TWI289558B - New compounds - Google Patents
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- TWI289558B TWI289558B TW093139247A TW93139247A TWI289558B TW I289558 B TWI289558 B TW I289558B TW 093139247 A TW093139247 A TW 093139247A TW 93139247 A TW93139247 A TW 93139247A TW I289558 B TWI289558 B TW I289558B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- methyl
- chloro
- phenyl
- atom
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 239000012453 solvate Substances 0.000 claims abstract 7
- 239000000460 chlorine Substances 0.000 claims description 132
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 92
- -1 pyrazol-4-ylmethylsulfanyl Chemical group 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 38
- 208000008589 Obesity Diseases 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 235000020824 obesity Nutrition 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 108020003175 receptors Proteins 0.000 claims description 19
- 102000005962 receptors Human genes 0.000 claims description 19
- GZVHEAJQGPRDLQ-UHFFFAOYSA-N 6-phenyl-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(C=2C=CC=CC=2)=N1 GZVHEAJQGPRDLQ-UHFFFAOYSA-N 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 13
- 125000004434 sulfur atom Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 150000002923 oximes Chemical class 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 230000003042 antagnostic effect Effects 0.000 claims description 4
- 230000008485 antagonism Effects 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 3
- 206010036790 Productive cough Diseases 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 210000003802 sputum Anatomy 0.000 claims description 3
- 208000024794 sputum Diseases 0.000 claims description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 3
- 238000006467 substitution reaction Methods 0.000 claims 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 2
- 150000002576 ketones Chemical class 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims 1
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical group SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 claims 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims 1
- 102000003808 Adiponectin Receptors Human genes 0.000 claims 1
- 108090000179 Adiponectin Receptors Proteins 0.000 claims 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 1
- 101100258233 Caenorhabditis elegans sun-1 gene Proteins 0.000 claims 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-O Pyrrolidinium ion Chemical compound C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 0.000 claims 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims 1
- 125000004849 alkoxymethyl group Chemical group 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 238000010422 painting Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 150000003254 radicals Chemical group 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- 125000004953 trihalomethyl group Chemical group 0.000 claims 1
- 208000016261 weight loss Diseases 0.000 claims 1
- 230000004580 weight loss Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 43
- 239000000543 intermediate Substances 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 2
- 229940123730 Orexin receptor antagonist Drugs 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 111
- 239000013078 crystal Substances 0.000 description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- 238000002844 melting Methods 0.000 description 30
- 230000008018 melting Effects 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- 235000019441 ethanol Nutrition 0.000 description 22
- 238000010992 reflux Methods 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 101150041968 CDC13 gene Proteins 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000005711 Benzoic acid Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 235000010233 benzoic acid Nutrition 0.000 description 9
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 210000003296 saliva Anatomy 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 3
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 238000009739 binding Methods 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003337 fertilizer Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SVNCRRZKBNSMIV-UHFFFAOYSA-N 3-Aminoquinoline Chemical compound C1=CC=CC2=CC(N)=CN=C21 SVNCRRZKBNSMIV-UHFFFAOYSA-N 0.000 description 2
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108090000189 Neuropeptides Proteins 0.000 description 2
- 102000003797 Neuropeptides Human genes 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
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Description
1289558 九 發明說明·· 【發明所屬之技術領域】 本發明係關於ϋ^⑴所材σ肥素細纟抗化合物:
R3 =其合物’又關係含此等物質之製藥… (I) 法之目的為通式⑴化合物之製法,以及此等1 【先前技術】 痴肥素(0rexines)另名易痴神經肽(hypocreti rrcpeptides),及其受體,是在聊年_分子生 性ΐ經肽大量形成於外血腦下部―内,㈣ 达神經系統的許多遙遠區域。i; 1驗,务'在生物干和二十四小時律動,以及經 過程中,痴肥性系統似乎在進食方面扮演關鍵^色。申u 痴肥素A和痴肥素B蛋白,係由其唯一 肥素原蛋白分子,利用酵錄解法形成。痴肥、=質勺人預$ 個胺基酸絲,有二分子內的二硫化物橋。痴肥、3 ^ =:包含28胺基酸殘基。於哺乳動物進化中素痴肥 妝基酸序列大部份受到保存。在人類、豬、狗 :、 素A肽的胺基酸序列完全„致,而痴肥素B蛋白 杳 胺基酸内不同。腦部的生產痴肥素之神經元,形成、= =群:-部份顯示減肥蛋白敏感性,其他部份為葡萄^ I289558 體:===素=在目標細胞表面上之特殊受 【發明内容】 2爲ί it痴肥素-1受體包含425胺基酸殘基,而痴肥素_ j為444胺基酸殘基,而其胺基酸序列係屬一致。 乳類(人、豬、狗、鼠)内發生的二_肥素受體 龆、,可以發現相當大的序列同系物(佔91_98%)。人 获、,肥’、1文體的胺基酸序列,與鼠的胺基酸序列有一 ,而人類和鼠的痴肥素_2受體序列有95%一致。 ”和Β肽以高度親和性結合於二種受體。二種受 性,係利用重組系'统(在⑽細胞上)内和 相^ΐ Ϊ的細_以+漠度測量決定。與'痴肥素Β 座乂^R Ί巴素A肽顯示對痴肥素-1受體有10-50倍的效 素-2 °^^種3對^巴素A具有選擇性。二種神經對痴肥 ’、又體』不類似的南度活性,即痴肥素-2受體對痴肥辛肽 ㈣照實_,痴肥糾受體經f 於G疋曰鱗脂酶β (PLCW,而痴肥素受體假設亦結合 徑。在痴肥麵胞突接合活性做效應中, t重大任務的是服離子通道的磷酸化。痴肥素 為 f 見於中樞神經系統(腦、脊椎骨髓),但亦可見ί 型(例如腦垂體、腎上腺、胃.腸道、胰臟和 二臟}痴,素在進食行為、麵觸、神經與内分 及複雜調整能量消化方面,扮演重要角色。中樞神婉 肥素與許多特殊神經元核有互應 & 中心、腦幹内的睡/醒中心、_神經和副交^【 的神、m以及邊緣系統。在腔室投服後,癌肥素^以劑 1289558 ,依存性方式增進食物攝取、清醒時間長度、運動活力、新 陳代謝·過程速度、心律以及血壓。最近的電生理學研究證 =丄在,整生產痴肥素的神經元功能中,有代謝過程中的重 體^予’諸如減肥蛋白、葡萄糖、抑仙、單胺類和乙酿 f ^,意即生產痴肥素的神經元發展出與進食中心、'腦幹内 鹼性中心,以及反映供應食物_素的功能性 __可發生痴肥纽其受體。痴肥素對腦 1^和,上腺激素分泌有直接效用,大為影響到沿胃腸管道 作用的消化和吸收過程度。 許哲素Α可體内和體外有效提高胰臟的胰島素分泌,和 脂質的減肥蛋白分泌。 ^ fb等觀察證明痴肥素神經肽及其受體,在能量攝取7消 、,以及較兩度調整適應性過程方面,扮演重要任務。 ⑽’職對痴肥素.1祕肥素_2受财拮抗效應 嘔 賴型:適於處理像肥胖症的疾病,包含非胰島素依 Ί心者之肥胖症,以供處理睡眠障礙、中風、噁心 吐° 【實施方式】 斜貧ft等目^在於製造新穎化合物,適於醫藥開發’ 月iti 痴肥私受體賦予強烈拮抗效應,尤其是_
物,肥(;)二合:,及其盘、異構物蝴 疾肥素q拮抗活ί肥受赌抗活性,尤其J 1289558
其中’ Ar代表苯基、5或& 以氮原子、氧原子或硫原子為^方^環’含w個雜原子, 厂;烧基、^氧基= 或以一叙驗轉喊餘代威, 媽蝴、 幾何形狀之-CH=CH-基;一 同代表順犁或反受
i A 曰卫j視而要以鹵素原子、c〗_4烷基 ίΐίί;部份或全部飽和的5或6節舰基環 鹵子、CM烷基或cM烷氧基單或複取代,· :石:全部飽和雜環基之環,含小3雜原子,以氮、氧 i單liit,可視需要以咖、子、c“絲或 R代表苄基、CM烷基_、cM羥烷基…c3-8烷氧羰烷 二二羰基。Q·7幾絲、胺絲,(Cl.4)絲、Cw炫 ίί $(Cm)烷基、胺基《<^4)烷基、Q-3烷胺棊U烷基、 1-4)燒基…或嗎嚇^幾基-(Ci_4)燒基、或苯,可視需要以 一或以上鹵素原子取代; 、R代表下列基之一,可視需要以一或以上鹵素原子、 經基、烷基、三齒甲基、硫代Q 4烷基、胺基、乂c==〇)-燒基或環烷基取代;苯基、苯乙基、萘基、氫茚基或 啼基、5或6節雜環基或部份或全部飽和之環基、含1-3個一 1289558 致或不同雜原子’以氮、氧或硫原子 一部份之基,辦贱全㈣㈣n的雜環基 3 ^ ^ J ^ 2 ^ R2代表風原子或烷基; 6節if 騎職氮軒,可代表部份或全部飽和之 /被取代的綠奸基㈣取代;
R代表齒素原子、氫原子、C
Cm烷氧基。 土匕1-4石爪尻基、 上述族類的化合物較佳係通式(I)中··
Ar代表苯基,有!或2個氮原子的 X代表硫原子、氧原子、亞甲基、_N(甲基); 份,· A代表隣伸苯基,或在隣位含二自由價之雜環基部 R代表Cl-4炫基…Cl-5羥烷基-、c3 8燒氧美藉甲其 t親基-或觀·,或以—或二 烷胺基羰基; I·4沉基取代之 環美,ΐϊίί0, I、2或3個雜原子之芳族或部份飽和双 ^ "不而要以-或以上CM烧基、鹵素原子或胺基取 R3代表氫原子; 、R5代表鹵素原子、cM烧基或Cm烷氧基。 通式(I)尤佳之化合物係其中·· 2氮原要以_子取代;或具有1或 /、千之6即雜方奴糸,可視需要以鹵素原子取代; Y代表亞甲基,· X代表亞甲基、帶硫原子、氧原子或氮原子之Ci4烷 y 1289558 A代表隣伸苯基’或在隣位含二自由價之雜芳族部 份; 、口丨 装—田《:代表直鏈或支鏈C1-4垸基、Ci-3經烧基或C3-6垸氧
一 R代表芳族或部份飽和之双環部份,可視需要以cM 烧基或齒素原子取代;或者芳族或部份飽和双環部份含工_3 個雜原子,以氮、硫或氧原子為宜; R丨代表氫原子; R代表氯原子、甲基或硫甲基。
Cl-4烧基係指直鏈或支鏈之碳鏈,諸如甲基、乙基、正 丙基、異丙基,或不同之丁基。 cM $氧基係直鏈或支鏈之碳鏈基,諸如甲氧基、乙氧 基、正丙氧基或異丙氧基,或不同之丁氧基。 ,素原子係指氟、氯、溴或碘原子。 二鹵甲基係指以3個一致或不同鹵素原子取代之甲基, 例如二鼠甲基或三氣甲基。 5戈6郎雜方族環,例如嗟吩、吱喃、。比洛、咪唾、吼 唑、吡啡、嘧啶、吡嗒畊或吡喃環。 双環雜芳族環可例如為喹啉、異喹啉、噚喹啉、喹唑 琳、苯并噻畊或苯并二氮畊環。 下列為本發明通式(I)之部份最重要化合物,但遠遠不 完整: 2-(3-苯基·5ϋ甲基_17^比唾冰基甲基疏烧基)_尽喹琳_ 3-基苯并醯胺,· . 2-(3-苯基士氯甲基_17^吡唑冬基甲基硫烷基)善萘_2_ 基苯弁酿胺; 2-(3-苯基-5-氣:曱基彳乐吡唾斗基曱基硫烧基)善喹琳-6-基苯并醯胺墙j复塩; 2<3_苯基各氯·1—甲基-1乐吡唑4-基甲基硫烷基)善氫茚_ 1289558 5-基苯并酿胺; 2_(5_氯小甲基-3-0比咬士基]私Ρ比唾冬基甲基硫院基)善 奈-2-基苯并酿胺; 2-(5-氯小甲*_3-σ比咬各基坐冬基甲基硫烧基)善 喹啉-3-基苯并醯胺; 2_(5_氯小甲基各峨咬士基-1丑-咖坐_4_基甲基硫烧基)善 萘-2-基苯并酿胺; 2_(5_氯-1-甲基_3-°比咬士基-1乐°比唾斗基甲基硫烧基)善 σ奎琳-6-基苯并酿胺; 2-(5-氯-1-曱基-3-°比咬士基_1^-0比°坐-4-基甲基硫烧基)善 喹啉-3-基苯并醯胺; ΛΜ;1-溴異喹琳-3-基)各(5-氯-1-甲基-3-吼啶-3-基-1//-吡 唑-4-基甲基硫烷基)苯并醯胺; 2-(5_氣小甲基-3-0比咬各基迅°比唾_4-基甲基硫烧基)# 異喹啉-3_基苯并醯胺; 2-(5_氯小曱基-3』比咬-4-基-1丑-σ比σ坐_4_基甲基硫烧基)# 萘-2-基苯并酿胺; 2-(5-氯_1-曱基-3-σ比咬冬基-1打·σ比嗤-4-基甲基硫烧基)-//-σ奎琳-3-基苯并酿胺; 2-(5-氯-1-甲基-3-°比咬-4-基-1私°比。坐-4-基甲基硫烧基)-尽 σ奎琳-6-基苯并醯胺; 2-(5-氯-1-甲基_3-吼咬-2-基-1从°比°坐-4-基甲基硫烧基)_7V· 啥琳-3-基苯并酿胺; 2-(5·氯-1-甲基-3-。比咬-4_基丑比唾-4·基甲基硫烧基)-尽 (1-甲基異喹啉-3-基)苯并醯胺; 2-(1-乙基!苯基各氯吡唑4-基甲基硫烧基)晏·喹樣_ 3-基苯并醯胺; 2-(3-苯基-5-氣-1-丙基-1//-吡唑-4-基曱基硫烷基)_1喹啉- 3-基苯并醯胺; 11 1289558 2·(1_丁基_3_苯基-5-氣_1//_吡唑_4-基甲基硫烷基)善喹啉-3-基苯并醯胺; {3-苯基-5-氣_4-〇(啥琳各基羰醯基)苯基硫烧基甲基]_ 1//-吡唑小基}乙酸乙酯; 2-[3-苯基小(2-經乙基)_5-氯-1//-吡唑_4_基甲基硫烷基]善 σ奎琳-3-基苯弁酿胺, 2-(3-苯基-1,5-二甲基]乐吡唑_4_基甲基硫烷基)善喹啉· 3-基苯并醯胺; 2-(3-苯基-1-甲基-5-甲基硫烷基_1//_吡唑4-基甲基硫烷基) -7V_喹啉-3-基苯并醯胺; · 2-(3-苯基_5_氯-1_甲基_1//_吡唑_4_基甲基硫烷基)』塞吩1 φ 羧酸萘-2-基醯胺; 2-(3•苯基-5-氣-1-甲基-1乐吡唑4-基曱氧基)善喹啉-3-基 苯并醯胺; 2-(3_苯基氯-1-甲基-1/7_σ比唑斗基甲氧基萘4基苯 并醯胺; 2-(5-氯-1-曱基_3-吡啶|基-1拓吡唑_4_基甲氧基)·#-喹啉_ 、 3-基苯并醯胺; · 2-(5-氯小甲基-3_吡啶+基-1//•吡唑-4-基曱氧基)-尽喹啉_ 3_基苯并醯胺; 2-(5_氯小甲基各吡啶1基-1//-吡唑冬基甲氧基)_尽喹琳_ _ 3-基苯并醯胺; 2_[3-(4_氟苯基)_5-氯小甲基吡唑斗基曱氧基]#啥 啉-3-基苯并醯胺; - 2-[2-(3-苯基)-5•氯+甲基_1/7_吡唑各基乙基]喹啉各 基苯并醯胺; 2-[2-(5-氯小甲基I吡啶_3_基·比唑_4_基)乙基^喹 啉_3_基苯并醯胺; 24(3-苯基冬氯小甲基-l/f-吡唑-4-基甲基)甲胺基]善口奎 12 1289558 啉-3-基苯并醯胺; 2_(5_氯小甲基各吡啶本基-1//-吡唑冬基甲基硫烷基 (3,4-二氣苯基)苯并醯胺; 2-[5_氯小甲基-3-(2_嗔吩基比σ坐_4_基甲氧基] 啉-3-基苯并醯胺; 2-[(5-氯小甲基-3-°比咬-3-基_17^比唾4-基甲基)甲胺基]-尽喹啉-3-基苯并醯胺; 2-(5_氯小甲基-3_σ比咬-3-基-l/^π比唾斗基曱氧基)善(6: 二氟喹啉-3-基)苯并醯胺; ’ 2_(5_氯_1_曱基各°比咬-3-基-1//ϋ冬基甲氧基)善喧秦 3-基苯并醢胺; 2-(5-氯小甲基_3-°比咬-4-基比唾_4雀甲氧基)善喧备 3-基苯并醯胺。 通式(I)化合物的拮抗效應1¾值,通常在i〇Q〇遍以 下’有益的化合物顯示在痴肥素受體IC5G值低於100nM。 為了證明,兹列通式(I)的三種化合物1€;5()值如下: 2-(3_苯基氯-1-甲基-1和比唑_4_基甲基硫烷基)_尽萘冬 基苯并醯胺,痴肥素-1 Κ:5〇33 nM,痴肥素-2lC5〇156nM。 2-(5-氯小甲基_3_吡啶-4-基-1//-吡唑冬基甲氧基)#喧琳· 3-基本弁酿胺’疾肥素-1 IC5〇 51 nM,疾肥素-2 IC50 1100 nM ° 2-[2_(5_氣_1_甲基_3』比唆_3_基_1好_σ比唾4_基)乙基]_^ 琳-3-基苯并醯胺,痴肥素-1 ic5G 57 nM,痴肥素-2 iC5〇 680 nM ° 反應式1和反應式2證明通式(I)化合物之製程。按照 第一製程,通式(II)之酸(式中Ατ,Υ,Χ,Α,ΙΙ1和R5意義 上)用醯鹵形成劑,最好是氯化亞磺醯基,轉型成醯氣,再 與通式(III)之胺(式中R2和R3意義同上),在惰性溶劑 (例如二氯曱烷、氯仿、乙酸乙酯)内,於塩基(例如三乙 13 1289558 胺)或吼咬存在下,在室溫或反應混合物之回流溫度反應。 按照通式(II)所示酸之另一具體例(式中^,又X,A, R1和R2意義同上),與通式(III)之胺(式中R2和R3意義 同上),於活化劑存在下反應。活化劑可為μ乙基各(3,二甲 胺基丙基)碳化二亞胺(EDC)、4-(4,6-二甲氧基-i,3,5-三哄-2-基)冬甲基嗎啉氣化物(DMTMM),或苯并三唑小基氧基三 各唆并鱗六氟磷酸塩(PyB〇p)。反應是在惰性溶劑(例如 N,N-二甲基甲醯胺、二氯甲炫、四氳呋喃、二曙烧),在室溫 或反應混合物的回流溫度進行。
Ar
Ν^γΥ、Χ 人 COOH + HNR2R3 反應式1 ,在另一製程内,通式(VI)之化合物(式中ArjE^R5意 義同上)’與通式(IX)之醯胺(式中χ,A,R2, R3意義同 上),在垣基(例如碳酸钾、碳酸鉋)存在下,惰性劍 (例如丙,、乙腈、乙醇、耶-二甲基甲醯胺)内^ 或反應混合物之回流溫度反應(反應式2)。
反應式2 ^式⑴化合物之官能基,可轉型為其他官能基(例如 R或R取代物轉型為另一 Ri或R3取代物)。
