CN106117140A - (‑)‑石杉碱甲方法及相关组合物和治疗方法 - Google Patents
(‑)‑石杉碱甲方法及相关组合物和治疗方法 Download PDFInfo
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- CN106117140A CN106117140A CN201610463124.2A CN201610463124A CN106117140A CN 106117140 A CN106117140 A CN 106117140A CN 201610463124 A CN201610463124 A CN 201610463124A CN 106117140 A CN106117140 A CN 106117140A
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- Prior art keywords
- alkyl
- substituted
- unsubstituted
- huperzine
- group
- Prior art date
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- 239000000203 mixture Substances 0.000 title abstract description 87
- ZRJBHWIHUMBLCN-MEBBXXQBSA-N (-)-Huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-MEBBXXQBSA-N 0.000 title abstract description 59
- ZRJBHWIHUMBLCN-UHFFFAOYSA-N Shuangyiping Natural products N1C(=O)C=CC2=C1CC1C(=CC)C2(N)CC(C)=C1 ZRJBHWIHUMBLCN-UHFFFAOYSA-N 0.000 title abstract description 53
- 238000000034 method Methods 0.000 title abstract description 45
- 238000002560 therapeutic procedure Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 70
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 150000002148 esters Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 150000001408 amides Chemical class 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 150000002170 ethers Chemical class 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 208000012902 Nervous system disease Diseases 0.000 abstract description 18
- 238000011282 treatment Methods 0.000 abstract description 11
- 230000002265 prevention Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 76
- -1 metformin) Chemical class 0.000 description 74
- 125000000217 alkyl group Chemical group 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 47
- 125000001424 substituent group Chemical group 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 41
- 125000000623 heterocyclic group Chemical group 0.000 description 40
- 125000004429 atom Chemical group 0.000 description 35
- 239000002585 base Substances 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 31
- 125000002947 alkylene group Chemical group 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 235000002639 sodium chloride Nutrition 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 26
- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 25
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000001257 hydrogen Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- 229910001868 water Inorganic materials 0.000 description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 22
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 20
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 125000002769 thiazolinyl group Chemical group 0.000 description 20
- 239000003814 drug Substances 0.000 description 19
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 19
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 18
- 229910052760 oxygen Inorganic materials 0.000 description 18
- 239000001301 oxygen Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 17
- 239000000376 reactant Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 16
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical group CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 16
- 150000002367 halogens Chemical group 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 239000011593 sulfur Substances 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical group OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 125000005842 heteroatom Chemical group 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000003513 alkali Substances 0.000 description 13
- 125000000304 alkynyl group Chemical group 0.000 description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 13
- 230000008859 change Effects 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 229930192474 thiophene Natural products 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 12
- 150000003233 pyrroles Chemical class 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- ZRJBHWIHUMBLCN-SEQYCRGISA-N Huperzine A Natural products N1C(=O)C=CC2=C1C[C@H]1/C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-SEQYCRGISA-N 0.000 description 11
- 150000001336 alkenes Chemical class 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 11
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 11
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 11
- ZRJBHWIHUMBLCN-BMIGLBTASA-N rac-huperzine A Natural products N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-BMIGLBTASA-N 0.000 description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 11
- 238000004483 ATR-FTIR spectroscopy Methods 0.000 description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- 239000012286 potassium permanganate Substances 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 9
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 150000003851 azoles Chemical class 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 230000018044 dehydration Effects 0.000 description 9
- 238000006297 dehydration reaction Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 150000004880 oxines Chemical class 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 238000004364 calculation method Methods 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 8
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 7
- VRGDDQOMGYAWIT-UHFFFAOYSA-N 3-bromo-2-(bromomethyl)-6-methoxypyridine Chemical compound COC1=CC=C(Br)C(CBr)=N1 VRGDDQOMGYAWIT-UHFFFAOYSA-N 0.000 description 7
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 7
- 239000007848 Bronsted acid Substances 0.000 description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 125000003368 amide group Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 7
- 150000005054 naphthyridines Chemical class 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 229950000688 phenothiazine Drugs 0.000 description 7
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 6
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 6
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 150000002460 imidazoles Chemical class 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 6
- 125000002757 morpholinyl group Chemical group 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 125000005936 piperidyl group Chemical group 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 5
- 238000006105 Hofmann reaction Methods 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 241001597008 Nomeidae Species 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 230000005595 deprotonation Effects 0.000 description 5
- 238000010537 deprotonation reaction Methods 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 150000007970 thio esters Chemical class 0.000 description 5
- NZGWDASTMWDZIW-MRVPVSSYSA-N (+)-pulegone Chemical compound C[C@@H]1CCC(=C(C)C)C(=O)C1 NZGWDASTMWDZIW-MRVPVSSYSA-N 0.000 description 4
