CN1277607A - 2-取代的1,2-苯并异噻唑衍生物及其作为血清素拮抗剂(5-ht1a,5-ht1b和5-ht1d)的应用 - Google Patents
2-取代的1,2-苯并异噻唑衍生物及其作为血清素拮抗剂(5-ht1a,5-ht1b和5-ht1d)的应用 Download PDFInfo
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- CN1277607A CN1277607A CN98810529A CN98810529A CN1277607A CN 1277607 A CN1277607 A CN 1277607A CN 98810529 A CN98810529 A CN 98810529A CN 98810529 A CN98810529 A CN 98810529A CN 1277607 A CN1277607 A CN 1277607A
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- China
- Prior art keywords
- alkyl
- piperazine
- chain
- piperidines
- branched
- Prior art date
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- -1 2-substituted 1,2-benzisothiazole Chemical class 0.000 title claims abstract description 8
- 239000003420 antiserotonin agent Substances 0.000 title abstract description 3
- 229940082988 antihypertensives serotonin antagonists Drugs 0.000 title abstract 2
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 title 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 title 1
- 101710138068 5-hydroxytryptamine receptor 1D Proteins 0.000 title 1
- 102100027493 5-hydroxytryptamine receptor 1D Human genes 0.000 title 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 165
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims abstract description 103
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 12
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 210
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003233 pyrroles Chemical class 0.000 claims description 4
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 3
- 208000024732 dysthymic disease Diseases 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 230000000697 serotonin reuptake Effects 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000003042 antagnostic effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 229940076279 serotonin Drugs 0.000 claims 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 abstract description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract 2
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical group FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 abstract 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 abstract 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 150000005054 naphthyridines Chemical class 0.000 description 9
- 102000007527 Autoreceptors Human genes 0.000 description 7
- 108010071131 Autoreceptors Proteins 0.000 description 7
- 239000000370 acceptor Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000001430 anti-depressive effect Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- CFNHVUGPXZUTRR-UHFFFAOYSA-N n'-propylethane-1,2-diamine Chemical compound CCCNCCN CFNHVUGPXZUTRR-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 230000003518 presynaptic effect Effects 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 2
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- JRZGPXSSNPTNMA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2C(N)CCCC2=C1 JRZGPXSSNPTNMA-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
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- VNICFCQJUVFULD-UHFFFAOYSA-N 1-(1-naphthalenyl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=CC=CC=C12 VNICFCQJUVFULD-UHFFFAOYSA-N 0.000 description 1
- GJOBEWYDAQTKDU-UHFFFAOYSA-N 1-(2,3-dihydro-1h-inden-4-yl)piperazine Chemical class C=12CCCC2=CC=CC=1N1CCNCC1 GJOBEWYDAQTKDU-UHFFFAOYSA-N 0.000 description 1
- HGYDREHWXXUUIS-UHFFFAOYSA-N 1-(naphthalen-1-ylmethyl)piperazine Chemical compound C=1C=CC2=CC=CC=C2C=1CN1CCNCC1 HGYDREHWXXUUIS-UHFFFAOYSA-N 0.000 description 1
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 1
- UQAWXKDXVXSCRD-UHFFFAOYSA-N 2-(2-chloroethyl)-3,3-diethyl-1,2-benzothiazole 1,1-dioxide Chemical compound C1=CC=C2C(CC)(CC)N(CCCl)S(=O)(=O)C2=C1 UQAWXKDXVXSCRD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- 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
- A61P25/24—Antidepressants
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- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及所示涉及式Ⅰ所示2-取代的1,2-苯并异噻唑衍生物,其中R1和R2独立地为(C1-6)烷基,R5和R6独立地为氢、(C1-6)支链或直链烷基、COPh、CO2tBu、CO-(C1-4)烷基,或者二者一起与所连氮原子形成可还含有另一个氮原子的5元或6元环(例如哌嗪),A是支链或直链(C1-10))亚烷基,或者包含至少一个选自O、S、NR7、环丙基、CHOH、双键或三键的基团Z的直链或支链(C2-10)亚烷基, B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪、和被一个亚甲基增大的相应的环状化合物,其中B是通过其中的一个氮原子与A连接的,且Ar是未取代或被下述基团取代的苯基:(C1-6)支链或直链烷基、O-(C1-6)支链或直链烷基、OH、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、氰基或苯基;或者Ar是萘满、二氢茚、未取代或被(C1-4)烷基或O-(C1-4)烷基取代的稠合芳系例如萘,或蒽或5元或6元芳香杂环,其中所述芳香杂环具有1个或2个独立地选自O和N的杂原子,并且还可以与其它可被苯基取代的芳基例如喹啉、异喹啉、2,3二氮杂萘、吲哚和喹唑啉稠合。本发明还涉及其制备以及作为血清素拮抗剂的应用。
Description
本发明涉及2-取代的1,2-苯并异噻唑衍生物、其制备以及在制备药物活性组分中的应用。
典型的抗抑郁剂、和较新的选择性血清素再摄取抑制剂(SSRIs)特别是通过抑制该递质再摄取到突触前神经末梢来发挥其抗抑郁作用的。不幸的是,在这种情况下,只有在治疗至少3周后才能开始产生抗抑郁作用,此外,大约有30%患者会对该治疗产生抵抗性。
阻滞突触前血清素自受体会通过消除负偶联而使得血清素释放增加,并因此使得突触裂中的瞬间递质浓度增加。递质浓度增加被认为是产生抗抑郁作用的主要因素。这种作用机制与以前公开的既活化突触前自受体又活化体树突自受体、并因此只有当将这些自受体失敏后才延迟产生作用的抗抑郁剂的作用机制不同。直接阻滞自受体可绕过这种延迟作用。
虽然在DE 3620643中公开的噻唑衍生物对5-HT1A受体有亲合力,但是它们没有任何5-HT1B亲和力。
依据常规知识,突触前血清素自受体是5-HT1B亚型(Fink等人,《药物文献》(Arch.Pharmacol.)352(1995),451)。5-HT1B/D拮抗剂的选择性阻滞增加血清素在大脑中的释放:G.W.Price等人,《大脑行为研究》(Behavioural Brain Research)73(1996),79-82;P.H.Hutson等人,《神经药理学》(Neuropharmacology)Vol.34,No.4(1995),383-392。
然而,令人惊讶的是,将选择性5-HT1B拮抗剂GR 127935系统给药后,血清素在皮层中的释放减少了。其中一种解释可能是,释放的血清素激活了在此缝区域的体树突5-HT1A受体,该激活受体抑制了血清素激活神经元的激动速度,并因此抑制了血清素分泌(M.Skingle等人,《神经药理学》(Neuropharmacology)Vol.34,No.4(1995),377-382,393-402)。
因此,在血清素起源区域中绕过这种自身抑制作用的一个策略的目标是阻滞突触前5-HT1B受体。下述观察支持了该假设:5-HT1B受体拮抗剂GR 127935增强了氟苯哌苯醚对大鼠背缝核中血清素释放的作用(Davidson和Stamford,《神经科学通讯》(Neuroscience Letts.),188(1995),41)。
第二个策略包括阻滞两种自受体,即阻滞5-HT1A受体以增强神经元激动,阻滞5-HT1B受体以增加末端血清素释放(Starkey和Skingle,《神经药理学》(Neuropharmacology)33(3-4)(1994),393)。
因此,单独或与5-HT1A受体拮抗剂联合使用的5-HT1B/D拮抗剂应该能使血清素在大脑中的释放显著增加,并且由此可能有助于治疗抑郁症和相关心理障碍。
其中
R1和R2独立地为(C1-6)烷基,
R3和R4独立地为氢、(C1-6)支链或直链烷基、OH、O-(C1-6)支链或直链烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、硝基、氰基、吡咯、苯基C1-4烷基,其中该苯基C1-4烷基可在其芳系上被F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、羟基、氨基、氰基或硝基取代,
R5和R6独立地为氢、(C1-6)支链或直链烷基、COPh、CO2tBu、CO-(C1-4)烷基,或者二者一起与所连氮原子形成可还含有另一个氮原子的5元或6元环(例如哌嗪),
R7是氢或(C1-6)支链或直链烷基,
A是支链或直链(C1-10)亚烷基,或者包含至少一个选自O、S、NR7、环丙基、CHOH、双键或三键的基团Z的直链或支链(C2-10)亚烷基,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪、和被一个亚甲基增大的相应的环状化合物,其中B是通过其中的一个氮原子与A连接的,且
Ar是未取代或被下述基团取代的苯基:(C1-6)支链或直链烷基、O-(C1-6)支链或直链烷基、OH、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、氰基或苯基;或者Ar是萘满(Tefralin)、二氢茚(Indan)、未取代或被(C1-4)烷基或O-(C1-4)烷基取代的稠合芳系例如萘,或蒽或5元或6元芳香杂环,其中所述芳香杂环具有1个或2个独立地选自O和N的杂原子,并且还可以与其它可被苯基取代的芳基例如喹啉、异喹啉、2,3二氮杂萘、吲哚和喹唑啉稠合。
优选的式I化合物是具有下述定义的式I化合物,其中
R1和R2独立地为甲基或乙基,
R3和R4独立地为氢、O-(C1-4)支链或直链烷基、F、Cl、Br、三氟甲基、NR5R6、硝基、氰基、和苯基,
R5和R6独立地为氢、COPh、CO2tBu、(C1-6)支链或直链烷基、和CO-(C1-4)烷基,
A是支链或直链(C2-5)亚烷基,或者包含选自CHOH、环丙基、双键或三键的基团Z的直链或支链(C2-5)亚烷基,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪、或1,4二氮杂环庚烷,其中B是通过其中的一个氮原子与A连接的,且
Ar是未取代或被下述基团取代的苯基:(C1-6)支链或直链烷基、O-(C1-6)支链或直链烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、氰基和苯基;或者Ar是萘满、二氢茚、未取代或被(C1-4)烷基或O-(C1-4)烷基取代的稠合芳系例如萘,或蒽和5元或6元芳香杂环,其中所述芳香杂环具有1个或2个独立地选自O和N的杂原子,并且还可以与其它芳基稠合。
特别优选的式I化合物是权利要求3的化合物
式II的化合物可具有一个式几个不对称中心。因此本发明不仅包括外消旋体,也包含相应的对应体和非对映异构体。本发明还包括相应的互变异构体。
式I新化合物可通过将式II化合物与式III仲胺以已知方式反应而制得,适当时可用生理可耐受酸将所得化合物转化成其加成盐,其中R1-R4和A的定义同上,Q是离去基团(例如Cl、Br、I、烷基磺酰氧基、芳基磺酰氧基),
H-B-Ar III
其中B和Ar的定义同上。式I化合物也可以通过将式IV化合物与式V化合物以已知方式反应而制得,
Q-A-B-Ar V
连接到式III化合物上。
式III化合物可这样制得:
1.将式VII化合物与式VIII化合物以已知方式连接,
W-B1 (VII)
其中B1是哌嗪或1,4二氮杂环庚烷,且W是氢或一种常用的氨基保护基(例如Boc或Cbz),
P-Ar (VIII)
其中P是B(OH)2、SnR3、OTf、Br、Cl、或I,且R是C1-C4-烷基;或
2.将式IX化合物与式X化合物连接,
W-B2-P1 (IX)
其中B2是4-四氢-1,2,3,6-吡啶,和被一个亚甲基增大的相应的环状化合物,且P1是Cl、Br、I、SnR3,其中R是C1-C4-烷基、或OTf
P-Ar (X)
其中W、P和Ar的定义同上,该反应是通过在例如下述文献中描述的已知方法进行的:
S.L.Buchwald等人,《美国化学会杂志》(J.Am.Chem.Soc.)1996,118,7215
J.F.Hartwig等人,《四面体通讯》(Tetrahedron Lett.)1995,36,3604
J.K.Stille等人,《应用化学》(Angew.Chem.)1986,98,504
S.L.Buchwald等人,《应用化学》(Angew.Chem.)1995,107,1456
J.F.Hartwig等人,《美国化学会杂志》(J.Am.Chem.Soc.)1996,118,7217
J.F.Hartwig等人,《有机化学杂志》(J.Org.Chem.)1997,62,1268
S.L.Buchwald等人,《有机化学杂志》(J.Org.Chem.)1997,62,1264及其引用的参考文献
S.L.Buchwald等人,《美国化学会杂志》(J.Am.Chem.Soc.)1997,119,6054
J.K.Stille等人,《应用化学》(Angew.Chem.)1986,98,504或
J.K.Stille等人,《有机化学杂志》(J.Org.Chem.)1990,55,3014
M.Pereyre等人,“锡在有机合成中”,Butterworth 1987;或
3.将式(XI)化合物还原成式(XII)化合物,
W-B2-Ar XI
其中B2的定义同上,
W-B3-Ar (XII)
其中B3是在1,4位连接的哌啶,和被一个亚甲基增大的相应的环状化合物;或
4.将式XIII化合物与式XIV化合物环化,以获得式XV化合物,
W-N-(C2H4Q)2(XIII)
其中W和Q的定义同上,
NH2-Ar(XIV)
其中Ar的定义同上,
W-B1-Ar(XV)
