CN1832927A - 新型γ-分泌酶抑制剂 - Google Patents
新型γ-分泌酶抑制剂 Download PDFInfo
- Publication number
- CN1832927A CN1832927A CNA2004800224543A CN200480022454A CN1832927A CN 1832927 A CN1832927 A CN 1832927A CN A2004800224543 A CNA2004800224543 A CN A2004800224543A CN 200480022454 A CN200480022454 A CN 200480022454A CN 1832927 A CN1832927 A CN 1832927A
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- Prior art keywords
- compound
- alkyl
- milliliters
- halogen
- yuan
- Prior art date
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- Granted
Links
- 239000003540 gamma secretase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 230000002265 prevention Effects 0.000 claims abstract description 5
- -1 substituent hydrocarbon Chemical class 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 208000014644 Brain disease Diseases 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000003412 degenerative effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 11
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 abstract description 7
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 abstract description 7
- 238000012545 processing Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 23
- 238000005406 washing Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 235000017168 chlorine Nutrition 0.000 description 17
- 239000000376 reactant Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 150000001299 aldehydes Chemical class 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 15
- 229920002554 vinyl polymer Polymers 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000000284 extract Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000012266 salt solution Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 150000004714 phosphonium salts Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 229910052710 silicon Inorganic materials 0.000 description 5
- 239000010703 silicon Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 4
- 102000014303 Amyloid beta-Protein Precursor Human genes 0.000 description 4
- 108010079054 Amyloid beta-Protein Precursor Proteins 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
- OFJBYLCQNJHFMI-UHFFFAOYSA-N 2,5-dihydro-1,2-oxazole Chemical compound C1ONC=C1 OFJBYLCQNJHFMI-UHFFFAOYSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 3
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- HFXSTBAHFYOVNK-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-methylpyridine Chemical compound C1=NC(C)=CC(C=2C=CC(F)=CC=2)=C1 HFXSTBAHFYOVNK-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- TUFBSQIBZRBVHQ-UHFFFAOYSA-N 5-(4-fluorophenyl)-1,3-oxazole-2-carbaldehyde Chemical compound C1=CC(F)=CC=C1C1=CN=C(C=O)O1 TUFBSQIBZRBVHQ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- PRFHZCFQTBBULM-UHFFFAOYSA-N FC1=CC=C(C=C1)C=1C=C(CC(C(=O)O)(C1)C)C(=O)O Chemical compound FC1=CC=C(C=C1)C=1C=C(CC(C(=O)O)(C1)C)C(=O)O PRFHZCFQTBBULM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000006933 amyloid-beta aggregation Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
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- 239000002552 dosage form Substances 0.000 description 2
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 150000005171 halobenzenes Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
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- 239000012442 inert solvent Substances 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
