CN1144791C - ***化合物及其作为多巴胺d3配体的应用 - Google Patents
***化合物及其作为多巴胺d3配体的应用 Download PDFInfo
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- CN1144791C CN1144791C CNB988069881A CN98806988A CN1144791C CN 1144791 C CN1144791 C CN 1144791C CN B988069881 A CNB988069881 A CN B988069881A CN 98806988 A CN98806988 A CN 98806988A CN 1144791 C CN1144791 C CN 1144791C
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- phenyl
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- -1 Triazole compounds Chemical class 0.000 title claims abstract description 92
- 239000003446 ligand Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 18
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229960003638 dopamine Drugs 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 239000003205 fragrance Substances 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000002464 receptor antagonist Substances 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims 2
- 125000002971 oxazolyl group Chemical group 0.000 claims 2
- 125000000335 thiazolyl group Chemical group 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims 1
- 102000004073 Dopamine D3 Receptors Human genes 0.000 abstract description 3
- 108090000525 Dopamine D3 Receptors Proteins 0.000 abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 52
- 238000000034 method Methods 0.000 description 34
- 239000002585 base Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000370 acceptor Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000499 gel Substances 0.000 description 10
- 229910052710 silicon Inorganic materials 0.000 description 10
- 239000010703 silicon Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4MTO Natural products CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [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
- 238000013016 damping Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 5
- 244000309464 bull Species 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 150000003852 triazoles Chemical group 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 4
- 101150065749 Churc1 gene Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000015554 Dopamine receptor Human genes 0.000 description 4
- 108050004812 Dopamine receptor Proteins 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- 102100038239 Protein Churchill Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- PTVZQOAHCSKAAS-UHFFFAOYSA-N 4-methyl-3-thiosemicarbazide Chemical compound CNC(=S)NN PTVZQOAHCSKAAS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-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
- 208000028017 Psychotic disease Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
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- 229910052751 metal Inorganic materials 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- BKDUWMJFLCNPKP-UHFFFAOYSA-N 4-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC=NC=N1 BKDUWMJFLCNPKP-UHFFFAOYSA-N 0.000 description 2
- AEJARLYXNFRVLK-UHFFFAOYSA-N 4H-1,2,3-triazole Chemical class C1C=NN=N1 AEJARLYXNFRVLK-UHFFFAOYSA-N 0.000 description 2
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- 102000004142 Trypsin Human genes 0.000 description 2
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 2
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- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及式(I)的***化合物,其中Ar1、A、B和Ar2具有说明书中的意义,本发明的化合物对于多巴胺-D3-受体有高亲合力,因而可用于治疗应答多巴胺-D3-受体的疾病。
Description
本发明是有关***化合物与此化合物的用途。所提及的化合物有有益的治疗特性,因此可用于治疗对多巴胺D3受体配体反应的疾病。
已揭示含有生理活性的此型化合物。US-A 4,338,453;4,408,049和4,577,020描述有抗过敏或抗精神病活性的***化合物。DE-A-4425144和WO 97/25 324描述对多巴胺D3受体配体反应的***化合物。DE-A-44 25 146,DE-A-44 25 143和DE 44 25 145揭示有相同结构形态但是带有其它杂环而非***环的化合物。
神经元特别是通过G蛋白质偶合受体而获得其信息。许多物质通过此些受体而执行作用。其中的一种物质为多巴胺。
多巴胺确实存在且其有神经递质的生理功能。对多巴胺反应的细胞与精神***症和帕金森氏症的病因有关。治疗此些和其它疾病的药剂与多巴胺受体反应。
1990年前,两种多巴胺受体亚型在药理学上明确地定义,亦即D1和D2受体。
近来已发现第三种亚型,亦即D3受体,其显然会传递一些抗精神病药剂的作用(J.C.史瓦兹(Schwartz)等人,新颖抗精神病药剂,多巴胺D3受体当为抗精神药剂的标靶,H.Y梅兹(Meltzer),瑞仿(Raven)出版社,纽约1992,135-144页)。
D3受体主要在边缘***表达,因而假设选择性的D3拮抗剂将可能有D2拮抗剂的抗精神病的特性但无神经上的副作用(P.索拉克夫(Solokoff)等人,D3多巴胺受体的定位与功能,
Arzneim.Forsch./Drug Res.42(1),224(1992);P.索拉克夫等人,当为神经安定剂标靶的新颖多巴胺受体(D3)的分子克隆和表征,
自然,347,146(1990)。
令人讶异地,现已发现某些***化合物显现对多巴胺D3受体高度的亲和性与D2受体的低亲和性。因此此些化合物为选择性的D3配体。
因此,本发明是有关式I化合物和其与生理上可耐受酸的盐:
其中
Ar1是苯基、萘基或含有1、2、3个独立选自O、S和N杂原子的5-或6-元杂环的芳香环,其中Ar1可有1、2、3或4个取代基,其彼此独立选自C1-C6-烷基,其任意被OH、OC1-C6-烷基、卤素或苯基取代,C1-C6-烷氧基、C2-C6-链烯基、C2-C6-炔基、C3-C6-环烷基、卤素、CN、COOR2、NR2R2、NO2、SO2R2、SO2NR2R2、或苯基,其任意被C1-C6-烷基、OC1-C6-烷基、NR2R2、CN、CF3、CHF2、或卤素取代,而其中提及的杂环芳香环可与苯环稠合。
A是直链或支链C4-C10-亚烷基或直链或支链C3-C10-亚烷基,其包含至少一个选自O、S、NR2、CONR2、COO、CO、或双键或三键的基团Z,
B是下基团:
或
或者,假若Ar1代表5或6元杂环或芳香环,其可被所示取代,则B亦可为下式基团
或