Rkii (IV)化合物(式巾^代表苯基,R1代表甲基, 代表虱原子,為文獻上所公知,見J. 0rg Chem 1992 57 1289558 2127),和通式(IV)其他化合物(式中 上)’可利用文卜P jtr»七、、L制:屯,Θ 和通式(IV)其他化合物(式中义,Rl 可利用文獻上已知方法製造(見表 t他化令、物L武肀Ar,R丨和R5音羞同 知方法製造(見表ιυ,通式tv门) (式中Ar代表苯基,Ri代表甲基,R5 -原子,A代表苯基,膦位附有硫原子 售5。通式(VI)、(VI〇和(11)之其他化合 R,X和A意義同上)為文學上未見之新化 上),可利用文獻上已知方法製造(見表 (V^和(Π)化合物(式中Ar代表苯基, 代表氯原子,X代表硫原子,A代表苯基, 和羧基),市面有售。通式(VI)、(VII)和 物(式中Ar,R1, R5, X釦a音義问卜、炎士 合物,可由反應式3所示反應程序製成(見表12_15)。通式 (IV) 化δ物之還原,利用蝴氫化納在乙醇内實施,通式 (V) 化合物之氯化’係使用氯化亞續醯在惰性溶劑(二氯 I烷或氯仿)内進行。通式(ΥΠΙ)之化合物(式中χ和A 意義同上,R代表氫或CM烷基),係以通式乂VI)之化合物 (式^ M R1和R5意義同上),在塩基(例如碳酸卸、碳酸 铯、二乙胺)存在下,於適當溶劑(例如乙醇、二甲基 甲醯胺、丙酮、乙腈、二氯甲烷、氯仿)内烷化。通式 (VII)之化合物(式中又又和八意義同上,而R 代表CM烧基)’以氳氧化納或氫氧化钾,在乙醇水溶液内, 水解成通式(II)之化合物(式中Ar5 R1,R5, γ5 X和A意義 同上)(見表13-14)。 〜
反應式3 通式(II)之化合物(式中Ar,R1,R5和A意義同上,乂 和Y代表CH2基,或Y和X —同形成基),可利用 1289558 反應式3所示反應程序製成。 -^式之化合物(式* M Rl和R5意義同上),與 i (例如甲苯、二甲苯)内,於反應混合
。通式⑻之鱗塩(式中m Ri和r5意 =上)在垣基(例如氫化納)存在下,於耶_二甲基甲酿 通式(XI)之化合物(式中A意義同上,而R代表 ^4燒基)反應。通式(VII)之酉旨(式* M R, Rl,尺5和A 思義同上)在鹼性媒質内水解,所得酸(II)在乙醇内,於 Pd/C觸媒存在内鹵化。
OHC-A—COOR 0(1 ^ KOH ->
lla
反應式4 …, _在反應式4中,通式(Vila)指通式(VII)中γ和X 一同形成-CH=CH_基; 通式(lla)指通式(II)中Y和X 一同形成_CH=CH-基; 通式(lib)指通式(II)中Y代表CHr基,X代表 基。 16 1289558 酸反庫if) 樂上可接受塩’可_盘基盘適每 i反通式⑴化合物之溶合物純水合物^、適田 採人ii B(Ii 物’可用來處 體拮抗=扮演任務之疾病,以及處理_肥素受 、☆〜(1)之痴肥素受體拮抗劑化合物,及其製荜上可接 ίϊϋΊ於處理肥胖症及第二型糖尿病(非月夷島+3 研處麵轉礙、失眠、啦絲、處理盘神 連的睡眠障礙、壓抑、焦慮、行為障礙、性能力、障 '神、座痛、與感染關連的疼痛(像HIV)、虛幻痛、手衔德 =通ίϋΓ合物及其«上可接受衍生物, 通式(I)之化合物及其製藥上可接受衍生物,
Ξ中,2=肥素受體拮抗劑處理之疾病。在治S 物藥組成物的形式使用,製藥組成 式⑴化合物或其製藥上可接受衍生物,加上 可接受的载劑和佐劑。i市上 僂轉iii1)化合物及其製藥上可接受街生物,可經由任何 先途贼服,例如經口、腸外、舌下、鼻腔、直腸、皮j =物=服情況而言,通式⑴化合物及其製藥上可接受 液、礼液、錠劑或膠囊。 〜于 液體輔在活性成份外,含適當液體賦形冑(例如水、 菩^ιΓί、聚乙二醇、油)’呈溶液或懸浮液形式,亦可含 者色劑和嗅味劑。 J s 糖和添加劑,例如硬脂_、_、乳糖、薦 硬質和軟質明膠膠囊,可利用標準操作製造。 %夕丨Sq^ έ名性戚份,呈溶液或懸浮液形式,係由無菌 Π 1289558 水性载劑或以適當油,例 酮、芝麻油或印磷脂。J艰乙一知伞乙埽基四氫鱗 氣溶’可應用氣溶劑、滴劑、凝膠劑或粉劑。 封閉二1/核’呈水性或非水性雜雌魏形式,在 封閉谷益内,呈單劑量或複劑量。 I武在 油或途’可_,含刪讎⑼如可可奶 ,膚用途方面可用軟膏、凝膠或皮膚貼藥。 上述疾病所用通式⑴化合物及其製藥上可 生物劑1,視疾病性質而定。以成人患者言,可用日 Μ里^) 1 mg至1000 mg,尤其是約2〇 mg至約7〇〇吨。 性副=述劑量攝取情況下,通式⑴化合物預料不會有毒 ibifi 基_1払吡唑斗衫基硫烷某) 一7V-唾
Ar^Ph (苯基),Rl=Me (曱基), R =3-喹啉^ R3=H r5=c1,x=s,Y=CH2,心隣伸苯基。, 包追^基_5_氯土里基基}jp醇(v ) Ar=Ph? R =Me? R5=C1 ~ 於3-苯基·5-氯小甲基4私吡唑斗甲醛(22〇 g,〇〇1 =〇1)和20毫升硼氫化鈉乙醇溶液(189g 〇 〇5m〇1)配成的 ✓谷液,在至溫添加,將混合物擾拌3小時。於此反應混合物 加100 ml水,用1〇%塩酸中和,以二氯甲烷〇 χ 4fml)萃 取,在硫酸鈉上乾燥,在真空内蒸發;殘餘物以二異丙醚 (10 ml)處理,把白色結晶物濾除。得1 %克(79%)白色 晶體,熔點125-126°C。 NMR,δΗ (200 MHz,DMS〇_d6): 3.85 (s,3H,pCH3),4.36 18 1289558 (d5 2H? J = 4.8 Hz? CH2OHX 5.15 ft 1H? J - 4.8 Hz5 CH20^) 7·36_7·48 (m5 3HX 7.79-7.84 (m,2H)。 ’ 企应蓋^-5-氣-4_氣甲基小甲基-IF-吡唑ivn Ar = Ph R1 = Me? R5 = Cl 取(3_苯基-5_氯_1_甲基-1从吡唑-4-基)甲醇(i.u g,〇〇〇5 mol)、氯化亞續醯(0.51 ml, 0.007 mol)和氯(15 mi)之混 合物,在回流狀況下加熱1·5小時,溶劑在真空内除去。得 1·11克(92%)淡褐色固體物。 ' ' NMR? δπ (200 MHz? DMSO-dg): 3.88 (s5 3H? I-CH3) 4 74 2¾ CH2C1)? 7.38-7.54 (m5 3H)? 7.66-7.73 (m? 2H) 〇 ’ :
(c)l-(3-苯基-5-氯-1-甲基彳甲基碚烷其、苹甲 基 於2-氫硫基苯甲酸(1.54 g,〇〇1福)、無水碳酸卸 g =.012 md)和水(15 ml)配成的溶液,添加3_苯 氯甲基小甲基跑㈣(241 g,ασι /r二的η:反應混合物授拌,在回流狀況下加熱 日in,發。於固體白色殘餘物加水⑽而),
°把白色結晶物齡,水洗 〇r 传1、在上標題酸’熔點192_193 應,DMS〇_d6): 3 88 (S,犯,ΚΗ3),4.1〇 (, M,CH2S),7·25 (m, 1H), 7·38 (m5 1H) 7 丨 2 甲基硫烧基)笨甲 取2-(3_苯基_5_氯小甲基-1私吡唑_4 酸巧79 g,0·0〇5 m〇1)和氯化亞魏(7;^之;^,名 回流狀況下待加熱i小時,所得黃色溶液冷卻到室溫, 19 1289558 添加二異丙醚(50 ml),將混合物攪拌10分鐘,把析出的白 色晶體濾除,用二異丙醚(15 ml)洗,得1.59克(84%)拷 題醯氯,賴勝赋。 (g)2-(3_笨基-5-氣_1-甲基基甲某絲检莘)_尽哈 笨并醯胺(I) Ar = Ph5 R1 = Me,R2:=: 3-啥琳基,r3 = H, R5-C15X-S5Y = CH2 5 方法A (反應式1) 2-(3_苯基-5_氯小曱基_1乐吡唑-4-基甲基硫烷基)苯曱醯 氯(0.60 g,0.0016 mol)、3-胺基喹琳(0.12 g, 0.0016 m〇i)、 三乙胺(0.17 g,0.00175 mol)和二氯曱烷(25 ml)之混合 物,在回流狀況下攪拌和加熱3小時。所得黃色溶液用水萃 取(3 X 25 ml),在硫酸鈉上乾燥,於真空内蒸發,殘餘物在 秒凝膠上,使用CHC^/MeOH 100/1混合物為洗提液層析, 得0·13 g (17%)淡黃色2-(3-苯基-5_氯_1-甲基_1和比σ坐基 甲基硫烷基喹啉-3_基苯甲醯胺半水合物,熔點84_85。(:。 NMR,δΗ (400 MHz, DMSO-d6): 3·82 (s,3H,1-CH3),4.17 (s, 2Η,CH2S),7·32 (m,1Η),7·38 (m5 3Η),7·51 (m,1Η),7.58 (m5 2H),7.64 (m,4¾ 7.96 (m,2¾ 8.84 (s5 1H),9.01 (s,1HX 1〇·86 (s5 1H) 〇 實施例2 M3_苯基-5-氯-1·甲基比哇_4-某甲基硫烧某 基苯并醯胺(I) Ar : Ph,R1 = Me, R2 = 2-萘基,R3 = R5 = Cl X=S,Y=CH2,A=鱗伸苯基 ’ ' ’ 方法B (反應式1) ·- 2-(3-苯基氯小甲基-1私吡唑基甲基硫烷基)苯甲酸 (0.36 g5 0.001 mol)、2-胺基萘(0.16 g,0.00112 mol)、1-乙 基-3-(3’-二甲胺基丙基)碳化二亞胺盘酸盘(edC) (0.22 g, 0.00114 mol)、1-羥基苯并三唑(HOBT) (0.014 g,0.0001 mol)和N,N-二甲基甲醯胺(3 ml)之混合物,在室溫攪拌 20 1289558 18小時,於反應混合物加水,以乙酸乙酯萃取,在硫酸鈉上 乾燥,於真空内蒸發,殘餘物在矽凝膠上,使用正庚烷/乙 酸乙酯7/1-3/1混合物為洗提液層析。生成物在二異丙醚内結 晶,得0.21克(43%)標題醯胺,熔點76°C。 按照上述方法製造實施例3-39化合物,如表1和表2所 示0 表1
R3=H,R5=C1,x=s5 Y=-CH2-,A=隣伸苯基,而R2如下: 實施例 方法 R2 熔點(°c) 實施例1· A ax 84-85 實施例2· B οσ 76 實施例3· A σ 58-60 實施例4· B 183 實施例5· B 110 實施例6. A 57-58 1 21 1289558 實施例7· A 10M02 實施例8· A 06 78-80 實施例9· B 145 實施例10. A 00 71 - 72 實施例11· A ςα 217-218 HC1 salt 實施例12· B xx> 69 實施例13· B U/-Me 78-79 實施例14· B H 193 實施例15· B X» H 179 實施例16· B Λ0Ο 60-61 實施例17· B H2"a> \ 79 實施例18· B 158 22 21289558
R1 二 CH3, R3 = H,R5 = Cl, X =: S,Y = -CH2-5 A=隣伸苯基
實施例 製法 Ar R2 熔點(°c) 實施例19. A c,xx ax 172-173 實施例20· A Cl 86-88 實施例21· A OMe Me〇tk οσ 84-87 實施例22· A a οσ 66-67 實施例23. A a οσ 203-204 實施例24· A a οσ 156-157 實施例25. A σ οσ 83-85 實施例26· A σ οσ 236-238 23 1289558 實施例27· A σ αχ 184-186 實施例28· A σ οφτ Br 172 實施例29· B σ οσ 74 (分解) 實施例30· B σ οσ k/CH3 ch3 70 實施例31· A σ 應 105-107 實施例32. A σ αχ 175-176 實施例33· B σ NY^Me ΟΗ 176 實施例34· B σ Vr^i CI 75 (分解) 實施例35· B σ ΎΝγ^] νη2 134 (分解) 實施例36· A σ 0 115 實施例37. L— — . 一_ A ό 'Ν αχ 239-241 24 1289558 實施例38· A ό Ν οσ 190-191 1 210 實施例39. A ό 、Ν 實施例40 2-(5_氪-1-甲某-3-吡畊-2-基-1乐吡岫篡甲基琉烷基WV-喹啉_3_基茉#醯胺(I) Ar =吡畊-2-基,R1: Me, R2= 3-喹啉 基,R3 = H,R5 = Cl5 X = S,Y = -CH2_,A =隣伸苯基 方法C (反應式1) 2-(5_氯小甲基各吡畊-2_基-1//•吡唑冰基甲基硫烷基)苯 曱酸(0·81 g,0.00224 mol),溶於四氫呋喃(35 ml)内,於 此溶液:攪拌5分鐘後加3-胺基音淋(0.35 g,0.00246 mol), 攪拌5分鐘後加N-曱基嗎啉(0·25 g,0.00246 mol),攪拌2 分鐘後加4-(4,6-二甲氧基_1,3,5_三哄-2-基)-4-甲基嗎咐氯化物 (0.68 g,0·0〇246 mol)。反應混合物在室溫授拌2小時,於回 流溫度加熱1小時。溶劑在真空内除去,於反應混合物加水 (100 ml) ’用二氯甲烧萃取(3 X 50 ml),水洗(3 X 50 ml) ’在硫酸納上乾燥,於真空内蒸發。殘餘物在矽凝膠上, 使用正己烧/乙HGG/5-iG()/2()()混合物為洗提液加以層 析。得^44克(40%)白色標題醯胺,呈半水合物形式,熔 點 67-69〇C 0 實施例41 吡啶-34,Ri=Me r2=1•甲其 3-異喧琳基,R3 = H, R5 = C1,χ = S,γ = _CH A,申甲土 方法g (反應式2) _甲本基 取3-(5-氯冰氯甲基-1-甲基-i办比唑_3_基)〇比啶(〇.22 g 25 1289558 0·9 mmol)、2_氫硫基善(μ甲基異喹啉士基)苯并醯胺(〇·2 g, 0.7^nmol)無水石厌酸钟(〇 124 g,〇 9 mmol),和二甲基 工,胺UG ml)的混合物,在室溫攪拌17小時。把反應混 二μ if'主在水和水混合物上,將析出物濾除,水洗,在矽凝 用CH2Cl2/MeOH 99/1混合物為洗提液加以層析。得 • 士(11%)標題醯胺,炫點ii2°c。 按類似方式,得實施例42之化合物,如表3所示。 表3