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- 239000011630 iodine Substances 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 238000001228 spectrum Methods 0.000 description 2
- GLBQVJGBPFPMMV-UHFFFAOYSA-N sulfilimine Chemical compound S=N GLBQVJGBPFPMMV-UHFFFAOYSA-N 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- PHBVXHIVWULVNF-UHFFFAOYSA-N (4-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(F)C=C1 PHBVXHIVWULVNF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Abstract
式(I)化合物:抑制γ-分泌酶对APP的切割,并因此有助于治疗或预防阿尔茨海默病。
Description
本发明涉及一类新型化合物、其盐、包含它们的药用组合物、其制备方法及其在人体治疗方面的应用。本发明尤其涉及抑制γ-分泌酶对APP的加工作用的新型磺酰胺(sulphonamide)和硫酰胺(sulphamide)衍生物,因此有利于治疗或预防阿耳茨海默病(Alzheimer′s disease)。
阿尔茨海默病(AD)是最常见的痴呆病症。尽管主要是一种老年病,65岁以上的老人患病率高达10%,但同时一部分遗传性易患病体质的年轻患者亦会发病。该病为一种神经变性疾病,临床特征为进行性记忆力衰退和认知障碍,病理特征为患者大脑相关区域及大脑皮层细胞外蛋白斑块沉积。这些斑块主要包含β-淀粉样肽(Aβ)的纤维状沉积。包括公认的γ-分泌酶的分泌酶,在将淀粉蛋白前体(APP)加工形成Aβ中的作用在相关文献已有详细记载及综述,例如WO01/70677。
文献中有关基于细胞分析检测抑制γ-分泌酶活性的化合物的相关报道很少。这在WO 01/70677中已有综述。相关化合物多数为肽或肽衍生物。
WO 01/70677和WO 02/36555分别公开了磺酰氨基(sulphonamido-)和硫酰氨基(sulphamido-)取代的桥连二环烷基衍生物,这些衍生物被认为有益于阿尔茨海默病的治疗,但未公开或谈及与本发明一致的化合物。
本发明提供了一类新型的桥连二环烷基磺酰胺和硫酰胺衍生物,这类化合物显示出特别强烈地抑制公认的γ-分泌酶对APP的加工作用,从而有益于阿尔茨海默病(AD)的治疗及预防。
依照本发明提供了式I化合物
或其药学上可接受的盐。
其中n为0或1;
X使5元或6元杂芳环形成,所述杂芳环带有取代基Ar,并且当n为1时,还带有取代基R5;
R5代表任选被至多3个卤素原子取代的1-5个碳原子的烃基;
Ar代表苯基或6元杂芳基,每一个都带有0-3个独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基的取代基;
Y代表连接键或NR3;
R1代表H,或者当Y代表NR3时,R1和R3可一起代表-CH2-;
R2代表任选被至多3个卤素原子取代的1-10个碳原子的烃基,或代表任选带有至多3个取代基的具5或6个环原子的杂芳基,所述取代基独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基;或当Y代表NR3时,R2和R3一起可使任选带有至多3个取代基的至多6元的杂环形成,所述取代基独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基;
R3代表H或C1-4烷基,或与R1一起代表-CH2-,或与R2一起使如上所定义的杂环形成;并且,
R4代表卤素或C1-4烷基。
在式I中,基团R4及包含X和Ar的乙烯部分连接在环双键的两端,对于本领域技术人员来说显而易见的是,式I化合物存在两种对映异构形式,如下式1a和式1b所示:
其中X、Y、Ar和R1-R4的含义同前。
需强调的是,本发明中与式I一致的每个化合物包含两种对映异构形式,或为纯手性化合物或为以任意比例混合的对映异构体的混合物。
除非另有说明,式I或取代基中变量出现不止一次的,所述变量的每次出现为相互独立的。
本文所用的表述“烃基”是指仅由碳原子和氢原子组成的基团。这样的基团可包含与所指明的最大碳原子数相符的单独的或任意组合的直链、支链或环状结构,并在指明的最大碳原子数许可的情况下,其可以是饱和的或不饱和的,包括芳香的。
本文所用的表述“C1-x烷基”,指的是其中x为大于1的整数的直链和支链烷基基团,其中结构碳原子总数在1-x之间。特别的烷基基团为甲基、乙基、正丙基、异丙基和叔丁基。引伸出的表述如“C2-6烯基”、“羟基C1-6烷基”、“杂芳基C1-6烷基”、“C2-6炔基”和“C1-6烷氧基”依照类似方式解释。这类基团中最合适的碳原子数不超过6。
本文所用的表述“C3-6环烷基”是指包含3至6个环原子的非芳香单环烃环体系。实例包括环丙基、环丁基、环戊基、环己基和环己烯基。
本文所用的表述“环烷基烷基”包括如环丙基甲基、环丁基甲基、环戊基甲基和环己基甲基。
本文所用的术语“卤素”包括氟、氯、溴和碘,其中优选氟和氯。
就医药用途而言,式I化合物可以是其药学上可接受的盐。而其他盐亦可以用来制备式I化合物或其药学上可接受的盐。本发明化合物的合适的药学上可接受的盐包括酸加成盐,其可由如下方法形成,比如将本发明化合物的溶液与药学上可接受的酸溶液混合,如盐酸、硫酸、甲磺酸、苯磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸或磷酸。或者,本发明的化合物带有酸性部分的,可用合适的碱中和所述的酸性部分形成其药学上可接受的盐。这样形成的药学上可接受的盐的实例包括碱金属盐如钠盐或钾盐;铵盐;碱土金属盐如钙盐或镁盐;以及与合适的有机碱形成的盐如胺盐(包括吡啶鎓盐)和季铵盐。
本发明的化合物具有至少一个不对称中心的,相应地可以对映异构体存在。本发明的化合物具有两个或更多的不对称中心的,则另外还可以非对映异构体存在。不言而喻,所有的这类异构体以及以任何比例混合的混合物都包括在本发明范围内。
式I化合物中,X使5元或6元的带有Ar取代基的杂芳环形成,并任选基团R5为取代基。除了式1所示的氮原子外,X使之形成的五元环优选包含至少一个杂原子,选自O、N和S。合适的五元环包括吡唑、噁唑、异噁唑、噻唑、异噻唑、咪唑、三唑、噁唑和噻二唑,其中优选吡唑、噁唑、噻唑、咪唑和1,2,4-三唑。合适的6元环包括吡啶、嘧啶和吡嗪,其中优选吡啶。
任选取代基R5是包含1-5个碳原子的烃基,其任选被至多3个卤素原子取代,并可包含环状或开链烃残基或其组合结构,饱和或不饱和,总共至多包含5个碳原子。R5代表的烃基优选未取代或被至多3个氟原子取代,实例包括甲基、乙基、正-丙基、异丙基、正-丁基、仲-丁基、叔-丁基、氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、环丙基、环丙甲基和稀丙基。优选甲基、乙基和2,2,2-三氟乙基。最优选的R5代表甲基。若化合价条件许可,R5可接在环碳原子或环氮原子上,包括式I所示的氮原子上,但并非优选。