Ar2是苯基、吡啶基、嘧啶基或三嗪基,其中Ar2可含有1至4个取代基,其彼此独立选自OR2、C1-C6烷基、C2-C6-链烯基、C2-C6-炔基、C1-C6-烷氧基-C1-C6-烷基、卤素-C1-C6-烷基、卤素-C1-C6-烷氧基、卤素、CN、NO2、SO2R2、NR2R2、SO2NR2R2、5或6元碳环,芳香或非芳香环与含有1或2个选自O、S或N的杂原子的5-或6-元杂环芳香或非芳香环,其中的碳环或杂环被C1-C6-烷基、苯基、苯氧基,卤素、OC1-C6-烷基、OH、NO2或CF3取代,而其中Ar2可稠合至上文定义的碳环或杂环,
R1是H、C3-C6-环烷基或C1-C6-烷基,其可被OH、OC1-C6-烷基或苯基取代;
R2基团可相同或相异为H或C1-C6-烷基,其可被OH、OC1-C6-烷基或苯基取代;
除下列化合物,及其盐之外:
本发明的化合物为选择性的多巴胺D3受体配体,其以区域选择性方式作用在边缘***,而且由于其对D2受体的低亲和性使其较D2受体拮抗剂的传统神经安定剂有较少的副作用。因此,此化合物可用于治疗对多巴胺D3受体拮抗剂或多巴胺D3受体激动剂反应的疾病,例如,治疗中枢神经***的疾病,特别是精神***症、抑郁症、神经机能病、精神病、帕金森氏症和焦虑症。
在本发明全文中,如下表述有其规定的意义:
烷基(亦指处于例如烷氧基、烷氨基等中的烷基)为直链或支链烷基,其含1至6个碳原子,且特别是1至4个碳原子。烷基可含有一或多个彼此独立选自OH、OC1-C6-烷基、卤素或苯基的取代基。
烷基的范例为甲基、乙基、正-丙基、异-丙基、正-丁基、异丁基、叔丁基等。
环烷基特别是指C3-C6-环烷基,就如环丙基、环丁基、环戊基和环己基。
亚烷基为直链或支链。假若A不含任何基团Z,则A含4至10个碳原子,较佳为4至8个碳原子。因此***的核和基团B之间的链至少有4个碳原子。假若A含至少一个该Z基团,则A含3至10个碳原子,较佳为3至8个碳原子。
假若亚烷基至少含一个Z基团,则其可排列于亚烷链中任意点或处于基团A的位置1或2(由Ar1基团看起)。CONR2和COO较佳者是以羰基面对***环的方式排列。式I化合物特别佳者为其中A为-Z-C3-C6-亚烷基,特别是-Z-CH2CH2CH2-、-Z-CH2CH2CH2CH2-、-Z-CH2CH=CHCH2-、-Z-CH2C(CH3)=CHCH2-、-Z-CH2C(=CH2)CH2-、-Z-CH2CH(CH3)CH2-或直线型-Z-C7-C10-亚烷基,而Z连于***环。Z较佳为CH2、O而特别是S。另外较佳为A-(CH2)4-、-(CH2)5-、-CH2CH2CH=CHCH2-、-CH2CH2C(CH3)=CHCH2-、-CH2C(=CH2)CH2-、或-CH2CH2CH(CH3)CH2-。
卤素为F、Cl、Br或I。
卤烷基可含一或多个,特别是1、2、3或4个卤原子,其可位在一或多个C原子上,较佳为在α或ω位置。特别佳者为CF3、CHF2、CF2Cl或CH2F。
酰基较佳为HCO或C1-C6-烷基-CO,特别是乙酰基。当Ar1为经取代时,取代基亦可位于氮杂原子上。
Ar1较佳为
其中
R3至R6为H或基团Ar1的上述取代基,
R7为H、C1-C6-烷基或苯基,而
X是N或CN。假若苯基为经取代时,则取代基较佳在间位或对位。
Ar1特别佳者为
其中R3和R4有如上的意义。特别佳者为提及的苯基、吡嗪基和吡咯基。基团R3至R6较佳为H、C1-C6-烷基、OR2、CN、被C1-C6-烷基、C1-C6-烷氧基或卤素取代的苯基、CF3和卤素,与特别是H、C1-C6-烷基、
OR2和卤素。本文中,R2有如上述的意义。
基团B较佳为
而特别是
基团Ar2可含有一、二、三或四个取代基,较佳为一或二个取代基,特别是其位于间位和/或对位。其较佳为彼此独立选自C1-C6-烷基、卤烷基、NO2、卤素,特别是氯、苯基、吡咯基、咪唑基、吡唑基、噻吩基、环戊基和环己基。当取代基中的一为C1-C6-烷基时,则较佳为支链基团与特别是异丙基或叔丁基。
Ar2较佳为未经取代或经取代苯基、2-、3-或4-吡啶基或2-、4(6)-或5-嘧啶基。
当基团Ar2的取代基中的一为5或6元杂环时,则此环为例如吡咯烷、哌啶、吗啉、吡啶、嘧啶、三嗪、吡咯、噻吩或吡唑基,而较佳为吡咯、吡咯烷、吡唑或噻吩基。
当Ar2基的取代其中的一为碳环基时,则后者的基团特别是为苯基、环戊基或环己基。
当Ar2稠合至碳环基时,则后者基团特别是为萘或二氢或四氢萘基。
根据本发明的具体实施例,其是有关式I化合物,其中Ar1为如上定义的杂环芳香环,B是
或
而A和Ar2意义如上。
本发明亦包括式I化合物与生理上可耐受的酸的酸加成盐。适合的生理上可耐受的有机和无机酸的范例为氢氯酸、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。其它有用的酸描述于Fortschritte der Arzneimittelforschung(药剂研究进展),卷10,224页及后续页,贝克赫索(Birkhauser)维雷格(Verlag),贝索(Basle)与史达特革得(Stuttgart),1966。
式I化合物可含一或多个不对称中心。因此本发明除了外消旋物外亦包括相关的对映异构体和非对映异构体。各自的互变异构构型亦包括在本发明中。
制备化合物(I)的方法包括
a)将式(II)化合物
其中Y1为习用的脱离基,就如Hal、烷磺酰氧基、芳基磺酰氧基,与式(III)化合物反应
HB-Ar2 (III);
或
b)将式(IV)化合物
其中Z1是O、NR2、或S而A1是C1-C10-亚烷基或键,与式(V)化合物反应
Y1-A2-B-Ar2 (V)
其中Y1如上述的意义而A2是C2-C10-亚烷基,其中A1和A2一起含3至10个C原子而A1和/或A2任选含至少一个基团Z:或
c)将式(VI)化合物
其中Y1和A1如上意义,与式(VII)化合物反应
H-Z1-A-B-Ar2 (VII)
其中Z1如上意义:
或d)将式(VIII)化合物
利用文献中已知药剂,例如1,3-丙二硫醇、KCN/水、TMSCN或KCN/吗啉,以例如
阿布莱特(Albright)的四面体(Tetrahedron),1983,
39,3207或D.西贝奇(Seebach)的合成学(Synthesis)1969,17和1979,19或H.史特得(Stetter)的Angew.Chem.Int.Ed,1976,
15,639或凡尼尔(Van Niel)等人的四面体,1989,
45,7643马丁(Martin)等人的合成学1979,633
所描述的法反向式(VIII)化合物的极性
以产生产物(VIIIa)(以范例法使用1,3-丙二硫醇)
再与式(IX)化合物链延伸
Y1-A3-B-Ar2 (IX)
其中Y1如上意义而A3为C3-C9-亚烷基,其可含基团Z,在去保护与还原后,产生式(Ia)化合物
其中Z2是CO、或亚甲基,而Z2和A2一起含4至10个C原子;或者
e)将式(VIII)化合物与式X化合物反应
Y2-A-B-Ar2 (X)
其中Y2是正膦或膦酸酯,其是通过类似由例如赫本魏尔(Houben Weyl)的“Handbuch der Organischen Chemie“〔有机化学手册〕,4版,沁(Thieme)维雷格史达特革得,5/1b卷,383页及后续页或5/1c卷,575页及后续页所描述的常规方法。
制备其中A包括基团COO或CONR2的式I化合物的方法包含将式(XI)化合物
其中Y3是OH、OC1-C4-、Cl或连同CO一起为活化羧基,而A4为C0-C9-亚烷基,与式(XII)化合物反应
Z3-A-B-Ar2 (XII)
其中Z3是OH或NH2。
式(III)化合物为制备式(V)、(VII)和(XII)化合物的起始物质,其被由例如J.A.奇瑞斯帝(Kiristy)等人,J.Med.Chem,1978,21,1303或C.B.波朗(Pollard),J.Am.Chem.Soc.1934,56,2199所描述的标准法制备,或通过
a)以已知法将式(XIII)化合物
其中Q是H或一般的胺保护基,与式(XIV)化合物反应
Y4-Ar2 (XIV)
其中Y4是B(OH)2、-SnR3(R3=丁基或苯基)、三氟甲烷磺酰氧基,或有如Y1的意义,而R是C1-C4-烷基:或
b)将式(XV)化合物
Q-B1 (XV)
其中B1是
或
其中Q是H或一般的氨基保护基,例如丁氧基羰基、苄基,或甲基,而Y4是脱离基,例如OTf、SnBu3、B(OH)2或卤素,与式(XIVa)化合物反应
Y5-Ar2 (XIVa)
其中假若Y4是卤素或三氟甲基磺酰氧基则Y5是硼衍生物,就如B(OH)2,或含金属脱离基,例如SnR3(R3=丁基或苯基)或卤化锌,或者假若Y4是硼衍生物,就如B(OH)2,或含金属脱离基,例如SnR3或卤化锌则Y5为卤素或三氟甲基磺酰氧基,就如同描述于S.布区瓦得(Buchwald)等人,Angew.Chem.1995,107,1456或J.F.哈特微格(IIartwig)等人,J.Am.Chem.Soc.1996,118,7217或S.布区瓦得J.Org.Chem.1997,62,1264或F.凯若根(Kerrigan)等人,Tetrah。Lett。1998,39,2219与在文章中所引述的文献,或J.K.史提尔(Stille),Angew.Chem.1986,98,504或J.K.史提尔等人,J.Org.Chem.1990,55,3014或M.派瑞尔(Pereyre)等人“有机合成中的锡”(“Tin in OrganicSynthesis”),布得瓦(Butterworth)1987,或
c)将式(XVI)化合物
或
其中Q如上意义,与M-Ar2化合物反应,其中M是金属,就如Li或MgY6,而Y6是Br,Cl或I。M-Ar2可以文献中已知法由式(XIV)化合物而得,或
d)通过文献中已知法还原,例如氢化通式Q-B3-Ar2(IIIa)化合物,其中B3是上述不饱和基B中的一,以制备式(XVII)化合物
Q-B2-Ar2 (XVII)
其中B2是
型B化合物为已知或通过与已知法类似的方式而得,例如1,4-二氮杂环烷:L.波杰森(Borjeson)等人,Acta Chem.Scand.1991,45,621;麻乔瑞何(Majahrzahl)等人,Acta.Pol.Pharm.1975,32,145;1-氮杂环庚酮:A.耀古(Yokoo)等人,Bull Chem.Soc.Jpn.1956,29,631和WO 97/25324。
上式中Ar1、R1、A、B、Z和Ar2如上定义。
Ar1-***,Ar2,Ar1型化合物为已知或使用已知法制备,例如S.古柏塔(Kubota)等人,Chem.Pharm.Bull 1975,23,955或A.R.卡卓兹奇(Katritzky),C.W.瑞斯(Rees)(编辑)“综合杂环化学”,柏革曼(Per gamon)出版社,或“杂环化合物化学”J.Wiley & Sons公司,纽约与文中所引述的文献。
式VIII化合物为新颖的,除其中R1代表H,且Ar1代表苯基,对-甲苯基,2-,3-,4-吡啶基,对-氯代苯基或对-硝基苯基的化合物之外,且同样地是本发明主题的一部分。