- 241000790917 Dioxys <bee> Species 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- 238000007295 Wittig olefination reaction Methods 0.000 description 4
- LVZGQWKTUCVPBQ-UHFFFAOYSA-N acetic acid;trifluoroborane Chemical compound CC(O)=O.FB(F)F LVZGQWKTUCVPBQ-UHFFFAOYSA-N 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000013329 compounding Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
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Abstract
本发明提供(1)制备基本上纯的(‑)石杉碱甲和基本上纯的(‑)石杉碱甲衍生物的方法;(2)可用于制备基本上纯的(‑)石杉碱甲和基本上纯的(‑)石杉碱甲衍生物的组合物;以及(3)使用基本上纯的(‑)石杉碱甲和基本上纯的(‑)石杉碱甲衍生物治疗或预防神经障碍的方法。
Description
分案申请
本申请为申请号201280020578.2、申请日2012年2月17日、题为“(-)-石杉碱甲方法及相关组合物和治疗方法”的分案申请。
相关申请案/研究支持
本申请要求2011年3月4日提交的名称为“Huperzine A”的美国临时申请序列号61/449,198的优先权权益,该临时申请的整个内容以引用方式并入本文。
背景技术
(-)-石杉碱甲(1)是一种由中草药千层塔(Huperzia serrata)产生的三环类生物碱。1(-)-石杉碱甲(1)是乙酰胆碱酯酶的强效、选择性和可逆的抑制剂(AChE,Ki=23nM)。2最近的研究已确立,可利用这种活性来抵抗有机磷酸酯化学战剂,诸如沙林和VX,机理是抑制它们对外周和脑AChE的共价修饰。3大量的证据还表明,(-)-石杉碱甲(1)可减缓神经变性疾病(包括阿尔茨海默病)的进展。4(-)-石杉碱甲(1)在人类中甚至在远高于其临床所需剂量的剂量下也耐受良好。5因此,(-)-石杉碱甲(1)的临床研究是制药和国防工业大力研究的课题。
(-)-石杉碱甲(1)临床开发的主要障碍之一是供应。从天然来源中提取的收率较低(干燥草药的平均收率=0.011%),4a并且过度采收已导致了石杉(Huperziaceae)资源的快速减少。6组合这些问题,生产用物种需要近20年才能达到成熟。6
全合成提供了石杉碱的替代性潜在来源。对映选择性合成是非常期望的,因为(+)-石杉碱甲的效力明显低于天然的(-)-对映体(1)。7(±)-石杉碱甲最早的全合成由Kozikowski和Xia8以及Qian和Ji。9进行了报道。随后,Kozikowski等人。10开发了基于手性助剂的路线。在之后的数年中,多个研究小组报道了对Kozikowski路线的改进,11以及石杉碱的完整、12部分、13和正式14路线。尽管如此,需要16步且收率为约2.8%的基于Kozikowski手性控制剂的路线10仍然是合成(-)-石杉碱甲(1)最有效的已公布的路径。15
鉴于制备(-)-石杉碱甲的已知方法的大量步骤和相对低的立体化学收率,以及(-)-石杉碱甲作为神经保护剂的重要性日渐增长,需要以有利于放大到商业制造的收率制备基本上纯的(-)-石杉碱甲的改进方法。
发明内容
发明概述
在一个实施方案中,本发明提供通过采用比已知技术明显更少的步骤的合成以相对高的收率制备基本上纯的(-)石杉碱甲和基本上纯的(-)石杉碱甲衍生物的新方法。
在另一个实施方案中,本发明提供制备可用于制造药学活性成分(包括基本上纯的(-)石杉碱甲和基本上纯的(-)石杉碱甲衍生物)的各种中间体的新方法。
在又一个实施方案中,本发明提供可用于制造药学活性成分(包括基本上纯的(-)石杉碱甲和基本上纯的(-)石杉碱甲衍生物)的各种新组合物。
在又一个实施方案中,本发明提供治疗或预防神经障碍的方法,包括向患有神经障碍或存在发生神经障碍危险的受试者施用基本上纯的(-)石杉碱甲或基本上纯的(-)石杉碱甲衍生物。
在又一个实施方案中,本发明提供制备基本上纯的具有下式的(-)石杉碱甲的新方法:
包括使下式的酰胺:
在水性或醇溶剂(优选地为甲醇)中并在存在双(三氟乙酰氧基碘)苯(PIFA)的情况下经历改进的霍夫曼反应(Hoffmann reaction)以形成中间体,使中间体完全脱保护以形成(-)石杉碱甲,以及纯化(-)石杉碱甲(例如通过结晶和/或快速柱色谱法)以得到基本上纯的(-)石杉碱甲。
如本文所用的“基本上纯的(-)石杉碱甲”包含高于约80重量%的(-)石杉碱甲和低于约20重量%的(+)石杉碱甲,更优选地高于约90重量%的(-)石杉碱甲和低于约10重量%的(+)石杉碱甲,甚至更优选地高于约95重量%的(-)石杉碱甲和低于约5重量%的(+)石杉碱甲,最优选地高于约99重量%的(-)石杉碱甲和低于约1重量%的(+)石杉碱甲。几乎纯的(-)石杉碱甲衍生物包含高于99.5重量%的(-)石杉碱甲和低于0.5重量%的(+)石杉碱甲,更优选地高于约99.9%的(-)石杉碱甲和低于约0.1%的(+)石杉碱甲。“基本上纯的(+)石杉碱甲衍生物”针对其(+)和(-)对映体的相对量相似地进行定义。
如本文所用,术语(±)石杉碱甲(或“外消旋石杉碱甲”或“石杉碱甲外消旋物”)意指包含约40-60%的(-)石杉碱甲和约40-60%的(+)石杉碱甲的组合物。石杉碱甲衍生物的外消旋物针对其(-)和(+)对映体相似地进行定义。
“石杉碱甲衍生物”(例如,如用在术语“基本上纯的(-)石杉碱甲衍生物”中)是指如美国专利号RE38460中所述的化合物,以及下文所述的式(II)和(III)的化合物。
在一个实施方案中,如上所述经历改进霍夫曼反应的酰胺优选地通过包括以下步骤的方法在一锅法中制备:使下式的氰醇:
在有机溶剂(优选地为甲苯)中在加热条件下并在存在伯吉斯试剂(Burgessreagent)的情况下脱水以形成脱水产物,以及使脱水产物在醇(优选地为含水乙醇)中并在存在铂催化剂的情况下经历热解以形成酰胺。该新反应也构成本发明的实施方案并且也可以分步进行。
在一个实施方案中,上述氰醇优选地通过以下方式在一锅法中制备:使基本上为E异构体形式并具有下式的烯化产物:
经历氧化脱甲硅烷基化(例如,通过在惰性溶剂例如DCM中与三氟化硼-乙酸络合物或布朗斯台德酸(Bronsted acid)诸如TFA、MSA、FMSA或四氟硼酸反应,或通过使用弗莱明-玉尾(Fleming-Tamao)氧化,然后使用氟化物、过氧化氢和碳酸钾)。除了质子酸外,移除甲硅烷基还涉及用氟化物、过氧化氢和碳酸钾进行处理的步骤。该新反应步骤也构成本发明的实施方案。
在一个实施方案中,上述烯化产物优选地在一锅法中在包括通过以下方式使下式的加成-烷基化产物去质子化的方法中制备:
使加成-烷基化产物与双(三甲基甲硅烷基)氨基锂(LHMDS)或二异丙基氨基锂(LDA)和亲电氰化物源(例如对甲苯磺酰氰、溴化氰等)在有机溶剂(例如THF或甲苯)中反应以形成α-氰基酮,使α-氰基酮在存在碱(最优选地为叔丁醇钠)和钯催化剂的情况下经历钯催化的(例如四(三苯基膦)钯、三(二亚苄基丙酮)二钯、钯双(三叔丁基膦))分子内烯醇化物杂芳基化以形成环化产物,以及在存在碱(例如正丁基锂、双(三甲基甲硅烷基)氨基钠、双(三甲基甲硅烷基)氨基锂、双(三甲基甲硅烷基)氨基钾或二异丙基氨基锂)的情况下并在有机溶剂(例如THF、乙醚或1,4-二噁烷)中以Wittig烯化反应对环化产物的酮官能进行立体选择性烯化以形成烯化产物,其中环化产物的立体选择性烯化在动力学上有利于E-异构体形式的烯化产物的形成。该新反应步骤也构成本发明的实施方案并且也可以分步进行。
在一个实施方案中,加成-烷基化产物在一锅法中在包括以下步骤的方法中制备:在共轭加成反应中使(R)-4-甲基-环己-2-烯-1-酮与二甲基苯基甲硅烷基铜酸锂反应以形成初始烯醇化物以及使初始烯醇化物通过3-溴-2-(溴甲基)-6-甲氧基吡啶)发生烷基化以形成加成-烷基化产物。该新反应步骤也构成本发明的实施方案并且也可以分步进行。
在又一个实施方案中,本发明提供使β-酮环化的方法,包括使α-氰基酮经历钯催化的分子内烯醇化物杂芳基化,如下文所详述。
在又一个实施方案中,本发明提供制备基本上纯的(-)石杉碱甲的新方法,包括:
(a)优选地在一锅法中,在共轭加成反应中使(R)-4-甲基-环己-2-烯-1-酮与二甲基苯基甲硅烷基铜酸锂反应以形成初始烯醇化物以及使初始烯醇化物通过3-溴-2-(溴甲基)-6-甲氧基吡啶)发生烷基化以形成具有下式的加成-烷基化产物:
(b)优选地在一锅法中,通过以下方式使加成-烷基化产物去质子化:使加成-烷基化产物与双(三甲基甲硅烷基)氨基锂(LHMDS)或二异丙基氨基锂(LDA)在有机溶剂(例如THF或甲苯)中反应以形成α-氰基酮,使α-氰基酮在存在碱(最优选地为叔丁醇钠)的情况下经历钯催化的分子内烯醇化物杂芳基化以形成环化产物,以及在存在碱(例如正丁基锂、双三甲基甲硅烷基)氨基钠、双三甲基甲硅烷基)氨基锂、双三甲基甲硅烷基)氨基钾或二异丙基氨基锂)的情况下并在有机溶剂(例如THF、乙醚或1,4-二噁烷)中以Wittig烯化反应对环化产物的酮官能进行立体选择性烯化以形成烯化产物,其中环化产物的立体选择性烯化在动力学上有利于E-异构体形式的烯化产物的形成并且其中烯化产物具有下式:
(c)使烯化产物经历氧化二甲硅烷基化(例如,通过在惰性溶剂例如DCM中与三氟化硼-乙酸络合物或布朗斯台德酸诸如TFA、MSA、FMSA或四氟硼酸反应,或通过使用弗莱明-玉尾氧化)以形成具有下式的氰醇:
(d)优选地在一锅法中,使氰醇在有机溶剂(优选地为甲苯)中在加热条件下并在存在伯吉斯试剂的情况下脱水以形成脱水产物,以及使脱水产物在醇(优选地为乙醇)中并在存在铂催化剂的情况下经历热解以形成具有下式的酰胺:
以及
(f)使酰胺在水性或醇溶剂(优选地为甲醇)中并在存在双(三氟乙酰氧基碘)苯(PIFA)的情况下经历改进的霍夫曼反应以形成中间体,使中间体完全脱保护以形成(±)石杉碱甲,以及纯化(±)石杉碱甲(例如通过快速柱色谱法)以得到基本上纯的(-)石杉碱甲:
在又一个实施方案中,本发明提供式(I)的化合物:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H、取代或未取代的C1-C6烷基和CN,前提条件是当R2或R5之一为CN时,另一者必须为H;
X为卤素;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R4选自Si(CH3)2Ph、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的芳基和取代或未取代的杂芳基;
A为C、N或S;
m为0、1或2;
n为0或1;
或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
在又一个实施方案中,本发明提供式(II)的化合物:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H和取代或未取代的C1-C6烷基;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R4选自H、OH和Si(CH3)2Ph;
R6选自NH2、酰胺、CN、羧酸衍生物(例如酯、酮、或仲胺或叔酰胺)、醇或醛;
R7为取代或未取代的C1-C6烷基、酯或取代或未取代的芳基;
A为C、N或S;并且
n为0或1;
或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
在一个实施方案中,将式(I)和(II)的化合物用于制备药理学活性组合物,包括基本上纯的(-)石杉碱甲和基本上纯的(-)石杉碱甲衍生物。
本发明的优选化合物包括:
其中R1和R2各自独立地为H或C1-C6烷基;
及其伯胺衍生物(其中CN转化成了CH2NR1R2基团,其中R1和R2与如上所述的相同);
及其伯胺衍生物(其中CN转化成了CH2NR1R2基团,其中R1和R2与如上所述的相同);以及
或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
在又一个实施方案中,本发明提供制备具有式(III)的基本上纯的(-)石杉碱甲或其衍生物的新方法:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H和取代或未取代的C1-C6烷基;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R4选自H、OH和Si(CH3)2Ph;
R7为取代或未取代的C1-C6烷基、酯或取代或未取代的芳基;
A为C、N或S;并且
n为0或1;
包括使具有下式(IV)的酰胺:
其中R1、R2、R3、R4、R5、R7、A和n如式(III)的化合物所定义,在水性或醇溶剂(优选地为甲醇)中并在存在双(三氟乙酰氧基碘)苯(PIFA)的情况下经历改进的霍夫曼反应以形成中间体,使中间体完全脱保护以形成(±)石杉碱甲或(±)石杉碱甲衍生物,以及纯化(±)石杉碱甲或(±)石杉碱甲衍生物(例如通过快速柱色谱法)以得到基本上纯的(-)石杉碱甲或基本上纯的(±)石杉碱甲衍生物。
在又一个实施方案中,本发明提供制备具有式(IV)的酰胺的方法:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H和取代或未取代的C1-C6烷基;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R4选自H、OH和Si(CH3)2Ph以及H;
R7为取代或未取代的C1-C6烷基、酯或取代或未取代的芳基;
A为C、N或S;并且
n为0或1;
包括使式(V)的氰醇:
其中R1、R2、R3、R5、R7、A和n如式(IV)的化合物所定义,在有机溶剂(优选地为甲苯)中在加热条件下并在存在伯吉斯试剂的情况下脱水以形成脱水产物,以及使脱水产物在醇(优选地为乙醇)中并在存在铂催化剂的情况下经历热解以形成酰胺,其中脱水和热解可以以一锅法或分步骤进行。
在又一个实施方案中,本发明提供制备式(V)的氰醇的方法:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H和取代或未取代的C1-C6烷基;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R7为取代或未取代的C1-C6烷基、酯或取代或未取代的芳基;
A为C、N或S;并且
n为0或1;
包括使基本上为E异构体形式并具有式(VI)的烯化产物:
其中R1、R2、R3、R5、R7、A和n如式(V)的化合物中所定义,经历氧化二甲硅烷基化(例如,通过在惰性溶剂例如DCM中与三氟化硼-乙酸络合物或布朗斯台德酸诸如TFA、MSA、FMSA或四氟硼酸反应,或通过使用弗莱明-玉尾氧化),其中该方法可以以一锅法或分步骤进行。
在另一个实施方案中,本发明提供制备基本上为E异构体形式并具有式(VI)的烯化产物的方法:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H和取代或未取代的C1-C6烷基;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R7为取代或未取代的C1-C6烷基、酯或取代或未取代的芳基;
A为C、N或S;并且
n为0或1;
包括使具有式(VII)的加成-烷基化产物:
其中R1、R2、R3、R5、A和n如(V)中所定义,R4选自Si(CH3)2Ph、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的芳基和取代或未取代的杂芳基,X为卤素,并且m为0、1或2,通过以下方式去质子化:使加成-烷基化产物与双(三甲基甲硅烷基)氨基锂(LHMDS)或二异丙基氨基锂(LDA)在有机溶剂(例如THF或甲苯)中反应以形成α-氰基酮,使α-氰基酮在存在碱(最优选地为叔丁醇钠)的情况下经历钯催化的分子内烯醇化物杂芳基化以形成环化产物,以及在存在碱(例如正丁基锂、双三甲基甲硅烷基)氨基钠、双三甲基甲硅烷基)氨基锂、双三甲基甲硅烷基)氨基钾或二异丙基氨基锂)的情况下并在有机溶剂(例如THF、乙醚或1,4-二噁烷)中以Wittig烯化反应对环化产物的酮官能进行立体选择性烯化以形成烯化产物,其中前述反应的每一个均可以以一锅法或分步骤进行。
本发明的这些和其他方面将在“具体实施方式”中进一步详述。
附图说明
图1展示合成的和天然的(-)-石杉碱甲的NMR数据的比较。
图2包括本发明组合物的核磁共振和红外光谱的目录。
图3示出根据本发明的方法制备的烯化产物的次要非对映体通过NOE分析(500MHz,CDCl3)经证实具有Z-构型。
具体实施方式
除了别的以外,以下术语用于描述本发明。应当理解,未具体定义的术语将具有与该术语在本领域普通技术人员所理解的本发明上下文中的使用相一致的含义。
除非另外指明,否则如本文所用的术语“化合物”是指本文所公开的任何具体的化合物,并包括其互变异构体、区域异构体、几何异构体以及适用时的光学异构体(如对映体)、立体异构体(非对映体),及其药学上可接受的盐和衍生物(包括前药形式)。术语“化合物”当在其上下文中使用时通常是指单一化合物,但也可以包括其他化合物,诸如所公开的化合物的立体异构体、区域异构体和/或光学异构体(包括外消旋混合物)以及具体的对映体或富含对映体的混合物以及非对映体和差向异构体(当在上下文中适用时)。该术语在上下文中还指经改性以有利于将化合物施用和递送到活性位点的化合物前药形式。
在本说明书通篇的上下文中使用术语“患者”或“受试者”来描述通过根据本发明的组合物对其提供治疗(包括预防性处置,即预防)的动物,通常为哺乳动物并且优选地为人类。对于治疗就具体动物例如人类患者而言的那些具体感染、病症或疾病,术语“患者”是指该具体动物。
在根据本发明的化合物中使用符号以表示原子之间的键根据化合物中使用该键的上下文而为单键或双键,这取决于用于限定该化合物的原子(和取代基)。因此,当使用碳(或其他)原子并且使用该原子的上下文要求双键或单键来将该原子与相邻原子连接起来以使所使用的原子保持适当的化合价时,则该键被认为是双键或单键。
“神经障碍”包括但不限于淀粉样相关障碍诸如阿尔茨海默病和下文所述的淀粉样障碍;精神障碍,诸如抽动秽语综合征、创伤后应激障碍(PTSD)、恐慌和焦虑障碍、强迫性精神障碍和精神分裂症;发育障碍,诸如脆性X综合征和孤独症;疼痛;药物成瘾,诸如酗酒;神经变性疾病,诸如帕金森病和亨廷顿舞蹈病;以及中风和缺血性脑损伤、肌萎缩性侧索硬化症和癫痫。“神经障碍”也包括与暴露于神经毒素相关或有关的任何障碍、症状或影响,所述神经毒素包括但不限于诸如化学战剂的神经毒素。
“淀粉样相关障碍”包括与可局限于一个器官(“局限性淀粉样变性”)或扩散到多个器官(“系统性淀粉样变性”)的淀粉样蓄积相关的疾病。继发性淀粉样变性可与慢性感染(诸如肺结核)或慢性炎症(诸如类风湿性关节炎)相关,包括也见于家族性地中海热(FMF)的家族性形式的继发性淀粉样变性以及存在于长期血液透析患者中的另一类型的系统性淀粉样变性。淀粉样变性的局部化形式包括但不限于II型糖尿病及其任何相关障碍、神经变性疾病(诸如痒病)、牛海绵状脑炎、克雅二氏病(Creutzfeldt-Jakob disease)、阿尔茨海默病、老年系统性淀粉样变性(SSA)、大脑淀粉样血管病、帕金森病和朊病毒蛋白相关障碍(例如朊病毒相关脑病)和类风湿性关节炎。
除非另外指明,否则术语“有效”在本文中用于描述化合物或组合物的量,该量在上下文中用于产生或实现预期的结果,而不论该结果是涉及对神经障碍的影响的抑制,还是涉及增强用于治疗神经障碍的补充治疗的效果(例如抗精神病药或如本文其他地方所述)。该术语包括在本申请其他地方描述的所有其他有效量或有效浓度术语(包括术语“治疗有效”)。
如本文所用的术语“治疗”(treat,treating,treatment等)是指为存在发生神经障碍危险或受神经障碍折磨的患者提供有益效果的任何措施,包括减轻或抑制神经障碍的至少一种症状,延迟神经障碍的进展,或降低发生神经障碍的可能性。如本文所用的“治疗”涵盖预防性和治疗性处置。
术语“药学上可接受的盐”或“盐”在说明书通篇中用于描述本文的组合物的一者或多者的盐形式,它们是为了增加化合物在盐水中的溶解性以用于肠胃外递送或增加化合物在患者胃肠道的胃液中的溶解性以便促进化合物的溶出和生物利用。药学上可接受的盐包括衍生自药学上可接受的无机或有机碱和酸的那些盐。合适的盐包括在制药领域熟知的许多其他酸之中衍生自碱金属(诸如钾和钠)、碱土金属(诸如钙、镁)的那些盐和铵盐。作为根据本发明的含羧酸和游离磷酸的中和盐的组合物,钠盐和钾盐可以是优选的。术语“盐”应指与根据本发明的化合物的使用一致的任何盐。在化合物用于药品适应症的情况下,术语“盐”应指与作为药剂的化合物的使用一致的药学上可接受的盐。
术语“共施用”应指将至少两种化合物或组合物同时施用给患者,使得两种或更多种化合物每一者的有效量或浓度可在给定的时间点存在于患者中。虽然根据本发明的化合物可同时地共施用给患者,但是该术语涵盖在相同的时间或不同的时间一起施用两种或更多种药剂,包括顺序施用。优选地,所有共施用化合物或组合物的有效浓度在给定的时间存在于受试者中。
例如,根据本发明的化合物可与可用于治疗淀粉样相关障碍或淀粉样相关障碍某一阶段的一种或多种药剂一起施用。共施用药剂的类型可根据特定的临床背景而千差万别。例如,共施用的药剂可包括抗凝血剂或凝血抑制剂、抗血小板剂或血小板抑制剂、凝血酶抑制剂、血栓或纤维蛋白溶解剂、抗心律失常剂、抗高血压剂、钙通道阻滞剂(L型和T型)、强心苷、利尿剂、盐皮质激素受体拮抗剂、磷酸二酯酶抑制剂、降胆固醇/血脂剂和全套血脂疗法(lipid profile therapy)、抗糖尿病剂、抗抑郁药、抗炎剂(甾体和非甾体)、抗骨质疏松剂、激素替代疗法、口服避孕药、抗肥胖剂、抗焦虑剂、抗增殖剂、抗肿瘤剂、抗溃疡和胃食管反流性疾病剂、生长激素和/或生长激素促分泌素、甲状腺模拟物(包括甲状腺受体拮抗剂)、抗感染剂、抗病毒剂、抗细菌剂和抗真菌剂。
更具体地讲,就阿尔茨海默病而言,可用的附加药剂包括但不限于胆碱酯酶抑制剂、抗氧化剂银杏叶提取物、非甾体抗炎剂和非特异性NMDA拮抗剂,诸如(美金刚)。就帕金森病而言,可用的附加药剂包括但不限于控制震颤、运动迟缓、平衡和僵化的卡比多巴/左旋多巴(Sinemet-Bristol Myers Squibb)。其他疗法包括多巴胺激动剂、卡比多巴/左旋多巴疗法、COMT抑制剂、抗胆碱能剂和MAO抑制剂,诸如司来吉兰/丙炔苯丙胺。就II型糖尿病而言,可用的附加药剂包括但不限于双胍类(例如二甲双胍)、葡萄糖苷酶抑制剂(例如阿卡波糖)、胰岛素(包括胰岛素促分泌素或胰岛素增敏剂)、氯茴苯酸类(例如瑞格列奈)、磺脲类(例如格列美脲、格列本脲和格列吡嗪)、双胍/格列本脲合剂(例如glucovance)、噻唑烷二酮类(例如曲格列酮、罗格列酮和吡格列酮)、PPAR-α激动剂、PPAR-γ激动剂、PPARα/γ双重激动剂、SGLT2抑制剂、脂肪酸结合蛋白的抑制剂(aP2)、胰高血糖素样肽-1(GLP-1)和二肽基肽酶IV(DP4)抑制剂。
术语“拮抗剂”和“抑制剂”可互换地用于指代本文具体公开的降低或抑制生物活性诸如抑制神经障碍的活动度的药剂,尤其包括化学药剂。“神经障碍的调节剂”抑制或增强神经障碍的活动度。
术语“酰基”是本领域公认的并指由通式烃基C(O)--优选烷基C(O)--表示的基团。
术语“酰氨基”是本领域公认的并指具有氨基和酰基的部分并可以包括与本文其他地方公开的相同取代基。
术语“脂族基团”是指直链、支链或环状脂族烃基并包括饱和和不饱和的脂族基团,诸如烷基、烯基和炔基。
如本文所用的术语“烯基”是指包含至少一个双键的脂族基团并旨在包括“未取代的烯基”和“取代的烯基”两者,后者是指具有取代烯基一个或多个碳上的氢的取代基的烯基部分。此类取代基可存在于一个或多个包含在或不包含在一个或多个双键中的碳上。此外,此类取代基可包括如本文所讨论的针对烷基设想的所有那些取代基,但在该部分的稳定性受到抑制时除外。例如,设想了通过一个或多个烷基、碳环基、芳基、杂环基或杂芳基取代烯基。
如本文所用的术语“烷氧基”(alkoxyl,alkoxy)是指具有连接到其上的氧自由基的如下定义的烷基。代表性烷氧基包括甲氧基、乙氧基、丙氧基、叔丁氧基等。
“醚”是通过氧共价连接的两个烃。因此,使烷基为醚的烷基的取代基为烷氧基或类似于烷氧基,诸如可由--O-烷基、--O-烯基、--O-炔基、--O--(CH2)m-取代基之一表示,其中m为0至6,并且取代基为芳基或取代的芳基、环烷基、环烯基、杂环或多环(两个或三个环),它们每一者都可被任选地取代。
术语“烷基”是指饱和脂族基团的自由基,包括直链烷基、支链烷基、环烷基(脂环烃基团)、烷基取代的环烷基和环烷基取代的烷基。在优选的实施方案中,直链或支链烷基在其主链中具有10个或更少的碳原子(例如直链的C1-C10,支链的C1-C10),更优选8个或更少,最优选6个或更少。同样,优选的环烷基在其环结构中具有3-10个碳原子,更优选地在环结构中具有5、6、7或8个碳。
此外,如在说明书、实施例和权利要求通篇中使用的术语“烷基”(或“低级烷基”)旨在包括“未取代的烷基”和“取代的烷基”两者,后者是指具有取代烃主链一个或多个碳上的氢的取代基的烷基部分。此类取代基包括例如卤素、羟基、羰基(诸如羧基、烷氧羰基、甲酰基或酰基)、硫代羰基(诸如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、次膦酸酯、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷硫基、硫酸酯、磺酸酯、氨磺酰基、磺酰胺基、磺酰基、杂环基、芳烷基或芳族或杂芳族部分或如本文其他地方所述。本领域的技术人员将会理解,各个取代基化学部分自身可被取代。例如,取代的烷基的取代基可包括以下基团的取代和未取代形式:氨基、叠氮基、亚氨基、酰胺基、磷酰基(包括磷酸酯和膦酸酯)、磺酰基(包括硫酸酯、磺酰胺基、氨磺酰基和磺酸酯)和甲硅烷基,以及醚、烷硫基、羰基(包括酮、醛、羧酸酯和酯)、--CF3、--CN等。示例的非限性制取代烷基在本文进行了描述。环烷基可进一步被烷基、烯基、炔基、烷氧基、烷硫基、氨基烷基、羰基取代的烷基、--CF3、--CN等取代。
可对烯基和炔基进行类似的取代,以产生例如但不限于氨基烯基、氨基炔基、酰胺基烯基、酰胺基炔基、亚氨基烯基、亚氨基炔基、硫代烯基、硫代炔基、羰基取代的烯基或炔基。
除非另外指定碳的数量,否则如本文所用的“低级烷基”意指如上定义的但在其主链结构中具有一至八个碳,更优选地一至六个碳原子的烷基。同样,“低级烯基”和“低级炔基”具有相似的链结构。在整个申请中,优选的烷基为低级烷基。在优选的实施方案中,本文指定的取代基为低级烷基。
如本文所用的术语“炔基”是指包含至少一个三键的脂族基团并旨在包括“未取代的炔基”和“取代的炔基”两者,后者是指具有取代炔基一个或多个碳上的氢的取代基的炔基部分。此类取代基可存在于一个或多个包含在或不包含在一个或多个三键中的碳上。此外,此类取代基可包括如上文所讨论的针对烷基设想的所有那些取代基,但在稳定性受到抑制时除外。例如,设想了通过一个或多个烷基、碳环基、芳基、杂环基或杂芳基取代炔基。
术语“烷硫基”是指具有连接到其上的硫自由基的如上定义的烷基。在优选的实施方案中,“烷硫基”通过--S-烷基、--S-烯基、--S-炔基和–S--(CH2)m--取代基之一表示,其中m为0或1至8的整数并且取代基与本文定义的和下文其他地方的(胺/氨基的R9和R10)相同。代表性烷硫基包括甲硫基、乙硫基等。
术语“胺”和“氨基”是本领域公认的并指未取代的和取代的胺两者,例如可通过但不限于以下通式表示的部分:
其中R9、R10和R'10各自独立地表示氢、烷基、烯基、--(CH2)m--R8,或R9和R10与它们所连接的N原子合在一起形成在环结构中具有4至8个原子的杂环;R8表示芳基、环烷基、环烯基、杂环或多环;并且m为零或1至8范围内的整数。在优选的实施方案中,R9或R10只有一个可以为羰基,例如R9、R10和氮在一起不形成酰亚胺。在某些此类实施方案中,R9和R10都不通过羰基连接到N,例如,胺不是酰胺或酰亚胺,并且胺优选地为碱性的,例如其共轭酸具有高于7的pKa。在甚至更优选的实施方案中,R9和R10(并任选地R'10)各自独立地表示氢、烷基、烯基或--(CH2)m--R8。因此,如本文所用的术语“烷基胺”意指具有连接到其上的取代或未取代烷基的如上定义的胺基,即R9和R10的至少一个为烷基。键合到胺基的每个基团在适用时可任选地被取代。
术语“酰胺基”在本领域公认为氨基取代的羰基,并包括可通过以下通式表示的部分:
其中R9、R10如上所定义。酰胺的优选实施方案将不包括可能不稳定的酰亚胺。
如本文所用的术语“芳烷基”是指被芳基(例如芳族或杂芳族基团)取代的烷基。
如本文所用的术语“芳基”包括5、6和7元单环或包含零至四个杂原子的芳族基团,例如苯、吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、三唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等。在环结构中具有杂原子的那些芳基也可称为“芳基杂环”、“杂芳族”或“杂芳基”。芳环可在一个或多个环位置被诸如本文其他地方所述的取代基取代,所述取代基例如为卤素、叠氮化物、烷基、芳烷基、烯基、炔基、环烷基、多环基、羟基、烷氧基、氨基、硝基、巯基、亚氨基、酰胺基、磷酸酯、膦酸酯、次膦酸酯、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、磺酰胺基、酮、醛、酯、杂环基、芳族或杂芳族部分、--CF3、--CN等。术语“芳基”也包括具有两个或更多个环的多环环系,其中两个或更多个碳为两个邻接的环所共有(环为“稠合环”),其中至少一个环为芳族的,例如另外的环可以环烷基、环烯基、环炔基、芳基和/或杂环基。
如本文所用的术语“碳环”是指其中环的每个原子均为碳的芳族或非芳族环。
术语“羰基”是本领域公认的并包括诸如可通过以下通式表示的部分:
其中X为键或表示氧或硫,并且R11表示(例如但不限于)氢、烷基、烯基、--(CH2)m--R8或药学上可接受的盐,R'11表示氢、烷基、烯基或--(CH2)m--R8,其中m和R8如本文其他地方所述但不限于此。若X为氧并且R11或R'11不为氢,则该式表示“酯”。若X为氧,并且R11如上所定义,则该部分在本文称为羧基,并且尤其当R11为氢时,该式表示“羧酸”。若X为氧,并且R'11为氢,则该式表示“甲酸酯”。一般来讲,若上式的氧原子被硫替代,则该式表示“硫代羰基”。若X为硫并且R11或R'11不为氢,则该式表示“硫酯”。若X为硫并且R11为氢,则该式表示“硫代羧酸”。若X为硫并且R'11为氢,则该式表示“硫代甲酸酯”。在另一方面,若X为键,并且R11不为氢,则上式表示“酮”基。若X为键,并且R11为氢,则上式表示“醛”基。
术语“吸电子基团”是指从吸电子基团所连接的原子或原子团吸引电子密度的化学基团。电子密度的吸引包括通过感应和通过离域/共振效应的吸引。连接到芳环的吸电子基团的实例包括全卤烷基(诸如三氟甲基)、卤素、叠氮化物、含羰基的基团(诸如酰基)、氰基和含亚胺的基团。
如本文所用的术语“酯”是指基团--C(O)O-取代基,其中取代基表示例如烃基或在本文其他地方描述的其他取代基。
如本文所用的术语“卤”和“卤素”意指卤素并包括氯、氟、溴和碘。
如本文所用的术语“杂芳烷基”是指被杂芳基取代的烷基。
