CN1088707C - 2-羰基噻唑衍生物及其用途 - Google Patents
2-羰基噻唑衍生物及其用途 Download PDFInfo
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- CN1088707C CN1088707C CN97199832A CN97199832A CN1088707C CN 1088707 C CN1088707 C CN 1088707C CN 97199832 A CN97199832 A CN 97199832A CN 97199832 A CN97199832 A CN 97199832A CN 1088707 C CN1088707 C CN 1088707C
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- UQUGDNFIHIOARL-UHFFFAOYSA-N 3h-1,3-thiazol-2-ylidenemethanone Chemical class O=C=C1NC=CS1 UQUGDNFIHIOARL-UHFFFAOYSA-N 0.000 title claims abstract description 20
- -1 pyrrolidino, piperidino, morpholino Chemical group 0.000 claims abstract description 40
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 40
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
- 229960003638 dopamine Drugs 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 239000002464 receptor antagonist Substances 0.000 claims description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 229940044551 receptor antagonist Drugs 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 201000000980 schizophrenia Diseases 0.000 abstract description 6
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 4
- 206010039966 Senile dementia Diseases 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 125000001544 thienyl group Chemical group 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 7
- 125000001424 substituent group Chemical group 0.000 abstract 2
- 229940124243 Dopamine D4 receptor antagonist Drugs 0.000 abstract 1
- 102000003962 Dopamine D4 receptors Human genes 0.000 abstract 1
- 108090000357 Dopamine D4 receptors Proteins 0.000 abstract 1
- 208000006011 Stroke Diseases 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 208000018300 basal ganglia disease Diseases 0.000 abstract 1
- 230000002969 morbid Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000003795 chemical substances by application Substances 0.000 description 31
- 235000019441 ethanol Nutrition 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012442 inert solvent Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 150000002170 ethers Chemical class 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000003513 alkali Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 239000004215 Carbon black (E152) Substances 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 229930195733 hydrocarbon Natural products 0.000 description 13
- 150000002430 hydrocarbons Chemical class 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 150000003053 piperidines Chemical class 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 150000001298 alcohols Chemical class 0.000 description 10
