CN1274357A - 抗精神病的取代哌啶衍生物 - Google Patents
抗精神病的取代哌啶衍生物 Download PDFInfo
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- CN1274357A CN1274357A CN98809976A CN98809976A CN1274357A CN 1274357 A CN1274357 A CN 1274357A CN 98809976 A CN98809976 A CN 98809976A CN 98809976 A CN98809976 A CN 98809976A CN 1274357 A CN1274357 A CN 1274357A
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- Prior art keywords
- compound
- alkyl
- piperidines
- solvate
- aryl
- Prior art date
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 21
- 230000000561 anti-psychotic effect Effects 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 105
- -1 heterocyclic radical Chemical class 0.000 claims description 59
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 45
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 37
- 239000012453 solvate Substances 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 125000001544 thienyl group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- AARAMQPQNNRZQN-UHFFFAOYSA-N Cl.Cl.C=N.C=N.C=N.C=N Chemical compound Cl.Cl.C=N.C=N.C=N.C=N AARAMQPQNNRZQN-UHFFFAOYSA-N 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- HHDQPLCWRRJGDI-SQDRRJMKSA-N C(\C=C/C(=O)O)(=O)O.C=N.C=N.C=N.C=N Chemical compound C(\C=C/C(=O)O)(=O)O.C=N.C=N.C=N.C=N HHDQPLCWRRJGDI-SQDRRJMKSA-N 0.000 claims description 4
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 claims description 3
- JIDACXQPXZWJGW-ODZAUARKSA-N azetidine;(z)-but-2-enedioic acid Chemical compound C1CNC1.OC(=O)\C=C/C(O)=O JIDACXQPXZWJGW-ODZAUARKSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical class OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 claims 1
- 208000028017 Psychotic disease Diseases 0.000 abstract description 2
- 238000013160 medical therapy Methods 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 229960004046 apomorphine Drugs 0.000 description 11
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 230000009194 climbing Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 8
- 230000006399 behavior Effects 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 238000007920 subcutaneous administration Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000009834 vaporization Methods 0.000 description 7
- 230000008016 vaporization Effects 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000009132 Catalepsy Diseases 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 206010047853 Waxy flexibility Diseases 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940064982 ethylnicotinate Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000015110 jellies Nutrition 0.000 description 4