术语“杂环”或“杂环基团”是指3至10元环结构,更优选3至7元环,其环结构包含一至四个杂原子。杂环可以为多环。杂环基团包括例如但不限于:噻吩、噻蒽、呋喃、吡喃、异苯并呋喃、色烯、氧杂蒽、吩噁噻、吡咯、咪唑、吡唑、异噻唑、异噁唑、吡啶、吡嗪、嘧啶、哒嗪、吲嗪、异吲哚、吲哚、吲唑、嘌呤、喹嗪、异喹啉、喹啉、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、咔唑、咔啉、菲啶、吖啶、嘧啶、菲咯啉、吩嗪、吩吡嗪、吩噻嗪、呋咱、吩噁嗪、吡咯烷、氧杂环戊烷、硫杂环戊烷、噁唑、哌啶、哌嗪、吗啉、内酯、内酰胺(诸如氮杂环丁酮和吡咯烷酮)、磺内酰胺、磺内酯等。杂环可在一个或多个环位置被诸如上文所述但不限于此的取代基取代,所述取代基例如为,卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚氨基、酰胺基、磷酸酯、膦酸酯、次膦酸酯、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、酮、醛、酯、杂环基、芳族或杂芳族部分、--CF3、--CN等以及如本文其他地方所述。
术语“杂芳基”(heteroaryl,hetaryl)包括取代或未取代的芳族单环结构,优选5至7元环,更优选5至6元环,其环结构包含至少一个杂原子,优选一至四个杂原子,更优选一至两个杂原子。术语“杂芳基”也包括具有两个或更多个环的最多20元多环环系,其中两个或更多个碳为两个邻接的环所共有,其中至少一个环为杂芳族的,例如另外的环可以环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂芳基包括例如吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等。
如本文所用的术语“杂原子”意指非碳或氢的任何元素的原子。优选的杂原子为氮、氧和硫。
因此,术语“杂环基”、“杂环”和“杂环的”是指取代的或未取代的芳族或非芳族环结构(其可以为环状的、双环的或稠合的环系),优选3至10元环,更优选3至7元环,其环结构包含至少一个杂原子,优选一至四个杂原子,更优选一或两个杂原子。术语“杂环基”和“杂环的”也包括具有两个或更多个环的多环环系,其中两个或更多个碳为两个邻接的环所共有,其中至少一个环为杂环的,例如另外的环可以环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂环基包括例如哌啶、哌嗪、吡咯烷、吗啉、内酯、内酰胺等。
如本说明书通篇中所用的术语“5至20元杂环基团”或“5至14元杂环基团”是指具有5至20个形成环的原子优选5至14个形成环的原子并在形成环的原子之中包含至少一个杂原子(诸如氮、硫或氧)的芳族或非芳族环状基团,其在前一情况中为“5至20元,优选5至14元芳族杂环基团”(也称为“杂芳基”或“杂芳族”)并在后一情况中为“5至20元”,优选“5至14元非芳族杂环基团”。
可提及的杂环基团包括含氮的芳族杂环,诸如吡咯、吡啶、吡啶酮、哒嗪、嘧啶、吡嗪、吡唑、咪唑、三唑、四唑、吲哚、异吲哚、吲嗪、嘌呤、吲唑、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、咪唑并吡啶、咪唑并三嗪、吡嗪并哒嗪、吖啶、菲啶、咔唑、咔唑啉、呸啶、菲咯啉、稠六苯(phenacene)、噁二唑、苯并咪唑、吡咯并吡啶、吡咯并嘧啶和吡啶并嘧啶;含硫的芳族杂环,诸如噻吩和苯并噻吩;含氧的芳族杂环,诸如呋喃、吡喃、环戊吡喃、苯并呋喃和异苯并呋喃;和包含2个或更多个选自氮、硫和氧的杂原子的芳族杂环,诸如噻唑、噻二唑、异噻唑、苯并噁唑、苯并噻唑、苯并噻二唑、吩噻嗪、异噁唑、呋咱、吩噁嗪、吡唑并噁唑、咪唑并噻唑、噻吩并呋喃、呋喃并吡咯、吡啶并噁嗪、呋喃并吡啶、呋喃并嘧啶、噻吩并嘧啶和噁唑。
作为“5至14元芳族杂环基团”的实例,可优选地提及吡啶、三嗪、吡啶酮、嘧啶、咪唑、吲哚、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹唑啉、噌啉、吖啶、稠六苯、噻吩、苯并噻吩、呋喃、吡喃、苯并呋喃、噻唑、苯并噻唑、吩噻嗪、吡咯并嘧啶、呋喃并吡啶和噻吩并嘧啶,更优选吡啶、噻吩、苯并噻吩、噻唑、苯并噻唑、喹啉、喹唑啉、噌啉、吡咯并嘧啶、嘧啶、呋喃并吡啶和噻吩并嘧啶。术语“杂环基团”通常应指3至20元杂环基团,优选3至14元杂环基团,并且归入杂环基团定义内的杂环基团的所有子集(包括非杂芳族或杂芳族)为3至20元杂环基团,优选3至14元杂环基团。
术语“8至20元杂环基团”或“8至14元杂环基团”是指具有8至20个、优选8至14个形成环(两个或三个环)的原子并在形成环的原子之中包含至少一个杂原子(诸如氮、硫或氧)的芳族或非芳族稠合双环或三环基团,其在前一情况中为“8至20-元”、优选“8至14元芳族杂环基团”(也称为“杂芳基”或“杂芳族”)并在后一情况中为“8至20元”、优选“8至14元非芳族杂环基团”。“8至20元杂环基团”和“8至14元杂环基团”通过以下结构表示:含氮原子的稠合双环、三环和四环结构,诸如吲哚、异吲哚、吲嗪、嘌呤、吲唑、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、咪唑并吡啶、咪唑并三嗪、吡嗪并哒嗪、吖啶、菲啶、咔唑、咔唑啉、呸啶、菲咯啉、稠六苯、苯并咪唑、吡咯并吡啶、吡咯并嘧啶和吡啶并嘧啶;含硫的芳族杂环,诸如噻吩和苯并噻吩;含氧的芳族杂环,诸如环戊吡喃、苯并呋喃和异苯并呋喃;以及含2个或更多个选自氮、硫和氧的杂原子的芳族杂环,诸如苯并噁唑、苯并噻唑、苯并噻二唑、吩噻嗪、苯并呋咱、吩噁嗪、吡唑并噁唑、咪唑并噻唑、噻吩并呋喃、呋喃并吡咯、吡啶并噁嗪、呋喃并吡啶、呋喃并嘧啶和噻吩并嘧啶等等。
如本说明书通篇中所用的术语“5至14元非芳族杂环基团”是指具有5至14个形成环的原子并在形成环的原子之中包含至少一个杂原子(诸如氮、硫或氧)的非芳族环状基团。作为具体实例,可以提及的是诸如吡咯烷基、吡咯啉基、哌啶基、哌嗪基、N-甲基哌嗪基、咪唑啉基、吡唑烷基、咪唑烷基、吗啉基、四氢吡喃基、氮杂环丁基、氧杂环丁基、氧硫杂环戊基(oxathiolanyl)、吡啶酮、2-吡咯烷酮、亚乙基脲、1,3-二氧戊环、1,3-二噁烷、1,4-二噁烷、邻苯二甲酰亚胺和琥珀酰亚胺的非芳族杂环。作为“5至14元非芳族杂环基团”的实例,可优选地提及吡咯烷基、哌啶基和吗啉基,更优选吡咯烷基、哌啶基、吗啉基和吡咯。
如在本说明书通篇中所用的术语“8至14元非芳族杂环基团”是指具有8至14个形成环(双环或三环)的原子并在形成环的原子之中包含至少一个杂原子(诸如氮、硫或氧)的非芳族稠合环系(通常具有两个或三个环)。
如本说明书通篇中所用的术语“5至14元杂环基团”是指具有5至14个形成环的原子并在形成环的原子之中包含至少一个杂原子(诸如氮、硫或氧)的芳族或非芳族环状基团,其在前一情况中为“5至14元芳族杂环基团”并在后一情况中为“5至14元非芳族杂环基团”。“5至14元杂环基团”的具体实例因此包括“5至14元芳族杂环基团”的具体实例和“5至14元非芳族杂环基团”的具体实例。
作为“5至14元杂环基团”,可优选地提及吡咯烷基、哌啶基、吗啉基、吡咯、吡啶、吡啶酮、嘧啶、咪唑、吲哚、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹唑啉、噌啉、吖啶、稠六苯、噻吩、苯并噻吩、呋喃、吡喃、苯并呋喃、噻唑、苯并噻唑、吩噻嗪和羰苯乙烯基(carbostyryl),更优选吡咯烷基、哌啶基、吗啉基、吡咯、吡啶、噻吩、苯并噻吩、噻唑、苯并噻唑、喹啉、喹唑啉、噌啉和羰苯乙烯基,甚至更优选噻唑、喹啉、喹唑啉、噌啉和羰苯乙烯基,等等。
如本说明书通篇中所用的术语“6至14元芳族杂环基团”是指由具有6至14个形成环的原子的“5至14元芳族杂环基团”限定的那些取代基。作为具体实例,可提及的是吡啶、吡啶酮、嘧啶、吲哚、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹唑啉、噌啉、吖啶、苯并噻吩、苯并呋喃、噻唑、苯并噻唑和吩噻嗪*。“8至14元芳族杂环基团”是指具有8至14个形成稠合的双环或三环环系的原子的那些取代基或自由基。具体实例包括吲哚、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹唑啉、噌啉、吖啶、苯并噻吩、苯并呋喃、苯并噻唑、吡咯并嘧啶、吡咯并吡嗪、呋喃并嘧啶和吩噻嗪等等。
如本说明书通篇中所用的术语“6至14元杂环基团”是指由具有6至14个形成环的原子的“5至14元杂环基团”限定的那些取代基。作为具体实例,可提及的是哌啶基、哌嗪基、N-甲基哌嗪基、吗啉基、四氢吡喃基、1,4-二噁烷和邻苯二甲酰亚胺。
如本说明书通篇中所用的术语“3至7元杂环基团”是指具有3至7个形成环的原子,优选5至6个形成环的原子的那些杂环取代基。
如本说明书通篇中所用的术语“8至14元杂环基团”是指限定具有8至14个形成稠合环系的原子的8至14元杂环基团的那些取代基。
如本文所用的术语“杂环烷基”是指被杂环基团取代的烷基。
如本文所用的术语“烃基”是指通过碳原子键合的并通常具有至少一个碳氢键和主要的碳链但可任选地包含杂原子的任选取代的基团。烃基包括但不限于芳基、杂芳基、碳环、杂环、烷基、烯基、炔基以及它们的组合。
术语“低级”当结合诸如酰基、酰氧基、烷基、烯基、炔基或烷氧基的化学部分使用时意在包括其中在取代基中存在十个或更少的原子优选六个或更少的原子的基团。“低级烷基”例如是指含有十个或更少的碳原子优选六个或更少的碳原子的烷基。在某些实施方案中,本文定义的酰基、酰氧基、烷基、烯基、炔基或烷氧基取代基分别为低级酰基、低级酰氧基、低级烷基、低级烯基、低级炔基或低级烷氧基,不论它们是单独出现还是与其他取代基结合出现,诸如在羟烷基和芳烷基列举中(在该情况下,例如,当对烷基取代基中的碳原子计数时,酰基内的原子不计算在内)。
如本文所用,术语“硝基”意指--NO2;术语“卤素”表示--F、--Cl、--Br或--I;术语“巯基”意指--SH;术语“羟基”意指--OH;并且术语“磺酰基”意指--SO2-。
术语“多环基”或“多环基团”是指其中两个或更多个原子为两个邻接的环所共有(例如,环为“稠合环”)的两个或更多个环(例如,环烷基、环烯基、环炔基、芳基和/或杂环基)。通过非相邻原子接合的环称为“桥”环。多环的环的每一个可被但不限于诸如上文所述的取代基取代,所述取代基例如为卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚氨基、酰胺基、磷酸酯、膦酸酯、次膦酸酯、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、酮、醛、酯、杂环基、芳族或杂芳族部分、--CF3、--CN等。
如本文所用的短语“保护基团”意指避免潜在活性官能团发生非期望的化学转化的临时取代基。此类保护基团的实例包括羧酸的酯、醇的甲硅烷基醚、醛和酮的缩醛和缩酮。保护基团化学领域已有人进行了综述(Greene,T.W.;Wuts,P.G.M.Protective Groupsin Organic Synthesis,2nd ed.;Wiley:New York,1991)。
术语“取代的”是指具有替代主链一个或多个碳上的氢的取代基的部分。应当理解,“取代”或“被...取代的”包括隐含的条件:此取代符合被取代的原子和取代基的允许价态,并且该取代产生稳定的化合物,例如,该化合物不自发发生转化,诸如通过重排、环化、消除等。
如本文所用,设想术语“取代的”包括有机化合物的所有允许的取代基。在广泛的方面,允许的取代基包括有机化合物的无环和环状的、支链和非支链的、碳环和杂环的、芳族、非芳族和无机取代基。针对合适的有机化合物,允许的取代基可以是一个或多个并且可以为相同或不同的。对于本发明而言,诸如氮的杂原子可具有氢取代基和/或本文所述有机化合物的任何允许取代基,该取代基满足杂原子的化合价。取代基可包括如本文其他地方描述的任何取代基(基团),例如卤素、羟基、羰基(诸如羧基、烷氧基羰基、甲酰基或酰基)、醚、硫醚、硫代羰基(诸如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、次膦酸酯、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷硫基、硫酸酯、磺酸酯、氨磺酰基、磺酰胺基、磺酰基、杂环基、芳烷基或者芳族或杂芳族部分。本领域的技术人员将会理解,在某一部分或化学基团上取代的部分本身可以被取代。
应当理解,“取代”或“被...取代”包括隐含的条件:此取代符合被取代的原子和取代基的允许价态,并且该取代产生稳定的化合物,例如,该化合物不自发发生转化,诸如通过重排、环化、消除等。应当承认,术语“未取代的”只是指氢取代基或在该术语的使用上下文中无取代基。
用于本发明的优选取代基在上下文中包括例如羟基、羧基、氰基(C≡N)、硝基(NO2)、卤素(优选1、2或3个卤素,尤其是在烷基上,尤其是甲基,诸如三氟甲基)、硫醇、烷基(优选C1-C6,更优选C1-C3)、烷氧基(优选C1-C6烷基或芳基,包括苯基)、醚(优选C1-C6烷基或芳基)、酯(优选C1-C6烷基或芳基)包括亚烷基酯(使得连接在亚烷基上,而不是在优选被C1-C6烷基或芳基取代的酯官能处)、硫醚(优选C1-C6烷基或芳基)(优选C1-C6烷基或芳基)、硫酯(优选C1-C6烷基或芳基)、卤素(F、Cl、Br、I)、硝基或胺(包括五或六元环状亚烷基胺,包括C1-C6烷基胺或C1-C6二烷基胺)、链烷醇(优选C1-C6烷基或芳基)或链烷酸(优选C1-C6烷基或芳基)。更优选地,术语“取代的”在其使用上下文中应指烷基、烷氧基、卤素、羟基、羧酸、硝基和胺(包括单或二烷基取代的胺)。根据本发明的化合物中任何可取代的位置均可在本发明中被取代,但优选地在单个环或环系上存在不超过5个,更优选地不超过3个取代基。优选地,术语“未取代的”应指被一个或多个H原子取代。
术语“氨磺酰基”是本领域公认的并包括由以下通式表示的部分:
其中R9和R10为如上所述的取代基。
术语“硫酸酯”是本领域公认的并包括由以下通式表示的部分:
其中R41为电子对、氢、烷基、环烷基或芳基。
术语“磺酰胺基”是本领域公认的并包括由以下通式表示的部分:
其中R9和R'11如上所述。
术语“磺酸酯”是本领域公认的并包括由以下通式表示的部分:
其中R41为电子对、氢、烷基、环烷基或芳基。
术语“亚砜”或“亚磺酰基”是本领域公认的并包括由以下通式表示的部分:
其中R44选自氢、烷基、烯基、炔基、环烷基、杂环基、芳烷基或芳基,所述基团可任选地被取代。
术语“硫酯”是本领域公认的并用于描述基团-C(O)SR9或-SC(O)R9,其中R9表示任选被取代的如本文其他地方所述的烃基。
如本文所用,烷基、m、n等的各表述的定义当其在任何结构中出现不止一次时旨在反映相同表述的定义在结构中的独立性。
以举例的方式,某些优选的芳族和脂族环及其衍生物和可在根据本发明的化合物中用作药效团或取代基的取代基包括但不限于:苯基、苄基、吡啶、环己二烯、二氢吡啶、四氢吡啶、哌啶、吡嗪、四氢吡嗪、二氢吡嗪、哌嗪、嘧啶、二氢嘧啶、四氢嘧啶、六氢嘧啶、嘧啶酮、三嗪、二氢三嗪、四氢三嗪、三嗪烷(triazinane)、四嗪、二氢四嗪、四氢四嗪、四嗪烷(tetrazinane)、吡咯、二氢吡咯、吡咯烷、咪唑烷、二氢咪唑烷、咪唑、二氢咪唑、氮杂环丁烷、三唑、二氢三唑、三唑烷、四唑、二氢四唑、四唑烷(tetrazolidine)、二氮杂环庚烷、四氢二氮杂、二氢二氮杂、二氮杂、噁唑、二氢噁唑、噁唑烷、异噁唑、二氢异噁唑、异噁唑烷、噻唑、二氢噻唑、噻唑烷、异噻唑、二氢异噻唑、异噻唑烷、噁二唑、二氢噁二唑、噁二唑烷、噻二唑、二氢噻二唑、噻二唑烷、噁嗪烷、二氢噁嗪烷、二氢噁嗪、噁嗪(包括吗啉)、噻嗪烷、二氢噻嗪烷、二氢噻嗪、噻嗪(包括硫代吗啉)、噻嗪、呋喃、二氢呋喃、四氢呋喃、噻吩、哒嗪-3,6-二酮、四氢噻吩、二氢噻吩、四氢噻吩、二硫杂环戊烷、二硫杂环戊二烯、二噻茂酮、二氧戊环、间二氧杂环戊烯、氧硫杂环戊二烯、氧硫杂环戊烷、吡啶酮、二噁烷、二噁烷二酮、苯醌、二氢二噁英、二噁英、吡喃、3,4-二氢2H-吡喃、吡喃酮、2H-吡喃-2,3(4H)-二酮、氧硫杂环己烷、二氢氧硫杂环己二烯、氧硫杂环己二烯、氧杂环丁烷、硫杂环丁烷、硫氮杂环、环己二烯酮、内酰胺、内酯、哌嗪酮、吡咯二酮、环戊烯酮、oxazete、噁嗪烷酮(oxazinanone)、二氧戊环、3,4-二氢-2H-噻喃-1,1-二氧化物、二氧杂戊环酮、噁唑烷酮、噁唑酮、硫化环戊烷-1-氧化物、硫代吗啉-1-氧化物、四氢噻喃、硫化环戊烷-1,1-二氧化物、二噁嗪烷(dioxazinane)、吡唑啉酮、1,3-噻嗪(1,3-thiazete)、噻嗪烷-1,1-二氧化物、6,7-二氢-5H-1,4-二氧杂环庚、1,2-二氢哒嗪-3(4H)-酮、吡啶-2,6(1H,3H)-二酮和糖(葡萄糖、甘露糖、半乳糖、岩藻糖、果糖、核糖)。