需要用作合成式I新化合物的原料的式III和V化合物是已知的,或者可通过已知方法(例如Organikum Barth Dt.Verl.der Wiss.1993或A.R.Katritzky,C.W.Rees(ed.)ComprehensiveHeterocyclic Chemistry Pergamon Press)由类似前体制得。
通过将依据1.或4.制得的式III化合物与式XVI化合物在已知条件下反应,然后去除所有保护基,可制得式V化合物,
H-B-Ar (III)
Q-A-Q’ (XVI)其中Q和Q’是离去基团。
需要用作合成式I新化合物的原料的式II、IV、VI化合物和式P-Ar、NH2-Ar、W-B1和W-B2-P1化合物是已知的,或者可由类似前体通过在文献中描述的方法制得(例如,B.Schulze,K.Illgen的《实用化学杂志》(J.Prakt.Chem.)1997,339,1或K.Auer,E.Hungerbuhler,R.W.Lang Chimia 1990,44,120或A.Yokoo等人《日本化学会通报》(Bull.Chem.Soc.Jpn.)1956,29,631或L.Borjeson等人《化学学报》(Acta Chem.Chem.)1991,45,621或Organikum Barth Dt.Verl.der Wiss.1993或A.R.Katritzky,C.W.Rees(ed.)Comprehensive Heterocyclic ChemistryPergamon Press或杂环化合物化学J.wiley & Sons Inc.NY及它们各自引用的参考文献)。
上述反应一般是在惰性溶剂中进行,例如二甲基甲酰胺、乙腈、二氯甲烷、二甲亚砜、二甲氧基乙烷、甲苯、乙酸乙酯、二甲苯、酮例如丙酮或甲基乙基甲酮、醇例如乙醇或正丙醇、环状饱和醚例如四氢呋喃或二氧杂环己烷。
反应一般在20℃-溶剂沸点温度下进行,并且通常在1-20小时内反应完全。如果需要的话,可使用酸结合剂例如碳酸钠或碳酸钾、甲醇钠、乙醇钠、氢化钠、有机金属化合物(丁基锂、烷基镁化合物)、叔丁醇钾、吡啶或三乙胺。
适当时,使用催化剂例如过渡金属及其络合物如Pd-C、Pd(PPh3)4、Pd(OAc)2、Pd(P(oTol)3)4、Pd2(dba)3或Ni(COD)2。
以常规方法分离粗产物,例如通过过滤、通过蒸馏除去溶剂、或萃取反应混合物来分离粗产物。
可通过用常规有机溶剂重结晶或通过柱色谱法来纯化式I新化合物。
本发明不仅包括游离的2-取代的1,2-苯并异噻唑衍生物,还包括式I化合物与生理可耐受酸形成的加成盐。适当的生理可耐受有机酸和无机酸的实例是盐酸、氢溴酸、磷酸、硫酸、草酸、马来酸、富马酸、乳酸、酒石酸、己二酸或苯甲酸。在“Forschritte derArzneimittelforschung”,第10卷,第224页et seq.,BirkhauserVerlag,Basel和Stuttgart,1966中描述了其它可使用的酸。
酸加成盐是以常规方法通过将游离碱与合适的酸混合,适当时在有机溶剂的溶液中混合而制得的,所述溶剂有例如低级醇如甲醇、乙醇或丙醇,醚如甲基叔丁基醚,酮例如丙酮或甲基乙基甲酮,或酯如乙酸乙酯。
本发明还涉及药物组合物,其中含有作为活性组分的式I化合物或其可药用酸加成盐和常规赋形剂以及稀释剂,还涉及式I新化合物在控制疾病中的应用。
本发明新化合物可以以常规方式给药,例如口服给药、非胃肠道给药、静脉内给药或肌内给药。给药剂量取决于患者的年龄、身体状况和体重以及给药方式。对于口服给药,活性组分的日剂量通常为约1-100mg/kg体重,对于非胃肠道给药,活性组分的日剂量通常为约0.1-10mg/kg体重。
本发明新化合物可以在常规固体或液体药物剂型中使用,例如未包衣或(薄膜)包衣片、胶囊、粉剂、粒剂、栓剂、溶液剂、软膏剂、霜剂或喷雾剂。这些剂型是以常规方法制得的。为了制成所需剂型,可将活性组分与常规药物辅料如片剂粘合剂、膨胀剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧化剂和/或推进气体进行加工处理(参见H.Sucker等人:Pharmazeutische Technologie,Thieme-Verlag,Stuttgart,1978)。以这种方式制得的给药剂型通常含有1-99%重量的活性组分。
本发明新化合物对5-HT1B、5-HT1D和5-HT1A血清素受体有高度亲和力。此外,本发明新化合物对这些受体的亲和力大约相同,至少是在相同数量级上。而且,一些本发明新化合物表现出了很好的血清素再摄取抑制作用,而血清素再摄取抑制作用是大多数抗抑郁剂实现其作用的主要途径。
这些化合物适于作为药物来治疗其中血清素浓度降低了、并且希望特异性地阻滞5-HT1B、5-HT1A和5-HT1D突触前受体活性而同时又不太影响其它受体以作为部分治疗效果的病症。这种病症的一个实例是抑郁症。
本发明化合物还适于治疗中枢神经引起的情绪失调,例如季节性情感障碍和精神抑郁症。它们还包括焦虑状态例如常规焦虑、恐慌发作、社会恐惧、强迫性神经机能病、和创伤后紧张症状、包括痴呆、遗忘症和老年记忆力损失在内的记忆紊乱、和精神性饮食障碍如神经性食欲缺乏和神经性食欲过盛。
本发明新化合物还适于治疗内分泌障碍例如乳糖过多,和治疗血管痉挛(尤其是脑血管痉挛)、高血压以及与能动性和血清素失调有关的胃肠道疾病。其它应用包括治疗性障碍。
下述实施例是为了举例说明本发明,而不是对本发明的限制。实施例13,3-二甲基-2-[3-(4-(5-萘满基)-1-哌嗪基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物制备原料
a)3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
用文献(K.Auer,E.Hungerbuhler,R.W.Lang Chimia 1990,44,120)中的已知方法制备该化合物。以类似方法制得了3,3-二乙基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点174℃)和3,3-二甲基-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点187℃)。
b)2-(3-氯丙-1-基)-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
在室温下,将3.7g(3.3mmol)叔丁醇钾加到3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物在150ml DMF内的溶液中,然后在氮气氛下将该化合物加热至80℃。迅速加入14.2g(9mmol)1-溴-3-氯丙烷,将该混合物在100℃搅拌30分钟。将混合物倒入冰水中,之后用乙醚萃取,将有机相用水洗涤,用硫酸钠干燥,然后蒸发,抽滤出所得晶体产物,获得了6.7g(82%)产物。熔点为107℃。
以类似方法制得了2-(3-氯丙-1-基)-3,3-二乙基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点70℃)、2-(3-氯丙-1-基)-3,3-二甲基-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点146℃)、2-(2-氯乙基)-3,3-二乙基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(油状物)、2-(2-氯乙基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(油状物)、2-(3-氯-2-亚甲基丙-1-基)-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点115℃)和2-(3-氯丙-1-基)-3,3-二甲基-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点146℃)。
c)1-(5-萘满基)哌嗪
将14.7g(0.1mol)5-氨基萘满与18g(0.11mol)盐酸二(β-氯乙基)胺在300ml正丁醇中回流48小时,冷却后,加入5.4g碳酸钠,将该混合物再回流20小时。将冷却时析出的沉淀抽滤出并置于水中,加入2N的氢氧化钠溶液。将水相用乙酸乙酯萃取,用水洗涤,用硫酸钠干燥,然后减压蒸发。分离到了10.7g(50%)产物,为油状物。
4-(1-哌嗪基)异喹啉
将4.51g(21.7mmol)4-溴异喹啉、4.56g(25.0mmol)哌嗪-N-甲酸叔丁酯、0.1g(0.11mmol)三(二亚苄基丙酮)二钯、0.11g(0.18mmol)2,2’-二(二苯基膦基)-1,1’-联萘和2.92g(30.4mmol)叔丁醇钠在50ml甲苯中混合,并在75℃搅拌2小时。将该反应混合物加到冰/氯化钠中,用乙酸乙酯萃取,将有机相用硫酸钠干燥,把溶剂在旋转蒸发仪中除去。将产物结晶出来,抽滤,并用戊烷洗涤。获得了5.5g(81%)Boc-保护的哌嗪(熔点111℃)。在0℃,将5.2g(16.6mmol)该产物置于17ml二氯甲烷中,缓慢地加入17ml(0.22mol)三氟乙酸。将该混合物在0℃搅拌4小时,倒入冰水中,用二氯甲烷萃取。将水相过滤、碱化,并用二氯甲烷萃取。用硫酸钠干燥,将溶剂基本上除去,然后用乙醚稀释,用乙醚合盐酸将其盐酸盐沉淀出来,获得了3.2g(67%)产物(熔点293℃)。
以与上述两种方法相类似的方法制得了下述化合物:1-(1-萘基)二氮杂环庚烷(85℃,盐酸盐)、1-(1-萘基甲基)哌嗪(油状物)、4-(1-哌嗪基)二氢茚(油状物)、1-(1-萘基)哌嗪(82℃)、4-氯-1-(1-哌嗪基)2,3二氮杂萘(205℃,分解温度)、和4-(1-哌嗪基)喹啉(320℃,盐酸盐)。其它衍生物可商购获得。
制备终产物
将1.1g(5.2mmol)1-(5-萘满基)哌嗪、1.5ml三乙胺和微量碘化钾加到1.64g(6.0mmol)2-(3-氯丙-1-基)-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物在40ml DMF内的溶液中。将该反应混合物在100℃搅拌4小时,然后倒入冰水中,抽滤出所得沉淀。用异丙醇重结晶,获得了1g(43%)产物(熔点140℃)。NMR:CDCl3δ7.8(d,1H),7.6(dd,1H),7.5《dd,1H),7.4(d,1H),7.1(dd,1H),6.9(d,1H),6.8(d,1H),3.4(t,2H),3.0-2.5(m,14H),2.1(tt,2H),1.8-1.7(m,4H),1.5(s,6H)ppm.
以类似方法制得了下述化合物:
实施例2:3,3-二甲基-2-[3-(4-(2-苯基喹唑啉-4-基)-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点269℃,盐酸盐)。
实施例3:3,3-二甲基-2-[3-(4-(2-喹啉基)-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点63℃)。
实施例4:3,3-二甲基-2-[3-(4-(1-萘基)-二氮杂环庚烷-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点126℃,盐酸盐)。
实施例5:3,3-二甲基-2-[3-(4-(4-氯-(1-2,3二氮杂萘基))-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点190℃)。
实施例6:3,3-二甲基-2-[3-(4-(1-萘基)-哌嗪-1-基)-2-亚甲基丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点193℃)。
实施例7:3,3-二甲基-2-[2-(4-(4-喹唑啉基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点178℃,盐酸盐)。
实施例8:3,3-二甲基-2-[2-(4-(1-萘基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点282℃,盐酸盐)。
实施例9:3,3-二甲基-2-[2-(4-(4-异喹啉-4-基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点243℃,盐酸盐)。
实施例10:3,3-二乙基-2-[2-(4-(1-萘基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(油状物)。
实施例11:3,3-二甲基-2-[3-(4-(1-萘基)-哌嗪-1-基)丙-1-基]-6-(1-吡咯基)-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点269℃,盐酸盐)。
该吡咯环是通过将3,3-二甲基-2-[3-(4-(1-萘基)-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物与2,5-二甲氧基四氢呋喃在冰醋酸中于100℃反应(1小时)而加上去的(产率为86%)。
实施例12:3,3-二甲基-2-[3-(4-(1-萘基)-哌嗪-1-基)丙-1-基]-6-苯甲酰氨基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点127℃)。
实施例13:3,3-二甲基-2-[3-(4-(1-萘基)-哌嗪-1-基)丙-1-基]-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点203℃)。
实施例14:3,3-二甲基-2-[2-(4-(2,3-二甲基苯基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点291℃,盐酸盐)。
实施例15:3,3-二甲基-2-[2-(4-(4-二氢茚基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点271℃,盐酸盐)。
实施例16:3,3-二甲基-2-[3-(4-(4-氯-(1-萘基))-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点151℃)。
实施例17:3,3-二甲基-2-[3-(4-(2-嘧啶基)-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点263℃,盐酸盐)。
实施例18:3,3-二甲基-2-[2-(4-(4-甲氧基苯基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点207℃,盐酸盐)。
实施例19:3,3-二甲基-2-[3-(4-(2-甲氧基苯基)-哌嗪-1-基)-2-羟基丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点160℃)。
实施例20:3,3-二乙基-2-[3-(4-(1-萘基)-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点179℃)。
实施例21:3,3-二甲基-2-[3-(4-(2,5-二甲基苯基)-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点218℃,盐酸盐)。
实施例22:3,3-二甲基-2-[2-(4-(2-氰基苯基)-哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点228℃,盐酸盐)。
实施例23:3,3-二甲基-2-[2-(4-(1-萘基)-哌嗪-1-基)乙-1-基]-4-氯-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物。
制备原料
a)4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物。如实施例1a)所述制得了该化合物。获得了7.8g(70%)。熔点为121℃。
b)2-(2,2-二乙氧基乙-1-基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
将7.7g(33mmol)4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物、8.25ml(55mmol)溴乙醛二乙基乙缩醛和7.0g碳酸钾置于100ml无水DMF中,在120℃搅拌5小时。将该反应混合物倒入冰水中,然后用乙酸乙酯萃取,将有机层用水洗涤,用硫酸钠干燥。将溶剂减压除去,通过柱色谱法纯化粗产物。获得了7.5g(65%)该产物,为油状物。
c)2-(2-氧代乙-1-基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
将7.5g(21.5mmol)2-(2,2-二乙氧基乙-1-基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物和25ml浓盐酸置于25ml水和150ml THF中,在40℃搅拌1.5小时。用氢氧化钠溶液将该反应混合物中和,用乙醚萃取,用硫酸钠将有机相干燥,并减压浓缩。分离到了5.8g(98%)产物,为油状物。制备终产物
在室温下,将1.5g(5.5mmol)24c)醛、1.06g(5mmol)萘基哌嗪(如实施例1c)所述制得的)和0.42g(7mmol)冰醋酸在50ml乙醇中搅拌30分钟,然后缓慢地加入0.5g(8mmol)氰基硼氢化钠。将该混合物在室温搅拌2小时,然后倒入冰/盐混合物中,用二氯甲烷萃取。用硫酸钠干燥,把溶剂通过蒸馏除去,然后用乙醇重结晶,获得了0.9g(39%)无色晶体(熔点156℃)。NMR:CDCl3δ=8.3(m,1H),7.8(m,1H),7.7(d,1H),7.6-7.3(m,6H),7.1(d,1H),3.5(t,2H),3.2(m,4H),3.0-2.8(m,6H),1.8(s,6H)ppm.实施例24制备3,3-二甲基-2-[2-(4-(1-萘基)四氢-1,2,3,6-吡啶-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物合成原料a)N-BoC-4-(三氟甲磺酰氧基)四氢-1,2,3,6-吡啶
在-78℃,用100ml正丁基锂(1.6M的己烷溶液)将13.2g(0.13mol)二异丙基胺在200ml THF中的溶液去质子化,在该温度下保持30分钟后,滴加溶于50ml THF中的20.0g(0.1mol)N-Boc-哌啶酮。在-78℃再保持3小时后,加入39.3g(0.11mol)N,N-二(三氟甲磺酰基)苯胺在50ml THF中的溶液,将该混合物在室温放置过夜。为了进行后处理,加入水,用乙醚萃取混合物,将有机层依次用碳酸氢钠溶液和水洗涤,用硫酸钠干燥,将溶剂蒸发去。通过快速色谱法纯化粗产物(硅胶色谱,流动相为庚烷/乙酸乙酯=3/1)。
产量:20.2g(产率为60%)1H-NMR:(270MHz,CDCl3[sic])δ=1.4(s,9H);2.4(m,2H);3.6(t,2H);4.1(m,2H);5.8(m,1H)ppm.b)N-Boc-4-(1-萘基)四氢-1,2,3,6-吡啶
