CN117396455A - 间苯二酚、其制造方法及其用途 - Google Patents
间苯二酚、其制造方法及其用途 Download PDFInfo
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- CN117396455A CN117396455A CN202280034811.6A CN202280034811A CN117396455A CN 117396455 A CN117396455 A CN 117396455A CN 202280034811 A CN202280034811 A CN 202280034811A CN 117396455 A CN117396455 A CN 117396455A
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- 238000004519 manufacturing process Methods 0.000 title claims description 29
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 title description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 246
- 238000000034 method Methods 0.000 claims abstract description 102
- 238000011282 treatment Methods 0.000 claims abstract description 51
- 230000008569 process Effects 0.000 claims abstract description 28
- 206010010904 Convulsion Diseases 0.000 claims description 54
- -1 cachet Substances 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 17
- 206010015037 epilepsy Diseases 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 230000003647 oxidation Effects 0.000 claims description 14
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 239000012279 sodium borohydride Substances 0.000 claims description 14
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 14
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 12
- 239000003921 oil Substances 0.000 claims description 12
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 11
- 230000009467 reduction Effects 0.000 claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 238000006735 epoxidation reaction Methods 0.000 claims description 8
- 239000004615 ingredient Substances 0.000 claims description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 6
- 229960001553 phloroglucinol Drugs 0.000 claims description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 5
- 239000005973 Carvone Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 208000028326 generalized seizure Diseases 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- 208000034308 Grand mal convulsion Diseases 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 235000010603 pastilles Nutrition 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 4
- 208000028325 tonic-clonic seizure Diseases 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 239000003086 colorant Substances 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- 239000006196 drop Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000006260 foam Substances 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 239000007937 lozenge Substances 0.000 claims description 3
- 230000000873 masking effect Effects 0.000 claims description 3
- 239000002324 mouth wash Substances 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000006072 paste Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 239000000080 wetting agent Substances 0.000 claims description 3
- QTTZLMGXPHZYKR-UHFFFAOYSA-N 1-(trifluoromethylsulfonyl)benzotriazole Chemical compound C1=CC=C2N(S(=O)(=O)C(F)(F)F)N=NC2=C1 QTTZLMGXPHZYKR-UHFFFAOYSA-N 0.000 claims description 2
- YGABUCCNCBMODG-UHFFFAOYSA-N 1-(trifluoromethylsulfonyl)imidazole Chemical compound FC(F)(F)S(=O)(=O)N1C=CN=C1 YGABUCCNCBMODG-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- UIFJOXOHICDFDO-UHFFFAOYSA-N benzene-1,3,5-triol Chemical compound OC1=CC(O)=CC(O)=C1.OC1=CC(O)=CC(O)=C1 UIFJOXOHICDFDO-UHFFFAOYSA-N 0.000 claims description 2
- TUFGVZMNGTYAQD-UHFFFAOYSA-N comins' reagent Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=C(Cl)C=N1 TUFGVZMNGTYAQD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003708 ampul Substances 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 229940051866 mouthwash Drugs 0.000 claims 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims 1
- 229940098465 tincture Drugs 0.000 claims 1
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 3
- 208000037765 diseases and disorders Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 238000004128 high performance liquid chromatography Methods 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 238000012360 testing method Methods 0.000 description 41
- 150000003839 salts Chemical class 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
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- 230000000694 effects Effects 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
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- 239000000543 intermediate Substances 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229960001755 resorcinol Drugs 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
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- 239000012267 brine Substances 0.000 description 11
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- 229910052736 halogen Inorganic materials 0.000 description 8
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- 238000002953 preparative HPLC Methods 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
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- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- BAVONGHXFVOKBV-UWVGGRQHSA-N (+)-cis-carveol Chemical compound CC(=C)[C@H]1CC=C(C)[C@@H](O)C1 BAVONGHXFVOKBV-UWVGGRQHSA-N 0.000 description 5
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- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
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- C07C39/42—Halogenated derivatives containing six-membered aromatic rings and other rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
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- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/34—One oxygen atom
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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Abstract
本发明涉及一组作为药物活性化合物的间苯二酚衍生物及其制备方法。间苯二酚衍生物已经被用于治疗多种疾病和紊乱。虽然这样的治疗保持前景,但在本领域中仍存在对更有效的治疗的需求,并且这已经通过本发明的间苯二酚衍生物实现。
Description
相关申请
本申请与2021年5月12日(12.05.2021)提交的GB 2106787.1相关,并且要求GB2106787.1的权益,GB 2106787.1的内容据此通过引用以其整体并入。
发明领域
本发明涉及一组间苯二酚衍生物、其制造方法以及这些化合物作为研究工具和作为药物的用途。
发明背景
众所周知,间苯二酚是一种通用的(versatile)化合物,广泛用于先进化学和技术的开发(Durairaj,2005)。间苯二酚已经被用于从医学到化学的大范围的应用,包括树脂、塑料、染料、药物和许多其他有机化合物的制造。
间苯二酚呈现为白色晶体或粉末,并且具有微弱的特征性芳香气味,具有微甜的苦味,并且易溶于水和醇。该化合物的其他名称包括间苯二酚(resorcin)、间二羟基苯、1,3-二羟基苯、1,3-苯二酚和3-羟基苯酚,并且其经验式是C6H6O2。在结构上,该化合物在芳香族环结构中具有两个羟基基团,这两个羟基基团位于相对于每个羟基基团的间位。间苯二酚的高反应性主要与苯环中的这两个羟基基团的位置相关,邻近羟基基团的氢原子是特别具有反应性的。
间苯二酚的产生可以经由若干种途径,或通过使用天然树脂诸如巴西木(brazilwood)的蒸馏物,使大量树脂(诸如古蓬香脂(galbanum)和阿魏胶(asafoetida))中的任何树脂熔化并且将其与氢氧化钾组合,或通过若干种合成方法。一种合成制造方法是将苯用硫酸磺化,并且将所得到的苯二磺酸与氢氧化钠融合(fuse),并且随后提取间苯二酚。
间苯二酚的用途中的一种是作为用于合成药物和其他有机化合物的化学中间体。例如,它被用于产生重氮染料和增塑剂,并且被用作树脂中的UV吸收剂。作为药物,间苯二酚在用于治疗皮肤紊乱和皮肤感染的外用(topical)药物产品中被用作防腐剂和消毒剂,所述皮肤紊乱和皮肤感染为诸如痤疮、脂溢性皮炎、湿疹、银屑病、鸡眼、胼胝和疣。间苯二酚通过帮助去除坚硬、鳞状或粗糙的皮肤来起作用,因为其发挥角质溶解活性。然而,间苯二酚的主要用途是在树脂生产中。与甲醛的反应产生树脂,该树脂用于使人造丝和尼龙易于被橡胶浸渍,并且用作粘合剂。
根据这些考虑已经设计了本发明。
发明简述
最一般地,本发明涉及一组间苯二酚化合物,该组间苯二酚化合物具有生物活性,并且因此可用于治疗疾病。这样的化合物可以通过多种途径施用,所述多种途径包括但不限于口服、经皮、含服、鼻、肺、直肠或眼部。这样的化合物可以用于治疗或预防包括但不限于癫痫的医学状况。
在本发明的第一方面中,提供了式(I)的化合物,或其盐:
其中:
R1是CH3、CH2CH3、Cl、
在本发明的第二方面中,提供了式(II)的化合物,或其盐:
其中:
R1是CH2CH2CH3、Br、
R2是CH3、F或Cl;并且
R3是H或CH3。
在本发明的第三方面中,提供了式(III)的化合物,或其盐:
其中:
R1是CH2CH2CH3或(CH2)4CH3;
R2是H或CH3;并且
R3是H或CH3。
在本发明的第四方面中,提供了式(IV)的化合物,或其盐:
其中:
R1是CH2CH2CH3或
在本发明的第六方面中,提供了一种药物组合物,该药物组合物包含第一方面、第二方面、第三方面、第四方面或第五方面的化合物或其盐,连同一种或更多种选自以下的成分:载体、稀释剂、赋形剂、辅料、填充剂、缓冲剂、粘合剂、崩解剂、防腐剂、抗氧化剂、润滑剂、稳定剂、增溶剂、表面活性剂(例如,润湿剂)、掩蔽剂、着色剂、调味剂和甜味剂。
在优选的实施方案中,第六方面的药物组合物呈选自液体、溶液、悬浮液、乳液、糖浆、冲剂(electuary)、漱口水、滴剂、片剂、颗粒剂、粉末、锭剂、软锭剂(pastille)、胶囊、扁囊剂、丸剂、安瓿、大丸剂(bolus)、栓剂(suppository)、阴道栓剂(pessary)、酊剂、凝胶、糊剂、软膏、乳膏、洗剂、油、泡沫、喷雾剂和气雾剂的形式。
在本发明的第七方面中,提供了第一方面、第二方面、第三方面、第四方面或第五方面的化合物,或其盐,或第六方面的药物组合物,用于在治疗方法中使用。
优选地,第七方面的治疗方法是癫痫、全身性癫痫发作、局灶起源癫痫发作或强直性-阵挛性癫痫发作的治疗方法。
在本发明的第八方面中,提供了第一方面、第二方面、第三方面、第四方面或第五方面的化合物,或其盐,或第六方面的药物组合物,用于作为药物使用。
优选地,第八方面的药物是用于治疗癫痫、全身性癫痫发作、局灶起源癫痫发作或强直性-阵挛性癫痫发作的药物。
在本发明的第九方面中,提供了一种治疗方法,该治疗方法包括向需要治疗的受试者施用治疗有效量的第一方面、第二方面、第三方面、第四方面或第五方面的化合物,或其盐,或第六方面的药物组合物。
在本发明的第十方面中,提供了一种制备式(I)的化合物的方法,该方法包括:
i)使式(V)的化合物与式(VI)的化合物反应:
其中:
R1是H、Ac、Piv、Bz或PMB;
R2和R3独立地是H、Ac或Piv;
R4和R5是OH,或者R4和R5一起形成-C(Me)2C(Me)2C-;
X1是Br、I或OTf;并且
Y选自:
在本发明的第十一方面中,提供了中间体,该中间体选自式(V)的化合物和式(IX)的化合物:
其中:
R1是H、Ac、Piv、Bz或PMB;
R2和R3独立地是H、Ac或Piv;
X1是Br、I或OTf;并且
R15是H、Bz或PMB。
下面更详细地描述本发明的这些和其他方面以及实施方案。
附图简述
参考下文列出的附图描述本发明:
图1示出了化合物2、化合物46和化合物56在小鼠的mini-MEST测试中的效果。
图2示出了化合物3在小鼠的mini-MEST测试中的效果。
图3示出了化合物5和化合物10在小鼠的mini-MEST测试中的效果。
图4示出了化合物8和化合物18在小鼠的mini-MEST测试中的效果。
图5示出了化合物15、化合物16、化合物45和化合物53在小鼠的mini-MEST测试中的效果。