双环和稠合环包括例如萘基、醌、喹啉酮、二氢喹啉、四氢喹啉、萘啶、喹唑啉、二氢喹唑啉、四氢喹唑啉、喹喔啉、二氢喹唑啉、四氢喹唑啉、吡嗪、喹唑啉-2,4(1H,3H)-二酮、异吲哚啉-1,3-二酮、八氢吡咯并吡啶、二氢吲哚、异吲哚啉、六氢吲哚酮、四氢吡咯并噁唑酮、六氢-2H-吡咯并[3,4-d]异噁唑、四氢-1,6-萘啶、2,3,4,5,6,7-六氢-1H-吡咯并[3,4-c]吡啶、1H-苯并[d]咪唑、八氢吡咯并[3,4-c]吡咯、3-氮杂双环[3.1.0]己烷、7-氮杂双环[2.2.1]庚-2-烯、二氮杂双环庚烷、苯并噁唑、吲哚、1,4-二氮杂双环[3.3.1]壬烷、氮杂双环辛烷、萘-1,4-二酮、茚、二氢茚、2,3,3a,7a-四氢-1H-异吲哚、2,3,3a,4,7,7a-六氢-1H-异吲哚、1,3-二氢异苯并呋喃、1-甲基-3a,4,5,6,7,7a-六氢-1H-吲哚、3-氮杂双环[4.2.0]辛烷、5,6-二氢苯并[b]噻吩、5,6-二氢-4H-噻吩并[2,3-b]噻喃、3,4-二氢吡嗪-2(1H)-酮、2H-苯并[b][1,4]噻嗪、萘啶-4(1H)-酮、八氢吡咯并[1,2-a]吡嗪、咪唑并哒嗪、四氢咪唑并哒嗪、四氢哒嗪、噻嗪酮、5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-8-酮、4-硫杂-1-氮杂双环[3.2.0]庚-7-酮、1,6,7,8-四氢咪唑并[4,5-d][1,3]二氮杂、8H-噻唑并[4,3-c][1,4]噁嗪-4-鎓、8H-噻唑并[4,3-c][1,4]噻嗪-4-鎓、蝶啶、噻唑并[3,4-a]吡嗪-4-鎓、7-(甲基亚氨基)-7H-吡咯并[1,2-c]噻唑-4-鎓、噻唑并吡嗪、3,7-二氧杂双环[4.1.0]庚-4-烯、6,7-二氢-5H-吡咯并[1,2-a]咪唑、3,3a-二氢呋喃并[3,2-b]呋喃-2(6aH)-酮、四氢-3aH-[1,3]二氧并[4,5-c]吡咯、7-亚乙基-7H-吡咯并[1,2-c]噻唑-4-鎓、六氢-1H-吡咯并[2,1-c][1,4]噁嗪、6,7,8,8a-四氢-1H-吡咯并[2,1-c][1,4]噁嗪、2-氮杂双环[2.2.2]辛-2-烯、6,6a-二氢噻吩并[3,2-b]呋喃-5(3aH)-酮、4,5-二氢吡啶-3(2H)-酮、4,7a-二氢-3aH-[1,3]二氧并[4,5-c]吡喃、6,7-二氢-1H-呋喃并[3,4-c]吡喃-1,3(4H)-二酮、3,3a,4,7a-四氢-2H-呋喃并[2,3-b]吡喃、2,4a,7,7a-四氢-1H-环戊[c]吡啶、4H-吡喃并[3,2-b]吡啶-4,8(5H)-二酮、1,2,3,3a,4,7a-六氢吡喃并[4,3-b]吡咯、2,3,8,8a-四氢吲嗪-7(1H)-酮、八氢-1H-吡啶并[1,2-a]吡嗪-1-酮、2,6,7,8,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-1-酮、6,7,8,8a-四氢吡咯并[1,2-a]吡嗪-1(2H)-酮、六氢吡咯并[1,2-a]吡嗪-1(2H)-酮、双环[2.2.1]庚-2,5-二烯。
螺部分:1,5-二氧杂螺[5.5]十一烷、1,4-二氧杂螺[4.5]癸烷、1,4-二氮杂双环[3.2.1]辛烷、5-氮杂螺[2.5]辛烷、5-氮杂螺[2.4]庚烷、3,9-二氮杂-6-氮阳离子螺[5.5]十一烷、3,4-二氢螺[苯并[b][1,4]噁嗪-2,1'-环己烷]、7-氧杂-4-氮杂螺[2.5]辛-5-烯。
包含与药学有效量的载体、添加剂或赋形剂相结合的有效量的至少一种根据本发明的STEP调节化合物和一种或多种本文其他地方所述的化合物(均为有效量)的组合的药物组合物代表本发明的另一个方面。
用于本发明的治疗方法的组合物和本发明的药物组合物可使用一种或多种药学上可接受的载体以常规方式配制并且还可以通过控释制剂施用。可用于这些药物组合物的药学上可接受的载体包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(诸如人血清蛋白)、缓冲物质(诸如磷酸盐、甘氨酸、山梨酸、山梨酸钾)、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(诸如硫酸谷醇溶蛋白(prolamine sulfate)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐)、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
用于本发明的治疗方法的组合物和本发明的药物组合物可经口、肠胃外、吸入喷雾、局部、直肠、鼻腔、颊面、阴道或植入贮存器而施用。如本文所用的术语“肠胃外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。优选地,组合物经口、腹膜内或静脉内施用。
用于本发明治疗方法的组合物的无菌注射用剂型可以是含水或含油混悬剂。这些混悬剂可根据本领域已知的技术使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂也可以为无毒、肠胃外可接受的稀释剂或溶剂中的无菌注射用溶液剂或混悬剂,例如作为1,3-丁二醇中的溶液。可以采用的可接受的媒介物和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外,通常将无菌、固定油用作溶剂或助悬介质。为此,可以采用任何温和的固定油,包括合成的单或二甘油脂。脂肪酸(诸如油酸)及其甘油酯衍生物可以药学上可接受的天然油(诸如橄榄油或蓖麻油)尤其是以其聚氧乙烯化形式用于制备注射剂。这些油溶液剂或混悬剂还可以包含长链醇稀释剂或分散剂,诸如瑞士药典级(Ph.Helv)醇或类似的醇。
本发明的药物组合物可以任何口腔可接受的剂型经口施用,这些剂型包括但不限于胶囊剂、片剂、水性混悬剂或溶液剂。经口服用片剂而言,常用的载体包括乳糖和玉米淀粉。还通常添加润滑剂,诸如硬脂酸镁。对于以胶囊剂型经口施用,可用的稀释剂包括乳糖和干燥的玉米淀粉。当需要口服用水性混悬剂时,将活性成分与乳化剂和助悬剂结合。如果需要,也可以添加某些甜味剂、矫味剂或着色剂。
作为另外一种选择,本发明的药物组合物可以经直肠施用的栓剂剂型施用。这些栓剂可通过以下方式制备:将药剂与在室温下为固体但在直肠温度下为液体并因此将在直肠中熔化以释放药物的合适的非刺激性赋形剂混合。此类材料包括可可油、蜂蜡和聚乙二醇类。
本发明的药物组合物也可以局部施用,尤其是治疗皮肤癌、牛皮癣或其他在皮肤中或皮肤上出现的疾病。合适的局部用制剂可针对这些区域或器官的每一者容易地制备。下肠道的局部应用可以直肠栓剂(参见上文)或以合适的灌肠剂实现。也可以使用局部可接受的透皮贴片。
对于局部应用,可在包含悬浮或溶解在一种或多种载体中的活性组分的合适油膏剂中配制药物组合物。用于本发明化合物局部施用的载体包括但不限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。
作为另外一种选择,可在包含悬浮或溶解在一种或多种药学上可接受的载体中的活性组分的合适乳液剂或霜剂中配制药物组合物。合适的载体包括但不限于矿物油、单硬脂酸脱水山梨醇酯、聚山梨酸酯60、鲸蜡酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苄醇和水。
对于眼科使用,可在等渗、pH调节过的无菌盐水中作为微粉化混悬剂,或优选地在等渗、pH调节过的无菌盐水中作为溶液剂配制药物组合物,其中含有或不含防腐剂,诸如苯扎氯铵。作为另外一种选择,对于眼科使用,可在油膏(诸如凡士林)中配制药物组合物。
本发明的药物组合物也可通过鼻喷雾或吸入方式施用。此类组合物可根据药物制剂领域熟知的技术制备,并可采用苄醇或其他合适的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或其他常规增溶剂或分散剂在生理盐水中作为溶液剂制备。
可与载体材料相结合以产生单一剂型的本发明药物组合物中化合物的量将根据宿主和所治疗的疾病、特定的给药方式而变化。优选地,应配制含有约0.05毫克至约750毫克或更多,更优选约1毫克至约600毫克,甚至更优选约10毫克至约500毫克活性成分的组合物,该活性成分单独或与至少一种另外的可用于治疗癌症、前列腺癌或转移性前列腺癌或其继发效应或病症的非抗体吸引化合物相结合。
还应当理解,任何特定患者的具体剂量和治疗方案将取决于多种因素,这些因素包括所采用的具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、给药时间、排泄率、联合用药、治疗医生的判断和所治疗的特定疾病或病症的严重性。
患有神经障碍或存在发生神经障碍危险的患者或受试者(例如男人)可以通过以下方式治疗:向患者(受试者)施用任选地在药学上可接受的载体或稀释剂中单独地或与其他已知药剂(优选可辅助治疗神经障碍或改善与神经障碍相关的继发效应和病症的药剂)相结合的有效量的根据本发明的(-)-石杉碱甲和相关方面及实施方案(包括其药学上可接受的盐、溶剂化物或多晶型物)而治疗。本治疗也可连同其他常规疗法一起施用,这些疗法诸如用于治疗阿尔茨海默病患者的认知和行为症状的药物(例如和)。
可通过任何合适的途径施用这些化合物,例如经口、肠胃外、静脉内、皮内、皮下或局部以液体、霜膏、凝胶或固体剂型或通过气雾剂型而施用。
将活性化合物以足以向患者的所需适应症递送治疗有效量而不会在所治疗的患者中导致严重毒副作用的量包含在药学上可接受的载体或稀释剂中。对于本文提及的所有病症,活性化合物的优选剂量在每天约10ng/kg至300mg/kg、优选每天0.1至100mg/kg、更通常每天每千克受体/患者体重为0.5至约25mg的范围内。典型的局部用剂量将在合适的载体中在0.01-3%wt/wt的范围内。
化合物通常以任何合适的单位剂型施用,包括但不限于每单位剂型包含低于1mg、1mg至3000mg、优选5至500mg活性成分的单位剂型。约25-250mg的口服剂量通常是适宜的。
优选地施用活性成分以达到约0.00001-30mM、优选约0.1-30μM活性化合物的峰值血浆浓度。这可例如通过静脉注射任选地在盐水或含水介质中的活性成分的溶液或制剂而实现或作为活性成分的丸剂(bolus)而施用。经口施用也适用于产生与局部施用的组合物一样的活性剂的有效血浆浓度。
活性化合物在药物组合物中的浓度将取决于吸收、分布、失活和药物的排泄率以及本领域技术人员已知的其他因素。应当注意,剂量值还将随要缓解的病症的严重性而变化。还应当理解,对于任何特定的受试者,具体的剂量方案应随着时间根据个体需要以及管理或监督组合物施用的人员的专业判断而调整,并且本文所示的浓度范围仅为示例性的并且不旨在限制受权利要求书保护的组合物的范围或实践。活性成分可一次性施用,或者可分成多个较小的剂量在不同的时间间隔施用。
口腔组合物将通常包含惰性稀释剂或可食用载体。它们可封装在明胶胶囊中或压制成片。对于口服治疗性施用之目的,活性化合物或其前药衍生物可与赋形剂复合并以片剂、锭剂或胶囊剂剂型使用。药学上相容的粘合剂和/或佐剂材料可包含在内作为组合物的一部分。
片剂、丸剂、胶囊剂、锭剂等可包含任何以下成分或类似性质的化合物:粘合剂,诸如微晶纤维素、黄蓍胶或明胶;赋形剂,诸如淀粉或乳糖;分散剂,诸如藻酸、Primogel或玉米淀粉;润滑剂,诸如硬脂酸镁或Sterotes;助流剂,诸如胶态二氧化硅;甜味剂,诸如蔗糖或糖精;或矫味剂,诸如胡椒薄荷、水杨酸甲酯或橙香精。当剂量单位形式为胶囊时,其除了以上类型的材料外还可以包含液体载体,诸如脂肪油。此外,剂量单位形式可以包含改变剂量单位的物理形式的各种其他材料,例如糖、虫胶或肠溶剂包衣。
活性化合物或其药学上可接受的盐可作为酏剂、混悬剂、糖浆剂、薄片、口香糖等的组分而施用。糖浆剂除了活性化合物外还可以包含作为甜味剂的蔗糖以及某些防腐剂、颜料和着色剂及香料。
活性化合物或其药学上可接受的盐也可与不对期望的作用造成损害的其他活性材料或与对期望的作用进行补充的其他材料(诸如其他抗癌剂、抗生素、抗真菌剂、消炎药或抗病毒化合物)混合。
用于肠胃外、皮内、皮下或局部应用的溶液剂或混悬剂可包含以下组分:无菌稀释剂,诸如注射用水、盐水溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成溶剂;抗菌剂,诸如苄醇或对羟基苯甲酸甲酯;抗氧化剂,诸如抗坏血酸或亚硫酸氢钠;螯合剂,诸如乙二胺四乙酸;缓冲剂,诸如乙酸盐、柠檬酸盐或磷酸盐;以及调节张力的试剂,诸如氯化钠或右旋糖。肠胃外制剂可封装在安瓿、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
如果经静脉内施用,则优选的载体是生理盐水或磷酸盐缓冲盐水(PBS)。
在一个实施方案中,将活性化合物与将避免化合物从体内快速消除的载体一起配制,诸如控释制剂,包括植入物和微囊化递送系统。可以使用可生物降解的生物相容性聚合物,诸如乙烯-乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。配制此类制剂的方法对本领域的技术人员而言将显而易见。
脂质体悬浮液也可是药学上可接受的载体。它们可根据本领域技术人员已知的方法制备,例如,如美国专利号4,522,811中所述(该专利整体以引用方式并入本文)。例如,脂质体制剂可通过以下方式制备:将合适的脂质(诸如硬脂酰磷脂酰乙醇胺、硬脂酰磷脂酰胆碱、花生四烯酰磷脂酰胆碱和胆固醇)溶解在无机溶剂中,然后蒸发溶剂,从而在容器的表面上留下干燥的脂质薄膜。然后将活性化合物的水溶液引入容器。接着用手涡旋容器使脂质材料脱离容器侧壁并将脂质聚集体分散,从而得到脂质体悬浮液。
本发明的示例性方法和化合物
下面的方案1示出本发明范围内的一个优选合成。
描述符号a、b、c表示通过产物的间歇水性后处理但无产物的纯化而进行的步骤。步骤3a和3d通过蒸发挥发物以及向反应烧瓶中直接添加试剂(无间歇后处理)而完成。合成5的路线从1以55%的总收率进行。
该路线可以低成本的对映纯试剂(+)-胡薄荷酮开始,这种试剂可通过四步程序转化成1,该程序之前已有公布。Lee,H.W.;Ji,S.K.;Lee,I.-Y.C.;Lee,J.H.J.Org.Chem.1996,61,254。
存在许多与示例性方案1相关的新特征。例如,原料的现有立体化学可用于控制产物2中的相对立体化学。
已知技术未提出2向3的转化。具体地讲,步骤2b是β-酮腈环化第一个已知的实例。
已知技术也未提出Wittig反应(步骤2c)。之前的工作人员已在产物中得到了烯烃异构体的混合物。我们对底物和反应条件进行了优化以得到所需的结果。
已知技术也未提出4向5的转化。之前的工作人员依赖于两步程序以消除醇官能(步骤4a)。我们发现这可以使用伯吉斯试剂在一个反应烧瓶中高效地进行。
已知技术也未提出步骤4b。在腈水化成伯酰胺中应用铂催化剂是罕见的。另外,在文献中已知的是,此类催化剂通常对于叔腈(诸如存在于4中)的水化无效。因此,使用该催化剂直接水化腈构成了已知合成方法的进展。
中间体3、4和5可潜在地用于获得其他天然产物。尤其是诸如5的化合物可以是合成其他生物活性化合物的有用支架。
通过本发明实现的收率的显著提高和方法步骤的明显减少通过与如下概述的已知方法的比较而展示。
之前合成法的概述:
1.Xia,Y.;Kozikowski,A.P.J.Am.Chem.Soc.1989,111,4116.