Ar代表苯基或6元杂芳环,两者都带有0-3个独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基的取代基。Ar代表的合适的6元杂芳基的实例包括吡啶基、吡嗪基、嘧啶基、哒嗪基和三嗪基,优选吡啶基。优选的苯基或杂芳基环带有0-2个取代基。优选的取代基包括卤素(尤其氯和氟)、CN、C1-6烷基(尤其甲基)、C1-6烷氧基(尤其甲氧基)、OCF3和CF3。若存在2个或多个取代基,优选非卤素或烷基的取代基数不超过一个。Ar代表的基团包括苯基、单卤苯基、双卤苯基、三卤苯基、氰基苯基、甲基苯基、甲氧基苯基、三氟甲基苯基、三氟甲氧基苯基、吡啶基、单卤吡啶基和三氟甲基吡啶基,其中“卤素”指氟或氯。合适的Ar基团特定价包括2-氟苯基、2-氯苯基、3-氟苯基、4-氟苯基、4-氯苯基、2,4-二氟苯基、2,4-二氯苯基、3,4-二氟苯基、3,4-二氯苯基、3-氯-4-氟苯基、3,4,5-三氟苯基、4-氰基苯基、4-甲基苯基、4-甲氧基苯基、2-(三氟甲基)苯基、4-(三氟甲基)苯基、4-(三氟甲氧基)苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、吡嗪-2-基、5-甲基吡啶-2-基、5-氟吡啶-2-基、5-氯吡啶-2-基、5-(三氟甲基)吡啶-2-基和6-(三氟甲基)吡啶-3-基。优选的实例包括2-氟苯基、2-氯苯基、3-氟苯基、4-氟苯基、4-氯苯基、2,4-二氟苯基、2,4-二氯苯基、3,4-二氟苯基、3,4-二氯苯基、3-氯-4-氟苯基、4-(三氟甲基)苯基、吡啶-2-基、吡啶-3-基和吡啶-4-基。
在特别优选实施方案中,Ar代表4-氟苯基。
Ar可连接在环碳原子或环氮原子上,优选在将由X使之形成的环与其余分子相连的双键的1,3位。
由X使之形成的杂芳基的优选实例包括5-芳基-1-甲基吡唑-3-基、5-芳基噁唑-2-基、4-芳基吡啶-2-基、1-芳基咪唑-4-基和1-芳基-[1,2,4]三唑-3-基,其中“芳基”指具有上述定义及优选的实例(identity)的Ar基团。特别优选的实例为5-(4-氟苯基)-1-甲基吡唑-3-基。
R4代表卤素(尤其指氯、溴或碘)或C1-4烷基如甲基、乙基、异丙基、正丙基或正丁基。优选的R4代表氯或甲基。在一个特定实施方案中,R4代表氯。
Y代表连接键或NR3。Y代表NR3时,R3任选与R1结合形成-CH2-基团。否则,R1为H。R1与R3以此种方式结合后,结果是式II的螺-联环硫酰胺:
其中n、X、R2、R4、R5和Ar的定义及优选的实例同前。
R2代表上文定义的任选取代的烃基。R2代表的合适的烃基包括烷基、环烷基、环烷基烷基、烯基、苯基和苄基基团,其任选带有至多3个卤素取代基,优选的卤素取代基为氟或氯,尤其是氟。所述烷基、环烷基、环烷基烷基和烯基基团典型地含有至多6个碳原子。R2所代表的烃基和氟代烃基的实例包括4-氟苯基、苄基、正丙基、2,2-二甲基丙基、正-丁基、异丙基、叔-丁基、2,2,2-三氟乙基、3,3,3-三氟丙基、烯丙基、2-甲基丙烯-3-基、环丙基、环丁基、环戊基和环丙基甲基。
R2代表的杂芳基为5元或6元的,任选被上文定义的取代基取代。优选的5元杂芳基包括含有硫原子的基团,如噻吩基、噻唑基和异噻唑基。优选的6元杂芳基包括吡啶基,特别是3-吡啶基。优选的取代基包括卤素(尤其是氯或氟)、CF3和烷基(如甲基)。若存在2个或多个取代基,优选非卤素或烷基的取代基数不超过一个。优选的杂芳基为未取代的或卤素单取代。
当R2代表任选取代的苯基或杂芳基,Y优选为连接键。
当Y代表NR3,R2可与R3结合使任选被前述取代基取代的至多6元的杂环形成。除使R2和R3互相连接的氮原子外,所述环优选包含至多一个选自O、N和S的杂原子。合适的环包括氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基和硫代吗啉基。优选的取代基包括CF3、卤素(尤其为氯或氟)和烷基如甲基。若存在2个或多个取代基,优选非卤素或烷基的取代基数不超过一个。
R3可选性代表H或C1-4烷基如甲基。优选的R3代表H或者与R2或R1使环形成。
式I化合物的一个子集中,Y为连接键,R2为任选带有至多3个氟或氯取代基的含至多6个碳原子的烃,或为5元或6元杂芳基,任选被如前述取代。在该子集中,合适的R2基团包括甲基、正丁基、4-氟苯基、2-噻吩基、5-氯-2-噻吩基、5-异噻唑基和6-氯-3-吡啶基。优选的R2实例为6-氯-3-吡啶基。
式I化合物的第二个子集中,Y为NH,R2代表任选被至多3个氟原子取代的含至多6个碳原子的烷基、烯基、环烷基或环烷基烷基。在该子集中,R2基团的优选实例包括正丙基、正丁基、2-甲基丙烯-3-基、环丁基和2,2,2-三氟乙基。
式I化合物的第三个子集中,Y代表NR3,R2与R3使如上所述的杂环形成,尤其为吡咯烷环。
式I化合物的第四个子集如前式II所定义,其中R2代表任选被至多3个氟原子取代的含至多6个碳原子的烷基、烯基、环烷基或环烷基烷基。在该子集中,合适的R2实例包括正丙基、2,2-二甲基丙基、正丁基、异丙基、叔丁基、2,2,2-三氟乙基、3,3,3-三氟丙基、烯丙基、环丁基和环丙基甲基,尤其是烯丙基、环丙基甲基、正丙基、正丁基、环丁基和2,2,2-三氟乙基。
与本发明一致的各个化合物将在随后的实施例部分阐述。
本发明的化合物具有作为γ-分泌酶抑制剂的活性。
本发明还提供了含有一个或多个本发明化合物以及药学上可接受载体的药用组合物。这些组合物优选以单位剂量形式存在,如片剂、丸剂、胶囊剂、散剂、颗粒剂、肠胃外无菌溶液或混悬剂、定量气雾剂或液体喷雾剂、滴剂、安瓿剂、透皮贴剂、自动注射器装置或栓剂;口服、肠胃外、鼻内、舌下或直肠给药,还有吸入剂或吹入剂。典型地,主要活性成分与药用载体,如传统的片剂成分例如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁和磷酸二钙;或树胶、分散剂、悬浮剂或表面活性剂如脱水山梨聚糖单油酸酯、聚乙二醇,和其他的药用稀释液如水等混合形成含有本发明化合物或其药学上可接受的盐的均相的剂型确定前组合物。当所指的剂型确定前组合物为均相时,意味着所述活性成分为均匀分布在组合物中,所以该组合物可容易地细分成含相等有效单位剂量的片剂、丸剂和胶囊剂。这些剂型确定前组合物随后被细分成上述剂型,本发明的活性成分含量从0.1克至约500毫克。典型单位剂型中活性成分含量从1毫克至100毫克,如1、2、5、10、25、50或100毫克。新型组合物的片剂或丸剂可被包衣或另外配制以提供具长效优点的剂型。例如,片剂或丸剂可包含内部剂量成分和外部剂量成分,外部剂量成分包住内部成分。这两种成分被肠溶层隔离,以抵抗药物在胃部的分解,确保内部有效成分完整地到达十二指肠或延迟释放。用来做肠衣或包衣的材料很多,这类材料包括许多聚合酸,或聚合酸与诸如虫胶、十六烷基醇、乙酸纤维素酯的混和物。
本发明新型组合物的液体剂型可口服或注射给药,包括水溶液、液体-或凝胶填充胶囊、适当矫味的糖浆、水或油混悬剂以及由棉花籽油、芝麻油、椰子油或花生油等食用油制成的矫味乳剂,以及酏剂和类似的药用剂型。合适的水混悬剂的分散剂或悬浮剂包括合成树胶和天然树胶,如黄芪胶、阿拉伯树胶、藻酸盐、右旋糖酐、羧甲基纤维素钠、甲基纤维素、聚(乙二醇)、聚(乙烯吡咯烷酮)或明胶。
本发明还提供用于人体治疗方法的本发明化合物或其药学上可接受的盐。优选用于治疗β-淀粉样沉积相关的病症。优选用于治疗与β-淀粉样沉积有关的神经系统疾病如阿尔茨海默病。
本发明进一步提供了本发明的化合物或其药学上可接受的盐在生产治疗或预防阿尔茨海默病的药物中的用途。
还公开了治疗患或易患阿尔茨海默病的患者的方法,该方法包含给予患者有效量的本发明的化合物或其药学上可接受的盐。
用于治疗或预防阿尔茨海默病的合适剂量水平为约每日0.01-250毫克/每公斤(体重),优选约每日0.01-100毫克/每公斤(体重),更优选约每日0.05-50毫克/每公斤(体重),最优选约每日0.1-10毫克/每公斤(体重)。该化合物可分每日1至4次服用。而在某些情况下,也可超量使用。
为清楚起见,本发明化合物的合成路线以提供式1a化合物示例,但对于本领域技术人员来说显而易见地的是,除非实施步骤对其中一种纯手性的中间体进行分离后用于后续的合成方案外,所述方法实际上提供的是化合物式1a和式1b的外消旋混和物。。
式II化合物可采用WO 02/36555中公开的类似的方法制备。而优选路线涉及胺R2NH2与式(1a)氮丙啶的反应。
其中n、X、R2、R4、R5和Ar的含义同前。该反应可在封管、100℃下的二甲基亚砜中进行。
或者,式II化合物可由式(1b)氮丙啶先后用胺R2NH2、NH2SO2NH2处理制得。式(1b)与胺的反应可在碘化锌存在下在回流二氯甲烷中进行,所得的二元胺可与硫酰胺在回流吡啶中反应。