图6示出了化合物17在小鼠的mini-MEST测试中的效果。
图7示出了化合物19、化合物41和化合物58在小鼠的mini-MEST测试中的效果。
图8示出了化合物7在小鼠的mini-MEST测试中的效果。
图9示出了化合物9、化合物49和化合物52在小鼠的mini-MEST测试中的效果。
图10示出了化合物26在小鼠的mini-MEST测试中的效果。
图11示出了化合物29、化合物30、化合物31和化合物33在小鼠的mini-MEST测试中的效果。
图12示出了化合物35、化合物42和化合物47在小鼠的mini-MEST测试中的效果。
发明详述
本发明涉及一组间苯二酚化合物,该组间苯二酚化合物具有生物活性,并且因此可用于治疗疾病。
间苯二酚
式(I)
在本发明的第一方面中,提供了式(I)的化合物,或其盐:
其中:
R1是CH3、CH2CH3、Cl、
在优选的实施方案中,R1是CH3、CH2CH3、Cl、
在更优选的实施方案中,R1是CH2CH3、Cl、
在甚至更优选的实施方案中,R1是Cl、
式(II)
在本发明的第二方面中,提供了式(II)的化合物,或其盐:
其中:
R1是CH2CH2CH3、Br、
R2是CH3、F或Cl;并且
R3是H或CH3。
在优选的实施方案中,R1是CH2CH2CH3、Br、
在优选的实施方案中,R2是CH3或Cl。
在优选的实施方案中,R3是H。
式(III)
在本发明的第三方面中,提供了式(III)的化合物,或其盐:
其中:
R1是CH2CH2CH3或(CH2)4CH3;
R2是H或CH3;并且
R3是H或CH3。
在优选的实施方案中,R1是CH2CH2CH3。
式(IV)
在本发明的第四方面中,提供了式(IV)的化合物,或其盐:
其中:
R1是CH2CH2CH3或
在优选的实施方案中,R1是CH2CH2CH3。
盐
在一些实施方案中,式(I)、式(II)、式(III)或式(IV)的化合物以游离碱形式提供。
可选择地,制备、纯化和/或处理化合物的对应盐例如药学上可接受的盐,可能是方便的或合意的。药学上可接受的盐的实例在“Pharmaceutical Salts:Properties,Selection,and Use”,第2版,2002,Stahl和Wermuth(编辑),Wiley-VCH,Weinheim,Germany中讨论。
因此,在一些实施方案中,式(I)、式(II)、式(III)或式(IV)的化合物作为盐提供,例如以质子化的形式与合适的抗衡阴离子一起提供。
合适的抗衡阴离子包括有机阴离子和无机阴离子两者。合适的无机阴离子的实例包括那些衍生自无机酸的阴离子,包括氯离子(Cl-)、溴离子(Br-)、碘离子(I-)、硫酸根(SO4 2-)、亚硫酸根(SO3 2-)、硝酸根(NO3 -)、亚硝酸根(NO2 -)、磷酸根(PO4 3-)和亚磷酸根(PO3 3-)。合适的有机阴离子的实例包括2-乙酰氧基苯甲酸根、乙酸根、抗坏血酸根、天冬氨酸根、苯甲酸根、樟脑磺酸根、肉桂酸根、柠檬酸根、依地酸根、乙二磺酸根、乙磺酸根、甲酸根、富马酸根、葡萄糖酸根、谷氨酸根、乙醇酸根、羟基苹果酸根、羧酸根、乳酸根、月桂酸根、马来酸根、苹果酸根、甲磺酸根、油酸根、草酸根、棕榈酸根、苯乙酸根、苯磺酸根、丙酸根、丙酮酸根、水杨酸根、硬脂酸根、琥珀酸根、磺胺酸根(sulfanilate)、酒石酸根、甲苯磺酸根和戊酸根。合适的聚合物有机阴离子的实例包括衍生自单宁酸和羧甲基纤维素的那些阴离子。
可选择地,在一些实施方案中,式(I)、式(II)、式(III)或式(IV)的化合物作为盐提供,例如以去质子化的形式与合适的抗衡阳离子一起提供。
合适的抗衡阳离子包括有机阳离子和无机阳离子两者。合适的无机阳离子的实例包括碱金属离子诸如Na+和K+、碱土金属阳离子诸如Ca2+和Mg2+和其他阳离子诸如Al3+。合适的有机阳离子的实例包括铵离子(即,NH4 +)和被取代的铵离子(例如,NH3R+、NH2R2 +、NHR3 +、NR4 +)。被取代的铵离子的实例包括衍生自乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺(meglumine)和氨丁三醇以及氨基酸诸如赖氨酸和精氨酸的那些。常见的季铵离子的实例是N(CH3)4 +。
溶剂化物
在一些实施方案中,式(I)、式(II)、式(III)或式(IV)的化合物以去溶剂化形式提供,例如以脱水形式提供。
可选择地,制备、纯化和/或处理该化合物的对应的溶剂化物可能是方便的或合意的。
因此,在一些实施方案中,式(I)、式(II)、式(III)或式(IV)的化合物以溶剂化物(溶质(例如,化合物、化合物的盐)和溶剂的复合物)的形式提供。溶剂化物的实例包括水合物,例如一水合物、二水合物和三水合物。
某些异构体
式(I)、式(II)、式(III)或式(IV)的某些化合物可以以一种或更多种特定的光学形式、对映异构体形式、非对映异构体形式、差向异构体形式、立体异构体形式、互变异构体形式或构象形式存在,包括但不限于D-形式和L-形式;d-形式和l-形式;(+)形式和(-)形式;顺式形式和反式形式;轴向-形式和赤道-形式;船形式、椅形式、扭船式形式、信封形式和半椅形式;及其组合,下文统称为“异构体”或“异构体形式”。
从如本文所使用的术语“异构体”中明确排除的是结构(或组成)异构体(即,不同之处在于原子之间的连接而不是仅仅在于原子在空间中的位置的异构体)。例如,提及甲氧基基团-OCH3不应被解释为提及其结构异构体羟甲基基团-CH2OH。
上述排除不适用于互变异构体形式,例如酮形式、烯醇形式和烯醇盐形式,例如如在以下互变异构体对中:酮/烯醇、亚胺/烯胺、酰胺/亚氨基醇、亚硝基/肟和内酰胺/内酰亚胺(lactim)。
术语“异构体”包括具有一个或更多个同位素取代的化合物。例如,H可以呈任何同位素形式,包括1H、2H(D)和3H(T);C可以呈任何同位素形式,包括12C、13C和14C;O可以呈任何同位素形式,包括16O和8O;等等。
除非另有说明,否则提及特定化合物包括所有这样的异构体形式,包括(全部或部分地)外消旋混合物和其其他混合物。
合成方法
间苯二酚的合成
PCT/GB2020/052942公开了合成大麻二酚(CBD)的6-羟基类似物的方法。PCT/GB2020/052944公开了合成次大麻二酚的6-羟基类似物的方法。这两种方法均涉及使用铬氧化剂氧化天然大麻素。
发明人已经发现了改进的合成方法,该改进的合成方法允许以较高收率和较高可靠性产生6-羟基化合物。此外,本发明的方法允许使用后期交叉偶联反应以在间苯二酚尾部安装多种官能团。最后,该方法避免使用有毒的、基于铬的氧化剂。
偶联步骤(步骤i):
本发明提供了制备式(I)的化合物的方法,该方法包括:
i)使式(V)的化合物与式(VI)的化合物反应:
其中:
R1是H、Ac、Piv、Bz或PMB;
R2和R3独立地是H、Ac或Piv;
R4和R5是OH,或者R4和R5一起形成-C(Me)2C(Me)2C-;
X1是Br、I或OTf;并且
Y选自:
步骤(i)可以被称为偶联步骤。
在优选的实施方案中,R1是H、Ac或Piv。在更优选的实施方案中,R1是H。
在优选的实施方案中,R2和R3是H。
在优选的实施方案中,X1是Br或OTf。在更优选的实施方案中,X1是OTf。
通常,步骤(i)包括使式(V)的化合物与式(VI)的化合物和钯催化剂反应。合适的钯催化剂包括Pd(dppf)Cl2、Pd(PPh3)4和SPhos-Pd-G2(氯(2-二环己基膦基-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(II))。
在优选的实施方案中,步骤(i)还包括使式(V)的化合物与式(VI)的化合物和碱反应。合适的碱包括氟化铯(CsF)、碳酸钠(Na2CO3)、碳酸铯(Cs2CO3)。
通常,步骤(i)在溶剂中进行。合适的溶剂包括二氧六环、四氢呋喃(THF)、二甲基甲酰胺(DMF)、水及其混合物。
步骤(i)通常在升高的温度(高于环境温度;约20℃)进行。用于在反应期间提供热的方法是已知的,并且包括例如使用具有外部加热夹套的反应容器或使用微波加热。
通常,步骤(i)包括在从60℃至140℃,优选地80℃至140℃,更优选地80℃至120℃的温度使式(V)的化合物与式(VI)的化合物反应。
步骤(i)可以进行持续足够的时间,以允许形成期望量的偶联产物。通常,进行步骤(i)直到大体上全部的式(QQ)的化合物已经被消耗。
通常,步骤(1a)包括使式(II)的化合物与式(III)的化合物反应持续1小时至12小时。
三氟甲磺酰化步骤(步骤ii):
本发明还提供了制备式(V)的化合物的方法,该方法包括:
ii)使式(VII)的化合物与三氟甲磺酰化试剂反应:
其中:
R6是H、Bz或PMB;
R7和R8独立地是H、Ac或Piv。
步骤(ii)可以被称为三氟甲磺酰化步骤。
在优选的实施方案中,R6是H或Bz。在更优选的实施方案中,R6或Bz。
在优选的实施方案中,R7和R8是OH。
合适的三氟甲磺酰化试剂包括三氟甲磺酸酐(Tf2O)、N-苯基双(三氟甲磺酰亚胺)(PhNTf2)、Comins试剂、1-(三氟甲磺酰基)-1H-苯并三唑、1-(三氟甲磺酰基)咪唑和N-(2-吡啶基)-双(三氟甲磺酰亚胺)。在优选的实施方案中,使用Tf2O或PhNTf2。在更优选的实施方案中,使用PhNTf2。
在优选的实施方案中,步骤(ii)包括使式(VII)的化合物与三氟甲磺酰化试剂和碱反应。合适的碱包括有机碱,诸如吡啶、二甲基吡啶、二甲基苄胺、咪唑、苯并咪唑、甲基咪唑、三乙胺、三丁胺、二异丙基乙胺、四甲基乙二胺、DABCO。在优选的实施方案中,使用三乙胺或二甲基吡啶。在更优选的实施方案中,使用三乙胺。
通常,步骤(ii)在溶剂中进行。合适的溶剂包括二氯甲烷。
步骤(ii)通常在降低的温度(低于环境温度;约20℃)进行。在反应期间用于去除热的方法是已知的,并且包括例如使用具有外部冷却夹套的反应容器。
通常,步骤(ii)包括在从-40℃至25℃、优选地-5℃至20℃、更优选地0℃至20℃的温度使式(VII)的化合物与三氟甲磺酰化试剂反应。
步骤(ii)可以进行持续足够的时间,以允许形成期望量的三氟甲磺酰化产物。通常,进行步骤(ii)直到大体上全部的式(VII)的化合物已经被消耗。
任选地,步骤(ii)还可以包括:
ii-a)使式(VIII)的化合物与卤素交换试剂反应
其中:
R9独立地是H、Bz或PMB;
R10和R11独立地是H、Ac或Piv。
在优选的实施方案中,R9是Bz或PMB。在更优选的实施方案中,R9是Bz。
在优选的实施方案中,R10和R11是Ac或Piv。在更优选的实施方案中,R10和R11是Piv。
步骤(ii-a)可以经过一个(直接卤素交换)或多个(间接卤素交换)步骤发生。
用于直接卤素交换的合适的卤素交换试剂包括[Cp*Ru(MeCN)3OTf]与溴化锂的组合。
用于间接卤素交换的合适的卤素交换试剂包括B2Pin2与钯催化剂的组合,钯催化剂为诸如Pd(POAc)2和任选的配体诸如dppf;接着是溴化铜(II)。通常,使用升高的温度,诸如从60℃至90℃。间接卤素交换可以通过式(VIIIa)的中间体进行:
其中:
R12独立地是H、Bz或PMB;
R13和R14独立地是H、Ac或Piv。
Friedel Crafts(步骤iii):
本发明还提供了制备式(VII)的化合物的方法,该方法包括:
iii)使式(IX)的化合物与间苯三酚(苯-1,3,5-三醇)反应
其中:
R15是H、Bz或PMB。
步骤(iii)可以被称为Friedel Crafts步骤。
在优选的实施方案中,R15是Bz或PMB。在更优选的实施方案中,R15是Bz。
在优选的实施方案中,步骤(iii)包括使式(IX)的化合物与间苯三酚和酸反应。合适的酸是Lewis酸诸如三氟化硼和布朗斯特(Bronsted)酸诸如三氟甲磺酸。在优选的实施方案中,使用三氟甲磺酸。
步骤(iii)通常在降低的温度(低于环境温度;约20℃)进行。通常,步骤(iii)包括在从-15℃至20℃,优选地0℃至15℃,更优选地5℃至15℃的温度使式(IX)的化合物与间苯三酚反应。
通常,步骤(iii)在溶剂中进行。合适的溶剂包括四氢呋喃和乙酸异丙酯。
优选的实施方案:
在优选的实施方案中,提供了一种方法,该方法包括:
iii)如在第[0080]段至第[0085]段所阐述的Friedel Crafts步骤;
ii)如在第[0064]段至第[0079]段所阐述的三氟甲磺酰化步骤;以及任选地
i)如在第[0052]段至第[0063]段所阐述的偶联步骤。
关键中间体的合成
发明人已经发现,6-羟基化合物可以由式(IX)的关键中间体通过Friedel Crafts反应产生。与后期氧化方法相比,这种方法以较高收率和较高可靠性提供了化合物。此外,本发明的方法允许使用后期交叉偶联反应以在间苯二酚尾部安装多种官能团。
烯丙基氧化(步骤iv):
本发明还提供了用于制备式(IX)的化合物的方法,该方法包括:
iv-a)使式(X)的化合物与二苯基联硒化物反应以产生式(XI)的化合物;以及
iv-b)使式(XI)的化合物与氧化剂反应,
其中:
R16和R17独立地是H、Bz或PMB。
步骤(iv-a)和步骤(iv-b)可以一起被称为烯丙基氧化步骤。
在优选的实施方案中,步骤(iv-a)包括使式(X)的化合物与二苯基联硒化物和还原剂反应。合适的还原剂包括硼氢化钠。
在优选的实施方案中,步骤(iv-a)包括使式(X)的化合物与二苯基联硒化物和碱反应。合适的碱包括氢氧化钠。
合适的氧化剂包括过氧化氢。在优选的实施方案中,使用过氧化氢。
步骤(iv-b)可以在升高的温度(高于环境温度;约20℃)进行。通常,步骤(iv-b)包括使式(XI)的化合物与氧化剂在从0℃至20℃的温度反应持续初始时间段(硒氧化),并且然后将温度升高至从20℃至60℃持续第二时间段(烯丙基氧化)。
通常,步骤(iv-a)和步骤(iv-b)在溶剂中进行。合适的溶剂包括四氢呋喃、2-甲基四氢呋喃和乙醇。
环氧化(步骤v):
本发明还提供了用于制备式(X)的化合物的方法,该方法包括:
v)使式(XII)的化合物(其可以被称为(+)-顺式-香芹醇)与过氧羧酸(过酸)反应
步骤(v)可以被称为环氧化步骤。
合适的过氧羧酸包括间氯过氧苯甲酸(mCPBA)和过苯甲酸。在优选的实施方案中,使用mCPBA。
步骤(v)通常在降低的温度(低于环境温度;约20℃)进行。通常,步骤(v)包括使式(QQ)的化合物与过氧羧酸在从-40℃至0℃的温度、优选地-20℃至0℃的温度反应。
通常,步骤(v)在溶剂中进行。合适的溶剂包括二氯甲烷。
步骤(v)产生式(Xa)的化合物,其可以被称为环氧-香芹醇
任选地,步骤(v)还可以包括:
v-a)使式(Xa)的化合物与对甲氧基苄基氯或苯甲酰氯反应。
在优选的实施方案中,步骤(v-a)还包括使式(Xa)的化合物与对甲氧基苄基氯或苯甲酰氯和碱反应。合适的碱包括氢化钠和三乙胺。
还原(步骤vi):
本发明还提供了用于制备式(Xa)的化合物的方法,该方法包括:
vi)使S-香芹酮与还原剂反应,
步骤(vi)可以被称为还原步骤。
合适的还原剂包括氢化铝锂、双(2-甲氧基乙氧基)氢化铝钠(红-Al)、二硼烷和硼氢化钠。在优选的实施方案中,使用硼氢化钠。
在一些优选的实施方案中,使用任选的添加剂诸如氯化铈(III)。
步骤(vi)通常在降低的温度(低于环境温度;约20℃)进行。通常,步骤(v)包括在从-80℃至20℃,优选地-40℃至0℃,更优选地-20℃至-10℃的温度使S-香芹酮与还原剂反应。
通常,步骤(v)在溶剂中进行。合适的溶剂包括四氢呋喃、2-甲基四氢呋喃、乙醇和甲醇。
优选的实施方案:
在优选的实施方案中,提供了一种方法,该方法包括:
vi)还原步骤,如在第[0103]段至第[0108]段所阐述的;
v)环氧化步骤,如在第[0095]段至第[0102]段所阐述的;以及任选地
iv)烯丙基氧化步骤,如在第[0088]段至第[0094]段所阐述的。
其他实施方案:
在一种实施方案中,提供了用于产生式(I)的化合物至式(IV)的化合物的工艺,该工艺包括以下步骤:
i)使香芹酮a还原成香芹醇b,随后进行环氧化以产生中间体c,并且与任何合适的保护基团反应以产生对应的环氧化物d;
ii)使环氧化物d在硼氢化钠中与二苯基联硒化物反应,并且用过氧化氢处理以给出粗品e,并且随后加热e以形成对应的烯丙醇f;或可选择地
使环氧化物d在二甲胺存在的情况下回流以给出粗品g,随后通过用过氧化氢处理使g氧化成N-氧化物h,并且回流以提供f;以及
iii)使烯丙醇f与间苯三酚i反应以给出化合物j,用乙酸酐处理j,随后在2,6-二甲基吡啶存在的情况下用三氟甲磺酸酐处理以产生化合物k,随后将k溴化以给出l,使用硝酸铈(IV)铵和随后的硼氢化钠使l脱保护以给出m,接着使用k或m进行随后的金属催化的偶联以获得式I至式V的化合物;或可选择地
使烯丙醇f和苯酚n反应以给出产物o,在含水氢氧化钠存在的情况下使o脱羧,随后用柠檬酸处理以给出苯酚p,使用硝酸铈(IV)铵使保护基团脱保护,以产生式I至式V的化合物。
优选地,第[0110]段中的实施方案使用以下保护基团中的一个:PMB、基于硅的保护基团(TMS、TES、TBS、TBDPS、SEM)、醚(MOM、MEM、BOM、Bn、PMB、DMB、烯丙基)、酯(Piv、Bz、Ac)、氨基甲酸酯和碳酸酯(Troc、二甲基氨基氨基甲酸酯)或无保护基团。
在一种实施方案中,提供了一种方法,该方法包括:
vi)还原步骤,如在第[0103]段至第[0108]段所阐述的;
v)环氧化步骤,如在第[0095]段至第[0102]段所阐述的;
iv)烯丙基氧化步骤,如在第[0088]段至第[0094]段所阐述的。
iii)Friedel Crafts步骤,如在第[0080]段至第[0085]段所阐述的;
ii)三氟甲磺酰化步骤,如在第[0064]段至第[0079]段所阐述的;以及任选地
i)偶联步骤,如在第[0052]段至第[0063]段所阐述的。
中间体
本发明还提供一种中间体,其选自式(V)的化合物和式(IX)的化合物:
其中:
R1是H、Ac、Piv、Bz或PMB;
R2和R3独立地是H、Ac或Piv;
X1是Br、I或OTf;并且
R15是H、Bz或PMB。
在优选的实施方案中,R1是H、Ac或Piv。在更优选的实施方案中,R1是H。
在优选的实施方案中,R2和R3是H。
在优选的实施方案中,X1是Br或OTf。在更优选的实施方案中,X1是OTf。
在优选的实施方案中,R15是Bz或PMB。在更优选的实施方案中,R15是Bz。
在更优选的实施方案中,中间体选自:
药物组合物
虽然式(I)、式(II)、式(III)或式(IV)的化合物可以单独施用,但优选的是施用包含式(I)、式(II)、式(III)或式(IV)的化合物以及一种或更多种其他药学上可接受的成分的药物组合物(例如,制剂、制品或药物)。
因此,本发明提供了一种药物组合物,该药物组合物包含式(I)、式(II)、式(III)或式(IV)的化合物或其盐以及一种或更多种药学上可接受的成分。
合适的药学上可接受的成分(例如载体、稀释剂、赋形剂等)可以在标准药学教科书中找到,例如Remington:The Science and Practice of Pharmacy,第20版,2000,pub.Lippincott,Williams&Wilkins;和Handbook of Pharmaceutical Excipients,第9版,2020,pub.Pharmaceutical Press。
