=95%水/5%甲醇/10mM乙酸铵
溶剂B=5%水/95%甲醇/10mM乙酸铵
柱=PHENOMENEX-LUNA3.0x50mm
方法5
起始%B=0,最终%B=100,经2分钟梯度
流速=4ml/min
波长=220
溶剂A=95%水/5%甲醇/10mM乙酸铵
溶剂B=5%水/95%甲醇/10mM乙酸铵
柱=Xbridge4.6x50mm5μC18
方法6
起始%B=40,最终%B=100,经2分钟梯度
流速=1ml/min
波长=220
溶剂A=95%水/5%甲醇/10mM乙酸铵
溶剂B=5%水/95%甲醇/10mM乙酸铵
柱=PHENOMENEX-LUNA C18,2.0x30,μm
方法7
起始%B=0,最终%B=100,经2分钟梯度
流速=5ml/min
波长=220
溶剂A=95%水/5%甲醇/10mM TFA
溶剂B=5%水/95%甲醇/10mM TFA
柱=PHENOMENEX-LUNA3.0x50mm S10
方法8
起始%B=0,最终%B=100,经2分钟梯度,保持100%B
流速=1mL/min
波长=220nm
溶剂A=95%水,5%甲醇,10mM乙酸铵
溶剂B=5%水,95%甲醇,10mM乙酸铵
柱=Phenomenex LUNA C18,2.0x30mm,3μm
方法9
起始%B=0%,最终%B=100,经2分钟梯度,保持100%B
流速=1.0mL/min
波长=220nm
溶剂A=90%水,10%甲醇,0.1%TFA
溶剂B=10%水,90%甲醇,0.1%TFA
柱=phenomenex-luna,2.0x30mm,3.0μm
化合物的制备
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
步骤1.制备苯甲酸((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-羟基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)二十氢-1H-环戊二烯并[a]-3a-基)甲基酯.
将(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)二十氢-1H-环戊二烯并[a]-9-醇(10g,22.59mmol)和DMAP(0.552g,4.52mmol)在吡啶(100ml)中的混悬液加热至50℃。加热时所有的固体溶解。经1小时向该溶液中分批(4份)加入苯甲酸酐(7.66g,33.9mmol),每次用5ml吡啶冲洗烧瓶壁。于50℃搅拌澄清的无色溶液4h,然后冷却至室温并在减压下浓缩。稠厚的琥珀色残留物用饱和的NaHCO3(200ml)稀释并用二氟甲烷(3x150ml)提取。合并的有机层用Na2SO4干燥,经过滤除去干燥剂,且滤液在减压下浓缩。残留物经快速层析纯化,使用0-25%EtOAc在己烷中的梯度液,得到标题化合物,为白色泡沫状物(8.6g,15.73mmol,69.6%得率)。1HNMR(500MHz,氯仿-d)δppm8.05(d,J=7.02Hz,2H),7.55(t,J=7.32Hz,1H),7.44(t,J=7.63Hz,2H),4.71(s,1H),4.60(s,1H),4.51(d,J=10.99Hz,1H),4.09(d,J=10.99Hz,1H),3.15-3.21(m,1H),2.52(td,J=10.99,5.80Hz,1H),1.89-2.08(m,3H),1.70(s,3H),1.06(s,3H),1.00(s,3H),0.96(s,3H),0.83(s,3H),0.75(s,3H),0.63-1.81(m,21H)。
步骤2.制备苯甲酸((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-9-氧代-1-(丙-1-烯-2-基)二十氢-1H-环戊二烯并[a]-3a-基)甲基酯.
向苯甲酸((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-羟基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)二十氢-1H-环戊二烯并[a]-3a-基)甲基酯(8.6g,15.73mmol)的CH2Cl2(100ml)溶液中加入PCC(5.09g,23.59mmol)。于室温下搅拌7.25h后,通过硅藻土和硅胶过滤该混合物并用二氟甲烷洗涤,然后用1∶1EtOAc∶己烷洗涤。在减压下浓缩滤液,得到标题化合物,为白色泡沫状物(8.26g,15.16mmol,96%得率)。1H NMR(500MHz,氯仿-d)δppm8.05(d,J=7.32Hz,2H),7.56(t,J=7.48Hz,1H),7.44(t,J=7.63Hz,2H),4.72(s,1H),4.61(s,1H),4.52(d,J=10.99Hz,1H),4.09(d,J=11.29Hz,1H),2.45-2.58(m,2H),2.34-2.43(m,1H),1.86-2.10(m,4H),1.70(s,3H),1.10(s,3H),1.06(s,3H),1.04-1.82(m,18H),1.02(s,3H),1.01(s,3H),0.94(s,3H)。
步骤3.制备苯甲酸((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(三氟甲基磺酰基氧基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基酯.
将苯甲酸((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-9-氧代-1-(丙-1-烯-2-基)二十氢-1H-环戊二烯并[a]-3a-基)甲基酯(10.1g,18.54mmol)的THF(100ml)溶液冷却至-78℃。向该溶液中加入KHMDS(0.5M在甲苯中)(74.2ml,37.1mmol)。于-78℃将该混合物搅拌15分钟并通过导管加入N-苯基-双(三氟甲烷磺酰亚胺(sulfonimide))(7.29g,20.4mmol)在THF(20ml)和甲苯(20ml)中的溶液。于-78℃将该混合物搅拌3.5h。TLC指示仍存在痕量的起始原料,因此将额外的0.7gN-苯基-双(三氟甲烷磺酰亚胺)加入到该混合物中并于-78℃继续搅拌1h。TLC指示该反应完成。该混合物用水(75ml)稀释并用乙酸乙酯(3x75ml)提取。合并的有机层用MgSO4干燥。经过滤除去干燥剂,且滤液在减压下浓缩。残留物经快速层析纯化,使用0-20%甲苯在己烷中的梯度液,然后使用在己烷中的20%甲苯,随后使用在己烷中的10-15%EtOAc,得到标题化合物,为白色泡沫状物(9.85g,14.55mmol,78%得率)。1H NMR(400MHz,氯仿-d)δppm0.94(s,3H),1.03(s,3H),1.04(s,3H),1.10-1.86(m,18H),1.12(s,3H),1.14(s,3H),1.73(s,3H),1.92-2.13(m,3H),2.18(dd,J=17.07,6.78Hz,1H),2.55(td,J=11.11,5.90Hz,1H),4.12(d,J=11.04Hz,1H),4.55(dd,J=11.04,1.25Hz,1H),4.64(s,1H),4.75(d,J=2.01Hz,1H),5.58(dd,J=6.65,1.88Hz,1H),7.43-7.49(m,2H),7.55-7.60(m,1H),8.05-8.09(m,2H)。
步骤4.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(苯甲酸基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
标题化合物经Suzuki偶合制备如下:
向苯甲酸((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(三氟甲基磺酰氧基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基酯(9.85g,14.55mmol)的1,4-二氧六环(50ml)溶液中加入2-丙醇(50.0ml)、水(20ml)、碳酸钠一水合物(5.41g,43.7mmol)、4-叔-丁氧羰基苯基硼酸(4.85g,21.83mmol)和四(三苯膦)钯(0)(0.504g,0.437mmo1)。也可使用碳酸钾和磷酸钾代替碳酸钠一水合物。烧瓶侧用额外的20ml二氧六环冲洗,混合物附着于回流冷凝器上,用N2吹洗,加热至回流。加热时,在混合物中的固体完全溶解。在回流下加热该溶液3.5h,冷却至室温并用200ml水稀释。该混合物用乙酸乙酯(3x150ml)提取,合并的有机层用Na2SO4干燥。经过滤除去干燥剂,且滤液在减压下浓缩。残留物经快速层析,使用0-15%EtOAc在己烷中的梯度液纯化,得到标题化合物,为白色泡沫状物(9.5g,~83%纯度,基于1HNMR积分)。产物无需另外的纯化而用于下一步骤。
步骤5.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(苯甲酸基甲基)-5a,5b,8,8,11a五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(9.5g,13.47mmol)的二氧六环(200ml)溶液中加入水(25ml)和氢氧化锂一水合物(1.696g,40.4mmol)。将该混合物加热至75℃。最初,在混合物中的固体是透明的,但是加热2h后,所有的固体均已溶解。加热23.5h后,混合物中的固体再次变得透明。将该混合物冷却至室温并加入250ml水。通过过滤收集已形成的固体并用水洗涤。使固体溶解于乙醚和二氟甲烷中并用MgSO4干燥。经过滤除去干燥剂,且在减压下浓缩滤液,得到标题化合物,为白色泡沫状物(5.6g,9.32mmol,64%两步得率。1HNMR(500MHz,氯仿-d)δppm7.87(2H,d,J=8.2Hz),7.16(2H,d,J=7.9Hz),5.26(1H,dd,J=6.3,1.7Hz),4.69(1H,d,J=2.1Hz),4.58(1H,s),3.82(1H,d,J=9.8Hz),3.35(1H,d,J=10.7Hz),2.40(1H,td,J=11.0,5.8Hz),2.09(1H,dd,J=17.1,6.1Hz),1.69(3H,s),1.58(9H,s),1.08(3H,s),1.01(3H,s),0.97(3H,s),0.91(6H,s),0.83-2.03(21H,m)。
步骤6.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(5.6g,9.32mmol)的二氟甲烷(100ml)溶液中加入PCC(3.01g,13.98mmol)。于室温下搅拌该混合物6.5h,然后通过硅藻土和硅胶垫过滤,用二氯甲烷洗涤之,然后用1∶1乙酸乙酯∶己烷洗涤。在减压下浓缩滤液,残留物经快速层析,使用0-10%EtOAc在己烷中的梯度液纯化,得到标题化合物,为白色固体(4.49g,7.50mmol,80%得率)。1H NMR(500MHz,氯仿-d)δppm9.68(1H,d,J=1.5Hz),7.87(2H,d,J=8.2Hz),7.16(2H,d,J=8.2Hz),5.26(1H,dd,J=6.4,1.8Hz),4.76(1H,d,J=1.8Hz),4.63(1H,s),2.88(1H,td,J=11.1,5.8Hz),2.02-2.15(3H,m),1.70(3H,s),1.58(9H,s),1.00(3H,s),0.97(3H,s),0.97(3H,s),0.91(6H,s),0.83-1.94(19H,m)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
将4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(59mg,0.099mmol)、N1,N1-二甲基乙烷-1,2-二胺(0.13ml,1.2mmol)、三乙酰氧基硼氢化钠(104mg,0.493mmol)和AcOH(0.023ml,0.394mmol)在DCE(3ml)中的混合物于室温下搅拌12h。真空除去溶剂。LCMS显示要求的产物和一些未还原的亚胺。使残留物溶于DCE(3ml)并再次用三乙酰氧基硼氢化钠(104mg,0.493mmol)和AcOH(0.023ml,0.394mmol)于室温下处理48h。真空除去溶剂,使残留物再溶解于二氯甲烷并经硅胶柱纯化(0-10%MeOH/CH2Cl2),得到标题化合物,为白色固体(65mg,98%得率)。1H NMR(400MHz,氯仿-d)δppm7.90(d,J=8.3Hz,2H),7.19(d,J=8.5Hz,2H),5.30(dd,J=6.1,1.6Hz,1H),4.72(d,J=1.5Hz,1H),4.63(s,1H),3.17-2.95(m,3H),2.72(t,J=5.9Hz,2H),2.54(d,J=12.3Hz,1H),2.48-2.41(m,1H),2.40(s,6H),2.21-1.10(m,22H),1.72(s,3H),1.61(s,9H),1.12(s,3H),1.03(s,3H),1.00(s,3H),0.95(s,6H)。
实施例1.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
用TFA(0.6ml,7.6mmol)处理
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(59mg,0.088mmol)的DCM(2ml)溶液并于室温下搅拌该混合物12h。真空除去溶剂以提供标题化合物,为白色固体(40mg,0.065mmol,74.0%得率)。LCMS:m/e615.7(M+H)+,2.00min(方法7).1H NMRMHz,MeOD)δppm7.94(d,J=8.3Hz,2H),7.24(d,J=8.0Hz,2H),5.33(d,J=4.8Hz,1H),4.78(s,1H),4.67(s,1H),3.73-3.42(m,4H),3.33(m,1H),2.99-2.94(m,1H),2.93(s,6H),2.53(td,J=10.6,5.6Hz,1H),2.99-1.29(m,2H),1.98-1.22(m,20H),1.76(s,3H),1.20(s,3H),1.10(s,3H),1.06(s,3H),0.99(s,3H),0.98(s,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-吗啉代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(1M在DCM中)(0.167ml,0.167mmol)和N-(3-氨基丙基)吗啉(0.029ml,0.200mmol)。将该混合物于室温下搅拌15分钟并加入三乙酰氧基硼氢化钠(0.071g,0.334mmol)。于室温下搅拌该混合物1.5h并加入额外的0.1g三乙酰氧基硼氢化钠。于室温下搅拌该混合物过夜,然后用7ml饱和的NaHCO3猝灭。该混合物用二氟甲烷(3x7ml)提取,合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且滤液在减压下浓缩。混合物经快速层析,使用0-10%MeOH在二氟甲烷中的梯度液纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物,为白色泡沫状物(69mg,0.095mmol,56.8%得率)。LCMS:m/e727.5(M+H)+,2.81min(方法6)。
实施例2.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-吗啉代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-吗啉代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(69mg,0.095mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物3h,然后在减压下浓缩。残留物经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物(36mg,0.054mmol,56.5%得率),为白色泡沫状物。LCMS:m/e671.5(M+H)+,2.17min(方法6).1HNMR(400MHz,氯仿-d)δppm7.94(d,J=8.03Hz,2H),7.15(d,J=8.03Hz,2H),5.29(d,J=4.52Hz,1H),4.71(br.s.,1H),4.62(br.s.,1H),3.73(br.s.,4H),3.09-3.26(m,3H),2.65(d,J=12.30Hz,1H),2.56(br.s.,6H),2.42(br.s.,1H),1.69(s,3H),1.07(s,3H),1.05-2.14(m,24H),1.00(s,3H),0.97(s,3H),0.93(br.s.,3H),0.93(br.s.,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1-乙基吡咯烷-2-基)甲基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(1M在DCM中)(0.167ml,0.167mmol)和2-(氨基甲基)-1-乙基吡咯烷(0.029ml,0.200mmol)。将该混合物于室温下搅拌15分钟并加入三乙酰氧基硼氢化钠(0.071g,0.334mmol)。于室温下搅拌该混合物1.5h,然后加入额外的0.1g三乙酰氧基硼氢化钠并将该混合物于室温下搅拌过夜。搅拌24h后,经TLC检测仍剩下一些起始原料。向该混合物中加入乙酸(1M在DCM中)(0.167ml,0.167mmol)、2-(氨基甲基)-1-乙基吡咯烷(0.029ml,0.200mmol)和三乙酰氧基硼氢化钠(0.071g,0.334mmol)。于室温下搅拌该混合物另外19h,然后用7ml饱和的NaHCO3稀释。该混合物用二氟甲烷(3x7ml)提取,合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且滤液在减压下浓缩。混合物经使用0-10%MeOH在二氟甲烷中的梯度液的快速层析纯化。分离为白色固体的两个产物。LC/MS指示两者具有相同的质量,但保留时间不同。1H NMR证实,分离出两种非对映体。分离出44mg非对映体1(经TLC检测为较小的极性斑点),同时分离出55mg非对映体2(更大的极性斑点)。非对映体1:LCMS:m/e711.4(M+H)+,3.34min(方法6).非对映体2:LCMS:m/e711.6(M+H)+,3.27min(方法6)。
实施例3(非对映体1)和实施例4(非对映体2).制备
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1-乙基吡咯烷-2-基)甲基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
将两种反应物放置在分开的容器中。向上面分离的每种非对映体(0.044g异构体1(较小的极性斑点))、(0.044g异构体2(更大的极性斑点))的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物3h,然后在减压下浓缩。残留物经制备型HPLC纯化。在减压下浓缩含有期望的产物的部分,得到非对映体1(31mg,0.047mmol)和非对映体2(37mg,0.056mmol),为灰白色泡沫状物。非对映体1:LCMS:m/e653.5(M-H)-,2.29min(方法6).1H NMR(400MHz,氯仿-d)δppm7.96(d,J=8.03Hz,2H),7.11-7.16(m,2H),5.31(d,J=6.27Hz,1H),4.71(br.s.,1H),4.60(s,1H),3.80-3.90(m,1H),2.32-3.45(m,9H),1.70(s,3H),1.17(d,J=13.30Hz,3H),1.01(br.s.,6H),0.99-2.19(m,29H),0.97(s,3H),0.90(d,J=5.27Hz,3H)。
非对映体2:LCMS:m/e653.5(M-H)-,2.30min(方法6).1H NMR(400MHz,氯仿-d)δppm7.96(d,J=8.03Hz,2H).7.09-7.18(m,2H),5.31(d,J=6.02Hz,1H),4.71(br.s.,1H),4.60(br.s.,1H),3.77-3.92(m,1H),2.31-3.44(m,9H),1.70(s,3H),1.17(d,J=12.05Hz,3H),1.01(s,6H),0.99-2.20(m,29H),0.97(s,3H),0.90(d,J=5.02Hz,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-(吡啶-2-基)乙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(1M在DCM中)(0.167ml,0.167mmol)和2-(2-吡啶基)乙胺(0.024ml,0.200mmol)。将该混合物于室温下搅拌15分钟并加入三乙酰氧基硼氢化钠(0.071g,0.334mmol)。于室温下搅拌该混合物1.5h,然后向该混合物中加入额外的0.1g三乙酰氧基硼氢化钠并将其搅拌23h。向该混合物中加入额外的乙酸(1M在DCM中)(0.167ml,0.167mmol)、2-(2-吡啶基)乙胺(0.024ml,0.200mmol)和三乙酰氧基硼氢化钠(0.071g,0.334mmol)。于室温下搅拌该混合物另外19h,用7ml饱和的NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥,经过滤除去干燥剂,且在减压下浓缩滤液。混合物经使用0-10%MeOH在二氟甲烷中的梯度液的快速层析纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物。LCMS:m/e705.4(M+H)+,2.90min(方法6)。
实施例5.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-(吡啶-2-基)乙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-(吡啶-2-基)乙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.119g,0.127mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物3.5h并在减压下浓缩该混合物。残留物经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物,为淡黄色泡沫状物(61mg,0.094mmol,74.3%得率)。LCMS:m/e647.4(M-H)-,2.20min(方法6)。1H NMR(400MHz,氯仿-d)δppm8.42-8.48(m,1H),7.95(d,J=8.28Hz,2H),7.65(td,J=7.65,1.76Hz,1H),7.17-7.24(m,2H),7.14(d,J=8.03Hz,2H),5.29(d,J=4.52Hz,1H),4.71(br.s.,1H),4.61(br.s.,1H),3.45-3.59(m,2H),3.18-3.32(m,3H),2.74(d,J=12.30Hz,1H),2.45(br.s.,1H),1.70(s,3H),1.05(s,3H),1.01(s,3H),0.98-2.13(m,24H),0.96(s,3H),0.94(br.s.,3H),0.92(br.s.,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羟基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(0.019ml,0.334mmol)和3-(二甲基氨基)丙基胺(0.084ml,0.668mmol)。向该混合物中加入三乙酰氧基硼氢化钠(0.177g,0.835mmol)并将其于室温下搅拌72h。搅拌72h后,反应物用7ml饱和的NaHCO3稀释,用二氟甲烷(3x7ml)提取,合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且在减压下浓缩滤液,得到期望的产物,4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(二甲基氨基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯。粗产物无需另外的纯化而用于下一步骤。LCMS:m/e685.6(M-H)-,2.92min(方法6)。
实施例6.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(二甲基氨基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(二甲基氨基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(114mg,0.167mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物5h并在减压下浓缩。残留物经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物,为白色固体(77mg,0.122mmol,73.3%得率)。LCMS:m/e629.6(M-H)-,2.22min(方法6).1H NMR(500MHz,乙酸)δppm8.03(d,J=8.24Hz,2H)7.30(d,J=8.24Hz,2H),5.37(d,J=4.58Hz,1H),4.79(s,1H),4.68(s,1H),3.32-3.44(m,3H),3.25-3.32(m,2H),2.96(d,J=13.12Hz,1H),2.89-2.94(m,6H),2.49-2.58(m,1H),2.30-2.38(m,J=8.09,7.86,7.74,7.74Hz,2H),1.75(s,3H),1.19(s,3H),1.13-2.23(m,22H),1.09(s,3H),1.08(s,3H),1.02(s,3H),1.00(s,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-乙酰胺基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(0.019ml,0.334mmol)和N-乙酰基乙二胺(0.048ml,0.501mmol)。将该混合物于室温下搅拌2h,然后向该混合物中加入三乙酰氧基硼氢化钠(0.177g,0.835mmol)。于室温下搅拌该混合物3天,然后用7ml饱和的NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥,经过滤除去干燥剂,且滤液在减压下浓缩。粗物质无需另外的纯化而用于下一步骤。LCMS:m/e685.4(M+H)+,3.86min(方法6)。
实施例7.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-乙酰氨基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-乙酰氨基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(114mg,0.167mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物3.5h,然后在减压下浓缩。使残留物溶于二氧六环和MeOH并经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物,为灰白色固体(40.7mg,0.065mmol,38.8%得率)。LCMS:m/e629.5(M+H)+,2.17min(方法6).1HNMR(500MHz,乙酸的)δppm8.03(d,J=8.24Hz,2H),7.30(d,J=8.24Hz,2H),5.37(d,J=4.58Hz,1H),4.79(s,1H),4.68(s,1H),3.61-3.70(m,2H),3.40-3.53(m,2H),3.37(d,J=13.12Hz,1H),2.98(d,J=12.82Hz,1H),2.49-2.57(m,1H),2.09(s,3H),1.75(s,3H),1.19(s,3H),1.14-2.24(m,22H),1.10(s,3H),1.07(s,3H),1.02(s,3H),1.00(s,3H)。
制备4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(叔-丁氧羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)乙基)哌嗪-1-甲酸叔丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(0.019ml,0.334mmol)和4-N-(2-氨基乙基)-1-N-Boc-哌嗪(0.077g,0.334mmol)。于室温下搅拌该混合物2h,然后向该混合物中加入三乙酰氧基硼氢化钠(0.177g,0.835mmol)。将该混合物于室温下搅拌3天,然后用7ml饱和的NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需进一步纯化而用于下一步骤。LCMS:m/e812.3(M+H)+,3.30min(方法6)。
实施例8.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(叔-丁氧羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)乙基)哌嗪-1甲酸叔-丁基酯(136mg,0.167mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物5h,然后在减压下浓缩。使残留物溶于二氧六环和MeOH并经制备型HPLC再纯化。合并含有期望的产物的部分并在减压下浓缩。HPLC显示仍存在某些不纯物,所以反应物经制备型HPLC纯化。在减压下浓缩所述部分,得到标题化合物,为白色固体(18mg,0.027mmol,16.43%得率)。LCMS:m/e656.6(M+H)+,2.24min(方法6)。1H NMR(500MHz,乙酸的)δppm8.03(d,J=8.24Hz,2H),7.30(d,J=8.24Hz,2H),5.37(d,J=4.58Hz,1H),4.79(s,1H),4.68(s,1H),3.50-3.67(m,6H),3.40(d,J=12.82Hz,1H),3.22-3.29(m,6H),2.99(d,J=13.12Hz,1H),2.49-2.58(m,1H),1.76(s,3H),1.19(s,3H),1.16-2.23(m,22H),1.10(s,3H),1.08(s,3H),1.02(s,3H),1.00(s,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(哌啶-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(0.019ml,0.334mmol)和N-(2-氨基乙基)哌啶(0.048ml,0.334mmol)。于室温下搅拌该混合物2h,然后加入三乙酰氧基硼氢化钠(0.177g,0.835mmol)。于室温下搅拌该混合物3天,然后用7ml饱和的NaHCO3稀释和用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。LCMS:m/e711.2(M+H)+,3.32min(方法6)。
实施例9.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(哌啶-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(哌啶-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(119mg,0.167mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物6h,然后在减压下浓缩。使残留物溶于二氧六环和MeOH并经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩。使残留物溶于二氧六环和甲醇,该混合物用热气枪加热至回流。缓慢加入水直至混合物稍显混浊。使该混合物冷却至室温,然后冷冻过夜。通过过滤收集形成的固体并用水洗涤得到标题化合物,为淡黄色固体(57mg,0.087mmol,52.1%得率)。LCMS:m/e655.6(M+H)+,2.28min(方法6).1HNMR(400MHz,乙酸d4)δppm7.99(d,J=8.28Hz,2H),7.25(d,J=8.28Hz,2H),5.32(d,J=4.52Hz,1H),4.75(s,1H),4.63(s,1H),3.72(s,2H),3.56-3.66(m,2H),3.33(d,J=12.80Hz,1H),2.98(d,J=12.80Hz,1H),2.48(br.s.,1H),1.71(s,3H),1.14(s,3H),1.09-2.22(m,32H),1.05(s,3H),1.03(s,3H),0.97(s,3H),0.96(s,3H)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)-2-(吡啶-3-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.1g,0.167mmol)的DCE(2ml)溶液中加入乙酸(0.019ml,0.334mmol)和(2-氨基-1-(3-吡啶基)乙基)二甲基胺(0.055g,0.334mmol)。于室温下搅拌该混合物2h,然后加入三乙酰氧基硼氢化钠(0.177g,0.835mmol)并于室温下搅拌3天。该混合物用7ml饱和的NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。LCMS:m/e748.3(M+H)+,3.47min(方法6)。
实施例10.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)-2-(吡啶-3-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)-2-(吡啶-3-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(125mg,0.167mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物4.5h,然后在减压下浓缩。使残留物溶于二氧六环和MeOH并经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩。仍存在不纯物,所以残留物再次经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩,得到标题化合物,为灰白色固体(16mg,13.8%)。LCMS:m/e692.5(M+H)+,2.30min(方法6).1HNMR(500MHz,乙酸)δppm8.83-8.98(m,2H),8.27-8.42(m,1H),7.99-8.11(m,2H),7.71-7.84(m,1H),7.27-7.35(m,2H),5.33-5.42(m,1H),5.22-5.30(m,1H),4.79(d,J=14.34Hz,1H),4.67(d,J=12.82Hz,1H),4.21-4.38(m,2H),3.34-3.52(m,1H),2.97-3.15(m,1H),2.83(br.s.,3H),2.82(br.s.,3H),2.43-2.58(m,1H),0.88-2.23(m,40H)。
制备4-((1R,3S,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-甲基哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁酯(0.1g,0.167mmo)的DCE(2ml)溶液中加入乙酸(0.019ml,0.334mmol)和2-(4-甲基-哌嗪-1-基)-乙胺(0.048g,0.334mmol)。于室温下搅拌该混合物2h,然后加入三乙酰氧基硼氢化钠(0.177g,0.835mmol)并于室温下搅拌3天。该混合物用7ml饱和NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。经过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。LCMS:m/e726.5(M+H)+,3.07min(方法6)。
实施例11.制备4-((1R,3aS,5aR,5bR,7aR,11aS,1bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-甲基哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-甲基哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(0.121g,0.167mmol)的DCM(1ml)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物5.5h,然后在减压下浓缩。使残留物溶于二氧六环和MeOH,经制备型HPLC纯化两次,得到标题化合物,为白色固体(0.044g,0.066mmol,39.3%得率)。LCMS:m/e670.6(M+H)+,2.23min(方法6).1H NMR(500MHz,乙酸)δppm8.03(d,J=8.24Hz,2H),7.30(d,J=8.55Hz,2H),5.37(d,J=4.58Hz,1H),4.79(s,1H),4.68(s,1H),3.43-3.66(m,6H),3.40(d,J=13.43Hz,1H),3.17-3.31(m,6H),2.98(d,J=12.82Hz,1H),2.92(s,3H),2.47-2.57(m,1H),1.75(s,3H),1.18(s,3H),1.15-2.23(m,22H),1.10(s,3H),1.08(s,3H),1.02(s,3H),1.00(s,3H)。
实施例12.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羧基-N-(2-(二甲基氨基)乙基)乙酰氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
步骤1:制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-叔-丁氧基-N-(2-(二甲基氨基)乙基)-3-氧代丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(27mg,0.040mmol)的DCE(2ml)溶液中加入Hunig′s碱(0.021ml,0.121mmol)、DMAP(1mg,8.19μmol)、丙二酸单-叔-丁基酯(0.012ml,0.080mmol),和O-苯并三唑-1-基-N,N,N′,N′-四甲基脲鎓四氟硼酸盐(19.38mg,0.060mmol)。于室温下搅拌该混合物。搅拌5h后,将该混合物直接装填到硅胶柱中并用0-5%MeOH在二氟甲烷中的梯度液纯化,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-叔-丁氧基-N-(2-(二甲基氨基)乙基)-3-氧代丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯,为白色泡沫状物(31.8mg,0.039mmol,97%得率)。LCMS:m/e813.4(M-H)-,3.46min(方法6).
步骤2:羧酸去保护.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-叔-丁氧基-N-(2-(二甲基氨基)乙基)-3-氧代丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(31mg,0.038mmol)的二氟甲烷(1ml)溶液中加入TFA(0.25ml,3.24mmol)。于室温下搅拌该混合物3h,然后在减压下浓缩。残留物经制备型HPLC纯化。合并含有期望的产物的部分并在减压下浓缩,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羧基-N-(2-(二甲基氨基)乙基)乙酰氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸,为白色固体(15mg,0.021mmol,56.1%得率)。LCMS:m/e701.5(M+H)+,2.11min(方法6).1HNMR(500MHz,乙酸-d3酸-d)δppm8.04(d,J=8.24Hz,2H),7.31(d,J=8.24Hz,2H),5.38(d,J=5.19Hz,1H),4.85(d,J=16.17Hz,1H),4.69(d,J=15.56Hz,1H),3.86-4.13(m,2H),2.97-3.82(m,6H),2.62-2.73(m,1H),2.13-2.24(m,2H),1.06-1.92(m,38H),1.03(s,3H),1.01(s,3H)。
实施例13.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基-N-(2-(二甲基氨基)乙基)丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(二甲基氨基)乙基)-4-甲氧基-4-氧代丁酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(48mg,0.072mmol)的DCE(2ml)溶液中加入Hunig′s碱(0.037ml,0.215mmol)、3-甲酯基丙酰氯(21.54mg,0.143mmol)和DMAP(1mg,8.19μmol)。于室温下搅拌该混合物5h,然后直接装填到硅胶柱中并用0-5%MeOH在二氟甲烷中的梯度液纯化,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(二甲基氨基)乙基)-4-甲氧基-4-氧代丁酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯,为白色泡沫状物(53.8mg,0.051mmol,71.8%得率)。LCMS:m/e785.6(M+H)+,3.21min(方法6)。
步骤2.制备4-((((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(叔-丁氧羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基)(2-(二甲基氨基)乙基)氨基)-4-氧代丁酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(二甲基氨基)乙基)-4-甲氧基-4-氧代丁酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(53mg,0.068mmol)的1,4-二氧六环(1ml)溶液中加入NaOH(0.338ml,0.338mmol)。将该混合物加热至75℃经3h。将该混合物冷却至室温并用1N HCl(3ml)猝灭,用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥,过滤,并在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。LCMS:m/e771.6(M+H)+,2.70min(方法6)。
步骤3.苯甲酸的去保护.