--- 實施例 '_ 實施例4(Κ [3, R3 = Η,] —— El5 = Cl5 X = s,Y = -CH2·,Α=隣伸苯基 製法 Ar R2 賴(°C) C σ 67-69 實施例41. 實施例42. ^----- Ε ό opr ch3 112 Ε ό oor V^CH3 ch3 85 (分解) 半實施例43-46和49-51之化合物,係按照實施例2之方 、 氣^,實施例53之化合物是按照實施例41之方法e。 26 1289558 實施例47 大氯-1//-吡唑斗基甲基硫烷基1#
Ar=苯基,ί^〇·ί2Οί2ΟΗ,112:=3_喹啉 基,R3=h,rLci,x=s,y_CH2- 於乙醇(70ml)内含{3_苯基冬氯_4私(喧啉各基胺基甲 醯基)苯基硫烷基甲基]4乐吡唑4_基}乙酸乙酯(〇34 g,〇6 mmol) ^’谷液’加虱蝴化納(〇護g,1 3 mmol),混合物在 室溫攪拌40小時,加氷/水,混合物以乙酸乙酯萃取,萃取 ,在真空内蒸發,殘餘物在矽凝膠上使用CH2Cl2/Me〇H 99/1 混合物為洗提液加以層析。得〇〇68克標題醯胺, 熔點95°C。 實施例48 ilr苯基·5-氣士噎啉-3-基胺墓甲醢某某疏烷某甲 基_1_1好_吡唑,1_基}^|曼⑴Ar =苯基,R1 =CH2C〇OH5 R2: 3-喹啉基,R3 = R5 = Cl5 X= s,Y = -CH2- 於乙醇(25 ml)内含{3-苯基-5-氯_4_[2-(噎啉各基胺基甲 醯基)苯基硫烷基甲基]_1乐吡唑小基}乙酸乙酯(〇·235 g,042 mmol)之溶液,加氫氧化鋰(〇 045 g,ι·〇7 _〇1)。反應混 合物在40°C攪拌2小時,溶劑在真空内除去。於殘餘物加 水,混合物用乙酸酸化至PH=4。把析出的結晶物濾除,用 Ci^C^/MeOH混合物萃取。濾液在真空内蒸發,得〇 12克 (53%)標題化合物,熔點145°C。 實施例53 2-『3-笨基_5_氯_1_(2-丙胺某乙基)-1//-°比峻小基甲基硫烧 基啥U-基笨并醢膝(I ) Ar :苯基,R1 = CH2CH2NHCH2CH2CH3, R2二 3-喹啉基,R3: H,R5= Cl, X= S, Y - -CH2- 於2-[3-苯基小(2-經乙基)-5-氯-1丑_°比唾《4-基甲基硫烧 基,]善喹啉各基苯并醯胺(〇·152 g,〇·29 mmol )、吡啶(〇·〇29 27 1289558 ml,0.36 mmol)和二氯甲烧(50 ml)之混合物,加甲苯石黃醯 氯(0.067 g5 0.36 mmol)。反應混合物攪拌18小時;溶劑在 真空内除去。於殘餘物加丙胺(0.5 ml),混合物在密閉管 内,於4〇t:加熱5小時,再蒸發。 殘餘物在矽凝膠上,使用a^Qz/MeOH 98/2混合物為洗 提液加以層析,得0.05克(31%)標題醯胺,熔點7〇°c。 實施例43d3内製成的化合物,如表4所示。實施例54-64内按照方法A和B製成的化合物,列於表5-7。、 表4
(I)
Ar 二苯基,R3 = H,R5 = Cl5 X= S5 Y = <:Η2-5 A =隣伸苯基 實施例 製法 --— R1 熔點fC) 實施例43· B Et 133 實施例44· B n-Pr 162 實施例45· B n-Bu 147 實施例46· B —-— CH2COOEt — 160 28 1289558 實施例47· 還原 CH2CH2OH 95 實施例48· 水解 ch2cooh 145 實施例49· Β CH2CONH-nPr 102 實施例50. Β CH2CONH2 235 (分解) 實施例51· Β Γ~\ Ο N-COCH, v_v 2 135 實施例52· Ε Γ~\ o'^n-oh2ch2 80 實施例53· 胺化 CH2CH2NH-n-Pr 70 表5
Ar =苯基,R1 := CH3, R2 = 3-喹啉基,R3 = Η, X = S, Y=-CH2、A=隣伸苯基 29 1289558 實施例 製法 R5 熔點(°c) 實施例54. A H 93 實施例55· B Me 142 實施例56. B SMe 79 表6
R1 = CH3, R2 = 2-萘基,R3 = H,R5 = Cl5 X = S5 Y = -CH2- 實施例 製法 A 熔點(°c) 實施例57· Β 众. 112 實施例58· Β XX 186 實施例59. Β c^9 173 30 1289558 實施例60· Β (s>^9 160-161 實施例61· Β β 66-67 表7
R1 := CH3, R5 = Cl, X = S5 Y = _CH2_,A =隣伸苯基 實施例 製法 Ar R2 R3 熔點(°c) 實施例62. A σ cxx Me 75-77 實施例63· A σ OjO 103-106 實施例64· A l J XF, 82-86 3 實施例65 2-(3-笨氯-1·甲 甲氧; 苯并醯胺(I) Ar = Ph, α,χ=ο, y 二-ch2- 31 1289558 基甲氳某^ 7 MSyiLL At - Ph? R1 =, Me5 R5 = Cl, X=〇 取3-苯基-5-氯冰氯甲基小甲基巧乐吡唑(〇44 g,〇〇35 mol )、1羥基苯甲酸乙酯(5·82 & 〇 〇35獅丨)、碳酸鉋 (】1·4〇 g5 0.035 mol)和乙腈(200 mi)之混合物,在攪拌下 加熱4 ^時。反應混合物在真空内蒸發,於殘餘物加水(3〇〇 ml),用氯仿(3 X 15〇如)萃取,於真空内蒸發。有機相經 水洗(3 X 1〇〇 mi),在硫酸鈉上乾燥,將溶劑在真空内除 去。殘餘橘色油,於加乙醇(1〇 ml)時結晶。收集晶體,用 。乙醇洗(2 X 5 ml),得5.48克(42%)白色結晶酯,熔點77 C ° NMR? δΗ (200 MHz, DMSO-d6): U〇 (t, J=7.1 Hz? 3H), 3.89 (s,3H,l_CH3),4.12(q,J=7,lHz52H)54.97(s52H5CH2O)57.03-7.10 (m,IH),7·29-7·75 (m5 8H)。 , 边基-5-氣-1-甲基比唾_4_某甲氣某)笨甲酸 ΜΙΣ Ar = Ph? R1 =: Me, R5= Cl5 X= 0 ^乙醇(35 ml)内含2_(3-苯基_5_氯小甲基-1//_吡唑-4-基甲氧基苯甲酸乙酯(5.40g,0_0145 in〇l)之溶液,加水(35 ml)=含氫氧化鉀(1_63 g5 0.029 mol)之溶液,將反應混合 物攪拌,回流加熱3小時。把溶液冷卻,於真空内蒸發。殘 ,物溶入水(30 ml)内,以1〇%塩酸酸化至pH=3。將白色 晶體濾除,甩水(2 X 1〇 ml)洗,經乾燥,由乙醇(35 ml) 再結晶’得3.43克(69%)白色結晶材料,熔點no-ill 〇C 〇 涵小甲基-!//^比峻-4_基甲氧D-N』奢啦各 基丰丑座胺⑴—Ar = Ph,R1二Me,R2= 3-喧琳基,r3= h,R5 = cl X - 0? Y = ch2 5 5 友生1(反應式1) 將2_(3〜苯基H小曱基比唑+基甲氧基)苯甲酸 32 1289558 (tf7,8,一0〇〇4m〇1)溶人二氯甲烧(50ml)内,於此溶液添 加苯并二唑-ι_基氧基三(u比咯啶并)鐫六氟磷酸酯 (PyBOP) (2·08 g,0.004 m〇1)、3_胺基啥啉(〇 58 g,〇 〇〇4 mol),和乙基二異丙胺(〇.9〇g,〇007m〇i)。將溶液攪拌,在 回流溫度加熱50小時;冷卻到室溫,用水(5〇 ml)、1〇%碳 酸氳鈉溶液(20 ml)、水(3 X 5〇 ml)萃取,於真空内蒸 發二於殘餘物加乙醇(10 ml),把所得白色結晶物濾除,g 乙醇(2 X 10 ml)洗。得ι·5ΐ克(80 7%)標題醯胺,熔點 169_170°C。由乙醇再結晶,熔點i7〇°c。 ' NMR, δΗ (400 MHz, DMSO-d6): 3.84 (s, 3H, 1-CH3)? 5.12 (s 2H,现0),7.16 (m,1H),7·29_7·34 (m,3H),7.41 (m,1H),7.56 (m? 2H)5 7.63-7.71 (m? 4H)? 7.88-7.94 (m^ 2H) 8 73 (s 2H) 10.62 (s,lH)。 … ,· 5 ), 實施例66-73之化合物已按照方法A,B,C或D製成。 實施例74 ’ 啉_3_基苯并蓮胺(I) R3= H,R5= Cl5 X= 0, Y= -CH2- 土5 方法E (反應式2) 3_(4_氟苯基)_5_氯氯甲基_1-甲基收_σ比唾(〇% 0-0015 mol)、2_羥基-ΛΗ喹琳各基)苯并醯胺(〇4〇 g 〇綱4’ mol)、碳酸鉋(0.49 g,0.0015 mol)和丙酉同(15而),之f人 物,經攪拌,回流加熱6小時。溶劑在真空内除去。於 物加水(25 ml)。把所得白色結晶物濾除,用-水(2〇、 〃 洗,得0.70克(96%)標題醯胺。由乙醇再結晶後, 199_200〇C。 〆 NMR,δΗ (400 MHz, DMSO-d6): 3.84 (s,3Η 1<:Η 12 2H? CH20)5 7.10-7.16 (m, 3H)? 7.41 (m5 1¾ 7·88-7·94 (m5 2H),8·73 (s5 2H),10.60 (s5 1H)。 ’ ), 33 1289558 實施例75-77之化合物已按照方法D或E製成。 實施例65-77化合物之資料,列於表8和表9。 表8
(I) R1 = CH3, R3 = H,R5 = Cl,X = 0, Y = -CH2-5 A =隣伸苯基 實施例 製法 Ar R2 熔點(°c) 實施例65. D σ αχ 170 實施例66· B σ 184 實施例67. D σ Ολ 186-187 實施例68. A σ αχ 179-180 實施例69· A ό αχ 177-178 實施例70· A α οσ 159-160 34 1289558 實施例71· C (J Ul J 133-134 實施例72. C clVk ax 212 實施例73· D IXX οσ 138 (EtOH) 實施例74. E Fxx αχ 199-200 (EtOH) 實施例75· D F>c众 οσ 133 (EtOH) 表9
Ar =苯基,R3 = H5 R5 = Cl, X = 0, Y = -CHr,A =隣伸苯基 實施例 製法 R1 熔點(°c) 實施例76· Ε 153 (EtOH) 實施例77· D 193 (EtOH) 35 1289558 實施例78-81之化合物已按照方法B製造,其資料列於 表10。 表10