合适的药学上可接受的成分的实例包括药学上可接受的载体、稀释剂、赋形剂、辅料、填充剂、缓冲剂、粘合剂、崩解剂、防腐剂、抗氧化剂、润滑剂、稳定剂、增溶剂、表面活性剂(例如,润湿剂)、掩蔽剂、着色剂、调味剂和甜味剂。
在优选的实施方案中,药物组合物包含以下中的一种或更多种:选自载体、油、崩解剂、润滑剂、稳定剂、调味剂、抗氧化剂、稀释剂的赋形剂以及另一种药学上有效的化合物。
药物组合物可以呈任何合适的形式。合适的形式的实例包括液体、溶液(例如,水性、非水性)、悬浮液(例如,水性、非水性)、乳液(例如,水包油、油包水)、糖浆、冲剂、漱口水、滴剂、片剂(包括例如包衣的片剂)、颗粒剂、粉末、锭剂、软锭剂、胶囊(包括例如硬明胶胶囊和软明胶胶囊)、扁囊剂、丸剂、安瓿、大丸剂、栓剂、阴道栓剂、酊剂、凝胶、糊剂、软膏、乳膏、洗剂、油、泡沫、喷雾剂和气雾剂。
在优选的实施方案中,药物组合物选自片剂、胶囊、颗粒剂、口服溶液、用于吸入的粉末、喷洒剂和悬浮液。
医学治疗
发明人已经发现,式(I)、式(II)、式(III)和式(IV)的化合物具有生物活性。工作实施例展示,式(I)、式(II)、式(III)和式(IV)的化合物在癫痫发作的小鼠模型中显示出抗惊厥活性。因此,式(I)、式(II)、式(III)和式(IV)的化合物,及其盐,以及包含式(I)、式(II)、式(III)或式(IV)的化合物或其盐的药物组合物将可用于医学治疗。
因此,本发明提供了用于治疗方法,例如用于通过疗法(therapy)治疗(treatment)人类或动物身体的方法(即疗法的方法)的式(I)、式(II)、式(III)或式(IV)的化合物或其盐。
本发明还提供了用作药物的式(I)、式(II)、式(III)或式(IV)的化合物或其盐。
本发明还提供了一种治疗方法,该方法包括向需要治疗的受试者施用治疗有效量的式(I)、式(II)、式(III)或式(IV)的化合物或其盐。
本发明还提供了式(I)、式(II)、式(III)或式(IV)的化合物或其盐用于制造药物的用途。
本发明还提供了式(I)、式(II)、式(III)或式(IV)的化合物或其盐在治疗方法中的用途。
所治疗的状况
发明人已经发现,式(I)、式(II)、式(III)和式(IV)的化合物在全身性癫痫发作的小鼠模型中显示出抗惊厥活性。因此,式(I)、式(II)、式(III)和式(IV)的化合物、其盐以及包含式(I)、式(II)、式(III)和式(IV)的化合物或其盐的药物组合物将可用于治疗与癫痫发作相关的某些状况。
类似地,式(I)、式(II)、式(III)和式(IV)的化合物、其盐以及包含式(I)、式(II)、式(III)和式(IV)的化合物或其盐的药物组合物将可用作用于治疗与癫痫发作相关的某些状况的药物(以及可用于制造用于治疗与癫痫发作相关的某些状况的药物)。
在优选的实施方案中,与癫痫发作相关的状况是癫痫。
在一种实施方案中,与癫痫发作相关的状况是全身性癫痫发作,诸如与癫痫相关的全身性癫痫发作。
在一种实施方案中,与癫痫发作相关的状况是局灶起源癫痫发作,诸如与癫痫相关的局灶起源癫痫发作。
在一种实施方案中,与癫痫发作相关的状况是强直性-阵挛性癫痫发作,诸如与癫痫相关的强直性-阵挛性癫痫发作。
受试者/患者
治疗方法通常包括向受试者或患者施用式(I)、式(II)、式(III)和式(IV)的化合物或其盐。
受试者/患者可以是脊索动物、脊椎动物、哺乳动物、胎盘哺乳动物、有袋动物(例如袋鼠、袋熊)、啮齿动物(例如豚鼠、仓鼠、大鼠、小鼠)、鼠(例如小鼠)、兔形目动物(例如兔)、鸟类(例如鸟)、犬科动物(例如狗)、猫科动物(例如猫)、马科动物(例如马)、猪科动物(例如猪)、羊科动物(例如绵羊)、牛科动物(例如牛)、灵长类动物、猿猴(例如猴或猿)、猴(例如狨猴、狒狒)、猿(例如大猩猩、黑猩猩、猩猩、长臂猿)或人类。
受试者/患者可以是任何其发育形式,例如,受试者/患者可以是婴儿或儿童。
在优选的实施方案中,受试者/患者是人类,更优选地成年人类。
受试者/患者还可以是在实验室研究中使用的非人类哺乳动物,诸如啮齿动物。啮齿动物包括大鼠、小鼠、豚鼠和南美洲栗鼠。
施用途径
所述治疗方法可以包括通过任何方便的施用途径,无论是全身/外周还是外用(即,在所需作用部位处),将式(I)、式(II)、式(III)或式(IV)的化合物或其盐施用至受试者。
施用途径可以是口服的(例如,通过摄食);含服的;舌下的;经皮的(包括例如通过贴剂、膏药等);经黏膜的(包括例如通过贴剂、膏药等);鼻内的(例如,通过鼻喷雾);眼部的(例如,通过滴眼液);肺的(例如,通过使用例如经由气雾剂,例如通过口或鼻的吸入或吹入疗法);直肠的(例如,通过栓剂或灌肠剂);阴道的(例如,通过阴道栓剂);肠胃外的,例如,通过注射或输注,包括皮下的、皮内的、肌内的、静脉内的、动脉内的、心内的、鞘内的、脊柱内的、囊内的、囊下的、眼眶内的、腹膜内的、气管内的、表皮下的、关节内的、蛛网膜下的和胸骨内的;通过植入储库(depot)或储器,例如,皮下地或肌内地。
剂量
治疗方法通常包括向受试者施用治疗有效量的式(I)、式(II)、式(III)或式(IV)的化合物或其盐。
式(I)、式(II)、式(III)和式(IV)的化合物、其盐以及包含式(I)、式(II)、式(III)或式(IV)的化合物或其盐的药物组合物的适当剂量可以因患者而异。确定最佳剂量通常将涉及平衡治疗益处水平与任何风险或有害副作用。所选择的剂量水平将取决于多种因素,包括但不限于式(I)、式(II)、式(III)或式(IV)的特定化合物的活性、施用途径、施用时间、化合物的排泄速率、治疗的持续时间、其他活性剂、组合使用的化合物和/或材料、状况的严重程度以及患者的物种、性别、年龄、体重、状况、一般健康状况和既往病史。剂量和施用途径最终将由临床医生决定,尽管通常剂量将被选择为在作用部位达到局部浓度,这实现期望的效果而不会引起实质性的有害(harmful)或有害(deleterious)的副作用。
在整个治疗进程中,可以以一次给药、连续地或间歇地(例如,以适当的间隔分剂量)进行施用。可以进行单次施用或多次施用,其中剂量水平和模式由治疗临床医生选择。
其他方面和实施方案
本文明确地公开了上文描述的实施方案的每个和每一个相容的组合,如同每个和每一个组合都是单独和明确地叙述的一样。
鉴于本公开内容,本发明的多种另外的方面和实施方案对于本领域的技术人员来说将是明显的。
在使用的情况下,“和/或”将被视为单独的每个相关组分或特征的具体公开内容以及组分或特征的组合的具体公开内容。例如,“A和/或B”将被视为i)A、ii)B和iii)A与B中的每一项的具体公开内容,就好像每一项都是单独阐述的一样。
除非上下文另有指示,否则上文阐述的特征的描述和定义不限于本发明的任何特定的方面或实施方案,并且同等地应用于所描述的所有方面和实施方案。
定义
为了帮助理解本发明,提供了以下定义。
癫痫被认为是由以下情况中的任一种定义的脑的疾病:(1)间隔>24 h发生的至少两次无缘无故的(或反射性)癫痫发作;(2)一次无缘无故的(或反射性)癫痫发作,并且在接下来的10年内发生的类似于在两次无缘无故的癫痫发作之后的一般复发风险(至少60%)的进一步癫痫发作的可能性(probability);(3)癫痫综合征的诊断(国际抗癫痫联盟(ILAE)对癫痫的实用临床定义,2014)。
术语“局灶性癫痫发作”(“局灶起源癫痫发作”)指的是起源于局限于一个半球的网络内的癫痫发作。它们可能是离散局部性的,或更广泛分布的。局灶性癫痫发作可能起源于皮质下结构(ILAE对癫痫发作类型的业务分类,2017)。
术语“全身性癫痫发作”(“全身性起源癫痫发作”)指的是被概念化为起源于脑内的一些点并且快速占据双侧分布的网络的癫痫发作(ILAE对癫痫发作类型的业务分类,2017)。
术语“药学上可接受的”涉及化合物、成分、材料、组合物、剂型等,这些化合物、成分、材料、组合物、剂型等在合理的医学判断范围内,适合于与所讨论的受试者(例如人类)的组织接触使用,而没有过度的毒性、刺激性、过敏反应或其他问题或并发症,与合理的益处/风险比相称。每种成分(例如,载体、稀释剂、赋形剂等)在与组合物的其他成分相容的意义上也必须是“可接受的”。
“间苯二酚”是具有以下结构或在其中包含这样的结构的任何超结构的化合物:
术语“治疗有效量”涉及化合物或者包含化合物的材料、组合物或剂型的这样的量,当根据所期望的治疗方案施用时,该量有效地产生与合理的益处/风险比相称的某些期望的治疗效果。
“强直性-阵挛性癫痫发作”以两个阶段发生,通常涉及肌肉僵硬和意识丧失的强直阶段和通常涉及四肢节律性抽搐的阵挛阶段。
终止于波浪线的键用于指示附接点。
Ac是乙酰基基团(-C(=O)CH3)。Bz是苯甲酰基基团(-C(=O)Ph)。Piv是新戊酰基基团(-C(=O)C(CH3)3)。PMB是对甲氧基苄基基团(-CH2-C6H4-OCH3)。Tf是三氟甲磺酸酯基团(-SO2CF3)。
工作实施例
本发明的某些方面和实施方案将不通过实例的方式并参考上文描述的附图来示出。
分析方法
NMR
Bruker Avance 400MHz,5mm QNP探针H、C、F、P,单Z梯度,双通道仪器,运行TopSpin 2.1
Bruker Avance III 400MHz,5mm BBFO Plus探针,单Z梯度,双通道仪器,运行TopSpin 3.1。
LCMS
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实施例1:新颖化合物的合成产生方法
该实施例描述了新颖的合成方法,该合成方法用于产生展示药理学活性的新颖间苯二酚(1-58)。
下文的方案1-方案3被编号以代表合成的每一个阶段。方案1提供制备中间体d的第一阶段;方案2A和方案2B是第二阶段的可选择的路线,该第二阶段使用来自方案1的中间体d制备中间体f;方案3A和方案3B描述了第三最终阶段,该第三最终阶段使用来自方案2A或方案2B中的任一个的中间体f制备本发明的新颖化合物(化合物I-化合物V),方案3A和方案3B各自也是同等可选择的路线。
应当理解,路线的任何组合都在本发明的范围内:方案1随后是方案2A随后是方案3A;方案1随后是方案2A随后是方案3B;方案1随后是方案2B随后是方案3A;方案1随后是方案2B随后是方案3B。
应当理解,任何合适的离去基团可以用于替换对甲氧基苄基(PMB)基团,并且因此本发明不限于这样的离去基团。可选择的保护基团包括基于硅的保护基团(TMS、TES、TBS、TBDPS、SEM)、醚(MOM、MEM、BOM、Bn、PMB、DMB、烯丙基)、酯(Piv、Bz、Ac)、氨基甲酸酯和碳酸酯(Troc、二甲基氨基氨基甲酸酯)或无保护基团(OH)。
方案1:制备中间体的合成路线
使用硼氢化钠和氯化铈(III)在0℃将(S)-(+)-香芹酮a还原以提供期望的(+)-顺式-香芹醇b。然后使用m-CPBA在-40℃在DCM中将(+)-顺式-香芹醇b的环内烯烃选择性地环氧化,产生环氧化物c。最后,在THF中在NaH和PMBCl存在的情况下将仲醇c保护,以在柱色谱法之后获得目标材料d。
方案2A:制备中间体的合成路线
方案2B:制备中间体的合成路线
方案2A:在RT在乙醇中在硼氢化钠存在的情况下,使环氧化物d与二苯基联硒化物反应。然后接着用在乙醇中的过氧化氢的水溶液处理以形成粗品e。随后在乙醇中加热e形成对应的烯丙醇f。
方案2B:在二甲胺存在的情况下,在IPA/水的混合物中将环氧化物d回流以给出粗品g。随后通过在乙腈和水中用过氧化氢处理将粗品g氧化成N-氧化物h。最终,将h在甲苯中回流持续30分钟以提供f。
方案3A:制备化合物I-化合物V的合成路线
方案3B:制备化合物I-化合物V的合成路线
方案3A:在间苯三酚i和催化量的Sc(OTf)3存在的情况下,将烯丙醇f在RT在DCM中搅拌,给出期望的化合物j,随后将化合物j在吡啶中用乙酸酐处理,接着在2,6-二甲基吡啶存在的情况下在DCM中用三氟甲磺酸酐处理以获得化合物k。k的钌催化的溴化产生l。在乙醇中使用硝酸铈(IV)铵和随后的硼氢化钠的最终脱保护提供期望的产物m。可以使用k或m进行随后的金属催化的偶联(使用Pd、Pt、Ni、Ru、Rh、Au、Mg、Zn等)以获得本发明的另外的类似物。
方案3B:在催化量的Sc(OTf)3存在的情况下将烯丙醇f和苯酚n在RT搅拌以给出产物o。随后在70℃在含水氢氧化钠存在的情况下,将o脱羧,随后用柠檬酸处理,产生期望的苯酚p。最后,在水和乙腈的混合物中使用硝酸铈(IV)铵将PMB保护基团脱保护,产生本发明的化合物。
中间体化合物a至中间体化合物p的化学名称在下文在表1中列出。
表1:中间体化合物的名称
实施例1-1:中间体的改进的合成产生方法
偶联配偶体的合成
阶段1:Friedel Crafts
在乙酸异丙酯(35体积)中使(1S,2R,5R)-2-羟基-2-甲基-5-(丙-1-烯-2-基)环己-3-烯-1-基苯甲酸酯(6-苯甲酰基氧代甲烷二烯醇)与间苯三酚(10.0当量)和三氟甲磺酸(0.125当量)反应。温度保持在7.5℃和12.5℃之间。
阶段2:三氟甲磺酰化
在DCM(15体积)中使(1R,2R,4S)-2’,4’,6’-三羟基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’-联苯基]-4-基苯甲酸酯与N-苯基双(三氟甲磺酰亚胺)(1.20当量)和三乙胺(4.5当量)反应。温度保持在0℃至20℃之间
阶段3:新戊酰化
在乙腈(10体积)中使(1R,2R,4S)-2’,6’-二羟基-5-甲基-2-(丙-1-烯-2-基)-4’-(((三氟甲基)磺酰基)氧基)-1,2,3,4-四氢-[1,1’-联苯基]-4-基苯甲酸酯与新戊酰氯(2.05当量)和碳酸铯(2.2当量)反应。温度保持在0℃至5℃。
阶段4:硼化
在乙腈(10体积)中使(1’R,2’R,4’S)-4’-(苯甲酰基氧基)-5’-甲基-2’-(丙-1-烯-2-基)-4-(((三氟甲基)磺酰基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基双(2,2-二甲基丙酸酯)与双(频哪醇合)二硼(2.0当量)、乙酸钯(II)(0.05当量)、乙酸钾(3.0当量)和dppf(0.1当量)反应。温度保持在80℃和85℃之间。
阶段5:溴化
在空气中,在丁醇(10当量)和水(5当量)中使(1’R,2’R,4’S)-4’-(苯甲酰基氧基)-5’-甲基-2’-(丙-1-烯-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基双(2,2-二甲基丙酸酯)与溴化铜(II)(1.0当量)反应。温度保持在80℃和85℃之间。
阶段6:脱保护
在THF(10体积)中使(1’R,2’R,4’S)-4’-(苯甲酰基氧基)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基双(2,2-二甲基丙酸酯)与甲基溴化镁(10.0当量)反应。将反应混合物从0℃加热至50℃。
6-苯甲酰基氧代甲烷二烯醇的合成
阶段1:还原
在甲醇中使S-香芹酮与硼氢化钠和七水合氯化铈(III)反应。温度保持在-20℃。
阶段2:环氧化
在二氯甲烷中使(1S,5S)-2-甲基-5-(丙-1-烯-2-基)环己-2-烯-1-醇((+)-顺式-香芹醇)与m-CPBA反应。温度保持在-20℃。
阶段3:硒化
在四氢呋喃中使(1S,2S,4R,6R)-1-甲基-4-(丙-1-烯-2-基)-7-氧杂双环[4.1.0]庚-2-醇与二苯基联硒化物、硼氢化钠和氢氧化钠反应。温度保持在20℃。
阶段4:保护
在2-甲基四氢呋喃中使(1S,2S,4R,6S)-1-甲基-6-(苯基硒基)-4-(丙-1-烯-2-基)环己烷-1,2-二醇与苯甲酰氯和DMAP反应。温度保持在20℃。
阶段5:烯丙基氧化
在2-甲基四氢呋喃中使(1S,2S,3S,5R)-2-羟基-2-甲基-3-(苯基硒基)-5-(丙-1-烯-2-基)环己基苯甲酸酯与过氧化氢反应。温度保持在0℃。将温度升高至55℃。
实施例1-2:新颖化合物的可选择的合成产生方法
中间体的合成
中间体1:5-(2-甲氧基乙基)苯1,3-二醇
2-(3,5-二苄基氧基苯基)乙醇
将在四氢呋喃(178mL)中的2-(3,5-二苄基氧基苯基)乙酸苄酯(12.3g,28.0mmol)在氮气气氛下在冰/水浴中冷却,并且用1M氢化铝锂(56mL,56.1mmol)逐滴处理。允许反应混合物升温至室温过夜,然后在冰/水浴中冷却。将反应用乙醚稀释,并且用依次逐滴添加的2.1mL的水、2.1mL的15%氢氧化钠水溶液和6.3mL的水猝灭。允许混合物升温至室温并且搅拌持续15分钟。添加硫酸镁,并且将反应混合物搅拌持续另外的15分钟。通过过滤去除固体,并且将滤液在真空中浓缩。残余物通过用在环己烷中的0%-100%乙醚洗脱的二氧化硅上的柱色谱法纯化,以给出作为白色固体的标题化合物(5.44g,58%)。
1H NMR(400MHz,DMSO)δ7.47-7.32(m,10H),6.52-6.49(m,3H),5.06(s,4H),4.63(t,J=5.3Hz,1H),3.62-3.56(m,2H),2.66(dd,J=7.2,7.2Hz,2H)。
1,3-二苄基氧基-5-(2-甲氧基乙基)苯
将在N,N-二甲基甲酰胺(80mL)中的氢化钠(在矿物油中的60%分散体,1.30g,32.5mmol)的悬浮液在氮气气氛下在冰/水浴中冷却,并且用2-(3,5-二苄基氧基苯基)乙醇(5.44g,16.3mmol)在N,N-二甲基甲酰胺(20mL)中的溶液处理,随后添加碘甲烷(2.0mL,32.5mmol)。将反应混合物升温至室温,搅拌持续3小时,然后用饱和含水氯化铵(30mL)猝灭,并且在水(40mL)和乙醚(100mL)之间分配。将含水层用乙醚(2×50mL)萃取,并且将合并的有机层用水(50mL)洗涤,干燥(MgSO4)并且在真空中浓缩以给出作为黄色油的标题化合物(5.88g,定量粗品收率)。其在没有进一步纯化的情况下被用于下一个步骤。
1H NMR(400MHz,DMSO)δ7.46-7.32(m,10H),6.54-6.50(m,3H),5.07(s,4H),3.52(t,J=6.9Hz,2H),3.24(s,3H),2.74(t,J=7.0Hz,2H)。
5-(2-甲氧基乙基)苯-1,3-二醇
将1,3-二苄基氧基-5-(2-甲氧基乙基)苯(5.80g,16.6mmol)和1-甲基-1,4-环己二烯(15mL,0.133mol)在乙醇(100mL)中的溶液用10%碳载钯(1.8g)处理,并且加热至75℃并且搅拌持续3小时。将反应混合物通过硅藻土垫过滤并且在真空中浓缩。残余物通过用在环己烷中的0%-100%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,以给出作为黄色油的标题化合物(2.98g,NMR示出存在乙酸乙酯,88%收率,考虑了乙酸乙酯含量)。
1H NMR(400MHz,DMSO)δ9.06(s,2H),6.07(d,J=2.2Hz,2H),6.05(t,J=2.2Hz,1H),4.04(q,J=7.1Hz,1H),3.46(t,J=7.0Hz,2H),3.24(s,3H),2.61(t,J=6.9Hz,2H)。
中间体2:4-甲基5-丙基苯-1,3-二醇
2-溴-1,5-二甲氧基-3-丙基-苯
将在二氯甲烷(30mL)中的1,3-二甲氧基-5-丙基-苯(2.50g,13.9mmol)在冰/水浴中冷却,并且用N-溴代琥珀酰亚胺(2.47g,13.9mmol)处理。将反应混合物搅拌持续2小时,然后用乙酸乙酯(100mL)稀释,用半饱和硫代硫酸钠溶液(100mL)、2M氢氧化钠水溶液(100mL)和水(100mL)洗涤。将有机层干燥(疏水性滤纸)并且在真空中浓缩以给出作为无色油的标题化合物(3.75g,定量粗品收率)。其在没有进一步纯化的情况下被用于下一个步骤。