制备(VIII)和(XI)型化合物,其中A和C0-亚烷基,通过金属化3-芳基-5-H-1,2,4(4H)-***
的方法以及通过在T.克夫曼(Kauffman)等人,Angew,Chem.Int.Ed.Engl.1972,11,846或通过A.R.卡卓兹奇,C.W.瑞斯(编辑)的“综合杂环化学”,柏格曼出版社,Vol.5,753页中所描述的类似法。
制备新颖化合物和起始物质与中间物亦通过开始引述的专利公开物中所描述的类似法。
上述反应一般是在溶剂中于室温与所使用溶剂的沸点之间进行。可用的溶剂范例为酯,就如乙酸乙酯,醚,就如***或四氢呋喃,二甲基甲酰胺,二甲基亚砜,二甲氧基乙烷,甲苯,二甲苯,酮,就如丙酮或甲基乙基酮,或醇,就如乙醇或丁醇。
若需要,可在含有酸结合剂中进行反应。适当的酸结合剂为无机碱,例如碳酸钠或钾、碳酸氢钠或钾、乙醇钠或氢化钠、或有机金属化合物,就如丁基锂,或烷基镁化合物,或有机碱,例如三乙胺或吡啶。后者可同时当为溶剂。
反应进行可使用催化剂,例如过渡金属与其配合物,如Pd(PPh3)4、Pd(OAc)2或Pd(P(oTol)3)4,或使用相转移催化剂,例如氯化四丁铵或溴化四丙铵。
粗产物可以习用法分离,例如,经过滤法,经蒸馏除去溶剂或由反应混合物萃取等等。所得化合物可以习用法纯化,例如通过溶剂再结晶,经色谱术或经转化成酸加成化合物。
制备酸加成盐是以习用法,通过混合自由碱与适当的酸,其适于在有机溶剂溶液中,例如低级醇,就如甲醇、乙醇或丙醇,醚,就如甲基叔丁基醚,酮,就如丙酮或甲基乙基酮,或酯,就如乙酸乙酯。
当用于治疗上述疾病时,新颖化合物是以习用法经口或非经肠(皮下、静脉内、肌肉内、或腹膜内)投药。其亦可以蒸气剂或喷雾剂经鼻/喉部位投药。
剂量依赖于患者年龄、病况和重量与投药模式。通常活性化合物的每日剂量在经口投药的情况下为每患者每天约10至1000毫克,而非经肠投药的情况下为每患者每天约1至500毫克。
本发明亦有关含新颖化合物的药剂。此些药剂是以一般医药投药型出现,以固体或液体型,例如片剂、薄膜片剂、胶囊、粉剂、粒剂、糖衣片剂、栓剂、溶液或喷雾剂。本文中,活性化合物可与习用的医药辅助物质组合在一起,就如片剂粘合剂、填充剂、防腐剂、片剂分解剂、流动剂、润滑剂、湿润剂、分散剂、乳化剂、增溶剂、阻滞剂、抗氧化剂和/或推进气体(参见H.沙克(Sucker)等人,PharmazeutischeTechnologie〔医药技术〕,沁-维雷格,史达特革得,1978)。所得投药型一般含活性化合物量为1至99重量%。
以下实施例用以解释本发明而非限定的。
实施例1
3-{3-[4-(2-叔丁基-6-三氟甲基嘧啶-4-基-)哌嗪-1-基]丙巯基}-4-甲基-5-苯基-1,2,4-(4H)-***
A.制备起始化合物:
A.1.以已知法将2-叔丁基-4-[4-(3-氯丙基)哌嗪-1-基]-6-三氟甲基嘧啶和2,2-二甲基丙酰亚胺与三氟乙酸乙酯反应以产生2-(2,2-二甲基乙基)-4-羟基-6-三氟甲基嘧啶。杂环化合物(J.Wiley & Sons公司约翰威利与其子,1994,Vol.52.D.J.布朗(编辑))。
C9H11F3N2O 熔点187-188℃
A.2.以亚硫酰氯氯化后,将粗产物以过量无水哌嗪处理,可得2-叔丁基-4-哌嗪-1-基-6-三氟甲基嘧啶。
C13H19F3N4 熔点78-80℃
A.3.所得化合物以1-溴基-3-氯丙烷在四氢呋喃中烷基化,可得2-叔丁基-4-[4-(2-氯丙基)哌嗪-1-基]-6-三氟甲基嘧啶。
C16H24ClF3N4 熔点83-84℃。
根据S.丘伯塔(Kubota)等人,Chem.Pharm.Bull,1975,23,955的方法,在吡啶中将相对应酰基氯与烷基硫代氨基脲反应,再在碳酸氢钠水溶液中环化,或通过在适当溶剂中将相对应酰基肼与硫代异氰酸烷基酯加成,若无另外说明,则可得到嵌入式***。
A.4
4-甲基-3-巯基-5-(苯硫-3-基-)1,2,4-(4H)-三 唑
分离钠盐
1H-NMR(DMSO-d6):3.7(3H);7.5(m,2H);7.8(m,1H)
熔点:146℃
C7H6N3S2Na(219)
A.5
4-甲基-3-巯基-5-(2,5-二甲基-呋喃-3-基)1,2,4- (4H)-***
1H-NMR(DMSO-d6):δ=2.3(s,3H);2.5(s,3H);3.7
(s,3H):6.1(s,1H)。
28710/30
A.6
4-甲基-3-巯基-5-(2,6-二氯苯基)1,2,4-(4H)-三 唑
分离钠盐
1H-NMR(DMSO-d6):δ=3.7(s,3H);7.4(dd,1H);7.6
(d,1H):8.2(d,1H)。
熔点:220-225℃。
A.7
4-甲基-3-巯基-5-(4-甲磺酰基-苯基)1,2,4-(4H) -***
1H-NMR(DMSO-d6):δ=3.7(s,3H);7.4(dd,1H);7.6
(d,1H):8.2(d,1H)。
熔点:238-239℃
A.8
4-甲基-3-巯基-5-(3-溴吡啶基-5)1,2,4-(4H)-三 唑
分离钠盐
1H-NMR(DMSO-d6):δ=3.7(s,3H);8.2(m,1H);8.9(m,2H).
A.9
4-甲基-3-巯基-5-(吡咯-2-基)1,2,4-(4H)-***
1H-NMR(DMSO-d6):δ:3.7(s,3H);6.2(m,1H);6.8(1,2H);7.0
(m,1H);11.8(s,1H);14.0(s,1H)。
熔点:200-201℃
A.10
4-甲基-3-巯基-5-(3-苯并噻吩基)1,2,4-(4H)-三 唑
分离钠盐
1H-NMR(DMSO-d6):3.8(s,3H);7.5(m,2H);8.0(m,3H).
A.11
4-甲基-3-巯基-5-(4-甲基-噻唑-5-基)1,2,4-(4H) -***
1H-NMR(DMSO-d6):2.4(s,3H);3.4(s,3H);9.2
(s,1H):14.1(s,1H)。
A.12
4-甲基-3-巯基-5-(6-氯-联苯基-2)1,2,4-(4H)- ***
1H-NMR(DMSO-d6):3.8(s,3H);7.6(m,1H);7.9(m,1H);8.1(m,3H);
8.4(s,1H)。
A.13
4-甲基-3-巯基-5-(2,4-二硝基苯基-)1,2,4-(4H) -***
熔点:250-251℃
MS:m/z:281[M+]
A.14
4-甲基-3-巯基-5-(4-CF3-苯基)1,2,4-(4H)-三唑
MS:m/z:259[M+]
A.15
4-丙基-3-巯基-5-(2-甲基噁唑-4-基)1,2,4-(4H) -***
分离钾盐。
在60毫升乙醇含4.9克(22.5毫摩尔)2-甲基噁唑-4-酰基肼-双盐酸盐(在甲醇溶液中通过肼解相对应甲酯而得)溶液中相继加入6.22克(95毫摩尔)碳酸钾与2.4毫升(23毫摩尔)异硫氰酸丙酯并沸腾加热4小时。
过滤所得悬浮液并浓缩,再经柱色谱术纯化残留物(6.5克)(硅凝胶,二氯甲烷-甲醇96∶4)。
产量:2.3克(39%理论值)
1H-NMR(CDCl3):δ=1.0(t,3H);1.7(m,2H);2.6(s,3H):4.2(sm,2H);
8.1(s,1H);12.6(s,1H)。
A.16
4-丙基-3-巯基-5-(2-氨基-噻唑-4-基)1,2,4-(4H) -***
分离钾盐
1H-NMR(DMSO-d6):0.8(t,3H);1.6(m,2HI);3.4(s,2H);4.3
(m,2H),7.4(s,1H);13.8。
A.17
4-甲基-3-巯基-5-(5-甲基咪唑-4-基)1,2,4-(4H) -***
分离钾盐
1H-NMR(DMSO-d6):2.3(s,3H);3.4(s,3H);7.5(s,1H)。
A.18
4-甲基-3-巯基-5-(酰胺基)1,2,4-(4H)-***
1H-NMR(DMSO-d6):3.7(s,3H);7.95(s,1H);8.25(s,1H);
14.2(s,1H).
MS:m/z:158[M+]
A.19
4-甲基-3-巯基-5-(N-甲基吡咯-2-基)1,2,4-(4H) -***
将10.6(101.1毫摩尔)4-甲基-3-硫代氨基脲与催化量的二甲氨基吡啶加入含于DMF中的10.2克(45.1毫摩尔)2-三氯乙酰氧基-N-甲基吡咯(根据瑞帕柏(Rappoport)等人,J.Org.Chem,1972,37,3618而得)并加热至90℃18小时。在室温将77毫升水加入所得产物,以10%HCl酸化并在0℃搅拌1小时,由不溶物中滤出,再以乙酸乙酯萃取原液。干燥有机层,蒸发,而所得粗产物与427毫升1M碳酸氢钠溶液加热至沸腾。反应完成后,滤出原液的不溶物,以浓HCl中止反应并酸化,分离沉淀固体。
产量:2.3克(27%理论值)
MS:m/z:194[M+]
1H-NMR(DMSO-d6):δ=3.6(s,3H);3.9(s,3H);6.2
(m,1H):6.6(m,1H);7.1(m,1H);14.0(1H)。
B.制备终产物:
在100℃加热576毫克(3毫摩尔)4-巯基-3-甲基-5-苯基-1,2,4-(4H)-***(根据S.丘伯塔(Kubota)与M.尤达(Uda),Chem,Pharm.Bull.(1975),23,955-966的方法制备,其是通过苯甲酰氯与N-甲基硫代氨基脲反应,再续而环化)与1.1克(3毫摩尔)在A.3描述的氯丙基化合物6小时,搅拌时,其与含于10毫升无水DMF的7.2毫克(3毫摩尔)氢氧化锂一起。冷却混合物后,将50毫升水加入,再以叔丁基甲基醚萃取全部物质3次。以硫酸钠干燥有机相并通过蒸发浓缩:经柱色谱术(硅凝胶)纯化残留物。续而利用含醚氢氯酸将所得纯物质(920毫克=59%)转化成其盐酸盐。
C25H33ClF3N7S(556)熔点191-193℃
列于下表的式(I)物质是以类似法而得。
表1
c=环,例如cProp=环丙基
实施例20-25和65的化合物是以下法获得。
实施例20
3-{3-[4-(2-叔丁基-6-三氟甲基嘧啶-4-基-)哌嗪-1-基]丙氧基}-4-甲基-5-苯基-1,2,4-(4H)-***
在60℃,将855毫克(3毫摩尔)3-碘-4-甲基-5-苯基-1,2,4-(4H)-***(以类似于Izv,Akad.Nauk SSSR,Ser.Khim(1975),616-619的法碘化4-甲基-5-苯基-1,2,4-(4H)-***而制备)与1.04克(3毫摩尔)2-叔丁基-4-[4-(3-羟丙基)哌嗪-1-基]-6-三氟甲基嘧啶(以类似于实施例1,A.3的法而制备,其是通过将描述于实施例1,A.2所得产物与3-氯丙醇反应)和含于DMF的氢化钠搅拌6小时。
处理时,将冰水加入混合物中,再以甲基叔丁基醚萃取所有物质数次。以硫酸钠干燥并移除溶剂所得的残留物经柱色谱术(硅凝胶,二氯甲烷/甲醇)纯化。产生140毫克(9%理论值)油物C25H32F3N7O(503)。
1H-NMR(CDCl3):
1.3(s,9H);2.1(m,2H);2.6-2.8(m,6H);3.5(s,3H);3.8(mbr,4H);4.6(t,2H);6.5(s,1H);7.6(m,3H);7.8(m,2H)。