氮丙啶(1a)可通过酮(2)与Me2NSO2NH2缩合,并且使所得的硫亚胺(sulfilimine)与碘化三甲基氧化锍反应制得。
其中n、X、R4、R5和Ar的含义同前。缩合可以在Ti(OEt)4存在下,在回流THF中进行,而生成氮丙啶(1)的反应是在室温、氢化钠存在下,在DMSO中进行。
氮丙啶(1b)可依据同样的方法用tBuSONH2来取代Me2NSO2NH2制得。
R1为H的式I化合物可通过R2-Y-SO2Cl与式(3)的胺反应制得。
其中R2、Y、n、X、R4、R5和Ar的含义同前。反应可在碱如三乙胺存在下在惰性溶剂如二氯甲烷中进行。或者,当Y代表NR3时,胺(3)可依次用儿茶酚硫酸酯和R2R3NH,以WO 02/36555中所述的方法处理。
胺(3)的制备可按上述方法将酮(2)与tBuSONH2缩合,随后所得的亚磺酰亚胺(sulfinimide)用硼氢化钠(如在0℃的甲醇溶液中)还原,继而水解所得的亚磺酰胺(sulfinamide)(在0℃用二噁烷与甲醇中的HCl处理)。
酮(2)可通过醛(4)与膦鎓盐(5)在强碱存在下反应,随后水解环状缩酮基团制得:
其中Hal代表卤素(优选氯、溴或碘),n、X、Ar、R4和R5的含义同前。反应可在0℃、在正BuLi存在下在诸如THF的惰性溶剂中进行。环状缩酮的水解可在60℃下,在THF中与稀盐酸进行作用。
R4为氯的醛(4)可通过酮(6)与POCl3和二甲基甲酰胺(DMF)的反应制得:
典型地,POCl3和二甲基甲酰胺(DMF)先在0℃的二氯甲烷溶液中预反应,然后在同一溶液中与酮回流。
R4为C1-4烷基的式(4)醛可通过相应氯化物(4)(R4=Cl)与适当的烷基铜衍生物在THF、-78℃条件下发生反应制得。烷基铜试剂可由相应烷基锂与碘化铜在0℃条件下预反应就地制得。
如本文所包括的实施例中所述,酮(6)可以通过如下途径从二环[4,2,1]壬-3-烯-9-酮(7)制得:(i)形成环状缩酮,(ii)硼氢化,以及(iii)氧化所得环烷醇。
化合物式II的另一种合成方案涉及膦鎓盐(5)和醛(8)的反应:
其中R2和R4的含义同前。该反应在与(5)与(4)的相同反应条件下发生。化合物(8)可通过如下途径从化合物(7)制得:依照前文所述将酮(2)转化为式II化合物的方式,将其酮基进行加工,随后依照前文所述(7)转化至(4)的方法,进行硼氢化、氧化以及用POCl3和二甲基甲酰胺(DMF)处理。
膦鎓盐(5)可通过卤化物(9)(a)与Ph3P的反应制得。如,在回流二甲苯中,卤化物(9)(a)可用常规途径制得.在该途径中,醇类(9)(b)可在室温下、二氯甲烷中用亚硫酰氯处理。醇类(9)(b)可通过还原醛(10)制得,如在乙醇中采用硼氢化钠进行还原:
其中n、X、Hal、R5和Ar的含义同前。醛(10)可通过杂环合成的常规方法制得,见实施例部分所述。卤化物(9)(a)的另一种制备方法涉及甲基衍生物(9)(Z为H)的溴化。
可以领会的是,通过反应可得到不止一种异构体,所得的异构体混合物可用常规方法进行分离。
上述制备本发明化合物的方法产生了立体异构体混合物的,这些异构体可采用如制备色谱法等常规方法分离。所述新型化合物可以外消旋形式制备或可通过对映专一性合成或通过拆分制得其单一对映异构体。所述新型化合物,例如,可采用标准方法,如手性高效液相色谱法拆分成它们的组份对映异构体;或通过与光学活性的酸,如二-对-甲苯酰-D-酒石酸和/或二-对-甲苯酰-L-酒石酸成盐以形成非对映异构体对,再进行分步结晶后再生为游离碱。所述新型化合物还可通过形成非对映异构的酯或酰胺,然后通过色谱分离并除去手性助剂进行拆分。或者,可以用此类技术外消旋合成目标化合物的前体。
上述合成方案所用的起始原料和试剂市场上买不到的,可采用常规方法制得。
在上述合成反应中,有必要和/或需要保护任何相关分子上的敏感基或活性基。可用常规保护基团进行,如J.F.W.McOmie PlenumPress,1973所著的Protective Groups In Organic Chemistry,和T.W.Greene & P.G.M.Wuts(John Wiley & Sons,1999)所著的ProtectiveGroups In Organic Chemistry书中所述的保护基团达到上述目的。可依照本领域中已知的方法在之后方便的阶段除去保护基团。作为本方案中的一个实施例,其益处在于:用对-甲氧苄基氯将化合物(8)及其前体中的硫酰胺NH基团烷基化,然后在其余合成步骤完成后除去对-甲氧苄基保护基团(例如用三氟醋酸处理)。
可用WO 01/70677中所述的试验确定本发明化合物的活性水平。优选WO 03/093252中所述的试验。
可选测定方法见Biochemistry 2000,39(30),8698-8704。
以及Neuroscience Methods 2000,102,61-68。
由上述试验测定的本发明化合物显示出意想不到的高亲和力。因此下列实施例的ED50均硝于100nM,典型的小于10nM,并且在上述试验中至少有一个通常小于1nM。一般而言,该化合物还显示出良好的口服生物利用度和/或脑渗透性,并且大多没有可能导致毒副作用的不良生物交互作用。
如下实施例详细阐述了本发明。
实施例
中间体A
步骤1
5-(4-氟苯基)-1-甲基-1H-吡唑-3-甲醛二甲缩醛
在-78℃下,向二异丙基氨基锂溶液(1.8M在THF中,160毫升,0.29mol)中逐滴加入在THF(150毫升)中的4-氟苯乙酮(17.6毫升,0.145mol)。反应物在-78℃下搅拌1小时,然后加入在THF(150毫升)中的二甲氧基醋酸甲酯(17.7毫升,0.145mol)。将反应物温热至25℃并搅拌16小时。在真空下除去溶剂,将残留物放入EtOH(250毫升)中,加入乙酸(17毫升,0.3mol),再加入甲肼(8毫升),将反应物加热回流2小时。在真空下除去乙醇,残留物用二氯甲烷(×3)萃取,有机层用盐水洗涤,经硫酸镁干燥并浓缩。残留物经硅胶进行层析,用50%的乙酸乙酯/己烷洗脱得到标题化合物(极性较大的异构体)及其异构体(极性较小的异构体)。
9g 1H NMR(360,CDCl3)δ7.38(m,2H),7.14(m,2H),6.34(s,1H),5.48(s,1H),3.85(s,3H),3.43(s,6H).
步骤2
5-(4-氟苯基)-1-甲基-1H-吡唑-3-甲醛
步骤1所得的化合物(9克)用三氟乙酸(30毫升)和水(30毫升)处理。在真空下除去三氟乙酸,反应混合物在乙酸乙酯和饱和碳酸氢钠中分配。有机层用饱和碳酸氢钠(×2)、盐水洗涤,并用硫酸镁干燥。在真空下除去溶剂,得到黄色油状物,从乙酸乙酯/己烷结晶,得到标题化合物。
4.6g 1H NMR(360,CDCl3)δ9.97(s,1H),7.38(m,2H),7.20(m,2H),6.80(s,1H),3.95(s,3H).
步骤3
[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]-甲基三苯基氯化鏻
将步骤2所得的醛(2.3克,11mmol)溶于乙醇中并加入硼氢化钠(0.832克,22mmol),反应物在25℃条件下搅拌1小时。用氯化铵溶液猝灭反应物,在真空下除去乙醇,将水相提取入乙酸乙酯(2X),用盐水洗涤,浓缩得到黄色油状物。将粗制醇溶解于二氯甲烷(20毫升)中,加入亚硫酰氯(1.6毫升,22mmol),所得反应物在25℃搅拌1小时。加入水,用二氯甲烷(2X)萃取产物,经硫酸镁干燥,浓缩,与甲苯共沸,得到固体。将固体溶于二甲苯(50毫升)中,加入三苯基膦(2.62克,10mmol),将反应物加热回流16小时。将生成的固体滤出,并用二甲苯洗涤。将滤液再加热回流16小时,将生成的固体滤出,并用二甲苯洗涤。合并固体得到2.15克标题化合物。
1H NMR(360,CDCl3)δ7.84(m,6H),7.7(m,3H),7.64(m,6H),7.22(m,2H),7.07(m,2H),6.38(d,J=1.7Hz,1H),5.50(d,J=13.84,2H),3.65(s,3H).