- 239000008274 jelly Substances 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000002524 organometallic group Chemical group 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- SKYZYDSNJIOXRL-BTQNPOSSSA-N (6ar)-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10,11-diol;hydrochloride Chemical compound Cl.C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 SKYZYDSNJIOXRL-BTQNPOSSSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical group OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 229960003990 apomorphine hydrochloride Drugs 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000002393 azetidinyl group Chemical group 0.000 description 3
- 230000037396 body weight Effects 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
- 210000000078 claw Anatomy 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000005936 piperidyl group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229920004011 Macrolon® Polymers 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- CECGBBNIUDXSHK-UHFFFAOYSA-N benzamide;oxalic acid Chemical compound OC(=O)C(O)=O.NC(=O)C1=CC=CC=C1 CECGBBNIUDXSHK-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 208000020016 psychiatric disease Diseases 0.000 description 2
- 210000002804 pyramidal tract Anatomy 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- OUGBUDUQDHSPFR-UHFFFAOYSA-N (4-oxo-4-piperidin-1-ylbutyl) methanesulfonate Chemical class CS(=O)(=O)OCCCC(=O)N1CCCCC1 OUGBUDUQDHSPFR-UHFFFAOYSA-N 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- YXTROGRGRSPWKL-UHFFFAOYSA-N 1-benzoylpiperidine Chemical class C=1C=CC=CC=1C(=O)N1CCCCC1 YXTROGRGRSPWKL-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- YYJBWYBULYUKMR-UHFFFAOYSA-N 2-bromo-3-methylthiophene Chemical compound CC=1C=CSC=1Br YYJBWYBULYUKMR-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 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 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- PKXHXOTZMFCXSH-UHFFFAOYSA-N 3,3-dimethylbut-1-ene Chemical compound CC(C)(C)C=C PKXHXOTZMFCXSH-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本发明涉及一些式(Ⅰ)所示新的取代的哌啶衍生物、其制备方法、含有它们的药物制剂,以及它们在医疗、尤其是在治疗精神障碍中的应用。
Description
本发明涉及一些新的取代的哌啶衍生物、其制备方法、含有它们的药物制剂,以及它们在医疗、尤其是在治疗精神障碍中的应用。
US 2739968公开了具有抗组胺、解痉、抗乙酰胆碱和止痛活性的取代的哌啶衍生物。US 4666905和US 4540780公开了能用作止吐剂、抗组胺剂、肺解痉剂的二苯基亚甲基衍生物。