实施例21
3-{4-[4-(2,6-二叔丁基嘧啶-4-基-)哌嗪-1-基]丁-1-烯基}-4-甲基-5-苯基-1,2,4-(4H)-***
a.3-甲酰基-4-甲基-5-苯基-1,2,4-(4H)-***
将18.5克(116毫摩尔)4-甲基-5-苯基-1,2,4-(4H)-***溶在235毫升无水THF中,再将溶液冷却至-70℃:在此温度将含于己烷中的85毫升(139毫摩尔)15%强度的丁基锂溶液以15分钟期间加入。45分钟后,将72毫升(1.16毫摩尔)甲酸甲酯以5分钟加入,其会造成温度升至-50℃,再续而在-50至-70℃将混合物再搅拌2小时并在-25℃搅拌30分钟:再将固体氯化铵加入,之后再加入冰水并以二氯甲烷萃取3次。干燥并蒸发溶剂后,余下22.8克残留物,以急骤色谱术(硅凝胶,乙酸乙酯/甲醇)纯化残留物。
产量:10.9克(46%理论值)
C10H9N3O(187)。
1H-NMR(CDCl3):
3.9(s,3H);7.6(m,3H);7.7(m,2H);10.2(s,1H)。
b.3-[4-(2,6-二-叔丁基嘧啶-4-基-)哌嗪-1-基]丙基-氯化三苯鏻
将3.52克(10毫摩尔)1-氯基-3-[4-(2,6-二-叔丁基嘧啶-4-基-)哌嗪-1-基]丙烷(以类似于实施例1,A.3法制备)与1.8克碘化钠(12毫摩尔)和3.41克(13毫摩尔)三苯基膦溶于75毫升丙酮中,再回流溶液24小时。
混合物冷却后,以吸滤法滤除沉淀物,在减压下经蒸发而浓缩滤液,残留物经柱色谱术(硅凝胶,二氯甲烷含3.5%甲醇)纯化。产量:6.25克(88%理论值)。
C37H48IN4P(706)。
1H-NMR(CDCl3):
1.3(5,9H);1.4(s,9H);1.9(m,2H);2.4(m,4H);2.7(m,2H);3.6(m,4H);3.9(mbr,2H);6.3(s,1H);7.6-7.9(m,15H)。
c.将在b制备的5.88克鏻盐溶在15毫升乙二醇二甲基醚中并将溶液冷却至0℃:将280毫克(9.2毫摩尔)氢化钠加入,混合物在室温搅拌15分钟后,再将溶在10毫升乙二醇二甲醚中的1.56克在以上a.中描述的醛在0℃滴加入。
在室温搅拌混合物1.5小时与40℃搅拌另外2小时后,以甲苯和水处理,再以过滤法将不溶物移除。在干燥与蒸发后由甲苯相得2.6克油状物。产量:粗产物,65%理论值。
以色谱术(硅凝胶,二氯甲烷/甲醇)纯化产物。
C29H41N7(487)。
1H-NMR(CDCl3):
1.3(s,9H);1.4(s,9H);2.6(m,8H);3.7(m,7H);6.2(s,1H);6.4(d,1H);7.0(td,1H);7.5(m,3H);7.7(m,2H)。
实施例22
3-{4-[4-(2,6-二-叔丁基嘧啶-4-基-)哌嗪-1-基]丁基}-4-甲基-5-苯基-1,2,4-(4H)-***
a.2-[4-甲基-5-苯基-1,2,4-(4H)-***-3-基]-1,3-二噻烷
将实施例21a所描述制备的6.12克(32.6毫摩尔)醛溶在16毫升氯仿中,之后在0℃将16毫升醋酸、3.28毫升(32.6毫摩尔)1,3-二巯基丙烷与160微升三氟化硼醚化物加入。将混合物回流2.5小时后,缓缓加入另外2.4毫升二巯基丙烷与三氟化硼醚化物再加热混合物另外6小时至醛完全反应。
混合物冷却至0℃后,以10%强度的氢氧化钠溶液调整至pH9-10,在0℃搅拌1小时再以二氯甲烷萃取3次。由干燥且蒸发过的溶剂相可得13.2克黄色油状物,再经柱色谱术(硅凝胶,乙酸乙酯)纯化。产量:4.3克(48%理论值)无色固体。
C13H15N3S2(277)。
1H-NMR(CDCl3):
2.1(m,2H);2.9(m,2H);3.3(m,2H);3.7(s,3H);5.3(s,1H);7.5(m,3H);7.7(m,2H)。
b.将上述831毫克(3毫摩尔)二噻烷溶在7.5毫升无水THF中,在-70℃将溶液以含于正-己烷中的2.2毫升(3.6毫摩尔)的15%强度丁基锂溶液处理。混合物在-70℃至-50℃搅拌60分钟后,滴加溶在5毫升THF的1.06克(3毫摩尔)1-氯基-3-[4-(2,6-二-叔丁基嘧啶-4-基)哌嗪-1-基]丙烷(由类似于实施例1,A.3的法制备)。再徐徐加温混合物至室温并在30-50℃另外加热60分钟以使反应完成。处理时,以固体氯化铵加入冷却的混合物并将后者加至冰块/水中:以二氯甲烷和甲基-叔丁基醚萃取混合物数次。干燥并浓缩余留1.74克(98%理论值)取代二噻烷残留物,其在40℃与超过12小时,使用阮内镍和氢在四氢呋喃中氢化。离去催化剂后,以色谱术(硅凝胶,二氯甲烷/甲醇)纯化残留物。产量:700毫克(49%理论值)。无色固体,熔点144-145℃。
C29H43N7(489)。
实施例23
3-{4-[4-(2-叔丁基-6-三氟甲基嘧啶-4-基)哌嗪-1-基]丁基}-4-甲基-5-苯基-1,2,4-(4H)-***盐酸盐
制备此化合物是通过类似于实施例22的法,使用由实施例1,A.3所得含氯化合物。
C29H34F3N7(502)。
1H-NMR(CDCl3):
1.3(s,9H);1.7(m,2H);1.9(q,2H);2.4(t,2 H);2.5(t,4H);2.8(t,2H);3.6(s,3H);3.75(m,4H);6.6(s,1H);7.4(m,3H);7.6(m,2H)。
实施例24
3-{3-[4-(2-叔丁基-6-三氟甲基嘧啶-4-基-)哌嗪-1-基]丙巯基}-5-(2,5-二甲基呋喃-3-基)-4-甲基***盐酸盐
获得2,5-二甲基呋喃-3-基-3-巯基-4-甲基-1,2,4-(4H)-***是通过2,5-二甲基呋喃-3-碳酰氯与N-甲基硫代氨基脲反应再续而根据丘伯塔和尤达,Chem,Pharm,Bull(1975),23,955-966的法环化。
C9H11N3OS(209)。
1H-NMR(CDCl3):
2.2(s,3H);2.3(s,3H);3.5(s,3H);6.5(1H).
上示化合物是经类似于实施例1B的法反应而得。熔点190-192℃。
C25H34F3N7O SHCl(574)。
实施例25
3-{3-[4-2-叔丁基-6-三氟甲基嘧啶-4-基-]哌嗪-1-基]丙巯基}-5-(吡嗪-2-基)-4-甲基***盐酸盐
获得3-巯基-4-甲基-5-吡嗪-2-基-1,2,4-(4H)-***是通过实施例24丘伯塔和尤达的类似法反应吡嗪-2-碳酰氯。
上示化合物同样是以类似于实施例1B的法制备。熔点164-169℃。
C23H31F3N9(522)。
实施例65
3-(3-(4-(2-叔丁基-6-三氟甲基嘧啶-4-基-)哌嗪-1-基)丙基巯基-4-甲基-5-((1H)-四唑基-5)-1,2,4-(4H)-***。
a)3-(3-(4-(2-叔丁基-6-三氟甲基嘧啶-4-基-)哌嗪-1-基)丙基巯基-4-甲基-1,2,4-(4H)-***-5-羧酰胺
950毫克(6.0毫摩尔)5-巯基-4-甲基-1,2,4-(4H)-***-3-羧酰胺与2.2克(6.0毫摩尔)得自根据实施例1.A3的含氯原料和144毫克氢氧化锂(6.0毫摩尔)在17毫升DMF中加热至100℃并搅拌3小时。将混合物冷却并加入100毫升水,以甲基-叔丁基醚萃取混合物。将溶剂层干燥并蒸发。以色谱术(硅凝胶,二氯甲烷甲醇95∶5)纯化残留物。
产量:1.65克(57%理论值)
熔点:141-143℃
C20H29F3N8OS(MG 486)。
b)3-(3-(4-(2-叔丁基-6-三氟甲基嘧啶-4-基-)哌嗪-1-基)丙基巯基-5-氰基-4-甲基-1,2,4,(4H)-***
将1.15克(24.0毫摩尔)上述化合物溶在20毫升二氯甲烷和2毫升(12.0毫摩尔)二丙基乙基胺中,冷却至0℃,另外再徐徐加入0.5毫升三氟乙酸酐。在室温搅拌3小时后,以水洗涤混合物两次,再以20%强度的NaHSO4溶液,再以饱和HaHCO3溶液,再以盐水洗涤:将有机层干燥并蒸发。残留物为0.9克油状物(81%理论值)。样品以含醚氯化氢转换成盐酸盐。
熔点:220-222℃
C20H27F3N8S(MG468)。
C20H28ClF3N8S(MG503.5)。
c)5-(3-(4-(2-叔丁基-6-三氟甲基嘧啶4-基-)哌嗪-1-基)丙基巯基-4-甲基-3-((1H)-四唑-5)-1,2,4-(4H)-***
将0.8克(1.7毫摩尔)上述物质溶于1毫升DMF中,再将122毫克(1.9毫摩尔)叠氮化钠与100毫克(1.9毫摩尔)氯化铵加入,将混合物加热至85℃并搅拌2小时。处理时,将一些水加入,以NaOH将溶液调至pH7并以二氯甲烷萃取。干燥并浓缩剩余约1克残留物,其经色谱术(硅凝胶,二氯甲烷甲醇8∶2)纯化。
产量:0.38克(43%理论值)
闪点:133°(分解)
C20H28F3N11S(MG511)
列于表2至9的化合物是以类似法而得。
表2
Ar1 R1 T R7 Z R9 R10 X-Y A
N-甲基-2-吡咯基 Et N tBut N 4-MeOPh H CH2-N COO-(CH2)4-
2-甲基-4-噁唑基 But N tBut N H OMe CH2-N S-CH2-CH=CH-CH2-
N-甲基-2-吡咯基 But N iProp CH tBut H CH2-CH S-(CH2)3-
4-咪唑基 Me N tBut CH iProp H CH2-N S-(CH2)7-
2,5-二-甲基呋喃基-3- cBut N 吡咯基 N Me H CH=C NH-(CH2)4
N-甲基-2-吡咯基 Me N tBut N tBut H CH2-CH S-(CH2)3-
2-吡咯基 Me N 2,4OMe-Ph N Cl H CH2-N O-(CH2)3-
2-吡嗪基- (CH2)4-OMe N tBut N 1-吡咯基 H CH2-N -(CH2)8-
2-甲基-吡啶-3-基 CH2Ph CH iProp N H OMe CH2-N -(CH2)4-
2-吡嗪基- cProp CH H N CH3 OMe CH=C O-(CH2)3-
3-Br-嘧啶-5-基 Et N Prop N cHex H CH=C O-(CH2)4-
嘧啶-3-基 Et N tBut N nHex H CH2-N S-CH2-C(CH3)=CH-CH2-
N-丙基-四唑基 CH2Ph N iProp N H OMe CH2-N S-(CH2)4-
2-甲基-吡啶-3-基 cProp N H N CH3 OMe CH=C O-(CH2)3-
N-乙基-吲哚-3-基 Me N H N iProp OMe CH2-N S-(CH2)3-
四唑基- Et N tBut N H CH3 CH2-N -(CH2)4-
6-氯基-联苯基-2 Me CH tBut N tBut OMe CH2-N CONH-(CH2)4-
4-甲基噻唑基 Me N 4-OMePh N Me Me CH2-N S-(CH2)7-
四唑基- iProp N tBut N Ph H CH2-N CO-(CH2)3-