1H NMR(400MHz,CDCl3)δ6.40(d,J=2.9Hz,1H),6.35(d,J=2.8Hz,1H),3.86(s,3H),3.79(s,3H),2.73-2.68(m,2H),1.69-1.59(m,2H),0.98(t,J=7.3Hz,3H)。
1,5-二甲氧基-2-甲基-3-丙基-苯
将在四氢呋喃(100mL)中的2-溴-1,5-二甲氧基-3-丙基-苯(3.46g,13.4mmol)在干冰-丙酮浴中冷却,并且经10分钟用2.5M正丁基锂溶液(12mL,29.4mmol)分批处理。将反应混合物搅拌持续15分钟,然后用碘甲烷(2.5mL,40.1mmol)处理,并且允许升温至室温过夜。将反应用饱和氯化铵溶液(10mL)猝灭,并且用在甲醇(5mL)中的7M氨处理。将混合物搅拌持续2小时,用乙酸乙酯(250mL)稀释,用水(2×250mL)洗涤,干燥(疏水性滤纸)并且在真空中浓缩。将粗制产物与已经以250mg规模在相同条件下运行的测试反应的产物合并,并且通过用在环己烷中的0%-60%二氯甲烷洗脱的二氧化硅上的柱色谱法纯化,以给出作为无色油的标题化合物(2.42g,100%)。
1H NMR(400MHz,CDCl3)δ6.32(s,2H),3.79(s,3H),3.79(s,3H),2.58-2.52(m,2H),2.09(s,3H),1.61-1.54(m,2H),0.97(t,J=7.3Hz,3H)。
4-甲基-5-丙基苯-1,3-二醇
将在二氯甲烷(75mL)中的1,5-二甲氧基-2-甲基-3-丙基-苯(2.4g,12.5mmol)在冰/水浴中冷却,并且用1M三溴化硼(31mL,31.4mmol)处理。允许混合物升温至室温过夜。将反应用甲醇(10mL)和饱和碳酸氢钠水溶液(10mL)猝灭,并且用二氯甲烷(75mL)稀释。将两相分离,并且将有机相用半饱和碳酸氢钠水溶液(100mL)洗涤。将含水层用乙酸乙酯(2×100mL)萃取,并且将合并的有机层干燥(疏水性滤纸)并且在真空中浓缩以给出棕色胶(1.73g,83%)。
1H NMR(400MHz,DMSO)δ8.92(s,1H),8.76(s,1H),6.14(d,J=2.4Hz,1H),6.03(d,J=2.1Hz,1H),2.42-2.37(m,2H),1.94(s,3H),1.52-1.42(m,2H),0.92(t,J=7.3Hz,3H)。
一般方法A
通过合成以下中间体3来说明一般方法A:(1’R,2’R)-4-(甲氧基甲基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇
将5-(甲氧基甲基)苯-1,3-二醇(2.68g,17.4mmol)和对甲苯磺酸一水合物(248mg,1.30mmol)在四氢呋喃(10mL)和二氯甲烷(120mL)中的溶液在冰/水浴中冷却至4℃。经60分钟逐滴添加(4R)-4-异丙烯基-1-甲基-环己-2-烯-1-醇(2.60ml,16.0mmol)。将反应混合物搅拌持续另外的2小时,然后用碳酸氢钠(450mg)在水(50mL)中的溶液猝灭。将层分离,将含水层用二氯甲烷(50mL)萃取,并且将合并的有机层干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过用在环己烷中的0%-100%乙醚洗脱的二氧化硅上的柱色谱法纯化,以给出作为棕色油的标题化合物(1.08g,23%)。
1H NMR(400MHz,DMSO)δ8.85(s,2H),6.20(s,2H),5.14(s,1H),4.55-4.52(m,1H),4.46(s,1H),4.21(s,2H),3.94-3.87(m,1H),3.28(s,3H),3.14-3.06(m,1H),2.20-2.11(m,1H),2.02-1.94(m,1H),1.78-1.67(m,2H),1.66(s,3H),1.64(s,3H)。
使用适当的间苯二酚,一般方法A用于生成以下化合物。
中间体4:(1’R,2’R)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇
1H NMR(400MHz,DMSO)δ9.37(s,2H),6.38(s,2H),5.08(s,1H),4.49(d,J=2.8Hz,1H),4.44(dd,J=1.6,2.8Hz,1H),3.86-3.83(m,1H),3.06-2.98(m,1H),2.12-2.07(m,1H),1.96-1.92(m,1H),1.63-1.59(m,8H)。
中间体5:(1’R,2’R)-4-(2-甲氧基乙基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇
1H NMR(400MHz,DMSO)δ8.73(s,2H),6.06(s,2H),5.09(s,1H),4.51(d,J=2.8Hz,1H),4.44-4.41(m,1H),3.87-3.83(m,1H),3.45(t,J=6.9Hz,2H),3.24(s,3H),3.09-3.01(m,1H),2.56(t,J=6.8Hz,2H),2.16-2.06(m,1H),1.97-1.89(m,1H),1.69-1.63(m,2H),1.62(s,3H),1.61(s,3H)。
中间体6:(1’R,2’R)-3,5’-二甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇
1H NMR(400MHz,DMSO)δ8.53(s,1H),7.27(s,1H),6.09(s,1H),5.15(s,1H),4.48(d,J=2.2Hz,1H),4.42(dd,J=1.4,2.7Hz,1H),3.94-3.88(m,1H),3.03-2.94(m,1H),2.39-2.32(m,2H),2.16-2.09(m,1H),2.00-1.92(m,1H),1.96(s,3H),1.73-1.66(m,2H),1.64(s,3H),1.60(s,3H),1.51-1.40(m,2H),0.91(t,J=7.3Hz,3H)。
中间体7:(1’R,2’R)-4-溴-3,5,5’-三甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇
1H NMR(400MHz,DMSO)δ8.16(s,1H),7.71(s,1H),5.18(s,1H),4.47(d,J=2.5Hz,1H),4.43(dd,J=1.4,2.5Hz,1H),4.03-3.99(m,1H),3.01(dt,J=3.3,11.0Hz,1H),2.18(s,6H),2.16-2.11(m,1H),2.04-1.96(m,1H),1.75-1.67(m,2H),1.65(s,3H),1.60(s,3H)。
一般方法B
通过制备以下中间体6来说明一般方法B:(1’R,2’R,4’S)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇
[3-乙酰氧基-5-溴-2-[(1R,6R)-6-异丙烯基-3-甲基-环己-2-烯-1-基]苯基]乙酸酯
将在乙腈(30mL)中的5-溴-2-[(1R,6R)-6-异丙烯基-3-甲基-环己-2-烯-1-基]苯-1,3-二醇(1305mg,4.04mmol)用碳酸铯(3289mg,10.1mmol)处理,随后用乙酸酐(0.95mL,10.1mmol)处理。将反应混合物搅拌持续1小时,然后在乙酸乙酯(100mL)和水(100mL)之间分配。将层分离,将含水层用乙酸乙酯(100mL)萃取,并且将合并的有机相干燥(疏水性滤纸)并且在真空中浓缩以给出作为橙色胶的标题化合物(1.60g,93.4%)。
1H NMR(400MHz,DMSO)δ7.33(s,2H),4.98(s,1H),4.55-4.52(m,1H),4.43(d,J=1.5Hz,1H),3.59-3.52(m,1H),2.70-2.61(m,1H),2.26-2.25(m,7H),2.03(d,J=16.9Hz,1H),1.79-1.72(m,2H),1.67(s,3H),1.62(s,3H)。
[3-乙酰氧基-5-溴-2-[(1R,6R)-6-异丙烯基-3-甲基-4-氧代-环己-2-烯-1-基]苯基]乙酸酯
将在乙酸乙酯(31.92mL)中的[3-乙酰氧基-5-溴-2-[(1R,6R)-6-异丙烯基-3-甲基-环己-2-烯-1-基]苯基]乙酸酯(1560mg,3.83mmol)和分子筛(3A,5g)用乙酸锰(III)二水合物(103mg,0.383mmol)处理,随后用在壬烷中的5.5M叔丁基过氧化氢溶液(3.5mL,19.2mmol)处理。将反应混合物在20℃搅拌过夜,然后用乙酸乙酯(50mL)稀释并且通过硅藻土垫过滤。将滤液用饱和含水硫代硫酸钠(30mL)和水(30mL)洗涤,分离,干燥(MgSO4),过滤并且在真空中浓缩。残余物通过用在环己烷中的0%-100%乙醚洗脱的二氧化硅上的柱色谱法纯化,以给出作为灰白色固体的标题化合物(561mg,34.8%)。
1H NMR(400MHz,DMSO)δ7.39(s,2H),6.38(t,J=1.8Hz,1H),4.56(s,1H),4.50(s,1H),4.04(td,J=2.3,10.6Hz,1H),3.20-3.11(m,1H),2.85-2.76(m,1H),2.35-2.19(m,7H),1.71(dd,J=1.5,2.5Hz,3H),1.62(s,3H)。
(1’R,2’R,4’S)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇
在0℃向[3-乙酰氧基-5-溴-2-[(1R,6R)-6-异丙烯基-3-甲基-4-氧代-环己-2-烯-1-基]苯基]乙酸酯(1.10g,2.61mmol)在甲醇(25.0mL)中的溶液中经30分钟的时间段以四等份添加硼氢化钠(0.22g,5.74mmol),并且允许混合物升温至室温过夜。将反应混合物在真空中浓缩并且将残余物在乙酸乙酯(75mL)和水(75mL)之间分配。将层分离,并且将有机相用盐水(50mL)洗涤,干燥(MgSO4)并且在真空中浓缩。残余物通过用在环己烷中的0%-80%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,以给出作为白色固体的标题化合物(508mg,57.4%)。
1H NMR(400MHz,DMSO)δ9.53(s,1H),9.32(s,1H),6.43-6.36(m,2H),5.07-5.05(m,1H),4.62(d,J=6.7Hz,1H),4.49-4.44(m,2H),4.12-4.06(m,1H),3.88-3.84(m,1H),3.20-3.12(m,1H),1.90(ddd,J=2.4,5.7,12.0Hz,1H),1.66-1.63(m,3H),1.63-1.55(m,4H)。
一般方法C
通过合成以下中间体7来说明一般方法C:(1’R,2’R,4’S)-2,4’,6-三羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基三氟甲磺酸酯
(1’R,2’R)-5’-甲基-2’-(丙-1-烯-2-基)-4-(((三氟甲基)磺酰基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基二乙酸酯
将(1’R,2’R)-2,6-二羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基三氟甲磺酸酯(10.0g,25.5mmol)在乙腈(200mL)中的溶液用碳酸铯(20.76g,63.7mmol)和乙酸酐(6.0mL,63.7mmol)处理。将反应混合物在室温搅拌整个周末。将混合物用乙酸乙酯(200mL)稀释,并且用水(100mL)和盐水(100mL)洗涤。将有机层干燥(相分离纸)并且在真空中浓缩。残余物通过用在环己烷中的0%-10%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,以给出作为淡黄色油的标题化合物(8.08g,67%)。
1H NMR(400MHz,CDCl3)δ6.91(s,2H),5.16(s,1H),4.55(s,1H),4.41(s,1H),3.61-3.56(m,1H),2.67-2.59(m,1H),2.20(s,6H),2.15-2.01(m,2H),1.85-1.70(m,2H),1.68(s,3H),1.57(s,3H)。
(1’R,2’R)-5’-甲基-4’-氧代-2’-(丙-1-烯-2-基)-4-(((三氟甲基)磺酰基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基二乙酸酯
将(1’R,2’R)-5’-甲基-2’-(丙-1-烯-2-基)-4-(((三氟甲基)磺酰基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基二乙酸酯(4.0g,8.40mmol)在乙酸乙酯(80mL)中的溶液用分子筛(4g)处理,随后用乙酸锰(III)二水合物(270mg,1.01mmol)和叔丁基过氧化氢(5.5M的在壬烷中的溶液,8.5mL,47.0mmol)处理。将反应混合物在室温搅拌过夜。将混合物通过硅藻土垫过滤,用乙酸乙酯(80mL)洗涤,并且将有机层用饱和硫代硫酸钠溶液(50mL)和盐水(50mL)洗涤,干燥(相分离纸)并且在真空中浓缩。残余物通过用在环己烷中的10%-25%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,以给出作为黄色油的标题化合物(1.26g,30%)。
1H NMR(400MHz,CDCl3)δ6.99(s,2H),6.51-6.48(m,1H),4.66-4.63(m,1H),4.52(s,1H),3.95-3.90(m,1H),3.25-3.16(m,1H),2.65-2.53(m,2H),2.24(s,6H),1.83-1.80(m,3H),1.61(s,3H)。
(1’R,2’R,4’S)-2,4’,6-三羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基三氟甲磺酸酯
将冷却至0℃的(1’R,2’R)-5’-甲基-4’-氧代-2’-(丙-1-烯-2-基)-4-(((三氟甲基)磺酰基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基二乙酸酯(1.26g,2.57mmol)在甲醇(20mL)中的溶液用硼氢化钠(243mg,6.42mmol)分批处理。将反应混合物升温至室温并且搅拌过夜。将混合物用乙酸乙酯(100mL)稀释并且用饱和碳酸氢钠溶液(50mL)洗涤。将含水层用乙酸乙酯(50mL)萃取,并且将有机层合并,用盐水(50mL)洗涤,干燥(相分离纸)并且在真空中浓缩。残余物通过用在环己烷中的10%-40%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,以给出作为白色固体的标题化合物(0.5g,48%)。
1H NMR(400MHz,DMSO)δ9.93(s,1H),9.74(s,1H),6.29(s,2H),5.13-5.10(m,1H),4.66(d,J=6.8Hz,1H),4.51-4.49(m,2H),4.19-4.11(m,1H),3.97-3.92(m,1H),3.24-3.16(m,1H),1.95(ddd,J=2.4,5.7,12.0Hz,1H),1.70(s,3H),1.64(s,3H),1.63-1.57(m,1H)。
最终化合物的合成
一般方法D
通过合成(1’R,2’R,4’S)-4-(5-甲氧基吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物20)来说明一般方法D
将在1,4-二氧六环(2.0mL)和水(0.50mL)中的5-溴-2-[(1R,4S,6R)-4-羟基-6-异丙烯基-3-甲基-环己-2-烯-1-基]苯-1,3-二醇(70mg,0.206mmol)、5-甲氧基-3-吡啶硼酸频哪醇酯(73mg,0.310mmol)和氟化铯(94mg,0.619mmol)用氮气脱气,并且用[1,1’-双(二苯基膦基)二茂铁]-二氯化钯(II)(7.7mg,0.0103mmol)处理。将反应混合物在80℃加热持续2小时。将反应混合物冷却至室温,倒入水(20mL)中并且用二氯甲烷(2×20mL)萃取。将合并的有机层干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过用在环己烷中的20%-80%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,并且从乙腈/水中冻干以给出作为白色固体的标题化合物(35.2mg,46%)。
1H NMR(400MHz,DMSO)δ9.34(s,1H),9.11(s,1H),8.28(d,J=1.9Hz,1H),8.25(d,J=2.8Hz,1H),7.39(dd,J=1.9,2.7Hz,1H),6.50(s,2H),5.11(q,J=1.7Hz,1H),4.62(d,J=6.5Hz,1H),4.55(d,J=2.5Hz,1H),4.46(q,J=1.4Hz,1H),4.17-4.10(m,1H),4.00-3.93(m,1H),3.89(s,3H),3.31-3.23(m,1H),1.93(ddd,J=2.2,5.6,12.1Hz,1H),1.67(s,3H),1.65(s,3H),1.63-1.55(m,1H)。MS(ESI):m/z 368(M+1)。HPLC纯度:99.7%。
使用适当的硼酸或硼酸酯,一般方法D用于生成以下化合物。
(1’R,2’R,4’S)-4-(2-甲氧基嘧啶-5-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物21)
1H NMR(400MHz,DMSO)δ9.38(s,1H),9.14(s,1H),8.70(s,2H),6.44(s,2H),5.12-5.09(m,1H),4.62(d,J=6.2Hz,1H),4.54(d,J=2.7Hz,1H),4.45(q,J=1.4Hz,1H),4.17-4.10(m,1H),4.00-3.94(m,4H),3.30-3.22(m,1H),1.93(ddd,J=2.4,5.8,12.1Hz,1H),1.66(s,3H),1.64(s,3H),1.62-1.55(m,1H)。MS(ESI):m/z 369(M+1)。HPLC纯度:99.3%。
(1’R,2’R,4’S)-4-(1,3-二甲基-1H-吡唑-4-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物11)