向4-((((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(叔-丁氧羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基)(2-(二甲基氨基)乙基)氨基)-4-氧代丁酸(47mg,0.061mmol)的DCM(1ml)溶液中加入TFA(0.25ml,3.24mmol)。于室温下搅拌该混合物。1.75h后,在减压下浓缩该混合物,用二氧六环和MeOH稀释并经制备型HPLC纯化,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基-N-(2-(二甲基氨基)乙基)丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸,为白色固体(25mg,0.035mmol,57.4%得率。LCMS:m/e715.4(M+H)+,2.16min(方法6)。
制备C28胺的通用程序
步骤1:制备C28胺
将4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(1eq.)、相应的胺(2eq.)和乙酸(2-5eq.)在DCE(2ml)中的混悬液于室温下搅拌30min。加入三乙酰氧基硼氢化钠(5eq.)。于室温下搅拌生成的混合物18-72h。反应混合物用5ml饱和碳酸钠稀释并用DCM(3x10ml)提取。合并的有机层经硫酸钠干燥,过滤并真空浓缩。粗产物经Biotage快速层析纯化或无需进一步纯化而直接用于下一步骤。
步骤2:通过水解相应的叔-丁基酯制备苯甲酸
向得自步骤1的相应的C28胺的DCM(2ml)溶液中加入TFA(0.5ml)。于室温下搅拌该混合物1-2h。真空浓缩反应混合物。粗产物经制备型HPLC纯化,得到要求的苯甲酸。
步骤3:还原性胺化以形成叔胺
向得自步骤2的物质(1eq.)的甲醇(2ml)溶液中加入相应的醛或缩酮(2eq.),随后加入乙酸(1eq)。将生成的溶液于室温下搅拌10min。加入三乙酰氧基硼氢化钠(3eq.)并将生成的混悬液于室温下搅拌2-48h。通过碳酸氢钠溶液猝灭反应混合物并用DCM(3x10ml)提取。合并有机层并经硫酸钠干燥。残留物经制备型HPLC纯化,得到要求的产物。
实施例14.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-(3-氨基丙基)硫代吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(56mg,57.5%)。LCMS:m/e719.5(MH+),2.60min(方法1).1H NMR(400MHz,MeOD)δppm7.90(2H,d,J=8.6Hz),7.20(2H,d,J=8.6Hz),5.20-5.34(1H,m),4.73(1H,s),4.62(1H,s),3.44-3.58(4H,m),3.39(4H,d,J=4.8Hz),3.12-3.26(3H,m),3.08(2H,t,J=7.2Hz),2.78-2.91(1H,m),2.39-2.58(1H,m),2.07-2.19(3H,m),1.97-2.08(1H,m),1.64-1.88(10H,m),1.39-1.63(8H,m),1.18-1.38(5H,m),1.15(3H,s),1.05(3H,s),1.02(3H,s),0.95(3H,s),0.87-0.94(3H,s)。
实施例15.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成、水解和叔胺形成所描述的通用程序,使用4-(3-氨基丙基)硫代吗啉1,1-二氧化物作为反应物胺和使用甲醛作为反应物醛,制备标题化合物。分离白色固体的产物(10mg,46.6%)。LCMS:m/e733.6(MH+),2.56min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.5Hz,2H),5.26-5.41(m,1H),4.80(d,J=1.5Hz,1H),4.69(s,1H),3.23-3.46(m,12H),3.03(s,3H),2.91(t,J=6.9Hz,2H),2.56(br.s.,1H),2.08-2.31(m,2H),1.98-2.08(m,1H),1.70-1.95(m,10H),1.47-1.70(m,9H),1.43(d,J=10.0Hz,1H),1.28-1.41(m,3H),1.15-1.23(m,4H),1.12(s,3H),1.05(s,3H),0.99(s,3H),0.97(s,3H)。
实施例16.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(10mg,0,014mmole)的CH2Cl2(0.5ml)溶液中加入二氢呋喃-2,5-二酮(4.18mg,0.042mmol),随后加入DMAP(1.953mg,0.014mmol)和DIPEA(2.429μL,0.014mmol)。于室温下搅拌该混合物18小时。真空除去溶剂和得到的残留物经制备型HPLC纯化,得到标题化合物,为白色固体(10mg,83%)。LCMS:m/e819.3(MH+),2.45min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.33(d,J=6.3Hz,1H),4.75(s,1H),4.63(s,1H),3.82(br.s.,2H),3.48-3.73(m,6H),3.44(br.s.,3H),3.20-3.31(m,2H),3.03-3.20(m,1H),2.56-2.80(m,5H),2.08(br.s.,4H),1.75(d,J=11.3Hz,8H),1.57(d,J=2.0Hz,5H),1.48(br.s.,2H),1.24-1.45(m,5H),1.22(s,4H),1.11-1.16(m,2H),1.02-1.11(m,6H),0.88-1.02(m,6H)。
实施例17.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1.N-乙酰化
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化(dioxido)-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(50mg,0,065mmole)的CH2Cl2(5ml)溶液中加入乙酸酐(6.58mg,0.065mmol),随后加入DMAP(9.06mg,0.065mmol)和DIPEA(11μL,0.065mmol)。将该混合物于室温下搅拌18小时。真空除去溶剂,得到的残留物无须进一步纯化而原样使用。LCMS:m/e817.3(MH+),2.75min(方法3)。
步骤2.苯甲酸酯的皂化
向得自步骤1的物质(6mg,7.34μmol)在二氧六环(1ml)和MeOH(5ml)的溶液中加入氢氧化钠(5.87mg,0.147mmol)(粉末),随后加入5滴水。将生成的溶液于70℃搅拌12h。真空除去溶剂,得到的残留物经制备型HPLC纯化。分离为白色固体的产物(6mg,100%)。LCMS:m/e761.3(MH+),2.51min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.26(m,2H),5.22-5.44(m,1H),4.76(s,1H),4.63(s,1H),3.82(br.s.,2H),3.59-3.68(m,3H),3.51-3.59(m,2H),3.40-3.51(m,4H),3.23-3.31(m,2H),3.02-3.16(m,1H),2.57-2.73(m,1H),2.12-2.22(m,4H),1.97-2.12(m,3H),1.85(d,J=12.3Hz,2H),1.65-1.80(m,6H),1.58(d,J=16.6Hz,4H),1.45-1.54(m,3H),1.26-1.45(m,4H),1.21(s,4H),1.11-1.19(m,3H),1.01-1.11(m,6H),0.92-1.01(m,6H)。
实施例18.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(甲基(苯基)氨基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用N1-甲基-N1-苯基丙烷-1,3-二胺作为反应物胺,制备标题化合物。分离为白色固体的产物(7mg,14.4%)。LCMS:m/e691.7(MH+),2.71min(方法1).1H NMR(500MHz,氯仿-d)δppm7.97(2H,d,J=7.9Hz),7.16-7.27(4H,m),6.65-6.84(3H,m),5.23-5.37(1H,m),4.70(1H,br.s.),4.61(1H,br.s.),3.30-3.48(2H,m),2.95-3.03(4H,m),2.93(3H,s),2.41-2.53(1H,m),2.00-2.14(2H,m),1.89-2.00(4H,m),1.73-1.89(7H,m),1.64-1.73(2H,m),1.60(2H,br.s.),1.52-1.58(2H,m),1.46-1.52(2H,m),1.44(2H,d,J=10.1Hz),1.18-1.33(2H,m),1.03-1.12(3H,m),1.02(2H,br.s.),0.98-1.01(6H,m),0.87-0.98(6H,m)。
实施例19.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(甲基氨基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-氨基丙基(甲基)氨基甲酸叔-丁基酯作为反应物胺,制备标题化合物。分离为白色固体的产物(26mg,51.6%)。LCMS:m/e615.5(MH+),2.50min(方法1).1H NMR(500MHz,乙酸-d)δppm8.03(2H,d,J=8.2Hz),7.29(2H,d,J=8.2Hz),5.36(1H,d,J=4.6Hz),4.79(1H,s),4.67(1H,s),3.36-3.43(1H,m),3.27-3.36(2H,m),3.21(2H,t,J=7.5Hz),2.94(1H,d,J=12.8Hz),2.78(3H,s),2.48-2.56(1H,m),2.24-2.38(2H,m),2.13-2.24(2H,m),2.00-2.13(5H,m),1.85-2.00(3H,m),1.68-1.85(6H,m),1.58-1.68(2H,m),1.41-1.58(3H,m),1.23-1.41(2H,m),1.12-1.23(5H,m),1.09(3H,s),1.07(3H,s),1.01(3H,s),1.00(3H,s)。
实施例20.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1H-咪唑-1-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-(1H-咪唑-1-基)乙胺(ethanamine)作为反应物胺,制备标题化合物。分离为白色固体的产物(15mg,51.7%)。LCMS:m/e638.6(MH+),2.49min(方法1).
1H NMR(500MHz,MeOD)δppm9.03(1H,s),7.94(2H,d,J=8.2Hz),7.73(1H,d,J=1.5Hz),7.65(1H,d,J=1.5Hz),7.24(2H,d,J=8.2Hz),5.25-5.36(1H,m),4.77(1H,s),4.74(2H,t,J=6.7Hz),4.66(1H,s),3.63-3.79(2H,m),3.36(1H,m),2.95(1H,d,J=12.8Hz),2.52(1H,dt,J=10.8,5.5Hz),2.12-2.27(1H,m),1.98-2.12(1H,m),1.83-1.98(2H,m),1.78-1.83(2H,m),1.70-1.78(6H,m),1.45-1.64(6H,m),1.35(2H,dd,J=11.3,8.2Hz),1.26-1.32(2H,m),1.22(1H,d,J=2.7Hz),1.18(5H,s),1.09(3H,s),1.05(3H,s),0.99(3H,s),0.97(3H,s)
实施例21.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(di乙基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用N1,N1-二乙基乙烷-1,2-二胺作为反应物胺,制备标题化合物。分离为白色固体的产物(27mg,86.0%)。LCMS:m/e643.6(MH+),2.52min(方法1).
1H NMR(500MHz,MeOD)δppm7.89(2H,m,J=7.6Hz),7.16(2H,m,J=7.9Hz),5.30(1H,d,J=4.6Hz),4.75(1H,br.s.),4.63(1H,br.s.),3.04-3.23(5H,m),2.88-3.02(4H,m),2.69(1H,d,J=11.9Hz),2.51(1H,d,J=5.5Hz),2.15(1H,dd,J=17.1,6.1Hz),2.09(1H,br.s.),1.93-2.00(6H,m),1.83-1.93(2H,m),1.79(2H,br.s.),1.73(4H,br.s.),1.42-1.59(5H,m),1.26(2H,br.s.),1.22(6H,t,J=7.2Hz),1.16(5H,br.s.),1.06(3H,br.s.),1.04(3H,br.s.),0.88-1.01(6H,m)。
实施例22.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(甲基氨基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-(2-甲基-1H-咪唑-1-基)丙-1-胺作为反应物胺,制备标题化合物。分离为白色固体的产物(40mg,66.5%)。LCMS:m/e666.5(MH+),2.48min(方法1).1H NMR(400MHzMeOD)δppm7.90(2H,d,J=8.6Hz),7.52(1H,d,J=2.3Hz),7.44(1H,d,J=2.0Hz),7.20(2H,d,J=8.3Hz),5.27(1H,d,J=4.8Hz),4.72(1H,s),4.61(1H,s),4.25(2H,t,J=7.2Hz),3.11-3.26(3H,m),2.79-2.92(1H,m),2.65(3H,s),2.39-2.58(1H,m),2.30(2H,dq,J=7.9,7.7Hz),2.12(1H,dd,J=17.2,6.4Hz),1.93-2.08(1H,m),1.76-1.93(2H,m),1.63-1.76(8H,m),1.57(1H,br.s.),1.54(1H,d,J=7.6Hz),1.38-1.52(6H,m),1.29-1.38(1H,m),1.22-1.29(2H,m),1.19(1H,br.s.),1.07-1.16(4H,m),1.04(3H,s),1.02(3H,s),0.96(3H,s),0.90(3H,s)。
实施例23.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(3-氧代哌嗪-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-(3-氨基丙基)哌嗪-2-酮作为反应物胺,制备标题化合物。分离为白色固体的产物(55mg,80%)。LCMS:m/e684.5(MH+),2.53min(方法1).
1H NMR(400MHz,MeOD)δppm7.91(2H,d,J=3.3Hz),7.21(2H,d,J=2.8Hz),5.28(1H,br.s.),4.74(1H,br.s.),4.63(1H,br.s.),3.93(2H,br.s.),3.52-3.69(4H,m),3.3(2h,m),3.04-3.27(3H,m),2.78-2.97(1H,m),2.41-2.63(1H,m),2.21-2.38(2H,m),1.97-2.21(2H,m),1.8(2H,m),1.71(8H,br.s.),1.51(8H,br.s.),1.25(2H,m),1.15(5H,br.s.),1.03(7H,d,J=13.8Hz),0.85-0.99(6H,m)。
实施例24.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(双(2-羟基乙基)氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2,2′-(2-氨基乙基脲二基(azanediyl))二乙醇作为反应物胺,制备标题化合物。分离为白色固体的产物(19mg,40.7%)。LCMS:m/e675.6(MH+),2.51min(方法1).1HNMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.18-5.37(m,1H),4.74(s,1H),4.62(s,1H),3.79-3.95(m,4H),3.45-3.66(m,4H),3.20-3.35(m,5H),2.78-3.00(m,1H),2.39-2.59(m,1H),2.13(dd,J=17.0,6.4Hz,1H),2.04(d,J=8.6Hz,1H),1.78-1.92(m,2H),1.63-1.78(m,8H),1.55(d,J=6.5Hz,2H),1.40-1.53(m,6H),1.22-1.40(m,4H),1.09-1.19(m,4H),1.05(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例25.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1H-咪唑-4-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-(1H-咪唑-4-基)乙胺作为反应物胺,制备标题化合物。分离为白色固体的产物(40mg,63.4%)。LCMS:m/e638.5(MH+),2.48min(方法1).
1HNMR(400MHz,MeOD)δppm8.86(d,J=1.3Hz,1H),7.90(d,J=8.3Hz,2H),7.45(s,1H),7.20(d,J=8.3Hz,2H),5.16-5.33(m,1H),4.74(s,1H),4.63(s,1H),3.36-3.53(m,2H),3.16-3.26(m,3H),2.90(d,J=12.8Hz,1H),2.40-2.59(m,1H),2.08-2.20(m,1H),1.98-2.08(m,1H),1.79-1.91(m,2H),1.62-1.79(m,7H),1.53-1.62(m,3H),1.41-1.53(m,5H),1.23-1.41(m,4H),1.09-1.23(m,5H),1.06(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例26.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((2-羟基乙基)(甲基)氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-((2-氨基乙基)(甲基)氨基)乙醇作为反应物胺,制备标题化合物。分离为白色固体的产物(21mg,45.7%)。LCMS:m/e645.5(MH+),2.49min(方法1).1H NMR(400MHz,MeOD)δppm7.90(m,J=8.3Hz,2H),7.20(m,J=8.3Hz,2H),5.21-5.34(m,1H),4.74(s,1H),4.63(s,1H),3.82-3.97(m,2H),3.50-3.75(m,4H),3.30-3.43(m,3H),2.98(s,3H),2.93(d,J=12.8Hz,1H),2.49(td,J=10.6,5.8Hz,1H),2.08-2.20(m,2H),1.79-1.93(m,2H),1.64-1.79(m,8H),1.40-1.64(m,8H),1.23-1.40(m,4H),1.13-1.23(m,4H),1.05(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例27.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-叔-丁氧基-4-氧代丁基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-氨基丁酸叔-丁基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(2mg,3.62%)。LCMS:m/e689.5(MH+),2.96min(方法1).1H NMR(400MHz,氯仿-d)δppm7.90(m,J=8.3Hz,2H),7.19(m,J=8.1Hz,2H),5.29(d,J=4.3Hz,1H),4.65(s,1H),3.21(s,2H),2.85(d,J=4.5Hz,1H),2.53-2.78(m,1H),2.28-2.45(m,1H),2.02-2.19(m,2H),1.80-2.02(m,2H),1.72(s,8H),1.61(s,9H),1.46-1.54(m,4H),1.43(d,J=7.1Hz,5H),1.18-1.36(m,6H),1.07-1.18(m,6H),1.03(s,3H),1.00(s,3H),0.76-0.97(m,6H)。
实施例28.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-氨基丁酸叔-丁基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(2mg,3.62%)。LCMS:m/e630.5(MH+),2.59min(方法1).1H NMR(400MHz,乙腈-d3)δppm7.93(d,J=8.3Hz,2H),7.23(d,J=8.3Hz,2H),5.25-5.36(m,1H),4.77(s,1H),4.66(s,1H),3.21-3.49(m,1H),3.16(t,J=7.7Hz,2H),2.87(d,J=12.8Hz,1H),2.43-2.60(m,3H),2.12-2.26(m,1H),1.92-2.12(m,3H),1.66-1.90(m,8H),1.59(d,J=6.0Hz,2H),1.46-1.57(m,6H),1.33-1.34(m,2H),1.28(d,J=15.4Hz,4H),1.19(s,4H),1.09(s,3H),1.05(s,3H),0.98(s,3H),0.96(s,3H)。
实施例29.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代吡咯烷-1-基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-氨基丁酸叔-丁基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(3mg,6.28%)。LCMS:m/e612.4(MH+),3.18min(方法1).
1H NMR(400MHz,MeOD)δppm7.88(m,J=8.3Hz,2H),7.17(m,J=8.3Hz,2H),5.14-5.31(m,1H),4.69(s,1H),4.56(s,1H),3.36-3.58(m,3H),3.13(d,J=14.4Hz,1H),2.46-2.61(m,1H),2.34(t,J=8.2Hz,2H),2.00-2.19(m,4H),1.97(s,1H),1.58-1.75(m,8H),1.47(br.s.,7H),1.30(d,J=7.1Hz,3H),1.24(s,4H),1.14(s,3H),1.00(s,3H),0.98(s,3H),0.92(s,3H),0.91(s,3H)。
实施例30.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-甲氧基-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(27mg,45.9%)。LCMS:m/e616.5(MH+),2.14min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.20-5.33(m,1H),4.72(s,1H),4.62(s,1H),4.05(d,J=3.8Hz,2H),3.86(s,3H),3.33-3.45(m,1H),2.89(d,J=12.6Hz,1H),2.45(td,J=10.8,5.7Hz,1H),1.93-2.18(m,2H),1.77-1.93(m,3H),1.63-1.77(m,7H),1.39-1.63(m,8H),1.18-1.39(m,5H),1.15(s,3H),1.06(s,3H),1.00(s,3H),0.95(s,3H),0.93(s,3H)。
实施例31.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((羧基甲基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以下描述的程序制备标题化合物:
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-甲氧基-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(50mg,0.081mmol)的二氧六环(2ml)溶液中加入氢氧化钠(0.162ml,0.162mmol)。将生成的混合物于70℃搅拌2h。蒸发溶剂,残留物经制备型HPLC纯化,得到标题化合物,为白色固体(18mg,35%)。LCMS:m/e602.4(MH+),2.32min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.18-5.40(m,1H),4.73(s,1H),4.62(br.s.,1H),3.96(d,J=5.0Hz,2H),2.78-2.94(m,1H),2.37-2.60(m,1H),2.10(s,2H),1.78-1.92(m,3H),1.62-1.78(m,6H),1.38-1.61(m,8H),1.16-1.38(m,6H),1.11-1.16(m,4H),1.07(s,3H),1.01(s,3H),0.95(s,3H),0.93(s,3H)。
实施例32.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-甲氧基-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(34mg,58.1%)。LCMS:m/e704.5(MH+),2.27min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.1Hz,2H),5.19-5.36(m,1H),4.74(s,1H),4.63(s,1H),3.18-3.35(m,5H),3.12(br.s.,6H),2.89-3.01(m,2H),2.86(d,J=13.8Hz,1H),2.41-2.61(m,1H),2.12(dd,J=17.1,6.3Hz,1H),1.93-2.07(m,1H),1.64-1.88(m,10H),1.41-1.62(m,8H),1.18-1.41(m,5H),1.15(s,3H),1.06(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例33.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-甲氧基-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成、水解和叔胺形成所描述的通用程序,使用4-(3-氨基乙基)硫代吗啉1,1-二氧化物作为反应物胺和甲醛作为反应物醛,制备标题化合物。分离为白色固体的产物(10mg,46.6%)。LCMS:m/e719.7(MH+),2.56min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,2H),7.25(m,2H),5.24-5.40(m,1H),4.80(d,J=1.5Hz,1H),4.69(s,1H),3.37-3.56(m,3H),3.16(d,J=8.3Hz,9H),3.05-3.11(m,3H),2.86-3.05(m,2H),2.56(td,J=11.1,5.4Hz,1H),2.17(dd,J=17.1,6.3Hz,1H),2.01(br.s.,2H),1.69-1.93(m,9H),1.44-1.69(m,9H),1.25-1.42(m,3H),1.13-1.25(m,4H),1.12(s,3H),1.05(s,3H),0.99(s,3H),0.98(s,3H)。
实施例34.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-氧代吡咯烷-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(2-氨基乙基)吡咯烷-2-酮作为反应物胺,制备标题化合物。分离为白色固体的产物(34mg,63.8%)。LCMS:m/e655.5(MH+),2.33min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(m,J=8.3Hz,2H),7.20(m,J=8.3Hz,2H),5.22-5.34(m,1H),4.74(d,J=1.8Hz,1H),4.62(s,1H),3.57-3.71(m,2H),3.53(t,J=7.2Hz,2H),3.27-3.35(m,2H),3.25(d,J=12.8Hz,1H),2.92(d,J=13.1Hz,1H),2.50(td,J=10.6,5.7Hz,1H),2.42(t,J=8.2Hz,2H),1.97-2.18(m,4H),1.62-1.87(m,10H),1.41-1.62(m,8H),1.20-1.41(m,4H),1.13-1.20(m,4H),1.06(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例35.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((4-氨磺酰基苄基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对C28胺形成和水解所描述的通用程序,使用4-(氨基甲基)苯磺酰胺作为反应物胺,制备标题化合物。分离为白色固体的产物(14mg,26.1%)。LCMS:m/e713.4(MH+),2.30min(方法3).1HNMR(400MHz,MeOD)δppm7.97-8.08(m,2H),7.90(m,J=8.3Hz,2H),7.74(m,J=8.3Hz,2H),7.19(d,J=8.3Hz,2H),5.15-5.35(m,1H),4.71(s,1H),4.60(s,1H),4.41-4.54(m,1H),4.29(d,J=13.3Hz,1H),2.95-3.12(m,1H),2.83(d,J=12.8Hz,1H),2.41(td,J=11.1,5.4Hz,1H),2.09(dd,J=17.1,6.3Hz,1H),1.78-1.99(m,1H),1.57-1.77(m,8H),1.30-1.54(m,9H),1.18-1.29(m,3H),1.03-1.16(m,2H),1.01(br.s.,1H),0.98(s,6H),0.94(s,3H),0.91(s,3H),0.78(s,3H)。。
实施例36.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((4-氨磺酰基苯乙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-(2-氨基乙基)苯磺酰胺作为反应物胺,制备标题化合物。分离为白色固体的产物(18mg,33.5%)。LCMS:m/e727.4(MH+),2.30min(方法3).1HNMR(400MHz,MeOD)δppm7.82-7.94(m,4H),7.48(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.28(d,J=4.8Hz,1H),4.74(s,1H),4.63(s,1H),3.31-3.39(m,2H),3.27-3.29(m,1H),3.09-3.19(m,2H),2.82-2.92(m,1H),2.49(td,J=10.6,5.9Hz,1H),2.09-2.20(m,1H),1.97-2.09(m,1H),1.78-1.89(m,2H),1.63-1.78(m,8H),1.40-1.62(m,8H),1.18-1.40(m,5H),1.15(s,3H),1.06(s,3H),1.02(s,3H),0.95(s,3H),0.90(s,3H)。
实施例37.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(50mg,0.070mmol)在MeOH(15ml)和乙酸(5.00ml)的溶液中加入披钯碳(15mg,0.141mmol)。于40psi、室温下,在Parr振荡器中进行反应16h。观察到30%的转化。真空除去溶剂。残留物经制备型HPLC纯化,得到标题化合物,为白色固体(10mg,19.0%)。LCMS:m/e721.2(MH+),2.39min(方法3).
1H NMR(400MHz,MeOD)δppm7.95(m,J=8.3Hz,2H),7.25(m,J=8.3Hz,2H),5.34(dd,J=6.1,1.6Hz,1H),3.10-3.29(m,11H),2.78-2.92(m,3H),2.20(dd,J=17.2,6.4Hz,1H),1.93-2.12(m,3H),1.78(d,J=12.0Hz,2H),1.75(d,J=7.8Hz,4H),1.43-1.67(m,10H),1.25-1.41(m,4H),1.18-1.25(m,3H),1.11(br.s.,2H),1.08(d,J=3.0Hz,6H),1.00(s,3H),0.98(s,3H),0.93(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H)。
实施例38.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-甲氧基-4-氧代丁基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-氨基丁酸甲基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(7mg,48.2%)。LCMS:m/e644.4(MH+),2.21min(方法3).
1H NMR(500MHz,MeOD)δppm7.82-8.02(m,2H),7.19-7.30(m,2H),5.22-5.39(m,1H),4.78(s,1H),4.67(br.s.,1H),3.72(s,3H),3.27(d,J=13.1Hz,1H),3.08-3.22(m,2H),2.88(d,J=12.8Hz,1H),2.43-2.62(m,3H),2.12-2.31(m,1H),1.96-2.12(m,3H),1.69-1.88(m,10H),1.47-1.67(m,8H),1.22-1.39(m,4H),1.14-1.22(m,4H),1.11(s,3H),1.06(s,3H),0.99(s,3H),0.97(s,3H)。
实施例39.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-氨基-N,N-二甲基乙酰胺盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(34mg,87.9%)。LCMS:m/e629.4(MH+),2.37min(方法3).1H NMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.3Hz,2H),5.26-5.38(m,1H),4.75(d,J=1.5Hz,1H),4.65(s,1H),4.00-4.21(m,2H),3.25-3.40(m,1H),2.98-3.12(m,6H),2.86(d,J=12.5Hz,1H),2.47(td,J=10.9,5.6Hz,1H),2.04-2.26(m,2H),1.85-2.04(m,3H),1.67-1.85(m,6H),1.43-1.67(m,8H),1.19-1.42(m,5H),1.13-1.19(m,4H),1.08(s,3H),1.05(s,3H),1.00(s,3H),0.93(s,3H)。
实施例40.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-2-异噻唑烷基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-氨基-N,N-二甲基乙酰胺盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(34mg,77.9%)。LCMS:m/e705.8(MH+),2.34min(方法3).1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.3Hz,2H),5.25-5.42(m,1H),4.78(d,J=1.5Hz,1H),4.66(s,1H),3.31-3.39(m,1H),3.13-3.30(m,8H),2.89(d,J=13.1Hz,1H),2.45-2.65(m,1H),2.30-2.45(m,2H),1.99-2.21(m,4H),1.67-1.91(m,10H),1.45-1.67(m,8H),1.24-1.45(m,4H),1.12-1.24(m,4H),1.09(s,3H),1.04(s,3H),0.99(s,3H),0.97(s,3H)。
实施例41.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(甲基磺酰基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-(甲基磺酰基)乙胺盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(22mg,47.8%)。LCMS:m/e650.3(MH+),2.09min(方法3).1H NMR(400MHz,氯仿-d)δppm8.01(m,J=8.3Hz,2H),7.25(m,J=8.3Hz,2H),5.32(d,J=4.5Hz,1H),4.74(s,1H),4.66(s,1H),3.64-3.88(m,4H),3.34(br.s.,1H),3.06-3.22(m,3H),2.84(d,J=11.8Hz,1H),2.32-2.45(m,1H),2.12(dd,J=17.2,6.4Hz,1H),2.05(m,1H),1.79(br.s.,2H),1.61-1.76(m,8H),1.56(d,J=8.3Hz,3H),1.39-1.51(m,4H),1.15-1.39(m,5H),1.07-1.15(m,4H),1.03(s,3H),1.00(s,3H),0.96(d,J=3.3Hz,6H)。
实施例42.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2,2-二乙氧基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2,2-二乙氧基乙胺作为反应物胺,制备标题化合物。分离为白色固体的产物(5mg,8.4%)。LCMS:m/e660.4(MH+),2.39min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.27-5.41(m,1H),4.92-4.98(m,1H),4.74-4.81(m,1H),4.67(d,J=1.8Hz,1H),3.79-3.95(m,J=9.5,7.1,7.1,7.1,7.1Hz,2H),3.63-3.79(m,J=9.6,7.0,7.0,7.0,2.9Hz,2H),3.48(d,J=13.8Hz,1H),3.22-3.31(m,2H),2.91-3.08(m,1H),2.47-2.55(m,1H),2.18(dd,J=17.1,6.3Hz,1H),2.05(m,1H),1.69-1.93(m,9H),1.62(br.s.,2H),1.46-1.61(m,6H),1.24-1.44(m,10H),1.13-1.24(m,5H),1.11(s,3H),1.06(s,3H),0.99(s,3H),0.98(s,3H)。
实施例43.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(哌嗪-1-基磺酰基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-(2-氨基乙基磺酰基)哌嗪-1甲酸叔-丁基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(47mg,91.0%)。LCMS:m/e720.3(MH+),2.31min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,2H),7.24(m,2H),5.20-5.41(m,1H),4.78(d,J=1.8Hz,1H),4.66(s,1H),3.64-3.74(m,6H),3.56-3.64(m,2H),3.35-3.41(m,4H),3.31-3.35(m,1H),2.96(d,J=13.1Hz,1H),2.47-2.61(m,1H),2.00-2.24(m,2H),1.69-1.92(m,10H),1.60(br.s.,2H),1.43-1.59(m,6H),1.26-1.43(m,3H),1.17-1.25(m,4H),1.14(d,J=2.8Hz,1H),1.09(s,3H),1.04(s,3H),0.99(s,3H),0.95(s,3H)。
实施例44.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((甲基(2-(4-甲基哌嗪-1-基磺酰基)乙基)氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成、水解和叔胺形成所描述的通用程序,使用4-(2-氨基乙基磺酰基)哌嗪-1甲酸叔-丁基酯盐酸盐作为反应物胺和甲醛作为反应物醛,制备标题化合物。分离为白色固体的产物(17mg,33.1%)。LCMS:m/e748.5(MH+),2.37min(方法3).1HNMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.23-5.40(m,1H),4.79(d,J=1.3Hz,1H),4.68(s,1H),4.00(br.s.,1H),3.77-3.95(m,4H),3.70(t,J=7.4Hz,4H),3.38-3.58(m,3H),3.26-3.37(m,1H),3.13-3.25(m,1H),3.07(s,3H),2.98(s,3H),2.56(dt,J=10.9,5.5Hz,1H),2.00-2.25(m,2H),1.79-2.00(m,3H),1.69-1.79(m,5H),1.46-1.69(m,9H),1.42(d,JJ=10.8Hz,1H),1.24-1.40(m,4H),1.21(s,3H),1.14-1.19(m,1H),1.11(s,3H),1.05(s,3H),1.01(s,3H),0.97(s,3H)。
实施例45.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-氨磺酰基乙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-氨基乙烷磺酰胺作为反应物胺,制备标题化合物。分离为白色固体的产物(23mg,59.3%)。LCMS:m/e651.3(MH+),2.35min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.5Hz,2H),5.18-5.40(m,1H),4.78(d,J=1.8Hz,1H),4.67(s,1H),3.57-3.65(m,2H),3.42(m,1H),3.33(dq,J=3.2,1.5Hz,2H),2.97(d,J=12.8Hz,1H),2.54(td,J=10.7,5.6Hz,1H),1.98-2.22(m,2H),1.67-1.92(m,10H),1.57(dd,J=19.8,7.5Hz,5H),1.50(d,J=13.8Hz,3H),1.24-1.45(m,4H),1.18-1.24(m,4H),1.10(s,3H),1.04(s,3H),0.99(s,3H),0.97(s,3H)。
实施例46.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-(甲氧基羰基)苯乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-(2-氨基乙基)苯甲酸甲基酯作为反应物胺,制备标题化合物。分离为白色固体的产物(35mg,90.0%)。LCMS:m/e706.3(MH+),2.34min(方法3).