将22ml 2M的碳酸钠溶液、7.63g(44.4mmol)萘-1-硼酸、4.13g(97.6mmol)氯化锂、0.85g(4.44mmol)碘化亚铜和2.1g(1.77mmol)四(三苯基)钯依次加到溶于115ml二甲氧基乙烷中的14.7g(44.4mmol)上述化合物中,将该混合物煮沸4小时。为了进行后处理,加入氨水溶液,用水和乙酸乙酯进行提取处理,用硫酸钠干燥并将溶剂蒸发后,将所得残余物通过快速色谱法纯化(硅胶色谱,流动相为庚烷/乙酸乙酯=4/1)。
产量:8.2g(产率为57%)1H-NMR(270MHz,CDCl3[sic]):δ=1.4(s,9H);2.5(m,2H);3.7(t,2H);4.1(m,2H);5.8(m,1H);7.2-7.5(m,3H);7.3-8.0(m,3H)ppm.c)4-(1-萘基)四氢-1,2,3,6-吡啶
将7.84g(25.3mmol)N-Boc-4-(1-萘基)-3,6-二氢-2H-吡啶与200ml乙醚合盐酸在室温搅拌过夜,滤出沉淀产物并干燥。
产量:5.5g(产率为88%)。d)将1.0g(4.1mmol)上述24c化合物溶于20ml甲醇,在2.22g(16.8mmol)氯化锌(II)存在下,先加入1.27g(5.3mmol)实施例23c所述醛,然后加入0.5g(8.14mmol)氰基硼氢化钠。在室温反应16小时后,进行上述后处理,将所得粗产物通过色谱法纯化(硅胶色谱,流动相为二氯甲烷/甲醇=97/3)。通过用乙醚合盐酸溶液将盐沉淀,获得了白色固体。
产量:0.9g(产率为47%)1H-NMR(270MHz,DMSO-d6[sic]):δ=1.6(m,6H);2.6(m,1H);3.1(m,1H);3.4-3.6(m,6H);4.0-4.2(m,2H);5.8(sbr,1H);7.6-8.0(m,7H);8.2(d,1H);12.0(s,1H)ppm.实施例25制备3,3-二甲基-2-[2-(4-(1-萘基)-1-哌啶基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物a)4-(1-萘基)哌啶
将3.7g(15.3mmol)4-(1-萘基)-1,2,3,6-四氢吡啶溶于甲醇,加入0.8g披钯碳,用氢气在室温下氢化48小时。滤出催化剂,将溶剂蒸发掉。
产量:1.8g(产率为56%)1H-NMR(270MHz,CDCl3[sic])δ=1.6-1.8(m,2H);2.0(m,2H);2.9(dt,2H);3.3(d,2H);3.5(tt,1H);7.4-7.6(m,4H);7.7(d,1H);7.9(d,1H);8.1(d,1H)ppm.制备终产物
将1.5g(7.1mmol)25a胺溶于20ml甲醇中,先加入3.8g(28.4mmol)氯化锌和2.21g(9.2mmol)实施例23c所述醛,然后分批加入0.89g(14.2mmol)氰基硼氢化钠。搅拌6小时后,滤出不溶物,将母液浓缩,并置于乙酸乙酯中。将有机相用水和饱和盐水洗涤,用硫酸钠干燥,过滤并浓缩,获得了淡黄色油状物。
产量:2.2g(产率为65%)1H-NMR(270MHz,CDCl3):δ=1.7-1.9(m,8H);2.0(m,2H);2.7-3.0(m,4H);3.2(m,2H);3.5(m,1H);3.7(t,2H);7.1(d,1H);7.3-7.7(m,9H);8.2(d,1H)ppm.
其它优选的式I化合物描述在下表中。
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
26 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Me-Ph |
27 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OH-Ph |
28 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Br-Ph |
29 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-CF3-Ph |
30 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OEt-Ph |
31 | Me | H | H | Me | Me | / | C2 | 4-哌嗪 | 2-NR5R6-Ph |
32 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-O(n-C4)-Ph |
33 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-NO2-Ph |
34 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-F-Ph |
35 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe-Ph |
36 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-CN-Ph |
37 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Cl-Ph |
38 | Me | H | H | / | / | H | C2 | 4-哌嗪 | 2-CO2R7-Ph |
39 | Me | H | H | / | / | Me | C2 | 4-哌嗪 | 2-CO2R7-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
40 | Me | H | H | H | H | / | C2 | 4-哌嗪 | 2-NR5R6-Ph |
41 | Me | H | H | n-C3 | n-C3 | / | C2 | 4-哌嗪 | 2-NR5R6-Ph |
42 | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌嗪 | 2-NR5R6-Ph |
43 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-I-Ph |
44 | Me | H | H | / | / | i-C3 | C2 | 4-哌嗪 | 2-CO2R7-Ph |
45 | Me | H | H | / | / | / | C2 | 4-哌嗪 | Ph |
46 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Et-Ph |
47 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-iC3-Ph |
48 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Ph-Ph |
49 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-tBu-Ph |
50 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Et-Ph |
51 | Me | H | H | / | / | Et | C2 | 4-哌嗪 | 3-CO2R7-Ph |
52 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-I-Ph |
53 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Cl-Ph |
54 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Br-Ph |
55 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-F-Ph |
56 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-CF3-Ph |
57 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-OH-Ph |
58 | Me | H | H | / | / | H | C2 | 4-哌嗪 | 3-CO2R7-Ph |
59 | Me | H | H | H | H | / | C2 | 4-哌嗪 | 3-NR5R6-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
60 | Me | H | H | Me | Me | / | C2 | 4-哌嗪 | 3-NR5R6-Ph |
61 | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌嗪 | 3-NR5R6-Ph |
62 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-CN-Ph |
63 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-OMe-Ph |
64 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-NO2-Ph |
65 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-OEt-Ph |
66 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-O(n-C5)Ph |
67 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-Ph-Ph |
68 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-iC3-Ph |
69 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-nC3-Ph |
70 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-nC6-Ph |
71 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-I-Ph |
72 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-F-Ph |
73 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-Br-Ph |
74 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-Cl-Ph |
75 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-OH-Ph |
76 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-CN-Ph |
77 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-CF3-Ph |
78 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-NO2-Ph |
79 | Me | H | H | H | H | / | C2 | 4-哌嗪 | 4-NR5R6-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
80 | Me | H | H | Me | Me | / | C2 | 4-哌嗪 | 4-NR5R6-Ph |
81 | Me | H | H | n-C4 | n-C4 | / | C2 | 4-哌嗪 | 4-NR5R6-Ph |
82 | Me | H | H | Me | Et | / | C2 | 4-哌嗪 | 4-NR5R6-Ph |
83 | Me | H | H | / | / | H | C2 | 4-哌嗪 | 4-CO2R7-Ph |
84 | Me | H | H | / | / | Me | C2 | 4-哌嗪 | 4-CO2R7-Ph |
85 | Me | H | H | / | / | n-C5 | C2 | 4-哌嗪 | 4-CO2R7-Ph |
86 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-OMe-Ph |
87 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-OEt-Ph |
88 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Cl,4-NO2-Ph |
89 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Cl,4-Me-Ph |
90 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-CN,6-CN-Ph |
91 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Me,6-Me-Ph |
92 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-NO2,4-CF3-Ph |
93 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Cl,4-Cl-Ph |
94 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Me,3-Me-Ph |
95 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Et,3-Et-Ph |
96 | Me | H | H | H | H | / | C2 | 4-哌嗪 | 2-NR5R6,4-Cl-Ph |
97 | Me | H | H | H | H | / | C2 | 4-哌嗪 | 2-NR5R6,4-Me-Ph |
98 | Me | H | H | Me | Me | / | C2 | 4-哌嗪 | 2-NR5R6,4-Cl-Ph |
99 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Me,4-Me-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
100 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-Cl,5-Cl-Ph |
101 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,4-OMe-Ph |
102 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-tBu,5-tBu-Ph |
103 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-tBu,5-CF3-Ph |
104 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,5-Cl-Ph |
105 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,5-OMe-Ph |
106 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,5-Ph-Ph |
107 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,4-OMe-Ph |
108 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-CF3,4-Cl-Ph |
109 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-NO2,4-CF3,5-NO2-Ph |
110 | Me | H | H | H | H | / | C2 | 4-哌嗪 | 2-NR5R6,4-Me,5-Cl-Ph |
111 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,3-Cl,5-Cl-Ph |
112 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,4-NO2,5-Me-Ph |
113 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe,4-Cl,5-Me-Ph |
114 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Me,4-Cl,5-CF3-Ph |
115 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 5-萘满 |
116 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-二氢茚 |
117 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 1-萘满 |
118 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 1-二氢茚 |
119 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 1-萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
120 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OMe-1-萘 |
121 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OEt-1-萘 |
122 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Me-萘 |
123 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Et-1-萘 |
124 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 8-OMe-1-萘 |
125 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 8-Me-1-萘 |
126 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 9-蒽 |