Ar =苯基,R1 = CH3, R3 = H,R5 = Cl5 X 二 0, Y = -CH2-, _ R2 = 2-萘基 實施例 製法 R6 熔點(°c) 實施例78· B 4-F 142 實施例79· B 5-C1 164 實施例80. B 4_MeO 148 實施例81· B 5-MeO 150
實施例82 茉基-5_氣小甲基-1//-吡唑斗基甲烷硫炔基W萘冬 基笨甲醯胺(I) Ar =苯基,R1 = Me,R2= 2_萘基,R3= H,R5 = C1,X-: S=05 Y = -CHr,A =隣伸苯基 於二氯甲烷(20 ml)内含2_(3-苯基冬氯-1-甲基比 36 1289558 唑斗基曱基硫烷基)-1萘_2-基苯并醯胺( 0.226 g,〇.47 mmol)之溶液,在5°C添加3-氯過苯甲酸。反應混合物在室 溫攪拌2小時,用乙醚稀釋,以1〇%碳酸氫鈉溶液洗,在真 空内蒸發。於殘餘物加二異丙醚,把晶體過濾,得0J2 ^ (51%)標題化合物,熔點195Ϊ。 實施例83 2-『2-(3_苯基_5:氣-1J基比嗤_4_基)乙烯基 3-基苯并醯胺(I) Ar =苯基,Rk Me,R2= 3-喹琳基,R3= η R5 = Cl,X = CH=,Υ = CH=,A =瞵伸苯基 ί§)(3-苯基-5:氬小唑_4_基甲基)三兢某事斗鱗 (X) 取3-苯基-5_氯-4-氯甲基小甲基吡唑(3 63 g,〇 〇15 mol)、二本膦(3·93 g,0.015 mol)和甲苯(75 ml)之混合 物,經擾拌,回流加熱24小時。冷卻後,把所得結晶物渡 除,用二異丙醚洗(2x15 mi),並乾燥。得5·36克(71%) 鱗塩,熔點>265°C〇 ife)242_(3_本基_5-私士甲基乙嫌某1笑甲酸 乙酯(Vila) 取(3_苯基_5_氯-1-甲基-比唾冬基甲基)三苯基氯化鱗 ^C7.86g,0.0156mol),溶入^_二甲基甲醯胺(6〇ml)和氮 氛圍下之60%氫化納(U5 g,〇 〇312⑽】),再加狀_二甲基 甲醢胺(20 ml)内含2-甲醯基苯甲酸乙酯(2·78 g,〇〇156 mop。反應混合物在室溫游3小時,傾注在永水(15〇 m )上’以職迄酸中和,用乙酸乙酯(3 乂⑽也)萃 Ϊα,ί先(2 X 1〇0 ml) ’在硫酸納上乾燥,並蒸發。得9·81 不ίί制除酯外含三苯膦氧化物雜質。生成物水解成酸, 个爭无精製。 37 1289558 於乙*醇(30 ml)内含2-[2_(3_苯基_5_氯_1_甲基〈如比哇· 冬乙烯基]苯甲酸乙酯(9.81 g,雜有三苯膦氧化物),添加 水(3曰0 ml)中含氫氧化鉀〇 75 g,〇 〇312 m〇〇之溶液,將 反應混合物攪拌,回流加熱2小時,在真空内蒸發。於殘餘 物加水(30 mi),混合物用二氯甲烷(30 m〇萃取。於水溶 f相加10%塩酸至pH=3,用二氯曱炫(3 x35ml)萃取,在 硫酸納上乾燥,並加以蒸發。殘餘物由二異丙醚(3〇瓜1)結 晶’由乙醇再結晶後,得2.40克(45%)非白色晶體,炫^ 161-163°C (E-異構物)。 NMR5 δΗ (400 MHz, DMSO-d6): 3.90 (s3 3H? 1-CH3)5 6.87 (d,J=16.6 Hz,1HX 7.36-7.60 (m5 7HX 7_70 (m5lH)5 7.81 (nUH) 7·90 (d,J=16.6 Hz, lH),13.0 (broad sJH)。 ?, 苯基_5-氣_1-甲基-m-吡唑斗基化、_ 毋-3-基苯并醯脸Π) 方法A(反應式Π 取2-P-(3_苯基_5_氯小甲基_1//_吡唑_4_基)乙烯基]苯甲酸 (E-異構物,l.oi g,〇·〇〇3 m〇i)和氯化亞磺醯(7 mi)之混合 物,攪拌和回流加熱2小時。溶液在真空内蒸發,於殘餘^ 加 3_胺基喹啉(0.43 g,0.003 mol)、三乙胺(〇·〇67 g, 〇〇〇6 mol)和二氯甲烷(30 mi)。溶液經攪拌,回流加熱$小時, 接續用水(50 ml)、10%碳酸氫鈉溶液(5〇 mi)和水(2 χ 50 ml)萃取’在硫酸鈉上乾燥,並加以蒸發。殘餘物在石夕凝 膠上,使用CHCls/MeOH 100/1混合物為洗提液加以層析, 得0.35克(25%)橘色結晶醯胺,熔點197-201 °C (E里播 物)。 苒 貫施例84 茗-基-5-氣士:甲基心乐吼查斗基)乙某1-AL 基本开酿胺(I) A =本基,R = Me,R2 = 3_喧琳基,R3 = η R5=α,X 二 ch2, γ=ch2, λ 二隣伸苯基 5 〜, 38 1289558 (a)2-[2-(3笨基-5-氣^] · (lib) 基)乙基1苯甲醅 2-[2_(3-苯基-5-氯小甲爲 (0.70 g,0.00207 mol)溶;^9 ^比,冰基)乙烯基]苯甲酸
Pd/C觸媒(0.15 g)存在下、,於〇乙^ (50 ml)内,在1〇% 媒濾除,溶劑於真空内除去,俨,1巴壓力加氫。把觸 -『2_(3-茉基y 〇§酸,形成淺黃色油° a) ~~ ^基 1.喹啉- 方法C (反應式1) ml),有機相用15%碳酸鋼溶液(75 ml)、水(75 ml)洗, 在硫酸納上乾燥,並加以蒸發。殘餘黃色油(0.95 g)在矽凝 膠上,使用正己烷/乙酸乙酯100/10-100/140溶劑混合物為 洗提液加以層析。得0.38克(41%)白色結晶醯胺,熔點 139-140°〇 〇 2-[2-(3_本基-5-氯=甲基你吼哇+基)乙基]苯甲酸(nc, 0·70 g,_2 m,),溶於四氫吱喃(35 _内,於此溶液 加:3-胺基喧琳(0.29 g5 _2 m〇1),餅3分鐘後,加%甲 ,嗎啉(0·2一g,0_0〇2 mol},再攪拌5分鐘後,加4<4,6二甲 氧基_1,3,5_二畊-2-基)冬甲基嗎琳氯化物(〇 55 g,〇 〇〇2 mol)。白色懸浮液在室溫攪拌2·5小時,再於回流溫度加熱3 小k ’於真空内蒸發。於殘餘物加水(丨⑻mi)和氯仿(1〇〇 實施例85 HH5-氣-1_甲某各吡啶-3-某-17/•吡唑_4_基)乙某喹 ♦3:基]蓋并酿胺CII Ar = 3-吡啶基,R1 = Me, R2= 3-喹啉基, R3 = H,R5 =: Cl,X = CH2, Y 二 CH2, A =隣伸苯基 氯-1:甲基-3_吡啶各某_1及_吡唑冰基甲基)三茉基氣 化鎮塩酸塩(X) 取3<5-氯-4-氯甲基+甲基-1//-吡唑-3-基)吡啶塩酸塩 (2·78 g5 〇.〇1 mol)、三苯膦(2.75 g, 0.0105 moi)和二甲苯 39 1289558 (50 ml)之混合物,經攪拌,在回流狀況下加熱18小時。 冷卻後’把析出晶體濾除,用二異丙醚(2 X 1〇 mi)洗,並 乾燥。得4.0克(68.2% )白色鱗塩。 企垃位必-氣小甲基_3-吼唆_3-基-1从吼^坐-4-某)乙煉基1_-苯甲酸乙ξϋ Vila) ,(5-氯+曱基-3-吡啶各基-17/-吡唑斗基甲基)三苯基氯化 鱗迄酸塩(X,5.68 g,0.0105 mol),溶於况从二甲基曱醢胺 (60 ml) ’在氮氛圍下加60%氳化納(1 14 g,0.026 mol)。於 所得懸浮液,加7V;尽二甲基甲醯胺(1〇 ml)内含2_曱醯基苯 甲酸乙酯(1.87 g5 0.0105 mol),混合物在室溫攪拌3小時, 再傾注於氷水(150 ml)上。把析出晶體濾除,水洗(25 ml),付1.59克(40.7%)標題酯。由乙醇再結晶後,溶點 102-103°C (E-異構物)。 NMR? δΗ (400 MHz? DMSO-d6): 1.26 (t5 J=7.08 Hz? 3H? COOCU2CH3X 3.92 (s5 3H? 1-CH3X 4.25 (q5 J=7.08 Hz? 2H5 COOCH2CB3X 6.91 (d, J=16.5 Hz, 1H), 7.38-7.40 (m, 1H)? 7.49-7.56 (m? 2H)? 7.73-7.79 (m, 3H)? 7.97-7.99 (m, 1H)5 8.60-8.62 (m? lH),8.78(d,J=l,4Hz, 1H)。 氯-lm』比啶_3-基:^吡唑_4_某)乙揄m 甲酸(Ila) 於242_〇氯_1-曱基各口比啶·3·基·吡唑冰基)乙烯基]苯 甲酸乙酯(VIIb5 0.94 g5 〇·〇〇25 mol)和乙醇(10 mi)之混合 物,添加水(l〇ml)中含氳氧化鉀(〇28 g,〇 〇〇5 m〇1)的溶 液。、反應混合物經擾拌,回流加熱2小時,在真空内蒸發。 於殘餘物加水(15 ml),混合物以10%塩酸溶液酸至 pH弓。把所得晶體濾除,水洗(2><1〇ml),得〇 66克(776 %)標題酸,熔點183-185t: (Ε-異構物)。 ILillb) 1289558 2-[2_(5_氯小甲基!吡啶-3备1床吡唑冰基)乙烯基]苯曱 酸(Ilb,0_66 g,0.00194 mol),按照實施例84a所述方法加 氫。得0.50克標題酸,形成淺黃色油。Rf 〇,45 (CHCl3/MeOH 9/1)〇 (巡:『2亞__氯士·甲基_3_。比咬吡唑_4_基)乙某n 喹啉-3-基茉并醯胺(I) 方法C (反應式1) 按照實施例84b所述方法,從厶曱基-3_吡啶_ 3备1胸匕唾_4_基)乙基]苯甲酸(Iic,〇97 g,〇〇〇28 m〇1)和 3-版基啥琳(0.40 g,0.0028 mol)出發,得 〇 25 克(18 4% ) 白色結晶標題醯胺,熔點142-144。(:。 實施例86 U(3-苯基-5-乳-1_甲基-1//_咐1逵:^_基甲基)胺某1_尽蕙_2_ 基本开目&胺(I) M二苯基,R1 = r2:z; 2-萘基R3= H R5-
Cl, X- NH, Y ^ CH2? A^ ’ 不土5 一 5 — 丰基-5-虱_1_見基基甲基)胺某1笑甲醅 乙酯(νπχ ;^乙醇(40 ml)内含3·苯基H4-氣甲基小甲基-1杯 tb坐2.03 g,0.00844 mol)之溶液,添加2_胺基苯甲酸乙酯 ^ 1.39 g,0.00844 mol)、無水碳酸鉀 〇 38 g5 0·01 mol)和水 、—之混合物。將反應混合物攪拌,回流加熱2小時, 内除去,於殘餘物加水(50 ml),混合物用· =>谷,中和,以乙酸乙酯(2 x 5G _萃取;有機相經水 洗,在硫酸鈉上乾燥,於真空内蒸發。殘餘物由乙 =日日’ ;^〇·5克(16%)白色結晶酯,熔點123它。 (基甲胺)胺某1 π苯基_5_氯甲基稱比峻冬基甲基)胺基]苯甲酸 乙酉曰(Vila,!·02 0.00276 m〇]),按照實施例%⑻所述方法 1289558 水解,得0.80克(85%)白色結晶酸。由乙醇再結晶後,、熔 點 192-193Τ:。 甲某)脸某 苯并醢胺(I) 方法C (反應式1) 按照實施例84(b)所述方法,從2_[(3_苯基_5_氯_丨_甲基_ 1乐吡唑冬基甲基)胺基]苯曱酸(IIa5〇96g 00〇28m〇1)和1 胺基奈(0.44 g,0.0031 mol)開始,得〇 3〇克(23%)白色 結晶醯胺,熔點83_85°C。 實施例87 1:(3-苯基二5-氣小甲基甲氳基丨_a^奈 广 T、 Λ