- 230000008030 elimination Effects 0.000 description 10
- 238000003379 elimination reaction Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000006837 decompression Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 235000010755 mineral Nutrition 0.000 description 9
- 239000011707 mineral Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 150000003556 thioamides Chemical class 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 230000002140 halogenating effect Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 6
- IJVLVRYLIMQVDD-UHFFFAOYSA-N 1,3-thiazole-2-carboxylic acid Chemical class OC(=O)C1=NC=CS1 IJVLVRYLIMQVDD-UHFFFAOYSA-N 0.000 description 5
- WAOQONBSWFLFPE-VIFPVBQESA-N 3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide Chemical compound CCN1CCC[C@H]1CNC(=O)C1=C(O)C(Cl)=CC(Cl)=C1OC WAOQONBSWFLFPE-VIFPVBQESA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000026030 halogenation Effects 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 229950001675 spiperone Drugs 0.000 description 5
- 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 4
- HPLPUAJRHGVMCE-UHFFFAOYSA-N 2-benzylidenepiperidine Chemical class N1CCCCC1=CC1=CC=CC=C1 HPLPUAJRHGVMCE-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 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
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- AQTZXLOUEHVKNI-UHFFFAOYSA-N ethyl 5-(2-chloroethyl)-4-(4-fluorophenyl)-1,3-thiazole-2-carboxylate Chemical compound S1C(C(=O)OCC)=NC(C=2C=CC(F)=CC=2)=C1CCCl AQTZXLOUEHVKNI-UHFFFAOYSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 150000002896 organic halogen compounds Chemical class 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- ORECNKBJIMKZNX-UHFFFAOYSA-N 1,3-thiazol-3-ium;chloride Chemical compound Cl.C1=CSC=N1 ORECNKBJIMKZNX-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KCAYCYGTQXNQCZ-UHFFFAOYSA-N 2-(oxamoylamino)ethanesulfonic acid Chemical class NC(=O)C(=O)NCCS(O)(=O)=O KCAYCYGTQXNQCZ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical class C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 235000019628 coolness Nutrition 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000005826 halohydrocarbons Chemical class 0.000 description 2
- 229960003878 haloperidol Drugs 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
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- 229910000105 potassium hydride Inorganic materials 0.000 description 2
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- 238000002360 preparation method Methods 0.000 description 2