有效的抗精神病(精神抑制)剂包括三环吩噻嗪、噻吨和二苯氮以及苯甲酰胺和丁酰苯。这些化合物阻断多巴胺D2受体并阻断多巴胺传导。作为其作用的结果,这些化合物会在男性中引起特征性神经病学上的副作用,例如锥体束外副作用如张力障碍和运动障碍(R.J.Baldessarini,1996,Goodman和Gilman’s,《治疗的药理基础》,第9版,eds J.G.Hardman等人)。在动物实验中,这类副作用自身表现为僵住症。因此,提供一系列不具有这些衰弱性副作用的精神抑制剂是有利的。
本发明提供了一些取代的哌啶衍生物,其具有强效的精神抑制活性,但是表现出很少或没有表现出任何僵住作用,因此在治疗剂量内不会引起锥体束外副作用。
因此,一方面,本发明提供了式(I)化合物或其可药用盐或溶剂化物:其中R1是苯并噻吩基、苯并呋喃基、萘基(其中所述苯并噻吩基、苯并呋喃基或萘基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代)、取代的噻吩基或取代的呋喃基(其中所述噻吩基或呋喃基部分被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代);R2是取代的苯基或取代的噻吩基(其中所述苯基或噻吩基部分被一个或多个选自C1-6烷基和卤素的取代基取代);R3是-(CH2)mXCONR4R5或-(CH2)mNR6COR7,其中R4是氢或C1-6烷基,R5是氢、C1-6烷基、C3-6环烷基、C6-12芳基、C6-12芳基C1-6烷基或C2-9杂环基(其中所述烷基、芳基或杂环基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代),或者R4和R5与它们所连的氮原子一起形成4-10元杂环基(该杂环基可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代),R6是氢或C1-6烷基,R7是C3-6环烷基、C3-6环烷基C1-6烷基、C6-12芳基、C6-12芳基C1-6烷基或C2-9杂环基(其中所述烷基、芳基或杂环基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代),X是键、C6-12芳基或5元或6元杂芳基(其中所述芳基或杂芳基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代);m是整数1、2、3或4。
本说明书所用术语烷基是指直链或支链烷基。这种烷基包括甲基、乙基、异丙基、正丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基和新己基。这种烷基优选为C1-4烷基。本说明书所用术语环烷基包括环丙基和环戊基。
本说明书所用术语链烯基包括E-型和Z-型链烯基或它们的混合物,并且当其包含至少3个碳原子时,可以是支链链烯基。这种链烯基优选为C1-4链烯基。具体链烯基的实例包括乙烯基、烯丙基、异丙烯基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基、异己烯基和新己烯基。
术语卤素包括氯、溴、氟和碘。
在本说明书中作为基团或基团的一部分而使用的术语芳基是指C6-12芳基,并包含一个或两个C6芳环。其实例包括苯基、萘基和联苯基,尤其是苯基。
本说明书所用术语C2-9杂环基是指芳香、饱和或部分饱和的C2-9杂环基。其包含1个或2个C3-5芳香、饱和或部分饱和的环,所述环含有一个或多个(例如1-3个)选自氧、硫和氮的杂原子。芳香C2-9杂环基的实例包括噻吩基、吡啶基、吡咯基、噻唑基、呋喃基、喹啉基和异喹啉基。不饱和C3-9杂环基的实例包括哌啶基、吡咯烷基和氮杂环丁烷基。
术语5元或6元杂芳基是指含有一个或多个(例如1-3个、优选1个)选自氧、硫和氮的杂原子的5元或6元芳香环。例如噻吩基、吡啶基、吡咯基、噻唑基和呋喃基。
术语4元-10元杂环是指含有一个或多个(例如1-3个、优选1个)选自氧、硫和氮的杂原子的芳香、饱和或部分饱和的4元、5元、6元、7元、8元、9元或10元环。这种芳香杂环基的实例包括噻吩基、吡啶基、吡咯基、噻唑基、呋喃基、喹啉基和异喹啉基。这种不饱和杂环基的实例包括哌啶基、吡咯烷基和氮杂环丁烷基。
苯并噻吩基、苯并呋喃基、萘基、取代的噻吩基和取代的呋喃基包括2-苯并噻吩基和3-苯并噻吩基、2-苯并呋喃基和3-苯并呋喃基、2-萘基和3-萘基、取代的2-噻吩基、取代的3-噻吩基、取代的2-呋喃基和取代的3-呋喃基。苯并噻吩基、苯并呋喃基、萘基、噻吩基和呋喃基环上的取代基可位于该环的任何可用的位置上。环取代基的具体实例包括氟、氯和甲氧基。
本发明还包括式(I)化合物或其可药用盐或溶剂化物,其中:(i)R1是苯并噻吩基或取代的噻吩基(其中所述噻吩基部分上的取代基是C1-6烷基,例如甲基和乙基);(ii)R2是取代的苯基(其中所述苯基部分上的取代基是卤素,例如氟);(iii)R3是-(CH2)mXCONR4R5,其中R4和R5与它们所连的氮原子一起形成4元、5元或6元杂环基,例如哌啶基、吡咯烷基和氮杂环丁烷基,X是键或C6芳基如苯基,且m是整数1、2、3或4,尤其是1或4;(iv)R3是-(CH2)mNR6COR7,其中R6是氢,R7是C3-6环烷基如环丙基、C3-6环烷基C1-6烷基如环戊基甲基、C6芳基,可任选地被一个或多个C1-6烷基取代,例如可任选地被甲基取代的苯基,m是整数1、2、3或4,尤其是2、3或4;(v)R1、R2和R3的定义同(i)-(iv)所述。
上面式(I)化合物的其它实例包括在实施例2和3中描述的化合物。