1H NMR(400MHz,DMSO)δ9.03(s,1H),8.80(s,1H),7.64(s,1H),6.29(s,2H),5.12-5.09(m,1H),4.59(d,J=6.6Hz,1H),4.54(d,J=2.4Hz,1H),4.45(q,J=1.4Hz,1H),4.15-4.09(m,1H),3.94-3.88(m,1H),3.77(s,3H),3.28-3.19(m,1H),2.25(s,3H),1.92(ddd,J=2.3,5.6,11.9Hz,1H),1.66(s,3H),1.63(s,3H),1.61-1.54(m,1H)。MS(ESI):m/z 355(M+1)。HPLC纯度:95%。
(1’R,2’R,4’S)-4-(2-甲氧基吡啶-4-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物16)
1H NMR(400MHz,DMSO)δ9.38(s,1H),9.16(s,1H),8.19(dd,J=0.6,5.4Hz,1H),7.07(dd,J=1.5,5.4Hz,1H),6.82(dd,J=0.7,1.6Hz,1H),6.54(s,2H),5.12-5.09(m,1H),4.62(d,J=6.5Hz,1H),4.53(d,J=2.5Hz,1H),4.45(q,J=1.5Hz,1H),4.17-4.10(m,1H),3.98-3.94(m,1H),3.89(s,3H),3.32-3.22(m,1H),1.93(ddd,J=2.2,5.7,11.9Hz,1H),1.66(s,3H),1.64(s,3H),1.62-1.55(m,1H)。MS(ESI):m/z 368(M+1)。HPLC纯度:99.2%。
(1R,2R,4S)-3”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物15)
1H NMR(400MHz,DMSO)δ9.24(s,1H),9.03(s,1H),7.38(t,J=8.0Hz,1H),7.08(d,J=7.6Hz,1H),7.02(t,J=2.0Hz,1H),6.93(ddd,J=0.8,2.5,8.3Hz,1H),6.52(s,2H),5.15(q,J=1.6Hz,1H),4.64(d,J=6.6Hz,1H),4.59(d,J=2.4Hz,1H),4.51-4.48(m,1H),4.21-4.12(m,1H),4.03-3.96(m,1H),3.84(s,3H),3.35-3.26(m,1H),1.97(ddd,J=2.3,5.6,11.9Hz,1H),1.70(s,3H),1.68(s,3H),1.67-1.58(m,1H)。MS(ESI):m/z 367(M+1)。HPLC纯度:97.3%。
(1’R,2’R,4’S)-4-(6-甲氧基吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物17)
1H NMR(400MHz,DMSO)δ9.29(s,1H),9.07(s,1H),8.31(dd,J=0.6,2.6Hz,1H),7.82(dd,J=2.5,8.6Hz,1H),6.92(dd,J=0.7,8.6Hz,1H),6.47(s,2H),5.16-5.14(m,1H),4.64(d,J=6.6Hz,1H),4.58(d,J=2.6Hz,1H),4.49(q,J=1.3Hz,1H),4.21-4.14(m,1H),4.01-3.98(m,1H),3.93(s,3H),3.34-3.26(m,1H),1.97(ddd,J=2.2,5.6,11.9Hz,1H),1.70(s,3H),1.68(s,3H),1.66-1.59(m,1H)。MS(ESI):m/z 368(M+1)。HPLC纯度:98.9%。
(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-(吡啶-3-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物22)
1H NMR(400MHz,DMSO)δ9.35(s,1H),9.12(s,1H),8.68(dd,J=0.9,2.4Hz,1H),8.53(dd,J=1.6,4.7Hz,1H),7.85(ddd,J=1.7,2.4,8.0Hz,1H),7.45(dd,J=4.8,8.3Hz,1H),6.49(s,2H),5.13-5.11(m,1H),4.62(d,J=6.5Hz,1H),4.55(d,J=2.5Hz,1H),4.46(s,1H),4.14-4.11(m,1H),3.98-3.95(m,1H),3.32-3.23(m,1H),1.93(ddd,J=2.3,5.7,12.1Hz,1H),1.67(s,3H),1.65(s,3H),1.63-1.55(m,1H)。MS(ESI):m/z 338(M+1)。HPLC纯度:99.1%。
(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-(6-(三氟甲基)吡啶-3-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物23)
1H NMR(400MHz,DMSO)δ9.47(s,1H),9.25(s,1H),8.88(d,J=2.1Hz,1H),8.13(dd,J=1.9,8.2Hz,1H),7.95(d,J=7.9Hz,1H),6.54(s,2H),5.13-5.11(m,1H),4.63(d,J=6.5Hz,1H),4.55(d,J=2.5Hz,1H),4.46(q,J=1.3Hz,1H),4.17-4.11(m,1H),4.06-3.97(m,1H),3.32-3.23(m,1H),1.94(ddd,J=2.4,5.6,12.1Hz,1H),1.68(s,3H),1.65(s,3H),1.63-1.56(m,1H)。MS(ESI):m/z 406(M+1)。HPLC纯度:98.5%。
(1’R,2’R,4’S)-4-(5-氯吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物24)
1H NMR(400MHz,DMSO)δ9.43(s,1H),9.18(s,1H),8.64(d,J=1.9Hz,1H),8.59(d,J=2.3Hz,1H),7.95(t,J=2.1Hz,1H),6.49(s,2H),5.11(d,J=1.5Hz,1H),4.63(d,J=6.7Hz,1H),4.54(d,J=2.5Hz,1H),4.47-4.44(m,1H),4.16-4.10(m,1H),3.99-3.95(m,1H),3.32-3.23(m,1H),1.94(ddd,J=2.3,5.5,12.0Hz,1H),1.67(s,3H),1.65(s,3H),1.62-1.56(m,1H)。MS(ESI):m/z 372(M+1)。HPLC纯度:96.2%。
(1’R,2’R,4’S)-5’-甲基-4-(2-甲基噻唑-5-基)-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物13)
1H NMR(400MHz,DMSO)δ9.33(s,1H),9.14(s,1H),7.70(s,1H),6.43(s,2H),5.10-5.08(m,1H),4.62(d,J=6.7Hz,1H),4.51(d,J=2.6Hz,1H),4.44(q,J=1.4Hz,1H),4.14-4.09(m,1H),3.94-3.90(m,1H),3.30-3.19(m,1H),2.65(s,3H),1.91(ddd,J=2.3,5.7,12.1Hz,1H),1.65(s,3H),1.62(s,3H),1.61-1.54(m,1H)。MS(ESI):m/z 358(M+1)。HPLC纯度:93.9%。
(1’R,2’R,4’S)-4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物43)
1H NMR(400MHz,DMSO)δ9.29-9.25(m,1H),9.11-9.07(m,1H),7.48-7.43(m,2H),7.30-7.26(m,1H),6.43-6.42(m,2H),5.11(d,J=1.5Hz,1H),4.62(d,J=6.5Hz,1H),4.54(d,J=2.6Hz,1H),4.47-4.45(m,1H),4.13(d,J=5.6Hz,1H),3.97-3.92(m,1H),3.30-3.22(m,1H),1.96-1.89(m,1H),1.67-1.63(m,6H),1.63-1.55(m,1H)。MS(ESI):m/z 417(M+1)。HPLC纯度:96.3%。
(1’R,2’R,4’S)-5’-甲基-4-(2-甲基吡啶-4-基)-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物28)
1H NMR(400MHz,DMSO)δ9.37-9.36(m,1H),9.14-9.12(m,1H),8.45(d,J=5.3Hz,1H),7.32(s,1H),7.25(dd,J=1.4,5.2Hz,1H),6.56(s,2H),5.11(d,J=1.5Hz,1H),4.63(d,J=6.7Hz,1H),4.53(d,J=2.6Hz,1H),4.45(dd,J=1.4,2.5Hz,1H),4.13(d,J=4.4Hz,1H),3.99-3.95(m,1H),3.29-3.22(m,1H),2.53(s,3H),1.96-1.90(m,1H),1.68-1.63(m,6H),1.62-1.55(m,1H)。MS(ESI):m/z 352(M+1)。HPLC纯度:98.4%。
(1R,2R,4S)-2”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物29)
1H NMR(400MHz,DMSO)δ9.06(s,1H),8.88-8.79(m,1H),7.35-7.30(m,1H),7.22(dd,J=1.8,7.6Hz,1H),7.10(d,J=7.6Hz,1H),7.04-7.00(m,1H),6.41-6.39(m,2H),5.16(d,J=1.5Hz,1H),4.65-4.62(m,2H),4.53-4.51(m,1H),4.18-4.14(m,1H),4.02-3.97(m,1H),3.80(s,3H),3.35-3.29(m,1H),2.05-1.94(m,1H),1.70-1.69(m,6H),1.66-1.58(m,1H)。MS(ESI):m/z 367(M+1)。HPLC纯度:99.5%。
(1R,2R,4S)-4”-氟-3”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物30)
1H NMR(400MHz,DMSO)δ9.26(s,1H),9.07-8.98(m,1H),7.32-7.21(m,2H),7.04(ddd,J=1.8,4.1,8.4Hz,1H),6.53-6.49(m,2H),5.15(s,1H),4.66-4.57(m,2H),4.49(s,1H),4.16(d,J=5.3Hz,1H),4.00-3.96(m,1H),3.95-3.93(m,3H),3.34-3.26(m,1H),1.99-1.95(m,1H),1.72-1.67(m,6H),1.66-1.59(m,1H)。MS(ESI):m/z 385(M+1)。HPLC纯度:97.4%。
(1R,2R,4S)-3”-(二氟甲氧基)-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物31)
1H NMR(400MHz,DMSO)δ9.36-9.28(m,1H),9.14-9.09(m,1H),7.55-7.15(m,5H),6.58-6.53(m,2H),5.17-5.14(m,1H),4.65(d,J=6.6Hz,1H),4.58(s,1H),4.49(s,1H),4.19-4.14(m,1H),4.01-3.98(m,1H),3.34-3.27(m,1H),1.98(dd,J=5.8,9.9Hz,1H),1.72-1.67(m,6H),1.67-1.59(m,1H)。MS(ESI):m/z 403(M+1)。HPLC纯度:95.1%。
(1R,2R,4S)-3”-(氨基甲基)-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物32)
1H NMR(400MHz,DMSO)δ9.10(s,1H),8.87(t,J=12.8Hz,1H),7.36-7.28(m,3H),7.15-7.13(m,1H),6.46-6.39(m,2H),5.05(d,J=1.3Hz,1H),4.54-4.45(m,2H),4.37(d,J=1.3Hz,1H),4.09-4.01(m,1H),3.90-3.86(m,1H),3.36(s,2H),3.24-3.15(m,1H),2.11-2.09(m,6H),1.88-1.78(m,1H),1.60-1.55(m,6H),1.55-1.48(m,1H)。MS(ESI):m/z 394(M+1)。HPLC纯度:92.7%。
(1R,2R,4S)-4”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物33)
1H NMR(400MHz,DMSO)δ9.26-9.19(m,1H),9.05-8.99(m,1H),7.51-7.48(m,2H),7.10-7.07(m,2H),6.52-6.51(m,2H),5.22-5.20(m,1H),4.71-4.63(m,2H),4.55-4.54(m,1H),4.25-4.18(m,1H),4.05-4.02(m,1H),3.89-3.88(m,3H),3.39-3.32(m,1H),2.06-1.99(m,1H),1.77-1.73(m,6H),1.71-1.64(m,1H)。MS(ESI):m/Z 367(M+1)。HPLC纯度:94.8%。
(1R,2R,4S)-5-甲基-2-(丙-1.烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物14)
1H NMR(400MHz,DMSO)δ9.29-9.20(m,1H),9.03(s,1H),7.53-7.44(m,4H),7.38-7.33(m,1H),6.53-6.51(m,2H),5.16(d,J=1.5Hz,1H),4.66-4.58(m,2H),4.51-4.49(m,1H),4.19-4.13(m,1H),4.01-3.96(m,1H),3.34-3.27(m,1H),2.00-1.94(m,1H),1.72-1.68(m,6H),1.67-1.59(m,1H)。MS(ESI):m/z 337(M+1)。HPLC纯度:99.2%。
(1’R,2’R,4’S)-4-(6-乙氧基吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物34)
1H NMR(400MHz,DMSO)δ9.31-9.20(m,1H),9.07-8.98(m,1H),8.24(d,J=2.5Hz,1H),7.76(dd,J=2.5,8.7Hz,1H),6.86-6.83(m,1H),6.43-6.40(m,2H),5.11(s,1H),4.61(d,J=6.5Hz,1H),4.54(s,1H),4.45(s,1H),4.33(q,J=7.0Hz,2H),4.15-4.11(m,1H),3.96-3.93(m,1H),3.30-3.26(m,1H),1.95-1.90(m,1H),1.68-1.63(m,6H),1.62-1.55(m,1H),1.34(t,J=7.1Hz,3H)。MS(ESI):m/z 382(M+1)。HPLC纯度:93.3%。
(1’R,2’R,4’S)-4-(2-甲氧基吡啶-4-基)-3,5,5’-三甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物52)
1H NMR(400MHz,DMSO)δ8.20(dd,J=0.6,5.2Hz,1H),7.89(s,1H),7.51(s,1H),6.73-6.67(m,1H),6.50(s,1H),5.18(s,1H),4.57(s,1H),4.48(dd,J=1.4,2.5Hz,1H),4.17-4.10(m,2H),3.89(s,3H),3.31(t,J=11.7Hz,1H),1.95(ddd,J=2.3,5.3,11.9Hz,1H),1.74(s,3H),1.71(s,3H),1.69(s,3H),1.65(s,3H),1.67-1.61(m,1H)。(未观察到OH)MS(ESI):m/z 396(M+1)。HPLC纯度:99%。
一般方法E
通过合成(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-(5-(三氟甲基)吡啶-3-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物25)来说明一般方法E
将在1,4-二氧六环(2.0mL)和水(0.50mL)中的[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)(7.3mg,9.79μmol)、(1’R,2’R,4’S)-2,4’,6-三羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基三氟甲磺酸酯(80mg,0.196mmol)、碳酸钠(83mg,0.784mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5-(三氟甲基)吡啶(59mg,0.215mmol)的混合物在密封管中在100℃加热持续1小时。将反应混合物用乙酸乙酯(50mL)稀释,并且用水(10mL)、盐水(10mL)洗涤,干燥(MgSO4),过滤并且在真空中浓缩。残余物通过用在环己烷中的0%-100%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,随后通过反相制备型HPLC纯化以给出作为灰白色固体的标题化合物(35mg,44%)。
1H NMR(400MHz,DMSO)δ9.44(s,1H),9.21(s,1H),8.99(d,J=2.0Hz,1H),8.94-8.92(m,1H),8.18(t,J=2.0Hz,1H),6.59-6.55(m,2H),5.13-5.10(m,1H),4.64(d,J=6.8Hz,1H),4.54(d,J=2.7Hz,1H),4.46(dd,J=1.4,2.7Hz,1H),4.17-4.09(m,1H),4.01-3.96(m,1H),3.31-3.23(m,1H),1.94(ddd,J=2.4,5.7,11.9Hz,1H),1.67(s,3H),1.65(s,3H),1.63-1.56(m,1H)。MS(ESI):m/z 406.3(M+1)。HPLC纯度:98.6%。
使用适当的硼酸或硼酸酯,一般方法E用于生成以下化合物。
(1’R,2’R,4’S)-4-(3,6-二氢-2H-吡喃-4-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物26)