丙醯胺(I) A 取3-(3-苯基-5-氯-1-甲基-1//_吡唑冰基甲氧基)丙_ (〇·75 g:,0.0025 mol)溶入二氯甲烷(25如)内,於此溶浴 苯并,唑·μ基氧基三(吡咯啶并)鱗六氟磷酸酿 (yBOP) (1.30 g,0.0025 m〇i)、3-胺基口純(〇 36 g 〇 〇〇2ί mol)和乙基二異丙胺(O56g 〇〇〇4375m〇1)。將溶液授拌, 加熱24小時,冷卻到室溫,接連用水(5〇而)、1〇%碳酸負 納溶液(15 ml)和水(2 x 5〇 m〇萃 於真空内蒸發。殘餘物在石夕凝膠上,使用卿二^ 100/1-100/10溶劑混合物為洗提液加以層析。所得材料由二異 丙醚(30 ml)結晶,得089克(84·7%)標継胺,形成半 水合物,炫點156-157¾。 實施例88 社H3-本基坐斗基)戍烷羧醢|屋啉各 1 醯胺⑴ A 二苯基,Rl: Me, R2: 3-啥琳基,R3 = H,R5二 ci X = -CH2、Y = -CH2、A = -CH2CH2- , 按照實施例87所述方法,從5分苯基甲基* 吡唑斗基)戊烷羧酸(〇 88 g,〇 〇〇3 m〇l),製得〇·73克(Μ 42 1289558 %)淺黃色醯胺,含1·5 mol結晶水,熔點53-55°C。 實施例89 2_「(3_笨基-5-氯小甲基-l/jj比唾-4-某曱基)甲胺基吟 並士基苯并醯胺(I) Ar = Ph,R1 = Me,R2= 3-喹啉基,R3= Η, R5=Cl,X = NMe,Y=-CH2- ’ (a)2-T(3-本基甲基_1//-°比哇>4-某甲基)甲胺某1笑甲 酯(VII) Ar = Ph, R1 = Me? R5 =: Cl, X = NMe 於2-[(3-苯基-5-氣-1-甲基-1//_吼嗤冰基甲基)胺基]苯甲酸 乙酯(1.28 g,3·46 mmol)、對甲醛(1·〇4 艮 34.64 mmol)和 乙酸(35 ml)之混合物,在1(TC攪拌下,加氰蝴氫化鈉 (1.09 g,17.34 mmol)。反應混合物在25°C攪拌20小時,再 傾注於25%氫氧化納溶液(90 ml)和氷水(no mi)之混合 物内,用二氯甲烷(3 X 100 ml)萃取;有機相經水洗(2 x 200 ml),在硫酸鈉上乾燥,於真空内蒸發。得〗〇9克(82 %)標題酯,[M-H]+384。 NMR,知(200 MHz,CDC13): 1.15 (t,J=7.2 Hz,3H),2.64 (s5 3H? NCH3)? 3.83 (s, 3¾ 1-CH3X 4.10 (s, 2H, CH2NCH3)5 4.19 (q? J=7,2 Hz,2H),6·82-6·92 (m5 2H),7·16·7·33 (m5 4H),7.55 (m5 3H) 〇 ? (b)^Ji3-苯基_5_氣小甲基-li/d比n基甲某)甲胺基i茉甲 Μ (π) Ar = Ph, R1 = Me? R5 = Cl, X = NMe 於乙醇(5 ml)内含2-[(3-苯基_5-氯小甲基-I//·。比σ坐斗 基甲基)甲胺基]苯甲酸乙酯(〇·99 2_43 mmol)之溶液,添 加水(5 ml)内含氫氧化納(0 29 g5 5.17 mmol)之溶液,反 應混合物經攪拌,在回流加熱4小時。把混合物冷卻,於真 空内蒸發。殘餘物溶入水(15 ml)内,用盘酸酸至 pH=3 ’以氯仿(50 ml)萃取,在硫酸鈉上乾燥,並蒸發。得 〇·79 克(91.8%)標題酸,[M-H]+356。 NMR, δΗ (200 MHz, CDC13): 2.63 (s? 3H, NCH3)? 3.79 (s? 43 1289558 3H,l-CH3), 4.21 (s5 2H, CH2NCH,h λ 7H),8.10 (m,1H)。 ⑹,7彻机 1H), 7.15-7.32 (m, 喹琳胺胺基他 R = Me,R2= I喹啉基, 方法d (反應式η 2 取2_[(3_苯基-5ϋ甲基_ι及 酸(0·79 g5 2·22 mmol),溶入二雀甲基)甲胺基]苯甲 液加苯并三嗤·1-基氧基三32(25 ml)内,於此溶 (PyBOP) (1·555 g5 2.22 m〇1)、、,并)鱗六氟磷酸酯 mmol)和乙基二異丙胺(0.5〇 g, ^胺基喧琳(〇·32 g,2·22 回流加熱88小時,冷卻至室溫,接mm〇l)。溶液經攪拌, 酸氫鈉溶液(25 ml}和水(3凰><5〇,,;^(5〇1111)、1〇%碳 燥,於真空内蒸發。於殘餘物加乙萃取,在硫酸鋼上乾 物濾除,用乙醇(2 X 5 ml)洗,得以0 =1) ’把淺κ色結晶 胺,熔點179_〗80°C。 、·克(64.5%)標題醯 3H, 1-CH3), 4.27 (s, 2H, CH2NCH3)5 7.13 m ^ 邱,7.37 (m,1¾ 7.44 (m,吨 7 5? 、n,m),7.18_7.22 (m, 7·89 (m5 1H),7_95 (m, 1H), 8.63 (s 則 ί^4Η),7 82 (m,1H), 1H)。 (S,1H),8.66 (s, 1H),11.71 (s,
iJ0/A
44 1289558 實施例 製法 Ar X R2 熔點 (°C) 實施例90. D CC ο αχ 143-144 實施例91· D (X 0 οσ 125 實施例92. D ό Ν S iX 155-157 實施例93· D Q- 0 οσ 187-188 實施例94· D σ ο 197-198 實施例95· D σ nch3 αχ 176-177 實施例96· D σ 0 JCC 133-134 實施例97. D σ ο 185
中間物之製造 表11 通式(IV)之新中間物,按照文獻所述製造(10疼· Chem· 1992, 57, 2127)。
45 1289558 實施例 Ar R1 R5 熔點。C或1H-NMR [DMSCX]或 LCMS [M+H】+ IV-1 a ch3 Cl J. Org. Chem. 1992, 57, 2127 IV-2 a ch3 Cl 94 °C 9.83 (s,1H,CHO),3.94 (s, 3H,NCH3) IV-3 9 ch3 Cl 109-110 °C 9.88 (s5 1H,CHO),3.94 (s, 3H,NCH3) IV-4 σ ch3 Cl 135-136 °C 10.58 (s,1H,CHO),3.91 (s, 3H,NCH3) IV-5 ::oc ch3 Cl 107-108 °C 9.67(s,1H,CHO),3.93 (s, 3H,NCH3) IV-6 :I:iX ch3 Cl 115-116 °C 9.84 (s,1H,CHO),3.90 (s, 3H,NCH3), 3.80 (s? 6H? OCH3) IV-7 cka ch3 Cl 77-78 °C 9.83 (s5 1¾ CHO),3.92 (s, 3H,NCH3) IV-8 (y ISJ, ch3 Cl 154-156 °C 10.42 (s5 1H,CHO),3.95 (s, 3H,NCH3) IV-9 a c2h5 Cl δ (CDC13): 1.49 (t,3H); 4.30 (q,2H),7.3-7.5 (m,3H), 7.68-7.79 (m? 2H); 9.92 (s 1H) IV-10 a c3h7 Cl 6(CDC13): 1.17(t? 3H); 2.11 (m,2H);4.34(t,2H);7.55-7.68 (m,3H); 7.85-7.97 (m, 2H); 10.07 (s,1H) IV-11 a C4H9 Cl δ (CDC13): 1.22 (t? 3H); 1.69 (m,2H);2.18(m,2H);4.52 (t,2H); 7·67_7·80 (m,3H); 7.95-8.08 (m? 2H); 10.19 (s? 1H) 46 1289558
IV-12 a ch2cooc2h5 Cl 293.3 IV-13 a ch2ch2ci Cl 269.2 IV-14 a O^N-. v_^ \_ Cl δ (CDCls): 2.51-2.61 (m3 4H); 2.92 (t,2H); 3.65-3.77 (m2H);4.38(t,2H);7.41-7.53 (m,3H); 7.71-7.83 (m, 2H); 9.98 (s,1H) IV-15 a ch3 ch3 δ (CDC13): 2.51 (s, 3H); 3.80 (s,3H); 7.29-7.42 (m,3H); 7.49-7.61 (m? 2H); 9.88 (s 1H) IV-16 a ch3 sch3 233.3 IV-17 I^a ch3 Cl 90-92 °C 9.83 (s,1H,CHO),3.93 (s5 3H,NCH3) IV-18 Fxx ch3 Cl 76-77 °C 9·82 (s,1H,CHO),3.91 (s, 3H,NCH3) IV-19 ch3 Cl 49-51 °C 9.85 (s,1H,CHO),3.93 (s, 3¾ NCH3) IV-20 aOMe ch3 Cl 97-98 °C IV-21 a H Cl 195-197 °C 9·83 (s,1H,CHO) IV-22 a Cl 9.87 (s,1H; CHO),5,53 (s, 2H,CH2Ph) IV-23 a XX Cl 78-82 °C 9.96 (s,1H,CHO) IV-24 ac, ch3 Cl 95-96 °C 1289558 IV-25 aF ch3 Cl 88-89 °C IV-26 ch3 Cl δ (CDC13): 9.93 (s,1H, CHO),3.85 (s,3H,NCH3) 表12 通式(V)之新中間物係按實施例1(a)所述製造。
R1 (V) 實施例 Ar R1 R5 熔點(°c) 或 ^-NMR [CDC13] V-l a ch3 Cl 125-126 °C 白色晶體 V-2 a ch3 Cl 189 °C 白色晶體 V-3 9 ch3 Cl 148-150 °C 白色晶體 V-4 σ ch3 Cl 112-113 °C 白色晶體 V_5 :xxc, ch3 Cl 114-116 °C 白色晶體 V_6 ch3 Cl 141-142°C 白色晶體 48 1289558 V-7 CKa ch3 Cl 126-128 °C (EtOH) 白色晶體 V-8 σ ch3 Cl 173-174 °C 非白色晶體 V-9 a c2h5 Cl 1.41 (t? 3H); 1.69 (t? 1H); 4·12 (q,2H); 4·62 (d, 2H); 7.41-7.58 (m,3H); 7.70-7.82 (m ? 2H) V-10 a c3h7 Cl 0.85 (t,3H); 1.48 (t,1H); L88 (m5 2H); 4.08 (t, 2H); 4.67 (d? 2H); 7.21-7.42 (m, 3H); 7.67-7.75 (m, 2H) V-ll a C4H9 Cl 0.88 (t,3H); 1.30 (m, 2H); 1.68-1.88 (m,3H); 4.08 (t, 2H); 4.49 (d9 2H); 7.21-7.39 (m, 3H); 7.65-7.75 (m,2H) V-12 a ch2cooc2h5 Cl 98°C V-13 a r~\ 0 N—Λ v_v V_ Cl [M+H]+ 322.3 V-14 a ch3 ch3 1.36(t,lH);2.19(s,3H); 3.72 (s,3H); 4.48 (d, 2H); 7.20-7.39 (m, 3H); 7.58-7.71 (m,2H) V_15 a ch3 sch3 1.58 (t,1H); 2.22 (s5 3H); 3.94 (s5 3H); 4.68 (d? 2H); 7.29-7.45 (m5 3H); 7.68-7.79.(m? 2H) V-16 a ch3 H [M+H]+ 189.3 V-17 ch3 Cl 185-187 °C 非白色晶體 49 1289558
V-18 Fxx ch3 Cl 154 °C 白色晶體 V-19 F3cJ^ ch3 Cl 124-125 °C 非白色晶體 V-20 cr ch3 Cl 82-83 °C 白色晶體 V- 21 α Η Cl 221-223 °C V-22 α Cl 114-115°C 白色晶體 V-23 α Cl 125-127°C V- 24 CC ch3 Cl 124-125 °C V-25 α ch3 Cl 106-107 °C V-26 ζΚ ch3 Cl 149-151 °C
表13 通式(VI)之新中間物係按實施例1(b)所述製造。