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 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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- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- ULMHMJAEGZPQRY-UHFFFAOYSA-N N-(tert-butoxycarbonyl)piperidin-2-one Chemical compound CC(C)(C)OC(=O)N1CCCCC1=O ULMHMJAEGZPQRY-UHFFFAOYSA-N 0.000 description 1
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- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical class CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 239000000442 dopamine 2 receptor blocking agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002641 lithium Chemical group 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- DSPAINDKHXXCMS-UHFFFAOYSA-N methyl 5-(2-chloroethyl)-4-phenyl-1,3-thiazole-2-carboxylate Chemical compound S1C(C(=O)OC)=NC(C=2C=CC=CC=2)=C1CCCl DSPAINDKHXXCMS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BDGDWWGTAFXEEW-UHFFFAOYSA-N methylsulfinylmethane;oxalyl dichloride Chemical compound CS(C)=O.ClC(=O)C(Cl)=O BDGDWWGTAFXEEW-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- OLQXJWPKNGBHKC-UHFFFAOYSA-N n,n-diethylethanamine;2-methylpropyl carbonochloridate Chemical compound CCN(CC)CC.CC(C)COC(Cl)=O OLQXJWPKNGBHKC-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002360 prefrontal effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- ZOFJBHYCGASUQK-UHFFFAOYSA-N sodium;trimethylsilylazanide Chemical compound [Na+].C[Si](C)(C)[NH-] ZOFJBHYCGASUQK-UHFFFAOYSA-N 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明为式(I)[式中Ar1和Ar2分别表示苯基、具有从“卤素原子、碳数1~5的烷基、三氟甲基、碳数1~5的烷氧基及羟基”中选出的1个或2个取代基的苯基或噻吩基,R1表示碳数1~5的烷氧基、羟基或式N(R3)R4(式中R3和R4分别表示氢原子或碳数1~5的烷基,或者R3和R4和它们所结合的氮原子一起形成吡咯烷基、哌啶子基、吗啉代基、哌嗪基、或具有1~4个从“碳数1~5的烷基、碳数1~5的烷氧基和羟基”中选出的取代基的吡咯烷基、哌啶子基、吗啉代基或哌嗪基的基团)所示的氨基,Y1-Y2表示CH-CO或C=C(R2)(式中R2表示氢原子或碳数1~5的烷基),n表示1~4的整数。]所示的2-羰基噻唑衍生物或其医药上允许的盐。此外,本发明提供了含有上述式(I)所示的2-羰基噻唑衍生物或其医药上允许的盐的药物及含有其作为有效成分的多巴胺D4受体拮抗剂,它作为与多巴胺D4受体有关的各种疾病、例如精神分裂症和脑血管障碍基老年性痴呆症所致的行为异常等疾病的预防和治疗药很有用,而且作为没有锥体外系障碍副作用的药物很有用。
Description
技术范围
本发明涉及具有抗精神病作用的2-羰基噻唑衍生物。
背景技术
抗精神病药除了用于精神分裂症的治疗外,也用于脑血管障碍、老年痴呆症造成的行为异常(攻击性行为、精神兴奋、徘徊、谵妄等)的治疗。但是,以往作为抗精神病药的多巴胺D2受体拮抗剂具有很强的锥体外系障碍的副作用,这成为很大的问题。
另一方面,近年来发现的多巴胺D4受体的构造及性质与多巴胺D2受体相似,其区另在于它们在大脑内的分布。多巴胺D4受体的分布是,在与精神分裂症有关的大脑皮质前额叶内浓度很高,在发现与锥体外系障碍有关的纹状体内很少。因此,多巴胺D4受体拮抗剂极有可能成为与多巴胺D2受体拮抗剂不同的、不具有锥体外系障碍副作用的新型精神分裂症治疗药(Nature,350,610~614(1991);Nature,358,109(1992);Nature,365,393(1993);Nature,365,441~445(1993))。
这类化合物例如有氯氮平。已有报道说氯氮平对多巴胺D4受体的亲和力比对多巴胺D2受体的亲和力高(Nature,350,610~614(1991))。而且氯氮平的临床试验表明,它和多巴胺D2受体拮抗剂不同,对药物抵抗性精神分裂症和阴性症状有效,并很少报告有锥体外系障碍(Arch.Gen.Psych.,45,789~796(1988))。但是,氯氮平被发现有粒细胞缺乏症的血液毒性,并报告有死亡例(Summaryand Clinical Data.Sandoz,Canada Inc.(1990)),这成为巨大的缺点。