中间体B
步骤1
5-(4-氟苯基)-1,3-噁唑-2-甲醛
-78℃下,将正BuLi(1.6M己烷中,3.45毫升,5.53mmol)逐滴地加入到5-(4-氟苯基)-1,3-噁唑(0.82克,5.03mmol)的THF(10毫升)的搅拌溶液中(Organic Letters(2001),(3)2,271-273)。混合物在-78℃下搅拌30分钟,然后用DMF(0.43毫升,5.53mmol)猝灭。将混合物逐渐温热至室温,再搅拌30分钟,用Et2O(30毫升)稀释,然后用1N的HCl中和。分离出有机层,用盐水(20毫升)洗涤,用硫酸镁干燥,真空浓缩。在硅胶上进行色谱纯化,用DCM洗脱,得5-(4-氟苯基)-1,3-噁唑-2-甲醛(0.58克,60%):
δH(360MHz,CDCl3)7.18(2H,t,J8.6),7.58(1H,s),7.77-7.81(2H,m),9.76(1H,s);m/z(ES+)192(MH+)。
步骤2
[5-(4-氟苯基)-1,3-噁唑-2-基]甲醇
将NaBH4(138毫克,3.6mmol)加入5-(4-氟苯基)-1,3-噁唑-2-甲醛(0.58克,3.03mmol)的甲醇(10毫升)溶液中。混合物在室温下搅拌2小时,然后倾入水(50毫升)中,用DCM(30毫升)萃取,用盐水(20毫升)洗涤,用硫酸镁干燥,真空浓缩得到460毫克(79%)标题化合物:
δH(360MHz,CDCl3)2.57(1H,m),4.79(2H,d,J5.5)7.12(2H,t,J8.5),7.24(1H,s),7.60-7.64(2H,m);m/z(ES+)194(MH+).
步骤3
[5-(4-氟苯基)-1,3-噁唑-2-基]-甲基三苯基氯化鏻
将[5-(4-氟苯基)-1,3-噁唑-2-基]甲醇(0.46克,2.4mmol)溶于DCM(5毫升)中,然后加入Et3N(0.3毫升,2.4mmol)和SOCl2(0.35毫升,4.7mmol)。反应混合物在氮气下于室温搅拌1小时。用DCM(20毫升)稀释混合物,然后小心地加入Na2CO3饱和溶液(20毫升)。分离有机层,用盐水(20毫升)洗涤,用硫酸镁干燥,在真空下浓缩,得到黄色油状物。如中间体A(步骤3)中所述,用等摩尔的三苯基膦处理该油状物(0.5克,2.38mmol),得到标题化合物。
δH(360MHz,DMSO)5.76(2H,d,J16.0),7.29(2H,t,J 7.0),7.39-7.46(2H,m),7.61(1H,s),7.74-7.95(15H,m).
中间体C
步骤1
4-(4-氟苯基)-2-甲基吡啶
在DME(150毫升)和2M Na2CO3(94毫升)中的4-氯-2-甲基吡啶(10克,79mmol)和(4-氟苯基)硼酸(13.2克,94mmol)的混合物先用氮气流脱气5分钟,加入Pd(PPh3)4(1.8克,2mol%)后回流过夜。将反应混合物冷却至室温,用乙酸乙酯(30毫升)稀释,用4N NaOH(40毫升)洗涤,再用盐水(50毫升)洗涤。用硫酸镁干燥有机层,真空浓缩,在硅胶上进行色谱纯化,用30-50%的乙酸乙酯/己烷梯度洗脱,得到9.0克标题化合物(61%):
δH(360MHz,CDCl3)2.62(3H,s),7.16(2H,t,J8.5),7.27(1H,d,J5.0),7.33(1H,s),7.58-7.62(2H,m),8.53(1H,d,J5.0);m/z(ES+)188(MH+).
步骤2
[4-(4-氟苯基)吡啶-2-基]甲基三苯基溴化鏻
将4-(4-氟苯基)-2-甲基吡啶(0.4克,2.1mmol)溶于苯(15毫升)中,然后加入NBS(570毫升,3.2mmol)和过氧化苯甲酰(52毫克,10mol%),所得混合物在150w灯泡照射下回流。1小时后,加入另外的570毫克NBS。再过1小时后,减压蒸发溶剂,残留物在硅胶上色谱纯化,用30%乙酸乙酯/己烷洗脱,得57毫克标题化合物,如中间体A中所述,用等摩尔的三苯基膦处理该化合物得标题化合物;m/z(ES+)448(M+)。
实施例1
[9-内(endo)]2′,3′,4′,5′-四氢-5′-(2,2,2-三氟乙基)螺(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯]-9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
步骤1
[9-内]2′,3′,4′,5′-四氢-5′-(2,2,2-三氟乙基)螺(二环[4.2.1]壬-3-烯)-9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
a)将二环[4.2.1]壬-3-烯-9-酮(60克,0.44mol,依照Synthesls1976,453制备)、叔-丁基亚磺酰胺(sulphinamide)(58.7克,0.485mol)、乙醇钛(IV)(184.8毫升,0.88mol)和无水四氢呋喃(900毫升)在氮气下加热回流4小时。将反应物冷却至室温,真空浓缩,倾入盐水(1.8升)/乙酸乙酯(54毫升)并剧烈搅拌1小时。用Hi-flo过滤混合物,用乙酸乙酯洗涤数次,各相分离。用硫酸镁干燥有机层并浓缩。
b)在氮气下,将碘化三甲基氧化锍(151.3克,0.69mol)溶于无水DMSO(660毫升),分批加入氢化钠(60%油分散液,27.5克,0.678mol)。搅拌反应物直至氢气停止放出,然后加入在DMSO的溶液中的(a)油状物,所得混合物在25℃搅拌2小时。将反应混合物倾入水(1.1升)和乙醚(1.1升)中。分离各相,用乙醚(2×550毫升)萃取水层。合并的有机层用盐水洗涤,经硫酸镁干燥,真空浓缩。
c)将(b)所得的油状物(128.4克,0.507mol)溶于无水二氯甲烷(770毫升)中,并加入三氟乙胺(251克,2.5mol)和碘化锌(161.7克,0.507mol)。将反应物加热回流并搅拌16小时,然后冷却,用碳酸氢钠稀释,用二氯甲烷萃取产物。有机层经硫酸镁干燥并浓缩。残留物经硅胶色谱纯化,用7%的MeOH/NH3(2N)/CH2Cl2洗脱,得到纯的产物。
d)将(c)所得的油状物(28.5克,0.115mol)溶于吡啶(171毫升)中,加入硫酰胺(12.1克,0.126mol)。将反应物加热回流3.5小时。真空除去溶剂,残留物在盐酸(2.5M,280毫升)和乙酸乙酯(280毫升)中分配。用乙酸乙酯(2×280毫升)萃取水层,合并有机物,用盐酸(2.5M,280毫升)和盐水洗涤,硫酸镁干燥。真空除去溶剂,残留物经乙酸乙酯/异己烷重结晶,得到膏状固体。
19.6g,1H NMR(500MHz,DMSO)δ4.52(m,2H),3.99(m,2H),2.5(s,2H),2.36(d,J=18Hz,2H),2.27(brs,2H),1.89(d,J=26Hz,2H),1.35(m,2H).