50 (VI) 1289558 實施例 Ar R1 R5 iH-NMR [DMS0-d6] 或 LCMS [M+H】+ VI-1 a ch3 Cl 白色晶體 3.88 (s,3H,NCH3),4.74 (s,2H,CH2C1) VI-2 a ch3 Cl 塩酸塩 3.93 (s,3H,NCH3),4.88 (s,2H,CH2C1) VI-3 9 ch3 Cl 塩酸塩 3.97 (s, 3H5 NCH3)? 4.93 (s,2H,CH2C1) VI-4 σ ch3 Cl 塩酸塩 3.91 (s,3H,NCH3),5.13 (s,2H,CH2C1) VI-5 :rc ch3 Cl 3.88 (s,3H,NCH3),4·54 (s,2H,CH2C1) VI-6 ::xx ch3 Cl 塩酸塩 3.80 (s,6H,OCH3),3.86 (s5 3H,NCH3),4.73 (s, 2H,CH2C1) VI-7 c,xx ch3 Cl 3.87 (s,3H,NCH3),4.74 (s,2H,CH2C1) VI-8 cNr ch3 Cl 塩酸塩 3.94 (s,3H,NCH3)5 5.07 (s,2H,CH2C1) VI-9 a c2h5 Cl [CDCls] 1.28 (t,3¾ 4.09 (q,2H); 4.44 (s, 2H); 7.13-7.67 (m? 5H) VI-10 a c3h7 Cl [CDC13] 0.89 (t,3H); 1.82 (m,2H); 4.12 (t, 2H); 4.56 (s, 2H); 7.27-7.42 (m? 3H); 7.60-7.70 (m, 2H) 51 1289558 VI-11 a c4h9 Cl [CDCls] 0.89 (t,3H); 1.31 (m,2H); 1.80 (m,2H); 4.09 (t,2H); 4.52 (s? 2H); 7.25-7.45 (m? 3H); 7.62-7.71 (m,2H) VI-12 a ch2cooc2h5 Cl [CDCI3] 1.15(t,3H);4.18(q,2H); 4.51 (s,2H); 4.88 (s,2H); 7.27-7.40 (m,3H); 7_63-7.71 (m,2H) VI-13 a v_y V_ Cl [M+H]+340,3 VI-14 a ch3 ch3 [CDCI3] 2.48 (s,3H); 4.27 (s,3H); 4.51 (s? 2H); 7.49-7.60 (m, 3H),7.78-7.91 (m 2H) VH5 a ch3 sch3 [M+H]+249,2 VI_16 a ch3 H 3.86 (s,3H,NCH3),4.82 (s,2H,CH2C1),7.92 (s5 1H,5_H) VI-17 I^a ch3 Cl 62-64 °C 3.88 (s,3H,NCH3),4.77 (s, 2H? CH2C1) VI_18 "a ch3 Cl 73-75 °C 3.85 (s,3H,NCH3),4.73 (s,2H,CH2C1) VI_19 ch3 Cl 42-44 °C 3 88 (s,3H,NCH3),4.78 (s,2H,CH2C1) VI-20 or ch3 Cl 68-69 °C VI-21 a ^0 Cl 103-104 °C [CDC13] 4.52 (s,2¾ CH2C1),5.32 (s,2H, CH2Ph) VI-22 a OLf Cl 74-76 °C 4.83 (s,2H,CH2C1) 52 1289558 VI-23 CC ch3 Cl [CDC13] 3.85 (s5 3H, NCH3),4.38 (s,2H, CH2C1) VI-24 CC ch3 Cl [CDC13] 3.84 (s,3H, NCH3),4.40 (s,2H, CH2C1) VI-25 ch3 Cl 84-85 °C [CDC13] 3.81 (s,3H, NCH3),4.58 (s,2H, CH2C1) 表14 通式(Vila)之新中間物係按照實施例65⑻所述製造。
(VII) 其中Y = -CH2_,A=隣伸苯基,11 =乙基 實施例 Ar R1 R5 X 熔點0c VII-1 a ch3 Cl 0 74-75 °C 白色晶體 VII-2 a ch3 Cl NH 123 °C (EtOH) -白色晶體 VII-3 Ok ch3 Cl 0 85-86 °C 白色晶體 VII-4 9 ch3 Cl 0 102 °C (EtOH) 白色晶體 53 1289558
VII-5 σ ch3 Cl 0 72-73 °C (EtOH) 白色晶體 VII-6 c'Ok ch3 Cl 0 73-74 °C 白色晶體 VII-7 σ ch3 Cl 0 98-99 °C (EtOH) VII-8 ΙΪΧ ch3 Cl 0 120-121 °C (EtOH) VII-9 f3CXX ch3 Cl 0 97 °C (EtOH) 白色晶體 VIMO α XX Cl 0 141-142 °C (EtOH) VII-11 ac, ch3 Cl 0 84-86 °C VII-12 aF ch3 Cl 0 69-72 °C VIM3 ch3 Cl 0 90-91 °C 表15 通式(Ila)之新中間物係分別按照實施例1(c) (X=S) 和實施例65(b) (X=0)所述製造。
II Y = -CHr,A=隣伸苯基 54 1289558 實施例 Ar R1 R5 X 熔點°c或 LCMS [M+H]+ II-1 α ch3 Cl s 195-196 °C (EtOH) 白色晶體 II-2 α ch3 H s 158-159 °C (EtOH) 白色晶體 ΙΙ-3 α ch3 Cl NH 192-193 °C (EtOH) 4水合物 白色晶體 ΙΙ-4 α ch3 Cl 0 110-111 °c (EtOH) 白色晶體 ΙΙ-5 α ch3 Cl s 197-198 °C (EtOH) 非白色晶體 Π_6 α ch3 Cl 0 74-76 °C 非白色晶體 ΙΙ-7 9 ch3 Cl s >270 °C (DMF) 非白色晶體 ΙΙ-8 9 ch3 Cl o 196 °C (EtOH) 非白色晶體 ΙΙ-9 σ ch3 Cl s 218-220 °C 白色晶體 11-10 σ ch3 Cl 0 -127°C 非白色晶體 II-11 ch3 Cl s 157-158 °C (EtOH-iPr20) 白色晶體 Π-12 ch3 Cl s 163-164 °C (EtOH) 白色晶體 55 1289558
IH3 c,xx ch3 Cl s 225 °C (EtOH) 半水合物 白色晶體 II-14 αΎΧ ch3 Cl 0 136-137 °C 二水合物 白色晶體 II-15 σ ch3 Cl s 158-159 °C (EtOH) 11-16 (y ch3 Cl 0 146-147 °C 半水合物 非白色晶體 IM7 α c2h5 Cl s 167°C II-18 α c3h7 Cl s 181°C ΙΙ_19 α C4H9 Cl s 192°C ΙΙ-20 α CH2COOC2H5 Cl s 188°C 11-21 α ch3 ch3 s 339.2 11-22 α ch3 sch3 s 371.3 ΙΙ-23 α ch3 Cl S〇2 126°C 11-24 ΐχχ ch3 Cl 0 149-150 °C 半水合物 非白色晶體 ΙΙ-25 ch3 Cl 0 144-145 °C 白色晶體 ΙΙ-26 α o、f ci 0 133 °C (EtOH) 白色晶體 56 1289558
-^-- 11-27 0C —------- ch3 Cl 0 153-154 °C (EtOH) 白色晶體 随 aF —-~~~-— ch3 Cl 0 124-126 °C 白色晶體 IL29 ch3 Cl 0 13M32 °C b 結合检塞定化合物對痴肥 ^ h=125i_痴肥素_A放射性配體競爭(置換)實驗架構 甲、,將固定濃度的hr」25I-痴肥素-A加以保溫,在帶有人體重 組f肥素-1 (hr-〇X-i)或人體重組痴肥素-2 (hr_〇x_2)受體 的,純度血漿膜存在下,提高未標記測試化合物之濃度。在 未標記化合物之各濃度,測量hr-125I·痴肥素_A對血漿膜的特 殊結合,因而發生競爭曲線,計算置換5〇%特殊結合 (ICso)的未標記化合物濃度。在競爭互應情況下,按照 Cheng_PruS0fif 方程式(Ki = IQ()/(1 + lid),計算未標記化 合物(Kq)的結合親和性常數。 在麗处内培養和製備含痴肥素受體之高純唐血举晅 部份 在細胞培養基(MEM培養基,補充40 mg/ι脯胺酸,20 mg/Ι慶大黴素5300mg/lgeneticin5 10%透析胎兒小牛血清)内 進行培養中國倉鼠卵巢細胞,表現人體重組痴肥素-1或痴肥 素-2 受體蛋白(CHO-hr-OX-i 或 cHO-hr-OX-2 )。 進行新法以分離富有痴肥素_1或痴肥素-2受體蛋白之血 清膜部份。 黏附細胞平板接種於Greiner燒瓶(1乃cm2)。4-6天 後,除去培養基,細胞在無鈣無鎂的磷酸塩緩衝生理食塩水 57 1289558 (PBS, 20 ml/燒瓶)内呈斜坡。細胞懸浮液以l5〇〇〇 g離心 5分鐘(4°C )。所得沉殿物再懸浮,並以鐵弗龍研磨棒勻化 (4°C),再分層於不連續蔗糖梯度,以i〇55〇〇〇 g離心,把 14和34%蔗糖層間的界面内積集之血漿膜部份分離,以 105,000 g再一次離心步驟60分鐘(4°C )加以沉殿。最後沉 澱物再懸浮於結合檢定緩衝液内,於-8(TC儲存到放射性配體 結合實驗日。 體外125Ι·痴肥素-A結合 為125Ι-痴肥素-Α競爭結合研究,把含hr-痴肥素-1或hr-痴肥素_2受體之細胞膜部份,整份與1251_痴肥素在結合檢 定緩衝液内,於25°C保溫60分鐘。非特殊結合在二者情況 下,均利用1 μΜ hr-痴肥素-A界定。 把測試化合物溶入濃度1 mM的二甲亞颯(DMSO) 内,從存量溶液(100% DMSO)以結合檢定鍰衝液製備系 列的稀釋液’其方式疋使各樣品在受體結合反應混合物内都 含有1% DMSO的最後濃度。保溫後,樣品使用SKATR〇N 細胞採集器,通過Whatman GF/C玻纖濾材過濾,濾材用5 ml冰冷緩衝液洗濯。留在濾材上的放射性,在伽瑪計數器 (Wallac自動伽瑪計數器1470 Wizard)計數。 縮寫代號 EGTA 乙二醇-双(β-胺乙基醚)-AWw,-四乙酸
Tris 三(羥甲基)胺基甲烷 HEPES尽2-經乙基六氫π比哄u-乙石黃酸 【圖式簡單說明】 【主要元件符號說明】 58
Claims (1)
- 申請專利範圍: ί、Γ96·ι2 轉(敏一 〜 _〜〜 I 日修: 1·一種通式(I)之化合物, 及其垣、異構物和溶合物:R3 R1 (I) 其中Ar代表本基、5或6節雜 氮原子、氧原子或硫原子為佳,各1-3個雜原子,以 C"烧美、r Λ f f ί何此等環均可被«原子、 -或二Cl_4絲取代之胺基單取代 j甲基&基’或以 Y代表-CH2·基; 代, X代表硫原子、氧原子、___ f Η基、_(叫或·S〇2基,或χ和γ 一 =^基』 何形狀2_CH=CH-基; 貝IA汉么成 A代表5或6節芳族環部份,在鱗 ^ . c,4 S J份ίίΓ飽和的5/\6口節環絲環,可視需要以齒素 基^,含w雜原子,以氮、以硫原㈡ ,·’可視$要以i素原子、CM絲或cM烧氧基單或複取 代, A rR ί表Γ基、C"⑥基_、C1-4羥烷基-、Q-8烷氧羰烷 基-、C2·7烷叛基-、Q_7羰烷基-、胺羰基_(Ci·4)烷基、q_3烷胺 羰基-(Cm)烷基、胺基-(Cl_4)烷基、Ci_3烷胺基_(Ci 4)烷基、嗎 #-(Cm)烧基-、或嗎琳幾基_(cM)燒基、或苯,可視需要以一 或以上鹵素原子取代; R2代表下列基之一,可視需要以一或以上鹵素原子、羥 基、CM烧基、三鹵甲基、硫代cM烧基、胺基、― 59 1289558 Ci-4烷基或環烷基取代; ^ 基、5或6節雜環基或部份^全二。3、鋪基或節 或不同雜原子,以氮之環基、含M個一致 份之基,鱗錢全龍和;含^^雜環基一部 6 炫氧基i代表鹵素原子、氫原子、&趙、C“概、C" 2·種通式⑴之化合物,及其垣、異構物和溶合物: Ar R1 Nχ Υ XR3 Ο (ΐ) 教Ί 郎雜芳族環’含w個雜原子,以 ίίf子為佳’任何此等環均可被*素原子、 4絲、CM細基、織、氰基、三ή甲基、胺基,或以 一或二CM烷基取代之胺基單取代或複取代; 一 Y代表-CH2-基; X代表硫原子、氧原子、-ΝΗ-基、-N(Cm烷基 〇ί2·基、-(S哪或初2基,或χ和γ 一同代表順型或反 何形狀之-CH=CH_基; A代表5或6節芳族環部份,在隣、間或對位含有二自 由價,並可視需要以鹵素原子、Cm烷基或Cm烷氧基單或複 取代;部份或全部飽和的5或6節環烷基環,可視需要以鹵素 原子、CM烧基或CM燒氧基單或複取代;或雜芳基、部份或 全部飽和雜環基之環’含1-3雜原子,以氮、氧或硫原子為 1289558 代;可視而要以齒素原子、Cm^*基或Cl_4燒氧基單或複取 基-、cR基、Cl.4絲·、C"減基_、C3_8烧氧親 羰基ϋΪί-、CM航基-、胺絲I1·4)烧基、Cl-3烧胺 啉^胺基_(Cl-4)烧基、C"院胺基_(C")烷基、嗎 或以土…或嗎啉羰基_((:1-4)烷基、或笨,可視需要以一 义从上齒素原子取代; 忐田代表下列基之一,可視需要以一或以上心禮基、三 取代代’烧基、胺基、_(c=〇>nh_cm烧基或環烧基 或部份或、入氫f基或茚基、5或6節雜環基 > $邛飽和之裱基、含1-3個一致或不同雜原子,以 全邻原^為佳’含双環的雜環基—部份之基,或部份或 双,雜環’有1或2或3個-致或不同之雜原 于以虱、軋或硫原子為佳; ^代表氫原子4cM烷基; 6〜R2和R3連_騎氮軒,可代表部份或全部飽和之 即衣’5可視需要以被取代的苯基或节基加以取代; 燒氧基i代表鹵素原子、氫原子、Cl_4絲、Cl·4硫絲、Cl-4 接」.