实施例47.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-羧基苯乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以下描述的程序制备标题化合物:
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-(甲氧基羰基)苯乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(5mg)在二氧六环(2ml)和MeOH(2ml)的溶液中,加入3mg氢氧化锂,随后加入0.5ml水。将生成的澄清溶液于50℃搅拌12h。真空除去溶剂,获得黄色固体。粗物质经制备型HPLC纯化,得到标题化合物,为白色固体(11mg,22.0%)。LCMS:m/e692.5(MH+),2.28min(方法3).
1H NMR(400MHz,MeOD)δppm6.50(d,J=8.3Hz,2H),6.38(d,J=8.3Hz,2H),5.91(d,J=8.3Hz,2H),5.68(d,J=8.3Hz,2H),3.75-3.81(m,1H),3.22(s,1H),3.11(s,1H),1.79-1.91(m,2H),1.66-1.75(m,1H),1.51-1.66(m,2H),1.33(s,1H),0.84-1.02(m,1H),0.44-0.68(m,2H),0.10-0.33(m,8H),0.12-0.10(m,6H),0.34-0.12(m,6H),0.42-0.34(m,6H),0.46(s,3H),0.49(s,3H),0.57(s,3H),0.59(s,3H)。
实施例48.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4,4-二氟哌啶-1-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-(4,4-二氟哌啶-1-基)乙胺作为反应物胺,制备标题化合物。分离为白色固体的产物(45mg,62.5%)。LCMS:m/e691.6(MH+),2.54min(方法3).1H NMR(400MHz,MeOD)δppm7.94(m,2H),7.24(m,2H),5.31(d,J=4.5Hz,1H),4.72-4.82(m,1H),4.66(s,1H),3.49-3.67(m,2H),3.36-3.49(m,2H),3.31(d,J=5.0Hz,5H),2.89-3.02(m,1H),2.52(dt,J=10.6,5.4Hz,1H),2.23-2.41(m,4H),2.01-2.23(m,2H),1.83-1.95(m,2H),1.67-1.83(m,8H),1.43-1.67(m,8H),1.27-1.43(m,3H),1.24(br.s.,1H),1.11-1.21(m,4H),1.09(s,3H),1.05(s,3H),0.99(s,3H),0.94(s,3H)。
实施例49.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((S)-1,4-di甲氧基-1,4-二氧代丁-2-基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用(S)-2-氨基琥珀酸二甲基酯作为反应物胺,制备标题化合物。分离为白色固体的产物(6mg,15.7%)。LCMS:m/e688.6(MH+),2.73min(方法3).
1H NMR(400MHz,MeOD)δppm7.96(m,2H),7.24(m,J=8.5Hz,2H),5.22-5.36(m,1H),4.78(s,1H),4.67(s,1H),4.62(dd,J=8.4,4.6Hz,1H),3.92(s,3H),3.83(s,3H),3.44(m,1H),3.22(m,1H),2.93-3.16(m,2H),2.38-2.62(m,1H),2.11-2.26(m,2H),2.07(br.s.,1H),1.88-2.03(m,2H),1.67-1.88(m,6H),1.45-1.67(m,8H),1.25-1.45(m,4H),1.15-1.25(m,3H),1.09-1.15(m,2H),1.06(s,3H),1.04(s,3H),1.00(s,3H),0.98(s,3H)。
实施例50.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-羧基环丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-氨基环丙烷羧酸甲基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(10mg,50%)。LCMS:m/e628.6(MH+),2.28min(方法3).1H NMR(400MHz,乙腈-d3)δppm7.91(m,J=7.8Hz,2H),7.24(m,=8.0Hz,2H),5.28(d,J=5.0Hz,1H),4.72(s,1H),4.62(br.s.,1H),3.43(d,J=12.5Hz,1H),2.94(d,J=12.5Hz,1H),2.47(br.s.,1H),2.12(dd,J=17.2,6.7Hz,1H),2.00-2.08(m,1H),1.92(d,J=2.5Hz,1H),1.85(br.s.,2H),1.62-1.77(m,8H),1.57(br.s.,5H),1.44(br.s.,6H),1.33(br.s.,1H),1.28(br.s.,3H),1.08-1.19(m,4H),1.04(s,3H),1.01(s,3H),0.86-0.97(m,6H)。
实施例51.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(甲氧基羰基)环丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-氨基环丙烷羧酸甲基酯盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(12mg,41.3%)。LCMS:m/e642.6(MH+),2.64min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,2H),7.25(m,2H),5.32(d,J=4.5Hz,1H),4.77(s,1H),4.66(s,1H),3.76-3.87(m,3H),3.53(d,J=12.5Hz,1H),3.05(d,J=12.8Hz,1H),2.44-2.62(m,1H),2.02-2.26(m,2H),1.87-2.01(m,3H),1.59-1.80(m,13H),1.48-1.57(m,6H),1.27-1.44(m,3H),1.13-1.27(m,5H),1.10(s,3H),1.06(s,3H),1.01(s,3H),0.95(s,3H)。
实施例52.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-((二乙基氨基)甲基)环丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-((二乙基氨基)甲基)环丙烷胺二盐酸盐作为反应物胺,制备标题化合物。分离为白色固体的产物(15mg,25.0%)。LCMS:m/e669.6(MH+),2.70min(方法3).
1H NMR(400MHz,MeOD)δppm7.95(m,2H),7.24(m,2H),5.31(d,J=4.5Hz,1H),4.79(d,J=1.5Hz,1H),4.67(s,1H),3.83-4.00(m,1H),3.30-3.54(m,6H),3.02(d,J=12.5Hz,1H),2.48-2.70(m,1H),2.16(dd,J=17.1,6.5Hz,1H),1.91-2.10(m,1H),1.64-1.88(m,10H),1.45-1.64(m,8H),1.36-1.45(m,7H),1.21-1.36(m,6H),1.11-1.21(m,5H),1.08(s,3H),1.05(s,3H),0.99(s,3H),0.97(s,3H)。
实施例53.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((呋喃-3-基甲基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用呋喃-3-基甲胺作为反应物胺,制备标题化合物。分离为白色固体的产物(60mg,41.0%)。LCMS:m/e624.6(MH+),2.61min(方法3).
1H NMR(400MHz,MeOD)δppm6.28-6.44(m,2H),6.17-6.28(m,1H),6.03-6.16(m,1H),5.53-5.73(m,2H),5.06(d,J=1.3Hz,1H),3.57-3.80(m,1H),3.09-3.20(m,1H),3.03(s,1H),2.47-2.71(m,2H),1.57(d,J=12.8Hz,1H),1.12-1.32(m,1H),0.85(td,J=11.1,5.6Hz,1H),0.52(dd,J=17.1,6.3Hz,1H),0.20-0.42(m,1H),0.04-0.19(m,8H),0.25-0.00(m,8H),0.39-0.25(m,4H),0.56-0.39(m,3H),0.58(s,6H),0.63(s,3H),0.64(s,3H),0.66(s,3H)。
实施例54.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((4-(1,1-二氧化-4-硫吗啉基)-4-氧代丁基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用硫吗啉酰胺作为反应物胺,制备标题化合物。分离为白色固体的产物(12mg,41.0%)。LCMS:m/e747.5(MH+),2.36min(方法3).
1H NMR(400MHz,MeOD)δppm7.97(m,2H),7.25(m,2H),5.27-5.34(m,1H),4.78(d,J=1.5Hz,1H),4.67(s,1H),4.05-4.19(m,2H),3.92-4.05(m,2H),3.20-3.30(m,3H),3.08-3.20(m,4H),2.82-2.97(m,1H),2.75(t,J=6.4Hz,2H),2.53(td,J=10.7,5.4Hz,1H),2.17(dd,J=17.1,6.3Hz,1H),1.99-2.13(m,3H),1.83-1.95(m,2H),1.67-1.83(m,8H),1.44-1.67(m,8H),1.25-1.44(m,4H),1.13-1.25(m,4H),1.10(s,3H),1.07(s,3H),1.00(s,3H),0.97(s,3H)。
实施例55.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1H-咪唑-1-基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-(1H-咪唑-1-基)丙-1-胺作为反应物胺,以15%得率制备标题化合物。MS:m/e652.6(MH+),1.63min(方法1).1HNMR(400MHz,氯仿-d)δppm0.86(s,3H)0.91(s,3H)0.99(s,3H)1.00(s.,3H)1.10(s,3H)1.69(s,3H)0.88-2.60(m,24H)2.29(d,J=11.58Hz,1H)2.61-2.78(m,3H)2.82(d,J=11.58Hz,1H)4.02-4.10(m,1H)4.12-4.21(m,1H)4.60(s,1H)4.70(s,1H)5.30(d,J=4.53Hz,1H)6.94(s,1H)7.15(s,1H)7.19(d,J=8.31Hz,2H)7.63(s,1H)7.99(d,J=8.31Hz,2H)。
实施例56.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(4-甲基哌嗪-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-(4-甲基哌嗪-1-基)丙-1-胺作为反应物胺。以69%得率制备标题化合物。MS:m/e684.6(MH+),1.64min(方法1).1H NMR(400MHz,氯仿-d)δppm0.91(s,3H)0.93(s,3H)0.97(s,3H)1.00(s,3H)1.08(s,3H)1.69(s,3H)2.38(s,3H)0.85-2.13(m,31H)2.55-2.66(m,4H)3.05-3.25(m,4H)4.62(s,1H)4.71(s,1H)5.30(d,J=4.78Hz,1H)7.17(d,J=8.31Hz,2H)7.95(d,J=8.06Hz,2H)。
实施例57.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二异丙基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序使用N1,N1-二异丙基乙烷-1,2-二胺作为反应物胺,以17%得率制备标题化合物。MS:m/e671.7(MH+),1.65min(方法1).1HNMR(400MHz,氯仿-d)δppm0.94(s,3H)0.94(s,3H)0.97(s,3H)1.00(s,3H)1.07(s,3H)1.69(s,3H)0.85-2.15(m,32H)2.09(dd,J=15.99,5.67Hz,1H)2.30-2.39(m,1H)2.76(d,J=12.09Hz,1H)3.25(d,J=12.09Hz,1H)3.58-3.70(m,6H)3.70-3.79(m,1H)4.62(s,1H)4.69(s,1H)5.29(d,J=4.53Hz,1H)7.23(d,J=8.31Hz,2H)7.98(d,J=8.31Hz,2H)。
实施例58.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-氧代吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(3-氨基丙基)吡咯烷-2-酮作为反应物胺,以55%得率制备标题化合物。MS:m/e669.6(MH+),1.77min(方法1).1HNMR(400MHz,氯仿-d)δppm0.94(s,6H)0.98(s,3H)1.01(s,3H)1.08(s,3H)1.70(s,3H)0.77-1.79(m,17H)1.97-2.18(m,8H)2.38(td,J=10.14,5.67Hz,1H)2.49(t,J=8.18Hz,2H)2.70(t,J=10.45Hz,1H)2.97-3.08(m,1H)3.08-3.17(m,1H)3.22(t,J=10.58Hz,1H)3.36-3.54(m,3H)3.48(t,J=7.05Hz,2H)4.62(s,1H)4.70(s,1H)5.30(d,J=4.78Hz,1H)7.23(d,J=8.06Hz,2H)7.99(d,J=8.06Hz,2H)。
实施例59.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-甲基-1H-咪唑-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-(2-甲基-1H-咪唑-1-基)乙胺作为反应物胺,以52%得率制备标题化合物。MS:m/e652.6(MH+),1.67min(方法1).
1HNMR(400MHz,MeOD)δppm0.95(s.,3H)0.96(s,3H)1.03(s,3H)1.08(s,3H)1.17(s,3H)1.73(s.,3H)0.90-1.93(m,21H)2.00-2.10(m,1H)2.14(dd,J=17.12,6.55Hz,1H)2.46-2.55(m,1H)2.69(s,3H)2.93(d,J=12.34Hz,1H)3.53-3.69(m,2H)4.54(t,J=7.30Hz,2H)4.65(s.,1H)4.75(s.,1H)5.27-5.33(m,1H)7.21(d,J=8.31Hz,2H)7.49-7.52(m,1H)7.54(d,J=2.01Hz,1H)7.91(d,J=8.31Hz,2H)。
实施例60.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(双(2-羟基乙基)氨基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2,2′-(3-氨基丙基脲二基)二乙醇作为反应物胺,以76%得率制备标题化合物。MS:m/e689.6(MH+),1.63min(方法1)
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,1H)0.85-1.89(m.29H)2.00-2.11(m,1H)2.15(dd,J=17.12,6.04Hz,1H)2.19-2.29(m,2H)2.46-2.56(m,1H)2.87(d,J=12.34Hz,1H)3.15-3.29(m,4H)3.90(t,J=4.78Hz,4H)4.65(s,1H)4.76(s,1H)5.28-5.33(m,1H)7.22(d,J=8.31Hz,2H)7.92(d,J=8.31Hz,2H)。
实施例61.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-羟基乙基氨基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,用2-(3-氨基丙基氨基)乙醇作为反应物胺,以35%得率制备标题化合物。MS:m/e645.6(MH+),1.65min(方法1).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.07(s,3H)1.16(s,3H)1.72(s,3H)0.85-1.89(m,21H)1.98-2.26(m,4H)2.45-2.55(m,1H)2.85(d,J=12.84Hz,1H)3.11-3.28(m,8H)3.78-3.84(m,2H)4.64(s,1H)4.75(s,1H)5.29(d,J=4.53Hz,1H)7.21(d,J=8.31Hz,2H)7.91(d,J=8.31Hz,2H)。
实施例62.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(2-羟基乙基氨基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,用2-(2-氨基乙基氨基)乙醇作为反应物胺,以83%得率制备标题化合物。MS:m/e631.5(MH+),1.65min(方法1).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.07(s,3H)1.17(s,3H)1.73(s,3H)0.85-1.93(m,22H)2.00-2.11(m,1H)2.15(dd,J=17.12,6.30Hz,1H)2.47-2.56(m,1H)2.93(d,J=12.84Hz,1H)3.22(dd,J=5.79,4.53Hz,2H)3.27-3.29(m,1H)3.46-3.56(m,4H)3.83(dd,J=5.67,4.41Hz,2H)4.64(br.s.,1H)4.76(s,1H)5.27-5.33(m,1H)7.21(d,J=8.31Hz,2H)7.91(d,J=8.31Hz,2H)。
实施例63.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-吗啉代乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用2-吗啉代乙胺作为反应物胺,以92%得率制备标题化合物。MS:m/e657.6(MH+),1.70min(方法1).
1HNMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.07(s,3H)1.16(s,3H)1.72(s,3H)0.83-1.90(m,21H)1.97-2.09(m,1H)2.14(dd,J=17.12,6.30Hz,1H)2.46-2.55(m,1H)2.82-2.95(m,5H)3.02-3.11(m,2H)3.39(t,J=6.42Hz,2H)3.81(t,J=4.03Hz,4H)4.64(s,1H)4.74-4.77(m,1H)5.27-5.31(m,1H)7.21(d,J=8.31Hz,2H)7.91(d,J=8.31Hz,2H)。
实施例64.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羧基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照所述对C28胺形成和水解的通用程序,用3-氨基丙酸叔-丁酯盐酸盐作为反应物胺,以74%得率制备标题化合物。MS:m/e616.4(MH+),1.69min(方法1).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.92-1.86(m,24H)1.99-2.10(m,1H)2.15(dd,J=17.12,6.30Hz,1H)2.47-2.56(m,1H)2.76(t,J=6.42Hz,2H)2.88(d,J=12.34Hz,1H)4.64(s,1H)4.76(s,1H)5.28-5.32(m,1H)7.22(d,J=8.56Hz,2H)7.91(d,J=8.31Hz,2H)。
实施例65.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-溴代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,用3-溴代丙-1-胺氢溴酸盐作为反应物胺,以23%得率制备标题化合物。MS:m/e664(MH+),1.58min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.85-1.85(m,19H)1.99-2.10(m,1H)2.15(dd,J=17.37,6.55Hz,1H)2.26-2.36(m,2H)2.47-2.56(m,1H)2.88(d,J=12.34Hz,1H)3.20-3.28(m,4H)3.56(t,J=6.30Hz,2H)4.64(s,1H)4.76(s,1H)5.28-5.32(m,1H)7.22(d,J=8.31Hz,2H)7.92(d,J=8.56Hz,2H)。
实施例66.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-(((1-(吡咯烷-1-基甲基)环丙基)甲基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用(1-(吡咯烷-1-基甲基)环丙基)甲胺作为反应物胺,以50%得率,制备标题化合物。MS:m/e681.3(MH+),1.51min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.03(s,3H)1.07(s,3H)1.15(s,3H)1.72(s,3H)0.84-1.97(m,27H)2.00-2.19(m,6H)2.48(td,J=10.95,5.79Hz,1H)2.89(d,J=13.09Hz,1H)3.21-3.45(m,6H)4.64(s,1H)4.75(s,1H)5.27-5.32(m,1H)7.22(d,J=8.31Hz,2H)7.91(d,J=8.31Hz,2H)。
实施例67.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-氨基丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-氨基丙基氨基甲酸叔-丁基酯作为反应物胺,以46%得率制备标题化合物。MS:m/e601.4(MH+),1.48min(方法2).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.06(s,3H)1.16(s,3H)1.72(s,3H)0.85-1.89(m,22H)1.99-2.20(m,4H)2.50(td,J=10.45,5.79Hz,1H)2.85(d,J=13.09Hz,1H)3.05(t,J=7.55Hz,2H)3.13-3.28(m,3H)4.63(s,1H)4.73-4.76(m,1H)5.27-5.31(m,1H)7.21(d,J=8.31Hz,2H)7.91(d,J=8.31Hz,2H)。
实施例68.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(吡咯烷-1-基)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,用3-(吡咯烷-1-基)丙-1-胺作为反应物胺,以52%得率制备标题化合物。MS:m/e655.4(MH+),1.49min(方法2).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.07(s,3H)1.16(s,3H)1.72(s,3H)0.85-1.89(m,25H)1.99-2.27(m,8H)2.50(td,J=10.32,5.54Hz,1H)2.87(d,J=13.09Hz,1H)3.19(dt,J=12.53,3.56Hz,2H)3.22-3.30(m,2H)4.64(s,1H)4.75(s,1H)5.27-5.31(m,1H)7.21(d,J=8.31Hz,2H)7.92(d,J=8.31Hz,2H)。
实施例69.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羟基丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-氨基丙-1-醇作为反应物胺,以31%得率制备标题化合物。MS:m/e602.4(MH+),1.52min(方法2).1HNMR(500MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.87-1.81(m,21H)1.91-1.99(m,2H)1.99-2.09(m,1H)2.15(dd,J=17.24,6.26Hz,1H)2.47-2.55(m,1H)2.86(d,J=12.51Hz,1H)3.21-3.27(m,3H)3.74-3.79(m,2H)4.64(s,1H)4.76(s,1H)5.27-5.32(m,1H)7.22(d,J=8.24Hz,2H)7.91(d,J=8.24Hz,2H)。
实施例70.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-氨基-1-(吡咯烷-1-基)丙-1-酮盐酸盐作为反应物胺,以43%得率制备标题化合物。MS:m/e669.4(MH+),1.58min(方法2).
1H NMR(500MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.87-1.86(m,20H)1.88-1.95(m,2H)1.97-2.11(m,3H)2.15(dd,J=17.09,6.41Hz,1H)2.48-2.56(m,1H)2.81(t,J=5.80Hz,2H)2.88(d,J=13.12Hz,1H)3.25(d,J=13.43Hz,1H)3.32-3.42(m,2H)3.42-3.52(m,4H)4.64(s,1H)4.76(s,1H)5.27-5.32(m,1H)7.22(d,J=7.93Hz,2H)7.91(d,J=8.24Hz,2H)。
实施例71.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2,5-二氧代吡咯烷-1-基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(3-氨基丙基)吡咯烷-2,5-二酮盐酸盐作为反应物胺,以25%得率制备标题化合物。MS:m/e683.4(MH+),1.56min(方法2).
1H NMR(500MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.85-2.19(m,26H)2.45-2.53(m,1H)2.71-2.75(m,2H)2.79-2.85(m,1H)3.09(q,J=6.56Hz,2H)3.18-3.24(m,1H)3.63(q,J-6.51Hz,2H)4.64(s,1H)4.75(s,1H)5.27-5.31(m,1H)7.22(d,J=8.24Hz,2H)7.91(d,J=8.24Hz,2H)。
实施例72.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(哌啶-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用3-(哌啶-1-基)丙-1-胺作为反应物胺,以49%得率制备标题化合物。MS:m/e683.4(MH+),1.50min(方法2).
1H NMR(500MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.03(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.81-2.11(m,27H)2.15(dd,J=17.24,6.26Hz,1H)2.22(dt,J=16.25,8.20Hz,2H)2.51(td,J=10.45,6.26Hz,1H)2.84-3.00(m,2H)3.13-3.28(m,6H)3.50-3.61(m,2H)4.65(s,1H)4.75(s,1H)5.30(d,J=6.10Hz,1H)7.21(dd,J=8.24,1.53Hz,2H)7.91(dd,J=8.24,1.53Hz,2H)。
实施例73.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((2E)-4-(1,1-二氧化-4-硫吗啉基)-2-丁烯-1-基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用(1,1-二氧化-4-硫吗啉基)-2-丁烯-1-胺作为反应物胺,以11%得率制备标题化合物。MS:m/e731.2(MH+),1.54min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.16(s,3H)1.72(s,3H)0.85-1.82(m,19H)1.95-2.09(m,1H)2.15(dd,J=17.07,6.53Hz,1H)2.49(td,J=10.67,5.52Hz,1H)2.81(d,J=13.05Hz,1H)3.05-3.12(m,4H)3.12-3.18(m,4H)3.19-3.26(m,2H)3.33-3.37(m,2H)3.69-3.82(m,2H)4.65(s,1H)4.76(d,J=1.51Hz,1H)5.30(dd,J=6.27,1.51Hz,1H)5.85(ddd,J=15.43,7.15,7.03Hz,1H)6.11(dt,J=15.25,6.31Hz,1H)7.21(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例74.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-(羟基甲基)吡咯烷-1-基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用(1-(3-氨基丙基)吡咯烷-2-基)甲醇作为反应物胺,以39%得率制备标题化合物。MS:m/e685.3(MH+),1.47min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.86-2.32(m,30H)2.50(td,J=10.85,5.65Hz,1H)2.87(d,J=13.55Hz,1H)3.15-3.23(m,4H)3.49-3.76(m,4H)3.90(dd,J=12.05,3.51Hz,1H)4.65(s,1H)4.75(d,J=1.51Hz,1H)5.30(dd,J=6.02,1.51Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例75.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(二甲基氨基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述对C28胺形成和水解的通用程序,用3-氨基-N,N-二甲基丙酰胺作为反应物胺,以39%得率制备标题化合物。MS:m/e643.3(MH+),1.53min(方法2).
1HNMR(400MHz,MeOD)δppm0.96(s,3H)0.98(s,3H)1.05(s,3H)1.10(s,3H)1.18(s,3H)1.74(s,3H)0.88-1.87(m,20H)2.01-2.11(m,1H)2.16(dd,J=17.07,6.53Hz,1H)2.53(td,J=10.67,5.52Hz,1H)2.85-2.92(m,3H)2.99(s,3H)3.08(s,3H)3.24-3.29(m,1H)3.34-3.39(m,2H)4.65-4.67(m,1H)4.77(d,J=1.76Hz,1H)5.31(dd,J=6.27,1.76Hz,1H)7.23(d,J=8.53Hz,2H)7.93(d,J=8.28Hz,2H)
实施例76.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((4-(1,1-二氧化-4-硫吗啉基)丁基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用4-(1,1-二氧化-4-硫吗啉基)丁基)胺作为反应物胺,以11%得率制备标题化合物。MS:m/e733.2(MH+),1.49min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.86-1.91(m,27H)1.98-2.09(m,1H)2.15(dd,J=17.19,6.40Hz,1H)2.51(td,J=10.35,5.40Hz,1H)2.81-2.87(m,1H)2.94(t,J=7.15Hz,2H)3.08-3.16(m,2H)3.18-3.27(m,2H)3.36-3.44(m,4H)4.65(s,1H)4.76(d,J=1.51Hz,1H)5.30(dd,J=6.02,1.51Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例77.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-氧代咪唑烷-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(2-氨基乙基)咪唑烷-2-酮作为反应物胺,以9%得率制备标题化合物。MS:m/e656.3(MH+),1.56min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.72(s,3H)0.87-1.87(m,20H)1.99-2.11(m,1H)2.15(dd,J=17.07,6.02Hz,1H)2.51(td,J=10.79,6.02Hz,1H)2.92(d,J=13.55Hz,1H)3.21-3.33(m,3H)3.42-3.59(m,6H)4.63-4.65(m,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例78.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-氧代哌啶-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(2-氨基乙基)哌啶-2-酮氢溴酸盐作为反应物胺,以28%得率制备标题化合物。MS:m/e669.6(MH+),2.13min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.85-1.92(26H)2.00-2.11(m,1H)2.15(dd,J=17.19,6.40Hz,1H)2.40(t,J=6.40Hz,2H)2.51(td,J=10.60,4.89Hz,1H)2.91(d,J=12.80Hz,1H)3.25(d,J=12.80Hz,1H)3.44(t,J=5.77Hz,2H)3.60-3.74(m,2H)4.64(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例79.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-甲基-3-(2-氧代吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(3-氨基-2-甲基丙基)吡咯烷-2-酮作为反应物胺,以76%得率制备标题化合物。MS:m/e683.6(MH+),1.62min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.10(d,J=7.03Hz,3H)1.17(s,3H)1.73(s,3H)0.91-1.99(m,21H)2.01-2.19(m,4H)2.28-2.55(m,4H)2.76-2.91(m,1H)3.04(dd,J=12.80,5.27Hz,1H)3.14(dt,J=15.00,3.80Hz,1H)3.18-3.27(m,1H)3.50-3.58(m,1H)3.58-3.67(m,2H)4.64(s,1H)4.75(s,1H)5.30(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例80.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2,6-二氧代哌啶-1-基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(3-氨基丙基)哌啶-2,6-二酮盐酸盐作为反应物胺,以60%得率制备标题化合物。MS:m/e697.5(MH+),1.63min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.92-1.91(m,20H)1.92-2.03(m,4H)2.03-2.11(m,1H)2.15(dd,J=17.07,6.78Hz,1H)2.45-2.54(m,1H)2.70(t,J=6.53Hz,4H)2.83(d,J=13.30Hz,1H)3.05(t,J=6.78Hz,2H)3.20(d,J=13.30Hz,1H)3.89(t,J=6.65Hz,2H)4.62-4.66(m,1H)4.75(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.38Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例81.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羟基-3-(2-氧代吡咯烷-1-基)丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(3-氨基-2-羟基丙基)吡咯烷-2-酮作为反应物胺,以22%得率制备标题化合物。MS:m/e685.5(MH+),1.72min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.82-1.91(m,20H)2.02-2.19(m,4H)2.38-2.46(m,2H)2.46-2.56(m,1H)2.89(d,J=13.05Hz,1H)3.01-3.19(m,2H)3.32-3.50(m,4H)3.53-3.70(m,2H)4.18-4.26(m,J=9.41,5.02,4.71,4.71Hz,1H)4.64(s,1H)4.75(d,J=1.76Hz,1H)5.29(dd,J=6.02,1.51Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例82.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((1-(哌啶-1-基甲基)环丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成和水解所描述的通用程序,使用1-(哌啶-1-基甲基)环丙胺盐酸盐作为反应物胺,以87%得率制备标题化合物。MS:m/e681.7(MH+),1.76min(方法2).1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.07(s,3H)1.17(s,3H)1.72(s,3H)0.87-1.90(m,38H)1.93-2.06(m,1H)2.15(dd,J=17.19,6.40Hz,1H)2.56(td,J=11.23,5.90Hz,1H)4.63(s,1H)4.75(s,1H)5.30(dd,J=6.02,1.51Hz,1H)7.22(d,J=8.28Hz,2H)7.92(d,J=8.53Hz,2H)。
实施例83.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((二甲基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上在步骤3中描述的程序,使用甲醛作为反应物醛和4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-氨基丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(实施例67)作为起始原料胺,制备标题化合物。分离为白色固体的产物(17mg,34.4%)。LCMS:m/e572.5(MH+),2.21min(方法3).
1H NMR(400MHz,MeOD)δppm6.37(d,J=8.5Hz,2H),5.67(d,J=8.3Hz,2H),3.75(dd,J=6.1,1.6Hz,1H),3.22(d,J=1.5Hz,1H),3.11(s,1H),1.79-1.93(m,1H),1.54(d,J=13.8Hz,1H),1.36-1.48(m,6H),0.97(td,J=11.0,5.4Hz,1H),0.60(dd,J=17.2,6.4Hz,1H),0.42-0.55(m,1H),0.31-0.38(m,1H),0.10-0.30(m,8H),0.11-0.10(m,8H),0.32-0.11(m,5H),0.44-0.32(m,4H),0.47(s,3H),0.52(s,3H),0.56(s,3H),0.60(s,3H)。
实施例84.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((环丙基(3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28胺形成、水解和叔胺形成所描述的通用程序,使用4-(3-氨基丙基)硫代吗啉1,1-二氧化物作为反应物胺和(1-乙氧基环丙氧基)三甲基硅烷作为反应物醛等价物,制备标题化合物。分离为白色固体的产物(5mg,22.5%)。LCMS:m/e759.6(MH+),2.56min(方法3).
1H NMR(400MHz,MeOD)δppm6.38(d,J=8.3Hz,2H),5.68(d,J=8.3Hz,2H),3.77(d,J=4.5Hz,1H),3.25(s,1H),3.13(s,1H),1.71-1.76(m,2H),1.56-1.71(m,8H),1.47(s,2H),1.24(br.s.,2H),1.01(br.s.,1H),0.79(br.s.,1H),0.61(d,J=4.8Hz,2H),0.49(m,1H),0.20(s,9H),0.06(br.s.,7H),0.06(br.s.,4H),0.29-0.13(m,4H),0.38-0.29(m,4H),0.46-0.38(m,5H),0.54-0.46(m,4H),0.57(s,3H),0.58(s,3H)。
制备其它的C28胺的通用程序:实施例85-86。
步骤1.还原性胺化
将4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(1eq.)、2,2-二乙氧基乙胺(2eq.)和乙酸(2-5eq.)在DCE(2ml)中的悬浮液于室温下搅拌30min。加入三乙酰氧基硼氢化钠(5eq.)。于室温下搅拌生成的混合物18-72h。该反应混合物用5ml饱和的碳酸钠稀释并用DCM(3x10ml)提取。合并的有机层经硫酸钠干燥,过滤并真空浓缩。粗产物经Biotage快速层析纯化,得到分离为白色固体的所需产物(88mg,15%)。LCMS:m/e716.6.4(MH+),2.96min(方法3)。
步骤2.缩醛转化为醛
向得自步骤1的4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2,2-二乙氧基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯的丙酮(10ml)溶液中加入2eq的4-甲基苯磺酸。将该混合物搅拌并回流14h。真空除去溶剂并使得到的残留物再溶于二氯甲烷并用碳酸氢钠溶液洗涤。分离有机层并经硫酸钠干燥。得到的黄色固体无需进一步纯化而用于下一步骤。LCMS:m/e674.6(M+CH3OH+),2.78min(方法3)。
步骤3.还原性胺化
将4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(1eq.)、相应的胺(2eq.)和乙酸(2-5eq.)在DCE(2ml)中的悬浮液于室温下搅拌30min。加入三乙酰氧基硼氢化钠(5eq.)。于室温下搅拌生成的混合物18-72h。该反应混合物用5ml饱和的碳酸钠稀释并用DCM(3x10ml)提取。合并的有机层经硫酸钠干燥,过滤并真空浓缩。粗产物经Biotage快速层析纯化或无需进一步纯化而直接用于下一步骤。
步骤4。
(a)酸水解-向得自步骤3的物质的DCM(4-5ml)溶液中加入TFA(0.4-0.5ml)。于室温下搅拌该混合物2-6h。真空蒸发溶剂。生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
(b)碱水解-向得自步骤3的物质的二氧六环(2ml)和甲醇(2ml)溶液中加入NaOH(75mg,1.875mmol)和H2O(0.5ml)。于70℃将生成的溶液搅拌5-10h。真空蒸发溶剂,生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
实施例85.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(甲基(2-(甲基磺酰基)乙基)氨基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上描述的通用程序,使用N-甲基-2-(甲基磺酰基)乙胺作为反应物胺,制备标题化合物。分离为白色固体的产物(10mg,184%)。LCMS:m/e707.7(MH+),2.55min(方法3).