127 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-吲哚 |
128 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-喹啉 |
129 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-喹啉 |
130 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-喹喔啉 |
131 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 1-2,3二氮杂萘 |
132 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-喹啉 |
133 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-喹啉 |
134 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-喹啉 |
135 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 5-喹啉 |
136 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 1-异喹啉 |
137 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-异喹啉 |
138 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 8-异喹啉 |
139 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 7-苯并呋喃 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
140 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-2H-色烯 |
141 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 5-色满 |
142 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 8-色满 |
143 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-嘧啶 |
144 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-tBu,4-CF3-6-嘧啶 |
145 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 5-OMe-4-嘧啶 |
146 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 4-嘧啶 |
147 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-吡嗪 |
148 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-异噁唑 |
149 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-吡啶 |
150 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-吡啶 |
151 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 3-吡咯 |
152 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-ph-4-喹唑啉 |
153 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 6-iC3-4-嘧啶 |
154 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 7-OMe-1-萘 |
155 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Me-Ph |
156 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OH-Ph |
157 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-Br-Ph |
158 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-CF3-Ph |
159 | Me | H | H | / | / | / | C2 | 4-哌嗪 | 2-OEt-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
160 | Me | H | H | Me | Me | / | C2 | 4-哌啶 | 2-NR5R6-Ph |
161 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-O(n-C4)-Ph |
162 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-NO2-Ph |
163 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-F-Ph |
164 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe-Ph |
165 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-CN-Ph |
166 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Cl-Ph |
167 | Me | H | H | / | / | H | C2 | 4-哌啶 | 2-CO2R7-Ph |
168 | Me | H | H | / | / | Me | C2 | 4-哌啶 | 2-CO2R7-Ph |
169 | Me | H | H | H | H | / | C2 | 4-哌啶 | 2-NR5R6-Ph |
170 | Me | H | H | n-C3 | n-C3 | / | C2 | 4-哌啶 | 2-NR5R6-Ph |
171 | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌啶 | 2-NR5R6-Ph |
172 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-I-Ph |
173 | Me | H | H | / | / | i-C3 | C2 | 4-哌啶 | 2-CO2R7-Ph |
174 | Me | H | H | / | / | / | C2 | 4-哌啶 | Ph |
175 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Et-Ph |
176 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-iC3-Ph |
177 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Ph-Ph |
178 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-tBu-Ph |
179 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Et-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
180 | Me | H | H | / | / | Et | C2 | 4-哌啶 | 3-CO2R7-Ph |
181 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-I-Ph |
182 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Cl-Ph |
183 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Br-Ph |
184 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-F-Ph |
185 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-CF3-Ph |
186 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-OH-Ph |
187 | Me | H | H | / | / | H | C2 | 4-哌啶 | 3-CO2R7-Ph |
188 | Me | H | H | H | H | / | C2 | 4-哌啶 | 3-NR5R6-Ph |
189 | Me | H | H | Me | Me | / | C2 | 4-哌啶 | 3-NR5R6-Ph |
190 | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌啶 | 3-NR5R6-Ph |
191 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-CN-Ph |
192 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-OMe-Ph |
193 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-NO2-Ph |
194 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-OEt-Ph |
195 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-O(n-C5)Ph |
196 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-Ph-Ph |
197 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-iC3-Ph |
198 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-nC3-Ph |
199 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-nC6-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
200 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-I-Ph |
201 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-F-Ph |
202 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-Br-Ph |
203 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-Cl-Ph |
204 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-OH-Ph |
205 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-CN-Ph |
206 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-CF3-Ph |
207 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-NO2-Ph |
208 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-NR5R6-Ph |
209 | Me | H | H | Me | Me | / | C2 | 4-哌啶 | 4-NR5R6-Ph |
210 | Me | H | H | n-C4 | n-C4 | / | C2 | 4-哌啶 | 4-NR5R6-Ph |
211 | Me | H | H | Me | Et | / | C2 | 4-哌啶 | 4-NR5R6-Ph |
212 | Me | H | H | / | / | H | C2 | 4-哌啶 | 4-CO2R7-Ph |
213 | Me | H | H | / | / | Me | C2 | 4-哌啶 | 4-CO2R7-Ph |
214 | Me | H | H | / | / | n-C5 | C2 | 4-哌啶 | 4-CO2R7-Ph |
215 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-OMe-Ph |
216 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-OEt-Ph |
217 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Cl,4-NO2-Ph |
218 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Cl,4-Me-Ph |
219 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-CN,6-CN-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
220 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Me,6-Me-Ph |
221 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-NO2,4-CF3-Ph |
222 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Cl,4-Cl-Ph |
223 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Me,3-Me-Ph |
224 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Et,3-Et-Ph |
225 | Me | H | H | H | H | / | C2 | 4-哌啶 | 2-NR5R6,4-Cl-Ph |
226 | Me | H | H | H | H | / | C2 | 4-哌啶 | 2-NR5R6,4-Cl-Ph |
227 | Me | H | H | Me | Me | / | C2 | 4-哌啶 | 2-NR5R6,4-Cl-Ph |
228 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Me,4,Me-Ph |
229 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-Cl,5-Cl-Ph |
230 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,4-OMe-Ph |
231 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-tBu,5-tBu-Ph |
232 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-tBu,5-CF3-Ph |
233 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,5-Cl-Ph |
234 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,5-OMe-Ph |
235 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,5-Ph-Ph |
236 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-OMe,4-OMe-Ph |
237 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-CF3,4-Cl-Ph |
238 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-NO2,4-CF3,5-NO2-Ph |
239 | Me | H | H | H | H | / | C2 | 4-哌啶 | 2-NR5R6,4-Me,5-Cl-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
240 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,3-Cl,5-Cl-Ph |
241 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,4-NO2,5-Me-Ph |
242 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe,4-Cl,5-Me-Ph |
243 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Me,4-Cl,5-CF3-Ph |
244 | Me | H | H | / | / | / | C2 | 4-哌啶 | 5-萘满 |
245 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-二氢茚 |
246 | Me | H | H | / | / | / | C2 | 4-哌啶 | 1-萘满 |
247 | Me | H | H | / | / | / | C2 | 4-哌啶 | 1-二氢茚 |
248 | Me | H | H | / | / | / | C2 | 4-哌啶 | 1-萘 |
249 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OMe-1-萘 |
250 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-OEt-1-萘 |