所以,不具有此副作用的多巴胺D4受体拮抗剂作为产生锥体外系障碍可能性极低的精神分裂症的治疗药物很有用。
发明的公开
本发明的目的在于提供不产生锥体外系障碍的、具有抗精神病作用的多巴胺D4受体拮抗的化合物。
本发明者们对2-羰基噻唑衍生物进行了深入研究,结果发现了对多巴胺D4受体显示出高亲和力的新型2-羰基噻唑衍生物,完成了本发明。
下面对本发明进行说明。
本发明为式(I)[式中Ar1和Ar2分别表示苯基、具有从“卤素原子、碳数1~5的烷基、三氟甲基、碳数1~5的烷氧基及羟基”中选出的1个或2个取代基的苯基或噻吩基,R1表示碳数1~5的烷氧基、羟基或式N(R3)R4(式中R3和R4分别表示氢原子或碳数1~5的烷基,或者R3和R4和它们所结合的氮原子一起形成吡咯烷(pyrrolidino)基、哌啶子基、吗啉代基、哌嗪(piperazino)基、或具有1~4个从“碳数1~5的烷基、碳数1~5的烷氧基和羟基”中选出的取代基的吡咯烷基、哌啶子基、吗啉代基或哌嗪基的基团)所示的氨基,Y1-Y2表示CH-CO或C=C(R2)(式中R2表示氢原子或碳数1~5的烷基),n表示1~4的整数。]所示的2-羰基噻唑衍生物或其医药上允许的盐。
对于本发明,卤素原子为氟原子、氯原子、溴原子或碘原子。碳数1~5的烷基为直链或支链烷基,碳数1~5的烷氧基为直链或支链烷氧基。所以,作为Ar1和Ar2所示的具有取代基的苯基,例如有2-氟苯基、3-氟苯基、4-氟苯基、4-氯苯基、4-溴苯基、3,4-二氯苯基、4-甲基苯基、3-三氟甲基苯基、4-甲氧基苯基、3,4-二甲氧基苯基、4-羟基苯基等。此外,作为式N(R3)R4所示的氨基,例如有氨基、甲基氨基、二甲基氨基、乙基氨基、丙基氨基、异丙基氨基、二丙基氨基、吡咯烷基、3-羟基吡咯烷基、哌啶子基、3-甲氧基哌啶子基、吗啉代基、哌嗪基、N-甲基哌嗪基等。
R2所示的碳数1~5的烷基是直链烷基、支链烷基或环烷基,例如有甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基甲基、环丁基等。
此外,作为本发明中医药上允许的盐,例如有硫酸、盐酸、磷酸等无机酸的盐,醋酸、草酸、乳酸、酒石酸、柠檬酸、富马酸、马来酸、三氟乙酸等有机羧酸的盐,甲磺酸、苯磺酸等有机磺酸的盐等。此外,作为R1为羟基时形成的盐,有一价或二价的金属盐,这里的金属例如有钠、钾、锂、钙等。
更优选的为式(III)(式中R3和R4的意义和上述相同,X1和X2分别表示氢原子、卤素原子或碳数1~5的烷基。)所示的2-羰基噻唑衍生物或其医药上允许的盐,在这之中最优选R3和R4皆为氢原子、且X1和X2皆为4位取代氟原子、X1为氢原子X2为4位取代氟原子、或X1为4位取代氟原子X2为3位取代氟原子的化合物或其医药上允许的盐。
式(I)的化合物可以按下述方法进行制造(在下面的反应式中,Ar1、Ar2、R1、R2、R3、R4、Y1、Y2、X1、X2和n的意义和上述相同,R5为R1所示的碳数1~5的烷基,R6为除去氢原子之外的R1,R7为碳数1~5的烷基或者二个R7以单键结合形成亚烷基,R8为叔丁氧基羰基、乙氧基羰基等的烷氧基羰基、乙酰基、苯甲酰基等的酰基、对甲苯磺酰基等的磺酰基、碳数1~5的烷基、苄基等的氮原子保护基团,R9为碳数1~5的烷基,X3为氯原子、溴原子或碘原子,M为钠原子、钾原子、锂原子、1/2钙原子等的碱金属原子或碱土金属原子或氢原子。)。(反应式1)
将酮(1)在惰性溶剂中用卤化剂卤化后,在存在或者不存在脱水剂或碱的情况下,在惰性溶剂中和硫代酰胺衍生物(2)反应生成噻唑衍生物(3),在存在或不存在碱的情况下,在惰性溶剂中将其和哌啶衍生物(4)反应,可以得到式(5)所示的本发明化合物。
在这里,作为惰性溶剂,例如有醋酸等有机羧酸,氯仿、四氯化碳等有机卤素化合物,乙醇、异丙醇等醇类,乙醚、四氢呋喃等醚类,甲苯等碳氢化合物,N,N-二甲基甲酰胺、乙腈、水或它们的混合溶剂。行为脱水剂,例如有分子筛3A、分子筛4A等分子筛,无水硫酸钠、无水硫酸镁、无水氯化钙等无机盐或五氧化二磷等。作为碱,例如有碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠等无机碱,甲醇钠、叔丁醇钾等醇盐,氨基钠等碱金属胺类,三乙基胺、N,N-二异丙基乙基胺、N-甲基吗啉、吡啶等有机碱,醋酸钠等有机羧酸盐等。作为卤化剂,例如有氯、溴、碘、磺酰氯等。(反应式2)
在惰性溶剂中,在存在或不存在活化剂的情况下,将2-烷氧基羰基衍生物(6)用胺(7)处理,可以得到式(8)所示的本发明化合物。
在这里,作为惰性溶剂,例如氯仿、四氯化碳等有机卤素化合物,乙醇、异丙醇等醇类,乙醚、四氢呋喃等醚类,甲苯等碳氢化合物,N,N-二甲基甲酰胺、乙腈、水或它们的混合溶剂。活化剂表示促进羧酸酯酰胺化的物质,例如有氰化钠等。
对于2-烷氧基羰基衍生物(6),将其羧酸酯在非活性溶剂中在碱或酸的存在下进行水解,得到式(9)所示的本发明化合物。
在这里,作为惰性溶剂,例如有乙醚、四氢呋喃、二噁烷等醚类,甲醇、乙醇等醇类,丙酮等酮类,醋酸等有机羧酸,N,N-二甲基甲酰胺、水等。作为碱例如有氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、氢氧化钙、碳酸钠等无机碱;作为酸例如有盐酸、氢溴酸、硫酸等无机酸,三氟乙酸、甲酸、对甲苯磺酸、甲磺酸等有机酸等。
在存在或不存在碱的情况下,在惰性溶剂中或无溶剂的情况下,将缩酮衍生物(10)和苯亚甲基哌啶衍生物(11)反应后,在惰性的溶剂中用酸进行处理,得到酮衍生物(12)。
在这里,作为碱例如有三乙基胺、N,N-二异丙基乙基胺、N-甲基吗啉、吡啶等有机胺,碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钾、氢氧化钠、氢化钠等无机碱。作为第1步中的惰性溶剂,例如有乙醚、四氢呋喃、二噁烷等醚类,苯、甲苯等碳氢化合物,乙醇等醇类,N,N-二甲基甲酰胺、乙腈、水或它们的混合溶剂等。作为第2步中的非活性溶剂,例如有乙醚、四氢呋喃、二噁烷等醚类,乙醇等醇类,乙酸乙酯等有机羧酸酯,丙酮等酮类,二氯甲烷、氯仿等卤代烃,醋酸等有机羧酸,N,N-二甲基甲酰胺、水或它们的混合溶剂等,作为酸,例如有盐酸、氢溴酸、硫酸等无机酸,三氟乙酸、甲酸、对甲苯磺酸、甲磺酸等有机酸或这些有机酸和吡啶成的盐等。