实施例86.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-硫代吗啉代乙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上描述的通用程序,使用硫吗啉作为反应物胺,制备标题化合物。分离为白色固体的产物(6mg,20.0%)。LCMS:m/e673.6(MH+),2.56min(方法3).1HNMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.3Hz,2H),5.33(d,J=4.3Hz,1H),4.79(d,J=2.0Hz,1H),4.68(s,1H),3.42-3.55(m,2H),3.33(m,2H),3.15(ddd,J=3.4,1.6,1.5Hz,5H),2.84-3.01(m,5H),2.53(br.s.,1H),2.18(dd,J=17.2,6.4Hz,2H),1.67-1.92(m,8H),1.47-1.67(m,8H),1.38(br.s.,2H),1.31(d,J=3.5Hz,3H),1.14-1.26(m,5H),1.11(s,3H),1.07(s,3H),0.99(s,3H),0.98(s,3H)。
用氟代苯甲酸制备C28胺的通用程序:实施例87-95.
步骤1:Suzuki偶合
向((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(三氟甲基磺酰氧基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基苯甲酸酯(675mg,1mmol)的1,4-二氧六环(5ml)溶液中加入2-丙醇(5ml)、H2O(2ml)、Na2CO3(317mg,3mmol)、相应的硼酸(296mg,1.5mmol)和Pd(Ph3P)4(34.6mg,0.030mmol)。将该混合物在氮气下回流4h。该反应混合物用H2O(10ml)稀释并用EtOAc(3x10ml)提取。合并的有机层经Na2SO4干燥,过滤并真空浓缩。粗产物经Biotage(Thomson25g硅胶柱;9∶1Hex/EtOAc)纯化。合并含有期望的产物的部分并真空浓缩,得到相应的氟代苯甲酸甲基酯。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(苯甲酸基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)-3-氟代苯甲酸甲基酯
按照对Suzuki偶合描述的程序,使用2-氟-4-(甲氧基羰基)苯基硼酸作为反应物,以62%得率制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.90(3H,s),0.95(3H,s),1.02(3H,s),1.05(3H,s),1.14(3H,s),1.73(3H,s),0.84-1.87(18H,m),1.91-2.10(3H,m),2.14(1H,dd,J=17.3,6.5Hz),2.56(1H,td,J=11.0,5.8Hz),3.93(3H,s),4.14(1H,d,J=10.3Hz),4.56(1H,d,J=9.8Hz),4.61-4.65(1H,m),4.75(1H,d,J=2.0Hz),5.36(1H,dd,J=6.3,1.8Hz),7.17(1H,t,J=7.5Hz),7.43-7.49(2H,m),7.55-7.60(1H,m),7.69(1H,dd,J=9.7,1.6Hz),7.74(1H,dd,J=7.9,1.6Hz),8.07(2H,dd,J=8.4,1.4Hz)。
制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(苯甲酸基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)-2-氟代苯甲酸甲基酯
按照对Suzuki偶合描述的程序,使用3-氟-4-(甲氧基羰基)苯基硼酸作为反应物,以66%得率制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.94(3H,s),0.95(3H,s),0.98(3H,s),1.05(3H,s),1.13(3H,s),1.73(3H,s),0.87-1.87(m,18H),1.91-2.08(3H,m),2.12(1H,dd,J=17.2,6.4Hz),2.56(1H,td,J=11.0,5.8Hz),3.93(3H,s),4.13(1H,d,J=10.0Hz),4.55(1H,d,J=10.0Hz),4.61-4.65(1H,m),4.74(1H,d,J=2.0Hz),5.33(1H,dd,J=6.3,1.8Hz),6.93(1H,dd,J=11.8,1.5Hz),6.98(1H,dd,J=8.0,1.5Hz),7.43-7.49(2H,m),7.54-7.60(1H,m),7.82(1H,t,J=7.9Hz),8.07(2H,dd,J=8.4,1.4Hz)。
步骤2:C28醇的去保护
向得自步骤1的氟代苯甲酸甲基酯的1,4-二氧六环(15ml)和H2O(2ml)溶液中加入氢氧化锂水合物(3.0eq)。于75℃将生成的混合物搅拌48h。LCMS显示反应未完成。将混合物分配在H2O(50ml)和DCM(50ml)之间并用1N HCl中和。有机层用H2O(2x50ml)洗涤,经Na2SO4干燥,过滤并真空浓缩。使该固体再溶于1,4-二氧六环(15ml)和MeOH(15ml)。加入氢氧化锂水合物(3eq)和H2O(2ml)。于75℃将生成的混合物搅拌24h。LC/MS表明该反应完成和甲基酯也已被裂解。使该混合物分配在H2O(50ml)和DCM(50ml)之间并用1N HCl中和。有机层用H2O(2x50ml)洗涤,经Na2SO4干燥,过滤并真空浓缩,得到为固体的粗C28醇,其无需进一步纯化而用于下一步骤。
制备3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯
按照以上描述的C28醇去保护程序,制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.91(3H,d,J=1.3Hz),0.96(3H,s),1.02(3H,s),1.03(3H,s),1.11(3H,s),1.71(3H,s),0.82-1.79(m,18H),1.84-2.03(3H,m),2.13(1H,dd,J=17.3,6.5Hz),2.42(1H,td,J=10.9,6.1Hz),3.37(1H,d,J=11.0Hz),3.84(1H,d,J=10.5Hz),4.60(1H,dd,J=2.1,1.4Hz),4.71(1H,d,J=2.0Hz),5.37(1H,dd,J=6.3,1.8Hz),7.21(1H,t,J=7.4Hz),7.73(1H,dd,J=9.5,1.5Hz),7.79(1H,dd,J=7.9,1.6Hz);MS m/z561.6(M-H)-,2.36min(方法6)。
制备2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯
按照以上描述的C28醇去保护程序,制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.95(3H,s),0.96(3H,s),0.98(3H,s),1.03(3H,s),1.10(3H,s),1.71(3H,s),0.83-1.79(m,18H),1.84-2.06(3H,m),2.12(1H,dd,J=17.4,6.4Hz),2.42(1H,td,J=10.7,6.1Hz),3.37(1H,d,J=10.8Hz),3.84(1H,d,J=10.5Hz),4.60(1H,s),4.71(1H,d,J=1.5Hz),5.34(1H,dd,J=6.1,1.6Hz),6.97(1H,dd,J=11.9,1.1Hz),7.02(1H,dd,J=8.2,1.4Hz),7.91(1H,t,J=7.9Hz);MS m/z561.6(M-H)-,2.33min(方法6)
步骤3.制备氟代苯甲酸甲基酯
向得自步骤2的物质在DCM(40ml)和MeOH(12ml)的混悬液中加入三甲基甲硅烷基重氮甲烷(2M在己烷中)(4.8eq.)。于氮气、室温下,将生成的混合物搅拌4天。真空浓缩反应混合物,得到为固体的粗产物,其无需进一步纯化而用于下一步骤。
制备3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯
按照以上对甲基酯形成描述的程序,制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.89(3H,d,J=1.0Hz),0.95(3H,s),1.01(3H,s),1.02(3H,s),1.10(3H,s),1.70(3H,s),0.81-1.78(m,18H),1.84-2.05(3H,m),2.12(1H,dd,J=17.1,6.3Hz),2.42(1H,td,J=11.0,5.9Hz),3.36(1H,dd,J=10.4,5.6Hz),3.84(1H,dd,J=9.8,5.3Hz),3.93(3H,s),4.60(1H,dd,J=2.3,1.3Hz),4.70(1H,d,J=2.0Hz),5.36(1H,dd,J=6.3,1.8Hz),7.17(1H,t,J=7.5Hz),7.68(1H,dd,J=9.5,1.5Hz),7.74(1H,dd,J=7.9,1.6Hz)。
制备2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯
按照以上对甲基酯形成描述的程序,制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.94(3H,s),0.95(3H,s),0.97(3H,s),1.02(3H,s),1.09(3H,s),1.70(3H,s),0.86-1.78(m,18H),1.84-2.02(3H,m),2.11(1H,dd,J=17.3,6.3Hz),2.42(1H,td,J=10.5,5.5Hz),3.36(1H,dd,J=10.3,6.0Hz),3.83(1H,dd,J=10.4,6.1Hz),3.93(3H,s),4.60(1H,dd,J=2.3,1.5Hz),4.70(1H,d,J=2.3Hz),5.32(1H,dd,J=6.1,1.9Hz),6.93(1H,dd,J=11.9,1.4Hz),6.98(1H,dd,J=8.0,1.5Hz),7.82(1H,t,J=7.9Hz)。
步骤4:制备C28醛
在氮气下,向草酰氯(1.2eq)的DCM(5ml)的-70℃溶液中滴加入DMSO(1.5eq)的DCM(5ml)溶液。将该混合物温热至-50℃。滴加入得自步骤3的粗产物的DCM(2ml)溶液。于-50℃搅拌15min后,滴加入Et3N(3eq),该混合物温热至rt。将该反应混合物用DCM(50ml)稀释并用H2O(2x50ml)洗涤,随后用盐水(50ml)洗涤,经Na2SO4干燥,过滤并真空浓缩。粗产物经Biotage(Thomson25g硅胶柱;9∶1Hex/EtOAc)纯化。合并含有期望的产物的部分并真空浓缩,得到相应的醛。
制备3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯
按照以上对C28醛形成描述的程序,以3步(步骤2-4)80%得率制备标题化合物。1H NMR(400MHz,氯仿-d)δ0.89(3H,d,J=1.3Hz),0.94(3H,s),0.99(3H,s),1.00(3H,s),1.02(3H,s),1.72(3H,s),1.96-0.81(m,19H),2.04-2.17(3H,m),2.90(1H,td,J=11.1,5.9Hz),3.92(3H,s),4.65(1H,dd,J=2.1,1.4Hz),4.78(1H,d,J=2.0Hz),5.36(1H,dd,J=6.3,1.8Hz),7.16(1H,t,J=7.5Hz),7.68(1H,dd,J=9.5,1.5Hz),7.74(1H,dd,J=7.9,1.6Hz),9.70(1H,d,J=1.5Hz).19F NMR(376MHz,MeOD)δppm-115.50(1F,s));MS m/z575.5(M+H)+,2.93min(方法2)。
制备2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯
按照以上对C28醛形成描述的程序,以3步(步骤2-4)84%得率制备标题化合物。1H NMR(400MHz,氯仿-d)δppm0.93(3H,s),0.94(3H,s),0.96(3H,s),0.98(3H,s),1.01(3H,s),1.72(3H,s),1.96-0.80(m,19H),2.04-2.16(3H,m),2.90(1H,td,J=11.1,5.9Hz),3.93(3H,s),4.65(1H,dd,J=2.0,1.5Hz),4.78(1H,d,J=2.0Hz),5.32(1H,dd,J=6.3,2.0Hz),6.93(1H,dd,J=11.9,1.4Hz),6.97(1H,dd,J=8.0,1.5Hz),7.82(1H,t,J=7.8Hz),9.70(1H,d,J=1.5Hz).19F NMR(376MHz,MeOD)δppm-114.87(1F,s):MS m/z575.5(M+H)+,2.78min(方法2)。
步骤5:制备C28胺
将相应的醛、胺(2eq.)和乙酸(2-5eq.)在DCE(2-5ml)中的悬浮液于室温下搅拌0.5-1h。加入三乙酰氧基硼氢化钠(5eq.)。将生成的混合物于室温下搅拌18-72h。该反应混合物用5ml饱和的碳酸钠稀释并用DCM(3x10ml)提取。合并的有机层经硫酸钠干燥,过滤并真空浓缩。粗产物经Biotage快速层析纯化或无需进一步纯化而直接用于下一步骤。
步骤6:制备苯甲酸
向得自步骤5的C28胺的1,4-二氧六环(1ml)和甲醇(0.5ml)溶液中加入1N氢氧化钠(0.5-1ml)。于65℃将该混合物搅拌2-5h。粗制反应混合物经制备型HPLC纯化,得到要求的苯甲酸。
实施例87.3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-氧代吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述步骤5和6,使用3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和1-(3-氨基丙基)吡咯烷-2-酮作为反应物胺,以79%得率制备标题化合物。MS:m/e687.5(MH+),1.71min(方法2).1HNMR(400MHz,MeOD)δppm0.91(s,3H)0.96(s,3H)1.05(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.85-1.91(m,20H)1.96-2.20(m,6H)2.44(t,J=8.03Hz,2H)2.47-2.56(m,1H)2.83(d,J=13.05Hz,1H)3.07(t,J=7.03Hz,2H)3.21(d,J=13.05Hz,1H)3.43(t,J=6.40Hz,2H)3.52(t,J=7.15Hz,2H)4.62-4.66(m,1H)4.75(d,J=1.51Hz,1H)5.35(dd,J=6.02,1.51Hz,1H)7.22(t,J=7.65Hz,1H)7.64(dd,J=9.79,1.51Hz,1H)7.75(dd,J=7.91,1.63Hz,1H).19F NMR(376MHz,MeOD)δppm-114.92(s,1F)。
实施例88.2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-氧代吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述步骤5和6,使用2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和1-(3-氨基丙基)吡咯烷-2-酮作为反应物胺,以82%得率制备标题化合物。MS:m/e687.5(MH+),1.71min(方法2).1HNMR(400MHz,MeOD)δppm0.96(s,3H)0.98(s,3H)1.02(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.90-1.91(m,20H)1.96-2.20(m,6H)2.44(t,J=8.03Hz,2H)2.47-2.55(m,1H)2.83(d,J=13.05Hz,1H)3.06(t,J=7.03Hz,2H)3.20(d,J=13.55Hz,1H)3.43(t,J=6.53Hz,2H)3.51(t,J=7.15Hz,2H)4.62-4.66(m,1H)4.75(d,J=1.76Hz,1H)5.35(dd,J=6.15,1.88Hz,1H)6.94(dd,J=11.80,1.25Hz,1H)7.02(dd,J=8.03,1.51Hz,1H)7.83(t,J=7.91Hz,1H).19F NMR(376MHz,MeOD)δppm-112.76(s,1F)。
实施例89.3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照步骤5和6,使用3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和3-氨基-1-(吡咯烷-1-基)丙-1-酮盐酸盐作为反应物胺,以72%得率制备标题化合物。MS:m/e687.5(MH+),1.76min(方法2).
1HNMR(400MHz,MeOD)δppm0.91(s,3H)0.96(s,3H)1.05(s,3H)1.09(s,3H)1.17(s,3H)1.73(s,3H)0.85-1.85(m,20H)1.87-1.96(m,2H)2.01(dt,J=13.36,6.74Hz,2H)2.04-2.12(m,1H)2.16(dd,J=17.07,6.53Hz,1H)2.48-2.57(m,1H)2.81(t,J=6.02Hz,2H)2.88(d,J=12.80Hz,1H)3.33-3.43(m,3H)3.43-3.52(m,4H)4.65(s,1H)4.76(d,J=1.25Hz,1H)5.35(dd,J=6.02,1.51Hz,1H)7.22(t,J=7.53Hz,1H)7.64(dd,J=9.79,1.25Hz,1H)7.75(dd,J=8.03,1.51Hz,1H).19F NMR(376MHz,MeOD)δppm-113.36(s,1F)。
实施例90.2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照步骤5和6,使用2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和3-氨基-1-(吡咯烷-1-基)丙-1-酮盐酸盐作为反应物胺,以67%得率制备标题化合物。MS:m/e687.5(MH+),1.74min(方法2).
1H NMR(400MHz,MeOD)δppm0.96(s,3H)0.98(s,3H)1.02(s,3H)1.08(s,3H)1.16(s,3H)1.73(s,3H)0.90-1.86(m,20H)1.88-1.96(m,J=6.78,6.78,6.65,6.40Hz,2H)1.97-2.10(m,1H)2.01(dt,J=13.74,6.81Hz,2H)2.16(dd,J=17.19,6.40Hz,1H)2.47-2.57(m,1H)2.81(t,J=6.02Hz,2H)2.88(d,J=12.55Hz,1H)3.33-3.42(m,3H)3.42-3.52(m,4H)4.65(s,1H)4.76(d,J=1.76Hz,1H)5.35(dd,J=5.77,1.00Hz,1H)6.94(d,J=11.80Hz,1H)7.02(dd,J=8.03,1.25Hz,1H)7.83(t,J=7.91Hz,1H).19F NMR(376MHz,MeOD)δppm-112.76(s,1F)。
实施例91.2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-氧代吡咯烷-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照步骤5和6,使用2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和1-(2-氨基乙基)吡咯烷-2-酮草酸盐作为反应物胺,以60%得率制备标题化合物。MS:m/e673.6(MH+),1.72min(方法2).
1H NMR(400MHz,MeOD)δppm0.96(s,3H)0.98(s,3H)1.02(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)2.01-2.21(m,4H)2.44(t,J=8.16Hz,2H)2.51(td,J=10.79,5.52Hz,1H)2.94(d,J=13.05Hz,1H)3.30(dt,J=3.26,1.63Hz,3H)3.55(t,J=7.15Hz,2H)3.58-3.70(m,2H)4.62-4.67(m,1H)4.76(d,J=1.76Hz,1H)5.35(dd,J=6.27,1.76Hz,1H)6.94(dd,J=11.92,1.38Hz,1H)7.02(dd,J=8.03,1.51Hz,1H)7.83(t,J=7.91Hz,1H).19F NMR(376MHz,MeOD)δppm-112.75(s,1F)。
实施例92.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)-3-氟代苯甲酸
按照步骤5和6,使用3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和4-(3-氨基丙基)硫代吗啉1,1-二氧化物作为反应物胺,制备标题化合物分离为白色固体的产物(70mg,68.0%)。LCMS:m/e737.5(MH+),2.59min(方法3).1HNMR(400MHz,MeOD)δppm7.77(d,J=7.8Hz,1H),7.67(d,J=9.8Hz,1H),7.19-7.31(m,1H),5.38(d,J=4.8Hz,1H),4.78(br.s.,1H),4.67(br.s.,1H),3.41(br.s.,4H),3.30-3.38(m,4H),3.27(d,J=12.5Hz,1H),3.21(br.s.,2H),3.00(t,J=6.4Hz,2H),2.90(br.s.,1H),2.53(br.s.,1H),2.10(br.s.,4H),1.84(br.s.,3H),1.75(br.s.,7H),1.54(br.s.,8H),1.36(br.s.,3H),1.20(br.s.,5H),1.11(br.s.,3H),1.07(br.s.,3H),0.98(br.s.,3H),0.94(br.s.,3H).19F NMR(376MHz,MeOD)δppm-113.31(s,1F)。
实施例93.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)-2-氟代苯甲酸.
按照步骤5和6,使用2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和4-(3-氨基丙基)硫代吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(50mg,55.0%)。LCMS:m/e737.5(MH+),2.53min(方法3).1HNMR(400MHz,MeOD)δppm7.85(d,J=3.8Hz,1H),7.01-7.14(m,1H),6.98(br.s.,1H),5.37(br.s.,1H),4.78(br.s.,1H),4.67(br.s.,1H),3.56(br.s.,4H),3.43(br.s.,4H),3.21(m,3H),3.12(br.s.,2H),2.90(br.s.,1H),2.53(br.s.,1H),2.16(br.s.,4H),1.75(br.s.,10H),1.53(br.s.,8H),1.31(br.s.,3H),1.19(br.s.,5H),1.10(br.s.,3H),1.05(br.s.,3H),0.99(d,J=8.5Hz,6H).19F NMR(376MHz,MeOD)δppm-112.6(s,1F)。
实施例94.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-二氧化-4-硫吗啉基)乙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)-3-氟代苯甲酸
按照步骤5和6,使用3-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和4-(3-氨基乙基)硫代吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(70mg,66.4%)。LCMS:m/e723.5(MH+),2.57min(方法3).1HNMR(400MHz,MeOD)δppm7.77(dd,J=7.9,1.6Hz,1H),7.67(dd,J=9.8,1.5Hz,1H),7.24(t,J=7.5Hz,1H),5.36(d,J=4.8Hz,1H),4.78(d,J=1.5Hz,1H),4.66(s,1H),3.23-3.45(m,3H),3.16(d,J=2.5Hz,8H),2.94-3.05(m,2H),2.91(d,J=13.1Hz,1H),2.55(td,J=10.5,5.8Hz,1H),2.17(dd,J=17.1,6.5Hz,1H),1.96-2.13(m,1H),1.68-1.93(m,10H),1.43-1.66(m,8H),1.28-1.43(m,3H),1.13-1.25(m,5H),1.09(s,3H),1.06(s,3H),0.98(s,3H),0.93(s,3H).19F NMR(376MHz,MeOD)δppm-113.10(s,1F)。
实施例95.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-二氧化-4-硫吗啉基)乙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)-2-氟代苯甲酸.
按照步骤5和6,使用2-氟-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯和4-(3-氨基乙基)硫代吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(53mg,70.7%)。LCMS:m/e723.5(MH+),2.56min(方法3).1HNMR(400MHz,MeOD)δppm7.74-7.96(m,1H),6.99-7.16(m,1H),6.78-6.99(m,1H),5.25-5.40(m,1H),4.77(d,J=1.5Hz,1H),4.58-4.70(m,1H),3.24-3.40(m,3H),3.06-3.24(m,8H),2.93-3.05(m,2H),2.81-2.93(m,1H),2.53(td,J=10.5,5.5Hz,1H),2.17(dd,J=17.2,6.4Hz,1H),1.94-2.12(m,1H),1.67-1.92(m,10H),1.42-1.66(m,8H),1.21-1.42(m,5H),1.18(s,3H),1.09(s,3H),1.04(s,3H),0.92-1.02(m,6H).19F NMR(376MHz,MeOD)δppm-112.49(s,1F),-112.51(s,1F),-112.54(s,1F)。
制备具有酰胺封端(end cap)的C28胺的通用程序(实施例96-130):
步骤1:制备氨基乙酸甲基酯或3-氨基丙酸甲基酯
向醛(200mg,0.334mmol)的DCE溶液中加入碳酸钾(185mg,1.336mmol)。于室温下搅拌30min后,加入乙酸(80mg,1.336mmol)和2-氨基乙酸甲基酯盐酸盐或3-氨基丙酸甲基酯盐酸盐(4eq.1.336mmol)。于室温下搅拌该混合物10min,然后加入三乙酰氧基硼氢化钠(566mg,2.67mmol)。将该混合物于室温下搅拌48h。用7ml饱和NaHCO3稀释该混合物并用DCM(3x7ml)提取。合并的有机层经硫酸钠干燥。经过滤除去干燥剂,且滤液在减压下浓缩,得到粗产物,其无需另外的纯化而用于下一步骤。
步骤2:制备氨基乙酸或3-氨基丙酸
向得自步骤1的物质的二氧六环(1ml)和甲醇(5ml)溶液中加入氢氧化锂(5eq.),随后加入H2O(0.5ml)。将澄清溶液于室温下搅拌12h。蒸发溶剂并使生成的黄色固体再溶于二氟甲烷,通过加入HCl将pH调节至~4。该混合物用DCM(3x10ml)提取。合并的有机层经硫酸钠干燥。经过滤除去干燥剂,且滤液在减压下浓缩,得到粗产物,其无需另外的纯化而用于下一步骤。
步骤3:制备氨基乙酰胺或3-氨基丙酰胺
向得自步骤2的物质(1eq.)的DMC的0℃溶液中加入相应的胺(1.5eq.)、HATU(2eq.),随后加入DIPEA(3eq.)。将生成的混悬液于室温下搅拌18h。LC/MS与期望的产物一致。真空除去溶剂,得到粗产物,其无需另外的纯化而用于下一步骤。
步骤4:制备苯甲酸
向物质得自步骤3的物质的DCM(4-5ml)溶液中加入TFA(0.4-0.5ml,)。于室温下搅拌该混合物2-16h。减压除去溶剂。生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
实施例96.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(哌啶-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端(end cap)的C28胺描述的通用程序,用哌啶作为反应物胺,以53%得率制备标题化合物。MS:m/e683.5(MH+),1.63min(方法2).1HNMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.87-1.85(m,26H)1.99-2.10(m,1H)2.15(dd,J=16.94,6.40Hz,1H)2.52(td,J=10.48,4.89Hz,1H)2.83-2.90(m,3H)3.26(d,J=13.80Hz,1H)3.32-3.38(m,2H)3.44-3.50(m,2H)3.54-3.60(m,2H)4.65(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=5.90,1.13Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例97.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4-(N,N-二甲基氨磺酰基)哌嗪-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用N,N-二甲基哌嗪-1-磺酰胺作为反应物胺,以81%得率制备标题化合物。MS:m/e791.5(MH+),1.74min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.89-1.86(m,20H)1.99-2.10(m,1H)2.15(dd,J=17.32,6.53Hz,1H)2.52(td,J=10.60,6.15Hz,1H)2.84(s,6H)2.85-2.93(m,3H)3.19-3.28(m,4H)3.33-3.44(m,3H)3.56-3.62(m,2H)3.63-3.76(m,2H)4.65(s,1H)4.76(d,J=1.51Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.22(d,J=8.53Hz,2H)7.92(d,J=8.53Hz,2H)。
实施例98.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4-(乙氧基羰基)哌啶-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用哌啶-4-甲酸乙基酯作为反应物胺,以35%得率制备标题化合物。MS:m/e755.5(MH+),1.62min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.17(d,J=1.25Hz,3H)1.24(t,J=7.03Hz,3H)1.73(s,3H)0.87-1.85(m,22H)1.91-2.10(m,3H)2.15(dd,J=16.94,6.40Hz,1H)2.46-2.56(m,1H)2.60-2.72(m,1H)2.81-2.95(m,4H)3.16-3.43(m,4H)3.82-3.90(m,1H)4.14(q,J=7.11Hz,2H)4.35-4.43(m,1H)4.65(s,1H)4.76(d,J=1.51Hz,1H)5.30(dd,J=6.02,1.51Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例99.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(3-(二甲基氨基)-3-氧代丙基氨基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基-N,N-二甲基丙酰胺盐酸盐作为反应物胺,以71%得率制备标题化合物。MS:m/e714.6(MH+),1.67min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.89-1.87(m,20H)1.98-2.10(m,1H)2.15(dd,J=17.19,6.40Hz,1H)2.52(td,J=10.98,5.65Hz,1H)2.61(t,J=6.53Hz,2H)2.67(t,J=6.27Hz,2H)2.87(d,J=13.05Hz,1H)2.93(s,3H)3.04(s,3H)3.26-3.37(m,3H)3.47(t,J=6.53Hz,2H)4.64(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.22(d,J=8.28Hz,2H)7.92(d,J=8.53Hz,2H)。
实施例100.(R)-1-(3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)丙酰基)吡咯烷-2-羧酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用(R)-吡咯烷-2-甲酸叔-丁基酯作为反应物胺,以45%得率制备标题化合物。MS:m/e713.5(MH+),1.59min(方法2).1HNMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.87-1.86(m,20H)1.99-2.11(m,4H)2.15(dd,J=17.07,6.02Hz,1H)2.24-2.32(m,1H)2.47-2.56(m,1H)2.84-2.92(m,3H)3.23-3.28(m,1H)3.38(t,J=5.90Hz,2H)3.51-3.69(m,2H)4.48(dd,J=8.41,3.14Hz,1H)4.64(s,1H)4.76(d,J=1.25Hz,1H)5.30(dd,J=6.02,1.76Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例101.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-((S)-2-(甲氧基羰基)吡咯烷-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用(S)-吡咯烷-2-甲酸甲基酯盐酸盐作为反应物胺,以43%得率制备标题化合物。MS:m/e727.5(MH+),1.60min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.87-1.84(m,22H)1.98-2.10(m,4H)2.15(dd,J=17.07,6.27Hz,1H)2.22-2.31(m,1H)2.84-2.91(m,3H)3.38(ddd,J=6.78,5.14,4.89Hz,2H)3.53-3.69(m,2H)3.73(s,3H)4.49(dd,J=8.66,3.39Hz,1H)4.64(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例102.(S)-1-(3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)丙酰基)吡咯烷-2-羧酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-((S)-2-(甲氧基羰基)吡咯烷-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(10mg,0.014mmol)的二氧六环(1ml)和甲醇(2ml)溶液中加入1N氢氧化钠(0.08ml,0.08mmol)和H2O(0.5ml)。于室温下搅拌生成的混合物45h。反应混合物用1N HCl中和并真空浓缩。残留物经制备型HPLC纯化,得到标题化合物(8.5mg,85%).MS:m/e713.5(MH+),1.68min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.87-1.86(m,20H)1.99-2.10(m,4H)2.15(dd,J=17.32,6.53Hz,1H)2.24-2.33(m,1H)2.52(td,J=9.60,4.14Hz,1H)2.83-2.92(m,3H)3.24-3.28(m,1H)3.38(t,J=6.15Hz,2H)3.52-3.68(m,2H)4.48(dd,J=8.41,3.39Hz,1H)4.64(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例103.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(3,3-二氟吡咯烷-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照所述制备具有酰胺封端的C28胺的通用程序,用3,3-二氟吡咯烷盐酸盐作为反应物胺,以76%得率制备标题化合物。MS:m/e705.5(MH+),1.69min(方法2).
1HNMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.86-1.86(m,22H)1.99-2.10(m,1H)2.15(dd,J=17.32,6.53Hz,1H)2.37-2.58(m,3H)2.79(t,J=6.02Hz,1H)2.84(t,J=6.02Hz,1H)2.89(d,J=13.05Hz,1H)3.36-3.41(m,1H)3.70(t,J=7.65Hz,1H)3.77(d,J=7.78Hz,1H)3.80(t,1H)3.92(t,J=12.55Hz,1H)4.65(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.22(d,J=8.53Hz,2H)7.92(d,J=8.53Hz,2H).19F NMR(376MHz,MeOD)δppm-104.01(d,J=74.56Hz,1F)-103.19(d,J=26.01Hz,1F)。
实施例104.1-(3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)丙酰基)哌啶-4-羧酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用哌啶-4-甲酸乙基酯作为反应物胺,随后如下所述对所述酯基团进行碱水解,以51%得率制备标题化合物:
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4-(乙氧基羰基)哌啶-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(16mg,0.021mmol)的二氧六环(1ml)和甲醇(2ml)溶液中加入1N氢氧化钠(0.3ml,0.1mmol)和H2O(0.5ml)。于室温下搅拌生成的混合物10天。反应混合物用1N HCl中和并真空浓缩。粗产物经制备型HPLC纯化,得到标题化合物(8mg).MS:m/e727.6(MH+),1.69min(方法2).
1HNMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.17(d,J=2.76Hz,3H)1.73(s,3H)0.87-1.86(m,23H)1.92-2.10(m,3H)2.15(dd,J=17.32,6.53Hz,1H)2.47-2.56(m,1H)2.57-2.67(m,J=7.34,7.12,7.12,3.76Hz,1H)2.83-2.94(m,4H)3.16-3.41(m,4H)3.82-3.91(m,1H)4.35-4.44(m,1H)4.64(s,1H)4.76(d,J=1.51Hz,1H)5.30(d,J=5.27Hz,1H)7.22(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例105.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(4-甲基哌嗪-1-基)-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用1-甲基哌嗪作为反应物胺,以54%得率制备标题化合物。MS:m/e698.5(MH+),1.64min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.96(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.84-1.88(m,22H)1.99-2.22(m,2H)2.46-2.58(m,1H)2.85-3.02(m,6H)3.15-3.51(m,11H)4.65(s,1H)4.76(d,J=1.00Hz,1H)5.30(d,J=3.76Hz,1H)7.21(d,J=8.03Hz,2H)7.92(d,J=8.28Hz,2H)。
实施例106.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(3,3,4,4-四氟吡咯烷-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3,3,4,4-四氟吡咯烷盐酸盐作为反应物胺,以62%得率制备标题化合物。MS:m/e741.5(MH+),1.75min(方法2).
1H NMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.17(s,3H)1.73(s,3H)0.85-1.85(m,20H)1.99-2.10(m,1H)2.15(dd,J=17.07,6.53Hz,1H)2.52(td,J=10.35,5.40Hz,1H)2.83(t,J=6.02Hz,2H)2.90(d,J=12.80Hz,1H)3.25-3.27(m,1H)3.40(td,J=5.96,2.13Hz,2H)4.05(t,J=13.93Hz,2H)4.21(t,J=13.43Hz,2H)4.65(s,1H)4.76(d,J=1.76Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H).19F NMR(376MHz,MeOD)δppm-125.84(dd,J=8.67,3.47Hz,2F)-125.07(d,J=6.94Hz,2F)。
实施例107.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-吗啉代-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用吗啉作为反应物胺,以54%得率制备标题化合物。MS:m/e685.6(MH+),1.74min(方法2).1HNMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.18(s,3H)1.73(s,3H)0.87-1.86(m,20H)1.99-2.10(m,1H)2.15(dd,J=17.57,6.53Hz,1H)2.48-2.56(m,1H)2.84-2.91(m,3H)3.23-3.26(m,1H)3.34-3.41(m,2H)3.49-3.54(m,2H)3.58-3.63(m,2H)3.68(ddd,J=10.10,4.96,4.77Hz,4H)4.65(s,1H)4.76(d,J=1.51Hz,1H)5.30(dd,J=6.27,1.76Hz,1H)7.22(d,J=8.28Hz,2H)7.92(d,J=8.28Hz,2H)。
实施例108.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-二氧化-4-硫吗啉基)-2-氧代乙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和硫吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(6.5mg,33.3%)。LCMS:m/e719.2(MH+),2.32min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.32(dd,J=6.1,1.6Hz,1H),4.76(d,J=1.5Hz,1H),4.66(s,1H),4.22-4.35(m,2H),4.18(br.s.,2H),3.92(br.s.,2H),3.35-3.41(m,1H),3.25-3.30(m,2H),3.20(d,J=9.0Hz,2H),2.86-2.94(m,1H),2.48(d,J=5.5Hz,1H),2.09-2.20(m,2H),1.90-2.04(m,3H),1.69-1.90(m,8H),1.58-1.66(m,3H),1.47-1.58(m,5H),1.25-1.41(m,3H),1.13-1.25(m,4H),1.11(s,3H),1.05(s,3H),0.92-1.02(m,6H)。
实施例109.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代-2-(吡咯烷-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和吡咯烷作为反应物胺,制备标题化合物。分离为白色固体的产物(12.9mg,53.2%)。LCMS:m/e655.3(MH+),2.13min(方法3).1HNMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.5Hz,2H),5.32(dd,J=6.1,1.6Hz,1H),4.76(d,J=1.8Hz,1H),4.66(s,1H),3.99-4.13(m,2H),3.52(dt,J=13.6,6.8Hz,4H),3.38(m,1H),2.81-2.99(m,1H),2.47(dt,J=11.0,5.5Hz,1H),2.12-2.27(m,2H),2.02-2.12(m,2H),1.84-2.02(m,J=6.7,6.7,6.5,6.3Hz,5H),1.77-1.84(m,1H),1.67-1.77(m,6H),1.44-1.67(m,8H),1.26-1.39(m,3H),1.19-1.26(m,1H),1.14-1.19(m,4H),1.08-1.14(m,3H),1.04(s,3H),0.99(s,3H),0.95(s,3H)。
实施例110.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代-2-(哌啶-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和哌啶作为反应物胺,制备标题化合物。分离为白色固体的产物(10.0mg,51.5%)。LCMS:m/e669.4(MH+),2.16min(方法3).1HNMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.5Hz,2H),5.32(dd,J=6.1,1.6Hz,1H),4.76(d,J=1.8Hz,1H),4.66(s,1H),4.13(s,2H),3.56-3.72(m,2H),3.35-3.46(m,2H),3.3(m,1H),2.86(d,J=12.5Hz,1H),2.48(dt,J=11.1,5.6Hz,1H),2.03-2.22(m,2H),1.84-2.03(m,3H),1.66-1.78(m,10H),1.48-1.65(m,10H),1.29-1.45(m,3H),1.24(d,J=10.5Hz,2H),1.14-1.20(m,4H),1.11(s,3H),1.05(s,3H),0.99(s,3H),0.98(s,3H)。
实施例111.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(乙氧基羰基)哌啶-1-基)-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和哌啶-4-甲酸乙基酯作为反应物胺,制备标题化合物。分离为白色固体的产物(10.0mg,68.5%)。LCMS:m/e741.6(MH+),2.34min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.27(m,2H),5.26-5.40(m,1H),4.76(d,J=1.8Hz,1H),4.66(s,1H),4.30-4.50(m,1H),4.11-4.24(m,4H),3.64-3.82(m,1H),3.18-3.30(m,2H),2.92-3.10(m,1H),2.87(dd,J=12.4,4.6Hz,1H),2.60-2.78(m,1H),2.43-2.55(m,1H),2.08-2.25(m,2H),1.85-2.08(m,6H),1.67-1.85(m,6H),1.46-1.67(m,8H),1.20-1.42(m,8H),1.13-1.19(m,3H),1.11(s,3H),1.04(s,3H),0.99(s,3H),0.96(s,3H)。
实施例112.制备1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)乙酰基)哌啶-4-羧酸.
按照下述程序制备标题化合物:
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(乙氧基羰基)哌啶-1-基)-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(12mg,0.016mmol)的MeOH(3.00ml)和二氧六环(3ml)溶液中加入氢氧化钠(10mg,0.250mmol),随后加入0.5ml水。于25℃将生成的混悬液搅拌4h。真空除去溶剂,经制备型HPLC分离为白色固体的产物(5mg,41.4%)。LCMS:m/e713.5(MH+),2.37min(方法3).1H NMR(400MHz,MeOD)δppm7.95(m,2H),7.27(m,2H),5.32(d,J=4.5Hz,1H),4.76(d,J=1.8Hz,1H),4.66(s,1H),4.29-4.46(m,1H),4.09-4.25(m,2H),3.64-3.85(m,1H),3.17-3.32(m,2H),3.05(m,1H),2.87(dd,J=12.8,4.8Hz,1H),2.67(tt,J=10.8,4.0Hz,1H),2.49(dt,J=10.9,5.5Hz,1H),2.07-2.29(m,2H),1.85-2.07(m,4H),1.67-1.85(m,8H),1.43-1.67(m,9H),1.36(br.s.,2H),1.32(d,J=6.5Hz,2H),1.24(d,J=14.8Hz,1H),1.13-1.20(m,4H),1.11(s,3H),1.04(s,3H),0.99(s,3H),0.98(s,3H)。
实施例113.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(N,N-二甲基氨磺酰基)哌嗪-1-基)-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和N,N-二甲基哌嗪-1-磺酰胺作为反应物胺,制备标题化合物。分离为白色固体的产物(9.0mg,61.1%)。LCMS:m/e777.6(MH+),2.39min(方法3).
1H NMR(400MHz,MeOD)δppm7.96(m,2H),7.24(m,J=8.5Hz,2H),5.28-5.38(m,1H),4.76(d,J=1.5Hz,1H),4.66(s,1H),4.19(s,2H),3.75(t,J=5.0Hz,2H),3.46-3.58(m,2H),3.33-3.38(m,3H),3.26-3.31(m,2H),2.79-2.95(m,7H),2.48(td,J=10.8,5.8Hz,1H),2.03-2.24(m,2H),1.90-2.03(m,3H),1.77-1.86(m,1H),1.67-1.77(m,6H),1.44-1.67(m,8H),1.34(d,J=12.0Hz,3H),1.20-1.28(m,1H),1.13-1.20(m,4H),1.11(s,3H),1.05(s,3H),0.99(s,3H),0.98(s,3H)
实施例114.制备(R)-1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)乙酰基)吡咯烷-2-羧酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和(R)-吡咯烷-2-甲酸叔-丁基酯作为反应物胺,制备标题化合物。分离为白色固体的产物(9.0mg,69.6%)。LCMS:m/e699.3(MH+),2.34min(方法3).
1H NMR(400MHz,MeOD)δppm7.88-8.01(m,2H),7.17-7.31(m,2H),5.32(d,J=4.8Hz,1H),4.75(d,J=1.8Hz,1H),4.61-4.69(m,1H),4.56(m,1H),4.02-4.24(m,2H),3.64-3.73(m,1H),3.51-3.64(m,1H),3.34-3.43(m,1H),2.75-2.97(m,1H),2.43-2.56(m,1H),2.24-2.43(m,1H),2.01-2.22(m,5H),1.86-2.01(m,3H),1.67-1.81(m,6H),1.44-1.67(m,8H),1.27-1.44(m,4H),1.13-1.27(m,5H),1.10(s,3H),1.04(s,3H),0.99(s,3H),0.96(s,3H)。
实施例115.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4,4-二氟哌啶-1-基)-2-氧代乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端(end cap)的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和4,4-二氟哌啶作为反应物胺,制备标题化合物。分离为白色固体的产物(28mg,86.0%)。LCMS:m/e705.5(MH+),2.36min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.32(dd,J=6.3,1.8Hz,1H),4.76(d,J=1.5Hz,1H),4.66(s,1H),4.22(s,2H),3.73-3.88(m,2H),3.50-3.67(m,2H),3.32-3.41(m,1H),2.88(d,J=12.5Hz,1H),2.47(td,J=10.9,5.5Hz,1H),2.02-2.19(m,5H),1.93-2.00(m,2H),1.68-1.85(m,7H),1.44-1.68(m,9H),1.20-1.42(m,5H),1.13-1.19(m,4H),1.09(s,3H),1.05(s,3H),1.00(s,3H),0.95(s,3H).19F NMR(376MHz,MeOD)δppm-99.61(p,J=13.5Hz,2F)。
实施例116.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1-((1,1-二氧化-4-硫吗啉基)羰基)环丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用1-氨基环丙烷羧酸甲基酯盐酸盐和硫吗啉-1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(3mg,37.5%)。LCMS:m/e745.6(MH+),2.76min(方法3).
1H NMR(400MHz,MeOD)δppm6.38(d,J=8.3Hz,2H),5.68(d,J=8.5Hz,2H),3.76(dd,J=6.3,1.8Hz,1H),3.20(d,J=2.0Hz,1H),3.08(s,1H),2.63(br.s.,4H),1.59-1.69(m,4H),1.45-1.58(m,1H),1.11-1.27(m,1H),0.87-1.07(m,1H),0.61(d,J=11.0Hz,1H),0.29-0.52(m,2H),0.08-0.25(m,9H),0.11-0.08(m,6H),0.28-0.11(m,6H),0.30(br.s.,2H),0.45-0.33(m,6H),0.48(s,3H),0.50(s,3H),0.57(s,3H),0.59(s,3H)。
实施例117.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4,4-二氟哌啶-1-基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和4,4-二氟哌啶作为反应物胺,制备标题化合物。分离为白色固体的产物(25mg,74.0%)。LCMS:m/e719.5(MH+),2.63min(方法3).
1H NMR(400MHz,MeOD)δppm7.95(m,J=8.5Hz,2H),7.23(m,2H),5.26-5.38(m,1H),4.78(d,J=1.8Hz,1H),4.67(s,1H),3.70-3.85(m,2H),3.59-3.70(m,2H),3.35-3.45(m,2H),3.30(d,J=13.3Hz,1H),2.84-3.01(m,3H),2.55(d,J=5.8Hz,1H),1.95-2.20(m,6H),1.68-1.92(m,10H),1.45-1.68(m,8H),1.38(d,J=3.5Hz,1H),1.32(br.s.,2H),1.13-1.27(m,5H),1.10(s,3H),1.06(s,3H),0.99(s,3H),0.97(s,3H).19F NMR(376MHz,MeOD)δppm-99.53(p,J=13.4Hz,2F)。
实施例118.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)-3-氧代丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和硫吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(25mg,72.6%)。LCMS:m/e733.5(MH+),2.55min(方法3).
1H NMR(400MHz,MeOD)δppm7.97(m,2H),7.25(m,2H),5.26-5.39(m,1H),4.78(d,J=1.8Hz,1H),4.67(s,1H),4.05-4.19(m,2H),3.92-4.05(m,2H),3.39-3.48(m,2H),3.28-3.32(m,1H),3.20-3.27(m,2H),3.12-3.20(m,2H),2.99(t,J=5.8Hz,2H),2.93(d,J=12.8Hz,1H),2.54(dt,J=10.6,5.4Hz,1H),2.00-2.24(m,2H),1.68-1.93(m,10H),1.44-1.68(m,8H),1.24-1.44(m,4H),1.13-1.24(m,4H),1.11(s,3H),1.04(s,3H),0.99(s,3H),0.97(s,3H)。
实施例119.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪作为反应物胺,制备标题化合物。分离为白色固体的产物(20mg,35.7%)。LCMS:m/e790.5(MH+),2.48min(方法3).1H NMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.23(m,2H),5.32(d,J=6.0Hz,1H),4.94-5.19(m,2H),4.78(s,1H),4.67(s,1H),4.32-4.44(m,1H),4.28(br.s.,1H),3.96-4.19(m,2H),3.40-3.59(m,2H),3.26-3.33(m,1H),2.99-3.18(m,2H),2.92(d,J=12.8Hz,1H),2.54(br.s.,1H),2.34(br.s.,1H),2.14(br.s.,3H),1.52(br.s.,12H),1.38(br.s.,2H),1.31(br.s.,3H),1.14-1.18(m,2H),0.94-1.12(m,17H)。
实施例120.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-1,3-噻唑烷-3-基)-3-氧代丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和砜作为反应物胺,制备标题化合物。分离为白色固体的产物(20mg,35.7%)。LCMS:m/e719.5(MH+),2.56min(方法3).1H NMR(400MHz,MeOD)δppm7.94(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),5.24-5.43(m,1H),4.8(s,1H),4.61-4.72(m,1H),4.02-4.20(m,2H),3.46-3.63(m,1H),3.43(t,J=7.3Hz,2H),3.35-3.41(m,2H),3.22-3.31(m,2H),2.95(br.s.,1H),2.88(s,1H),2.73(m,1H),2.44-2.64(m,1H),2.05-2.22(m,2H),1.67-1.90(m,8H),1.44-1.67(m,8H),1.39(br.s.,5H),1.16-1.27(m,5H),1.11(s,3H),1.07(s,3H),0.99(s,3H),0.98(s,3H)。
实施例121.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-((1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷-3-基)-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和(1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷作为反应物胺,制备标题化合物。分离为白色固体的产物(7mg,71.7%)。LCMS:m/e724.5(MH+),2.41min(方法3).
1H NMR(400MHz,MeOD)δppm7.92(m,2H),7.23(m,2H),5.25-5.41(m,1H),4.79(d,J=1.8Hz,1H),4.67(s,1H),4.47-4.61(m,1H),4.03-4.09(m,2H),4.00(d,J=1.8Hz,1H),3.68(d,J=14.1Hz,1H),3.39-3.48(m,2H),3.16-3.26(m,1H),2.98-3.13(m,1H),2.78-2.98(m,4H),2.50-2.61(m,1H),2.25-2.47(m,2H),2.13-2.23(m,1H),1.99-2.13(m,2H),1.72-1.91(m,10H),1.50-1.68(m,8H),1.32-1.38(m,3H),1.28-1.32(m,2H),1.24-1.28(m,2H),1.14-1.24(m,4H),1.11(s,3H),1.05(s,3H),0.99(s,3H),0.98(s,3H)。
实施例122.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-硫代吗啉代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和硫吗啉作为反应物胺,制备标题化合物。分离为白色固体的产物(6mg,61.6%)。LCMS:m/e701.5(MH+),2.67min(方法3).1HNMR(400MHz,MeOD)δppm7.81-8.00(m,2H),7.18-7.31(m,2H),5.24-5.47(m,1H),4.79(d,J=1.5Hz,1H),4.67(s,1H),3.85-3.99(m,2H),3.80(ddd,J=4.8,2.9,2.6Hz,2H),3.36-3.49(m,2H),3.25-3.32(m,1H),2.83-2.92(m,3H),2.61-2.79(m,4H),2.47-2.61(m,1H),1.99-2.23(m,2H),1.67-1.92(m,10H),1.47-1.67(m,8H),1.24-1.45(m,4H),1.20(s,4H),1.11(s,3H),1.05(s,3H),0.99(s,3H),0.96(s,3H)。
实施例123.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮作为反应物胺,制备标题化合物。分离为白色固体的产物(7.6mg,77%)。LCMS:m/e766.6(MH+),2.63min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.33(d,J=4.5Hz,1H),4.79(s,1H),4.67(s,1H),4.38(d,J=13.6Hz,1H),3.90(d,J=14.3Hz,1H),3.45(t,J=6.9Hz,2H),3.34-3.42(m,2H),3.33(m,1H),3.28(dd,J=5.4,2.1Hz,1H),3.02-3.15(m,1H),2.91-2.96(m,3H),2.80-2.88(m,3H),2.55(br.s.,1H),2.01-2.24(m,4H),1.67-1.92(m,12H),1.46-1.67(m,10H),1.39(br.s.,1H),1.23-1.36(m,3H),1.14-1.23(m,4H),1.11(s,3H),1.02-1.09(s,3H),1.00(s,3H),0.98(s,3H)。
实施例124.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端(end cap)的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和1-(2-(甲基磺酰基)乙基)哌嗪作为反应物胺,制备标题化合物。分离为白色固体的产物(7.0mg,71.2%)。LCMS:m/e790.6(MH+),2.51min(方法3).
1HNMR(400MHz,MeOD)δppm7.94(m,2H),7.26(m,2H),5.24-5.42(m,1H),4.79(d,J=1.8Hz,1H),4.67(s,1H),4.00(s,2H),3.83(d,J=5.3Hz,2H),3.63-3.75(m,2H),3.53-3.63(m,2H),3.38-3.47(m,2H),3.35-3.38(m,2H),3.28(dd,J=3.9,2.1Hz,3H),3.12(s,3H),2.88-3.00(m,3H),2.54(br.s.,1H),2.12-2.27(m,1H),2.09(d,J=2.8Hz,1H),1.67-1.91(m,10H),1.47-1.67(m,8H),1.39(br.s.,1H),1.28-1.36(m,2H),1.25(br.s.,1H),1.14-1.21(m,4H),1.11(s,3H),1.05(s,3H),1.01(s,3H),0.96(s,3H)。
实施例125.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(甲基(2-(甲基磺酰基)乙基)氨基)-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端(end cap)的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和N-甲基-2-(甲基磺酰基)乙胺作为反应物胺,制备标题化合物。分离为白色固体的产物(5.0mg,50.0%)。LCMS:m/e735.5(MH+),2.24min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.3Hz,2H),5.33(dd,J=6.3,1.8Hz,1H),4.79(s,1H),4.67(d,J=1.5Hz,1H),3.85-4.06(m,2H),3.35-3.48(m,4H),3.25-3.32(m,1H),3.13(s,3H),3.07(s,3H),2.82-2.96(m,3H),2.55(br.s.,1H),2.13-2.27(m,1H),2.11(d,J=12.3Hz,1H),1.66-1.91(m,8H),1.57-1.66(m,2H),1.52(d,J=13.8Hz,3H),1.29-1.47(m,4H),1.20(s,3H),1.11(s,3H),1.06(s,3H),0.99(s,3H),0.95(s,3H)。
实施例126.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和1,4-二氧杂-8-氮杂螺[4.5]癸烷作为反应物胺,制备标题化合物。分离为白色固体的产物(3mg,30%)。LCMS:m/e741.6(MH+),2.65min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.33(dd,J=6.3,1.8Hz,1H),4.79(d,J=1.5Hz,1H),4.67(s,1H),3.89-4.03(m,4H),3.65-3.81(m,2H),3.61(dd,J=7.3,4.5Hz,2H),3.36-3.43(m,2H),3.22-3.31(m,1H),2.85-3.00(m,3H),2.54(br.s.,1H),2.18(dd,J=16.9,6.4Hz,1H),2.08(br.s.,1H),1.67-1.91(m,11H),1.48-1.67(m,8H),1.24-1.48(m,6H),1.13-1.24(m,5H),1.11(s,3H),1.02-1.09(m,3H),1.00(s,3H),0.98(s,3H)。
实施例127.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(甲基氨基)-3-氧代丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和甲基胺作为反应物胺,制备标题化合物。分离为白色固体的产物(5.0mg,50.0%)。LCMS:m/e629.6(MH+),2.58min(方法3)。
实施例128.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-氧代-3-(4-氧代哌啶-1-基)丙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和哌啶-4-酮作为反应物胺,制备标题化合物。分离为白色固体的产物(2mg,21.6%)。LCMS:m/e697.6(MH+),2.61min(方法3).1HNMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.3Hz,2H),5.25-5.39(m,1H),4.79(s,1H),4.67(s,1H),3.50-3.63(m,2H),3.35-3.47(m,6H),3.28(dt,J=3.3,1.6Hz,2H),3.13-3.25(m,1H),2.81-2.97(m,3H),2.44-2.64(m,1H),2.18(dd,J=17.2,6.4Hz,2H),1.67-1.91(m,8H),1.60(br.s.,3H),1.46-1.57(m,4H),1.24-1.46(m,6H),1.15-1.24(m,5H),1.11(s,3H),1.01-1.09(m,3H),1.00(s,3H),0.98(s,3H)。
实施例129.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,3-二羟基-2-甲基丙-2-基氨基)-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用3-氨基丙酸酯盐酸盐和N,3-二甲基氧杂环丁烷-3-胺作为反应物胺,制备标题化合物。分离为白色固体的产物(1mg,11.6%)。LCMS:m/e703.7(MH+),2.47min(方法3)。
实施例130.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代-2-(哌啶-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备具有酰胺封端的C28胺描述的通用程序,使用2-氨基乙酸甲基酯盐酸盐和哌啶作为反应物胺,制备标题化合物。分离为白色固体的产物(10.0mg,51.5%)。LCMS:m/e669.4(MH+),2.16min(方法3).1HNMR(400MHz,MeOD)δppm7.94(m,J=8.5Hz,2H),7.24(m,J=8.5Hz,2H),5.32(dd,J=6.1,1.6Hz,1H),4.76(d,J=1.8Hz,1H),4.66(s,1H),4.13(s,2H),3.56-3.72(m,2H),3.35-3.46(m,2H),3.3(m,1H),2.86(d,J=12.5Hz,1H),2.48(dt,J=11.1,5.6Hz,1H),2.03-2.22(m,2H),1.84-2.03(m,3H),1.66-1.78(m,10H),1.48-1.65(m,10H),1.29-1.45(m,3H),1.24(d,J=10.5Hz,2H),1.14-1.20(m,4H),1.11(s,3H),1.05(s,3H),0.99(s,3H),0.98(s,3H)。
实施例131.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基-1-(3,3-二氟吡咯烷-1-基)-1-氧代丙-2-基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1:制备C28胺
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(100mg,0.167mmol))的DCE溶液中加入(S)-2-氨基琥珀酸1-叔-丁基酯4-甲基酯盐酸盐(120mg,0.501mmol)和乙酸(10.03mg,0.167mmol)。于室温下搅拌该混合物10min,然后加入三乙酰氧基硼氢化钠(106mg,0.501mmol)并于室温下搅拌48h。该混合物用7ml饱和碳酸钠水溶液稀释并用DCM(3x7ml)提取。合并的有机层经硫酸钠干燥。经过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。MS:m/e786.6(MH+),3.03min(方法3).1H NMR(400MHz,氯仿-d)δppm0.92(s,3H)0.92(s,3H)0.98(s,3H)0.99(s,3H)1.09(s,3H)1.48(s,9H)1.58(s,9H)1.68(s,3H)0.84-1.78(m,20H)1.86-2.01(m,2H)2.09(dd,J=17.19,6.40Hz,1H)2.33(d,J=11.29Hz,1H)2.40(td,J=11.04,5.52Hz,1H)2.53-2.63(m,2H)2.67-2.75(m,1H)3.53(dd,J=7.28,6.27Hz,1H)3.68(s,3H)4.57(s,1H)4.68(d,J=2.01Hz,1H)5.27(dd,J=6.02,1.51Hz,1H)7.16(d,J=8.28Hz,2H)7.88(d,J=8.28Hz,2H)。。
步骤2:甲基酯的水解
向得自步骤1的粗物质(0.112g,0.142mmol)的二氧六环(1.5ml)溶液中加入氢氧化锂(6.82mg,0.285mmol)。将该反应物加热至最高63℃经4h。蒸发溶剂,粗产物经制备型HPLC纯化(YMC Combiprep ODS30x50mm S5,MeOH/H2O/TFA).MS:m/e772.6(MH+),3.02min(方法3)。合并含有要求的产物的部分并减压浓缩。残留物无须进一步纯化而用于下一步骤。
步骤3:制备酰胺封端化合物
向得自步骤2的物质(30mg,0.039mmol)、3,3-二氟吡咯烷盐酸盐(6.69mg,0.047mmol)的DCM(1ml)的混合物中加入DIPEA(0.034ml,0.194mmol),随后加入HATU(22.16mg,0.058mmol)。将生成的溶液于室温下搅拌1h。真空浓缩反应混合物,得到粗产物,其无须进一步纯化而用于下一步骤。MS:m/e861.6(MH+),2.07min(方法2).
步骤4:制备二酸.
向得自步骤3的粗物质的DCM(2ml)混合物中加入TFA(0.5ml,6.49mmol)。于室温下搅拌该混合物2h,然后真空浓缩。粗产物经制备型HPLC纯化(YMCCombiprep ODS30x50mm S5,MeOH/H2O/TFA),得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基-1-(3,3-二氟吡咯烷-1-基)-1-氧代丙-2-基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(15mg,51%).MS:m/e749.6(MH+),1.74min(方法2).
1HNMR(400MHz,MeOD)δppm0.95(s,3H)0.97(s,3H)1.04(s,3H)1.08(s,3H)1.19(s,3H)1.72(s,3H)0.86-2.02(m,24H)2.15(dd,J=16.56,6.27Hz,1H)2.38-2.61(m,3H)2.71(t,J=11.54Hz,1H)2.78-2.89(m,1H)2.93-3.04(m,1H)3.75-4.03(m,3H)4.61-4.65(m,1H)4.73(d,J=1.76Hz,1H)5.30(dd,J=6.40,1.88Hz,1H)7.22(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H).19F NMR(376MHz,MeOD)δppm-105.07--101.67(m,2F)。
实施例132.制备4-硫吗啉丁酸,
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((1S)-1-(羧基甲基)-2-(1,1-二氧化-4-硫吗啉基)-2-氧代乙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基-1-(3,3-二氟吡咯烷-1-基)-1-氧代丙-2-基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(实施例131)描述的程序,在步骤1和3中分别使用(S)-2-氨基琥珀酸1-叔-丁基酯4-甲基酯盐酸盐和硫吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(21mg,63.8%)。LCMS:m/e777.4(MH+),2.60min(方法3).1HNMR(400MHz,MeOD)δppm7.78-8.01(m,2H),7.13-7.31(m,2H),5.32(d,J=4.8Hz,1H),4.77(d,J=1.0Hz,1H),4.66(s,1H),4.18(d,J=4.3Hz,2H),3.94-4.15(m,2H),3.37-3.49(m,1H),3.19-3.28(m,4H),2.91-3.15(m,3H),2.71-2.86(m,1H),2.48(d,J=5.8Hz,1H),2.16(dd,J=17.1,6.3Hz,1H),1.95-2.09(m,2H),1.90(d,J=14.6Hz,1H),1.68-1.87(m,8H),1.60(br.s.,2H),1.47-1.60(m,6H),1.36-1.44(m,1H),1.25-1.36(m,3H),1.16-1.25(m,4H),1.10(s,3H),1.05(s,3H),0.99(s,3H),0.96(s,3H)。
制备C28反式酰胺的通用程序:实施例133-147。
步骤1:制备C28肟
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(270mg,0.451mmol)的乙醇(20ml)混悬液中加入羟胺盐酸盐(433mg,6.23mmol)和碳酸钾(862mg,6.23mmol)。于~50℃搅拌该混悬液2h。该混合物用7ml饱和NaHCO3溶液稀释并用二氟甲烷(3x7ml)提取。合并的有机层经硫酸钠干燥。经过滤除去干燥剂,并减压下浓缩滤液。粗产物(定量的)无须进一步纯化而用于下一步骤。1H NMR(400MHz,氯仿-d)7.90(2H,d,J=8.3Hz),7.59(1H,s),7.19(2H,d,J=8.3Hz),6.96(1H,s),5.29(1H,dd,J=6.2,1.6Hz),4.75(1H,d,J=1.8Hz),4.64(1H,d,J=2.0Hz),2.56(1H,td,J=11.1,5.4Hz),2.12(1H,dd,J=16.9,6.3Hz),1.96-2.02(2H,m),1.92-1.96(1H,m),1.81-1.92(2H,m),1.76-1.81(2H,m),1.73(4H,s),1.63-1.70(2H,m),1.61(9H,s),1.56(2H,br.s.),1.48(2H,br.s.),1.31-1.42(2H,m),1.27(3H,s),1.08-1.20(2H,m),1.07(3H,s),1.04(3H,s),1.00(3H,s),0.94(6H,s)。
步骤2:还原C28肟
向得自步骤1的粗物质(1.205g,1.963mmol)的EtOH(40ml)澄清溶液中加入过量的乙酸铵(1.059g,13.74mmol)和氰基硼氢化钠(863mg,13.74mmol)。将该混合物在冰浴中搅拌直至其冷却。向该混悬液中加入氯化钛(III)(20%溶液,10ml,1.963mmol)。使生成的混合物覆盖在氮气下,并室温下搅拌1小时。用氢氧化钠(10N)溶液(3ml在25ml水中),同时使用30ml二氯甲烷处理所述深蓝绿色的溶液。在户外将该混合物剧烈搅拌直至水相变成淡蓝色。通过短纤维素纸垫过滤除去悬浮的钛残留物。分离澄清的滤液,用二氯甲烷(2X25ml)提取含水相。合并有机层,在高真空下蒸发至干,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(1.3g,100%).1H NMR(400MHz,氯仿-d)δ0.94(s,6H),1.00(s,3H),1.03(s,3H),1.05-1.09(m,1H),1.10(s,3H),1.19-1.35(m,3H),1.35-1.57(m,13H),1.61(s,9H),1.65-1.69(m,1H),1.72(s,3H),1.75-2.02(m,3H),2.12(dd,J=17.00,6.17Hz,1H),2.36(d,J=13.09Hz,1H),2.44(td,J=10.89,5.41Hz,1H),2.89(d,J=13.09Hz,1H),3.73(s,1H),4.61(s,1H),4.72(s,1H),5.29(d,J=4.53Hz,1H),7.19(d,J=8.06Hz,2H),7.90(d,J=8.31Hz,2H)。
步骤3:酰化
向得自步骤2的物质(4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯)和相应的羧酸(2eq.)的DCM(5-8ml)的0℃溶液中加入HATU(2-3eq.),随后加入DIPEA(4eq.)。于室温下搅拌该混合物2-18h。真空蒸发溶剂,生成的粗产物经Biotage快速层析纯化或无需进一步纯化而直接用于下一步骤。
步骤4:制备苯甲酸
(a)酸水解-向得自步骤3的物质的DCM(4-5ml)溶液中加入TFA(0.4-0.5ml)。将混合物于室温下搅拌2-6h。真空蒸发溶剂。生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
(b)碱水解-向得自步骤3的物质的二氧六环(2ml)和甲醇(2ml)溶液中加入NaOH(75mg,1.875mmol)和H2O(0.5ml)。将生成的溶液于70℃搅拌5-10h。真空蒸发溶剂,生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
实施例133.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-氧代吡咯烷-1-基)乙酰氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用2-(2-氧代吡咯烷-1-基)乙酸作为反应物酸并进行酸水解,以55%得率制备标题化合物。MS:m/e725.4(MH+),1.78min(方法2).