251 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Me-1-萘 |
252 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Et-1-萘 |
253 | Me | H | H | / | / | / | C2 | 4-哌啶 | 8-OMe-1-萘 |
254 | Me | H | H | / | / | / | C2 | 4-哌啶 | 8-Me-1-萘 |
255 | Me | H | H | / | / | / | C2 | 4-哌啶 | 9-蒽 |
256 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-吲哚 |
257 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-喹唑啉 |
258 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-喹唑啉 |
259 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-喹喔啉 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
260 | Me | H | H | / | / | / | C2 | 4-哌啶 | 1-酞嗪 |
261 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-喹啉 |
262 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-喹啉 |
263 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-喹啉 |
264 | Me | H | H | / | / | / | C2 | 4-哌啶 | 5-喹啉 |
265 | Me | H | H | / | / | / | C2 | 4-哌啶 | 1-异喹啉 |
266 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-异喹啉 |
267 | Me | H | H | / | / | / | C2 | 4-哌啶 | 8-异喹啉 |
268 | Me | H | H | / | / | / | C2 | 4-哌啶 | 7-苯并呋喃 |
269 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-2H-色烯 |
270 | Me | H | H | / | / | / | C2 | 4-哌啶 | 5-色满 |
271 | Me | H | H | / | / | / | C2 | 4-哌啶 | 8-色满 |
272 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-嘧啶 |
273 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-tBu,4-CF3-6-嘧啶 |
274 | Me | H | H | / | / | / | C2 | 4-哌啶 | 5-OMe-4-嘧啶 |
275 | Me | H | H | / | / | / | C2 | 4-哌啶 | 4-嘧啶 |
276 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-吡嗪 |
277 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-异噁唑 |
278 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-吡啶 |
279 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-吡啶 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
280 | Me | H | H | / | / | / | C2 | 4-哌啶 | 3-吡咯 |
281 | Me | H | H | / | / | / | C2 | 4-哌啶 | 2-Ph-4-喹唑啉 |
282 | Me | H | H | / | / | / | C2 | 4-哌啶 | 6-iC3-4-嘧啶 |
283 | Me | H | H | / | / | / | C2 | 4-哌啶 | 7-OMe-1-萘 |
284 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Me-Ph |
285 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OH-Ph |
286 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Br-Ph |
287 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-CF3-Ph |
288 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OEt-Ph |
289 | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6-Ph |
290 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-O(n-C4)-Ph |
291 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NO2-Ph |
292 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-F-Ph |
293 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
294 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-CN-Ph |
295 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Cl-Ph |
296 | Me | H | H | / | / | H | C2 | 4-四氢-1,2,3,6-吡啶 | 2-CO2R7-Ph |
297 | Me | H | H | / | / | Me | C2 | 4-四氢-1,2,3,6-吡啶 | 2-CO2R7-Ph |
298 | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6-Ph |
299 | Me | H | H | n-C3 | n-C3 | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6-Ph |
300 | Me | H | H | i-C3 | i-C3 | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6-Ph |
301 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-I-Ph |
302 | Me | H | H | / | / | i-C3 | C2 | 4-四氢-1,2,3,6-吡啶 | 2-CO2R7-Ph |
303 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | Ph |
304 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Et-Ph |
305 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-iC3-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
306 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Ph-Ph |
307 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-tBu-Ph |
308 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Et-Ph |
309 | Me | H | H | / | / | Et | C2 | 4-四氢-1,2,3,6-吡啶 | 3-CO2R7-Ph |
310 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-I-Ph |
311 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Cl-Ph |
312 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Br-Ph |
313 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-F-Ph |
314 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-CF3-Ph |
315 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-OH-Ph |
316 | Me | H | H | / | / | H | C2 | 4-四氢-1,2,3,6-吡啶 | 3-CO2R7-Ph |
317 | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-NR5R6-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
318 | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-NR5R6-Ph |
319 | Me | H | H | i-C3 | i-C3 | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-NR5R6-Ph |
320 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-CN-Ph |
321 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-OMe-Ph |
322 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-NO2-Ph |
323 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-OEt-Ph |
324 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-O(n-C5)Ph |
325 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-Ph-Ph |
326 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-iC3-Ph |
327 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-nC3-Ph |
328 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-nC6-Ph |
329 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-I-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
330 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-F-Ph |
331 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-Br-Ph |
332 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-Cl-Ph |
333 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-OH-Ph |
334 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-CN-Ph |
335 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-CF3-Ph |
336 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-NO2-Ph |
337 | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-NR5R6-Ph |
338 | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-NR5R6-Ph |
339 | Me | H | H | n-C4 | n-C4 | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-NR5R6-Ph |
340 | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-NR5R6-Ph |
341 | Me | H | H | / | / | H | C2 | 4-四氢-1,2,3,6-吡啶 | 4-CO2R7-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
342 | Me | H | H | / | / | Me | C2 | 4-四氢-1,2,3,6-吡啶 | 4-CO2R7-Ph |
343 | Me | H | H | / | / | n-C5 | C2 | 4-四氢-1,2,3,6-吡啶 | 4-CO2R7-Ph |
344 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-OMe-Ph |
345 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-OEt-Ph |
346 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Cl,2,3,6-NO2-Ph |
347 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Cl,2,3,6-Me-Ph |
348 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-CN,6-CN-Ph |
349 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Me,6-Me-Ph |
350 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NO2,2,3,6-CF3-Ph |
351 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Cl,2,3,6-Cl-Ph |
352 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Me,3-Me-Ph |
353 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Et,3-Et-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
354 | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6,2,3,6-Cl-Ph |
355 | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6,2,3,6-Me-Ph |
356 | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6,2,3,6-Cl-Ph |
357 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Me,2,3,6-Me-Ph |
358 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-Cl,5-Cl-Ph |
359 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,2,3,6-OMe-Ph |
360 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-tBu,5-tBu-Ph |
361 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-tBu,5-CF3-Ph |
362 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,5-Cl-Ph |
363 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,5-OMe-Ph |
364 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,5-Ph-Ph |
365 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,2,3,6-OMe-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
366 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-CF3,2,3,6-Cl-Ph |
367 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NO2,2,3,6-CF3,5-NO2-Ph |
368 | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6,2,3,6-Me,5-Cl-Ph |
369 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,3-Cl,5-Cl-Ph |
370 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,2,3,6-NO2,5-Me-Ph |