如巾請專利範圍第1項之通式(1)化合物,及其垣、異 構物和溶合物,其中·· Ar代表苯基,有】或2個氮原子的6節雜芳族環,直 中方族環可視需要以鹵素原子或q_4烧氧基單或複取代;/、 Y代表亞甲基; X代表硫原子、氧原子、亞甲基、-N(甲基),· Aj代表隣伸苯基,或在隣位含二自由價之雜環基部份; r甘代表、CM烧基·、Cl-5經炫基-、C3-8烧氧基幾甲基、 基—或甲絲絲,或以―或二個h絲取代之烧 版基系基, 61 1289558 基,可23個雜原子之芳族或部份飽和双環 “R5由^击由素原子、Cl_4絲或Cl_4垸氧基者。 構物和圍第1項之通式⑴化合物,及魏、異 氮$子可概要㈣素原子取代;或具有1或2 原子=即雜方族環’可視需要以齒素原子取代; γ代表亞甲基; 基;X代表亞甲基、帶硫原子、氧原子或氮原子之C"烷 表隣伸苯基,或在隣位含二自由價之雜芳族部份; 幾甲基 鍵或支鍵C1-4烧基、C1·3經烧基或h燒氧基 其+ 代表芳族或部份飽和之双環部份,可視需要以Cu炫 、、素原子取代;或者芳族或部份飽和双環部份 原子,職、硫缝軒為宜; j個雜 R3代表氫原子; R5代表氯原子、甲基或硫曱基者。 和溶5合、異構物 琳_3_基ΐ并氯_1 基甲基魏基)錢 基苯并2酿(^基_5_氯-1-甲基·1如比嗤·4·基甲基魏基从如- 啾6 At(t笨基_5_氣小甲基U比嗤_4_基曱基硫烷基)#眩 啉·6·基本开醯胺塩酸塩; 土 料基ί并=f 基甲基硫燒基)錢 62 1289558 2-(5-氮-1-曱基-3-σ比17定-2-基-1//-°比口坐-4_基曱基硫烧基)_」V~ 萘-2-基苯并醯胺; 2-(5-氯-1-甲基-3-吡啶-2-基-177-吡唑-4-基甲基硫烷基)-#_ 唾琳-3-基苯弁酿胺; 2-(5-氯-1-曱基-3_吡啶-2-基-1//-吡唑-4-基曱基硫烷基)-7V_ 奈-2-基苯弁酿胺, 2_(5·氣_1-曱基-3-11比咬-2-基-ITT·11比〇坐_4-基曱基硫烧基)-7V_ 嗤琳-6-基苯弁酿胺, 2-(5-氯-1-甲基-3-吡啶-2-基_1从吡唑-4-基甲基硫烷基)-#- 喹啉-3-基苯并醯胺; 7\^_(1->臭異唾琳·3·基)-2-(5-氯晒1画曱基·3·口比口定-3_基_1//口比 唑-4-基曱基硫烷基)苯并醯胺; 2-(5•氯_1_甲基-3-吡啶-3-基-1丑-吡唑-4_基甲基硫烷基 異喹啉-3-基苯并醯胺; 2-(5-氯-1-甲基-3_吡啶-4-基_l//-吡唑-4-基甲基硫烷基)-Λ^ 秦-2-基苯弁酿胺; 2-(5-氯-1-甲基-3-σ比σ定_4·基比α坐-4-基甲基硫烧基)-Λ^_ 嗤琳-3-基苯弁酸胺; 2-(5-氯-1-甲基-3-吡啶-4-基-17/-吡唑-4-基甲基硫烷基 嗤琳-6-基苯弁酿胺, 2·(5_氣_1_甲基-3-σ比σ定-2-基_1//_口比σ坐-4-基曱基石荒燒基)·Λ^ 喹啉-3-基苯并醯胺; 2-(5-氯-1-甲基_3-吡啶-4-基-1//-吡唑_4_基甲基硫烷基)-#-(1-甲基異喹啉-3-基)苯并醯胺; 2-(1-乙基-3-苯基-5_氣_1//-°比嗤-4-基甲基硫烧基嗤 琳-3-基苯弁酿胺, 2-(3-苯基-5-氯-1-丙基比嗤-4-基甲基硫烧基)-#_嗤 琳-3-基苯弁酿胺, 2-(1-丁基-3-苯基-5-氯-1//-。比0坐_4_基曱基硫烧基)-#-唾 63 1289558 琳-3-基苯弁酿胺, {3-苯基-5-氯-4-[2-(喹啉-3-基羰醯基)苯基硫烷基甲基]-1//-吡唑-l-基}乙酸乙酯; 2-[3-苯基_1-(2_羥乙基)_5_氯-1//-吼唑_4-基曱基硫烷基]-7V-嗤琳-3-基苯弁酿胺, 2_(3_苯基-1,5-二甲基-1//-吡唑_4_基甲基硫烷基)-尽喹啉-3-基苯弁酿胺, 2-(3•苯基-1_甲基_5·曱基硫烷基_1从吡唑-4-基甲基硫烷 基)-7V-嗤琳-3-基苯弁龜胺, 2-(3-苯基_5_氯-1-曱基-1//-吼唑-4-基曱基硫烷基)_噻吩_2· 羧酸萘-2-基醯胺; 2-(3-苯基-5-氯-1-甲基-I//』比唑-4-基曱氧基)-7V-喹啉_3·基 苯并醯胺; 2_(3_苯基-5-氯-1-甲基-I//』比唑-4-基甲氧基)_7V-萘-2-基苯 并醯胺; 2_(5_氯-1-甲基-3-吡啶-3-基_1//吡唑_4_基曱氧基)喹 琳-3-基苯弁酿胺, 2-(5氯-1-曱基-3-吡啶-4-基-1从吡唑-4·基甲氧基)_尽喹 琳-3-基苯弁酿胺, 2-(5氯-1-甲基-3_吡啶_2_基_1从吡唑-4-基曱氧基)-7V-喹 琳-3-基苯并酿胺, 2-[3-(4-氟苯基)-5-氯-1-甲基-17/^比唑_4_基曱氧基]-TV-喹 琳-3-基苯弁蕴胺, 2-[2-(3-苯基)-5-氯-1-甲基-1从吡唑-4-基乙基]-7V-喹啉-3-基苯并醯胺; 2-[2-(5·氯-1-甲基-3-吡啶-3-基-1//-吡唑-4-基)乙基]_尽喹 琳-3-基苯弁酿胺, 2-[(3-苯基-5-氯-1_甲基比唑-4-基甲基)甲胺基]喹 啉-3-基苯并醯胺; 64 1289558 2-(5-氯-1-曱基-3_吡啶_4-基-1从吡唑4-基甲基硫烷基)W-(3,4-二氯苯基)苯并醯胺; 2_[5_氯-1-甲基-3_(2_噻吩基)-1从吡唑·4_基曱氧基]善喹 啉_3-基苯并醯胺; 2-[(5-氯小甲基-3-吡啶-3-基-1从吡唑斗基甲基)甲胺基]_ 7V-嗤琳-3-基苯并酿胺; 2-(5-氯-1-甲基-3_吡啶-3_基-1//·吡唑_4_基甲氧基)_尽(6,7-一氟嗤琳_3_基)苯并醯胺; 2_(5·氯-1-甲基-3·吡啶-3_基-1从吡唑_4_基曱氧基)_Y_喹 琳_3_基苯并酿胺; 2_(5_氯-1-甲基-3_吡啶_4-基-1^吡唑斗基曱氧基)#喹 翁 琳-3-基苯并醯胺者。 6·—種具有基於痴肥素拮抗效應的減肥效應之製藥組成 物’其特徵為,含有申請專利範圍第1項通式(I)化合物 j其中Ar,Y,X,A,Ri,R2,R3,R4意義如申請專利範圍第i項所界 定),或其塩、異構物或溶合物者。 Λ ^ 7·如青專利範圍第6項具有基於痴肥素拮抗效應的減肥 i f應之製藥組成物,其中含有如申請專利範圍第5項之化合 、 勿,或其塩、異構物或溶合物者。 物,ϋ具有基於痴肥素抬抗效應的減肥效應之製藥組成參 (ιϊ t徵為’含有申請專利範圍第1項通式(1)之化合物 定i或^’^^,^,^,^意義如申請專利範圍第丨項所界 劑者:杈、異構物或溶合物,以及製藥業所用至少一賦形 Ar,Y,X,Aj^2^f^第1項通式⑴之化合物,其中 以製造藥品、之意義如申請專利範圍第1項所界定,用 素_1和痴肥素=組成物、適於拮抗痴肥素-1受體,或痴肥 有關之疾病文體’因而適於處理或預防與痴肥素受體活性 65 1289558 〇·—種申請專利範圍第1項通式(〗)化合物及其塩、昱 構物和溶合物之製法,通式(1)中Ar,Y,x,A,Rl,R2,R3,R5之^ 義如申請專利範圍第1項所界定,其特徵為 … ⑻將通式(II)之酸 Ar>VN/R1COOH (ii) (式中之意義如申請專利範圍第丨項所界定 轉型為活性衍生物,並與通式(II)之胺反應: HN R2 r3 (HI) (式中R2和R3如申請專利範圍第丨項所界定),或 (b)領通式(VI)之氯甲基衍生物: ArN N Cl R5 (VI) (式中Ai^R^R5之意義如申請專利範圍第!項所界定),與 式(IX)之醯胺反應: ” Η X——A — N R 2 R 3 (IX) 0 (式中足八太2及3之意義如申請專利範圍第1項所界定),如 所需要’將所得化合物從其塩釋出,或轉型為其塩者。 11·如申請專利範圍第10項之製法(a),其中通式(11)之 66 1289558 化合,’藉用L乙基各(3,-二甲胺基丙基)碳化二亞胺、4_(4,6_ 二I氧基_1,3,5-三啡冬基)斗甲基嗎啉氯化物,或苯并三唾 基氧基三(吡咯啶并)鱗六氟磷酸酯,轉型為其醯 ^ 化,並以此型式與通式(π)之胺反應者。 虱力以活 12·—種通式(VII)之化合物:(VII) 式中ArXXAR^R5之意義如申請專利範圍第1項所界定,而 R代表Cp4烷基者。 67
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2004
- 2004-12-15 WO PCT/HU2004/000117 patent/WO2005060959A1/en not_active Application Discontinuation
- 2004-12-15 DE DE602004022458T patent/DE602004022458D1/de active Active
- 2004-12-15 JP JP2006546344A patent/JP4861829B2/ja not_active Expired - Fee Related
- 2004-12-15 AT AT04806274T patent/ATE438395T1/de not_active IP Right Cessation
- 2004-12-15 EP EP04806274A patent/EP1699454B1/en not_active Not-in-force
- 2004-12-17 TW TW093139247A patent/TWI289558B/zh not_active IP Right Cessation
- 2004-12-22 AR ARP040104839A patent/AR046793A1/es not_active Application Discontinuation
-
2006
- 2006-06-21 US US11/425,583 patent/US7659298B2/en not_active Expired - Fee Related
-
2010
- 2010-02-03 US US12/699,231 patent/US20110059964A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO2005060959A8 (en) | 2006-01-12 |
US7659298B2 (en) | 2010-02-09 |
JP2007519630A (ja) | 2007-07-19 |
EP1699454B1 (en) | 2009-08-05 |
HUP0304101A2 (hu) | 2005-09-28 |
US20070021459A1 (en) | 2007-01-25 |
HUP0304101A3 (en) | 2008-10-28 |
TW200526632A (en) | 2005-08-16 |
ATE438395T1 (de) | 2009-08-15 |
EP1699454A1 (en) | 2006-09-13 |
HU0304101D0 (en) | 2004-03-29 |
DE602004022458D1 (de) | 2009-09-17 |
US20110059964A1 (en) | 2011-03-10 |
AR046793A1 (es) | 2005-12-21 |
WO2005060959A1 (en) | 2005-07-07 |
JP4861829B2 (ja) | 2012-01-25 |
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