在惰性溶剂中,在碱的存在下将酮衍生物(12)和O-硅烷化剂反应生成乙烯甲硅烷醚后,在惰性溶剂中和卤化剂反应,得到卤化酮衍生物(13)。按(反应式1)所示的方法将卤化酮衍生物(13)同样地和硫代酰胺衍生物(2)反应,得到式(14)所示的本发明化合物。
在这里,作为O-硅烷化的惰性溶剂,例如有乙醚、四氢呋喃、二噁烷等醚类,苯、甲苯等碳氢化合物,N,N-二甲基甲酰胺、乙腈等。作为碱,例如有二异丙基氨基锂、二(三甲基硅烷基)氨基钠、氨基钠等氨基碱金属类,氢化钠、氢化钾等氢化碱金属类,三乙基胺、N,N-二异丙基乙基胺等有机胺类等,可根据需要合用碘化钠、碘化钾等。作为0-硅烷化剂,例如有以氯代三甲基硅烷等卤代三烷基硅烷为代表的各种硅烷化剂。作为卤化的惰性溶剂,例如有氯仿、四氯化碳等有机卤素化合物,乙醇、异丙醇等醇类,乙醚、四氢呋喃等醚类,苯、甲苯等碳氢化合物,N,N-二甲基甲酰胺、乙腈、水或它们的混合溶剂等。作为卤化剂,例如有氯、溴,碘等卤素,N-氯代琥珀酰亚胺、N-溴代琥珀酰亚胺等N-卤代亚胺,氯化铜、溴化铜、氯化亚铁等卤素金属盐等。(反应式5)
按(反应式1)所示方法,同样地将酮酸(15)卤化后,和硫代酰胺衍生物(16)反应,可以得到噻唑羧酸衍生物(17)。
噻唑羧酸衍生物(17)经过酰卤化物或混合酸酐等,或和缩合剂一起与苄叉哌啶衍生物(11)反应,可以得到式(18)所示的酰胺衍生物。
将酰胺衍生物(18)按例如Jurnal of OrganiC Chemistry,42,2082(1977)上记载的方法和卤化剂反应,接着在用还原剂进行反应,可以得到式(20)所示的本发明化合物。
在这里,酸卤化物表示氯代酸、溴代酸等,例如将亚硫酰氯、乙二酰氯、四氯化碳-三苯基磷等的卤化剂在例如四氢呋喃等醚类,甲苯、苯等碳氢化合物,氯仿、二氯甲烷等卤化溶剂,乙腈、N,N-二甲基甲酰胺等非活性溶剂中反应得到。混合酸酐表示羧酸和碳酸的酸酐等,例如将氯代碳酸乙酯、氯代碳酸异丁酯等卤代碳酸酯在三乙基胺、二异丙基乙基胺、甲替吗啉、吡啶等有机碱或氢化钠、碳酸钠等无机碱的存在下,在例如四氢呋喃等醚类,甲苯、苯等碳氢化合物,氯仿、二氯甲烷等卤化溶剂,乙腈、N,N-二甲基甲酰胺等非活性溶剂中进行反应得到。缩合剂表示通常所用的酰胺化试剂,例如有二苯基磷酰胺,氰基磷酸二乙酯,羰基咪唑,N,N’-双环碳化二亚胺、N-乙基-N’-二甲基氨基丙基碳化二亚胺盐酸盐所代表的碳化二亚胺类等,必要时可以和N-羟基琥珀酰亚胺、1-羟基苯并三唑或3-羟基-4-氧-3,4-二氢-1,2,3-苯并三嗪等一起在非活性溶剂中反应,非活性溶剂例如1,2-二甲氧基乙烷,四氢呋喃等醚类,甲苯、苯等碳氢化合物,氯仿、二氯甲烷等卤化溶剂,乙腈、N,N-二甲基甲酰胺等。
(反应式6)
噻唑羧酸衍生物(17)的羧酸被还原剂还原成醇后,此醇再被氧化剂氧化,得到噻唑醛衍生物(21)后,在还原剂的存在下将其和苯亚甲基哌啶衍生物(11)进行反应,,可以得到式(20)所示的本发明化合物。
在这里,羧酸的还原剂表示例如乙硼烷、硼烷·四氢呋喃络合物等羧酸的选择性还原剂,在例如1,2-二甲氧基乙烷、四氢呋喃等醚类、甲苯、苯等碳氢化合物等的非活性溶剂中使用。醇的氧化剂系指例如用乙二酰氯-二甲基亚砜的Swern’s氧化,铬类氧化剂、二氧化锰等金属氧化剂,在例如1,2-二甲氧基乙烷,四氢呋喃等醚类,甲苯、苯等碳氢化合物,氯仿、二氯甲烷等卤系溶剂,乙腈、N,N-二甲基甲酰胺、丙酮等惰性溶剂中使用。最后步骤所用的还原剂例如有乙硼烷、硼烷·四氢呋喃络合物、硼氢化钠、氰基硼氢化钠等,在乙醇、异丙醇等醇类,乙醚、四氢呋喃等醚类,苯、甲苯等碳氢化合物等的惰性溶剂中,可以根据需要加入盐酸、氯化氢、醋酸等酸进行反应。
(反应式7)
将哌啶酮衍生物(22)在碱的存在下、惰性溶剂中和三苯基芳香基甲基磷鎓盐(23)或二烷基芳香基甲基磷酸盐(24)进行缩合后,用脱保护剂除去保护基团,可以得到式(11)所示的4-苯亚甲基哌啶衍生物。
在这里,碱例如有氢化钠、氢化钾、甲醇钠、叔丁醇钾、正丁基锂、二异丙基氨基锂、二(三甲基硅烷基)氨基锂、氨基钠等,可根据需要合用15-冠烷-5-醚、18-冠烷-6-醚等催化剂,四甲基乙二胺、六甲基磷酰胺等。作为惰性溶剂,例如有乙醚、四氢呋喃、二噁烷等醚类,苯、甲苯等碳氢化合物,乙醇等醇类,N,N-二甲基甲酰胺、二甲基亚砜、水等。作为脱保护时的反应溶剂,例如有乙醚、四氢呋喃、二噁烷等醚类,苯、甲苯等碳氢化合物,乙醇等醇类,乙酸乙酯等有机羧酸酯,丙酮等酮类,二氯甲烷、氯仿等卤代烃,醋酸等有机羧酸,N,N-二甲基甲酰胺、水等。作为脱保护剂,R4为烷氧基羰基、酰基、磺酰基时,作为酸例如有盐酸、氢溴酸、硫酸等无机酸,三氟乙酸、甲酸、甲磺酸等有机酸,氯化氢的二噁烷溶液或乙酸乙酯溶液;作为碱,例如有氢氧化钠、氢氧化钾、氢氧化钡等无机碱。R4为碳数1~5的烷基或苄基时,在存在或不存在氯甲酸乙酯等卤化甲酸烷基酯和碱的情况下进行反应,转化成烷氧基羰基后,进行和上述相同的脱保护。更进一步当R4为苄基时,可以用Birch’s还原进行脱保护。
本发明的化合物显示出对多巴胺D4受体优良的亲和力,另一方面显示出对多巴胺D2受体的低亲和力、优良的解离性。因此,本发明的化合物作为精神分裂症和脑血管障碍及老年痴呆症等所致的行为异常等疾病的预防和治疗药物很有用,而且作为没有锥体外系障碍副作用的药物很有用。
为达到上述目的,可以往本发明的化合物中添加增量剂、粘合剂、崩解剂、pH调节剂、助溶剂等,按常用的制剂技术制成片剂、丸剂、胶囊剂、颗粒剂、粉剂、溶液剂、乳剂、混悬剂、注射剂等。
本发明的化合物,对于成人患者可以以0.1~500mg/天的剂量1次或分数次口服或非口服给药。此给药量可以根据疾病的种类、患者的年龄、体重、症状等适当增减。
发明实施的最佳形式
下面就实施例和实验例对本发明进行详细的说明。
实施例1
2-乙氧基羰基-5-(2-氯乙基)-4-(4-氟苯基)噻唑的合成