371 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe,2,3,6-Cl,5-Me-Ph |
372 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Me,2,3,6-Cl,5-CF3-Ph |
373 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-萘满 |
374 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-二氢茚 |
375 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 1-萘满 |
376 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 1-二氢茚 |
377 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 1-萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
378 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OMe-1-萘 |
379 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-OEt-1-萘 |
380 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Me-1-萘 |
381 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Et-1-萘 |
382 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 8-OMe-1-萘 |
383 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 8-Me-1-萘 |
384 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 9-蒽 |
385 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-吲哚 |
386 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-喹唑啉 |
387 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-喹唑啉 |
388 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-喹喔啉 |
389 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 1-2,3二氮杂萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
390 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-喹啉 |
391 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-喹啉 |
392 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-喹啉 |
393 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 5-喹啉 |
394 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 1-异喹啉 |
395 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-异喹啉 |
396 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 8-异喹啉 |
397 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 7-苯并呋喃 |
398 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-2H-色烯 |
399 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 5-色满 |
400 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 8-色满 |
401 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-嘧啶 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
402 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-tBu,2,3,6-CF3-6-嘧啶 |
403 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 5-OMe-4-嘧啶 |
404 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 4-嘧啶 |
405 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-吡嗪 |
406 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-异噁唑 |
407 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-吡啶 |
408 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-吡啶 |
409 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 3-吡咯 |
410 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 2-Ph-4-喹唑啉 |
411 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 6-iC3-4-嘧啶 |
412 | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6-吡啶 | 7-OMe-1-萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
413 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Me-Ph |
414 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-OH-Ph |
415 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Br-Ph |
416 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-CF3-Ph |
417 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-OMe-Ph |
418 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-CN-Ph |
419 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | Ph |
420 | Me | H | H | H | H | / | C2 | 4-1,4二氮杂环庚烷 | 2-NR5R6-Ph |
421 | Me | H | H | Me | Me | / | C2 | 4-1,4二氮杂环庚烷 | 2-NR5R6-Ph |
422 | Me | H | H | / | / | H | C2 | 4-1,4二氮杂环庚烷 | 2-CO2R7-Ph |
423 | Me | H | H | / | / | Me | C2 | 4-1,4二氮杂环庚烷 | 2-CO2R7-Ph |
424 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-tBu-Ph |
425 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-Me-Ph |
426 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-CF3-Ph |
427 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-Cl-Ph |
428 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-OMe-Ph |
429 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 4-NO2-Ph |
430 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 4-Ph-Ph |
431 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 4-F-Ph |
432 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-Cl,4-Me Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
433 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Me,6-Me Ph |
434 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Me,3-Me Ph |
435 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Et,3,-Et Ph |
436 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3t-Bu,5-CF3 Ph |
437 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-OMe,5-Ph Ph |
438 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-OMe,4-Cl,5-Me Ph |
439 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Me,4-Cl,5-CF3 Ph |
440 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 5-萘满 |
441 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 4-二氢茚 |
442 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 1-萘 |
443 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-OMe-1-萘 |
444 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-Me-1-萘 |
445 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 7-OMe-1-萘 |
446 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 8-Me-1-萘 |
447 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-喹唑啉 |
448 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 3-吲哚 |
449 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 1-酞嗪 |
450 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-喹啉 |
451 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 1-异喹啉 |
452 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-嘧啶 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
453 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-tBu,4-CF3-6-嘧啶 |
454 | Me | H | H | / | / | / | C2 | 4-1,4二氮杂环庚烷 | 2-吡啶 |
455 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-Me-Ph |
456 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | Ph |
457 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-OMe-Ph |
458 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-Cl-Ph |
459 | Me | H | H | H | H | / | C2 | 氮杂环庚烷 | 2-NR5R6Ph |
460 | Me | H | H | / | / | Me | C2 | 氮杂环庚烷 | 2-CO2R7Ph |
461 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 3-tBu Ph |
462 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 4-Ph-Ph |
463 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-Me,3-Me-Ph |
464 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-Me,4-Cl,5-CF3Ph |
465 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 4-萘满 |
466 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 4-二氢茚 |
467 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 1-萘 |
468 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-OMe-1-萘 |
469 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-嘧啶 |
470 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-喹啉 |
471 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 1-2,3二氮杂萘 |
472 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-tBu,4-CF3-6-嘧啶 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
473 | Me | H | H | / | / | / | C2 | 2-吡啶 | |
474 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 4-NO2-Ph |
475 | Me | H | H | / | / | / | C2 | 氮杂环庚烷 | 2-OH-Ph |
476 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-Me-Ph |
477 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | Ph |
478 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-OMe-Ph |
479 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-Cl-Ph |
480 | Me | H | H | H | H | / | C2 | 四氢-2H-氮杂 | 2-NR5R6-Ph |
481 | Me | H | H | / | / | Me | C2 | 四氢-2H-氮杂 | 2-CO2R7-Ph |
482 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 3-tBu-Ph |
483 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 4-Ph-Ph |
484 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-Me,3-Me-Ph |
485 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-Me,4-Cl,5-CF3Ph |
486 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 5-萘满 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
487 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 4-二氢茚 |
488 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 1-萘 |
489 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-OMe-1-萘 |
490 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-嘧啶 |