步骤2
[9-内]2′,3′,4′,5′-四氢-2′-(4-甲氧苄基)-5′-(2,2,2-三氟乙基)螺(二环[4.2.1]壬-3-烯)9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
将步骤1所得产物(6.6克,0.021mol)溶于丙酮(100毫升)中,加入碳酸钾(4.3克,0.031mol),再加入碘化四-正-丁基铵(0.760克,2.05mol)和对-甲氧苄基氯(6.4克,0.041mol)。在25℃、氮气下搅拌反应物36小时,过滤,并真空浓缩滤液。残留物经乙酸乙酯/己烷重结晶,得到白色固体(碘化四-正-丁基铵)。浓缩母液,残留物经乙酸乙酯/己烷处理,得到固体标题化合物。
5.65g 1H NMR(500MHz,CDCl3)δ7.25(d,2H),6.85(d,2H),5.59(d,2H),4.58(2H,2H),3.78(s,3H),3.71(m,2H),3.39(s,2H),2.47(m,4H),2.16(m,2H),1.88(m,2H),1.50(m,2H).
步骤3
[9-内]2′,3′,4′,5′-四氢-2′-(4-甲氧苄基)-5′-(2,2,2-三氟乙基)螺(3-羟基二环[4.2.1]壬-3-烯)9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
将步骤2所得产物(5.65克,0.013mol)溶于无水THF中,冷却至0℃,逐滴加入硼烷(1M的THF溶液,26毫升,0.026mol)。将反应物温热至25℃,然后加热回流2小时。将烧瓶再次冷却至0℃,逐滴加入NaOH(4M,19.5毫升,0.078mol),再加入过氧化氢(35%w/w,7.6毫升,0.078mol)。反应物在25℃搅拌16小时。反应混合物在水和乙酸乙酯中分配。有机层用水和盐水洗涤,经硫酸镁干燥,蒸发溶剂。残留油状物经硅胶层析,用50%-60%的乙酸乙酯/己烷洗脱,得到无色油状标题化合物(差向异构体混合物)。
4.6g 1H NMR(500MHz,CDCl3)δ7.35-7.40(m),6.87-6.89(m),4.43-4.48(m),4.30(m),4.09-4.14(m),3.79(s),3.69-3.81(m),3.41-3.43(m),3.23-3.32(m),2.66(m),2.54(m),2.04-2.43(m),1.33-2.0(m).
步骤4
[9-内]2′,3′,4′,5′-四氢-2′-(4-甲氧苄基)-5′-(2,2,2-三氟乙基)螺(3-氧代二环[4.2.1]壬-3-烯)9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
将步骤3所得产物(4.6克,0.01mol)溶于二氯甲烷(200毫升)中,加入分子筛(4,2.5克)、N-甲基吗啉N-氧化物(1.8克,0.015mol)和过钌酸四丙铵(tetrapropylammonium perruthenate)(0.151克,0.042mol)。反应混合物在氮气下搅拌1.5小时,用乙酸乙酯稀释,经硅垫过滤,再用乙酸乙酯洗涤。浓缩滤液,残留物经硅层析,用40%-50%的乙酸乙酯/己烷洗脱,得到油状标题化合物,静置结晶。
4.0g 1H NMR(500MHz,CDCl3)δ7.24(d,2H),6.87(d,2H),4.39(s,2H),3.79(s,3H),3.71-3.74(m,2H),3.38(dd,2H),3.16(dd,1H),2.71(m,1H),2.62(dt,1H),2.50(m,2H),2.35(dd,1H),2.32(m,1H),2.04(m,1H),1.92(m,2H),1.77(m,1H),1.62(m,1H).
步骤5
[9-内]2′,3′,4′,5′-四氢-2′-(4-甲氧苄基)-5′-(2,2,2-三氟乙基)螺(3-氯-4-甲酰基二环[4.2.1]壬-3-烯)9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
在氮气下,向干燥烧瓶中加入二氯甲烷(5毫升)和二甲基甲酰胺(0.9毫升,0.671mol),将烧瓶冷却至0℃。逐滴加入磷酰氯(0.9毫升,0.671mol),将反应物温热至25℃并搅拌15分钟。将步骤4所得产物(1.0克,0.224mol)的二氯甲烷(20毫升)溶液加入反应混合物中。将烧瓶加热至60℃,持续2小时,然后冷却至0℃,加入水(20毫升)。搅拌反应混合物10分钟,倾入乙酸乙酯中。收集有机层,用饱和碳酸氢钠溶液、盐水洗涤,经硫酸镁干燥。蒸发有机层,得到油状标题化合物与其区域异构体(regioisomer)。0.95克(各异构体的比例为4∶1,所需的异构体占优)
1H NMR(500MHz,CDCl3)δ10.17(s),9.69(s),7.25(d),7.06(d),6.83-6.88(m),4.38-4.55(m),3.86(d),3.78(2Xs),3.71(m),3.56(m),3.33-3.43(m),3.15(m),2.95(m),2.45-2.8(m),2.35(d),1.9-2.1(m),1.8(m),1.7(m),1.4(m).
步骤6
[9-内]2′,3′,4′,5′-四氢-2′-(4-甲氧基苄基)-5′-(2,2,2-三氟乙基)螺(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯]9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
将中间体A(0.100克,0.2mmol)的THF悬浮液冷却至0℃,并用正-丁基锂(2.5M己烷溶液,0.08毫升,0.188mol)处理,所得橙色溶液在0℃下搅拌15分钟。将步骤5所得的氯-乙醛(0.092克,0.188mmol)的THF(1毫升)溶液加入内鎓盐中,所得溶液在0℃下再搅拌20分钟。用饱和氯化铵溶液和乙酸乙酯稀释反应混合物。收集有机层,并用盐水洗涤,经硫酸镁干燥,并真空浓缩。残留物经硅色谱纯化,用20%-50%的乙酸乙酯/己烷洗脱,得到油状标题化合物。
0.040g 1H NMR(360MHz,CDCl3)δ7.38-7.46(m,3H),7.37(m,2H),7.15(t,2H),6.87(d,2H),6.57(d,1H),6.46(s,1H),4.49(s,2H),3.84(s,3H),3.78(s,3H),3.72(m,2H),3.34(m,3H),2.58-2.81(m,3H),1.54-1.89(m,3H).MS(m/z)665(M+H).
步骤7
步骤6所得产物(0.04克,0.006mmol)用三氟乙酸(3毫升)处理,所得混合物在25℃条件下搅拌2小时。并真空浓缩反应混合物,残留物用乙酸乙酯和饱和碳酸氢钠溶液分配。收集有机层,并盐水洗涤,经硫酸镁干燥,蒸发。残留物经硅色谱纯化,用50%-70%的乙酸乙酯/己烷洗脱,得到产物的白色固体。
0.012g 1HNMR(500MHz,CDCl3)δ7.45(d,J=15Hz,1H),7.39(m,2H),7.16(m,2H),6.62(d,J=15Hz,1H),6.47(s,1H),4.59(s,1H),3.84(s,3H),3.64-3.67(m,2H),3.39(dd,J=20Hz,5Hz,2H),3.15(d,J=18Hz,1H),2.68-2.79(ddd,J=10Hz,18Hz,24Hz,2H),2.56(m,1H),2.48(m,1H),2.37(m,1H),1.87(m,2H),1.72(m,1H),1.6(m,1H).MS(m/z)585(M+H).