1H NMR(500MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.18(s,3H)1.70(s,3H)0.89-2.18(m,24H)2.38-2.45(m,2H)2.52(td,J=10.83,5.80Hz,1H)2.99-3.06(m,1H)3.45-3.51(m,2H)3.53-3.61(m,1H)3.97(d,J=2.14Hz,2H)4.59(s,1H)4.72(s,1H)5.27-5.32(m,1H)7.22(d,J=8.24Hz,2H)7.91(d,J=8.55Hz,2H)。
实施例134.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2,6-二氧代哌啶-4-甲酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用2,6-二氧代哌啶-4-羧酸作为反应物酸并进行酸水解,以60%得率制备标题化合物。MS:m/e683.2(MH+),1.70min(方法2).
1H NMR(500MHz,MeOD)δppm0.97(s,3H)0.99(s,3H)1.06(s,3H)1.07(s,3H)1.19(s,3H)1.73(s,3H)0.90-1.79(m,18)1.81-1.96(m,2H)2.03-2.12(m,1H)2.17(dd,J=16.79,6.41Hz,1H)2.54(td,J=11.14,5.49Hz,1H)2.73(d,J=6.41Hz,4H)3.05(dd,J=13.58,5.95Hz,1H)3.07-3.14(m,1H)3.55(dd,J=13.28,5.95Hz,1H)4.62(s,1H)4.74(s,1H)5.32(d,J=5.80Hz,1H)7.24(d,J=7.32Hz,2H)7.94(d,J=7.32Hz,2H)。
实施例135.制备4-(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((R)-2-氨基-4-(甲基磺酰基)丁酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用(R)-2-(叔-丁氧羰基氨基)-4-(甲基磺酰基)丁酸作为反应物酸并进行酸水解,以77%得率制备标题化合物。MS:m/e707.2(MH+),1.54min(方法2).1H NMR(400MHz,MeOD)δppm0.96(s,3H)0.98(s,3H)1.05(s,3H)1.07(s,3H)1.19(s,3H)1.73(s,3H)0.88-1.80(m,18H)1.81-1.96(m,2H)2.04-2.12(m,1H)2.16(dd,J=17.07,6.27Hz,1H)2.33-2.42(m,2H)2.54(td,J=11.04,5.52Hz,1H)3.04(s,3H)3.08(d,J=13.80Hz,1H)3.15-3.24(m,1H)3.68(d,J=13.30Hz,1H)3.99(s,1H)4.08(t,J=6.27Hz,1H)4.62(dd,J=2.13,1.38Hz,1H)4.75(d,J=1.76Hz,1H)5.31(dd,J=6.15,1.63Hz,1H)7.23(d,J=8.28Hz,2H)7.93(d,J=8.53Hz,2H)。
实施例136.制备4-(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-(((S)-吡咯烷-2-甲酰胺基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用(S)-1-(叔-丁氧羰基)吡咯烷-2-羧酸作为反应物酸并进行酸水解,以31%得率制备标题化合物。MS:m/e641.7(MH+),1.77min(方法2).1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.05(s,3H)1.17(s,3H)1.71(s,3H)0.86-2.10(m,24H)2.14(dd,J=17.19,6.65Hz,1H)2.39-2.47(m,1H)2.52(td,J=11.17,5.52Hz,1H)3.01(dd,J=13.55,5.02Hz,1H)3.33-3.36(m,1H)3.38-3.47(m,1H)3.69(dd,J=13.93,5.90Hz,1H)4.23(dd,J=8.03,7.03Hz,1H)4.61(s,1H)4.73(d,J=1.76Hz,1H)5.30(dd,J=6.02,1.51Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)8.13(t,J=6.02Hz,1H)。
实施例137.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-(((R)-吡咯烷-2-甲酰胺基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用(R)-1-(叔-丁氧羰基)吡咯烷-2-羧酸作为反应物酸并进行酸水解,以30%得率制备标题化合物。MS:m/e641.7(MH+),1.78min(方法2).1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.05(s,3H)1.17(s,3H)1.71(s,3H)0.88-2.10(m,24H)2.15(dd,1H)2.38-2.48(m,1H)2.53(td,J=11.23,5.14Hz,1H)3.18(dd,J=12.92,6.65Hz,1H)3.31-3.33(m,1H)3.38-3.49(m,1H)3.53(dd,J=12.92,4.39Hz,1H)4.23(dd,J=7.78,6.78Hz,1H)4.60(s,1H)4.73(d,J=2.01Hz,1H)5.30(dd,J=6.27,1.51Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H)8.13(t,J=6.53Hz,1H)。
实施例138.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((S)-1-乙酰基吡咯烷-2-甲酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用(S)-1-乙酰基吡咯烷-2-羧酸作为反应物酸并进行酸水解,以9%得率制备标题化合物。MS:m/e683.6(MH+),2.01min(方法2).
1HNMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.18(s,3H)1.70(s,3H)2.08(s,3H)0.84-2.23(m,26H)2.47-2.56(m,1H)2.99(dd,J=12.67,4.89Hz,1H)3.52-3.70(m,3H)4.39(dd,J=8.66,3.89Hz,1H)4.59(s,1H)4.72(d,J=2.26Hz,1H)5.29(dd,J=5.90,1.63Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例139.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(甲基氨基)乙酰氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用2-(叔-丁氧羰基(甲基)氨基)乙酸作为反应物羧酸并进行酸水解,制备标题化合物。分离为白色固体的产物(14mg,76%)。LCMS:m/e615.5(MH+),2.68min(方法3).
1H NMR(500MHz,MeOD)δppm7.94(2H,d,J=8.5Hz),7.24(2H,d,J=8.2Hz),5.23-5.37(1H,m),4.75(1H,br.s.),4.62(1H,d,J=1.2Hz),3.81(2H,s),3.61(1H,d,J=13.4Hz),3.11(1H,d,J=13.4Hz),2.74(3H,s),2.45-2.64(1H,m),2.17(1H,dd,J=17.2,6.3Hz),2.02-2.12(1H,m),1.81-1.99(2H,m),1.65-1.81(8H,m),1.58(2H,dd,J=9.3,2.6Hz),1.45-1.54(4H,m),1.34-1.45(2H,m),1.30(3H,s),1.18(3H,s),1.09-1.16(2H,m),1.07(3H,s),1.05(3H,s),1.00(3H,s),0.97(3H,s)。
实施例140.制备4-(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((S)-2-氨基-3-(1H-咪唑-4-基)丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用(S)-2-(叔-丁氧羰基氨基)-3-(1H-咪唑-4-基)丙酸作为反应物羧酸并进行酸水解,制备标题化合物。分离为白色固体的产物(11mg,64.2%)。LCMS:m/e681.5(MH+),2.59min(方法3).
1H NMR(400MHz,MeOD)δppm8.88(d,J=1.3Hz,1H),7.90(d,J=8.6Hz,2H),7.43(s,1H),7.20(d,J=8.3Hz,2H),5.19-5.36(m,1H),4.70(s,2H),4.58(s,1H),4.25(t,J=7.1Hz,1H),3.61(d,J=13.3Hz,1H),3.33-3.42(m,1H),3.26-3.30(m,1H),2.97(d,J=13.8Hz,1H),2.48(d,J=5.3Hz,1H),2.13(dd,J=17.1,6.0Hz,1H),1.89-2.08(m,1H),1.72-1.87(m,2H),1.63-1.72(m,5H),1.52-1.63(m,4H),1.50(d,J=7.3Hz,1H),1.46(d,J=13.6Hz,4H),1.37(br.s.,2H),1.31(d,J=3.3Hz,1H),1.20-1.29(m,3H),1.16(s,3H),0.96-1.07(m,6H),0.95(s,3H),0.92(s,3H)。
实施例141.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(哌嗪-1-基)丙酰胺基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28反式酰胺制备和酸水解描述的通用程序,使用3-(4-(叔-丁氧羰基)哌嗪-1-基)丙酸作为反应物羧酸,制备标题化合物。分离为白色固体的产物(17mg,77.0%)。LCMS:m/e684.6(MH+),2.66min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.22-5.33(m,1H),4.70(s,1H),4.58(s,1H),3.49-3.62(m,1H),3.38-3.49(m,4H),3.30-3.36(m,4H),3.24-3.27(m,2H),3.02(d,J=13.6Hz,1H),2.68(t,J=6.7Hz,2H),2.50(td,J=11.1,5.8Hz,1H),2.13(dd,J=17.1,6.5Hz,1H),2.05(d,J=10.3Hz,1H),1.86-1.96(m,1H),1.76-1.86(m,1H),1.60-1.76(m,7H),1.55(br.s.,2H),1.45-1.52(m,4H),1.30-1.42(m,2H),1.18-1.30(m,4H),1.14(s,3H),1.06-1.12(m,2H),1.03(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例142.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(二甲基氨基)丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用3-(二甲基氨基)丙酸作为反应物羧酸并进行酸水解,制备标题化合物。分离为白色固体的产物(12mg,24.8%)。LCMS:m/e643.5(MH+),2.34min(方法3).1H NMR(400MHz,MeOD)δppm7.80-7.99(m,2H),7.20(d,J=8.3Hz,2H),5.22-5.35(m,1H),4.70(s,1H),4.58(s,1H),3.55(d,J=13.6Hz,1H),3.37(t,J=6.5Hz,2H),2.95-3.11(m,1H),2.86(s,6H),2.68-2.81(m,2H),2.50(td,J=11.1,5.3Hz,1H),1.99-2.21(m,2H),1.76-1.99(m,2H),1.60-1.76(m,7H),1.54(d,J=6.8Hz,2H),1.42-1.52(m,4H),1.31-1.42(m,2H),1.20-1.31(m,3H),1.11-1.20(m,4H),1.06-1.11(m,2H),1.03(s,3H),1.01(s,3H),0.95(s,3H),0.93(s,3H)。
实施例143.制备3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基甲酰基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用3-(甲氧基羰基)苯甲酸作为反应物羧酸并进行碱水解,制备标题化合物。分离为白色固体的产物(22mg,46.0%)。LCMS:m/e692.4(MH+),2.68min(方法3).1H NMR(400MHz,氯仿-d)δppm8.43(s,1H),8.27(d,J=7.6Hz,1H),8.12(d,J=7.8Hz,1H),8.02(d,J=8.3Hz,2H),7.62(t,J=7.8Hz,1H),7.24-7.33(m,2H),6.06-6.25(m,1H),5.26-5.41(m,1H),4.77(d,J=1.5Hz,1H),4.65(s,1H),4.00(s,3H),3.73-3.88(m,1H),3.28-3.41(m,1H),2.55-2.65(m,1H),2.04-2.25(m,2H),1.83-2.03(m,2H),1.64-1.82(m,6H),1.61(s,2H),1.51(br.s.,4H),1.32-1.48(m,3H),1.23-1.32(m,2H),1.19(s,3H),1.12(br.s.,1H),1.06(s,3H),1.02(s,3H),0.97(s,3H),0.96(s,3H)。
实施例144.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((4-氨磺酰基苯甲酰胺基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对反式酰胺制备描述的通用程序,使用4-氨磺酰基苯甲酸作为反应物羧酸并进行碱水解,制备标题化合物。分离为白色固体的产物(35mg,53.6%)。LCMS:未比对所要求的产物(方法3)。1H NMR(400MHz,MeOD)δppm7.82-7.97(m,6H),7.09-7.28(m,2H),5.29(d,J=4.5Hz,1H),4.73(d,J=1.8Hz,1H),4.60(s,1H),3.70-3.81(m,1H),3.12-3.26(m,1H),2.58(td,J=11.1,5.7Hz,1H),2.14(dd,J=17.2,6.4Hz,2H),1.85-2.00(m,1H),1.61-1.85(m,8H),1.34-1.59(m,8H),1.23-1.33(m,3H),1.21(s,3H),1.07-1.19(m,3H),1.05(s,3H),1.03(s,3H),0.95(s,3H),0.93(s,3H)。
实施例145.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((1,1-二氧化-4-硫吗啉基)乙酰基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用4-硫吗啉乙酸1,1-二氧化物作为反应物羧酸并进行碱水解,制备标题化合物。分离为白色固体的产物(14mg,35.8%)。LCMS:m/e719.3(MH+),2.40min(方法3).1H NMR(500MHz,MeOD)δppm7.86-8.01(m,2H),7.24(d,J=8.2Hz,2H),5.32(d,J=6.4Hz,1H),4.75(s,1H),4.63(s,1H),3.58-3.71(m,3H),3.42(d,J=4.3Hz,4H),3.33-3.38(m,4H),3.04-3.15(m,1H),2.55(td,J=11.1,5.6Hz,1H),2.13-2.23(m,2H),1.92-2.04(m,1H),1.81-1.92(m,1H),1.64-1.81(m,8H),1.46-1.64(m,6H),1.35-1.46(m,2H),1.24-1.35(m,2H),1.20(s,3H),1.14-1.19(m,1H),1.11(d,J=10.4Hz,2H),1.07(s,3H),1.05(s,3H),0.99(s,3H),0.97(s,3H)。
实施例146.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙酰基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对反式酰胺制备描述的通用程序,使用3-(1,1-二氧代-λ16,4-噻嗪烷-4-基(thiazinan-4-y1)丙酸作为反应物羧酸并进行碱水解,制备标题化合物。分离为白色固体的产物(14mg,35.8%)。LCMS:m/e733.3(MH+),2.33min(方法3).1H NMR(500MHz,MeOD)δppm7.94(d,J=8.2Hz,2H),7.24(d,J=8.2Hz,2H),5.32(d,J=4.9Hz,1H),4.74(d,J=1.5Hz,1H),4.62(s,1H),3.77(br.s.,1H),3.76(d,J=6.1Hz,3H),3.58(d,J=13.4Hz,1H),3.50-3.54(m,4H),3.48(t,J=6.7Hz,2H),3.07(d,J=13.7Hz,1H),2.77(t,J=6.7Hz,2H),2.53(td,J=11.2,5.6Hz,1H),2.17(dd,J=17.2,6.3Hz,1H),2.03-2.13(m,1H),1.93(td,J=13.6,4.0Hz,1H),1.85(td,J=12.2,3.4Hz,1H),1.64-1.81(m,8H),1.46-1.64(m,6H),1.34-1.46(m,2H),1.22-1.34(m,3H),1.19(s,3H),1.10-1.12(m,2H),1.07(s,3H),1.05(s,3H),0.99(s,3H),0.97(s,3H)。
实施例147.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((1,1-二氧化-1,2-噻嗪烷-2-基(thiazinan-2-yl))乙酰基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对C28反式酰胺制备描述的通用程序,使用(1,2-二氧代-1,6-[1,2]噻嗪烷-2-基(thiazinan-2-yl))乙酸作为反应物羧酸并进行碱水解,制备标题化合物。分离为白色固体的产物(30mg,34.8%)。LCMS:m/e719.6(MH+),2.99min(方法3).1HNMR(400MHz,氯仿-d)δppm7.98(m,J=8.3Hz,2H),7.23(m,J=8.3Hz,2H),6.60(t,J=6.0Hz,1H),5.25-5.34(m,1H),4.73(d,J=2.0Hz,1H),4.62(s,1H),3.85-3.95(m,2H),3.51-3.61(m,1H),3.37-3.51(m,2H),3.06-3.20(m,3H),2.51(td,J=11.1,5.6Hz,1H),2.19-2.33(m,2H),2.07-2.18(m,1H),2.04(d,J=8.8Hz,1H),1.89(br.s.,4H),1.81(td,J=11.8,4.0Hz,2H),1.60-1.75(m,8H),1.50-1.60(m,2H),1.37-1.50(m,4H),1.16-1.37(m,4H),1.05-1.16(m,4H),1.02(s,3H),1.00(s,3H),0.91-0.97(m,6H)。
实施例148.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(二甲基氨基)乙酰氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(甲基氨基)乙酰氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸,实施例139,(10mg,0.016mmol)和甲醛(0.488mg,0.016mmol)的MeOH(1ml)溶液中加入乙酸(1.860μL,0.033mmol)和氰基硼氢化钠(1.022mg,0.016mmol)。混合后不久形成澄清溶液。于室温下搅拌该混合物2h,LC/MS显示有大量的期望产物。该混合物用7ml饱和NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。经过滤除去干燥剂,且在减压下浓缩滤液,得到标题化合物,为白色固体(2mg,18.6%)。LCMS:m/e629.4(MH+),2.72min(方法3).1H NMR(400MHz,MeOD)δppm7.90(d,J=8.6Hz,2H),7.20(d,J=8.3Hz,2H),5.19-5.42(m,1H),4.72(d,J=1.8Hz,1H),4.59(s,1H),3.93(s,2H),3.58(br.s.,1H),3.04-3.17(m,1H),2.89(s,6H),2.46-2.60(m,1H),2.10-2.18(m,2H),1.80(br.s.,2H),1.65-1.77(m,7H),1.63(s,1H),1.58(br.s.,2H),1.38-1.55(m,4H),1.19-1.34(m,4H),1.13-1.19(m,4H),1.06-1.13(m,2H),1.04(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
实施例149.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((二甲基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1.酯水解
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(苯甲酸基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(7.2g,10.21mmol)的1,4-二氧六环(75ml)和水(25ml)溶液中加入氢氧化锂(1.285g,30.6mmol),将该混合物于75℃搅拌。加入二氧六环(50ml)以溶解所有的固体并继续搅拌24h。除去溶剂,使残留物再溶于CH2Cl2,收集不溶性白色固体,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(2.2g,39.5%)LCMS:m/e545.4(MH+),2.68min(方法2).
步骤2.甲基酯形成
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(4.23g,10mmol)在CH2Cl2(50ml)和MeOH(5ml)的混合物的溶液中加入(三甲基甲硅烷基)重氮甲烷(5.00ml,10.00mmol)。于室温、氮气下搅拌该溶液2h。LC/MS显示无SM剩下。浓缩反应混合物,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(4.37g,100%)。化合物无需进一步纯化而用于下一步骤。LCMS:m/e559.4(MH+),3.29min(方法2).1H NMR(400MHz,氯仿-d)δppm7.95(m,J=8.3Hz,2H),7.22(m,J=8.6Hz,2H),5.22-5.39(m,1H),4.72(d,J=2.0Hz,1H),4.49-4.67(m,1H),3.94(s,3H),3.87(s,1H),3.38(d,J=10.6Hz,1H),2.37-2.60(m,1H),2.05-2.21(m,1H),1.96(d,J=11.1Hz,2H),1.90(d,J=13.1Hz,1H),1.61-1.82(m,7H),1.55(br.s.,8H),1.37-1.52(m,2H),1.18-1.37(m,4H),1.08-1.18(m,3H),1.04(s,3H),1.00(s,3H),0.95(s,6H)。
步骤3.C28醇被氧化为醛
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(羟基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(1g,1.789mmol)的CH2Cl2(70ml)溶液中加入PCC(1157g,5.37mmol)。将生成的深棕色混合物于室温下搅拌4h。TLC分析表明该反应完成。混合物通过硅藻土和硅胶的短柱过滤,用过量的CH2Cl2洗涤。真空浓缩滤液。粗混合物经Biotage在正相胶上纯化。合并含有期望的产物的部分并真空浓缩,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯,为固体(0.8g)。LCMS:m/e557.2(MH+),3.67min(方法2).
步骤4.肟形成
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(800mg,1.437mmol)的乙醇(60ml)的混悬液中加入羟胺盐酸盐(1298mg,18.68mmol))和碳酸钾(2581mg,18.68mmol)。于室温下搅拌生成的混合物12h。该反应混合物用17ml饱和NaHCO3溶液稀释并用二氟甲烷(3x20ml)提取。合并的有机层经Na2SO4干燥。经过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。LCMS:m/e572.3(MH+),3.26min(方法2).
步骤5.肟还原
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((羟基亚氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(800mg,1.399mmol)的乙醇(40ml)溶液中加入过量的乙酸铵(1078mg,13.99mmol)和氰基硼氢化钠(879mg,13.99mmol)。将混合物在冰浴中搅拌直至冷却。向该混悬液中加入氯化钛(III)的水溶液(Aldrich Chemicals,20%溶液,供货即可使用,10ml,1.963mmol)。生成的混合物用氮气覆盖,移去冰浴并于室温下继续搅拌1小时。LCMS表明该反应完成。此时,混合物为深蓝绿色的。将氢氧化钠(3ml,10N)的25ml水溶液与30ml二氯甲烷一起加入到反应混合物中。剧烈搅拌该混合物直至深蓝色相浮在有机相的顶部。混合物通过纤维素纸垫过滤。滤液为澄清的。收集有机层并用CH2Cl2(2X20ml)提取含水层。合并的有机相经Na2SO4干燥。真空除去溶剂以得到
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯,为灰白色固体(~800mg)。粗物质无需进一步纯化而用于下一步骤。LCMS:m/e558.5(MH+),2.53min(方法2)。
步骤6.胺的酰化
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(30mg,0.054mmol)的DCM(2ml)溶液中加入二氢呋喃-2,5-二酮(16.15mg,0.161mmol),随后加入DMAP(6.57mg,0.054mmol)和DIPEA(9.39μl,0.054mmol)。于室温下搅拌该混合物18小时。真空除去溶剂和得到的含有4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(甲氧基羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)-4-氧代丁酸的残留物无须进一步纯化而用于下一步骤。LCMS:m/e658.5(MH+),3.27min(方法3)。
步骤7.酰胺偶合
于0℃向4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(甲氧基羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基氨基)-4-氧代丁酸(35.4mg,0.054mmol)的DCM(3ml)溶液中加入硫吗啉-1,1-二氧化物(7.27mg,0.054mmol)、HATU(40.9mg,0.108mmol),随后加入N-乙基-N-异丙基丙-2-胺(20.86mg,0.161mmol)。将生成的溶液于室温下搅拌18h。真空除去溶剂,得到的固体无需进一步纯化而用于下一步骤。LCMS:m/e775.5(MH+),2.95min(方法3)。
步骤8.苯甲酸酯的皂化
向得自步骤7的物质(40mg,52mmol)的二氧六环(1.5ml)溶液中加入氢氧化钠(0.5ml,1N,500mmol)。将生成的溶液于63℃搅拌12h。真空除去溶剂,得到的残留物经制备型HPLC纯化。分离为白色固体的产物(26mg,62.9%)。LCMS:m/e761.6(MH+),2.57min(方法3).1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.25-5.38(m,1H),4.74(d,J=2.0Hz,1H),4.62(s,1H),3.98-4.12(m,4H),3.56(s,1H),3.28(br.s.,2H),3.07-3.22(m,2H),3.01(d,J=13.6Hz,1H),2.69-2.83(m,2H),2.46-2.65(m,3H),2.17(dd,J=17.2,6.4Hz,2H),1.84(d,J=12.5Hz,2H),1.64-1.81(m,8H),1.45-1.64(m,6H),1.39(br.s.,2H),1.22-1.33(m,4H),1.12-1.22(m,4H),1.06(d,J=3.5Hz,6H),0.87-1.04(m,6H)。
实施例150.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((S)-1-甲基吡咯烷-2-甲酰胺基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1:制备C28酰胺
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(25mg,0.045mmol)、(S)-1-(叔-丁氧羰基)吡咯烷-2-羧酸(11.58mg,0.054mmol)在DCM(1ml)的混合物中加入DIPEA(29mg,0.224mmol),随后加入HATU(25.6mg,0.067mmol)。将生成的溶液于室温下搅拌1h。真空浓缩反应混合物,得到粗产物,其无须进一步纯化。MS:m/e755.7(MH+),2.84min(方法2).
步骤2:胺的去保护
向得自步骤1的粗物质的DCM(2ml)溶液中加入TFA(0.3ml,3.89mmol)。于室温下搅拌该混合物2h。真空浓缩混合物,得到粗产物,其无需进一步纯化而用于下一步骤。MS:m/e655.6(MH+),1.96min(方法2).
步骤3:胺的烷基化
向得自步骤2的粗物质的甲醇(2ml)溶液中加入甲醛(37%在H2O中)(6.9mg,0.086mmol)和乙酸(4.9μl,0.086mmol)。于室温下搅拌生成的混合物30min。加入氰基硼氢化钠(5.4mg,0.086mmol)并于室温下搅拌该混合物3h。真空浓缩反应混合物,得到粗产物,其无须进一步纯化。MS:m/e669.7(MH+),1.97min(方法2).
步骤4:制备苯甲酸.
向得自步骤3的粗物质的1,4-二氧六环(1ml)和甲醇(0.5ml)溶液中加入1N氢氧化钠(0.5ml)。将生成的溶液于65℃搅拌2h。粗产物经制备型HPLC纯化(YMCCombiprep ODS30x50mm S5)(MeOH/H2O/TFA),得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((S)-1-甲基吡咯烷-2-甲酰胺基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸,为固体(13mg,44%,4步骤).MS:m/e655.7(MH+),1.73min(方法2).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.18(s,3H)1.71(s,3H)0.86-2.25(m,24H)2.14(dd,J=17.19,6.40Hz,1H)2.47-2.63(m,2H)2.91(s,3H)3.03(dd,J=13.55,4.77Hz,1H)3.20(dt,J=11.23,8.44Hz,1H)3.66-3.76(m,2H)4.04(t,J=8.16Hz,1H)4.61(s,1H)4.73(d,J=2.01Hz,1H)5.29(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.53Hz,2H)7.91(d,J=8.53Hz,2H)8.23(t,J=6.15Hz,1H)。
实施例151.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((R)-1-甲基吡咯烷-2-甲酰胺基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上在制备实施例150的
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((S)-1-甲基吡咯烷-2-甲酰胺基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸中描述的程序,使用(R)-1-甲基吡咯烷-2-羧酸作为反应物酸,以37%得率制备标题化合物。MS:m/e655.7(MH+),1.73min(方法2).
1HNMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.05(s,3H)1.17(s,3H)1.71(s,3H)0.85-2.25(m,24H)2.14(dd,J=17.07,6.27Hz,1H)2.48-2.62(m,2H)2.90(s,3H)3.15-3.25(m,2H)3.50-3.57(m,1H)3.67-3.76(m,1H)4.04(t,J=8.16Hz,1H)4.61(s,1H)4.73(d,J=2.01Hz,1H)5.29(dd,J=6.15,1.63Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)8.24(t,J=5.90Hz,1H)。
实施例152.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-(二甲基氨基)乙基氨基)-2,2-二氟-3-氧代丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1:制备C28反式酰胺
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(200mg,0.333mmol)的甲醇(5ml)和1,4-二氧六环(5ml)溶液中加入2,2-二氟丙二酸二乙基酯(654mg,3.33mmol)。将生成的溶液于室温下搅拌6天。真空浓缩反应混合物。粗产物经Biotage(Thomson25g硅胶柱;4∶1Hex/EtOAc)纯化,得到116mg(47%)产物。MS:m/e736.6(MH+),2.86min(方法2).1H NMR(400MHz,氯仿-d)δppm0.93(s,6H)0.99(s,3H)1.02(s,3H)1.13(s,3H)1.60(s,9H)1.71(s,3H)0.85-1.83(20H)1.98-2.10(m,1H)2.10(dd,J=17.07,6.27Hz,1H)2.49(td,J=11.04,5.27Hz,1H)3.16(dd,J=13.55,6.27Hz,1H)3.65(dd,J=14.43,7.15Hz,1H)3.95(s,3H)4.61-4.65(m,1H)4.73(d,J=1.76Hz,1H)5.28(dd,J=6.15,1.63Hz,1H)6.28(t,J=7.03Hz,1H)7.18(d,J=8.53Hz,2H)7.89(d,J=8.28Hz,2H).19F NMR(376MHz,CHLOROFORM-d)δppm-112.49(s,2F)。
步骤2:制备酰胺封端化合物
向得自步骤1的酰胺(30mg,0.041mmol)的甲醇(1ml)和1,4-二氧六环(1ml)溶液中加入N1,N1-二甲基乙烷-1,2-二胺(17.97mg,0.204mmol)。将生成的溶液于室温下搅拌3天。真空浓缩反应混合物,得到粗产物,其无须进一步纯化。MS:m/e792.7(MH+),2.06min(方法2).