N-甲基-2-吡咯基 Prop N Me CH 吡咯基 H CH=C CH2-CH2-C(CH3)=CH-CH2-
4-咪唑基 cProp N n-丙基 N tBut H CH=C NH-(CH2)3-
2-吡咯基 Me N 4-OMePh N Me Me CH=C S-(CH2)8-
3-噻吩基 Me CH 4-OMePh N Me Me CH2-N CH2-CH2-C(=CH2)-CH2-
2-甲基-4-噁唑基 Et N tBut N 吡咯基 H CH2-N S-CH2-C(=CH2)-CH2-
2-甲基-4-噁唑基 cProp N tBut CH Me H CH2-N S-CH2-CH=CH-CH2-
N-丙基-四唑基 Me N CF3 CH Me 丁基 CH=C CH2-CH2-CH(CH3)-CH2
3-噻吩基 cProp N CF3 N Me 丁基 CH=C CH2-CH2-CH(CH3)-CH2
N-丙基-四唑基 Me N CF3 N H H CH2-N -(CH2)4-
3-噻吩基 cBut N CHF2 CH H H CH2-N -(CH2)4-
2,5-二甲基-呋喃基-3- Me N 吡咯基 CH Me H CH=C NH-(CH2)4-
噁二唑-2-基 Prop N Me N 吡咯基 H CH2-N -(CH2)4-
N-丙基-2-吡咯基 Prop N Me N 吡咯基 H CH=C CH2-CH2-C(CH3)=CH-CH2-
3-苯并噻吩基 iProp N tBut N Ph H CH2-N CH2-CH2-CH(CH3)-CH2-
5-甲基咪唑-4基 Me N 2,4OMe-Ph CH Cl H CH2-N O-(CH2)3-
2-氨基噻唑-4基 Prop N Cl CH iProp H CH2-N CH2-CH2-C(CH3)=CH-CH2-
N-甲基-2-吡咯基 iProp CH tBut N tBut H CH2-CH S-(CH2)3-
N-丙基-2-吡咯基 Prop N Me CH tBut H CH=C CH2-CH2-CH(CH3)-CH2-
3-苯并噻吩基 iProp N tBut CH H Ne CH2-N S-CH2-C(CH3)=CH-CH2-
2-吡咯基 Me CH iProp N Me H CH2-CH NH-(CH2)3-
2-苯基-呋喃-3-基 cProp N CF3 CH CH CH CH=C S-(CH2)3
3-Br-嘧啶-5-基 Me CH iProp N tBut H CH2-N CO-(CH2)7-
2-氨基噻唑-4基 Et N CH Cl CH CH CH2-N CONH-(CH2)4-
6-甲基-苯并吲哚-3-基 Me N iProp CH 呋喃基 H CH2-N CH2-CH2-C(CH3)=CH-CH2-
2,5-二甲基-呋喃基-3- cBut CH 吡咯基 N Me H CH=C NH-(CH2)4-
四唑基- iProp N tBut CH H Cl CH2-N CO-(CH2)8-
4-咪唑基 (CH2)4-OMe CH tBut N H H CH2-N -(CH2)8-
嘧啶-3-基 Et CH 吡咯基 N cHex H CH=C S-(CH2)4-
4-咪唑基 Me N iProp N iProp H CH2-N S-(CH2)7-
N-丙基-四唑基 Et CH tBut N nHex H CH2-N S-CH2-C(CH3)=CH-CH2-
表3
R1 R2 R3 R4 R5 T R7 Z R9 R10 X-Y A
Me H CN H CN N tBut N tBut H CH2-CH S-(CH2)3-
Me OMe H OMe H N iprop N iProp H CH2-N S-(CH2)7-
Me H H MeSO2 H N H N CF2Cl H CH2-N O-(CH2)3-
Me H Me CN H CH tBut N tBut H CH2-N CONH-(CH2)4-
cProp H Me CN H N 正丙基 N tBut H CH=C NH-(CH2)3-
Me OMe H tBut H N 4-OMePh N Me Me CH=C S-(CH2)8-
Me H iProp H Me CH 4-OMePh N Me Me CH2-N S-(CH2)7-
Et H H H H N Me N 吡咯基 H CH2-N -(CH2)4-
iProp H H H H N 吡咯基 N Me H CH2-N CO-(CH2)8-
Et Me H Br Br CH tBut N 吡咯基 H CH2-N S-CH2-C(=CH2)-CH2-
Et H H 4-MePh H N tBut N 2-萘基 H CH2-N COO-(CH2)4-
-(CH2)4-OMe H Cl Cl H N tBut N 1-吡咯基 H CH2-N -(CH2)8-
Prop Me H Br H CH Me N 吡咯基 H CH2-N S-CH2-C(=CH2)-CH2-
Et H MeSO2 Me MeSO2N Prop N cHex H CH=C O-(CH2)4-
Et Me H Br H N tBut N nHex H CH2-N S-CH2-C(CH3)=CH-CH2-
But H OMe H OMe N tBut N H OMe CH2-N S-CH2-CH=CH-CH2-
CH2Ph I OMe H H N iProp N H OMe CH2-N S-(CH2)4-
cProp H Me CN H N n-丙基 CH tBut Me CH=C S-(CH2)7-
cProp F H F H N H N CH3 OMe CH=C O-(CH2)3-
Me H iProp H H N 4-OMePh N Me Me CH2-N S-(CH2)7-
Me OMe H tBut H N 4-OMePh N Me Me CH2-N CH2-CH2-C(=CH2)-CH2-
iProp H CN CN H N tBut CH H Me CH=C S-CH2-CH(CH3)-CH2-
Et Me H Br H N tBut N 吡咯基 H CH2-N S-CH2-C(=CH2)-CH2-
Me H OMe H Prop N iProp N 呋喃基 H CH2-N CH2-CH2-C(CH3)=CH-CH2-
Me H CN H H N tBut CH tBut H CH2-CH S-(CH2)3-
Me OMe H OMe H N iProp CH iProp H CH2-N -(CH2)4-
Me H H MeSO2 H N H C-Me CF3 H CH2-N CONH-(CH2)4
Me H iProp H H N Me CH Me H CH2-N S-(CH2)7-
Prop SO2Me H SO2Me H N 4-OMePh CH 吡咯基 H CH=C CH2-CH2-C(CH3)=CH-CH2-
Me OMe H tBut H N 4-OMePh CH Me Me CH2-N CH2-CH2-C(=CH2)-CH2-
Prop SO2Me H SO2Me H N Me N 吡咯基 H CH=C CH2-CH2-C(CH3)=CH-CH2-
iProp OMe Ph H H N tBut N Ph H CH2-N CH2-CH2-CH(CH3)-CH2-
H H Br H NH2 N Cl CH tBut H CH2-N S-CH2-C(=CH2)-CH2-
Prop H C≡CH H H CH tBut N H CH3 CH2-N CH2-CH2-CH(CH3)-CH2-
cProp SO2Me H SO2Me H CH Me N 吡咯基 H CH=C CH2-CH2-C(CH3)=CH-CH2-
iProp OMe Ph H H CH tBut N 4-OMePh H CH2-N -(CH2)4-
Me H H H H N Me N H But CH=C -(CH2)8-
Prop NO2 H H Me N Me N 吡咯基 H CH2-N -(CH2)4-
iProp H iProp H Me N tBut N Ph H CH2-N CO-(CH2)3-
Me OMe H tBut H CH 4-OMePh N Me Me CH2-CH CH2-CH2-C(=CH2)-CH2-
表4
Rt R2 R3 R4 R5 R6 R7 R8 R9 R10 X-Y A
Me OMe H tBut H H tBut H tBut H CH2-N S-CH2-C(=CH2)-CH2-
cProp H H MeSO2 H H tBut F Ph H CH2-N O-(CH2)4-
Me H iProp H H H tBut H 1-吡咯基 H CH2-N S-CH2-C(CH3)=CH-CH2-
Prop SO2Me H SO2Me H H n-丙基 H tBut H CH=C S-CH2-CH=CH-CH2-
Me H Me CN H H CF3 H tBut H CH2-N S-(CH2)4-
Me OMe H tBut H Me Me H iProp H CH2-N S-CH2-CH(CH3)-CH2
Me H H Cl Cl H iProp H p-OMe-Ph H CH2-N O-(CH2)3-
cProp H Me CN H OMe tBut CN CF3 H CH=C S-(CH2)7-
Et Me H Br Br H iProp H Me Me CH=C CH2-CH2-C(=CH2)-CH2-
Et H H 4-MePh H H iProp H F OMe CH2-N S-(CH2)7-
-(CH2)4-OMe H Cl Cl H H CHF2 H But H CH2-N S-CH2-C(=CH2)-CH2-
Prop SO2Me H SO2Me H H Ph C≡CH tBut H CH2-N CH2-CH2-C(CH3)=CH-CH2-
iProp OMe Ph H H H CHF2 H H H CH=C S-(CH2)3-
cProp F H F H H CF3 H H H CH2-CH -(CH2)4-
表5
Ar1 R1 R6 R7 R8 R9 R10 X-Y A
4-咪唑基 Me H tBut H tBut H CH2-N S-CH2-C(=CH2)-CH2-
2-吡嗪基 cProp H tBut F Ph H CH2-N O-(CH2)4-
2-甲基-4噁唑基 Me H tBut H 1-吡咯基 H CH2-N S-CH2-C(CH3)=CH-CH2-
2-吡咯基 Prop H 丙基 H tBut H CH=C S-CH2-CH=CH-CH2-
3-Br-嘧啶-5-基- Me H CF3 H tBut H CH2-N S-(CH2)4-
嘧啶-3-基- Me Me Me H iProp H CH2-N S-CH2-CH(CH3)-CH2