491 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-喹啉 |
492 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 1-2,3二氮杂萘 |
493 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-tBu,4-CF3-6-嘧啶 |
494 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-吡啶 |
495 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 4-NO2-Ph |
496 | Me | H | H | / | / | / | C2 | 四氢-2H-氮杂 | 2-OH-Ph |
497 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-Me-Ph |
498 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-OMe-Ph |
499 | Me | H | H | H | H | / | C3 | 哌嗪 | 2-NR5R6-Ph |
500 | Me | H | H | / | / | Me | C3 | 哌嗪 | 2-CO2R7-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
501 | Me | H | H | / | / | / | C3 | 哌嗪 | 3-tBu-Ph |
502 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-Me,3-Me-Ph |
503 | Me | H | H | / | / | / | C3 | 哌嗪 | 5-萘满 |
504 | Me | H | H | / | / | / | C3 | 哌嗪 | 4-二氢茚 |
505 | Me | H | H | / | / | / | C3 | 哌嗪 | 1-萘 |
506 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-Me-1-萘 |
507 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-嘧啶 |
508 | Me | H | H | / | / | / | C3 | 哌嗪 | 1-2,3二氮杂萘 |
509 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-Me-Ph |
510 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-OMe-Ph |
511 | Me | H | H | H | H | / | C3 | 哌嗪 | 2-NR5R6-Ph |
512 | Me | H | H | / | / | Me | C3 | 哌嗪 | 2-CO2R7-Ph |
513 | Me | H | H | / | / | / | C3 | 哌嗪 | 3-tBu-Ph |
514 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-Me,3-Me-Ph |
515 | Me | H | H | / | / | / | C3 | 哌嗪 | 5-萘满 |
516 | Me | H | H | / | / | / | C3 | 哌嗪 | 4-二氢茚 |
517 | Me | H | H | / | / | / | C3 | 哌嗪 | 1-萘 |
518 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-Me-1-萘 |
519 | Me | H | H | / | / | / | C3 | 哌嗪 | 2-嘧啶 |
520 | Me | H | H | / | / | / | C3 | 哌嗪 | 1-2,3二氮杂萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
521 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 2-Me-Ph |
522 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 2-OMe-Ph |
523 | Me | H | H | H | H | / | C3 | 4-四氢-1,2,3,6-吡啶 | 2-NR5R6-Ph |
524 | Me | H | H | / | / | Me | C3 | 4-四氢-1,2,3,6-吡啶 | 2-CO2R7-Ph |
525 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 3-tBu-Ph |
526 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 2-Me,3-Me-Ph |
527 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 5-萘满 |
528 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 4-二氢茚 |
529 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 1-萘 |
530 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 2-Me-1-萘 |
531 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 2-嘧啶 |
532 | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶 | 1-2,3二氮杂萘 |
533 | Me | H | H | / | / | / | C3 | 1,4二氮杂庚烷 | 2-Me-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
534 | Me | H | H | / | / | / | C3 | 1,4二氮杂庚烷 | 2-Me,3-Me-Ph |
535 | Me | H | H | / | / | / | C3 | 1,4二氮杂庚烷 | 5-萘满 |
536 | Me | H | H | / | / | / | C3 | 1,4二氮杂庚烷 | 1-萘 |
537 | Me | H | H | / | / | / | C3 | 1,4二氮杂庚烷 | 2-Me-1-萘 |
538 | Me | H | H | / | / | / | C3 | 1,4二氮杂庚烷 | 2-嘧啶 |
539 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-Me-Ph |
540 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-Me,3-Me-Ph |
541 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 5-萘满 |
542 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 1-萘 |
543 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-OMe-1-萘 |
544 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-嘧啶 |
545 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-喹啉 |
546 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-Me-Ph |
547 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-Me,3-Me-Ph |
548 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 5-萘满 |
549 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 1-萘 |
550 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-OMe-1-萘 |
551 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-嘧啶 |
552 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 哌嗪 | 2-喹啉 |
553 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 四氢吡啶 | 2-Me-Ph |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
554 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 四氢吡啶 | 2-Me,3-Me-Ph |
555 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 四氢吡啶 | 5-萘满 |
556 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 四氢吡啶 | 1-萘 |
557 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 四氢吡啶 | 2-OMe-1-萘 |
558 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 四氢吡啶 | 2-嘧啶 |
559 | Me | H | H | CH2-C(CH2)-CH2 | 四氢吡啶 | 2-喹啉 | |||
560 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 2-Me-Ph |
561 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 2Me,3-Me-Ph |
562 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 5-萘满 |
563 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 1-萘 |
564 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 2-OMe-1-萘 |
565 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 2-嘧啶 |
566 | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 1,4二氮杂环庚烷 | 2-喹啉 |
567 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 哌嗪 | 2-Me-Ph |
568 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 哌嗪 | 2-Me,3-Me-Ph |
569 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 哌嗪 | 5-萘满 |
570 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 哌嗪 | 1-萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
571 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 哌啶 | 2-OMe-1-萘 |
572 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 四氢吡啶 | 2-嘧啶 |
573 | Me | H | H | / | / | / | CH2-CH(OH)CH2 | 1,4二氮杂环庚烷 | 2-喹啉 |
574 | Me | H | H | / | / | / | C2-N(Me)-C2 | 哌嗪 | 2-Me-Ph |
575 | Me | H | H | / | / | / | C2-N(Me)-C2 | 哌嗪 | 2-Me,3-Me-Ph |
576 | Me | H | H | / | / | / | C2-N(Me)-C2 | 哌嗪 | 5-萘满 |
577 | Me | H | H | / | / | / | C2-N(Me)-C2 | 哌嗪 | 1-萘 |
578 | Me | H | H | / | / | / | C2-N(Me)-C2 | 哌嗪 | 2-OMe-1-萘 |
579 | Me | H | H | / | / | / | C2-N(Me)-C2 | 四氢吡啶 | 2-嘧啶 |
580 | Me | H | H | / | / | / | C2-N(Me)-C2 | 1,4二氮杂环庚烷 | 2-喹啉 |
581 | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 哌嗪 | 5-萘满 |
582 | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 哌嗪 | 1-萘 |
583 | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 哌嗪 | 2-Me,3-Me-Ph |
584 | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 四氢吡啶 | 2-嘧啶 |
585 | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 1,4二氮杂环庚烷 | 2-OMe-萘 |
586 | Me | H | H | / | / | / | C8 | 哌嗪 | 5-萘满 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
587 | Me | H | H | / | / | / | C8 | 哌嗪 | 1-萘 |
588 | Me | H | H | / | / | / | C8 | 哌嗪 | 2Me,3-Me-Ph |
589 | Me | H | H | / | / | / | C8 | 四氢吡啶 | 2-嘧啶 |
590 | Me | H | H | / | / | / | C8 | 1,4-二氮杂环庚烷 | 2-OMe-萘 |
591 | Me | 5-Me | H | / | / | / | C2 | 哌嗪 | 5-萘满 |
592 | Me | 5-Me | H | / | / | / | C2 | 哌嗪 | 1-萘 |
593 | Me | 5-Me | H | / | / | / | C2 | 哌嗪 | 2-OMe-Ph |
594 | Me | 5-Me | H | / | / | / | C2 | 哌嗪 | 2-嘧啶 |
595 | Me | 5-Me | H | / | / | / | C2 | 哌嗪 | 2-OMe-萘 |
596 | Me | 5-Me | H | / | / | / | C2 | 哌嗪 | 2-Me,3-Me-Ph |
597 | Me | 5-Me | H | / | / | / | C2 | 四氢吡啶 | 2-喹啉 |
598 | Me | 5-Me | H | / | / | / | C2 | 1,4-二氮杂环庚烷 | 2-Cl-Ph |
599 | Me | 5-Me | H | / | / | / | C3 | 哌嗪 | 5-萘满 |
600 | Me | 5-Me | H | / | / | / | C3 | 哌嗪 | 1-萘 |
601 | Me | 5-Me | H | / | / | / | C3 | 哌嗪 | 2-嘧啶 |
602 | Me | 5-Me | H | / | / | / | C3 | 四氢吡啶 | 2-Me,3Me Ph |
603 | Me | 5-Me | H | / | / | / | C3 | 1,4-二氮杂环庚烷 | 2-OMe-萘 |
604 | Me | 4-Cl | H | / | / | / | C2 | 哌嗪 | 1-萘 |
605 | Me | 5-OH | H | / | / | / | C2 | 哌嗪 | 1-萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
606 | Me | 6-OMe | H | / | / | / | C2 | 哌嗪 | 1-萘 |
607 | Me | 4-F | H | / | / | / | C2 | 哌嗪 | 1-萘 |
608 | Me | 6-OMe | H | / | / | / | C2 | 哌嗪 | 1-萘 |
609 | Me | 4-CF3 | H | / | / | / | C2 | 哌嗪 | 1-萘 |
610 | Me | 6-CO2R7 | H | / | / | H | C2 | 哌嗪 | 1-萘 |
611 | Me | 6-CO2R7 | H | / | / | Me | C2 | 哌嗪 | 1-萘 |
612 | Me | 6-NO2 | H | / | / | / | C2 | 哌嗪 | 1-萘 |
613 | Me | 4-CN | H | / | / | / | C2 | 哌嗪 | 1-萘 |
614 | Me | 6-Pyrrol | H | / | / | / | C2 | 哌嗪 | 1-萘 |
615 | Me | 4(-C2-Ph) | H | / | / | / | C2 | 哌嗪 | 1-萘 |
616 | Me | 4[-C4-(4-Cl)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
617 | Me | 4[-C2-(2-OMe)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
618 | Me | 4[C2-(3-CF3)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
619 | Me | 4[C2-(2-Me)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