将50.00克4-氯-4’-氟丁酰苯溶于250毫升四氯化碳,花30分钟滴入41.30克溴。将此反应混合物在室温下搅拌1小时后,进行减压浓缩。得到的残渣和33.20克硫代草氨酸乙酯在250毫升乙醇中在加热回流下搅拌15小时。将反应混合物在减压下浓缩,往残渣中加入乙酸乙酯,依次用饱和碳酸氢钠水溶液、饱和氯化钠水溶液清洗,用无水硫酸钠干燥,滤去干燥剂后,将滤液减压浓缩。 此残渣用快速柱层析(硅胶:Wako胶C200(和光纯药制造),展开剂∶己烷-乙酸乙酯=10∶1-9∶1)精制后,用二异丙基醚重结晶,得到2-乙氧基羰基-5-(2-氯乙基)-4-(4-氟苯基)噻唑29.14克。熔点:81.5-82.5℃按相同方法得到以下的化合物。2-乙氧基羰基-5-(2-氯乙基)-4-苯基噻唑
NMR(CDCl3)δ(ppm);
1.44(3H,t,J=7.1),3.41-3.77(4H,m),4.49(2H,q,J=7.1),7.27-7.61(5H,m)MS m/e;
298(M++1),296(M++1),59(100%)2-乙氧基羰基-5-(2-氯乙基)-4-(4-甲基苯基)噻唑熔点:79.0~80.0℃(用二异丙基醚重结晶)2-氨基甲酰基-5-(2-氯乙基)-4-(4-氟苯基)噻唑熔点:136.0~138.0℃(用乙醚-己烷重结晶)2-甲氧基羰基-5-(2-氯乙基)-4-苯基噻唑熔点:80.0~82.0℃(快速柱层析精制后,放置)2-乙氧基羰基-5-(2-溴乙基)-4-苯基噻唑
NMR(CDC13)δ(ppm);
1.44(3H,t,J=7.1),3.54-3.57(4H,m),4.49(2H,q,J=7.1),7.2 7-7.61(5H,m)MS m/e;
342(M++1),340(M++1),59.(100%)2-乙氧基羰基-5-(2-溴乙基)-4-(4-甲基苯基)噻唑
NMR(CDC13)δ(ppm);
1.44(3H,t,J=7.1),2.40(3H,s),3.53-3.56(4H,m),4.49(2H,q,J=7.1),
7.24-7.28(2H,m),7.45-7.50(2H,m)MS m/e;
356(M++1),354(M++1,100%)2-乙氧基羰基-5-(2-溴乙基)-4-(4-氟苯基)噻唑
NMR(CDCl3)δ(ppm);
1.44(3H,t,J=7.1),3.46-3.60(4H,m),4.49(2H,q,J=7.1),7.11-7.20(2H,m),
7.54-7.61(2H,m)MS m/e;
360(M++1),358(M++1,100%)
实施例2
2-乙氧基羰基-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑盐酸盐的合成
将1.50克2-乙氧基羰基-4-(4-氟苯基)-5-(2-氯乙基)噻唑、1.10克4-(3-氟苯亚甲基)哌啶盐酸盐和2.50克N,N-二异丙基乙基胺于3毫升乙醇中,在80℃下搅拌40分钟。将反应液减压浓缩,残渣用乙酸乙酯和饱和碳酸氢钠水溶液分层。有机层用饱和氯化钠水溶液清洗后,用无水硫酸钠干燥,滤去干燥剂。将滤液减压浓缩后,残渣用快速柱层析(Wako胶C200(和光纯药制造),展开剂:己烷-乙酸乙酯=5∶1)精制,接着再通过Chromatolex NH NHDM1020(富士Devison化学公司制造)(展开剂:己烷-乙酸乙酯=10∶1)进行精制。用4N氯化氢/1,4-二噁烷溶液处理后,以乙醇重结晶,得到2-乙氧基羰基-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑盐酸盐1.14克。熔点:206.5-207.5℃按与本化合物相同方法所得化合物的结构和物理性质数据如表1所示。
实施例3
2-氨基甲酰基-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑的合成
将315毫克2-乙氧基羰基-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑和0.05毫升28%氨水于1.5毫升乙醇中搅拌3天。加入0.50毫升28%氨水,再反应3天。将反应液减压浓缩后,残渣用快速柱层析(Wako胶C200(和光纯药制造),展开剂:己烷-乙酸乙酯=3∶1~1∶1)精制,用乙醇重结晶,得到2-氨基甲酰基-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑201毫克。熔点:171.5-172.5℃按与本化合物相同方法所得的化合物的结构和物理性质数据如表1所示。
实施例4
2-羧酸-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑钾盐的合成
往277毫克2-乙氧基羰基-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑中加入2N氢氧化钠水溶液0.33毫升,搅拌一夜。将反应液减压浓缩后,残渣用柱层析(DIAIONHP20(三菱化学公司制造),水→50%乙醇→乙醇)进行精制,得到2-羧酸-4-(4-氟苯基)-5-[2-[4-(3-氟苯亚甲基)哌啶-1-基]乙基]噻唑钾盐209毫克。NMR(CDCl3)δ(ppm);
2.30-2.63(10H,m),3.00-3.10(2H,m),6.30(1H,s),6.99-7.07(3H,m),
7.23-7.43(3H,m),7.62-7.69(2H,m)MS m/e;
517(M++K),479(M++1),204(100%)按与本化合物相同方法所得的化合物的结构和物理性质数据如表1所示。
实施例5
2-氨基甲酰基-4-苯基-5-[2-[4-(4-氟苯亚甲基)哌啶-1-基]乙基]噻唑的合成
(1)将6.80克2-苯基-2-(3-氟丙基)-1,3-二氧戊环、6.83克4-(4-氟苯亚甲基)哌啶盐酸盐、16毫升N,N-二异丙基乙基胺和16毫升甲醇的混合物在80℃下搅拌50小时。将反应液减压浓缩,往残渣中加入饱和碳酸氢钠水溶液和氯仿,分离有机层。有机层用水清洗后,以无水硫酸镁干燥,滤去干燥剂后,将滤液减压浓缩。