实施例2
[9-内]2′,3′,4′,5′-四氢-5′-(2,2,2-三氟乙基)螺[3-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}-4-甲基二环[4.2.1]壬-3-烯]-9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
步骤1
[9-内]2′,3′,4′,5′-四氢-2′-(4-甲氧苄基)-5′-(2,2,2-三氟乙基)螺(4-甲基-3-甲酰基二环[4.2.1]壬-3-烯)9,3′-[1,2,5]噻二唑-1′,1′-二氧化物)
在0℃下,将甲基锂(1.6M乙醚,9毫升,14mmol)加入碘化铜(1.33克,7mmol)的THF(5毫升)悬浮液中。所得反应物在0℃下搅拌10分钟,快速升温至10℃,再冷却至-78℃。加入实施例1步骤5的产物(2.46克,5mmol)的THF(10毫升)溶液,反应物在-78℃下搅拌1小时。反应用氯化铵溶液猝灭,用乙酸乙酯萃取产物。有机层经硫酸镁干燥,蒸发。所得残留物经硅色谱纯化,用20%的乙酸乙酯/己烷洗脱,得到标题化合物。
0.409g 1H NMR(500MHz,CDCl3)δ10.10(s,1H),7.27(d,2H),6.85(d,2H),4.44(dd,J=25Hz,15Hz,2H),3.76(s,3H),3.7(m,2H),3.35(dd,J=45Hz,10Hz,2H),3.24(d,J=15Hz,1H),3.02(dd,J=15Hz,5Hz,1H),2.75(t,1H),2.52(t,1H),2.23(m,4H),1.85(m,1H),1.69(m,1H),1.46(m,1H),1.32(m,1H).
步骤2
依照实施例1步骤6、7处理步骤1所得产物(0.409克,0.9mmol),得到标题化合物(0.055克)。
1H NMR(500MHz,CDCl3)δ7.39(m,2H),7.25(d,2H),7.15(m,2H),6.47(d,1H),6.38(s,1H),4.52(s,1H),3.82(s,3H),3.63(m,2H),3.38(m,2H),2.65-2.75(m,2H),23-2.5(m,3H),2.18(m,2H),1.94(s,3H),1.8(m,2H).MS(m/z)525(M+H).
实施例3
[9-内]2′,3′,4′,5′-四氢-5′-(2,2,2-三氟乙基)螺(3-氯-4-{(E)-2-[5-(4-氟苯基)-1,3-噁唑-2-基]乙烯基}二环[4.2.1]壬-3-烯]-9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
依照实施例1的方法,使用步骤6的中间体B,制备得到。
δH(400MHz,CDCl3):1.73(1H,m),1.93(2H,m),2.39(1H,m),2.53(1H,m),2.61(1H,m),2.69(1H,m),2.73(1H,m),2.79(1H,m),3.18(1H,m),3.42(2H,q,J6.0),3.65-3.69(2H,m),4.54(1H,s),6,47(1H,d,J 16.5),7.13(2H,t,J 8.5),7.34(1H,s),7.63-7.67(2H,m),7.92(1H,d,J 16.5);m/z(ES+)532(MH+).
实施例4
[9-内]2′,3′,4′,5′-四氢-5′-(2,2,2-三氟乙基)螺(3-氯-4-{(E)-2-[4-(4-氟苯基)吡啶-2-基]乙烯基}二环[4.2.1]壬-3-烯]-9,3′-[1,2,5]噻二唑-1′,1′-二氧化物
依照实施例1的方法,用步骤6的中间体C,制备得到。
δH(500MHz,CDCl3):1.75(1H,m),1.91(3H,m),2.39(1H,m),2.52(1H,m),2.62-2.68(1H,m),2.73-2.87(2H,m),3.14-3.20(1H,m),3.39-3.45(2H,m),3.63-3.69(2H,m),4.52(1H,s),6.76(1H,d,J 18.0),7.19(2H,t,J 8.5),7.30-7.32(1H,m),7.51(1H,s),7.60-7.65(2H,m),8.02(1H,d,J 18.0),8.61(1H,d,J 5.5);m/z(ES+)542(MH+).
实施例5
N-(-3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-基)-N-丙基硫酰胺
步骤1
螺[二环[4.2.1]壬-3-烯-9,2′-[1,3]二氧戊环]
将甲苯(250毫升)中的二环[4.2.1]壬-3-烯-9-酮(10克,73mmol)、乙二醇(12.3毫升,220mmol)和对-甲苯磺酸一水合物(100毫克)的混合物放入Dean-Stark设备中回流4小时。将反应混合物冷却至室温,依次用水(3×50毫升)、盐水(100毫升)洗涤。有机萃取物经硫酸镁干燥,并真空浓缩,得到螺[二环[4.2.1]壬-3-烯-9,2′-[1,3]二氧戊环](13.12克,99.5%)。
步骤2
3-{(E)-2-[4-氯螺[二环[4.2.1]壬-3-烯-9,2′-[1,3]二氧戊环]-3-基]乙烯基}-5-(4-氟苯基)-1-甲基-1H-吡唑
步骤1的产物用类似于实施例1步骤3-6的方法制备得到。
δH(400MHz,CDCl3)1.31-1.66(2H,m),1.81-1.96(2H,m),2.04-2.08(1H,m),2.15-2.19(1H,m),2.53-2.59(2H,m),2.65-2.71(1H,m),3.12(1H,d,J17.0),3.83(3H,s),3.96-3.99(4H,m),6.48(1H,s),6.62(1H,d,J 16.5),7.13-7.18(2H,m),7.37-7.42(2H,m),7.48(1H,d,J 16.5).
步骤3
3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-酮
将2N盐酸(100毫升)和步骤2产物(18.0克,43mmol)的混合物在THF(100毫升)中于60℃搅拌2小时。用饱和碳酸氢钠使反应混合物碱化,然后用乙酸乙酯(3×200毫升)萃取。用盐水洗涤有机萃取物,经硫酸镁干燥,并真空浓缩。残留物经快速色谱纯化,用乙酸乙酯∶己烷(1∶1)洗脱,得到3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-酮(14.96克,94%)。
δH(400MHz,CDCl3)1.59-1.71(2H,m),1.76-1.83(1H,m),2.02-2.10(2H,m),2.38-2.51(2H,m),2.58-2.62(1H,m),2.87-2.90(1H,m),2.96-3.01(1H,m),3.84(3H,s),6.49(1H,s),6.64(1H,d,J16.5),7.14-7.18(2H,m),7.38-7.42(2H,m),7.54(1H,d,J 16.5).