6-氯-联苯基-2- Me H iProp H p-OMe-Ph H CH2-N O-(CH2)3-
2,5-二-甲基-呋喃基-3- cProp OMe tBut CN CF3 H CH=C S-(CH2)7-
N-丙基-四唑基 Et H iProp H Me Me CH=C CH2-CH2-C(=CH2)-CH2-
N-甲基-2-吡咯基- Et H iProp H F OMe CH2-N S-(CH2)7-
3-噻吩基 -(CH2)4-OMe H CHF2 H But H CH2-N S-CH2-C(=CH2)-CH2-
3-苯并噻吩基- Prop H Ph C≡CH tBut H CH2-N CH2-CH2-C(CH3)=CH-CH2-
2-甲基-4噁唑基- iProp H CHF2 H H H CH=C S-(CH2)3-
4-甲基噻唑基- Et H CHF2 H But H CH2-N CH2-CH2-C(CH3)=CH-CH2-
3-苯并噻吩基- iProp H iProp H p-OMe-Ph H CH2-N NH-(CH2)4-
5-基咪唑-4基 Me But Me H H H CH2-N O-(CH2)3-
2-氨基-噻唑-4基- Prop H H C≡CH But H CH2-N -(CH2)4-
N-甲基-2-吡咯基 Me H CF3 H tBut H CH=C CO-(CH2)3-
2-甲基-4-噁唑基 iProp H tBut F Ph H CH=C S-(CH2)9-
2,5-二-甲基-呋喃基- Me Me H CN H H CH2-N S-CH2-CH=CH-CH2
N-乙基-吲哚-3-基 -(CH2)4-OMe H CHF2 H H H CH=C S-(CH2)3-
2,5-二-甲基呋喃基-3- iProp H iProp H 2,4-OMe-Ph Me CH2-CH- -COO-(CH2)4-
2-氨基噻唑-4基- Me H iProp H 2,4-OMe-Ph H CH=C- -S-CH2-CH=CH-CH2-
3-Br-嘧啶-5-基 Me H Me H Et Me CH2-N S-(CH2)3-
5-乙基咪唑-4基- cProp Prop H C≡CH But H CH2-N -(CH2)4-
正丁基-四唑基- But H Et CN OH H CH=C -(CH2)4-
3-苯并噻吩基 Me H CHF2 H H H CH2-CH- S-(CH2)2-
N-甲基2-吡咯基 Me H CF3 H tBut H CH2-CH- S-(CH2)3
四唑基- cProp H CF3 H iProp H CH2-CH- -(CH2)4-
噁二唑-2-基 cProp H CF3 H H H CH=C -(CH2)4-
表6
Ar1 R1 R6 R8 R9 R10 X-Y A
N-甲基-2-吡咯基 Prop 4-MeOPh H tBut H CH2-N -S-(CH2)7-
2-甲基-4-噁唑基 Me H H iProp Me CH2-N S-CH2-CH=CH-CH2-
4-咪唑基 Me iProp Me But H CH2-N COO-(CH2)4
2,5-二甲基-呋喃基- But Me CC Me H CH=C (CH2)4-
3-噻吩基 Me H H 吡咯基 Cl CH2-CN S-CH2-C(CH3)=CH-CH2-
2-吡嗪基 cProp H CN iProp OMe CH2-N -(CH2)4-
3-Br-嘧啶-5-基 Hex H H iProp OMe CH2-N O-(CH2)3-
嘧啶-3-基 Et cHex H Prop H CH=C NH-(CH2)4
2-吡嗪基- Et H H Pent Et CH2-N -(CH2)4-
2-甲基-吡啶-3-基 Me H Cl Me H CH2-N CONH-(CH2)4-
2,5-二-甲基-呋喃基-3- cProp CH3 H H OMe CH=C -(CH2)4-
N-乙基-吲哚-3-基- cProp CH3 Me H OMe CH=C S-CH2-C(=CH2)CH2
四唑基- Et cHex H Prop H CH=C S-(CH2)3-
3-苯并噻吩基- iProp H H cProp But CH2-N S-(CH2)8-
N-丙基-四唑基 CH2Ph H H iProp OMe CH2-N S-(CH2)4-
2-氨基噻唑-4-基 Me H CN CHF2 H CH2-N -(CH2)4-
表7
R1 R2 R3 R4 R5 R6 R8 R9 R10 X-Y A
Prop H MeSO2 Me MeSO2 Et H tBut H CH2-N COO-(CH2)4-
Me Me H Br H H H tBut H CH2-N S-CH2-CH=CH-CH2-
Me H OMe H OMe iProp Me tBut H CH2-N -(CH2)4-
But OMe H OMe H Me C≡CH 吡咯基 H CH=C CONH-(CH2)4
Me H Me CN H H H Me Cl CH2-N -(CH2)4-
cProp F H F H H H iProp OMe CH2-N S-CH2-C(=CH2)CH2-
cProp H iProp H Me CH3 Me H OMe CH=C O-(CH2)3-
Et OMe H tBut H cHex H Prop H CH=C S-(CH2)3-
Et H H H CN nHex CN tBut H CH2-N S-CH2-C(CH3)=CH-CH2-
iProp H CF3 H Me H CC 4OMe-Ph H CH2-CH S-CH2-CH=CH-CH2-
Hex H H H H2NSO2 H H CHF2 H CH2-N -CO-(CH2)3-
Me H H H H H H iProp H CH=C S-(CH2)3-
CH2Ph NO2 H NO2 H H H iProp OMe CH2-N S-(CH2)4-
表8
Ar1 R1 T R7 Z R9 R10 X-Y-W A
N-甲基-2-吡咯基 Et N tBut N 4-MeOPh H CH2-N-CH2 COO-(CH2)4-
2-甲基4-噁唑基 But N tBut N H OMe CH=C-CH2 S-CH2-CH=CH-CH2-
噁二唑-2-基 Prop N Me N 吡咯基 H CH2-CH-CH2 -(CH2)4-
四唑基 i-Prop N tBut N Ph H CH2-CH-CH2 CO-(CH2)3-
N-甲基-2-吡咯基 Prop N Me CH 吡咯基 H CH=C-CH2 CH2-CH2-C(CH3)=CH-CH2-
4-咪唑基 cProp N 正丙基 N tBut H CH2-C=CH NH-(CH2)4-
2-吡咯基 Me N 4-OMePh N Me Me CH2-N-CH2 S-(CH2)8-
N-甲基-2-吡咯基 But N iProp CH tBut H CH2-C=CH S-(CH2)3-
N-甲基-2-吡咯基 Me N tBut N tBut H CH2-N-CH2 S-(CH2)3-
2-吡咯基 Me N 2,4 OMe-Ph N Cl H CH2-C=CH CONH-(CH2)4-
2-吡嗪基 (CH2)4-OMe N tBut N 1-吡咯基 H CH2-C=CH O-(CH2)3-
2-甲基-吡啶-3-基 CH2Ph CH iProp N H OMe CH2-N-CH2 -(CH2)4-
2-吡嗪基 cProp CH H N CH3 OMe CH2-N-CH2 -(CH2)8-
3-Br-嘧啶-5-基- Et N Prop N cHex H CH=C-CH2 O-(CH2)4-
嘧啶-3-基- Et N tBut N nHex H CH2-C=CH S-CH2-C(CH3)=CH-CH2-
N-丙基-四唑基- CH2Ph N iProp N H OMe CH2-N-CH2 S-(CH2)4-
2-甲基-吡啶-3-基- cProp N H N CH3 OMe CH2-N-CH2 O-(CH2)3-
4-咪唑基 Me N tBut CH iProp H CH2-N-CH2 S-(CH2)7-
2,5-二甲基-呋喃基-3- cBut N 吡咯基 N Me H CH2-N-CH2 NH-(CH2)4
N-乙基-吲哚-3-基- Me N H N iProp OMe CH=C-CH2 S-(CH2)3-
四唑基- Et N tBut N H CH3 CH2-C=CH -(CH2)4-
6-氯-联苯基-2 Me CH tBut N tBut OMe CH=C-CH2 CONH-(CH2)4
4-甲基噻唑- Me N 4-OMePh N Me Me CH=C-CH2 S-(CH2)7-
3-噻吩基- cBut N CHF2 CH H H CH2-N-CH2 -(CH2)4
2,5-二甲基-呋喃基-3- Me N 吡咯基 CH Me H CH2-N-CH2 NH-(CH2)4
3-噻吩基 Me CH 4-OMePh N Me Me CH2-N-CH2 CH2-CH2-C(=CH2)-CH2-
2-甲基-4-噁唑基 Et N tBut N 吡咯基 H CH2-C=CH S-CH2-C(=CH2)-CH2-
2-甲基-4-噁唑基- cProp N tBut CH Me H CH2-N-CH2 CH2-CH2-CH(CH3)-CH2
N-丙基-四唑基- Me N CF3 CH Me 丁基 CH2-N-CH2 CH2-CH2-CH(CH3)-CH2
3-噻吩基- cProp N CF3 N Me 丁基 CH2-N-CH2 S-CH2-CH=CH-CH2-
N-丙基-四唑基- Me N CF3 N H H CH2-CH-CH2 -(CH2)4
N-丙基-2-吡咯基 Prop N Me N 吡咯基 H CH2-N-CH2 CH2-CH2-C(CH3)=CH-CH2-
3-苯并噻吩基 iProp N tBut N Ph H CH2-N-CH2 CH2-CH2-CH(CH3)-CH2
5-甲基咪唑-4-基- Me N 2,4OMe-Ph CH Cl H CH=C-CH2 O-(CH2)3-
2-氨基噻唑-4基- Prop N Cl CH iProp H CH=C-CH2 CH2-CH2-C(CH3)=CH-CH2-
N-甲基-2-吡咯基 iProp CH tBut N tBut H CH2-CH-CH2 S-(CH2)3-
N-丙基-2-吡咯基 Prop N Me CH tBut H CH=C-CH2 CH2-CH2-CH(CH3)-CH2
3-苯并噻吩基- iProp N tBut CH H Ne CH2-N-CH2 S-CH2-C(CH3)=CH-CH2-
2-吡咯基 Me CH iProp N Me H CH2-N-CH2 N-(CH2)3-
2-苯基-呋喃-3-基 cProp N CF3 CH CH CH CH2-CH-CH2 S-(CH2)3