往残渣中加入2N盐酸30毫升和四氢呋喃30毫升,在室温下搅拌16小时。将反应液减压浓缩,往残渣中加入2N氢氧化钠水溶液和乙酸乙酯,分离有机层。水层再用乙酸乙酯提取,合并有机层,用饱和氯化钠水溶液清洗后,用无水硫酸镁干燥,滤去干燥剂。将滤液减压浓缩后,残渣用快速柱层析(Merck硅胶230-400目,展开剂:己烷-乙酸乙酯=1∶1)进行精制,再用己烷结晶,得到1-(4-苯基-4-氧代丁基)-4-(4-氟苯亚甲基)哌啶7.36克。
(2)用2.1毫升二异丙基胺和10毫升1.63M正丁基锂制成二异丙基氨基锂的四氢呋喃(15毫升)溶液,在-50℃冷却下往其中滴入5.24克1-(4-苯基-4-氧代丁基)-4-(4-氟苯亚甲基)哌啶溶于20毫升四氢呋喃的溶液。滴入后进一步搅拌20分钟后,加入3毫升氯化三甲基硅烷。在这之后是反应液温度逐渐上升,在室温下搅拌16小时。在冷却下往反应混合物中加入氯仿和饱和碳酸氢钠水溶液,分离有机层。水层进一步用氯仿提取,合并有机层,用水清洗。用无水硫酸镁干燥,滤去干燥剂,将滤液减压浓缩,得到1-(4-苯基-4-三甲基硅烷氧-3-丁烯-1-基)-4-(4-氟苯亚甲基)哌啶6.21克。
(3)将6.21克1-(4-苯基-4-三甲基硅烷氧-3-丁烯-1-基)-4-(4-氟苯亚甲基)哌啶溶于30毫升四氢呋喃,在-50℃冷却下,一点一点地加入2.83克N-溴化琥珀酰亚胺。在-50℃下将反应混合物再搅拌1小时后,逐渐使温度升至-20℃,加入饱和碳酸氢钠水溶液和氯仿,分离有机层。水层进一步用氯仿提取,合并有机层,用水清洗。用无水硫酸镁干燥后,滤去干燥剂,在冰冷却下往滤液中加入8毫升4N氯化氢二噁烷溶液。减压馏去溶剂,往残渣中加入乙醚进行结晶,得到1-(3-溴-4-苯基-4-氧代丁基)-4-(4-氟苯亚甲基)哌啶盐酸盐6.00克。
将5.90克1-(3-溴-4-苯基-4-氧代丁基)-4-(4-氟苯亚甲基)哌啶盐酸盐、2.26克硫代草氨酸乙酯、3.26克分子筛4A和25毫升1,2-二甲氧基乙烷的混合物在搅拌下加热回流12小时。冷却至室温后,滤取析出的物质,用乙醚清洗。将其溶于氯仿,滤去不溶物。往滤液中加入3.6毫升三乙基胺后,再加入氯仿和饱和碳酸氢钠水溶液,分离有机层。水层进一步用氯仿提取,合并有机层,用水清洗。用无水硫酸镁干燥,滤去干燥剂,将滤液减压浓缩。
将残渣溶于25毫升乙醇,加入8毫升28%氨水,在室温下搅拌3天。将反应液减压浓缩,往残渣中加入氯仿和水,分离有机层。水层进一步用氯仿提取,合并有机层,用水清洗。用无水硫酸镁干燥,滤去干燥剂,将滤液减压浓缩,往残渣中加入乙醚进行结晶,得到2-氨基甲酰基-4-苯基-5-[2-[4-(4-氟苯亚甲基)哌啶-1-基]乙基]噻唑2.34克。按与本化合物相同方法所得的化合物的结构和物理性质数据如表1所示。
实施例6
4-(4-氟苯亚甲基)哌啶盐酸盐的合成
往搅拌的含有1.65克15-冠烷-5-醚的13.20克60%氢化钠(油中)在650毫升四氢呋喃的混悬液中,在冰冷却下花20分钟滴入59.78克N-叔丁氧基羰基哌啶酮和81.25克4-氟苄基磷酸二乙酯溶于150毫升四氢呋喃的溶液。在室温下搅拌1天后,小心加入饱和碳酸氢钠水溶液,然后用乙酸乙酯提取。提取液依次用饱和碳酸氢钠水溶液、饱和食盐水清洗后,用无水硫酸钠干燥,滤去干燥剂后,将滤液减压浓缩,用快速柱层析(硅胶:Wako胶C200(和光纯药制造),展开剂:己烷-乙酸乙酯=20∶1)进行精制,得到N-叔丁氧基羰基-4-(4-氟苯亚甲基)哌啶55.23克。所得油状物质在室温下放置1夜析出结晶。熔点:69-70℃
冰冷下往55.00克N-叔丁氧基羰基-4-(4-氟苯亚甲基)哌啶中加入冷却的475毫升4N氯化氢二噁烷溶液,在室温下搅拌2小时。将反应溶液减压浓缩,所得结晶用异丙醇重结晶,得到4-(4-氟苯亚甲基)哌啶盐酸盐40.72克。
熔点:184-185.5℃按与本化合物相同方法所得化合物的结构和物理性质参数如表2所示。
合成α-烷基苯亚甲基哌啶衍生物时,其中的碱用二异丙基氨基锂代替氢化钠(含15-冠烷-5-醚),反应温度是在-50℃下滴入后升至室温。
表1表1(续表)Comp.No.:化合物序号Ex.No.:化合物合成时使用的实施例序号重结晶溶剂;EtOH:乙醇,IPA:异丙醇,IPE:二异丙基醚*1:结晶化溶剂*2:开始分解的温度*3:化合物A-11NMR(CDC13)δ(ppm);
2.30-2.63(10H,m),3.00-3.10(2H,m),6.30(1H,s),6.99-7.07(3H,m),
7.23-7.43(3H,m),7.62-7.69(2H,m)
MS m/e;
517(M++K),479(M++1),204(100%)*4:化合物A-23NMR(CDCl3)δ(ppm);
1.54-1.82(4H,m),2.22-2.32(2H,m),2.62-2.69(2H,m),2.98-3.10(4H,m),
3.35-3.45(1H,m),7.22-7.42(4H,m),7.59-7.68(2H,m),8.02-8.11(2H,m)MS m/e;
533(M++K),495(M++1),154(100%)
表2Com.No.:化合物序号重结晶溶剂;IPA:异丙醇,IPE:二异丙基醚实验例(受体结合实验)
1.多巴胺D4受体结合实验
作为受体样品使用表达人D4.2受体的中国仓鼠卵巢(CHO)细胞膜。
作为[3H]标记配基使用[3H]-螺环哌啶酮。
用[3H]标记配基的结合反应按Eur.J.Pharmacol.,233,173(1993年)记载的下述方法进行。
人D4.2受体结合实验:将表达人D4.2受体的CHO细胞膜,[3H]-螺环哌啶酮(0.5nM)和被测药品在含有5mM EDTA、1.5mM CaCl2、5mMKCl,120mMNaCl的50mM tris盐酸缓冲液(pH7.4)中,在27℃下反应2小时。
反应结束后,用玻璃滤器(GF/B)抽滤,再用液体闪烁分光计测定滤纸的放射性。
将10μM氟哌啶醇存在下反应时的结合作为[3H]-螺环哌啶酮的非特异结合,总结合和非特异结合的差作为特异的结合。将一定浓度的[3H]-螺环哌啶酮和变换浓度的被测药品在上述条件下进行反应,得到抑制曲线,从此曲线求出[3H]-螺环哌啶酮结合被抑制50%的被测药品浓度(IC50),结果如表3所示。
2.多巴胺D2受体结合实验
作为受体样品使用大鼠纹状体膜。
作为[3H]标记配基使用[3H]-Raclopride.