优选的本发明化合物包括如下的式(I)化合物或其可药用盐或溶剂化物,其中X是C6-12芳基或5元或6元杂芳基(其中所述芳基或杂芳基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代)。
特别优选的本发明化合物是:1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶(1∶1)乙烷二甲酸盐;1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]吡咯烷二盐酸盐;1-[4-[4-[(3-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶盐酸盐;1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶;1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷盐酸盐;1-[3-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶马来酸盐;1-[3-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷马来酸盐;1-[3-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶富马酸盐;1-[3-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷二盐酸盐;4,4-二甲基-1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]氮杂环丁烷马来酸盐;和它们的可药用盐和溶剂化物。
对于治疗应用而言,式(I)化合物的盐是其中的抗衡离子是药物可接受的盐。然而,不可药用的酸加成盐也可能具有实用价值,例如可在制备或纯化可药用化合物的过程中使用。本发明化合物的所有盐,无论是否是可药用的,都包括在本发明范围内。
可药用酸加成盐的实例包括由下述酸衍生而来的盐:无机酸,例如盐酸、氢溴酸、氢碘酸、磷酸、偏磷酸、硝酸和硫酸,和有机酸,例如酒石酸、乙酸、三氟乙酸、柠檬酸、苹果酸、乳酸、马来酸、丙二酸、富马酸、苯甲酸、抗坏血酸、丙酸、乙醇酸、葡糖酸、琥珀酸、甲磺酸和芳基磺酸如苯磺酸或对甲苯磺酸。
优选的本发明盐包括盐酸盐、马来酸盐、琥珀酸盐和富马酸盐。
本发明溶剂化物包括水合物。
另一方面,本发明提供了用于治疗、特别是用于治疗或预防精神障碍如精神分裂、躁狂、活动过强、物质滥用、呕吐和精神分裂型障碍的式(I)化合物及其可药用盐和溶剂化物。
本发明还包括治疗患有或易患有包括任一上述疾病在内的精神障碍的动物,如包括人在内的哺乳动物的方法,包括将有效量的式(I)化合物或其可药用盐或溶剂化物给药。
另一方面,本发明提供了式(I)化合物或其可药用盐或溶剂化物在制备用于治疗或预防任一上述疾病的药物中的应用。
当然,在本说明书中还被称为活性组分的式(I)化合物或其可药用盐或溶剂化物为达到治疗效果所需的量将随具体化合物、给药途径、受者的年龄和身体状况、以及所治疗的具体障碍或疾病而变化。
对于任一上述疾病,适当的日剂量为0.001-25mg/kg受者(例如人)体重/天,优选为0.1-10mg/kg体重/天,最优选为0.25-5mg/kg体重/天。所需剂量可以分成1、2、3、4、5或5个以上次剂量在一天的适当间隔内给药。
虽然活性组分可单独给药,但是优选将其以药物制剂的形式使用。因此,本发明还提供了药物制剂,其中含有式(I)化合物或其可药用盐或溶剂化物和可药用载体,并且还可任选地含有其它治疗剂。载体在与制剂的其它组分配伍和不对受治疗者造成伤害方面必须是“可接受的”。
制剂包括适于口服给药、直肠给药、经鼻给药、局部给药(包括透皮给药、颊给药(buccal)和舌下给药)、阴道给药或非胃肠道给药(包括皮下给药、肌内给药、静脉内给药、真皮内给药和玻璃体内给药)的制剂。制剂可通过制药领域众所周知的方法制得,例如使用在Gennaro等人的《Remington药物学》(Remington’s PharmaceuticalSciences)(第18版,Mack出版公司,1990,尤其参见第8部分:药物制剂及其生产)中描述的方法。这些方法包括将活性组分与由一种或多种辅助组分构成的载体相混合的步骤。所述辅助组分包括本领域常用辅料,例如填充剂、粘合剂、稀释剂、崩解剂、润滑剂、着色剂、调味剂和润湿剂。
可将适于口服给药的制剂制成分别含有预定量活性组分的离散单位,例如丸剂、片剂或胶囊;粉剂或粒剂;溶液剂或悬浮剂。还可以将活性组分配制成药团或糊剂的形式,或者将活性组分包含在脂质体中。
可将直肠给药制剂制成栓剂或灌肠剂。
对于非胃肠道给药制剂,合适的制剂包括水或非水无菌注射剂。这类制剂可以装在单剂量或多剂量容器如密封小瓶和安瓿中,并且可以在冷冻干燥(冷冻干燥)的条件下贮藏,在使用前仅需加入无菌液体载体例如水即可。
适于通过鼻内吸入给药的制剂包括粉尘剂或喷雾剂,其可通过增压密封气雾剂、喷雾器或吹入器以一定剂量来产生。
本发明还包括制备式(I)化合物的下述方法。
式(I)化合物可依据有机化学领域的各种常规方法制得。所用原料是已知的并且可从化学公司方便地获得,或者其自身可通过常规技术制得。例如,可以用在《杂环化合物化学》(The Chemistry ofHeterocyclic Compounds),第44卷,“噻吩及其衍生物”,第1-5部分,Ed S.Gronowitz J.Wiley和Sons,和A.R.Katritsky和C.W.Rees,《综合杂环化学》(Comprehensive Heterocyclic Chemistry),第4部分,Ed C.W.Bird和G.H.Cheesman,Pergamon出版社中描述的方法合成所述化合物。