3-Br-嘧啶-5-基 Me CH iProp N tBut H CH=C-CH2 CO-(CH2)7-
2-氨基噻唑-4-基 Et N CH Cl CH CH CH2-N-CH2 CONH-(CH2)4-
6-甲基-苯并吲哚-3-基 Me N iProp CH 呋喃基 H CH2-N-CH2 CH2-CH2-C(CH3)=CH-CH2-
2,5-二甲基-呋喃基-3- cBut CH 吡咯基 N Me H CH2-CH-CH2 NH-(CH2)4
四唑基- iProp N tBut CH H Cl CH2-N-CH2 CO-(CH2)8
4-咪唑基 (CH2)4-OMe CH tBut N H H CH2-N-CH2 -(CH2)8-
嘧啶-3-基- Et CH 吡咯基 N cHex H CH=C-CH2 S-(CH2)4-
4-咪唑基- Me N iProp N iProp H CH2-CH-CH2 S-(CH2)7-
N-丙基-四唑基- Et CH tBut N nHex H CH2-N-CH2 S-CH2-C(CH3)=CH-CH2-
表9
Ar1 R1 R6 R7 R8 R9 R10 X-Y-W A
N-乙基-吲哚-3-基 -(CH2)4-OMe H CHF2 H H H CH2-C=CH S-(CH2)3-
2,5-二甲基-呋喃基-3- iProp H iProp H 2,4-OMe-Ph Me CH=C-CH2 COO-(CH2)4-
3-Br-嘧啶-5-基 Me Me Me H iProp H CH2-C=CH S-CH2-CH(CH3)-CH2
嘧啶-3-基 Hexyl H CF3 H tBut H CH=C-CH2 S-(CH2)4-
6-氯-联苯基-2- Me H iProp H p-OMe-Ph H CH2-N-CH2 O-(CH2)3-
N-丙基-四唑基 Et H iProp H Me Me CH2-N-CH2 CH2-CH2-C(=CH2)-CH2-
N-甲基-2-吡咯基- Et H iProp H F OMe CH2-C=CH S-(CH2)7-
3-噻吩基 -(CH2)4-OMe H CHF2 H But H CH2-C=CH S-CH2-C(=CH2)-CH2-
2,5-二甲基-呋喃基-3- cProp OMe tBut CN CF3 H CH2-C=CH CO-(CH2)3-
2-氨基噻唑-4-基- Me H iProp H 2,4-OMe-Ph H CH=C-CH2 S-CH2-CH=CH-CH2-
3-苯并噻吩基- Pentyl H Ph C≡CH tBut H CH2-N-CH2 CH2-CH2-C(CH3)=CH-CH2-
4-甲基噻唑基 Et H CHF2 H But H CH=C-CH2 CH2-CH2-C(CH3)=CH-CH2-
3-苯并噻吩基- iProp H iProp H p-OMe-Ph H CH2-C=CH -CONH-(CH2)4
5-甲基咪唑-4-基 Me But Me H H H CH2-N-CH2 O-(CH2)3-
2-氨基噻唑-4-基- Prop H H C≡CH But H CH2-N-CH2 -(CH2)4-
2-甲基-4-噁唑基- iProp H CHF2 H H H CH2-N-CH2 S-(CH2)3-
N-甲基-2-吡咯基 Me H CF3 H tBut H CH2-C-CH2 S-(CH2)7-
2-甲基-4-噁唑基 iProp H tBut F Ph H CH2-N-CH2 CONH(CH2)4-
2,5-二甲基-呋喃基 Me Me H CN H H CH=C-CH2 S-CH2-CH=CH-CH2
3-Br-嘧啶-5-基- Me H Me H Et Me CH2-N-CH2 S-(CH2)3-
正-丁基-四唑基- But H Et CN OH H CH2-N-CH2 (CH2)4-
3-苯并噻吩基 Me H CHF2 H H H CH2-C=CH S-(CH2)3-
N-甲基-2-吡咯基 Me H CF3 H tBut H CH2-C-CH2 S-(CH2)3
四唑基- cProp H iProp H CF3 H CH2-N-CH2 -(CH2)4-
丙基-四唑基- Et H CF3 H nProp H CH2-N-CH2 -(CH2)4-
噁二唑-2-基- cProp H CF3 H H H CH2-N-CH2 -(CH2)4-
5-乙基咪唑-4-基- cProp Prop H C≡CH But H CH2-N-CH2 -(CH2)4-
4-咪唑基- Me H tBut H tBut H CH2-N-CH2 S-CH2-C(=CH2)-CH2-
2-吡嗪基- cProp H tBut F Ph H CH=C-CH2 O-(CH2)4-
2-甲基-4-噁唑基- Me H tBut H 1-吡咯基 H CH2-CH-CH2 S-CH2-C(CH3)=CH-CH2-
4-嘧啶基- Et H Pent H 2,4-OMe-Ph H CH2-N-CH2
噁二唑-2-基- Hex H CF3 H tBut H CH2-N-CH2- S-(CH2)4-
药理给药形式的范例
A)片剂
在压缩片剂机器上,以习用法塑模以下组成物的片剂:
40毫克实施例1物质
120毫克玉米淀粉
13.5毫克明胶
45毫克乳糖
2.25毫克Aerosil(化学纯硅酸,细碎成亚微大小)。
6.75毫克马铃薯淀粉(其为6%强度糊剂)
B)糖衣片剂
20毫克实施例4物质
60毫克核心物质
70毫克糖化物质
核心物质是由9份玉米淀粉,3份乳糖和1份乙烯基吡咯烷酮/醋酸乙烯酯60∶40混合聚合物组成的。糖化物质由5份蔗糖,2份玉米淀粉,2份碳酸钙和1份滑石组成。因此以此法制备的糖衣片剂提供抗胃液的被膜。
生物研究-受体结合研究
1)D3-结合测试
得自Res.Biochemicals Internat.,单史卓模(One Strathmore)路,耐狄克(Natick),美国麻萨诸塞01760-2418的无性繁殖的人类D3受体表达CCL 1,3鼠成纤维细胞用以结合研究。
细胞制备
D3表达细胞在含10%牛胎血清(吉柏克(GIBCO)041-32400N号):100单位/毫升盘尼西林和0.2%链霉素(吉柏克BRL,盖尔氏堡(Gaithersburg),美国马里兰)的RPMI-1640中增殖。48小时后,细胞以PBS洗涤并以含0.05%胰蛋白酶的PBS培育5分钟。之后,以培养液中和混合液并在300g离心收集细胞。为了溶解细胞,将团粒以溶解缓冲液(5mM tris-HCL,pH7.4,其含10%甘油)快速洗涤,再以107细胞/毫升溶解缓冲液的浓度在4℃培育30分钟。在200g离心细胞10分钟再将团粒贮存在液态氮中。
结合测试
在D3受体结合测试中,膜片是以约106细胞/250微升测试混合物的浓度悬浮在培育缓冲液(50mM Tris-HCl,pH7.4,其含120mM NaCl、5mM KCl、2mM CaCl2、2mM MgCl2、10μM喹啉醇、0.1%抗坏血酸和0.1%BSA)中,并在30℃于含有与不含有测试物质中与0.1nM125碘sulpride培育。非特异性结合是以10-6M螺环哌丁苯测定。
60分钟后,在史科壮(Skatrorn)细胞收集器(史科壮,挪威里尔(Lier))上经GF/B玻璃纤维滤器过滤分离游离和结合放射配体,再以冰冷tris-HCl缓冲液,pH7.4洗涤滤器。滤器上收集到的放射活性是利用帕卡(Packard)2200 CA液体闪烁计数器定量。
使用LIGAND程式通过非线性回归分析法测得Ki值。
2)D2结合测试
细胞培养
将具备稳定表达人类多巴胺D2A受体的HEK-293细胞培育在含Glutamax ITM的RPMI 1640和含10%牛胎血清白蛋白的25mM HEPES中。所有培养液均含每毫升100单位盘尼西林和100微克/毫升链霉素。细胞保持在37℃含5%CO2的潮湿大气中。
制备用于结合研究的细胞是在室温以胰蛋白酶(0.05%胰蛋白酶溶液)处理3-5分钟。之后,细胞在250g离心10分钟并在4℃以溶解缓冲液(5mM tris-HCl,10%甘油,pH7.4)处理30分钟。接着在250g离心10分钟,残留物贮存在-20℃至使用。
受体结合测试
多巴胺D2受体“低亲和性状态”是使用125I螺环哌丁苯(81TBq/mmol,杜邦公司,Dreieich)
混合物(1毫升)由含于培育缓冲液(50mM tris,120mM NaCl、5mMKCl、2mM MgCl2和2mM CaCl2,以HCl使成pH7.4)中的1×105细胞和0.1nM 125I-螺环哌丁苯(全部结合)所组成,或者另外含有1μM氟哌丁苯(非特异性结合)或测试物质。
在25℃培育60分钟后,混合物在史科壮细胞收集器(任什(Zinsser),法兰克佛(Frankfurt))上经GF/B玻璃纤维滤器(怀特曼(Whatman),英格兰)过滤,再以冰冷50mM tris-HCl缓冲液pH7.4洗涤滤器。滤器收集得的放射活性利用帕卡2200 CA液体闪烁计数器定量。
以a)描述法进行评估
使用LIGAND程式通过非线性回归分析法或以陈(Cheng)和布鲁索夫(Prusoff)公式转换IC50值以测得Ki值。
此些测试中,新颖化合物显示对D3受体极佳的亲和性(<1微摩尔,特别是<100毫微摩尔)并对D3受体有高度选择性。
Claims (15)
1.一种式I的***化合物及其与生理上可耐受酸的盐
其中
Ar1是苯基、萘基或选自吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、噁唑基、噁二唑基、四唑基、吡啶基、吡嗪基、嘧啶基、苯并噻吩基或吲哚基的5-或6-元杂环芳香环,其中Ar1任意具有1、2或3个取代基,其是彼此独立选自可被OC1-C6-烷基或卤素取代的C1-C6-烷基,C1-C6-烷氧基、C2-C6-炔基、卤素、CN、NR2R2、NO2、SO2R2,或可被C1-C6-烷基取代的苯基;
A是直链或支链C4-C10-亚烷基,或直链或支链C3-C10-亚烷基,其至少包含一个选自O、S、NR2、CONR2、COO、CO或双键的基团Z,B是下式基团:
或者,假若Ar1代表可如所示经取代的5-或6-元杂环芳香环,则B亦可为下式基团
或
Ar2是苯基、吡啶基、嘧啶基或三嗪基,其中Ar2任意具有1至4个取代基,其彼此独立选自OR2、C1-C6-烷基、C2-C6-炔基、卤素-C1-C6-烷基,卤素-C1-C6-烷氧基、卤素、CN、NR2R2、6元碳环、芳香或非芳香环与具有1或2个选自O和N的杂原子的5元杂环芳香环,其中碳环或杂环可经C1-C6-烷基、苯基、苯氧基、卤素、OC1-C6-烷基取代和/或任意稠合至苯环,而其中Ar2可稠合至6元碳环芳香环;
R1是H、C3-C6-环烷基或C1-C6-烷基,其可被OC1-C6-烷基或苯基取代;
R2基团可为相同或相异,为H或C1-C6-烷基,其可被苯基取代:除下列化合物,及其盐之外:
2.根据权利要求1的式I化合物及其与生理上可耐受酸的盐,其中:
Ar1是苯基、萘基或选自吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、噁唑基、噁二唑基、四唑基、吡啶基、吡嗪基、嘧啶基、苯并噻吩基或吲哚基的5-或6-元杂环芳香环,其中Ar1任意具有1、2或3个取代基,其是彼此独立选自可被OC1-C6-烷基或卤素取代的C1-C6-烷基、C1-C6-烷氧基、C2-C6-炔基、卤素、CN、NR2R2、NO2、SO2R2、可被C1-C6-烷基取代的苯基;
A是直链或支链C4-C10-亚烷基,或直链或支链C3-C10-亚烷基,其至少包含一个选自O、S、NR2、CONR2、COO、CO或双键的基团,B是下式基团:
Ar2是苯基、吡啶基、嘧啶基或三嗪基,其中Ar2任意具有1至4个取代基,其彼此独立选自OR2、C2-C6-炔基、C1-C6-烷基、卤代-C1-C6-烷基,卤代-C1-C6-烷氧基、卤素、CN、NR2R2、6元碳环、芳香或非芳香环与具有1-2个选自O和N的杂原子的5元杂环芳香环,其中碳环或杂环可被C1-C6-烷基、苯基、苯氧基、卤素、OC1-C6-烷基取代,而其中Ar2可稠合至具有上述定义性质的碳环,
R1是H、C3-C6-环烷基或C1-C6-烷基,其任意被OC1-C6-烷基或苯基取代:
R2基可为相同或相异为H或C1-C6-烷基,其任意被苯基取代。及其含生理上可耐受酸的盐。
3.根据权利要求1或2的式I化合物,其中A是C4-C10亚烷基,或C3-C10-亚烷基,其任意含至少-个选自O、S和双键的基团Z。
4.根据权利要求1或2的式I化合物,其中Ar1是苯基、噻吩基、呋喃基、四唑基、吡咯基或吡嗪基,且其可如权利要求1所示为已取代。
5.根据权利要求1或2的式I化合物,其中Ar1是未经取代或具有1、2或3个彼此独立选自CN、C1-C6-烷基、OC1-C6-烷基,苯基和卤素的取代基。
6.根据权利要求1或2的式I化合物,其中R1是H、C1-C6-烷基或C3-C6-环烷基。
7.根据权利要求1或2的式I化合物,其中Ar2是苯基、吡啶基或嘧啶基,其可具有一或二个取代基,此取代基彼此独立选自C1-C6-烷基、C2-C6-炔基、卤素、CN、卤代烷基、O-烷基、苯基、吡咯基、吲哚基和环己基。
8.根据权利要求7的式I化合物,其中取代基是彼此独立选自C1-C6-烷基、苯基和卤代烷基。
9.根据权利要求8的式I化合物,其中卤代烷基选自CF3、CHF2和CF2C1。
11.根据权利要求10的式I化合物,其中
Ar1是苯基,其可被C1-C6-烷基、OC1-C6-烷基或卤素取代;而
A是-S(CH2)3-10-或-(CH2)4-10-。
13.一种药用制剂,其包含至少一种根据权利要求1至12项中任一项的化合物,任意包含生理上可接受的载剂和/或佐剂。
14.根据权利要求1至12项中任意一项的化合物在制备对多巴胺D3受体拮抗剂或多巴胺激动剂有反应的疾病的治疗药剂中的应用。
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DE19728996A DE19728996A1 (de) | 1997-07-07 | 1997-07-07 | Triazolverbindungen und deren Verwendung |
DE19728996.7 | 1997-07-07 |
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CN1262678A CN1262678A (zh) | 2000-08-09 |
CN1144791C true CN1144791C (zh) | 2004-04-07 |
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US (1) | US6472392B1 (zh) |
EP (1) | EP0994865B1 (zh) |
JP (1) | JP2002507999A (zh) |
KR (1) | KR20010021538A (zh) |
CN (1) | CN1144791C (zh) |
AR (1) | AR015713A1 (zh) |
AT (1) | ATE214057T1 (zh) |
AU (1) | AU748810B2 (zh) |
BG (1) | BG65029B1 (zh) |
BR (1) | BR9810984A (zh) |
CA (1) | CA2296102A1 (zh) |
CO (1) | CO4950565A1 (zh) |
CZ (1) | CZ302359B6 (zh) |
DE (2) | DE19728996A1 (zh) |
DK (1) | DK0994865T3 (zh) |
ES (1) | ES2174465T3 (zh) |
HR (1) | HRP20000014A2 (zh) |
HU (1) | HUP0003332A3 (zh) |
ID (1) | ID24839A (zh) |
IL (1) | IL133603A0 (zh) |
NO (1) | NO20000048D0 (zh) |
NZ (1) | NZ502181A (zh) |
PL (1) | PL193704B1 (zh) |
PT (1) | PT994865E (zh) |
SI (1) | SI0994865T1 (zh) |
SK (1) | SK285342B6 (zh) |
TR (1) | TR200000009T2 (zh) |
TW (1) | TW538041B (zh) |
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-
1997
- 1997-07-07 DE DE19728996A patent/DE19728996A1/de not_active Withdrawn
-
1998
- 1998-07-03 ID IDW991726A patent/ID24839A/id unknown
- 1998-07-03 EP EP98938687A patent/EP0994865B1/de not_active Expired - Lifetime
- 1998-07-03 AU AU87316/98A patent/AU748810B2/en not_active Ceased
- 1998-07-03 IL IL13360398A patent/IL133603A0/xx unknown
- 1998-07-03 KR KR1020007000096A patent/KR20010021538A/ko not_active Application Discontinuation
- 1998-07-03 BR BR9810984-7A patent/BR9810984A/pt not_active IP Right Cessation
- 1998-07-03 CZ CZ20000036A patent/CZ302359B6/cs not_active IP Right Cessation
- 1998-07-03 TR TR2000/00009T patent/TR200000009T2/xx unknown
- 1998-07-03 SK SK1737-99A patent/SK285342B6/sk not_active IP Right Cessation
- 1998-07-03 PT PT98938687T patent/PT994865E/pt unknown
- 1998-07-03 CN CNB988069881A patent/CN1144791C/zh not_active Expired - Fee Related
- 1998-07-03 DE DE59803292T patent/DE59803292D1/de not_active Expired - Lifetime
- 1998-07-03 PL PL98337904A patent/PL193704B1/pl unknown
- 1998-07-03 HU HU0003332A patent/HUP0003332A3/hu unknown
- 1998-07-03 DK DK98938687T patent/DK0994865T3/da active
- 1998-07-03 ES ES98938687T patent/ES2174465T3/es not_active Expired - Lifetime
- 1998-07-03 WO PCT/EP1998/004138 patent/WO1999002503A1/de not_active Application Discontinuation
- 1998-07-03 AT AT98938687T patent/ATE214057T1/de not_active IP Right Cessation
- 1998-07-03 CA CA002296102A patent/CA2296102A1/en not_active Abandoned
- 1998-07-03 ZA ZA9805867A patent/ZA985867B/xx unknown
- 1998-07-03 NZ NZ502181A patent/NZ502181A/xx not_active IP Right Cessation
- 1998-07-03 SI SI9830098T patent/SI0994865T1/xx unknown
- 1998-07-03 AR ARP980103235A patent/AR015713A1/es not_active Application Discontinuation
- 1998-07-03 JP JP50810899A patent/JP2002507999A/ja not_active Ceased
- 1998-07-04 TW TW087110844A patent/TW538041B/zh not_active IP Right Cessation
- 1998-07-07 CO CO98038391A patent/CO4950565A1/es unknown
-
1999
- 1999-12-28 US US09/446,520 patent/US6472392B1/en not_active Expired - Lifetime
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2000
- 2000-01-04 BG BG104056A patent/BG65029B1/bg unknown
- 2000-01-06 NO NO20000048A patent/NO20000048D0/no not_active Application Discontinuation
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