1H NMR(400MHz,DMSO)δ9.05(s,1H),8.83(s,1H),6.29(s,2H),6.01-5.98(m,1H),5.08(q,J=1.5Hz,1H),4.60(d,J=6.8Hz,1H),4.50(d,J=2.4Hz,1H),4.42(q,J=1.4Hz,1H),4.19(q,J=2.7Hz,2H),4.15-4.07(m,1H),3.92-3.86(m,1H),3.79(t,J=5.4Hz,2H),3.26-3.17(m,1H),2.33-2.27(m,2H),1.91(ddd,J=2.3,5.7,12.1Hz,1H),1.65(s,3H),1.61(s,3H),1.60-1.53(m,1H)。MS(ESI):m/z 342.4(M+1)。HPLC纯度:94.4%。
一般方法F
通过合成(1’R,2’R,4’S)-4-(3,5-二甲基异噁唑-4-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’一联苯基]-2,4’,6-三醇(化合物12)来说明一般方法F
将(1’R,2’R,4’S)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(100mg,0.295mmol)溶解在干燥的N,N-二甲基甲酰胺(1.70mL)和水(0.30mL)中。将混合物脱气,并且添加3,5-二甲基异噁唑-4-硼酸频哪醇酯(92mg,0.413mmol)、氟化铯(90mg,0.590mmol)和四(三苯基膦)钯(0)(34mg,0.0295mmol)。将混合物在95℃加热过夜。将反应用乙酸乙酯(4mL)稀释,并且用水(2mL)和盐水(3mL)洗涤。将含水层用乙酸乙酯(2×4mL)进一步萃取。将有机相合并,干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过反相制备型HPLC纯化,以给出作为灰白色固体的标题化合物(12.0mg,10.7%)。
1H NMR(400MHz,DMSO)δ9.24(s,1H),9.01(s,1H),6.21(s,2H),5.13-5.10(m,1H),4.61(d,J=6.4Hz,1H),4.55(d,J=2.6Hz,1H),4.46(q,J=1.4Hz,1H),4.16-4.09(m,1H),3.96-3.92(m,1H),3.29-3.21(m,1H),2.39(s,3H),2.21(s,3H),1.93(ddd,J=2.4,5.7,12.0Hz,1H),1.66(s,3H),1.64(s,3H),1.62-1.54(m,1H)。MS(ESI):m/z 355.4(M+1)。HPLC纯度:93.7%。
使用适当的硼酸或硼酸酯,一般方法F用于生成以下化合物。
(1R,2R,4S)-4”-氟-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物18)
1H NMR(400MHz,DMSO)δ9.24(s,1H),9.01(s,1H),7.51-7.47(m,2H),7.28-7.23(m,2H),6.44(s,2H),5.13-5.10(m,1H),4.62(d,J=6.7Hz,1H),4.54(d,J=2.6Hz,1H),4.47-4.44(m,1H),4.17-4.08(m,1H),3.97-3.93(m,1H),3.29-3.21(m,1H),1.93(ddd,J=2.3,5.7,11.9Hz,1H),1.67(s,3H),1.65(s,3H),1.62-1.55(m,1H)。MS(ESI):m/z 355(M+1)。HPLC纯度:98.3%。
一般方法G
通过合成(1’R,2’R,4’S)-4-(苯并[d][1,3]二氧杂环戊烯-5-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物41)来说明一般方法G
将(1’R,2’R,4’S)-2,4’,6-三羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基三氟甲磺酸酯(80mg,0.196mmol)在1,4-二氧六环(4.0mL)和水(1.0mL)中的溶液用3,4-(亚甲基二氧基)苯基硼酸(49mg,0.294mmol)和碳酸钠(62mg,0.588mmol)处理,随后用SPhos Pd G2(14mg,0.0196mmol)处理。将反应混合物在微波辐照下在120℃加热持续1小时。将混合物用水(5mL)稀释并且用乙酸乙酯(30mL)萃取。将有机层用盐水(5mL)洗涤,干燥(相分离纸)并且在真空中浓缩。残余物通过反相制备型HPLC纯化,以给出作为灰白色固体的标题化合物(24mg,32%)。
1H NMR(400MHz,DMSO)δ9.22-9.17(m,1H),8.94(s,1H),6.98-6.93(m,3H),6.39-6.37(m,2H),6.05(s,2H),5.11(d,J=1.4Hz,1H),4.62-4.53(m,2H),4.47-4.45(m,1H),4.15-4.08(m,1H),3.95-3.91(m,1H),3.29-3.22(m,1H),1.95-1.89(m,1H),1.67-1.63(m,6H),1.62-1.55(m,1H)。MS(ESI):m/z 381(M+1)。HPLC纯度:99.1%。
使用适当的硼酸或硼酸酯,一般方法G用于生成以下化合物。
(1’R,2’R,4’S)-4-(6-(二氟甲氧基)吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物19)
1H NMR(400MHz,DMSO)δ9.36-9.32(m,1H),9.13(s,1H),8.35-8.35(m,1H),7.99(dd,J=2.7,8.7Hz,1H),7.74(t,J=72.9Hz,1H),7.17-7.14(m,1H),6.47-6.44(m,2H),5.11(d,J=1.5Hz,1H),4.63-4.61(m,1H),4.55(d,J=2.5Hz,1H),4.46(dd,J=1.4,2.6Hz,1H),4.13(d,J=5.4Hz,1H),3.99-3.94(m,1H),3.31-3.22(m,1H),1.97-1.89(m,1H),1.65(d,J=7.0Hz,6H),1.63-1.55(m,1H)。MS(ESI):m/z 404(M+1)。HPLC纯度:99%。
(1’R,2’R,4’S)-4-(苯并[d][1,3]二氧杂环戊烯-4-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物42)
1H NMR(400MHz,DMSO)δ9.24-9.18(m,1H),9.00(d,J=3.8Hz,1H),7.00-6.90(m,3H),6.64(s,2H),6.09(s,2H),5.16(d,J=1.5Hz,1H),4.65-4.57(m,2H),4.49(dd,J=1.4,2.7Hz,1H),4.17-4.13(m,1H),4.02-3.96(m,1H),3.34-3.26(m,1H),2.00-1.94(m,1H),1.71-1.67(m,6H),1.66-1.59(m,1H)。MS(ESI):m/z 381(M+1)。HPLC纯度:95.8%。
(1’R,2’R,4’S)-4-(2-甲氧基吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物35)
1H NMR(400MHz,DMSO)δ9.10-8.99(m,1H),8.82(s,1H),8.03(dd,J=1.9,4.9Hz,1H),7.52(dd,J=1.8,7.3Hz,1H),6.96(dd,J=5.1,7.3Hz,1H),6.33(bs,2H),5.02(d,J=1.5Hz,1H),4.52-4.47(m,2H),4.39-4.38(m,1H),4.07-4.00(m,1H),3.89-3.84(m,1H),3.79(s,3H),3.22-3.15(m,1H),1.88-1.80(m,1H),1.58-1.55(m,6H),1.53-1.46(m,1H)。MS(ESI):m/z 368(M+1)。HPLC纯度:99.2%。
1-(4-((1’R,2’R,4’S)-2,4’,6-三羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮(化合物36)
1H NMR(400MHz,DMSO)δ9.08(s,1H),8.91-8.83(m,1H),6.32-6.28(m,2H),5.97(d,J=3.8Hz,1H),5.12(d,J=1.3Hz,1H),4.62(d,J=6.6Hz,1H),4.53(d,J=2.3Hz,1H),4.46(s,1H),4.18-4.07(m,3H),3.95-3.90(m,1H),3.68-3.60(m,2H),3.29-3.21(m,1H),2.45(s,1H),2.35-2.31(m,1H),2.09(d,J=15.9Hz,3H),1.98-1.91(m,1H),1.70-1.64(m,6H),1.64-1.57(m,1H)。MS(ESI):m/z 384(M+1)。HPLC纯度:97.1%。
(1R,2R,4S)-3”-(2-甲氧基乙氧基)-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物37)
1H NMR(400MHz,DMSO)δ9.21-9.16(m,1H),9.01-8.98(m,1H),7.33(t,J=8.0Hz,1H),7.05-6.97(m,2H),6.90(dd,J=1.8,8.2Hz,1H),6.47-6.46(m,2H),5.11(d,J=1.5Hz,1H),4.61(d,J=6.7Hz,1H),4.55(d,J=2.5Hz,1H),4.46(d,J=1.3Hz,1H),4.16-4.10(m,3H),3.98-3.93(m,1H),3.70-3.67(m,2H),3.29-3.22(m,4H),1.96-1.90(m,1H),1.68-1.63(m,6H),1.63-1.55(m,1H)。MS(ESI):m/z 411(M+1)。HPLC纯度:97%。
(1’R,2’R,4’S)-5’-甲基-4-((E)-丙-1-烯-1-基)-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物7)
1H NMR(400MHz,DMSO)δ8.99-8.93(m,1H),8.76(s,1H),6.21-6.11(m,3H),5.97(ddd,J=4.5,11.1,17.7Hz,1H),5.08(d,J=1.5Hz,1H),4.59(d,J=6.7Hz,1H),4.49(d,J=2.6Hz,1H),4.42(dd,J=1.4,2.6Hz,1H),4.09(d,J=5.1Hz,1H),3.91-3.85(m,1H),3.24-3.15(m,1H),1.91-1.83(m,1H),1.82-1.79(m,3H),1.64(s,3H),1.60(s,3H),1.57-1.52(m,1H)。MS(ESI):m/z 301(M+1)。HPLC纯度:97.4%。
(1’R,2’R,4’S)-4-(环戊-1-烯-1-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物9)
1H NMR(400MHz,DMSO)δ8.99-8.94(m,1H),8.76(s,1H),6.35-6.27(m,2H),5.97(d,J=1.9Hz,1H),5.08(d,J=1.5Hz,1H),4.60-4.57(m,1H),4.50-4.47(m,1H),4.43-4.41(m,1H),4.10(d,J=5.4Hz,1H),3.90-3.87(m,1H),3.25-3.16(m,1H),2.48-2.41(m,2H),1.97-1.88(m,3H),1.66-1.59(m,9H)。MS(ESI):m/z 327(M+1)。HPLC纯度:97.3%。
(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-(6-(三氟甲氧基)吡啶-3-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物38)
1H NMR(400MHz,DMSO)δ9.47-9.42(m,1H),9.26-9.18(m,1H),8.50(d,J=2.0Hz,1H),8.11(dd,J=2.5,8.6Hz,1H),7.41-7.37(m,1H),6.57-6.48(m,2H),5.15(d,J=1.5Hz,1H),4.67-4.57(m,2H),4.51-4.49(m,1H),4.17(dd,J=2.8,5.1Hz,1H),4.03-3.99(m,1H),3.34-3.27(m,1H),2.01-1.94(m,1H),1.72-1.68(m,7H)。MS(ESI):m/z 422(M+1)。HPLC纯度:97.8%。
(1’R,2’R,4’S)-4-(2-(二氟甲氧基)吡啶-4-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物39)
1H NMR(400MHz,DMSO)δ9.47-9.40(m,1H),9.28-9.20(m,1H),8.28(d,J=5.4Hz,1H),7.75(t,J=73.1Hz,1H),7.36(dd,J=1.6,5.4Hz,1H),7.08(d,J=0.9Hz,1H),6.59-6.53(m,2H),5.11(d,J=1.5Hz,1H),4.64-4.62(m,1H),4.53(d,J=2.5Hz,1H),4.45(dd,J=1.4,2.6Hz,1H),4.14-4.10(m,1H),4.00-3.96(m,1H),3.30-3.22(m,1H),1.97-1.90(m,1H),1.68-1.63(m,7H)。MS(ESI):m/z 404(M+1)。HPLC纯度:95.4%。
(1’R,2’R,4’S)-4-(2-(二氟甲氧基)吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物40)
1H NMR(400MHz,DMSO)δ9.32-9.26(m,1H),9.10-9.06(m,1H),8.23-8.21(m,1H),7.86-7.78(m,2H),7.34(dd,J=4.9,7.5Hz,1H),6.42-6.39(m,2H),5.13(d,J=1.5Hz,1H),4.63-4.56(m,2H),4.49-4.48(m,1H),4.13(d,J=5.5Hz,1H),3.99-3.96(m,1H),3.32-3.25(m,1H),1.97-1.90(m,1H),1.68-1.64(m,7H)。MS(ESI):m/z 404(M+1)。HPLC纯度:98.9%。
(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-(2-(三氟甲基)吡啶-4-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物58)
1H NMR(400MHz,DMSO)δ9.49-9.45(m,1H),9.27-9.25(m,1H),8.79(d,J=5.1Hz,1H),7.88(s,1H),7.80(dd,J=1.4,5.1Hz,1H),6.66(d,J=1.9Hz,2H),5.11(d,J=1.5Hz,1H),4.64(d,J=6.7Hz,1H),4.53(d,J=2.5Hz,1H),4.45(dd,J=1.4,2.6Hz,1H),4.16-4.09(m,1H),4.01-3.97(m,1H),3.31-3.24(m,1H),1.97-1.90(m,1H),1.68-1.63(m,7H)。MS(ESI):m/z 406(M+1)。HPLC纯度:99.2%。
(1’R,2’R,4’S)-4-(6-(2,2-二氟乙基)-5-氟吡啶-3-基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物59)
1H NMR(400MHz,DMSO)δ9.47-9.20(m,2H),8.23-8.22(m,1H),8.07-7.97(m,1H),7.63-7.61(m,1H),6.57-6.50(m,2H),5.14(d,J=1.5Hz,1H),4.67-4.64(m,1H),4.58(d,J=2.5Hz,1H),4.50(d,J=1.3Hz,1H),4.17(d,J=5.6Hz,1H),4.04-4.00(m,1H),3.34-3.26(m,1H),2.01-1.93(m,1H),1.72-1.67(m,7H)。MS(ESI):m/z 422(M+1)。HPLC纯度:95.2%。
使用适当的4-取代的(1’R,2’R)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇,一般方法B(3步氧化和LAH还原)用于生成以下化合物。
(1’R,2’R,4’S)-5’-甲基-4-(1-甲基-1H-吡唑-4-基)-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物10)
1H NMR(400MHz,DMSO)δ9.06(s,1H),8.82(s,1H),7.83(s,1H),7.54(s,1H),6.34(s,2H),5.12-5.11(m,1H),4.60(d,J=6.7Hz,1H),4.53-4.50(m,1H),4.45-4.43(m,1H),4.15-4.08(m,1H),3.94-3.87(m,1H),3.86-3.85(m,3H),3.25-3.19(m,1H),1.91(ddd,J=2.3,5.8,12.0Hz,1H),1.67-1.61(m,6H),1.57(d,J=22.7Hz,1H)。MS(ESI):m/z 341(M+1)。HPLC纯度:98.6%。
(1’R,2’R,4’S)-4-(甲氧基甲基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物4)
1H NMR(400MHz,DMSO)δ9.00(s,1H),8.78(s,1H),6.18(s,2H),5.08(q,J=1.9Hz,1H),4.58(d,J=6.7Hz,1H),4.49(d,J=2.7Hz,1H),4.42(q,J=1.4Hz,1H),4.17(s,2H),4.14-4.06(m,1H),3.93-3.86(m,1H),3.24(s,3H),3.23-3.17(m,1H),1.91(ddd,J=2.4,5.6,12.0Hz,1H),1.65(s,3H),1.60(s,3H),1.60-1.54(m,1H)。MS(ESI):m/z 303(M-1)(仅观察到负离子)。HPLC纯度:92.5%。
(1’R,2’R,4’S)-4-(2-甲氧基乙基)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物5)