步骤3:制备苯甲酸
向得自步骤2的粗物质(20mg,0.025mmol)的DCM(5ml)溶液中加入TFA(0.5ml,6.49mmol)。于室温下搅拌该混合物2h。真空浓缩混合物,粗产物经制备型HPLC纯化(YMC Combiprep ODS30x50mm S5,MeOH/H2O/TFA),得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-(二甲基氨基)乙基氨基)-2,2-二氟-3-氧代丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(18mg,96%).MS:m/e736.6(MH+),1.79min(方法2).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.05(s,3H)1.18(s,3H)1.71(s,3H)0.84-1.88(m,20H)1.97-2.20(m,2H)2.15(dd,J=17.44,6.65Hz,1H)2.53(td,J=10.98,5.40Hz,1H)2.96(s,6H)3.09(d,J=13.05Hz,1H)3.32-3.36(m,1H)3.61-3.71(m,3H)4.59-4.62(m,1H)4.73(d,J=2.01Hz,1H)5.30(dd,J=6.15,1.63Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.53Hz,2H).19F NMR(376MHz,MeOD)δppm-114.91(d,J=17.34Hz,2F)。
实施例153.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-羧基-2,2-二氟乙酰氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向得自步骤1的产物,实施例152,
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2,2-二氟-3-甲氧基-3-氧代丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(20mg,0.027mmol)的1,4-二氧六环(1ml)和甲醇(0.5ml)溶液中加入1N氢氧化钠(0.5ml,0.500mmol)。将生成的溶液于65℃搅拌2h。粗产物经制备型HPLC纯化(YMC Combiprep ODS30x50mm S5)(MeOH/H2O/TFA),得到为固体的标题化合物(2mg,9%).MS:m/e666.5(MH+),1.96min(方法2).1HNMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.18(s,3H)1.71(s,3H)0.86-1.89(m,20H)1.93-2.05(m,1H)2.14(dd,J=17.07,6.27Hz,1H)2.53(td,J=11.29,5.52Hz,1H)3.09(d,J=13.55Hz,1H)3.62(d,J=14.05Hz,1H)4.58-4.61(m,1H)4.73(d,J=1.76Hz,1H)5.29(dd,J=6.02,1.51Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.28Hz,2H).19F NMR(376MHz,MeOD)δppm-112.65(s,2F)。
制备C28脲衍生物的通用程序
合成路线1:
步骤1:制备脲
于0℃,向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(100mg,0.167mmol)的DCM(5ml)溶液中加入二吡啶-2-基碳酸酯(43.2mg,0.200mmol),随后加入DIPEA(0.070ml,0.400mmol)。将生成的溶液于室温下搅拌2h。加入相应的胺(1.2eq.),随后加入DIPEA(3eq.)。将该混合物搅拌18h。真空除去溶剂,生成的粗产物无须进一步纯化而使用。
步骤2.制备苯甲酸
向得自步骤1的脲的二氧六环(2.0ml)和甲醇(2.0ml)溶液中加入氢氧化钠(5eq.)和H2O(0.5ml)。将生成的溶液于70℃搅拌5-10h。真空除去溶剂,粗产物经制备型HPLC纯化,得到要求的苯甲酸。
合成路线2:
于0℃,向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(1eq.)和相应的异氰酸酯(2eq.)的DCM(8ml)溶液中加入DIPEA(3eq.)。于室温下搅生成的该混合物18h。蒸发溶剂,粗产物经制备型HPLC纯化,得到要求的苯甲酸。
实施例154.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-(2-氧代吡咯烷-1-基)乙基)脲基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述的合成路线1,使用1-(2-氨基乙基)吡咯烷-2-酮草酸盐作为反应物胺,以19%得率制备标题化合物。MS:m/e698.3(MH+),1.77min(方法2).1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.17(s,3H)1.70(s,3H)0.86-1.92(m,20H)2.03(quin,J=7.59Hz,3H)2.14(dd,J=17.19,6.40Hz,1H)2.35(t,J=8.16Hz,2H)2.51(td,J=10.98,5.40Hz,1H)2.93(d,J=13.05Hz,1H)3.31-3.37(m,4H)3.43(d,J=13.05Hz,1H)3.51(t,J=7.03Hz,2H)4.56-4.62(m,1H)4.71(d,J=2.26Hz,1H)5.29(dd,J=6.27,1.76Hz,1H)7.22(d,J=8.53Hz,2H)7.91(d,J=8.53Hz,2H)。
实施例155.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(3-(2-氧代吡咯烷-1-基)丙基)脲基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述的合成路线1,使用1-(3-氨基丙基)吡咯烷-2-酮作为反应物胺,以32%得率制备标题化合物。MS:m/e712.3(MH+),1.85min(方法2).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.18(s,3H)1.67-1.72(m,3H)0.87-1.93(m,22H)2.04(quin,J=7.65Hz,3H)2.14(dd,J=16.94,6.40Hz,1H)2.38(t,J=8.03Hz,2H)2.51(td,J=11.04,5.02Hz,1H)2.95(d,J=13.55Hz,1H)3.11(t,J=6.65Hz,2H)3.32-3.44(m,3H)3.46(t,J=7.03Hz,2H)4.57-4.61(m,1H)4.71(d,J=2.01Hz,1H)5.29(dd,J=6.27,1.51Hz,1H)7.21(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例156.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-乙氧基-2-氧代乙基)脲基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述的合成路线2,使用2-异氰酸基乙酸乙基酯作为反应物异氰酸酯,,制备标题化合物,分离为白色固体的产物(5mg,40.4%)。LCMS:m/e673.5(MH+),2.90min(方法3).1HNMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.15-5.36(m,1H),4.70(s,1H),4.57(s,1H),4.16(q,J=7.1Hz,2H),3.44(d,J=13.6Hz,1H),3.29(dt,J=3.3,1.6Hz,2H),2.95(d,J=13.6Hz,1H),2.50(td,J=11.1,5.5Hz,1H),2.12(dd,J=17.2,6.4Hz,1H),1.94-2.08(m,1H),1.76-1.94(m,3H),1.60-1.76(m,8H),1.41-1.60(m,6H),1.28-1.41(m,2H),1.20-1.28(m,5H),1.10-1.20(m,4H),1.05-1.10(m,1H),1.02(s,3H),1.01(s,3H),0.94(s,3H),0.89(s,3H)。
实施例157.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(羧基甲基)脲基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
使4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-乙氧基-2-氧代乙基)脲基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(7mg,10.40μmol)溶于二氧六环(2ml)。加入氢氧化钠溶液,1N(0.021ml,0.021mmol)。将该混合物于70℃搅拌2h。蒸发溶剂,残留物经制备型HPLC纯化,得到标题化合物,为白色固体(4mg,32.8%)。LCMS:m/e645.3(MH+),2.58min(方法3).1H NMR(400MHz,MeOD)δppm7.90(m,J=8.3Hz,2H),7.20(m,J=8.3Hz,2H),5.21-5.36(m,1H),4.70(d,J=1.8Hz,1H),4.57(s,1H),3.83(s,2H),3.44(d,J=13.8Hz,1H),2.95(d,J=13.6Hz,1H),2.38-2.60(m,1H),2.13(dd,J=17.1,6.5Hz,1H),1.93-2.08(m,1H),1.76-1.93(m,2H),1.60-1.76(m,8H),1.40-1.60(m,6H),1.35-1.40(m,1H),1.29-1.35(m,1H),1.18-1.29(m,3H),1.16(s,3H),1.05-1.13(m,2H),1.03(s,3H),1.02(s,3H),0.97(s,3H),0.92(s,3H)。
实施例158.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-甲氧基-2-氧代乙基)脲基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
使4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-乙氧基-2-氧代乙基)脲基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(7mg,10.40μmol)溶于二氧六环(2ml)和甲醇(1ml)。加入氢氧化钠溶液(1N,0.021ml,0.021mmol)。将该混合物于70℃搅拌2h。减压除去溶剂,残留物经制备型HPLC纯化,得到标题化合物,为白色固体(2mg,29.2%)。LCMS:m/e659.4(MH+),2.84min(方法3).
1H NMR(500MHz,MeOD)δppm7.86(d,J=8.2Hz,2H),7.14(d,J=7.9Hz,2H),5.23-5.38(m,1H),4.74(s,1H),4.62(s,1H),3.91(s,2H),3.71-3.78(m,3H),2.95-3.10(m,1H),2.46-2.62(m,1H),2.12-2.25(m,1H),2.05(s,1H),1.99-2.03(m,1H),1.91-1.99(m,6H),1.89(br.s.,2H),1.76-1.83(m,2H),1.71-1.76(m,4H),1.69(br.s.,1H),1.48(br.s.,4H),1.31(br.s.,4H),1.19(s,3H),1.07(br.s.,3H),1.05(s,3H),0.97(s,3H),0.96(s,3H)。
实施例159.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-吡啶-3-基脲基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述的合成路线2,使用3-异氰酸吡啶作为反应物异氰酸酯,制备标题化合物。分离为白色固体的产物(5mg,38.9%)。LCMS:m/e664.5(MH+),2.80min(方法3).1H NMR(400MHz,MeOD)δppm9.22(d,J=2.5Hz,1H),8.35(d,J=5.3Hz,1H),8.13-8.28(m,1H),7.76-7.99(m,3H),7.20(d,J=8.3Hz,2H),5.23-5.37(m,1H),4.72(d,J=2.0Hz,1H),4.60(s,1H),3.56(s,1H),3.04(d,J=13.3Hz,1H),2.45-2.64(m,1H),2.10-2.20(m,2H),1.84(br.s.,2H),1.62-1.79(m,8H),1.56(br.s.,2H),1.47(d,J=10.6Hz,4H),1.39(d,J=13.6Hz,1H),1.21-1.34(m,3H),1.18(s,3H),1.10(d,J=11.3Hz,3H),1.05(s,3H),1.03(s,3H),0.95(s,3H),0.93(s,3H)。
实施例160.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4-(甲氧基羰基)苯基)脲基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述的合成路线2,使用4-异氰酸基苯甲酸甲基酯作为反应物异氰酸酯,制备标题化合物。分离为白色固体的产物(5mg,37.7%)。LCMS:m/e721.5(MH+),3.07min(方法3).
1H NMR(400MHz,MeOD)δppm7.86-7.94(m,4H),7.39-7.51(m,2H),7.15-7.26(m,2H),5.21-5.33(m,1H),4.72(s,1H),4.59(s,1H),3.86(s,3H),3.51(s,1H),3.03(d,J=13.8Hz,1H),2.42-2.60(m,1H),2.14(dd,J=17.0,6.7Hz,2H),1.61-1.76(m,8H),1.48(br.s.,6H),1.22-1.35(m,5H),1.15-1.22(m,4H),1.14(br.s.,3H),1.04(s,3H),1.03(s,3H),0.96(s,3H),0.93(s,3H)。
实施例161.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((2-(1,1-二氧化-4-硫吗啉基)乙基)氨基甲酰基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照上述的路线1,使用N-(2-氨基乙基)硫代吗啉1,1-二氧化物作为反应物胺,制备标题化合物。分离为白色固体的产物(8mg,20.4%)。LCMS:m/e748.3(MH+),2.33min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(m,J=8.3Hz,2H),7.20(m,J=8.3Hz,2H),5.28(d,J=4.8Hz,1H),4.70(s,1H),4.59(s,1H),3.71(br.s.,4H),3.35-3.56(m,7H),3.20(t,J=5.3Hz,2H),2.94(d,J=13.6Hz,1H),2.37-2.57(m,1H),2.13(dd,J=17.1,6.3Hz,1H),1.94-2.08(m,1H),1.80(br.s.,2H),1.61-1.77(m,8H),1.55(br.s.,2H),1.48(br.s.,4H),1.39(br.s.,2H),1.31(br.s.,1H),1.19-1.29(m,2H),1.17(s,3H),1.06-1.12(m,2H),1.04(s,3H),1.02(s,3H),0.95(s,3H),0.93(s,3H)。
制备C28反式氨基甲酸酯衍生物的通用程序
合成路线1:
步骤1:制备氨基甲酸酯
于0℃,向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(100mg,0.167mmol)的DCM(5ml)溶液中加入二吡啶-2-基碳酸酯(43.2mg,0.200mmol),随后加入DIPEA(0.070ml,0.400mmol)。将该反应混合物搅拌2h。于0℃向生成的溶液中加入2-5eq相应的醇和3-6eq的DIPEA。将该混合物搅拌另外18h。真空除去溶剂,生成的粗产物无须进一步纯化而使用。
步骤2:制备苯甲酸
a)酸水解-向得自步骤1的物质的DCM(4-5ml)溶液中加入TFA(0.4-0.5ml)。于室温下搅拌该混合物2-6h。真空蒸发溶剂。生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
b)碱水解-向得自步骤1的物质的二氧六环(2ml)和甲醇(2ml)溶液中加入氢氧化钠(75mg,1.875mmol)和H2O(0.5ml)。于70℃将生成的溶液搅拌5-10h。真空蒸发溶剂,生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
合成路线2:
步骤1.制备氨基甲酸酯
向双(2,5-二氧代吡咯烷-1-基)碳酸酯(75mg,0.293mmol)和相应的醇(0.322mmol)的DCM(2ml)混悬液中加入TEA(0.041ml,0.293mmol)。于室温搅拌反应混合物2-4h。向中间体加入4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(1eq.)的DCM(5ml)溶液,随后加入DIPEA(2eq.)。将生成的溶液搅拌2小时。蒸发溶剂,生成的粗产物经Biotage纯化,得到要求的氨基甲酸酯。
步骤2:制备苯甲酸
向得自步骤3的物质的二氧六环(2ml)和甲醇(2ml)溶液中加入氢氧化钠(75mg,1.875mmol)和H2O(0.5ml)。于70℃将生成的溶液搅拌5-10h。真空蒸发溶剂,生成的粗产物经制备型HPLC纯化,得到要求的苯甲酸。
实施例162.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((2-(2-氧代吡咯烷-1-基)乙氧基)羰基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备C28反式氨基甲酸酯描述的合成路线2,使用1-(2-羟基乙基)吡咯烷-2-酮作为反应物醇,以23%得率制备标题化合物。MS:m/e699.3(MH+),1.79min(方法2).
1H NMR(400MHz,MeOD)δppm0.94(s,3H)0.96(s,3H)1.03(s,3H)1.04(s,3H)1.17(s,3H)1.70(s,3H)0.87-1.96(m,20H)2.03(dq,J=7.91,7.65Hz,3H)2.14(dd,J=17.19,6.40Hz,1H)2.36(t,J=8.16Hz,2H)2.49(td,J=11.04,5.27Hz,1H)2.91(d,J=13.05Hz,1H)3.39-3.46(m,1H)3.48-3.57(m,4H)4.17(ddd,J=5.02,2.89,2.64Hz,2H)4.59(s,1H)4.71(d,J=2.01Hz,1H)5.29(dd,J=6.40,1.88Hz,1H)7.22(d,J=8.28Hz,2H)7.91(d,J=8.28Hz,2H)。
实施例163.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((2-(哌嗪-1-基)乙氧基)羰基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备C28反式氨基甲酸酯描述的合成路线1,使用4-(2-羟基乙基)哌嗪-1甲酸叔-丁基酯作为反应物醇并进行酸水解,制备标题化合物。分离为白色固体的产物(1.5mg,3.82%)。LCMS:m/e700.4(MH+),2.69min(方法3).
1H NMR(400MHz,MeOD)δppm7.90(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),5.19-5.37(m,1H),4.70(s,1H),4.58(s,1H),4.18(t,J=5.4Hz,2H),3.77-4.02(m,2H),3.49-3.66(m,2H),3.38(m,1H),3.13-3.24(m,3H),3.03(s,1H),2.80-2.86(m,2H),2.76(t,J=5.3Hz,1H),2.43-2.55(m,1H),2.04-2.23(m,2H),1.97(br.s.,1H),1.61-1.76(m,8H),1.52-1.61(m,2H),1.41-1.52(m,4H),1.20-1.41(m,8H),1.16(s,3H),1.02(d,J=4.0Hz,6H),0.95(s,3H),0.93(s,3H)。
实施例164.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((3-(1,1-二氧化-4-硫吗啉基)丙氧基)羰基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备C28反式氨基甲酸酯描述的合成路线2,使用4-(3-羟基丙基)硫吗啉1,1-二氧化物作为反应物醇,制备标题化合物。分离为白色固体的产物(15mg,38.2%)。LCMS:m/e763.3(MH+),2.32min(方法3).1H NMR(500MHz,MeOD)δppm7.88-7.99(m,2H),7.14-7.32(m,2H),5.25-5.40(m,1H),4.74(s,1H),4.62(br.s.,1H),4.16(t,J=6.1Hz,2H),3.67(br.s.,4H),3.38-3.53(m,5H),3.14-3.28(m,2H),2.95(d,J=13.7Hz,1H),2.51(t,J=6.3Hz,1H),2.17(dd,J=17.2,6.3Hz,1H),2.01-2.12(m,3H),1.83(d,J=11.9Hz,1H),1.64-1.80(m,8H),1.44-1.64(m,6H),1.32-1.44(m,3H),1.22-1.32(m,3H),1.12-1.22(m,5H),1.03-1.09(m,6H),0.99(s,3H),0.97(s,3H)。
实施例165.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((((2-(1,1-二氧化-4-硫吗啉基)乙氧基)羰基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备C28反式氨基甲酸酯描述的合成路线2,使用4-(2-羟基乙基)硫吗啉1,2-二氧化物作为反应物醇,制备标题化合物。分离为白色固体的产物(22mg,44.9%)。LCMS:m/e749.3(MH+),2.54min(方法3).1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.24(m,J=8.5Hz,2H),5.32(dd,J=6.1,1.6Hz,1H),4.74(d,J=2.0Hz,1H),4.62(s,1H),4.18-4.40(m,2H),3.52(dd,J=6.5,3.8Hz,4H),3.40-3.49(m,1H),3.25-3.38(m,6H),3.22(t,J=5.0Hz,2H),2.97(d,J=13.8Hz,1H),2.53(td,J=11.1,5.6Hz,1H),2.17(dd,J=17.2,6.4Hz,1H),2.00-2.13(m,1H),1.84(dd,J=12.2,3.4Hz,2H),1.65-1.81(m,8H),1.53-1.65(m,4H),1.50(d,J=11.0Hz,3H),1.34-1.46(m,2H),1.22-1.34(m,2H),1.19-1.22(m,2H),1.10-1.15(m,1H),1.03-1.10(m,6H),0.99(s,3H),0.97(s,3H)。
实施例166.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-(((3-(2-氧代吡咯烷-1-基)丙氧基)羰基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
按照以上对制备C28反式氨基甲酸酯描述的合成路线2,使用1-(3-羟基丙基)吡咯烷-2-酮作为反应物醇,制备标题化合物。分离为白色固体的产物(12mg,32.4%)。LCMS:m/e713.3(MH+),2.43min(方法3).1H NMR(400MHz,MeOD)δppm7.93(m,2H),7.24(m,2H),5.32(dd,J=6.3,1.8Hz,1H),4.74(d,J=2.0Hz,1H),4.62(s,1H),3.94-4.12(m,2H),3.45-3.56(m,2H),3.34-3.45(m,3H),2.95(d,J=13.8Hz,1H),2.52(td,J=11.2,5.6Hz,1H),2.32-2.45(m,2H),2.17(dd,J=17.2,6.4Hz,1H),2.01-2.13(m,3H),1.81-2.01(m,4H),1.64-1.81(m,8H),1.45-1.64(m,6H),1.34-1.45(m,2H),1.23-1.34(m,2H),1.20(s,3H),1.15(dt,J=8.6,4.4Hz,1H),1.09-1.12(m,1H),1.02-1.09(m,7H),0.99(s,3H),0.97(s,3H)。
实施例167.制备4-(N-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基)氨磺酰基)苯甲酸.
步骤1.制备4-(N-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(叔-丁氧羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基)氨磺酰基)苯甲酸。
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(25mg,0.042mmol)的DCM(2ml)溶液中加入4-(氯代磺酰基)苯甲酸(9.19mg,0.042mmol)和DIPEA(7.28μl,0.042mmol)。将生成的混合物于室温下搅拌48h。该混合物用7ml饱和NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。经过滤除去干燥剂,且滤液在减压下浓缩。粗产物无需另外的纯化而用于下一步骤。
步骤2:苯甲酸去保护
将得自步骤1的4-(N-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(叔-丁氧羰基)苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基)氨磺酰基)苯甲酸(10mg,0.013mmol)溶于二氧六环(1ml)和MeOH(5ml)。加入氢氧化钠(10.20mg,0.255mmol)(粉末),随后加入5滴水。于70℃,将生成的混悬液搅拌6h。该反应完成后,真空除去所有的挥发性物质。使残留物再溶于MeOH并经制备型HPLC纯化,得到
4-(N-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-羧基苯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-3a-基)甲基)氨磺酰基)苯甲酸,为白色固体(1.8mg,18.4%)。LCMS:m/e728.2(MH+),2.11min(方法3).1HNMR(400MHz,MeOD)δppm8.24(m,J=8.5Hz,2H),8.01(m,J=8.5Hz,2H),7.94(m,J=8.3Hz,2H),7.24(m,J=8.3Hz,2H),5.31(d,J=4.3Hz,1H),4.70(d,J=2.3Hz,1H),4.59(s,1H),3.05(s,1H),2.62(d,J=13.1Hz,1H),2.37(br.s.,1H),2.11(m,1H),1.76-2.01(m,4H),1.65-1.76(m,6H),1.53-1.65(m,4H),1.44(br.s.,5H),1.31(d,J=2.8Hz,6H),1.03(s,6H),1.01(s,3H),0.99(s,3H),0.96(s,3H)。
实施例168.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1,1-二氧化-4-硫吗啉基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1.串联式双重迈克尔加成
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(120mg,0.215mmol)的二氧六环(0.5ml)和乙醇(0.5ml)溶液中加入TEA(0.09ml,0.645mmol)和乙烯基磺酰基乙烯(50.8mg,0.430mmol),于85℃加热反应混合物3h。真空除去溶剂,粗制固体无须进一步纯化而用于下一步骤。LCMS:m/e676.6(MH+),3.28min(方法3)。
步骤2.水解甲基酯
向得自步骤1的粗物质(88mg,0.130mmol)的二氧六环(1.5ml)溶液中加入氢氧化钠溶液(0.5ml,1N,0.500mmol)。将反应混合物加热至55℃4h。真空除去溶剂,得到的固体经制备型HPLC纯化,得到4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1,1-二氧化-4-硫吗啉基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸,为白色固体(30mg,33.1%)。LCMS:m/e662.5(MH+),2.98min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(m,J=8.3Hz,2H),7.23(m,J=8.3Hz,2H),5.24-5.39(m,1H),4.75(s,1H),4.65(s,1H),3.64(br.s.,4H),3.42(br.s.,4H),3.17-3.25(m,1H),2.86(m,1H),2.55(m,1H),2.08-2.23(m,1H),1.94(br.s.,2H),1.74(s,6H),1.61(br.s.,2H),1.55(br.s.,6H),1.21-1.41(m,6H),1.15-1.21(m,4H),1.07-1.15(m,4H),1.05(s,3H),0.98(s,3H),0.96(s,3H)。
实施例169.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羧基丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(20mg,0.037mmol)的DCM(2ml)溶液中加入二氢呋喃-2,5-二酮(11.04mg,0.110mmol),随后加入DMAP(4.49mg,0.037mmol)和DIPEA(6.42μl,0.037mmol)。于室温下搅拌该混合物18h。真空除去溶剂,得到的残留物经制备型HPLC纯化。分离为白色固体的产物(5mg,21.1%)。LCMS:m/e644.5(MH+),2.80min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(d,J=8.5Hz,2H),7.16-7.34(m,2H),5.32(dd,J=6.4,1.6Hz,1H),4.74(d,J=2.0Hz,1H),4.62(s,1H),3.54(d,J=13.6Hz,1H),3.04(d,J=13.8Hz,1H),2.57-2.71(m,2H),2.44-2.57(m,2H),2.17(dd,J=17.2,6.4Hz,1H),2.09(dd,J=13.1,1.8Hz,1H),1.85(dd,J=12.2,3.4Hz,2H),1.65-1.82(m,8H),1.61(br.s.,2H),1.53(d,J=10.5Hz,3H),1.48(d,J=2.0Hz,1H),1.35-1.45(m,3H),1.24-1.35(m,3H),1.16-1.24(m,4H),1.02-1.16(m,8H),0.99(s,3H),0.95(s,3H)。
实施例170.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-甲氧基-4-氧代丁酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-羧基丙酰胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(20mg,0.037mmol)的甲醇(2ml)溶液中加入TFA,以形成0.1%v/v TFA-甲醇溶液。于室温下搅拌该混合物28h。真空除去溶剂,得到的残留物经制备型HPLC纯化。分离为白色固体的产物(11mg,4.55%)。LCMS:m/e658.5(MH+),2.90min(方法3).
1H NMR(400MHz,MeOD)δppm7.94(d,J=8.5Hz,2H),7.16-7.34(m,2H),5.32(dd,J=6.4,1.6Hz,1H),4.74(d,J=2.0Hz,1H),4.62(s,1H),3.68(s,3H),3.54(d,J=13.6Hz,1H),3.04(d,J=13.8Hz,1H),2.57-2.71(m,2H),2.44-2.57(m,2H),2.17(dd,J=17.2,6.4Hz,1H),2.09(dd,J=13.1,1.8Hz,1H),1.85(dd,J=12.2,3.4Hz,2H),1.65-1.82(m,8H),1.61(br.s.,2H),1.53(d,J=10.5Hz,3H),1.48(d,J=2.0Hz,1H),1.35-1.45(m,3H),1.24-1.35(m,3H),1.16-1.24(m,4H),1.02-1.16(m,8H),0.99(s,3H),0.95(s,3H)。
实施例171.制备N-(二甲基氨磺酰基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酰胺.
步骤1.仲胺的BOC保护
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(57mg,0.079mmol)的DCM(2ml)溶液中加入二碳酸二-叔-丁基酯(26.0mg,0.119mmol),随后加入DMAP(9.68mg,0.079mmol)和DIPEA(0.014ml,0.079mmol)。于室温下搅拌该混合物18h。真空除去溶剂,得到的固体无须进一步纯化而进行下一步骤。LCMS:m/e819.3(MH+),2.65min(方法3).
步骤2.偶合
向得自步骤1的物质(57mg,0.070mmol)的THF(2ml)溶液中加入羰基二咪唑(19.36mg,0.119mmol)。于室温下搅拌该混合物2h。加入N,N-二甲基磺酰胺(24.11mg,0.199mmol),随后加入DBU(0.030ml,0.199mmol)。将生成的混合物于室温下搅拌12h。用1N HCl猝灭反应,用乙酸乙酯(3X10ml)提取。收集有机层并经硫酸钠干燥。获得的物质无须进一步纯化而用于下一步骤。LCMS:m/e925.6(MH+),2.56min(方法3).
步骤3.De-BOC水解
向得自步骤2的物质(5mg,0.0054mmol)的DCM(5ml)溶液中加入TFA(0.5ml,6.49mmol)。于室温下将该混合物搅拌16h。在减压下浓缩混合物。使残留物溶于二氧六环和MeOH并经制备型HPLC纯化,得到N-(二甲基氨磺酰基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酰胺,为白色固体(1.3mg,29.2%)。LCMS:m/e825.5(MH+),2.41min(方法3).
1H NMR(400MHz,MeOD)δppm7.81(m,J=8.3Hz,2H),7.28(m,J=8.5Hz,2H),5.27-5.40(m,1H),4.78(s,1H),4.68(s,1H),3.23-3.31(m,1H),3.13-3.23(m,6H),3.09(br.s.,4H),3.00(s,6H),2.88(s,1H),2.74(t,J=6.7Hz,2H),2.54(br.s.,1H),2.17(s,1H),1.96(d,J=8.5Hz,2H),1.76(s,8H),1.54(br.s.,8H),1.39(d,J=3.5Hz,3H),1.31(br.s.,4H),1.17-1.23(m,4H),1.11(s,3H),1.07(s,3H),1.00(s,3H),0.98(s,3H)。
实施例172.制备苯甲酰胺,N-(环丙基磺酰基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酰胺.
按照以上对制备N-(二甲基氨磺酰基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酰胺,实施例181描述的程序,使用环丙烷磺酰胺作为反应物胺,制备标题化合物。分离为白色固体的产物(32mg,68.5%)。LCMS:m/e822.5(MH+),2.38min(方法3).1H NMR(400MHz,MeOD)δppm7.84(m,2H),7.29(m,2H),5.22-5.38(m,1H),4.78(d,J=1.5Hz,1H),4.66(s,1H),3.49-3.65(m,4H),3.36-3.46(m,4H),3.19-3.31(m,3H),3.14-3.19(m,1H),3.11(t,J=7.4Hz,2H),2.89(d,J=13.1Hz,1H),2.53(td,J=10.5,5.6Hz,1H),2.00-2.24(m,4H),1.66-1.91(m,10H),1.43-1.66(m,8H),1.28-1.43(m,5H),1.12-1.28(m,7H),1.09(s,3H),1.05(s,3H),0.99(s,3H),0.97(s,3H)。
实施例173.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((4-((环丙基磺酰基)氨基)-4-氧代丁酰基)(3-(1,1-二氧化-4-硫吗啉基)丙基)氨基)甲基)-1-异丙烯基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸.