例如,式(I)化合物可通过与US 4540780中公开的方法相类似的方法制得。
在下述描述中,除非另外指明,否则符号R1、R2、R3、R4、R5、R6、R7、X和m的定义与在式(I)中描述的相同。
式(I)化合物可通过使式(II)化合物与式R3-L化合物反应制得,其中L是适当离去基团,例如卤素如氯、溴或碘,或甲磺酰基或甲苯磺酰基。该反应一般是在溶剂例如甲苯或乙醇存在下、于60-110℃温度下进行的。
一般是在室温或至多为回流温度的较高温度下、在酸清除剂例如三乙胺或碳酸钾存在下、在甲苯或乙醇中,将式(II)化合物与试剂如1-(3-卤甲基苯甲酰基)哌啶、1-(3-卤甲基苯甲酰基)吡咯烷、(4-卤-1-氧代丁基)哌啶(其中卤素包括氯、溴或碘)或相应的甲磺酰基或甲苯磺酰基衍生物如(4-甲磺酰氧基-1-氧代丁基)哌啶反应。
或者,通过将式(III)胺酰化可制得式(I)化合物。例如,将式(III)化合物与适当的式R7COCl酰氯反应可制得式(I)化合物。
通过用化学文献中的已知方法,例如用乙基碘、或在酰化前通过甲酸热解进行甲基化、或用还原烷基化方法,将相应的其中R6是氢的式(III)化合物胺烷基化可制得其中R6是烷基的式(III)化合物胺。
在其中一个上述方法之后,当必须或需要时,可以以任意顺序进行一个或多个下述的进一步步骤:(i)将式(I)化合物的可药用盐或溶剂化物转化成式(I)化合物。(ii)将式(I)化合物的可药用盐或溶剂化物转化成式(I)化合物的另一种可药用盐或溶剂化物。(iii)将式(I)化合物转化成式(I)化合物的可药用盐或溶剂化物。
通过式(IV)化合物的脱水可方便地制得式(II)化合物,其中R8是氢或氮保护基例如三苯甲基。一般是用无机酸例如盐酸或用三氯氧磷来进行脱水。可以用醇脱水标准条件方便地进行该反应。例如,可在80-120℃温度下、在适当溶剂例如吡啶存在下、用三氯氧磷来进行该反应。
可以使用本领域技术人员众所周知或可从化学文献中方便地查阅到的其它方法来进行该脱水反应,包括使用硫酸、4-甲基苯磺酸、三氟乙酸、甲磺酸、三氟甲磺酸、亚硫酰氯进行脱水或者使用Martin硫烷(sulphurane)脱水剂来进行脱水(必要时采用适当溶剂)。
使用本领域技术人员众所周知或可从化学文献中方便地查阅到的方法,可将其中R8是氮保护基如三苯甲基的上述式(IV)化合物同时或依次脱水和脱保护以形成式(II)化合物。
用适当有机金属试剂处理式(V)化合物可制得式(IV)化合物,其中R8是氢或氮保护基,所述有机金属试剂例如是格氏试剂,或衍生自R2-L的锂试剂,其中L是合适的卤素如溴或氯,或衍生自活化的芳基氢原子的锂试剂。例如,在标准反应条件下,用合适的卤素取代的卤化苯基镁处理式(V)化合物,可方便地制得其中R2是被卤素原子取代的苯基的式(IV)化合物。
式(IV)化合物也可以通过用适当的有机金属试剂处理式(VI)化合物来制得,其中R8是氢或氮保护基,所述有机金属试剂例如是格氏试剂,或衍生自R1-L的锂试剂,其中L是合适的卤素如溴或氯,或衍生自活化的芳基氢原子的锂试剂。该反应一般是在-60~67℃温度下、在非极性非质子传递溶剂例如醚或四氢呋喃存在下进行的。
式(V)化合物可通过化学文献中的已知方法制得。例如,如实施例1所述,通过适当取代的卤代苯甲酰基噻吩的氯化可制得其中R1是4-氯-噻吩基或2,3-二氯噻吩基的式(V)化合物。这些化合物可商购获得,或者可用本领域已知方法制得,例如可通过将噻吩或R1代表的其它基团进行弗瑞德-克来福特苯甲酰化来制得。
式(V)和(VI)化合物可通过例如将适当的格氏试剂加到N-甲基异烟酸乙酯或N-三苯甲基异烟酸乙酯中来制得。N-甲基异烟酸乙酯或N-三苯甲基异烟酸乙酯可商购获得,或者可用本领域已知方法由可商购获得的化合物制得。
或者,其中R8是酰基或氢且R2是4-氟苯基的式(VI)化合物可依据在《药物化学杂志》(J.Med.Chem.),1970,
13,1中描述的方法制得。其中R8是三苯甲基的式(V)化合物可由其中R8是氢的式(V)化合物制得,例如使用在下文实施例4中描述的方法,通过将其中R8是氢的式(V)化合物与三苯甲基溴反应可制得其中R8是三苯甲基的式(V)化合物。上述式R3-L化合物可例如用本领域技术人员已知方法,通过使适当的碳酰氯与适当胺反应而制得。
上述式(III)化合物可这样制得:采用本领域已知方法,将式(II)化合物与适当的卤代烷基邻苯二甲酰亚胺反应,然后用肼处理所得N-烷基邻苯二甲酰亚胺中间体。
或者,其中m是2且R6是氢的式(III)化合物可这样制得:例如在碳酸钾和乙腈或DMF存在下,用溴乙腈处理式(II)化合物,随后用适于将腈还原成胺的试剂将该中间体还原。合适的还原剂包括氢化物例如氢化铝锂。
通过用适当碱,例如碱金属氢氧化物、碱土金属氢氧化物或氢氧化铵,或者适当有机酸或无机酸例如盐酸、富马酸或马来酸处理式(I)化合物可制得本发明盐。
本发明还包括在本说明书中描述的所有新的中间体,尤其是式(II)化合物。
下述实施例仅是为了举例说明,而绝不是以任何方式限制本发明范围。实施例14-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶盐酸盐
在-25℃、氮气氛下,用17分钟依次将氯化铝(71g)粉末和2-溴-3-甲基噻吩(50g)的二氯甲烷(300ml)溶液加到不断搅拌的4-(1-乙酰基哌啶基)碳酰氯(50g)的二氯甲烷(690ml)溶液中。30分钟后,向反应中滴加水(240ml),同时将反应温度升至约+20℃。再搅拌30分钟后,通过用dicalite垫过滤将无机成分除去。分离各层,将有机层用水洗涤2次,干燥(Na2SO4),之后减压蒸发。将粗产物(73g)进行色谱纯化,获得了2-(5-溴-4-甲基噻吩基)-4-(1-乙酰基哌啶)甲酮(62.2g);熔点105-108.5℃(分解温度)。