用[3H]标记配基的结合反应按Mol.Pharmacol.,43,749(1993年)记载的下述方法进行。
受体样品的配制:用50mM tris盐酸缓冲液(pH7.4)将大鼠纹状体匀浆,以48000×g离心分离,残渣用tris盐酸缓冲液清洗1次。将残渣混悬于含有120mM NaCl、5mM KCl、2mMCaCl2、1mM MgCl2的50mM tris盐酸缓冲液(pH7.4)中,作为膜样品。
多巴胺D2受体结合实验:将膜样品(0.5毫克蛋白质/毫升)、[3H]-Raclopride(1nM)及被测药品在25℃下反应1小时。
反应结束后,用玻璃滤器(GF/B)抽滤,再用液体闪烁分光计测定滤纸的放射性。
将10μM氟哌啶醇存在下反应时的结合作为[3H]-Raclopride的非特异结合,总结合和非特异结合的差作为特异的结合。将一定浓度的[3H]-Raclopride和变换浓度的被测药品在上述条件下进行反应,得到抑制曲线,从此曲线求出[3H]-Raclopride结合被抑制50%的被测药品浓度(IC50),结果如表3所示。
表3
*1:化合物序号(和表1相同)
Comp. IC50(nM)No.*1 D4 D2 |
A-02 5.46 ≥1000A-09 13.9 >1000A-10 4.53 559.1A-11 10.5 ≥1000A-13 3.13 142.8A-15 18.3 432.9A-17 5.99 628.0A-20 9.55 187.4A-21 3.43 >1000A-22 3.13 72.2 |
产业上的利用可能性
本发明的化合物显示出对多巴胺D4受体优良的亲和力,另一方面显示出对多巴胺D2受体的低亲和力、优良的解离性。
因此,本发明的化合物作为精神分裂症和脑血管障碍及老年痴呆症等所致的行为异常等疾病的预防和治疗药物很有用,而且作为没有锥体外系障碍副作用的药物很有用。
Claims (10)
2.权利要求1的2-羰基噻唑衍生物或其医药上允许的盐,其中Y1-Y2表示C=C(R2),如下式所示:
4.根据权利要求3记载的2-羰基噻唑衍生物或其医药上允许的盐,其中R3和R4为氢原子。
5.根据权利要求4记载的2-羰基噻唑衍生物或其医药上允许的盐,其中X1和X2皆为4位取代氟原子、X1为氢原子X2为4位取代氟原子、或X1为4位取代氟原子X2为3位取代氟原子。
7.含有权利要求1~6任一项记载的2-羰基噻唑衍生物或其医药上允许的盐的药物。
8.多巴胺D4受体拮抗剂,含有以权利要求1~6任一项记载的2-羰基噻唑衍生物或其医药上允许的盐作为有效成分。
9.权利要求1~6任一项记载的2-羰基噻唑衍生物或其医药上允许的盐用于制备药物的应用。
10.权利要求1~6任一项记载的2-羰基噻唑衍生物或其医药上允许的盐用于制备多巴胺D4受体拮抗剂的应用。
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KR100394086B1 (ko) * | 2000-12-04 | 2003-08-06 | 한국과학기술연구원 | 도파민 d3 및 d4 수용체의 선택적 활성을 지닌 신규이소옥사졸릴알킬피페라진 유도체와, 이의 제조방법 |
KR100394083B1 (ko) * | 2000-12-04 | 2003-08-06 | 학교법인 성신학원 | 도파민 d3 및 d4 수용체의 선택적 활성을 지닌 신규4,5-디히드로이소옥사졸릴알킬피페라진 유도체와, 이의제조방법 |
WO2008128189A1 (en) * | 2007-04-13 | 2008-10-23 | The Penn State Research Foundation | Anti-cancer compositions and methods |
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EP0409048A2 (de) * | 1989-07-18 | 1991-01-23 | BASF Aktiengesellschaft | Aminoalkylsubstituierte 2-Aminothiazole und diese enthaltende therapeutische Mittel |
WO1992022539A1 (de) * | 1991-06-15 | 1992-12-23 | Basf Aktiengesellschaft | Aminoalkylsubstituierte thiazolin-2-one, ihre herstellung und verwendung |
WO1996029330A1 (fr) * | 1995-03-22 | 1996-09-26 | Taisho Pharmaceutical Co., Ltd. | Derives de la thiazole |
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US4123529A (en) * | 1976-04-23 | 1978-10-31 | Lilly Industries Limited | Phenylpiperazine derivatives |
-
1997
- 1997-09-19 CA CA002267258A patent/CA2267258A1/en not_active Abandoned
- 1997-09-19 DK DK97940436T patent/DK0940401T3/da active
- 1997-09-19 KR KR1019990702355A patent/KR20000048480A/ko not_active Application Discontinuation
- 1997-09-19 AT AT97940436T patent/ATE227286T1/de not_active IP Right Cessation
- 1997-09-19 AU AU42223/97A patent/AU718519B2/en not_active Ceased
- 1997-09-19 PT PT97940436T patent/PT940401E/pt unknown
- 1997-09-19 ES ES97940436T patent/ES2186923T3/es not_active Expired - Lifetime
- 1997-09-19 CN CN97199832A patent/CN1088707C/zh not_active Expired - Fee Related
- 1997-09-19 EP EP97940436A patent/EP0940401B1/en not_active Expired - Lifetime
- 1997-09-19 US US09/269,021 patent/US6166033A/en not_active Expired - Fee Related
- 1997-09-19 WO PCT/JP1997/003342 patent/WO1998012195A1/ja not_active Application Discontinuation
- 1997-09-19 DE DE69716939T patent/DE69716939T2/de not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0409048A2 (de) * | 1989-07-18 | 1991-01-23 | BASF Aktiengesellschaft | Aminoalkylsubstituierte 2-Aminothiazole und diese enthaltende therapeutische Mittel |
WO1992022539A1 (de) * | 1991-06-15 | 1992-12-23 | Basf Aktiengesellschaft | Aminoalkylsubstituierte thiazolin-2-one, ihre herstellung und verwendung |
WO1996029330A1 (fr) * | 1995-03-22 | 1996-09-26 | Taisho Pharmaceutical Co., Ltd. | Derives de la thiazole |
Also Published As
Publication number | Publication date |
---|---|
DK0940401T3 (da) | 2003-03-03 |
US6166033A (en) | 2000-12-26 |
DE69716939T2 (de) | 2003-07-03 |
ES2186923T3 (es) | 2003-05-16 |
KR20000048480A (ko) | 2000-07-25 |
EP0940401A1 (en) | 1999-09-08 |
CN1237971A (zh) | 1999-12-08 |
PT940401E (pt) | 2003-03-31 |
DE69716939D1 (de) | 2002-12-12 |
CA2267258A1 (en) | 1998-03-26 |
EP0940401A4 (en) | 2001-04-11 |
ATE227286T1 (de) | 2002-11-15 |
AU4222397A (en) | 1998-04-14 |
WO1998012195A1 (fr) | 1998-03-26 |
EP0940401B1 (en) | 2002-11-06 |
AU718519B2 (en) | 2000-04-13 |
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