2.Qian,L.;Ji,R.Tetrahedron Lett.1989,30,2089.
3.Yamada,F.;Kozikowski,A.P.;Reddy,E.R.;Pang,Y.P.;Miller,J.H.;McKinney,M.J.Am.Chem.Soc.1991,113,4695.
4.Lucey,C.;Kelly,S.A.;Mann,J.Org.Biomol.Chem.2007,5,301.
5.Koshiba,T.;Yokoshima,S.;Fukuyama,T.Org.Lett.2009,11,5354.
本发明方法的进一步描述
大多数合成石杉碱甲的方法都依赖于将四碳片段引入双环结构(如下所示1中a和b键的逆合成裂解)。
(-)-石杉碱甲(1)的逆合成分析。
下面的方案2提供对用于如上所述的方案1方法中的化学技术的进一步详述,并指出在我们的方法的各步骤中生成的未分离中间体。
参见方案1和2,我们开发了新的方法,其中两个可供选择的键(参见上文“(-)-石杉碱甲(1)的逆合成分析”中的2)的断开分别形成基于酮和吡啶酮的合成子3和4。前者可得自(R)-4-甲基-环己-2-烯-1-酮(5)而3-溴-2-(溴甲基)-6-甲氧基吡啶(6)将作为4的官能等同物。将5中的C-4立构中心用在我们的路线中以控制目标中的相对和绝对立体化学。已经报道了制备(R)-4-甲基环己-2-烯-1-酮(5)的多种便利方法。16在优选的实施方案中,可以使用从(+)-胡薄荷酮开始的直接四步序列。16a诸如6的二卤代吡啶已用于不同的并且明显更长的合成(-)-石杉碱甲(1)的路线,14c以及用于其他石松属(Lycopodium)生物碱的合成。17
方案2(-)-石杉碱甲(1)的对映选择性合成。试剂和条件:
(1)Ph(CH3)2SiLi,CuI,HMPA,THF,-78→-23→-78℃,然后6,-78→-23℃,84-91%;(2a)LHMDS,p-TsCN,甲苯,-78℃;(2b)Pd(Pt-Bu3)2(5摩尔%),NaOt-Bu,甲苯,110℃;(2c)EtPPh3Br,LHMDS,Et2O,24℃,从7中71-76%,E:Z=5:1;(3a)TfOH,DCM,0→24℃,然后TBAF,H2O2,K2CO3,DMF,40℃,E:Z=5:1;(3b)12,甲苯,110℃,E:Z=5:1;(3c)13(2摩尔%),EtOH-H2O(2:1),95℃,E:Z=5:1;(3d)PIFA,CH3OH,回流,然后TMSI,CHCl3,回流,然后CH3OH,回流,从10中56-70%。
在上文的方案2中显示了该策略的成功实施。为了使该路线适于大规模合成,我们深入优化了每个步骤,这使得有效简略了许多转化(最终合成路线需要三个色谱纯化步骤)。我们的工作从二甲基苯基甲硅烷基铜酸锂与(R)-4-甲基-环己-2-烯-1-酮(5)的共轭加成开始。通过3-溴-2-(溴甲基)-6-甲氧基吡啶(6)进行初始烯醇化物的烷基化得到了作为单一可检测非对映体(1H NMR分析)的加成-烷基化产物7,在纯化(2.0-4.5g规模)后以84-91%的收率分离。
7的动力学控制去质子化以及通过对甲苯磺酰氰对所得的烯醇化物进行捕获,18然后对产物混合物进行立即后处理以高纯度(估计>95%,1H NMR分析)形成了α-氰基酮8。产物的快速分离至关重要,因为如果让混合物老化,则α-氰基酮8会经历向原料(7)和α,α-二氰基酮(未示出)的歧化。
然后让未纯化的α-氰基酮8经历钯催化的分子内烯醇化物杂芳基化。19在进行研究的多种催化剂前体中,通过Dai和Fu的方法制备的双(三叔丁基膦)钯(0)20作为最有效的出现。观察到了引人注目的对碱的依赖(表1)。
表1:烯醇化物杂芳基化的优化。
a
a所有反应均使用Pd(Pt-Bu3)2作为预催化剂在甲苯中在110℃下进行3h。b通过快速柱色谱法纯化后的分离收率。c通过未纯化的反应混合物的1H NMR和LC/MS分析而估计。Dec.=分解。
因此,在存在碳酸盐碱(条目1、2)的情况下,原型脱溴(protodebrominated)产物15占支配地位。氢化钠(条目3)提高了环化产物(9)的转化率,然而也出现了大量的分解。最终,我们确定了叔丁醇钠(条目5)为最佳的,并且使用这种碱以基本上定量的收率(1H NMR分析)获得了产物。序列的下一步要求9的酮官能的立体选择性烯化。通过衍生自溴化乙基三苯基磷鎓的锂叶立德处理9(醚,24℃)以高收率得到烯化产物10。在E:Z选择性与浓度之间观察到了明显的趋势(在1.0、0.1和0.01M下E/Z分别为1.1、1.8、5),这与盐效应一致并表明所需的E-异构体是动力学有利的产物。21在优化的条件下,通过快速柱色谱法(4.3-7.4g规模)作为E/Z异构体的5:1混合物从7中以71-76%的收率分离了烯化产物10。通过这种方法,以较高的总收率并以数克的规模在四个步骤中形成了1的完整碳骨架。
用三氟甲磺酸处理烯化产物(10)然后进行氧化脱甲硅烷基化得到了高纯度(1HNMR分析)的氰醇11。未纯化的氰醇11通过加热在甲苯中用伯吉斯试剂(12)进行了有效脱水。在含水乙醇中在存在铂催化剂1322的情况下进行脱水产物的热解(未示出)得到了酰胺14。最后,霍夫曼重排[双(三氟乙酰氧基)碘代苯]、完全脱保护以及通过快速柱色谱法纯化单独地得到了(-)-石杉碱甲(1,经四项操作56-70%)及其烯烃异构体(未示出,11-14%)。合成的(-)-石杉碱甲(1)在所有方面(1H NMR、13C NMR、IR、三个TLC溶剂体系、LC/MS保留时间、旋光度)均与真实样品相同。已制备了高达1.6g批量的(-)-1。
迄今为止,通过上文描绘的路线已制备了超过3.5g的(-)-石杉碱甲(1)。我们的合成以35-45%的总收率(效率是任何其他之前报道的对映选择性路线的16倍)进行,并且只需要三次色谱纯化。我们展望,这种化学技术将能可靠地供应合成的(-)-石杉碱甲(1),并将大大促进其在神经保护和抗神经变性应用中的临床开发。
本领域的普通技术人员将会意识到,用在本发明方法中的各种反应物、试剂和反应可以许多方式加以变化而不影响如本文所述的效率和收率。
例如,由酰胺14生成(±)石杉碱可通常根据Loudon,G.M.;Radhakrishna,A.S.;Almound,M.R.;Blodgett,J.K.;Boutin,R.H.J.Org.Chem.,1984,49,4272-4276;Zhang,L.;Kaufmann,G.S.;Pesti,J.A.;Yin,J.J.Org.Chem.,1997,62,6918-6920或Schmuck,C.;Geiger,L.Chem.Comm.2005,772-774中所述的方法使用双(三氟乙酰氧基碘)苯(PIFA)通过改进的霍夫曼反应实现。乙醇、丙醇或水可在酰胺14的霍夫曼重排中代替甲醇。
使用伯吉斯试剂进行氰醇11的脱水可通过多种方式完成,例如通过使用K.C.Nicolaou,D.Y.-K.Chen,X.Huang,T.Ling,M.Bella,S.A.Snyder,"Chemistry andBiology of Diazonamide A:First Total Synthesis and Confirmation of the TrueStructure"J.Am.Chem.Soc.126,12888-12896(2004)中所述的技术。
如本文所述的烯化产物10向氰醇11的转化可通过多种方式实现。例如,脱甲硅烷基化可通过与三氟化硼-乙酸络合物或布朗斯台德酸(诸如TFA、MSA、FMSA或四氟硼酸)在惰性溶剂(例如DCM)中反应而实现。当使用三氟化硼-乙酸络合物时,烯化产物10可用过氧化氢和KHCO3氧化。当使用布朗斯台德酸时,烯化产物10可用过氧化氢、KHCO3和KF氧化。可用于将甲硅烷基转化成羟基的方法还在Fleming,I.(Chemtracts-Organic Chemistry 1996,9,1-64)和Jones,G.R.et al.(Tetrahedron,1996,52,7599-7662)中有所描述。
用于将环化产物9转化成烯化产物10的Wittig烯化反应可通过多种方式加以改进,例如通过在诸如THF、乙醚或1,4-二噁烷的溶剂中使用诸如正丁基锂、双(三甲基甲硅烷基)氨基钠、双(三甲基甲硅烷基)氨基锂、双(三甲基甲硅烷基)氨基钾或二异丙基氨基锂的碱。参见Chem.Rev.1989,89,863;Modem Carbonyl Olefination 2004,1-17;LiebigsAnn.Chem.1997,1283。
在通过加成-烷基化产物7的去质子化生成的烯醇化物的氰化中,可用THF替换氰化反应中的甲苯。参见D.Kahne and D.B.Collum,Tetrahedron Lett.,5011(1981),并且可用双(三甲基甲硅烷基)氨基锂(LHMDS)替换二异丙基氨基锂(LDA)。
在注释16的参考文献中所述的任何方法均可用于制备原料(R)-4-甲基-环己-2-烯-1-酮1。
有关上述方法的进一步详述在下文的示例性实验章节中给出。
实验章节
一般实验程序。除非另外指明,否则所有反应均在装有橡胶隔垫的单颈、火焰干燥的圆底烧瓶中在正氩气压下进行。对空气和水分敏感的液体通过注射器或不锈钢插管转移,或在充满氮气的干燥箱中进行处理(工作氧气含量<1ppm)。通过在30-33℃下旋转蒸发而浓缩有机溶液。如Still等人1所述采用购自Sorbent Technologies(Atlanta,GA)的硅胶(40-63μm粒度)进行了快速柱色谱法。使用浸渍了荧光指示剂(254nm)的硅胶(1.0mm,孔尺寸)预涂覆玻璃板进行分析型薄层色谱(TLC)。TLC板通过暴露于紫外光(UV)或/和浸入高锰酸钾水溶液(KMnO4)然后在热板上短暂加热(120℃,10-15s)而观察。
材料。除了以下例外,商业溶剂和试剂均按取得状态使用。将苯、二氯甲烷、醚和甲苯根据Pangborn等人的方法进行了纯化。2将四氢呋喃在即将使用前在氮气氛围下从钠/二苯甲酮中蒸馏。将甲醇在即将使用前在氮气氛围下从甲醇镁中蒸馏。将六甲基磷酰胺在氮气下从氢化钙中蒸馏并在氮气下储存。将分子筛通过在真空下加热过夜而活化(200℃,200毫托),储存在重力烘箱(120℃)中,在即将使用前在真空(100毫托)下火焰干燥。根据Fleming及其同事的程序制备了苯基二甲基甲硅烷基锂的四氢呋喃溶液。3根据Lee及其同事的程序由(+)-胡薄荷酮制备了(R)-4-甲基-环己-2-烯-1-酮(5)。4根据Kelly及其同事的程序制备了3-溴-2-(溴甲基)-6-甲氧基吡啶(6)。5根据Dai和Fu的程序制备了双(三叔丁基膦)钯(0)。6根据Burgess及其同事的程序制备了N-(三乙基铵磺酰基)氨基甲酸甲酯(伯吉斯试剂,12)。7根据Ghaffar和Parkins的程序制备了氢化(羟基二甲基膦)[氢双(羟基二甲基膦)]铂(II)(13)。8对溴化乙基三苯基磷鎓在水中进行了重结晶,将所得的晶体在真空中在50℃干燥了24h。
仪器。除非另外指明,否则质子核磁共振光谱(1H NMR)均在400或500MHz和24℃下记录。化学位移在四甲基硅烷低场处以份每一百万份(ppm,δ坐标)表示并参照NMR溶剂(CHCl3,δ7.26)中的残余氕。数据表示如下:化学位移,多重性(s=单重峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰和/或多重共振、br=宽,app=表观),积分,耦合常数(赫兹)和归属。除非另外指明,否则质子去耦合碳核磁共振光谱(13C NMR)均在100或125MHz和24℃下记录。化学位移在四甲基硅烷低场处以份每一百万份(ppm,δ坐标)表示并参照溶剂(CDCl3,δ77.0)的碳共振。除非另外指明,否则极化转移光谱的无畸变增强[DEPT(135)]均在100或125MHz和24℃下记录。将13C NMR和DEPT(135)数据合并,并表示如下:化学位移,碳类型[得自DEPT(135)实验]。衰减全反射傅立叶变换红外光谱(ATR-FTIR)使用参照聚苯乙烯标准品的Thermo Electron Corporation Nicolet 6700FTIR光谱仪获得。数据表示如下:吸收频率(cm-1),吸收强度(s=强,m=中,w=弱,br=宽)。高分辨率质谱(HRMS)数据使用配备双重API/ESI高分辨率质谱检测器和光电二极管阵列检测器的Waters UPLC/HRMS仪器获得。除非另外指明,否则均将样品在反相C18柱(1.7μm粒度,2.1×50mm)上以5%乙腈-含0.1%甲酸的水→95%乙腈-含0.1%甲酸的水的线性梯度经4分钟,然后通过含0.1%甲酸的100%乙腈经1分钟以600μL/分钟的流速洗脱。旋光度在配备钠(589nm,D)灯的PerkinElmer旋光计上测量。旋光度数据表示如下:比旋光度([α]20 n),浓度(g/mL)和溶剂。
合成程序。9
步骤1:(R)-4-甲基-环己-2-烯-1-酮(5)的加成-烷基化(加成-烷基化产物7):
在24℃下,将六甲基磷酰胺(11.4mL,65.4mmol,3.60当量)通过注射器逐滴加入到碘化亚铜(3.46g,18.2mmol,1.00当量)的四氢呋喃(36mL)搅拌悬浮液中。将所得的混合物冷却到-78℃。将二甲基苯基甲硅烷基锂的四氢呋喃溶液(0.46M,79.0mL,36.3mmol,2.00当量)通过注射器泵经30分钟逐滴加入到冷的棕色悬浮液中。完成添加后,将混合物温热至0℃。将所得的溶液在0℃搅拌1h。然后将混合物冷却到-78℃。通过注射器经5分钟将(R)-4-甲基-环己-2-烯-1-酮(5,2.00g,18.2mmol,1.00当量)逐滴加入。完成添加后,将反应混合物温热至-23℃。将温热的溶液在-23℃搅拌3h。然后将反应混合物冷却到-78℃。将3-溴-2-(溴甲基)-6-甲氧基吡啶(6)的四氢呋喃溶液(0.50M,40.0mL,20.0mmol,1.10当量)通过插管经30分钟逐滴加入到冷的反应混合物中。完成添加后,将反应混合物温热至-23℃。将温热的溶液在-23℃搅拌1h。然后将产物混合物经30分钟温热至24℃。将温热的产物混合物通过硅藻土垫(长度/直径=3/9cm)洗脱。将硅藻土垫依次用饱和碳酸氢钠水溶液(100mL)、乙酸乙酯(250mL)、饱和碳酸氢钠水溶液(100mL)和乙酸乙酯(250mL)洗涤。收集双相滤液,转移到分液漏斗。分离所形成的层。将有机层依次用饱和碳酸氢钠水溶液(2×200mL)、蒸馏水(200mL)和饱和氯化钠水溶液(200mL)洗涤。将洗涤的有机层经硫酸钠干燥。将干燥的溶液过滤,浓缩滤液。将所得的残余物通过快速柱色谱法纯化(用5%乙酸乙酯-己烷洗脱)得到浅黄色粘稠油状加成-烷基化产物7(7.37g,91%)。