1H NMR(400MHz,DMSO)δ8.89(s,1H),8.66(s,1H),6.08(s,2H),5.08-5.05(m,1H),4.58(d,J=7.0Hz,1H),4.50(d,J=2.6Hz,1H),4.42(q,J=1.4Hz,1H),4.13-4.05(m,1H),3.91-3.85(m,1H),3.45(t,J=6.9Hz,2H),3.24(s,3H),3.23-3.16(m,1H),2.55(t,J=6.9Hz,2H),1.89(ddd,J=2.5,5.7,12.0Hz,1H),1.64(s,3H),1.60(s,3H),1.59-1.51(m,1H)。MS(ESI):m/z 319(M+1)。HPLC纯度:95.6%。
(1’R,2’R,4’S)-4,5’-二甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物1)
1H NMR(400MHz,DMSO)δ8.86(s,1H),8.62(s,1H),6.00(s,2H),5.07(q,J=1.6Hz,1H),4.58(d,J=6.5Hz,1H),4.49(d,J=2.8Hz,1H),4.41(q,J=1.4Hz,1H),4.14-4.05(m,1H),3.89-3.83(m,1H),3.24-3.15(m,1H),2.05(s,3H),1.89(ddd,J=2.5,5.8,12.2Hz,1H),1.64(s,3H),1.60(s,3H),1.59-1.52(m,1H)。MS(ESI):m/z 275(M+1)。HPLC纯度:95.2%。
(1’R,2’R,4’S)-4-乙基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物3)
1H NMR(400MHz,DMSO)δ8.87(s,1H),8.64(s,1H),6.04(s,2H),5.08-5.05(m,1H),4.58(d,J=6.3Hz,1H),4.50(d,J=2.6Hz,1H),4.42(q,J=1.3Hz,1H),4.13-4.06(m,1H),3.89-3.84(m,1H),3.24-3.16(m,1H),2.35(q,J=7.6Hz,2H),1.90(ddd,J=2.4,5.6,12.0Hz,1H),1.64(s,3H),1.61(s,3H),1.59-1.52(m,1H),1.09(t,J=7.6Hz,3H)。MS(ESI):m/z 289(M+1)。HPLC纯度:99.6%。
2-((1’R,2’R,4’S)-2,4’,6-三羟基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-4-基)乙腈(化合物6)
1H NMR(400MHz,DMSO)δ9.32-9.27(m,1H),9.06-9.04(m,1H),6.22(s,2H),5.12-5.10(m,1H),4.64-4.62(m,1H),4.53(d,J=2.8Hz,1H),4.46(dd,J=1.4,2.7Hz,1H),4.14(d,J=5.8Hz,1H),3.98-3.91(m,1H),3.84(s,2H),3.29-3.20(m,1H),1.98-1.91(m,1H),1.70-1.63(m,6H),1.62-1.58(m,1H)。MS(ESI):m/z 298(M-1)(仅观察到负离子)。HPLC纯度:93.4%。
(1’R,2’R,4’S)-3,5’-二甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物44)
1H NMR(400MHz,DMSO)δ8.69-8.41(m,1H),7.70-7.26(m,1H),6.13-6.05(m,1H),5.15-5.07(m,1H),4.61-4.47(m,2H),4.41(s,1H),4.12(s,1H),3.93-3.89(m,1H),3.25-3.12(m,1H),2.38-2.32(m,2H),1.99-1.92(m,3H),1.91-1.87(m,1H),1.68-1.57(m,7H),1.48-1.43(m,2H),0.94-0.89(m,3H)。MS(ESI):m/z 317(M+1)。HPLC纯度:93.7%。
(1’R,2’R,4’S)-4-溴-3,5,5’-三甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物51)
1H NMR(400MHz,DMSO)δ8.21(s,1H),7.85(s,1H),5.13(dd,J=1.5,3.3Hz,1H),4.67(d,J=6.5Hz,1H),4.46(d,J=2.5Hz,1H),4.42(dd,J=1.4,2.5Hz,1H),4.15-4.11(m,1H),4.06-4.02(m,1H),3.22(ddd,J=2.2,10.7,12.8Hz,1H),2.19(s,3H),2.16(s,3H),1.92(ddd,J=2.4,5.7,12.0Hz,1H),1.67(s,3H),1.65-1.61(m,1H),1.60(s,3H)。MS(ESI):m/z 367/369(M+1)。HPLC纯度:95.2%。
使用适当的4-取代的(1’R,2’R)-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇,一般方法C(3步氧化和NaBH4还原)用于生成以下化合物。
(1’R,2’R,4’S)-4-氯-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物2)
1H NMR(400MHz,DMSO)δ9.53(s,1H),9.32(s,1H),6.24(s,2H),5.11-5.04(m,1H),4.66-4.57(m,1H),4.51-4.42(m,2H),4.12-4.10(m,1H),3.92-3.86(m,1H),3.20-3.11(m,1H),2.14-2.07(m,1H),1.95-1.87(m,1H),1.68-1.56(m,6H)。峰变宽可能是由阻旋异构引起的。MS(ESI):m/z 293,295(M+1)。HPLC纯度:99.2%。
一般方法H
通过合成(1’R,2’R,4’S)-3-氟-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物45)来说明一般方法H
将在甲醇(2.0mL)中的(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(50mg,0.165mmol)用Selectfluor(R)氟化试剂(59mg,0.165mmol)处理,并且在室温搅拌过夜。将反应混合物倒入饱和氯化铵溶液(10mL)中,并且用二氯甲烷(2×10mL)萃取。将合并的有机层干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过用在环己烷中的10%-80%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,随后通过反相制备型HPLC纯化以给出作为灰白色固体的标题化合物。
1H NMR(400MHz,DMSO)δ8.92-8.65(m,2H),6.02(s,1H),5.10(s,1H),4.62(d,J=6.7Hz,1H),4.48(d,J=2.0Hz,1H),4.45-4.42(m,1H),4.14-4.06(m,1H),3.92-3.87(m,1H),3.24-3.15(m,1H),2.45-2.36(m,2H),1.91(ddd,J=2.2,5.6,12.0Hz,1H),1.65(s,3H),1.60(s,3H),1.58-1.46(m,3H),0.89(t,J=7.3Hz,3H)。MS(ESI):m/z 319(M-1)(仅观察到负离子)。HPLC纯度:94.9%。
一般方法H用于生成以下化合物。
(1’R,2’R,4’S)-3-氟-5’-甲基-4-(1-甲基-1H-吡唑-4-基)-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物48)
1H NMR(400MHz,DMSO)δ9.14-8.83(m,2H),7.94(d,J=1.6Hz,1H),7.64(s,1H),6.38(s,1H),5.15-5.11(m,1H),4.64(d,J=6.7Hz,1H),4.51(d,J=2.0Hz,1H),4.46-4.43(m,1H),4.15-4.09(m,1H),3.95-3.90(m,1H),3.89(s,3H),3.26-3.18(m,1H),1.93(ddd,J=2.4,5.9,12.0Hz,1H),1.66(s,3H),1.62(s,3H),1.60-1.55(m,1H)。MS(ESI):m/z 359(M+1)。HPLC纯度:90.9%。
一般方法I
通过合成(1’R,2’R,4’S)-3-氯-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物46)来说明一般方法I
将在甲醇(2.0mL)中的(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(50mg,0.165mmol)用N-氯代琥珀酰亚胺(22mg,0.165mmol)处理,并且在室温搅拌过夜。将反应混合物倒入水(25mL)中并且用乙酸乙酯(2×25mL)萃取。将合并的有机层干燥(疏水性滤纸)并且在真空中浓缩。残余物通过用在环己烷中的30%-80%乙醚洗脱的二氧化硅上的柱色谱法纯化,以给出作为灰白色固体的标题化合物(30.2mg,54%)。
1H NMR(400MHz,CD3CN)δ6.93-6.48(m,2H),6.32(s,1H),5.29-5.26(m,1H),4.52-4.49(m,2H),4.32-4.25(m,1H),4.04-3.98(m,1H),3.13-3.06(m,1H),2.89(d,J=6.7Hz,1H),2.63-2.55(m,2H),2.04(ddd,J=2.4,5.7,12.1Hz,1H),1.76(s,3H),1.74-1.67(m,4H),1.66-1.56(m,2H),0.97(t,J=7.3Hz,3H)。MS(ESI):m/z 335(M-1)(仅观察到负离子)。HPLC纯度:96.2%。
一般方法I用于生成以下化合物。
(1R,2R,4S)-3’-氯-3”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇化合物49
乙腈代替甲醇用作溶剂。1H NMR(400MHz,DMSO)δ9.50-9.27(m,1H),8.79-8.60(m,1H),7.33(t,J=7.9Hz,1H),6.95-6.87(m,3H),6.34-6.29(m,1H),5.16-5.13(m,1H),4.67(d,J=6.5Hz,1H),4.56(d,J=2.4Hz,1H),4.51-4.48(m,1H),4.17-4.12(m,1H),4.05-4.01(m,1H),3.79-3.78(m,3H),3.29-3.25(m,1H),1.97-1.92(m,1H),1.69-1.65(m,6H),1.64-1.58(m,1H)。MS(ESI):m/z 399(M-1)(仅观察到负离子)。HPLC纯度:92.1%。
(1’R,2’R,4’S)-4-溴-3-氯-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇化合物47
1H NMR(400MHz,DMSO)δ9.80-9.58(m,1H),9.20-9.03(m,1H),6.68-6.62(m,1H),5.12-5.07(m,1H),4.67(d,J=6.5Hz,1H),4.46(s,2H),4.11(d,J=5.0Hz,1H),3.96-3.95(m,1H),3.21-3.15(m,1H),1.94-1.90(m,1H),1.67-1.60(m,6H),1.59-1.56(m,1H)。MS(ESI):m/z 371/373(M-1)(仅观察到负离子)。HPLC纯度:93.3%。
(1’R,2’R,4’S)-4’-甲氧基-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二醇(化合物53)
将在乙腈(10mL)中的(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(200mg,0.66mmol)和碳酸铯(474mg,1.45mmol)用2-(三甲基甲硅烷基)乙氧基甲基氯(0.25mL,1.39mmol)经20分钟逐滴处理。将反应混合物搅拌过夜,然后倒入水(50mL)中,并且用二氯甲烷(3×50mL)萃取,随后用乙酸乙酯(3×50mL)萃取。将有机层干燥(疏水性滤纸)并且在真空中浓缩以给出作为无色胶的粗制(1R,2R,4S)-5-甲基-2-(丙-1-烯-2-基)-4’-丙基-2’,6’-双((2-(三甲基甲硅烷基)乙氧基)甲氧基)-1,2,3,4-四氢-[1,1’-联苯基]-4-醇(316mg,85%)。在没有进一步纯化的情况下,将其一部分(233mg,0.41mmol)溶解在N,N-二甲基甲酰胺(3.0mL)中,用氢化钠(在矿物油中的60%分散体,25mg,0.62mmol)处理,随后用碘甲烷(39μL,0.62mmol)处理。将反应混合物搅拌过夜,然后用更多的氢化钠(25mg,在矿物油中的60%分散体,0.62mmol)处理,随后用碘甲烷(39μL,0.62mmol)处理,并且搅拌整个周末。将反应混合物用饱和氯化铵水溶液(1mL)猝灭,用乙酸乙酯(20mL)稀释,并且用水(2×20mL)洗涤。将有机层干燥(疏水性滤纸)并且在真空中浓缩以给出作为紫色胶的粗制((((((1’R,2’R,4’S)-4’-甲氧基-5’-甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基)双(氧基))双(亚甲基))双(氧基))双(乙-2,1-二基))双(三甲基硅烷)(148mg,62%)。在没有进一步纯化的情况下,将在甲醇(10mL)中的该粗品的一部分(120mg,0.21mmol)用2M含水盐酸(2mL,2mmol)处理并且搅拌过夜。将反应混合物用饱和碳酸氢钠溶液(10mL)猝灭,用乙酸乙酯(50mL)稀释,用水(2×50mL)洗涤并且在真空中浓缩。残余物通过用在环己烷中的0%-80%乙酸乙酯洗脱的二氧化硅上的柱色谱法纯化,随后通过反相制备型HPLC纯化以给出作为灰白色固体的化合物(10.4mg,16%)。
1H NMR(400MHz,DMSO)δ8.85(s,1H),8.69(s,1H),6.03(s,2H),5.20-5.16(m,1H),4.51(d,J=2.5Hz,1H),4.46-4.42(m,1H),3.92-3.84(m,2H),3.29(s,3H),3.25-3.16(m,1H),2.30(t,J=7.6Hz,2H),2.10-2.04(m,1H),1.63(s,3H),1.62(s,3H),1.57-1.46(m,3H),0.88(t,J=7.3Hz,3H)。MS(ESI):m/z 317(M+1)。HPLC纯度:97.2%。
一般方法J
通过合成(1’R,2’R)-4’,5’-二甲基-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物54)来说明一般方法J
将四氢呋喃(10mL)中的(1’R,2’R)-5’-甲基-4’-氧代-2’-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,6-二基二乙酸酯(184mg,0.479mmol)冷却至-78℃,并且用在二甲氧基甲烷中的3.1M甲基锂溶液(1.5mL,4.79mmol)处理。将反应混合物在-78℃搅拌持续2小时,然后允许经2小时升温至室温。将反应混合物用饱和氯化铵(5mL)猝灭,并且倒入水(50mL)中,并且用二氯甲烷(50mL)萃取。将含水层用盐酸酸化至pH2,并且用另外的二氯甲烷(2×50mL)萃取。将合并的有机层干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过用在环己烷中的10%-50%乙醚洗脱的二氧化硅上的柱色谱法纯化,随后通过反相制备型HPLC纯化,以给出作为灰白色固体的标题化合物(14.2mg,9.1%)。
1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(s,1H),6.08-6.03(m,2H),5.00(s,1H),4.56-4.53(m,1H),4.47(s,1H),4.33(s,1H),3.91-3.84(m,1H),3.35-3.27(m,1H),2.33(t,J=7.9Hz,2H),1.84(t,J=12.9Hz,1H),1.70-1.68(m,1H),1.67(s,3H),1.65(s,3H),1.59-1.48(m,2H),1.34(s,3H),0.91(t,J=7.3Hz,3H)。MS(ESI):m/z 315(M-1)。HPLC纯度:96.8%。
使用适当的烯酮,一般方法J还用于生成以下化合物。
(1’R,2’R)-4’,5’-二甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物55):
1H NMR(400MHz,DMSO)δ8.82(d,J=0.9Hz,1H),8.67(s,1H),6.04-5.98(m,2H),4.97-4.94(m,1H),4.50(d,J=2.5Hz,1H),4.45-4.42(m,1H),4.30(s,1H),3.86-3.80(m,1H),3.31-3.23(m,1H),2.30(t,J=7.6Hz,2H),1.80(t,J=12.8Hz,1H),1.65-1.64(m,1H),1.64-1.62(m,3H),1.61(s,3H),1.52-1.43(m,2H),1.33-1.23(m,7H),0.87(t,J=7.0Hz,3H)。MS(ESI):m/z 343(M-1)。HPLC纯度:93.3%。
(1’R,2’R,4’S)-4-环丙基-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物8)
将(1’R,2’R,4’S)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(60mg,0.177mmol)、环丙基三氟硼酸钾(39mg,0.265mmol)和磷酸三钾(113mg,0.531mmol)在甲苯(2.0mL)和水(0.5mL)中的溶液用氮气脱气,并且用双(二叔丁基(4-二甲基氨基苯基)膦)二氯化钯(II)(6.3mg,8.84μmol)处理。将反应混合物在100℃加热持续90分钟,然后倒入水(20mL)中并且用乙酸乙酯(2×30mL)萃取。将合并的有机层干燥(疏水性滤纸)并且在真空中浓缩。残余物通过用在环己烷中的20%-100%乙醚洗脱的二氧化硅上的柱色谱法纯化,随后通过反相制备型HPLC纯化,以给出作为灰白色固体的标题化合物(0.78mg,1.5%)。
1H NMR(400MHz,DMSO)δ8.84(s,1H),8.63(s,1H),5.91(s,2H),5.07-5.04(m,1H),4.57(d,J=6.7Hz,1H),4.49(d,J=2.6Hz,1H),4.43-4.40(m,1H),4.13-4.05(m,1H),3.87-3.82(m,1H),3.22-3.15(m,1H),1.89(ddd,J=2.3,5.6,11.7Hz,1H),1.63(s,3H),1.59(s,3H),1.59-1.52(m,2H),0.86-0.80(m,2H),0.49-0.45(m,2H)。MS(ESI):m/z 301(M+1)。HPLC纯度:96.3%。