步骤4
N((9Z)-3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-亚基)-2-甲基丙烷-2-亚磺酰胺(sulfinamide)
依次将叔-丁基亚磺酰胺(3.0,24mmol)、乙醇钛(IV)(4.6毫升,36mmol)加入步骤3所得产物(4.56克,11mmol)的无水THF(10毫升)的搅拌溶液中,所得溶液加热回流18小时。将反应物倾入盐水(200毫升)的搅拌溶液中,然后加入乙酸乙酯(100毫升),混合物经celite过滤。分配滤液,水层再用乙酸乙酯(2×50毫升)萃取。合并有机萃取物,用盐水洗涤,经硫酸镁干燥,并真空浓缩,得到N((9Z)-3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-亚基)-2-甲基丙烷-2-亚磺酰胺(5.19克,99%)。m/z(ES+)474(MH+)。所得化合物直接用于下一步骤。
步骤5
N(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-基)-2-甲基丙烷-2-亚磺酰胺
在0℃下,将硼氢化钠(0.83克,22mmol)分批加入步骤4所得产物(5.19克,11mmol)的甲醇(150毫升)搅拌溶液中。混合物在0℃下搅拌1小时,冷却至室温,继续搅拌2小时。真空浓缩反应混合物,用水稀释,并用乙酸乙酯(3×100毫升)萃取。有机萃取物经盐水洗涤,经硫酸镁干燥,真空浓缩,得N(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-基)-2-甲基丙烷-2-亚磺酰胺(5.71克,79%)。
δH(400MHz,CDCl3)1.20-1.27(9H,m),1.86-1.91(2H,m),2.40-2.50(1H,m),2.56-2.67(4H,m),3.06-3.18(1H,m),3.30-3.39(1H,m),3.67-3.77(2H,m),3.82(3H,s),6.47(1H,d,J 5.5),6.63(1H,d,J 160),7.15(2H,t,J 8.5),7.38-7.42(2H,m),7.47(1H,d,J 16.0).
步骤6
(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-基)胺
在0℃下,将盐酸(在二氧六环中,4M,50毫升)加入步骤5所得产物(5.71克,12mmol)的甲醇(100毫升)的溶液中。溶液在0℃下搅拌1小时后在室温继续搅拌1小时。反应混合物真空浓缩,用饱和碳酸氢钠稀释,并用乙酸乙酯(3×100毫升)萃取。有机萃取物经盐水洗涤,经硫酸镁干燥,并真空浓缩,经SCX柱(cartridge)(50克)用甲醇(100毫升)溶液洗脱,再用含氨的甲醇(2M,50毫升)溶液洗脱。并真空浓缩含有产物的流分,得(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-基)胺(3.76克,84%)。
δH(400MHz,CDCl3)1.33-1.61(4H,m),1.74-1.92(2H,m),2.15-2.23(1H,br),2.30-2.39(1H,br),2.54-2.69(3H,m),3.12(1H,d,J 18.0),3.34(1H,t,J 6.5),3.82(3H,s),6.47(1H,s),6.65(1H,d,J 16.5),7.15(2H,t,J 8.5),7.37-7.41(2H,m),7.47(1H,d,J 16.5)
步骤7
将步骤6所得的产物(100毫克,0.27mmol)、三乙胺(110毫克,1.1mmol)和丙基氨磺酰氯(170毫克,1.1mmol)的混合物在DCM(5毫升)中在室温下搅拌18小时。反应混合物用水(20毫升)稀释,并用乙酸乙酯(3×20毫升)萃取。有机萃取物经盐水(50毫升)洗涤,经硫酸镁干燥,并真空浓缩。残留物经快速色谱纯化,并用乙酸乙酯∶己烷(1∶4)洗脱,得N-(3-氯-4-{(E)-2-[5-(4-氟苯基)-1-甲基-1H-吡唑-3-基]乙烯基}二环[4.2.1]壬-3-烯-9-基)-N-丙基磺酰胺(98毫克,74%)。
δH(400MHz,CDCl3)0.98(3H,t,J 7.5),1.42-1.48(1H,m),1.54-1.62(4H,m),1.82-1.90(2H,m),2.38-2.62(3H,m),2.68-2.76(2H,m),2.98-3.08(3H,m),3.72-3.77(1H,m),3.82(2H,s),4.13-4.18(1H,m),4.33(1H,d,J 9.0),6.48(1H,s),6.64(1H,d,J 16.5),7.12-7.18(2H,m),7.37-7.43(2H,m),7.45(1H,d,J 16.5).
下列实施例由实施例5的方法,在最后一步采用适当的氨磺酰氯或磺酰氯制备:
实施例 | R |
6 | 环丁基氨基 |
7 | 甲基 |
8 | 正丁基氨基 |
9 | 吡咯烷-1-基 |
10 | 6-氯吡啶-3-基 |
11 | 2,2,2-三氟乙基氨基 |
12 | (2-甲基丙烯-3-基)氨基 |
13 | 4-氟苯基 |
14 | 二甲基氨基 |
15 | 2-噻吩基 |
Claims (10)
1.一种式I化合物或其药学上可接受的盐,
其中n为0或1;
X使5元或6元杂芳环形成,所述杂芳环带有取代基Ar,并且当n为1时,还带有取代基R5;
R5代表任选被至多3个卤素原子取代的1-5个碳原子的烃基;
Ar代表苯基或6元杂芳基,每一个都带有0-3个独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基的取代基;
Y代表连接键或NR3;
R1代表H,或者当Y代表NR3时,R1和R3可一起代表-CH2-;
R2代表任选被至多3个卤素原子取代的1-10个碳原子的烃基,或任选带有至多3个取代基的具5或6个环原子的杂芳基,所述取代基独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基;或当Y代表NR3时,R2和R3一起可使任选带有至多3个取代基的至多6元的杂环形成,所述取代基独立选自卤素、CF3、CHF2、CH2F、NO2、CN、OCF3、C1-6烷基和C1-6烷氧基;
R3代表H或C1-4烷基,或与R1一起代表-CH2-,或与R2一起使如上所定义的杂环形成;并且,
R4代表卤素或C1-4烷基。
2.一种式II的权利要求1的化合物或其药学上可接受的盐:
其中n、X、R2、R4、R5和Ar如权利要求1所定义。
3.权利要求1的化合物,其中Y为连接键,R2为任选带有至多3个氟或氯取代基的至多6个碳原子的烃,或为权利要求1所定义的任选取代的5元或6元杂芳基。
4.权利要求1的化合物,其中Y代表NR3,并且或者R3为H且R2代表任选被至多3个氟原子取代的至多6个碳原子的烷基、烯基、环烷基或环烷基烷基;或者R2和R3使杂环形成。
5.权利要求2的化合物,其中R2代表任选被至多3个氟原子取代的至多6个碳原子的烷基、烯基、环烷基或环烷基烷基。
6.前述权利要求中任一项的化合物,其中X使杂芳基形成,所述杂芳基选自5-芳基-1-甲基吡唑-3-基、5-芳基噁唑-2-基、4-芳基吡啶-2-基、1-芳基咪唑-4-基和1-芳基-[1,2,4]三唑-3-基,其中“芳基”指权利要求1所定义的基团Ar。
7.一种药用组合物,所述药用组合物包含前述权利要求中任一项的化合物和药学上可接受的载体。
8.权利要求1-6中任一项的化合物,该化合物用在人体治疗方法中。
9.权利要求1-6中任一项的化合物在生产治疗或预防阿耳茨海默病药物中的用途。
10.一种治疗患或易患阿耳茨海默病的受试者的方法,所述方法包括给予所述受试者有效量的权利要求1的化合物。
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