Rf=0.27(5%乙酸乙酯-己烷,KMnO4)。[α]20 n=-40.8(c 0.10,CHCl3)。1H NMR(500MHz,CDCl3),δ7.55(d,1H,J=8.5Hz,H1),7.45(dd,2H,J=8.0,2.0Hz,H12),7.33-7.29(m,3H,H12),6.42(d,1H,J=8.5Hz,H2),3.79(s-,3H,H3),3.22-3.12(m,2H,H4/H5),2.84(dd,1H,14.5,4.5Hz,H4),2.58-2.52(m,1H,H9),2.23-2.17(m,1H,H9),2.05-1.94(m,2H,H7/H8),1.82-1.75(m,1H,H8),1.15(t,1H,J=6.5Hz,H6),1.00(d,3H,6.5Hz,H10),0.32(app s,6H,H11)。13C NMR(125MHz,CDCl3),δ214.8(C),162.2(C),154.7(C),142.4(CH),138.1(C),134.0(CH),129.3(CH),128.0(CH),112.2(C),110.1(CH),53.6(CH3),47.1(CH),40.3(CH2),37.3(CH2),34.3(CH),31.1(CH2),29.3(CH),23.9(CH3),-3.0(CH3),-3.6(CH3)。IR(ATR-FTIR),cm-1:2951(br),1709(s),1575(s),1459(s),1417(s),1295(m),1250(m),1111(m),1037(m),1014(m),820(s),734(m),701(m)。HRMS-CI(m/z):[M+H]+C22H29BrNO2Si计算值446.1146/448.1125;实测值446.1147/448.1124。
步骤2a-c:烯化产物10的合成:
步骤2a:加成-烷基化产物7的氰化(α-氰基酮8):
在-78℃下,将六甲基二硅基胺基锂的甲苯溶液(1.00M,49.7mL,49.7mmol,3.00当量)通过注射器泵经15分钟逐滴加入到加成-烷基化产物7(7.37g,16.6mmol,1.00当量)的甲苯(170mL)搅拌溶液中。完成添加后,将反应混合物温热至0℃。将温热的溶液在0℃搅拌15分钟。然后将混合物冷却到-78℃。将对甲苯磺酰腈的甲苯溶液(1.00M,18.2mL,18.2mmol,1.10当量)通过注射器快速(<1分钟)加入到冷的反应混合物中。将反应混合物在-78℃搅拌1分钟。将冷的产物混合物用100mM磷酸钠缓冲水溶液(pH 7,30mL)快速稀释。在搅拌下,让产物混合物经30分钟温热至24℃。将温热的产物混合物用乙酸乙酯(200mL)稀释。将稀释的产物混合物转移到已装有100mM磷酸钠缓冲水溶液(pH 7,150mL)的分液漏斗。分离所形成的层。将含水层用乙酸乙酯(3×150mL)萃取。合并有机层,将合并的有机层经硫酸钠干燥。将干燥的溶液过滤,浓缩滤液得到浅黄色粘稠油状未纯化的α-氰基酮8。1H NMR分析(400MHz,CDCl3)表明>95%转化为氰基酮8((R)-α-氰基酮、(S)-α-氰基酮和β-羟基-α,β-不饱和腈异构体的混合物)。将如此获得的产物直接用于下一步。
据发现α-氰基酮8对快速柱色谱法纯化不稳定。因此,未尝试进一步表征。
步骤2b:α-氰基酮8的环化(三环9):
向连接到涂覆有特氟龙的阀门的500mL圆底烧瓶中加入未纯化的α-氰基酮8(16.6mmol,1.00当量,假设在前一步骤中为定量收率)。将残余物通过与苯(5.0mL)共沸蒸馏而干燥。将容器密封,然后将密封的容器转移到充满氮气的干燥箱。将叔丁醇钠(1.75g,18.2mmol,1.10当量)、双(三叔丁基膦)钯(0)(423mg,828μmol,0.05当量)和甲苯(170mL)按顺序加入到烧瓶中。将容器密封,然后将密封的容器从干燥箱中取出。将反应容器置于已预热到110℃的油浴中。将反应混合物在110℃下搅拌并加热12h。将反应容器从油浴中取出,让产物混合物经30分钟冷却到24℃。将冷却的产物混合物用二氯甲烷(300mL)稀释。将稀释的混合物转移到已装有饱和碳酸氢钠水溶液(400mL)的分液漏斗中。分离所形成的层。将含水层用二氯甲烷(3×500mL)萃取。合并有机层,将合并的有机层经硫酸钠干燥。将干燥的溶液过滤,浓缩滤液得到浅黄色粘稠油状未纯化的环化产物9。1H NMR分析(400MHz,CDCl3)表明向环化产物9的转化率>95%。将如此获得的产物直接用于下一步。通过快速柱色谱法(用5%乙酸乙酯-己烷洗脱)得到了环化产物9的分析纯样品:
Rf=0.23(5%乙酸乙酯-己烷,KMnO4)。1H NMR(500MHz,CDCl3),δ7.64(d,1H,J=9.0Hz,H1,7.51(dd,2H,J=7.0,1.5Hz,H11),7.39-7.29(m,3H,H11),6.74(d,1H,J=8.5Hz,H2),3.91(s,3H,H3),3.14(dd,1H,7=18.0,4.5Hz,H4),2.95-2.92(m,1H,H5),2.82-2.77(m,2H,H4/H8),2.15(dd,1H,J=13.5,10.0Hz,H8),1.85-1.78(m,1H,H7),1.32(dd,1H,J=10.0,6.5Hz,H6),0.75(d,3H,J=6.5Hz,H9),0.40(s,3H,H10),0.37(s,3H,H10)。13C NMR(125MHz,CDCl3),δ206.0(C),164.1(C),149.5(C),138.5(CH),136.9(C),134.1(CH),129.8(CH),128.3(CH),125.1(C),119.2(C),111.0(CH),53.9(CH3),52.4(CH2),49.9(C),44.9(CH),42.4(CH2),38.1(CH),28.2(CH),21.8(CH3),-3.4(CH3),-3.8(CH3)。IR(ATR-FTIR),cm-1:2955(br),2268(w),1736(s),1713(w),1599(m),1576(w),1476(s),1424(m),1321(m),1264(m),1130(m),1112(m),1028(m),824(s),737(w),704(m)。HRMS-CI(m/z):[M+H]+C23H27N2O2Si计算值391.1837;实测值391.1839。
步骤2c:环化产物9的烯化(烯烃10):
在充满氮气的干燥箱中,向500mL圆底烧瓶中依次加入溴化乙基三苯基磷鎓(7.38g,19.9mmol,1.20当量)和六甲基二硅基胺基锂(3.33g,19.9mmol,1.20当量)。将烧瓶用橡胶隔垫密封,然后将密封的烧瓶从干燥箱中取出。将醚(200mL)通过注射器加入到烧瓶中。将所得的橙色悬浮液在24℃搅拌1h。在此期间,固体溶解形成了澄清的橙色溶液。在单独的烧瓶中,制备了未纯化的环化产物9(16.6mmol,1.00当量,假设在前一步骤中为定量收率)的醚(1.5L)溶液。在24℃下,将橙色的叶立德溶液通过插管经10分钟转移到装有环化产物9的烧瓶。将反应混合物在24℃搅拌12h。将产物混合物倒入已装有蒸馏水(500mL)和乙酸乙酯(500mL)的分液漏斗中。分离所形成的层。将含水层用乙酸乙酯(2×500mL)萃取。合并有机层,将合并的有机层经硫酸钠干燥。将干燥的溶液过滤,浓缩滤液。将所得的残余物通过快速柱色谱法纯化(用5%乙酸乙酯-己烷洗脱)得到浅黄色粘稠油状烯化产物10(4.74g,从7中71%,E/Z非对映体的5:1混合物)。
Rf=0.20(5%乙酸乙酯-己烷,KMnO4)。1H NMR(400MHz,CDCl3,非对映体的5:1混合物):E-烯烃(主要非对映体),δ7.69(d,1H,J=8.4Hz,H1),7.54-7.48(m,2H,H11),7.39-7.34(m,3H,H11),6.64(d,1H,J=8.8Hz,H2),5.95(q,1H,J=6.8Hz,H12),3.90(s,3H,H3),3.37-3.34(m,1H,H5),2.86(dd,1H,J=17.6,4.8Hz,H4),2.60-2.55(m,1H,H4),2.50(dd,1H,J=12.4,6.0Hz,H8),1.79-1.68(m,2H,H7/H8),1.72(d,3H,J=6.8Hz,H13),0.77(dd,1H,J=8.8,5.6Hz,H6),0.63(d,3H,J=6.8Hz,H9),0.37(s,3H,H10),0.36(s,3H,H10);Z-烯烃(次要非对映体),δ7.78(d,1H,J=8.8Hz,H1),7.54-7.48(m,2H,H11),7.39-7.34(m,3H,H11),6.67(d,1H,J=8.8Hz,H2),5.60(q,1H,J=7.6Hz,H12),3.91(s,3H,H3),2.94(dd,1H,J=17.6,4.8Hz,H4),2.75-2.70(m,1H,H5),2.62-2.46(m,2H,H4/H8,2.02(d,3H,J=8Hz,H13),1.79-1.68(m,2H,H7/H8),0.67-0.60(m,1H,H6),0.62(d,3H,J=6Hz,H9),0.36(s,3H,H10),0.33(s,3H,H10)。13C NMR(100MHz,CDCl3,非对映体的5:1混合物):E-烯烃(主要非对映体),δ163.3(C),151.9(C),138.3(C),137.9(CH),134.2(C),134.0(CH),129.4(CH),128.1(CH),127.4(C),122.7(C),118.2(CH),109.5(CH),53.7(CH3),50.4(CH2),44.4(C),42.2(CH2),34.7(CH),30.7(C),27.7(CH),22.3(CH3),12.7(CH3),-2.9(CH3),-3.3(CH3);Z-烯烃(次要非对映体),δ163.3(C),152.3(C),138.4(C),138.0(CH),134.0(CH),132.7(C),129.3(CH),128.0(CH),127.2(C),124.6(C),120,6(CH),109.6(CH),53.8(CH3),51.1(CH2),43.3(CH2),41.9(CH),39.7(C),34.7(CH),27.9(CH),22.0(CH3),12.8(CH3),-3.0(CH3),-3.5(CH3)。IR(ATR-FTIR),cm-1:2952(br),1598(m),1578(w),1476(s),1426(m),1320(m),1264(m),1112(w),1031(w),824(m),733(w),702(w)。HRMS-CI(m/z):[M+H]+C25H31N2OSi计算值403.2201;实测值403.2198。
通过NOE分析(500MHz,CDCl3)表明次要非对映体具有Z-构型。参见图3。
步骤3a-d:烯化产物10向(-)-石杉碱甲(1)的转化:
步骤3a:烯化产物10的玉尾-弗莱明氧化(醇11):
在0℃下,将三氟甲磺酸(2.29mL,26.0mmol,2.20当量)通过注射器经5分钟逐滴加入到烯化产物10(4.74g,11.8mmol,1.0当量)的二氯甲烷(59mL)搅拌溶液中。将反应混合物经10分钟温热至24℃。将反应混合物在24℃搅拌1h。减压蒸发掉溶剂。将所得的残余物溶于N,N-二甲基甲酰胺(94mL)。然后按顺序将碳酸钾(4.89g,35.4mmol,3.00当量)和蒸馏水(47mL)加入。将所得的乳状溶液在24℃下搅拌15分钟。将四丁基氟化铵的四氢呋喃溶液(1.0M,177mL,177mmol,15.0当量)加入,将所得的混合物在24℃搅拌1h。然后将过氧化氢的水溶液(35%,30.4mL,354mmol,30.0当量)快速加入,将所得的混合物温热至40℃。将反应混合物在40℃下搅拌并加热12h。将产物混合物经10分钟冷却到24℃。将冷却的产物混合物转移到已装有蒸馏水(300mL)和50%乙酸乙酯-己烷(v/v,500mL)的分液漏斗中。分离所形成的层。将有机层依次用水(5×300mL)和饱和氯化钠水溶液(2×300mL)洗涤。将洗涤的有机层经硫酸钠干燥。将干燥的溶液过滤,浓缩滤液得到浅黄色固体状未纯化的醇11(3.35g)。1H NMR分析(400MHz,CDCl3)表明向醇11的转化率>95%。将如此获得的产物直接用于下一步。
通过快速柱色谱法(用50%乙酸乙酯-己烷洗脱)得到了醇11的分析纯样品:
Rf=0.30(50%乙酸乙酯-己烷,KMnO4)。1H NMR(500MHz,CDCl3,非对映体的5:1混合物);E-烯烃(主要非对映体),δ7.69(d,1H,J=8.5Hz,H1),6.64(d,1H,J=8.5Hz,H2),6.12(q,1H,J=6.5Hz,H10),3.89(s,3H,H3),3.54(dd,1H,J=6.0,3.5Hz,H6),3.29-3.27(m,1H,H5),3.10(dd,1H,J=18.5,6.5Hz,H4),2.99(d,1H,J=17.5Hz,H4),2.59(dd,1H,J=13.5,7.0Hz,H8),1.79(d,3H,J=7.0Hz,H11),1.87-1.76(m,2H,H7/H8),0.71(d,3H,7.5Hz,H9);Z-烯烃(次要非对映体),δ7.78(d,1H,J-8.5Hz,H1),6.67(d,1H,J=8.5Hz,H2),5.65(q,1H,J=7.5Hz,H10),3.90(s,3H,H3),3.43(dd,1H,J=5.5,3.5Hz,H6),3.17(dd,1H,J=18.0,7.0Hz,H4),2.94(d,1H,J=18.0Hz,H4),2.70(dd,1H,J=13.5,7.5Hz,H8),2.62-2.60(m,1H,H5),2.07(d,3H,J=7.0Hz,H11),1.87-1.76(m,2H,H7/H8),0.68(d,3H,J=7.5Hz,H9)。13C NMR(125MHz,CDCl3,非对映体的5:1混合物);E-烯烃(主要非对映体),δ163.5(C),152.3(C),137.7(CH),131.5(C),126.4(C),122.0(C),120.4(CH),109.7(CH),78.4(CH),53.8(CH3),44.7(CH2),44.5(C),39.1(CH),37.9(CH2),34.2(CH),17.9(CH3),12.8(CH3);Z-烯烃(次要非对映体),δ163.5(C),152.6(C),137.5(CH),129.8(C),126.0(C),122.8(CH),122.0(C),109.7(CH),77.9(CH),53.8(CH3),49.3(CH),45.5(CH2),44.5(C),37.9(CH2),34.2(CH),17.9(CH3),12.8(CH3)。IR(ATR-FTIR),cm-1:3431(br),2925(br),1598(m),1577(w),1476(s),1422(m),1323(m),1267(m),1033(m),828(w),658(w)。HRMS-CI(m/z):[M+H]+C17H21N2O2计算值285.1598;实测值285.1597。