(1’R,2’R,4’S)-5’-甲基-2’-(丙-1-烯-2-基)-4-(吡啶-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(化合物27)
将(1’R,2’R,4’S)-4-溴-5’-甲基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯基]-2,4’,6-三醇(100mg,0.295mmol)在干燥的1,4-二氧六环(2.0mL)中的溶液用氮气脱气,用2-(三丁基甲锡烷基)吡啶(150μL,0.463mmol)和四(三苯基膦)钯(0)(34mg,0.0295mmol)处理,并且在95℃加热过夜。将反应混合物用乙酸乙酯(4mL)、水(2mL)和盐水(3mL)稀释并且过滤。将含水层用乙酸乙酯(2×4mL)进一步萃取。将合并的有机层干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过反相制备型HPLC纯化,以给出作为灰白色固体的标题化合物(3.1mg,3.1%)。
1H NMR(400MHz,DMSO)δ9.25(s,1H),9.03(s,1H),8.60(ddd,J=0.9,1.8,4.8Hz,1H),7.84(dt,J=1.9,7.8Hz,1H),7.64(d,J=7.4Hz,1H),7.29(ddd,J=1.0,4.8,7.5Hz,1H),6.95(s,2H),5.15-5.12(m,1H),4.62(d,J=6.8Hz,1H),4.52(d,J=2.6Hz,1H),4.44(dd,J=1.4,2.6Hz,1H),4.16-4.09(m,1H),4.00-3.94(m,1H),3.30-3.22(m,1H),1.93(ddd,J=2.3,5.6,12.1Hz,1H),1.67(s,3H),1.64(s,3H)1.65-1.57(m,1H)。MS(ESI):m/z338(M+1)。HPLC纯度:99.5%。
(1R,2R,4S)-3’-氟-3”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(化合物50)
将(1R,2R,4S)-3”-甲氧基-5-甲基-2-(丙-1-烯-2-基)-1,2,3,4-四氢-[1,1’:4’,1”-三联苯基]-2’,4,6’-三醇(130mg,0.355mmol)在干燥二氯甲烷(12mL)中的溶液在冰/水浴中冷却,并且用1-氟吡啶鎓三氟甲磺酸盐(100mg,0.405mmol)处理。允许反应混合物升温至室温过夜,并且随着冰融化搅拌,并且然后在室温过夜,然后用另外的1-氟吡啶鎓三氟甲磺酸盐(100mg,0.405mmol)处理。在另外的24小时之后,将反应用水(5mL)和饱和碳酸氢钠水溶液(1mL)稀释。将层分离,并且将含水层用二氯甲烷(2×4mL)进一步萃取。将合并的有机层干燥(疏水性过滤玻璃料)并且在真空中浓缩。残余物通过用在环己烷中的0%-100%乙醚洗脱的柱色谱法纯化,以给出作为灰白色固体的标题化合物(15.0mg,10%)。
1H NMR(400MHz,DMSO)δ9.28-8.99(m,2H),7.42-7.37(m,1H),7.07-6.96(m,3H),6.32-6.30(m,1H),5.16(s,1H),4.68(d,J=6.6Hz,1H),4.59(d,J=1.8Hz,1H),4.52-4.52(m,1H),4.19-4.14(m,1H),4.02-3.98(m,1H),3.83-3.83(m,3H),3.34-3.27(m,1H),2.01-1.94(m,1H),1.72-1.67(m,6H),1.67-1.59(m,1H)。MS(ESI):m/z 383(M-1)。HPLC纯度:92.0%。
化合物清单
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实施例2:在使用最小样品量的小鼠(mini MEST)中使用最大电休克癫痫发作阈值
(MEST)测试来评价新颖间苯二酚的抗惊厥活性
新颖间苯二酚2、3、5、8、10、15、16、17、18、19、41、45、46、53、56和58的效力在全身性癫痫发作的新颖小鼠模型,mini-MEST(最大电休克癫痫发作阈值)测试中测试,该测试使用比通常使用的更低的n数。
最大电休克癫痫发作阈值(MEST)测试在临床前被广泛地用于评价测试化合物的促惊厥或抗惊厥性质(Loscher等人,1991)。
在MEST测试中,药物改变诱发后肢强直性伸肌抽搐(hind limb tonic extensorconvulsion)所需的癫痫发作阈值电流的能力根据电击调整(shock titration)的“上下(up and down)”方法(Kimball等人,1957)来测量。癫痫发作阈值的增加指示抗惊厥作用。包括钠通道阻滞剂(例如,拉莫三嗪)的抗癫痫药物在小鼠的该测试中全部呈现出抗惊厥性质,所述抗癫痫药物具有针对全身性强直性-阵挛性癫痫发作的临床上被证明的效力。
相反地,癫痫发作阈值的降低指示促惊厥作用,如使用已知的惊厥剂(convulsantagent)诸如印防己毒素(picrotoxin)所观察到的。
测试化合物改变诱发强直性后肢伸肌抽搐的出现所需的、以电流(mA)表示的刺激强度的能力在MEST中被评估。在治疗组中50%的动物中,从产生强直性后肢伸展的电流观察到的强直性后肢伸肌抽搐的出现(+)或不出现(0)的结果(CC50)决定了治疗组的癫痫发作阈值,并且然后将效果与媒介物对照组的CC50进行比较。
方法
研究细节:
使首次用于实验的小鼠适应它们的居住笼中的操作室持续多达7天,其中食物和水可自由摄取。
在研究开始时对所有动物称重,并且基于各组间体重的平均分布随机分配到治疗组。所有动物经由腹膜内(i.p)注射以10mL/kg给药,使用媒介物、以5mg/kg-50mg/kg的测试化合物或以2.5mg/kg的地西泮。
在媒介物给药后30min、测试化合物给药后15min-30min(取决于化合物)和地西泮给药后30min,根据单次电休克单独评估动物的强直性后肢伸肌抽搐的产生。
以所预期的或所估计的CC50电流对治疗组中的第一只动物给予电击。对于随后的动物,电流根据来自前一只动物的抽搐结果以log标度的间隔降低或升高。
从每个治疗组产生的数据用于计算治疗组的CC50±SEM值。
测试化合物:
媒介物:(5%乙醇,10%solutol在85%盐水中)制备如下:将1mL的乙醇、2mL的solutol在17mL的盐水中升温至60℃(1:2:17)。
阳性对照:地西泮以2.5mg/kg使用。
使用的测试化合物是2、3、5、8、10、15、16、17、18、19、41、45、46、53、56和58。测试化合物以1:2:17的乙醇:solutol:盐水制剂以5mg/kg-50mg/kg(i.p.)施用。
样品收集:
根据1986年动物(科学程序)法案的附表1的动物人道处死,每只动物在产生抽搐之后立即通过以下被人道地处死:通过撞击颅骨而破坏脑,然后确认由于斩首的循环的永久停止。斩首之后进行末梢血(terminal blood)和脑的收集。
将血液收集在锂-肝素管中,并且在4℃以1500×g离心持续10分钟。取出所得到的血浆(>100μL)并且分到2等分试样的0.5mL Eppendorf管中,该Eppendorf管包含10μL的抗坏血酸(100mg/mL)用于稳定化。将脑取出,在盐水中洗涤并且分成两半。将每一半放入单独的2mL螺旋盖冷冻管中,称重并且在干冰(cardice)上冷冻。
统计学分析
每个治疗组的数据被记录为在所使用的每个电流水平的+和0的数字,并且然后该信息被用于计算CC50值(50%的动物表现出癫痫发作行为所需的电流)±标准误差。
测试化合物效果还被计算为与媒介物对照组相比的CC50的百分比变化。
根据Litchfield和Wilcoxon(1949)来评估经药物治疗的动物和对照之间的显著差异。
结果
图1至图7和表2至表8描述了该实验中产生的数据。
在媒介物组中,CC50值被计算为22.5mA-26.5mA。
在测试之前30分钟i.p.施用的地西泮(2.5mg/kg)治疗组中,CC50值是85.0mA-128.0mA。与其相应的媒介物对照相比,这些结果是统计学上显著的(p<0.001)。
在测试之前15分钟和30分钟之间i.p.施用的测试化合物治疗组中,所有13种化合物都在至少一种剂量产生与媒介物相比统计学上显著的CC50值。
这样的数据指示,这些化合物将具有治疗益处。
表2:化合物2、化合物46和化合物56在mini-MEST测试中的效果的评价
n.s.-未观察到与媒介物相比统计学上显著的差异
#未确定统计学显著性,因为未达到CC50。
表3:化合物3在mini-MEST测试中的效果的评价
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表4:化合物5和化合物10在mini-MEST测试中的效果的评价
n.s.-未观察到与媒介物相比统计学上显著的差异
表5:化合物8和化合物18在mini-MEST测试中的效果的评价
n.s.-未观察到与媒介物相比统计学上显著的差异
表6:化合物15、化合物16、化合物45和化合物53在mini-MEST测试中的效果的评价
#未确定统计学显著性,因为未达到CC50。
表7:化合物17在mini-MEST测试中的效果的评价
#未确定统计学显著性,因为未达到CC50。
表8:化合物19、化合物41和化合物58在mini-MEST测试中的效果的评价
#未确定统计学显著性,因为未达到CC50。
表9:化合物7在mini-MEST测试中的效果的评价
表10:化合物9、化合物49和化合物52在mini-MEST测试中的效果的评价
表11:化合物26在mini-MEST测试中的效果的评价
表12:化合物29、化合物30、化合物31和化合物33在mini-MEST测试中的效果的评价
表13:化合物35、化合物42和化合物47在mini-MEST测试中的效果的评价
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结论
这些数据展示了化合物的治疗效果。
这些数据具有显著性,因为它们提供了迄今未知的证据,即这些新颖间苯二酚可以具有治疗价值。
所测试的化合物是作为化合物2、化合物3、化合物5、化合物8和化合物10、化合物15、化合物16、化合物17、化合物18、化合物19、化合物41、化合物45、化合物46、化合物53、化合物56和化合物58详述的那些化合物。这样的化合物是通式I至通式V的新颖间苯二酚的实例。
测试的另外的化合物是作为化合物7、化合物9、化合物26、化合物29、化合物30、化合物31、化合物33、化合物35、化合物42、化合物47、化合物49和化合物52详述的那些化合物。
由于代表性化合物在mini-MEST测试中示出效力,因此这样的治疗效力可以归因于本发明的通式I至通式V的新颖化合物。
Claims (48)
1.一种式(I)的化合物或其盐:
其中:
R1是CH3、CH2CH3、Cl、
2.根据权利要求1所述的化合物,其中R1是CH2CH3、Cl、
3.一种式(II)的化合物或其盐:
其中:
R1是CH2CH2CH3、Br、
R2是CH3、F或Cl;并且
R3是H或CH3。
4.根据权利要求3所述的化合物,其中R1是CH2CH2CH3。
5.根据权利要求3或4所述的化合物,其中R2是F或Cl。
6.根据权利要求3至5中任一项所述的化合物,其中R3是H。
7.一种式(III)的化合物或其盐:
其中:
R1是CH2CH2CH3或(CH2)4CH3;
R2是H或CH3;并且
R3是H或CH3。
8.根据权利要求7所述的化合物,其中R1是CH2CH2CH3。
9.一种式(IV)的化合物或其盐:
其中:
R1是CH2CH2CH3或
10.根据权利要求9所述的化合物,其中R1是CH2CH2CH3。
11.一种药物组合物,包含权利要求1至10中任一项所述的化合物连同一种或更多种选自载体、稀释剂、赋形剂、辅料、填充剂、缓冲剂、粘合剂、崩解剂、防腐剂、抗氧化剂、润滑剂、稳定剂、增溶剂、表面活性剂(例如,润湿剂)、掩蔽剂、着色剂、调味剂和甜味剂的另外的成分。
12.根据权利要求11所述的药物组合物,其中所述药物组合物呈选自液体、溶液、悬浮液、乳液、糖浆、冲剂、漱口水、滴剂、片剂、颗粒剂、粉末、锭剂、软锭剂、胶囊、扁囊剂、丸剂、安瓿、大丸剂、栓剂、阴道栓剂、酊剂、凝胶、糊剂、软膏、乳膏、洗剂、油、泡沫、喷雾剂和气雾剂的形式。
13.根据权利要求1至10中任一项所述的化合物,或根据权利要求11或12所述的药物组合物,用于在治疗方法中使用。
14.根据权利要求1至10中任一项所述的化合物,或根据权利要求11或12所述的药物组合物,用于在治疗癫痫的方法中使用。
15.根据权利要求1至10中任一项所述的化合物,或根据权利要求11或12所述的药物组合物,用于在治疗全身性癫痫发作、局灶起源癫痫发作或强直性-阵挛性癫痫发作的方法中使用。
16.根据权利要求1至10中任一项所述的化合物,或根据权利要求11或12所述的药物组合物,用于作为药物使用。
17.根据权利要求1至10中任一项所述的化合物,或根据权利要求11或12所述的药物组合物,用于作为用于治疗癫痫的药物使用。
18.根据权利要求1至10中任一项所述的化合物,或根据权利要求11或12所述的药物组合物,用于作为用于治疗全身性癫痫发作、局灶起源癫痫发作或强直性-阵挛性癫痫发作的药物使用。
19.一种治疗方法,包括向需要治疗的受试者施用治疗有效量的权利要求1至10中任一项所述的化合物或者权利要求11或12所述的药物组合物。
20.一种治疗癫痫的方法,包括向需要治疗的受试者施用治疗有效量的权利要求1至10中任一项所述的化合物或者权利要求11或12所述的药物组合物。
21.一种治疗全身性癫痫发作、局灶起源癫痫发作或强直性-阵挛性癫痫发作的方法,包括向需要治疗的受试者施用治疗有效量的权利要求1至10中任一项所述的化合物或者权利要求11或12所述的药物组合物。
22.一种制备式(I)的化合物的方法,所述方法包括:
i)使式(V)的化合物与式(VI)的化合物反应:
其中:
R1是H、Ac、Piv、Bz或PMB;
R2和R3独立地是H、Ac或Piv;
R4和R5是OH,或者R4和R5一起形成-C(Me)2C(Me)2C-;
X1是Br、I或OTf;并且
Y选自:
23.根据权利要求22所述的方法,其中R1是H、Ac或Piv。
24.根据权利要求22或权利要求23所述的方法,其中R2和R3是H。
25.根据权利要求22至24中任一项所述的方法,其中X1是Br或OTf。
26.根据权利要求22至25中任一项所述的方法,其中步骤(i)包括使式(V)的化合物与式(VI)的化合物和钯催化剂反应,所述钯催化剂诸如包括Pd(dppf)Cl2、Pd(PPh3)4和SPhos-Pd-G2(氯(2-二环己基膦基-2′,6′-二甲氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(II))。
27.根据权利要求22至26中任一项所述的方法,其中步骤(i)还包括使式(V)的化合物与式(VI)的化合物和碱反应,所述碱诸如选自氟化铯(CsF)、碳酸钠(Na2CO3)、碳酸铯(Cs2CO3)的碱。
28.一种制备式(V)的化合物的方法,所述方法包括:
ii)使式(VII)的化合物与三氟甲磺酰化试剂反应:
其中:
R6是H、Bz或PMB;并且
R7和R8独立地是H、Ac或Piv。
29.根据权利要求28所述的方法,其中R6是H或Bz。
30.根据权利要求28或权利要求29所述的方法,其中R7和R8是OH。
31.根据权利要求28至30中任一项所述的方法,其中所述试剂选自三氟甲磺酸酐(Tf2O)、N-苯基双(三氟甲磺酰亚胺)(PhNTf2)、Comins试剂、1-(三氟甲磺酰基)-1H-苯并三唑、1-(三氟甲磺酰基)咪唑和N-(2-吡啶基)-双(三氟甲磺酰亚胺)。
32.根据权利要求28至31中任一项所述的方法,其中步骤(ii)包括使式(VII)的化合物与三氟甲磺酰化试剂和有机碱反应,所述有机碱诸如选自吡啶、二甲基吡啶、二甲基苄胺、咪唑、苯并咪唑、甲基咪唑、三乙胺、三丁胺、二异丙基乙胺、四甲基乙二胺、DABCO的有机碱。
33.一种制备式(VII)的化合物的方法,所述方法包括:
iii)使式(IX)的化合物与间苯三酚(苯-1,3,5-三醇)反应
其中:
R15是H、Bz或PMB。
34.根据权利要求33所述的方法,其中R15是Bz或PMB。
35.根据权利要求33或权利要求34所述的方法,其中步骤(iii)包括使式(IX)的化合物与间苯三酚和酸反应,所述酸诸如选自三氟化硼和三氟甲磺酸的酸。
36.一种制备式(I)的化合物的方法,所述方法包括:
iii)根据权利要求33至35中任一项所阐述的Friedel Crafts步骤;
ii)根据权利要求28至32中任一项所阐述的三氟甲磺酰化步骤;以及任选地
i)根据权利要求22至27中任一项所阐述的偶联步骤。
37.一种用于制备式(IX)的化合物的方法,所述方法包括:
iv-a)使式(X)的化合物与二苯基联硒化物反应以产生式(XI)的化合物;以及
iv-b)使所述式(XI)的化合物与氧化剂反应,
其中:
R16和R17独立地是H、Bz或PMB。
38.根据权利要求37所述的方法,其中步骤(iv-a)包括使式(X)的化合物与二苯基联硒化物和还原剂诸如硼氢化钠反应。
39.根据权利要求37或权利要求38所述的方法,其中步骤(iv-a)包括使式(X)的化合物与二苯基联硒化物和碱诸如氢氧化钠反应。
40.根据权利要求37至39中任一项所述的方法,其中所述氧化剂是过氧化氢。
41.一种用于制备式(X)的化合物的方法,所述方法包括:
v)使式(XII)的化合物与过氧羧酸(过酸)反应
42.根据权利要求41所述的方法,其中所述过氧羧酸选自间氯过氧苯甲酸(mCPBA)和过苯甲酸。
43.一种用于制备式(Xa)的化合物的方法,所述方法包括:
vi)使S-香芹酮与还原剂反应,
44.根据权利要求44所述的方法,其中所述还原剂选自氢化铝锂、双(2-甲氧基乙氧基)氢化铝钠(红-Al)、二硼烷和硼氢化钠。
45.一种制备式(V)的化合物的方法,所述方法包括:
vi)根据权利要求43或权利要求44所阐述的还原步骤;
v)根据权利要求41或权利要求42所阐述的环氧化步骤;
iv)根据权利要求37至40中任一项所阐述的烯丙基氧化步骤。
46.一种制备式(I)的化合物的方法,所述方法包括:
vi)根据权利要求43或权利要求44所阐述的还原步骤;
v)根据权利要求41或权利要求42所阐述的环氧化步骤;
iv)根据权利要求37至40中任一项所阐述的烯丙基氧化步骤;
iii)根据权利要求33至35中任一项所阐述的Friedel Crafts步骤;
ii)根据权利要求28至32中任一项所阐述的三氟甲磺酰化步骤;以及任选地
i)根据权利要求22至27中任一项所阐述的偶联步骤。
47.一种中间体,选自式(V)的化合物和式(IX)的化合物:
其中:
R1是H、Ac、Piv、Bz或PMB;
R2和R3独立地是H、Ac或Piv;
X1是Br、I或OTf;并且
R15是H、Bz或PMB。
48.根据权利要求47所述的中间体,其中所述中间体选自:
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