620 | Me | 4[C2-(2-NH2)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
621 | Me | 4[C2-(4-NO2)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
622 | Me | 4[C2-(4-OH)Ph] | H | / | / | / | C2 | 哌嗪 | 1-萘 |
623 | Me | 6-NR5R6 | H | Me | H | / | C2 | 哌嗪 | 1-萘 |
624 | Me | 6-NR5R6 | H | CO Ph | H | / | C2 | 哌嗪 | 1-萘 |
625 | Me | 6-NR5R6 | H | CO Me | H | / | C2 | 哌嗪 | 1-萘 |
626 | Me | 6-NR5R6 | H | CO2tBu | H | / | C2 | 哌嗪 | 1-萘 |
No | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar |
627 | Me | 6-NR5R6 | H | H | H | / | C2 | 哌嗪 | 1-萘 |
628 | Me | 6-NR5R6 | H | 哌嗪 | / | C2 | 哌嗪 | 1-萘 | |
629 | Me | 6-NR5R6 | H | Me | H | / | C3 | 哌嗪 | 5-萘满 |
630 | Me | 6-NR5R6 | H | CO Ph | H | / | C3 | 哌嗪 | 5-萘满 |
631 | Me | 6-NR5R6 | H | CO Me | H | / | C3 | 哌嗪 | 5-萘满 |
632 | Me | 6-NR5R6 | H | / | / | / | C3 | 哌嗪 | 5-萘满 |
633 | Me | 6-Pyrrol | H | / | / | / | C3 | 哌嗪 | 5-萘满 |
634 | Me | 6-NO2 | H | / | / | / | C3 | 哌嗪 | 5-萘满 |
635 | Et | H | H | / | / | / | C2 | 哌嗪 | 1-萘 |
636 | Et | H | H | / | / | / | C2 | 哌嗪 | 2-OMe-Ph |
637 | Et | H | H | / | / | / | C2 | 哌嗪 | 2-嘧啶 |
638 | Et | H | H | / | / | / | C2 | 哌嗪 | 2-OMe-1-萘 |
639 | Et | H | H | / | / | / | C2 | 哌嗪 | 2-Me,3-Me-Ph |
Claims (7)
其中
R1和R2独立地为(C1-6)烷基,
R3和R4独立地为氢、(C1-6)支链或直链烷基、OH、O-(C1-6)支链或直链烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、硝基、氰基、吡咯、苯基C1-4烷基,其中该苯基C1-4烷基可在其芳系上被F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、羟基、氨基、氰基或硝基取代,
R5和R6独立地为氢、(C1-6)支链或直链烷基、COPh、CO2tBu、CO-(C1-4)烷基,或者二者一起与所连氮原子形成可还含有另一个氮原子的5元或6元环(例如哌嗪),
R7是氢或(C1-6)支链或直链烷基,
A是支链或直链(C1-10)亚烷基,或者包含至少一个选自O、S、NR7、环丙基、CHOH、双键或三键的基团Z的直链或支链(C2-10)亚烷基,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪、和被一个亚甲基增大的相应的环状化合物,其中B是通过其中的一个氮原子与A连接的,且
Ar是未取代或被下述基团取代的苯基:(C1-6)支链或直链烷基、O-(C1-6)支链或直链烷基、OH、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、氰基或苯基;或者Ar是萘满、二氢茚、未取代或被(C1-4)烷基或O-(C1-4)烷基取代的稠合芳系例如萘,或蒽或5元或6元芳香杂环,其中所述芳香杂环具有1个或2个独立地选自O和N的杂原子,并且还可以与其它芳基稠合。
2.权利要求1的2-取代的1,2-苯并异噻唑衍生物,其中
R1和R2独立地为(C1-2)烷基,
R3和R4独立地为氢、O-(C1-4)支链或直链烷基、F、Cl、Br、三氟甲基、NR5R6、硝基、氰基、和苯基,
R5和R6独立地为氢、COPh、CO2tBu、(C1-6)支链或直链烷基、和CO-(C1-4)烷基,
A是支链或直链(C2-5)亚烷基,或者包含选自CHOH、环丙基、双键或三键的基团Z的直链或支链(C2-5)亚烷基,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪、或1,4二氮杂环庚烷,其中B是通过其中的一个氮原子与A连接的,且
Ar是未取代或被下述基团取代的苯基:(C1-6)支链或直链烷基、O-(C1-6)支链或直链烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、氰基和苯基;或者Ar是萘满、二氢茚、未取代或被(C1-4)烷基或O-(C1-4)烷基取代的稠合芳系例如萘,或蒽和5元或6元芳香杂环,其中所述芳香杂环具有1个或2个独立地选自O和N的杂原子,并且还可以与其它芳基稠合。
3.权利要求1的2-取代的1,2-苯并异噻唑衍生物,其中
R1和R2是甲基,
R3和R4独立地为氢、硝基、Cl、NR5R6、和吡咯,
R5和R6独立地为氢、COPh、和CO-(C1-2)烷基,
A是(C2-3)亚烷基,
B是4-哌啶、4-哌嗪、和4-四氢-1,2,3,6-吡啶,其中B是通过其中的一个氮原子与A连接的,且
Ar是未取代或在2-位和3-位被(C1-2)烷基取代的苯基,或萘满、二氢茚、和未取代或被(C1-4)烷基或O-(C1-2)烷基取代的萘。
4.权利要求1-3任一项的化合物在制备药物中的应用。
5.权利要求4的应用,其中所述药物是用于治疗抑郁症和相关病症的药物。
6.权利要求1-3任一项的化合物作为选择性5-HT1B和5-HT1A拮抗剂的应用。
7.权利要求6的应用,其中所述选择性血清素拮抗作用通过抑制血清素再摄取而被加强。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19746612.5 | 1997-10-22 | ||
DE19746612A DE19746612A1 (de) | 1997-10-22 | 1997-10-22 | 2-Substituierte 1,2-Benzisothiazol-Derivate, ihre Herstellung und Verwendung |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1277607A true CN1277607A (zh) | 2000-12-20 |
Family
ID=7846266
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN98810529A Pending CN1277607A (zh) | 1997-10-22 | 1998-10-05 | 2-取代的1,2-苯并异噻唑衍生物及其作为血清素拮抗剂(5-ht1a,5-ht1b和5-ht1d)的应用 |
Country Status (23)
Country | Link |
---|---|
US (1) | US6346622B1 (zh) |
EP (1) | EP1034170A1 (zh) |
JP (1) | JP2001520224A (zh) |
KR (1) | KR20010031297A (zh) |
CN (1) | CN1277607A (zh) |
AR (1) | AR016968A1 (zh) |
AU (1) | AU748613B2 (zh) |
BG (1) | BG104332A (zh) |
BR (1) | BR9812948A (zh) |
CA (1) | CA2307199A1 (zh) |
CO (1) | CO4980863A1 (zh) |
DE (1) | DE19746612A1 (zh) |
HR (1) | HRP980555A2 (zh) |
HU (1) | HUP0003758A3 (zh) |
IL (1) | IL135256A0 (zh) |
NO (1) | NO20001937L (zh) |
NZ (1) | NZ503604A (zh) |
PL (1) | PL340033A1 (zh) |
SK (1) | SK4572000A3 (zh) |
TR (1) | TR200001080T2 (zh) |
TW (1) | TW517052B (zh) |
WO (1) | WO1999020616A1 (zh) |
ZA (1) | ZA989571B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101151249B (zh) * | 2005-03-31 | 2011-04-06 | 辉瑞产品公司 | 环戊吡啶及四氢喹啉衍生物 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19900544A1 (de) * | 1999-01-11 | 2000-07-13 | Basf Ag | Verwendung von Verbindungen der Formel I zur Prophylaxe und Therapie der zerebralen Ischämie |
JP2006503106A (ja) * | 2002-09-17 | 2006-01-26 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | 統合失調症を処置するためのヘテロ環式置換ピペラジン |
US20040127501A1 (en) * | 2002-09-24 | 2004-07-01 | Zhengming Chen | Therapeutic agents useful for treating pain |
DE60334016D1 (de) | 2002-11-05 | 2010-10-14 | Glaxo Group Ltd | Antibakterielle mittel |
KR100472988B1 (ko) | 2002-11-27 | 2005-03-10 | 씨제이 주식회사 | 조직감, 취반성 및 안전성이 우수한 발아 현미의 제조방법및 이로부터 얻은 발아 현미 |
KR101682058B1 (ko) * | 2008-12-11 | 2016-12-02 | 비이브 헬쓰케어 컴퍼니 | 카르바모일피리돈 hiv 인테그라제 억제제를 위한 제조방법 및 중간체 |
WO2020183011A1 (en) | 2019-03-14 | 2020-09-17 | Institut Curie | Htr1d inhibitors and uses thereof in the treatment of cancer |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3620643A1 (de) * | 1985-06-22 | 1987-01-22 | Sandoz Ag | Thiazole, ihre herstellung und verwendung |
NL8601494A (nl) | 1985-06-22 | 1987-01-16 | Sandoz Ag | Thiazolen, hun bereiding en farmaceutische preparaten die ze bevatten. |
FR2662696A2 (fr) * | 1989-12-13 | 1991-12-06 | Rhone Poulenc Sante | Antagonistes de la serotonine, leur preparation et medicaments les contenant. |
FR2675800A1 (fr) * | 1991-04-26 | 1992-10-30 | Rhone Poulenc Rorer Sa | Derives heterocycliques antiserotonines leur preparation et les medicaments les contenant. |
JPH0912562A (ja) * | 1995-06-22 | 1997-01-14 | Suntory Ltd | 置換ベンゾチアジン誘導体 |
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1997
- 1997-10-22 DE DE19746612A patent/DE19746612A1/de not_active Withdrawn
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1998
- 1998-10-05 BR BR9812948-1A patent/BR9812948A/pt not_active IP Right Cessation
- 1998-10-05 CN CN98810529A patent/CN1277607A/zh active Pending
- 1998-10-05 NZ NZ503604A patent/NZ503604A/en unknown
- 1998-10-05 KR KR1020007004286A patent/KR20010031297A/ko not_active Application Discontinuation
- 1998-10-05 WO PCT/EP1998/006300 patent/WO1999020616A1/de not_active Application Discontinuation
- 1998-10-05 JP JP2000516958A patent/JP2001520224A/ja active Pending
- 1998-10-05 SK SK457-2000A patent/SK4572000A3/sk unknown
- 1998-10-05 PL PL98340033A patent/PL340033A1/xx unknown
- 1998-10-05 IL IL13525698A patent/IL135256A0/xx unknown
- 1998-10-05 EP EP98954330A patent/EP1034170A1/en not_active Withdrawn
- 1998-10-05 TR TR2000/01080T patent/TR200001080T2/xx unknown
- 1998-10-05 AU AU11497/99A patent/AU748613B2/en not_active Ceased
- 1998-10-05 CA CA002307199A patent/CA2307199A1/en not_active Abandoned
- 1998-10-05 US US09/529,828 patent/US6346622B1/en not_active Expired - Lifetime
- 1998-10-05 HU HU0003758A patent/HUP0003758A3/hu unknown
- 1998-10-20 TW TW087117331A patent/TW517052B/zh active
- 1998-10-20 CO CO98060934A patent/CO4980863A1/es unknown
- 1998-10-21 AR ARP980105243A patent/AR016968A1/es not_active Application Discontinuation
- 1998-10-21 ZA ZA9809571A patent/ZA989571B/xx unknown
- 1998-10-21 HR HR19746612.5A patent/HRP980555A2/hr not_active Application Discontinuation
-
2000
- 2000-04-11 BG BG104332A patent/BG104332A/xx unknown
- 2000-04-13 NO NO20001937A patent/NO20001937L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101151249B (zh) * | 2005-03-31 | 2011-04-06 | 辉瑞产品公司 | 环戊吡啶及四氢喹啉衍生物 |
Also Published As
Publication number | Publication date |
---|---|
NO20001937D0 (no) | 2000-04-13 |
PL340033A1 (en) | 2001-01-15 |
BR9812948A (pt) | 2000-08-08 |
AR016968A1 (es) | 2001-08-01 |
BG104332A (en) | 2001-02-28 |
WO1999020616A1 (de) | 1999-04-29 |
CO4980863A1 (es) | 2000-11-27 |
KR20010031297A (ko) | 2001-04-16 |
EP1034170A1 (en) | 2000-09-13 |
TW517052B (en) | 2003-01-11 |
US6346622B1 (en) | 2002-02-12 |
NZ503604A (en) | 2002-03-01 |
AU1149799A (en) | 1999-05-10 |
HRP980555A2 (en) | 1999-08-31 |
ZA989571B (en) | 2000-04-25 |
NO20001937L (no) | 2000-04-13 |
IL135256A0 (en) | 2001-05-20 |
TR200001080T2 (tr) | 2001-01-22 |
AU748613B2 (en) | 2002-06-06 |
JP2001520224A (ja) | 2001-10-30 |
SK4572000A3 (en) | 2000-10-09 |
CA2307199A1 (en) | 1999-04-29 |
HUP0003758A3 (en) | 2001-12-28 |
DE19746612A1 (de) | 1999-04-29 |
HUP0003758A1 (hu) | 2001-10-28 |
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