步骤3b:玉尾-弗莱明氧化产物11的脱水(烯烃16):
向连接到涂覆有特氟龙的阀门的100mL圆底烧瓶中依次加入未纯化的玉尾-弗莱明氧化产物11(11.8mmol,1.00当量,假设在前一步骤中为定量收率)和N-(三乙基铵磺酰基)氨基甲酸甲酯12(3.09g,13.0mmol,1.10当量)。将苯(10mL)加入,然后将所得的溶液在24℃搅拌15分钟。将溶液浓缩至干,将所得的残余物溶于甲苯(59mL)。将反应容器密封,然后将密封的容器置于已预热到110℃的油浴中。将反应混合物在110℃下搅拌并加热12h。将产物混合物经30分钟冷却到24℃。将冷却的产物混合物用乙酸乙酯(200mL)稀释,将稀释的溶液转移到已装有饱和碳酸氢钠水溶液(200mL)的分液漏斗。分离所形成的层。将含水层用乙酸乙酯(200mL)萃取。合并有机层,将合并的有机层经硫酸钠干燥。将干燥后的溶液过滤,浓缩滤液得到了灰白色固体状烯烃16(3.19g)。1H NMR分析(400MHz,CDCl3)表明向烯烃16的转化率>95%。将如此获得的产物直接用于下一步。通过快速柱色谱法(用10%乙酸乙酯-己烷洗脱)得到了烯烃16的分析纯样品:
Rf=0.32(10%乙酸乙酯-己烷,KMnO4)。1H NMR(400MHz,CDCl3,非对映体的5:1混合物):E-烯烃(主要非对映体),δ7.70(d,1H,J=8.8Hz,H1),6.63(d,1H,J=8.8Hz,H2),5.95(q,1H,J=6.8Hz,H9),5.48(m,1H,H6),3.89(s,3H,H3),3.62(m,1H,H5),2.98(dd,1H,J=17.2,5.2Hz,H4),2.88-2.80(m,2H,H4/H7),2.38(d,1H,J=16.8Hz,H7),1.76(d,3H,J=6.8Hz,H10),1.55(s,3H,H8);Z-烯烃(次要非对映体),δ7.78(d,1H,J=8.4Hz,H1),6.66(d,1H,J=8.4Hz,H2),5.65(q,1H,J=7.2Hz,H9),5.46(d,1H,J=4.8Hz,H6),3.89(s,3H,H3),3.10-2.77(m,4H,2x H4/H5/H7),2.38(d,1H,J=16.8Hz,H7),2.06(d,3H,J=7.6Hz,H10),1.54(s,3H,H8)。13C NMR(100MHz,CDCl3,非对映体的5:1混合物):E-烯烃(主要非对映体),δ163.5(C),152.9(C),137.7(CH),132.3(C),130.7(C),125.2(CH),124.8(C),121.7(C),116.7(CH),109.2(CH),53.7(CH3),47.5(CH2),44.6(C),39.8(CH2),31.6(CH),22.6(CH3),12.7(CH3);Z-烯烃(次要非对映体),δ163.5(C),153.2(C),137.7(CH),130.9(C),130.2(C),126.3(CH),124.6(C),121.7(C),119.0(CH),109.3(CH),53.7(CH3),48.3(CH2),42.1(CH),40.7(CH2),40.1(C),22.5(CH3),12.3(CH3)。IR(ATR-FTIR),cm-1:2934(br),1598(m),1576(w),1476(s),1421(m),1323(m),1268(m),1028(w),826(w)。HRMS-CI(m/z):[M+H]+C17H19N2O计算值267.1492;实测值267.1492。
步骤3c:腈16的水解(酰胺14):
在24℃下,将氢化(羟基二甲基膦)[氢双(羟基二甲基膦)]铂(II)(13,101mg,240μmol,0.02当量)加入到未纯化的腈16(11.8mmol,1.00当量,假设在前一步骤中为定量收率)的乙醇(6.6mL)和水(3.3mL)的溶液中。将所得的混合物置于已预热到95℃的油浴中。将反应混合物在95℃下搅拌并加热24h。将产物混合物经10分钟冷却到24℃。将冷却的混合物浓缩至干燥。将所得的残余物溶于二氯甲烷(15mL)和氯仿(15mL),将所得的溶液经硫酸钠垫过滤。将滤液浓缩得到了灰白色固体状酰胺14(3.60g)。1H NMR分析(400MHz,CDCl3)表明向酰胺14的转化率>95%。将如此获得的产物直接用于下一步。通过快速柱色谱法(用50%乙酸乙酯-己烷洗脱)得到了酰胺14的分析纯样品:
Rf=0.20(50%乙酸乙酯-己烷,KMnO4)。1H NMR(500MHz,CDCl3,非对映体的5:1混合物):E-烯烃(主要非对映体),δ7.33(d,1H,J=8.5Hz,H1),6.57(d,1H,J-8.5Hz,H2),5.62(br s,1H,H11),5.40(q,1H,J=7.0Hz,H9),5.38-5.35(m,1H,H6),5.17(br s,1H,H11),3.90(s,3H,H3),3.60(m,1H,H5),3.09-3.01(m,2H,H4/H7),2.88(d,1H,J=16.5Hz,H4),2.11(d,1H,J=17.5Hz,H7),1.70(d,3H,J=7.0Hz,H10),1.53(s,3H,H8);Z-烯烃(次要非对映体),δ7.37(d,1H,J=8.4Hz,H1),6.58(d,1H,J=8.4Hz,H2),5.58(br s,1H,H11),5.54(q,1H,J=16.5Hz,H9),5.38-5.35(m,1H,H6),5.30(br s,1H,H11),3.90(s,3H,H3),3.15-3.01(m,3H,H4/H5/H7),2.83(d,1H,J=16.5Hz,H4),2.18(d,1H,J=17.0Hz,H7),1.73(d,3H,J=7.5Hz,H10),1.53(s,3H,H8);13CNMR(125MHz,CDCl3,非对映体的5:1混合物):E-烯烃(主要非对映体),δ176.9(C),162.9(C),153.8(C),138.9(CH),138.1(C),133.7(C),128.5(C),124.1(CH),115.3(CH),108.9(CH),54.4(C),53.7(CH3),45.3(CH2),39.8(CH2),33.0(CH),23.0(CH3),13.0(CH3);Z-烯烃(次要非对映体),δ178.4(C),162.9(C),153.1(C),138.5(CH),137.1(C),133.6(C),128.3(C),125.9(CH),117.5(CH),109.2(CH),53.7(CH3),51.2(C),45.1(CH2),44.2(CH),39.7(CH2),23.0(CH3),13.0(CH3)。IR(ATR-FTIR),cm-1:HRMS-CI(m/z):3346(br),2926(br),1710(w),1664(s),1597(m),1576(w),1475(s),1422(m),1322(m),1267(w),1028(m),824(w)。[M+H]+C17H21N2O2计算值285.1598;实测值285.1601。
步骤3d:酰胺14转化成(-)-石杉碱甲(1):
将[双(三氟乙酰氧基)碘]苯(5.58g,13.0mmol,1.10当量)加入到未纯化的酰胺14(11.8mmol,1.00当量,假设在前一步骤中为定量收率)的甲醇(240mL)搅拌溶液中。将所得的混合物加热到回流(浴温=65℃)。将反应混合物在65℃下搅拌并加热2h。将产物混合物经30分钟冷却到24℃。将冷却的混合物浓缩至干燥。将所得的残余物溶于氯仿(120mL)。将三甲基碘硅烷(8.40mL,59.0mmol,5.00当量)加入,将反应混合物加热到回流(浴温=61℃)。将反应混合物在61℃下搅拌并加热3h。然后将混合物经30分钟冷却到24℃。将甲醇(120mL)加入,将所得的混合物加热至回流(浴温=65℃)。将反应混合物在65℃下搅拌并加热12h。然后将产物混合物经30分钟冷却至24℃。将冷却的产物混合物浓缩至干燥。将所得的残余物溶于50%二氯甲烷-氯仿(v/v,200mL)。将所得的溶液转移到已装有1.0N硫酸水溶液(200mL)的分液漏斗。分离所形成的层。然后将含水层用50%二氯甲烷-氯仿(v/v,2×200mL)萃取。合并有机层并丢弃。将含水层用饱和氢氧化铵水溶液碱化(100mL,最终pH=12-13)。将碱化的含水层用50%二氯甲烷-氯仿(v/v,4×200mL)萃取。合并有机层,将合并的有机层经硫酸钠干燥。将干燥的溶液过滤,浓缩滤液。将所得的残余物通过快速柱色谱法(用10%甲醇-乙酸乙酯洗脱)得到了(-)-石杉碱甲(1,1.61g,56%,灰白色固体)和烯烃异构体(异石杉碱甲,17,310mg,11%,灰白色固体)。
合成的(-)-石杉碱甲(1)在所有方面[1H NMR、13C NMR、LC/MS保留时间、IR、TLC溶剂体系(10%甲醇-乙酸乙酯、5%甲醇-二氯甲烷、5%甲醇-二氯甲烷+1%氢氧化铵)和旋光度]均与真实样品相同。
(-)-石杉碱甲(1):Rf=0.15(10%甲醇-乙酸乙酯,KMnO4)。tR=0.91。[α]20 n-144(c0.23,CHCl3),文献[α]20 n=-150(c 0.12,CHCl3)。10 1H NMR(500MHz,CDCl3),δ13.25(br s,1H,H3),7.88(d,1H,9.5Hz,H1,6.37(d,1H,J=9.0Hz,H2),5.46(q,1H,J=6.5Hz,H9),5.38(d,1H,J=4.5Hz,H6),3.59-3.55(m,1H,H5),2.86(dd,1H,J=17.0,5.0,H4),2.73(dd,1H,J=16.5,1.0Hz,H4),2.12(app s,2H,H7),1.88(br s,2H,H11),1.64d,3H,J=6.5Hz,H10),1.51(s,3H,H8).13C NMR(125MHz,CDCl3),δ165.5(C),143.3(C),142.4(C),140.3(CH),134.1(C),124.4(CH),122.8(C),117.1(CH),111.4(CH),54.4(C),49.2(CH2),35.4(CH2),33.0(CH),22.7(CH3),12.5(CH3)。IR(ATR-FTIR),cm-1:3355(br),1644(s),1608(s),1552(m),1452(m),1121(m),837(m)。HRMS-CI(m/z):[M+H]+C15H19N2O计算值243.1492;实测值243.1493。
异石杉碱甲(17):Rf=0.15(5%甲醇-二氯甲烷+1%氢氧化铵,KMnO4)。[α]20 n=-121(c0.01,CHCl3)。1H NMR(400MHz,CDCl3),δ13.10(br s,1H,H3),7.86(d,1H,7=9.6Hz,H1),6.42(d,1H,J=9.6Hz,H2),5.41(q,1H,J=7.2Hz,H9),5.37(br s,1H,H6),3.00-2.88(m,2H,H4/H5),2.70(d,1H,J=16.0Hz,H4),2.40(d,1H,J=16.8,H7),2.05(d,1H,H7),1.93(d,3H,J=7.2Hz,H10),1.90(brs,2H,H11),1.53(s,3H,H8)。13C NMR(100MHz,CDCl3),δ165.5(C),143.4(C),140.2(C),140.0(CH),133.7(C),125.4(CH),123.0(C),117.3(CH),115.7(CH),56.6(C),49.8(CH2),44.0(CH),36.4(CH2),22.6(CH3),14.0(CH3)。IR(ATR-FTIR),cm-1:3380(br),2909(br),1653(s),1611(m),1551(m),1459(m),833(m),755(m),651(m)。HRMS-CI(m/z):[M+H]+C15H19N2O计算值243.1492;实测值243.1494。
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Claims (4)
1.一种式(I)的化合物:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H、取代或未取代的C1-C6烷基和CN,前提条件是当R2或R5之一为CN时,另一者必须为H;
X为卤素;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R4选自Si(CH3)2Ph、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的芳基和取代或未取代的杂芳基;
A为C、N或S;
m为0、1或2;
n为0或1;
或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
2.根据权利要求1所述的化合物或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物,其中所述化合物为:
3.一种式(II)的化合物:
其中:
R1选自取代或未取代的C1-C6烷基和取代或未取代的醚;
R2和R5独立地选自H和取代或未取代的C1-C6烷基;
R3在每次出现时独立地选自H、取代或未取代的C1-C6烷基、醚、氨基和烷氧基;
R4选自H、OH和Si(CH3)2Ph;
R6选自NH2、酰胺、CN、羧酸衍生物、醇或醛;
R7为取代或未取代的C1-C6烷基、酯或取代或未取代的芳基;
A为C、N或S;并且
n为0或1;
或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物。
4.根据权利要求3所述的化合物或其药学上可接受的盐、对映体、非对映体、溶剂化物或多晶型物,其中所述化合物选自:
其中R1和R2各自独立地为H或C1-C6烷基;
及其其中CN转化成了CH2NR1R2基团的伯胺衍生物,其中R1和R2各自独立地为H或C1-C6烷基;以及
及其其中CN转化成了CH2NR1R2基团的伯胺衍生物,其中R1和R2各自独立地为H或C1-C6烷基。
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