在60℃及氮气氛下,将锌粉(22g)、碘化钠(11g)、三苯基膦(16.5g)和氯化镍六水合物(2.56g)在脱氧的甲醇(340ml)(通过将甲醇在氮气流下沸腾2小时制得)中的悬浮液搅拌15分钟。将上面所得溴代化合物(62.2g)在脱氧的甲醇(150ml)中的溶液加到此混合物中,将反应混合物在氮气氛下沸腾回流22小时。将反应冷却,通过用dicalite垫过滤将无机成分除去。将滤液蒸发,把残余物溶于二氯甲烷。依次用稀的无机酸、水将该溶液洗涤至中性,干燥(Na2SO4),并减压蒸发至干。将粗产物(61.3g)通过快速色谱法纯化,用二氯甲烷/乙醚重结晶,分两批得到了2-(4-甲基噻吩基)-4-(1-乙酰基哌啶)甲酮(41.2g);熔点120-125℃。将该甲酮(41.2g)在5N盐酸(140ml)中的溶液回流16小时,然后减压蒸发,用甲苯与剩余的水共沸。将残余物用乙醚研制,获得了粗产物(38.8g),通过过滤将其分离。用甲醇和乙醚的混合物重结晶,分两批获得了2-(4-甲基噻吩基)-4-哌啶甲酮盐酸盐(29.5g);熔点217.5-218.5℃(200℃以上时晶型发生变化)。
将上面所得盐酸盐(28g)的水溶液碱化,并在0℃及氮气氛下,将该碱化产物(24.1g)在二氯甲烷(240ml)和三乙胺(48ml)中的溶液进行搅拌。将三苯甲基氯(33.7g)以使反应温度维持在0±2℃的速度分批加入。30分钟后,用水(240ml)将该混合物小心地稀释,并萃取到二氯甲烷中。将萃取液洗涤,干燥(Na2SO4),并减压蒸发,用庚烷部分替代二氯甲烷并使其结晶。将晶体过滤,用4∶1的庚烷和二氯甲烷的混合物洗涤,获得了2-(4-甲基噻吩基)-4-(1-三苯甲基哌啶)甲酮(46.9g);熔点219-221℃(分解)。
在搅拌下,将溴乙烷(1.5ml)加到镁屑(6.4g)在含有碘晶体的无水乙醚(100ml)内的悬浮液中。将该放热反应的温度维持在32-36℃,同时小心地加入4-溴氟苯(29ml)的无水乙醚(170ml)溶液。将所得混合物温和地回流30分钟,然后冷却至0℃。用15分钟将上面所得甲酮(23.5g)的无水乙醚(280ml)溶液滴加到该混合物中,同时将温度维持在0-5℃。然后用大约30分钟将反应温度升至室温,用乙酸乙酯萃取产物。将萃取液用水洗涤,干燥(Na2SO4),并减压蒸发,获得了胶状物(32.4g),将该胶状物溶于乙酸(261ml)和水(130ml)的混合物中,把该溶液回流18小时。加入水(130ml),将反应冷却至5℃以下。滤除固体物质(三苯基甲醇),将滤液减压蒸发至很小体积。用浓氨水将所得残余物碱化,把产物萃取到乙酸乙酯中。将萃取液用氯化钠水溶液洗涤,干燥(Na2SO4),并减压蒸发至干,获得了胶状残余物(15.0g)。将氯化氢的甲醇溶液加到该残余物的乙醚溶液中,使其结晶,获得了
4-[(4-氟苯基)(4-甲基噻吩-2- 基)亚甲基]哌啶盐酸盐(9.0g);熔点191-206℃(分解)。实施例21-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶(
2a)
将3-氯甲基苯甲酰氯(1.45ml)加到哌啶(1ml)的三乙胺(2ml)溶液中,将该混合物在5℃、氮气氛下搅拌45分钟。加入水,用二氯甲烷萃取产物,并将萃取液用水洗涤,用硫酸钠干燥并蒸发,获得了1-(3-氯甲基苯甲酰基)哌啶(2.32g),为油状物。
将此苯甲酰基哌啶(2.3g)、实施例1所得4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶(3g)和三乙胺(3ml)在甲苯中的溶液回流5小时。将混合物冷却,加入水,分离各层,分离出甲苯层,用盐水洗涤,用硫酸钠干燥并蒸发。将所得油状物(5.6g)溶于二氯甲烷,用二氧化硅进行色谱纯化。用含有递增量甲醇的二氯甲烷/氢氧化铵(1%)洗脱,将所得洗脱级分蒸发,获得了
标题化合物(4.36g)。用氯化氢的乙醚溶液处理该化合物的乙醚溶液。将沉淀收集并干燥,获得了其盐酸盐(3.6g),熔点118-142℃。
用合适的卤代烷基酰氯以类似方式制得了下述化合物:2b:1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷盐酸盐,熔点118-127℃2c:1-[4-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶二盐酸盐,m/e 4542d:1-[4-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]吡咯烷二盐酸盐,熔点167.4℃2e:1-[4-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶二盐酸盐,熔点117-121℃2f:1-[4-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]吡咯烷马来酸盐,m/e 4622g:1-[3-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶马来酸盐,熔点179-183℃2h:1-[3-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷马来酸盐,熔点157-163℃2i:1-[3-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶富马酸盐,熔点173.4℃2j:1-[3-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷二盐酸盐,熔点167.4℃2k:4,4-二甲基-1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]氮杂环丁烷马来酸盐,熔点173.7℃2l:1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶(1∶1)乙烷二甲酸盐,熔点172-174℃2m:1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]吡咯烷二盐酸盐,熔点144-146℃2n:1-[4-[4-[(3-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶盐酸盐,熔点148-154℃实施例3 制备N-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基丁 基]苯甲酰胺乙二酸盐(