步骤1.甲基酯形成
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸(300mg,0.42mmol)的CH2Cl2(50ml)/MeOH(5ml)溶液中加入(二氮杂甲基)三甲基硅烷(2.053ml,4.11mmol)。在氮气下,将生成的溶液于室温下搅拌2h。LC/MS显示无SM剩余。浓缩反应混合物,得到(100%)粗产物。LCMS:m/e733.3(MH+),2.52min(方法2)。
步骤2.酰化
向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((3-(1-二氧代-硫代吗啉代)丙基氨基)甲基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸甲基酯(16mg,0.022mmole)的CH2Cl2(0.5ml)溶液中加入二氢呋喃-2,5-二酮(3.28mg,0.033mmol),随后加入DMAP(3.07mg,0.022mmol)和DIPEA(0.011ml,0.065mmol)。于室温下搅拌该混合物18h。真空除去溶剂,得到的残留物无须进一步纯化而用于下一步骤。LCMS:m/e833.3(MH+),2.45min(方法3)。
步骤3.磺酰胺形成
向得自步骤2的物质(20mg,0.024mmol)的THF(2ml)溶液中加入CDI(4.67mg,0.029mmol)。于室温下搅拌该混合物2小时。向生成的溶液中加入环丙烷磺酰胺(5.82mg,0.048mmol),随后加入DBU(7.24μl,0.048mmol)。于室温下,将该反应混合物搅拌6h。减压除去溶剂,使残留物再溶于CH2Cl2,该溶液用碳酸氢钠水溶液洗涤。收集有机层并经硫酸钠干燥。获得的物质无须进一步纯化而用于下一皂化步骤。LCMS:m/e936.6(MH+),2.60min(方法3)。
步骤4.甲基酯的碱性水解
向得自步骤3的物质(18mg,0.019mmol)的二氧六环(1.5ml)溶液中加入氢氧化钠(0.5ml,1N,500mmol)。于63℃将生成的溶液搅拌12h,真空除去溶剂和得到的残留物经制备型HPLC纯化,得到标题化合物,为白色固体(8mg,42%)。LCMS:m/e922.5(MH+),2.42min(方法3),1H NMR(400MHz,MeOD)δppm7.94(m,J=8.0Hz,2H),7.24(m,J=8.0Hz,2H),5.33(d,J=6.3Hz,1H),4.76(s,1H),4.68(s,1H),3.84(br.s.,2H),3.59-3.75(m,4H),3.48-3.59(m,3H),3.40-3.48(m,2H),3.06-3.21(m,1H),2.84-3.06(m,2H),2.75-2.84(m,2H),2.54-2.75(m,3H),2.03-2.27(m,4H),1.91(d,J=16.6Hz,2H),1.81(br.s.,2H),1.65-1.79(m,6H),1.52-1.65(m,5H),1.48(br.s.,2H),1.35-1.45(m,2H),1.17-1.35(m,8H),1.10-1.17(m,4H),1.02-1.10(m,6H),0.91-1.02(m,6H)。
采用先前对制备中间体3描述的程序,使用酮中间体B2作为起始原料(29%),制备标题化合物。1H NMR(400MHz,氯仿-d)δppm0.65(s,3H),0.91(s,3H),0.94(s,3H),0.97(s,3H),1.04(s,3H),1.05-1.12(m,1H),1.14(s,6H),1.16-1.28(m,3H),1.28-1.42(m,2H),1.42-1.54(m,2H),1.57-1.65(m,2H),1.68(d,J=14.56Hz,2H),1.73(d,J=4.52Hz,1H),1.78-1.84(m,2H),1.86(dd,J=5.90,4.14Hz,1H),1.90-1.97(m,1H),1.98-2.04(m,1H),2.12(dd,J=17.07,6.78Hz,1H),2.93(dd,J=13.93,4.14Hz,1H),5.03-5.14(m,3H),5.33(t,J=3.51Hz,1H),5.58(dd,J=6.78,2.01Hz,1H),7.34-7.38(m,5H);19F NMR(376.46MHz,氯仿-d)δppm-74.84。
实施例174.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
步骤1.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((E)-(羟基亚氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲酰基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(200mg,0.334mmol)的EtOH(20mL)悬浮液中加入羟胺盐酸盐(186mg,2.67mmol)和碳酸钾(369mg,2.67mmol),将该混合物于室温下搅拌过夜。LC/MS显示有大量的期望的产物。该混合物用7mL饱和NaHCO3稀释并用二氟甲烷(3x7ml)提取。合并的有机层用Na2SO4干燥。通过过滤除去干燥剂,且滤液在减压下浓缩。粗产物为灰白色泡沫状物(~100%),无需另外的纯化而用于下一步骤。LCMS:m/e614.53(MH+),3.82min(方法3).1HNMR(400MHz,氯仿仿-d)δppm7.90(2H,m,J=8.3Hz),7.60(1H,s),7.19(2H,m,J=8.3Hz),5.23-5.35(1H,m),4.76(1H,d,J=1.8Hz),4.64(1H,s),2.56(1H,td,J=11.0,5.4Hz),2.05-2.19(1H,m),1.92-2.05(2H,m),1.83-1.92(2H,m),1.64-1.82(7H,m),1.58-1.64(9H,m),1.38-1.57(9H,m),1.22-1.31(2H,m),1.10-1.20(2H,m),1.07(3H,s),1.04(3H,s),0.97-1.01(3H,m),0.85-0.97(6H,m)。
步骤2.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯向在100mL梨形烧瓶中的得自以上的含4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((羟基亚氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(100mg,0.163mmol)的粗产物中加入EtOH(12mL),以形成澄清溶液。向其中加入过量的NH4Cl(400mg,5.19mmol)和氰基硼氢化钠(300mg,4.77mmol)。在冰浴中搅拌混合物直至冷却。向该混悬液中加入氯化钛(III)(4mL,0.163mmol)的20%溶液。生成的混合物用氮气覆盖。移去冰浴并于室温下继续搅拌1小时。LCMS显示该反应完成。此时,混合物为带绿色的深蓝紫色。将氢氧化钠溶液(3mL,10N in25mL水)加入到反应混合物中,加入二氯甲烷(30mL)。将该混合物剧烈搅拌直至深蓝色相悬浮于有机相的顶部。混合物通过纸塞过滤,得到澄清滤液。对该两相滤液的顶相(pH)的pH和底相的LCMS进行测试。收集有机层且含水层用CH2Cl2(2x20mL)提取。合并有机层并经NaSO4干燥,得到灰白色固体(95mg,97.0%),其无须进一步纯化而用于下一步骤)。LCMS:m/e600.58(MH+),3.03min(方法3).1H NMR(400MHz,氯仿-d)δppm7.90(2H,m,J=8.3Hz),7.19(2H,m,J=8.3Hz),5.29(1H,dd,J=6.2,1.6Hz),4.71(1H,d,J=2.3Hz),4.61(1H,s),2.89(1H,d,J=12.8Hz),2.44(1H,td,J=11.0,5.7Hz),2.36(1H,d,J=13.3Hz),2.11(1H,dd,J=17.1,6.5Hz),1.75-1.99(2H,m),1.71(5H,s),1.57-1.70(9H,m),1.36-1.57(9H,m),1.18-1.32(5H,m),1.06-1.18(6H,m),1.01-1.06(3H,m),1.00(3H,s),0.90-0.97(6H,m)。
步骤3.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(15mg,0.025mmol)的DCM(4mL)溶液中加入TFA(0.4ml,5.19mmol),于室温下搅拌该混合物。溶液的颜色转变成粉红色。6小时后,真空除去溶剂,粗产物经反相制备型HPLC纯化,得到标题化合物,为白色泡沫状物(12mg,80%).LCMS:m/e544.49(MH+),2.60min(方法3).1HNMR(500MHz,MeOD)δppm7.94(2H,d,J=8.5Hz),7.24(2H,d,J=8.5Hz),5.32(1H,dd,J=6.3,1.7Hz),4.77(1H,d,J=1.8Hz),4.66(1H,s),3.10-3.24(1H,m),2.73-2.84(1H,m),2.50(1H,td,J=10.6,5.6Hz),2.17(1H,dd,J=17.1,6.4Hz),1.98-2.11(1H,m),1.67-1.89(8H,m),1.54-1.66(3H,m),1.44-1.56(5H,m),1.33-1.45(2H,m),1.27-1.34(3H,m),1.23-1.28(1H,m),1.15-1.24(4H,m),1.11(3H,s),1.06(3H,s),0.92-1.02(6H,m)。
实施例175.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((异丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
在4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((E)-(羟基亚氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁酯的硅胶层析纯化中,使用丙酮。结果形成少量相应的丙酮酰亚胺(acetone aldimine)。如上述用TiCl3、NaBCNH3处理该化合物,得到(4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((异丙氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁酯)。LCMS:m/e642.69(M+H)+,2.611min(方法9起始%B=75%).1H NMR(400MHz,氯仿-d)δ7.90(d,J=8.3Hz,2H),7.19(d,J=8.3Hz,2H),5.30(dd,J=6.3,1.8Hz,1H),4.72(d,J=2.3Hz,1H),4.61(dd,J=2.1,1.4Hz,1H),2.82-2.75(m,J=12.8Hz,1H),2.79-2.71(m,1H),2.79-2.71(m,1H),2.48(td,J=11.0,5.8Hz,1H),2.21(d,J=11.5Hz,1H),2.12(dd,J=17.2,6.4Hz,1H),2.02-1.75(m,5H),1.75-1.63(m,7H),1.72(s,3H),1.61(s,9H),1.60-1.53(m,3H),1.51-1.35(m,6H),1.12(s,3H),1.11(d,J=6.3 Hz,3H),1.10(d,J=6.3Hz,3H),1.02(s,3H),1.00(s,3H),0.94(s,6H).13C NMR(101MHz,氯仿-d)δ165.6,159.8,150.3,147.9,145.9,129.55,129.37,128.0,123.6,109.2,80.4,52.4,49.0,48.6,47.0,42.3,41.3,40.4,38.9,37.1,36.8,35.9,33.7,33.1,29.4,29.1,28.9,27.9,26.7,24.9,20.9,20.7,19.4,18.9,16.1,15.3,14.4。
随后如上所述用TFA处理以除去保护基团,得到标题化合物。LCMS:m/e586.64(M+H)+,2.14min(方法9).部分的1H NMR(400MHz,氯仿-d)δ7.99(d,J=8.3Hz,2H),7.23(d,J=8.3Hz,2H),5.35-5.28(m,1H),4.73(d,J=1.5Hz,1H),4.66-4.62(m,1H),1.72(s,3H),1.51(s,3H),1.49(s,3H),1.12(s,3H),1.03(s,3H),1.00(s,3H),0.95(s,6H)。
实施例176.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-甲氧基-3-氧代丙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对C-28胺形成和水解描述的通用程序,使用3-氨基丙酸甲基酯作为反应物胺,制备标题化合物。分离为白色固体的产物(26mg,27.5%).LCMS:m/e630.3(MH+),2.39min(方法9).1H NMR(400MHz,氯仿-d)δ8.00(d,J=8.0Hz,2H),7.24(d,J=8.3Hz,2H),5.31(d,J=4.5Hz,1H),4.73(s,1H),4.65(s,1H),3.76(s,3H),3.52-3.27(m,3H),2.90(m,2H),2.81(br.s.,1H),2.47-2.33(m,1H),2.18-1.95(m,2H),1.93-1.79(m,2H),1.77-1.61(m,2H),1.59-1.38(m,7H),1.37-1.17(m,7H),1.10(s,4H),1.02(s,3H),0.99(s,3H),0.96(s,3H),0.87-0.95(s,3H)。
实施例177.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
步骤1.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯使4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氨基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(200mg,0.667mmol)溶于DMF(10.00mL)和THF(10.00mL),加入乙烷-1,2-二基双(4-甲基苯磺酸酯)(247mg,0.667mmol),随后加入K2CO3(184mg,1.333mmol),将该混合物于100℃搅拌直至经LCMS检测不到起始原料。经LC-MS观察到M+1=626.7。使反应混合物溶于CH2Cl2(100mL),用水(2x50mL)洗涤,有机层经硫酸钠干燥。真空除去溶剂,生成的残留物经硅胶层析,使用乙酸乙酯/己烷的混合物纯化。得到白色的泡沫状物(130mg,65%)LCMS:m/e426.7(MH+),4.393min(方法8).1H NMR(400MHz,氯仿-d)δ7.90(d,J=8.3Hz,2H),7.24-7.11(m,2H),5.30(d,J=1.8Hz,1H),4.70(d,J=2.0Hz,1H),4.60(dd,J=2.3,1.3Hz,1H),2.56(d,J=21.1Hz,1H),2.44-2.33(m,1H),2.26-2.05(m,3H),2.04-1.89(m,1H),1.86(d,J=12.0Hz,1H),1.82-1.58(m,18H),1.56-1.37(m,7H),1.35-1.21(m,6H),1.19-1.06(m,6H),1.03(s,3H),0.99(s,3H),0.93(m,6H)。
步骤2.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸向4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(62mg,0.099mmol)的DCM(4mL)溶液中加入TFA(0.4ml,5.19mmol)。于室温下搅拌该混合物6h。真空除去溶剂,残留物经反相制备型HPLC纯化,得到标题化合物,为白色泡沫状物(15mg,26.6%)LCMS:m/e570.36(MH+),2.363min(方法9).1H NMR(400MHz,甲醇-d4)δ8.02-7.84(m,2H),7.24(d,J=8.3Hz,2H),5.33(s,1H),4.78(s,1H),4.66(s,1H),3.28-3.14(m,1H),2.93-2.72(m,1H),2.59-2.41(m,1H),2.24-1.95(m,2H),1.92-1.68(m,12H),1.56(br.s.,8H),1.31(m,5H),1.19(m,5H)1.10(s,3H),1.06(s,3H),0.99(s,3H),0.97(s,3H)。
实施例178.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羟基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对合成4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸描述的通用程序,使用2-溴代乙醇作为步骤1中的烷化剂,制备标题化合物。分离为白色固体的产物(21.9mg,79.9%).LCMS:m/e588.9(MH+),2.373min(方法9).1H NMR(500MHz,DMSO-d6)δ7.88(d,J=8.2Hz,2H),7.23(d,J=8.2Hz,2H),5.25(d,J=4.9Hz,1H),4.72(s,1H),4.61(s,1H),3.74(m,2H),3.14(br.s.,1H),3.08(m,2H),2.80-2.68(m,1H),2.45(m,1H),2.12-1.94(m,2H),1.93-1.79(m,2H),1.74-1.58(m,8H),1.57-1.29(m,8H),1.28-1.13(m,4H),1.08(s,4H)1.00(3H,s),0.96(3H,s),0.91(6H,s)。
实施例179.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺酰基)哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
步骤1.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺酰基)哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯在密封管中,将4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(30mg,0.048mmol)和1-(甲基磺酰基)哌嗪(78.7mg,0.48mmol)在丙酮(5mL)中的混合物在回流下加热18h。经LCMS检测要求的化合物(M+1=790.7,2.96min,方法9)。
步骤2.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺酰基)哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对步骤2合成4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸描述的通用程序,制备标题化合物。分离为白色固体的产物(48mg,47.5%).LCMS:m/e734.5(MH+),2.35min(方法9).1H NMR(400MHz,甲醇-d4)δ7.95(d,J=8.3Hz,2H),7.24(d,J=8.3Hz,2H),5.36-5.27(m,1H),4.78(s,1H),4.67(s,1H),3.56-3.42(m,6H),3.30(m,3H),3.24-3.09(m,4H),3.06-2.87(m,4H),2.58-2.50(m,1H),2.23-1.99(m,2H),1.94-1.68(m,10H),1.65-1.46(m,8H),1.42-1.24(m,4H)1.19(m,4H)1.10(3H,s),1.06(3H,s),0.99(3H,s),0.97(3H,s)。
实施例180.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-甲氧基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对合成4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺酰基)哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸描述的程序,使用甲醇作为步骤1中的试剂,由4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯制备标题化合物。分离为白色固体的产物(1.6mg,5.2%).LCMS:m/e602.49(MH+),2.40min(方法9).1H NMR(500MHz,甲醇-d4)δ7.85(d,J=7.6Hz,2H),7.12(d,J=7.6Hz,2H),5.29(s,1H),4.79-4.76(s,1H),4.66(s,1H),3.67-3.64(m,2H),3.43(s,3H),3.21-3.15(m,3H),2.69-2.62(m,1H),2.52(m,1H),2.19-2.10(m,1H),2.07-2.00(m,1H),1.79(m,8H),1.57(m,8H),1.40-1.24(m,7H),1.18(m,4H),1.09(3H,s),1.05(3H,s),0.97(3H,s),0.96(3H,s)。
实施例181.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(羟基甲基)哌啶-1-基)乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
按照以上对合成4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺酰基)哌嗪-1-基)乙基氨基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸描述的程序,使用哌啶-4-基甲醇作为步骤1中的试剂,由4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯制备标题化合物。分离为白色固体的产物(5mg,16.7%).LCMS:m/e685.5(MH+),2.33min(方法9).1HNMR(400MHz,甲醇-d4)δ7.90(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),5.28(d,J=4.5Hz,1H),4.74(br.s.,1H),4.63(br.s.,1H),3.74-3.38(m,8H),3.07(br.s.,2H),2.98-2.85(m,2H),2.48(br.s.,1H),2.21-1.93(m,4H),1.90-1.64(m,11H),1.63-1.40(m,10H),1.39-1.24(m,4H),1.23-1.09(m,4H),1.04(m,6H),0.94(m,6H)。
实施例182.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代噁唑烷-3-基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸
步骤1.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((叔-丁氧羰基(2-羟基乙基)氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯使4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羟基乙基氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(600mg,0.932mmol)溶于CH2Cl2(10mL),加入BOC2O(0.260mL,1118mmol),随后加入Hunig′s碱(0.163mL,0.932mmol)以形成无色溶液,将其于0℃搅拌6hrs。LCMS指示形成要求的产物(M+23=767)。真空除去溶剂,得到的白色固体原样用于下一步骤。
步骤2.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((叔-丁氧羰基(2-羟基乙基)氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯使4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((叔-丁氧羰基)(2-羟基乙基)氨基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸叔-丁基酯(133mg,0.179mmol)溶于CH2Cl2(5mL)并使该溶液在0℃冷却。加入甲烷磺酰氯(30.7mg,0.268mmol),随后加入TEA(0.050mL,0.357mmol)并将该混合物搅拌18h。除去溶剂,得到的残留物经硅胶层析纯化,得到标题化合物,为白色固体(100mg,83.3%).1HNMR(400MHz,氯仿-d)δ7.95-7.86(m,J=8.3Hz,2H),7.24-7.10(m,J=8.3Hz,2H),5.36-5.24(m,1H),4.82-4.68(m,1H),4.62(s,1H),4.39-4.26(m,2H),3.75-3.59(m,2H),3.46(d,J=13.8Hz,1H),3.10(d,J=14.3Hz,1H),2.58-2.39(m,1H),2.24-2.04(m,2H),1.98-1.69(m,8H),1.69-1.58(m,12H),1.57-1.39(m,8H),1.36-1.22(m,4H),1.21-1.07(m,5H),1.07-0.97(m,6H),0.97-0.80(m,6H)。
步骤3.制备4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-氧代噁唑烷-3-基)甲基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸按照以上对合成4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮杂环丙烷-1-基甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-八氢-1H-环戊二烯并[a]-9-基)苯甲酸描述的程序的步骤2,制备标题化合物。分离为白色固体的产物(15mg,14.7%).LCMS:m/e614.5(MH+),2.47min(方法8).1H NMR(400MHz,氯仿-d)δ8.02(d,J=8.3Hz,2H),7.24(d,J=8.3Hz,2H),5.32(d,J=4.5Hz,1H),4.74(s,1H),4.62(s,1H),4.34(t,J=7.9Hz,2H),3.81-3.59(m,2H),3.47(m,2H),3.20-3.00(m,1H),2.51(td,J=11.2,5.5Hz,1H),2.26-2.06(m,2H),1.97-1.66(m,10H),1.50-1.22(m,10H),1.15(s,4H),1.06-0.83(m,13H)。
实施例的生物学数据
·“μM”意指微摩尔;
·“mL”意指毫升;
·“μl”意指微升;
·“mg”意指毫克;
·“μg”意指微克;
用于获得表1-2中报告的结果的物质和实验程序在下文描述。
HIV细胞培养测定-MT-2细胞和293T细胞自NIH AIDS研究和参考试剂计划(NIH AIDS Research and Reference Reagent Program)获得。MT-2细胞在补充有10%热灭活胎牛血清、100μg/ml青霉素G和至多100单位/ml链霉素的RPMI1640培养基中繁殖。293T细胞在补充有10%热灭活胎牛血清(FBS)、100单位/ml青霉素G和100μg/ml链霉素的DMEM培养基中繁殖。NL4-3的前病毒DNA克隆自NIH AIDS研究和参考试剂计划(NIH AIDS Research and Reference ReagentProgram)获得。重组NL4-3病毒,其中来自NL4-3的nef基因的片段被Renilla荧光素酶基因替换,被用作参照病毒。此外,残基Gag P373被转化为P373S。简言之,重组病毒通过改变的NL4-3前病毒克隆的转染来制备。转染在293T细胞中使用得自Invitrogen(Carlsbad,CA)的LipofectAMINE PLUS,依据生产商的指示进行。病毒在MT-2细胞中使用荧光素酶活性作为标记物来滴定。荧光素酶使用得自Promega(Madison,WI)的二元荧光素酶试剂盒,采用修改的生产商的方案进行定量。使稀释的被动溶胞溶液与再悬浮的荧光素酶分析试剂和再悬浮的终止和Glo底物(Stop&Glo Substrate)预混合(2∶1∶1比例)。将五十(50)μL的该混合物加入测定板上的每一个抽吸空中,而荧光素酶活性立即在Wallac TriLux(Perkin-Elmer)上测定。抑制剂对重组病毒的抗病毒活性通过在抑制剂的系列稀释液的存在下,测定感染NLRluc重组体4-5天的细胞中荧光素酶活性进行定量。化合物的EC50数据示于表2。表1是表2中的数据的检索表。
结果
表1.EC50的生物学数据的检索表
EC50>0.1μM的化合物 | EC50<0.1μM的化合物 |
“B”组 | “A”组 |
表2
前文所述仅仅是说明性的且不应该理解为以任何方式限制本发明范围或基本原理。确实,本发明的各种修饰,除了本文所述和所示的那些外,对本领域技术人员而言,将从以下实施例和前文的描述中而变得显而易见。这样的修饰也意欲落入所附的权利要求书的范围内。
Claims (15)
1.化合物,包括其药学上可接受的盐,其选自:
式I化合物
式II化合物
式III化合物
其中R1为异丙烯基或异丙基;
J和E独立地为–H或–CH3和当存在双键时,E不存在;
X为被A取代的苯基或杂芳基环,其中A为选自以下基团的至少一个成员:-H、-卤代、-羟基、-C1-6烷基、-C1-6烷氧基和-COOR2;
R2为-H、-C1-6烷基或-烷基取代的C1-6烷基或–芳基取代的C1-6烷基;
Y选自–COOR2,-C(O)NR2SO2R3、-C(O)NHSO2NR2R2、-NR2SO2R2、-SO2NR2R2、-C3-6环烷基-COOR2、-C1-6烯基-COOR2、-C1-6炔基-COOR2、-C1-6烷基-COOR2、-NHC(O)(CH2)n-COOR2、-SO2NR2C(O)R2、-四唑和–CONHOH,其中n=1-6;
R3为-C1-6烷基或烷基取代的C1-6烷基;
R4选自H、-C1-6烷基、-C3-6环烷基、-C1-6 取代的烷基、-C1-6烷基-杂芳基、-C1-6烷基-取代的杂芳基、-C1-6烷基-NR6R7、-C1-6烷基-CONR8R9、-C3-6环烷基-CONR8R9、-C3-6环烷基-(CH2) 1-3-NR6R7、-(CH2) 1-3-C3-6环烷基-NR6R7、-(CH2) 1-3-C3-6环烷基-(CH2)1-3-NR6R7、-C1-6烷基-Q1、C3-6环烷基-Q1、-COR10、-SO2R3和-SO2NR2R2;
Q1 = -羟基、-COOR2、-卤代、-SO2Ra;
Rb= -H、-C1-6烷基、-COR3、-SO2R3、-SONR3R3;
R4也可选自:
R5选自-H、-C1-6烷基、-C3-6环烷基、-C1-6烷基取代的烷基、-COR10、-SO2R3和-SO2NR2R2;
前提是R4或R5只有一个可选自-COR10、–SO2R3和-SO2NR2R2;
或R4和R5与邻近的N结合在一起形成环如
R10选自-H、-C1-6烷基、-C1-6烷基-NR6R7、-NR11R12、-OR13、-C1-6烷基-Q2、-C3-6环烷基-Q2、芳基-Q2,其中n =1-6,
其中Q2 = 羟基、-COOR2、-卤代、SO2Ra、-CONHSO2R3、-CONHSO2NR2R2;
R10也可选自:
R6和R7独立地选自-H、-C1-6烷基、-C1-6 取代的烷基、芳基、杂芳基、取代的芳基、取代的杂芳基,和-C1-6烷基-Q1,
或者R6和R7与邻近的N结合在一起形成选自以下的环
Rc= C1-6烷基, NR2R2、-COOR3;
R8和R9独立地选自-H、-C1-6烷基、-C3-6环烷基、-C1-6 取代的烷基、-C1-6烷基-杂芳基、-C1-6烷基-取代的杂芳基、-C1-6烷基-NR2R2、-C1-6烷基-CONR2R2、-C1-6烷基-Q1、C3-6环烷基-Q1,
或者R8和R9也可独立地选自
或R8和R9与邻近的N结合在一起形成选自以下的环:
以及R11和R12独立地选自-H、-C1-6烷基、-C3-6环烷基,和-C1-6烷基取代的烷基;
或者R11和R12与邻近的N结合在一起形成选自以下的环
R13选自–H、C1-6烷基、-C1-6烷基取代的烷基,和-C1-6烷基NR14R15,其中
R14和R15独立地选自–H、-C1-6烷基,和-C1-6烷基取代的烷基,或R14和R15与邻近的N结合在一起形成选自以下的环
2.权利要求1要求的化合物,其中所述化合物具有式I。
3.权利要求2要求的化合物,其中X为苯基环,和Y在对位。
4.权利要求3要求的化合物,其中X为取代的苯基环。
5.权利要求4要求的化合物,其中所述苯基环被A取代,且A为选自以下基团的至少一个成员:–H、-OH和-F。
6.权利要求5要求的化合物,其中Y为-COOH。
7.权利要求4要求的化合物,其中X为苯基环和Y为依据式Ia的对位的-COOH
。
8.权利要求7要求的化合物,其中A为选自以下基团的至少一个成员:–H、-OH和-F。
9.权利要求8要求的化合物,其中A为–H或-F。
12.一种药用组合物,其包含与一种或多种药学上可接受的载体、赋形剂或稀释剂一起的抗病毒有效量的一种或多种权利要求1要求的化合物。
13.用于治疗HIV的感染的权利要求12的药用组合物,其另外包含抗病毒有效量的选自以下的AIDS治疗剂:
(a) AIDS抗病毒剂;
(b) 抗-感染剂;
(c) 免疫调节剂;和
(d) 另一种HIV进入抑制剂。
14.一种治疗感染HIV病毒的哺乳动物的方法,其包括给予所述哺乳动物抗病毒有效量的权利要求1要求的化合物,以及一种或多种药学上可接受的载体、赋形剂或稀释剂。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107250151A (zh) * | 2014-11-14 | 2017-10-13 | Viiv保健英国第五有限公司 | 扩展的桦木酸类似物 |
CN107250153A (zh) * | 2014-11-14 | 2017-10-13 | Viiv保健英国第五有限公司 | 氧代羽扇豆烯衍生物 |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2012312485B2 (en) | 2011-09-21 | 2016-09-01 | VIIV Healthcare UK (No.5) Limited | Novel betulinic acid derivatives with antiviral activity |
US8906889B2 (en) * | 2012-02-15 | 2014-12-09 | Bristol-Myers Squibb Company | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
US8889854B2 (en) | 2012-05-07 | 2014-11-18 | Bristol-Myers Squibb Company | C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity |
RU2516952C1 (ru) * | 2012-11-09 | 2014-05-20 | Леонид Леонидович Клопотенко | Фармацевтическая композиция, содержащая инкапсулированную тритерпеновую кислоту или ее производные |
RU2519133C1 (ru) * | 2012-11-09 | 2014-06-10 | Леонид Леонидович Клопотенко | Мазь, содержащая инкапсулированную тритерпеновую кислоту или ее производные |
CN103214543B (zh) * | 2012-12-25 | 2015-09-02 | 中国人民解放军海军医学研究所 | 新山楂酸衍生物、其制备方法及其在抗肿瘤药物中的应用 |
EP2953960A1 (en) * | 2013-02-06 | 2015-12-16 | Bristol-Myers Squibb Company | C-19 modified triterpenoids with hiv maturation inhibitory activity |
KR20150121712A (ko) * | 2013-02-25 | 2015-10-29 | 브리스톨-마이어스 스큅 컴퍼니 | Hiv의 치료에 유용한 c-3 알킬 및 알케닐 개질된 베툴린산 유도체 |
MA39374A1 (fr) | 2014-04-11 | 2018-06-29 | Viiv Healthcare Uk No 4 Ltd | Triterpénoïdes présentant une activité d'inhibition de la maturation du vih, substitués en 3ème position par un cycle non aromatique portant un substituant halogénoalkyle |
US9920090B2 (en) | 2014-06-19 | 2018-03-20 | VIIV Healthcare UK (No.5) Limited | Betulinic acid derivatives with HIV maturation inhibitory activity |
RU2017118576A (ru) | 2014-11-14 | 2018-12-14 | ВАЙВ ХЕЛТКЕР ЮКей (N5) ЛИМИТЕД | C-17-арил-замещённые аналоги бетулиновой кислоты |
US10221208B2 (en) * | 2015-04-14 | 2019-03-05 | ViiV Healthcare UK (No.4) Limited | Methods of producing an HIV maturation inhibitor |
WO2017017609A1 (en) | 2015-07-28 | 2017-02-02 | Glaxosmithkline Intellectual Property (No.2) Limited | Betuin derivatives for preventing or treating hiv infections |
JP2018521107A (ja) * | 2015-07-28 | 2018-08-02 | グラクソスミスクライン、インテレクチュアル、プロパティー、(ナンバー2)、リミテッドGlaxosmithkline Intellectual Property (No.2) Limited | Hiv感染を予防または治療するためのベツイン誘導体 |
KR20180054826A (ko) | 2015-09-24 | 2018-05-24 | 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 | Hiv 성숙 억제 활성을 갖는 화합물 |
WO2017125870A1 (en) | 2016-01-20 | 2017-07-27 | Glaxosmithkline Intellectual Property (No.2) Limited | Amine derivatives of lupanes with hiv maturation inhibitory activity |
AR107512A1 (es) | 2016-02-04 | 2018-05-09 | VIIV HEALTHCARE UK Nº 5 LTD | Triterpenoides modificados en c-3 y c-17 como inhibidores del vih-1 |
EP3478703A1 (en) * | 2016-06-30 | 2019-05-08 | ViiV Healthcare UK (No.5) Limited | Triterpenoid inhibitors of human immunodeficiency virus replication |
EP3681507B8 (en) * | 2017-09-13 | 2024-03-13 | Emmyon, Inc. | Ursolic acid morpholine and diethanolamine salts |
CN111417384A (zh) | 2017-09-14 | 2020-07-14 | 菲尼克斯生物技术公司 | 用于治疗神经系统病况的方法和改进的神经保护性组合物 |
IL285232B (en) | 2017-09-14 | 2022-07-01 | Phoenix Biotechnology Inc | Preparations containing oleandrin for the treatment of viral infection |
JP7436385B2 (ja) | 2018-04-24 | 2024-02-21 | ヴィーブ ヘルスケア ユーケー(ナンバー5)リミテッド | Hiv成熟阻害活性を有する化合物 |
PL237998B1 (pl) | 2018-05-28 | 2021-06-28 | Narodowy Inst Lekow | Fosfonowe pochodne kwasu 3-karboksyacylobetulinowego, sposób ich otrzymywania oraz ich zastosowanie |
US10343997B1 (en) | 2018-12-04 | 2019-07-09 | King Saud University | Ursolic acid derivatives |
KR20220151038A (ko) | 2020-03-31 | 2022-11-11 | 피닉스 바이오테크놀러지 인코포레이티드. | 코로나바이러스 감염 예방를 위한 조성물 |
EP4009981B1 (en) | 2020-03-31 | 2023-08-16 | Phoenix Biotechnology, Inc. | Method and compositions for treating coronavirus infection |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101142227A (zh) * | 2004-11-12 | 2008-03-12 | 帕纳克斯医药公司 | 新颖的桦木醇衍生物、其制备和其用途 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5413999A (en) | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
US5962527A (en) | 1995-03-21 | 1999-10-05 | The Board Of Trustees Of The University Of Illinois | Method and composition for treating cancers |
US5869535A (en) | 1995-03-21 | 1999-02-09 | The Board Of Trustees Of The University Of Illinois | Method and composition for selectively inhibiting melanoma |
US5679828A (en) | 1995-06-05 | 1997-10-21 | Biotech Research Labs, Inc. | Betulinic acid and dihydrobetulinic acid derivatives and uses therefor |
US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
US7365221B2 (en) | 2002-09-26 | 2008-04-29 | Panacos Pharmaceuticals, Inc. | Monoacylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof |
US20050014730A1 (en) | 2003-04-02 | 2005-01-20 | Carlson Robert M. | Anti-fungal formulation of triterpene and essential oil |
US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
US20050239748A1 (en) | 2004-03-17 | 2005-10-27 | Panacos Pharmaceuticals, Inc. | Pharmaceutical salts of 3-O-(3',3'-dimethylsuccinyl) betulinic acid |
TW200628161A (en) | 2004-11-12 | 2006-08-16 | Panacos Pharmaceuticals Inc | Novel betulin derivatives, preparation thereof and use thereof |
WO2008127364A2 (en) | 2006-10-13 | 2008-10-23 | Myriad Genetics, Inc. | Antiviral compounds and use thereof |
US20110144069A1 (en) | 2006-10-16 | 2011-06-16 | Myriad Genetics, Incorporated | Compounds for treating viral infections |
CA2714049A1 (en) | 2008-02-14 | 2009-08-20 | Virochem Pharma Inc. | Novel 17.beta. lupane derivatives |
US9067966B2 (en) | 2009-07-14 | 2015-06-30 | Hetero Research Foundation, Hetero Drugs Ltd. | Lupeol-type triterpene derivatives as antivirals |
WO2011153315A1 (en) * | 2010-06-04 | 2011-12-08 | Bristol-Myers Squibb Company | Modified c-3 betulinic acid derivatives as hiv maturation inhibitors |
EP2576586B1 (en) * | 2010-06-04 | 2015-08-12 | Bristol-Myers Squibb Company | C-28 amides of modified c-3 betulinic acid derivatives as hiv maturation inhibitors |
BR112013019419A2 (pt) * | 2011-01-31 | 2019-12-03 | Bristol-Myers Squibb Company | triterpenoides modificados por c-17 e c-3 com atividade inibitória de maturação de hiv |
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2012
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101142227A (zh) * | 2004-11-12 | 2008-03-12 | 帕纳克斯医药公司 | 新颖的桦木醇衍生物、其制备和其用途 |
Non-Patent Citations (1)
Title |
---|
YONG-MING ZHU,等: "Synthesis and Anti-HIV Activity of Oleanolic Acid Derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107250151A (zh) * | 2014-11-14 | 2017-10-13 | Viiv保健英国第五有限公司 | 扩展的桦木酸类似物 |
CN107250153A (zh) * | 2014-11-14 | 2017-10-13 | Viiv保健英国第五有限公司 | 氧代羽扇豆烯衍生物 |
Also Published As
Publication number | Publication date |
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EP2670764B1 (en) | 2015-09-02 |
MX2013008359A (es) | 2013-08-27 |
SMT201500303B (it) | 2016-01-08 |
DK2670764T3 (en) | 2015-12-07 |
BR112014010105A2 (pt) | 2017-06-13 |
EP2670764A1 (en) | 2013-12-11 |
EA201391098A1 (ru) | 2013-12-30 |
SI2670764T1 (sl) | 2016-03-31 |
PT2670764E (pt) | 2015-11-20 |
PL2670764T3 (pl) | 2016-02-29 |
ES2552512T3 (es) | 2015-11-30 |
CN103339141B (zh) | 2016-08-24 |
US20130029954A1 (en) | 2013-01-31 |
HUE026371T2 (en) | 2016-05-30 |
CA2826257A1 (en) | 2012-08-09 |
RS54352B1 (en) | 2016-02-29 |
US8748415B2 (en) | 2014-06-10 |
JP6000283B2 (ja) | 2016-09-28 |
EA023578B1 (ru) | 2016-06-30 |
WO2012106188A1 (en) | 2012-08-09 |
CY1116989T1 (el) | 2017-04-05 |
JP2014507422A (ja) | 2014-03-27 |
HRP20151212T1 (hr) | 2015-12-04 |
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