3a)
将4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶(2g)、4-溴丁基邻苯二甲酰亚胺(1.76g)和三乙胺(2ml)在甲苯(20ml)中的溶液回流4小时。将该溶液冷却,用水稀释,分离出甲苯层,蒸发,获得了邻苯二甲酰亚胺(3g),为深色油状物,其是以乙二酸盐形式纯化的。
将前述邻苯二甲酰亚胺(1.88g)和水合肼(0.37ml)在乙醇(20ml)中的溶液回流2小时。减压蒸发除去乙醇,加入水和碳酸钠。用二氯甲烷萃取产物,将萃取液用水洗涤,干燥并蒸发,获得了1-(4-氨基丁基)-4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶(1.16g),为油状物。
将苯甲酰氯加到前述胺在含有三乙胺(1ml)的二氯甲烷内的溶液中,将该溶液在室温搅拌2小时。向该溶液中加入水和二氯甲烷,分离各层,将二氯甲烷层干燥并蒸发,获得了深色胶状物(1.56g)。将该胶状物用二氧化硅进行色谱纯化,用含有递增量甲醇的二氯甲烷洗脱,并将纯化产物转化成乙二酸盐,用甲醇/乙醚将该乙二酸盐结晶,获得了标题化合物,熔点95-98℃。
以类似方式制得了下述化合物:3b:N-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]丙基]苯甲酰胺盐酸盐,熔点95-97℃3c:4-甲基-N-[2-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]乙基]苯甲酰胺乙二酸盐,熔点189-191℃3d:4-甲基-N-[2-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]乙基]-N-甲基苯甲酰胺,熔点114-116℃3e:N-[2-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]乙基]环丙基甲酰胺乙二酸盐,熔点98-101℃3f:N-[2-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]乙基]环戊基甲酰胺乙二酸盐,熔点145-148℃
实施例4
在小鼠中进行的阿朴吗啡爬升试验
多巴胺受体拮抗剂在啮齿动物中抑制由多巴胺激动剂例如阿朴吗啡引起的行为作用的能力是预测这些药物在人类中精神抑制效力的良好标准(参见Bowman和M.J.Rand,《药理学教科书》(Textbook ofPharmacology),第2版,1980,15,6)。在这方面特别相关的试验是,测定多巴胺拮抗剂在小鼠中抑制由皮下或口服给药阿朴吗啡引起的爬升行为的能力的阿朴吗啡爬升试验(ACT)。在该试验中,系统或口服给药后测定的活性已被广泛用作精神抑制活性、即抗精神分裂活性的预测参数(参见,例如J.T.Strupczewski等人,《药物化学杂志》(J.Med.Chem.),1995,38,1119)。用盐酸阿朴吗啡给药的小鼠趋向于沿着丝网圆柱筒的壁采取垂直姿势站立或爬升。这种爬升行为被认为是由于阿朴吗啡介导的刺激多巴胺受体所致。很多药物影响这种爬升行为,但是多巴胺受体拮抗剂在小鼠中通常以不影响运动活性和/或运动协调性的剂量抑制爬升行为。调节这种爬升行为的测试化合物可能具有精神抑制活性。
在小鼠中将各种治疗随机分配。每一试验由1+n个治疗组构成:1是由12只皮下接受阿朴吗啡和载体的小鼠组成的对照组,或者是由12只皮下接受阿朴吗啡和口服接受载体的小鼠组成的对照组;n(通常是4)是由12只皮下接受阿朴吗啡和测试化合物的小鼠组成的化合物组,或者是由12只皮下接受阿朴吗啡和口服接受测试化合物的小鼠组成的化合物组。
试验分3轮进行,每轮20只小鼠。将小鼠标记和称重,把测试化合物或载体皮下给药并将小鼠置于大小为17×11×13cm的Macrolon笼子中,每个笼子放5只小鼠,或者把测试化合物或载体口服给药并将小鼠置于大小为29×11×13cm的Macrolon笼子中,每个笼子放5只小鼠。30分钟后,将盐酸阿朴吗啡以0.75mg/kg的剂量对用载体或测试化合物皮下给药处理的小鼠给药,或者将盐酸阿朴吗啡以0.75mg/kg的剂量对用载体或测试化合物口服给药处理的小鼠给药,并把小鼠独自放在丝网圆柱筒(直径是12cm,高14cm)中。
用阿朴吗啡处理10分钟后,观察各小鼠的爬升行为,并依据下述评分等级记分:4只爪子在底板上 0分1或2只爪子扒在墙壁上 1分3或4只爪子扒在墙壁上 2分
用阿朴吗啡处理20分钟后,再次观察爬升行为并打分。对于每一治疗组,确定每只小鼠的平均分。对照组的得分应当至少为1.0,否则的话就舍弃该试验。以相对于对照组的百分比表示各组的最终结果。
测试化合物的试验结果如表I所示(测试化合物皮下给药)。表I化合物
ACT(ED 50 )mg/kg(皮下给药)化合物
21 0.3化合物
2m 0.14化合物
2n 0.342l=1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶(1∶1)乙烷二甲酸盐2m=1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]吡咯烷二盐酸盐2n=1-[4-[4-[(3-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶盐酸盐
实施例5
大鼠僵住症状
使用雄性Wistar大鼠(100-125g,Olac UK)进行僵住试验。如上所述(Broekkamp等人,Naunyn-Schmiedeberg’s Arch.Pharmacol.338,191,1988)来评价僵住症状。简言之,在6个不同的观察试验中测试大鼠,其中将大鼠以异常体位放置,对保持该强加姿势10秒的计一分正分。强加的姿势有:垂直紧贴网格上;直立并且前爪支撑在高的支撑物上;使后腿伸长;背朝下放置;在嘴中放置压舌片;和在丝网圆柱筒中旋转。
理论上能达到最高分6分。在将药物给药60分钟和120分钟后评价僵住症状。通过双向方差分析(2 way ANOVAR)和之后进行NewmanKools post hoc检验(Newman Kools post hoc test)来评价数据,并计算ED50值(表II)。表II化合物
CATR(ED 50 )mg/kg化合物
2m >7mg/kg化合物
2n >17mg/kg
Claims (10)
1.式(I)化合物或其可药用盐或溶剂化物:其中R1是苯并噻吩基、苯并呋喃基、萘基(其中所述苯并噻吩基、苯并呋喃基或萘基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代)、取代的噻吩基或取代的呋喃基(其中所述噻吩基或呋喃基部分被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代);R2是取代的苯基或取代的噻吩基(其中所述苯基或噻吩基部分被一个或多个选自C1-6烷基和卤素的取代基取代);R3是-(CH2)mXCONR4R5或-(CH2)mNR6COR7,其中R4是氢或C1-6烷基,R5是氢、C1-6烷基、C3-6环烷基、C6-12芳基、C6-12芳基C1-6烷基或C2-9杂环基(其中所述烷基、芳基或杂环基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代),或者R4和R5与它们所连的氮原子一起形成4-10元杂环基,并且该杂环基可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代,R6是氢或C1-6烷基,R7是C3-6环烷基、C3-6环烷基C1-6烷基、C6-12芳基、C6-12芳基C1-6烷基或C2-9杂环基(其中所述烷基、芳基或杂环基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的基团取代),X是键、C6-12芳基或5元或6元杂芳基(其中所述芳基或杂芳基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代);m是整数1、2、3或4。
2.权利要求1的化合物或其可药用盐或溶剂化物,其中R1是苯并噻吩基或取代的噻吩基(其中所述噻吩基部分上的取代基是C1-6烷基)。
3.权利要求1的化合物或其可药用盐或溶剂化物,其中R2是取代的苯基(其中所述苯基部分上的取代基是卤素)。
4.权利要求1的化合物或其可药用盐或溶剂化物,其中R3是-(CH2)mXCONR4R5,其中R4和R5与它们所连的氮原子一起形成4元、5元或6元杂环基,X是键或C6芳基,且m是整数1、2、3或4;或者R3是-(CH2)mNR6COR7,其中R6是氢,R7是可任选地被一个或多个C1-6烷基取代的C3-6环烷基、C3-6环烷基C1-6烷基、C6芳基,m是整数1、2、3或4。
5.权利要求1的化合物或其可药用盐或溶剂化物,其中R1是苯并噻吩基或取代的噻吩基(其中所述噻吩基部分上的取代基是C1-6烷基);R2是取代的苯基(其中所述苯基部分上的取代基是卤素);R3是-(CH2)mXCONR4R5,其中R4和R5与它们所连的氮原子一起形成4元、5元或6元杂环基,X是键或C6芳基,且m是整数1、2、3或4,或者R3是-(CH2)mNR6COR7,其中R6是氢,R7是可任选地被一个或多个C1-6烷基取代的C3-6环烷基、C3-6环烷基C1-6烷基、C6芳基,m是整数1、2、3或4。
6.权利要求1的化合物或其可药用盐或溶剂化物,其中X是C6-12芳基或5元或6元杂芳基(其中所述芳基或杂芳基部分可任选地被一个或多个选自卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基和C1-6链烯基的取代基取代)。
7.根据权利要求1-5任一项的化合物或其可药用盐或溶剂化物,其中所述化合物或其可药用盐或溶剂化物选自:1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶(1∶1)乙烷二甲酸盐;1-[4-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]吡咯烷二盐酸盐;1-[4-[4-[(3-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基]-1-氧代丁基]哌啶盐酸盐;1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶;1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷盐酸盐;1-[3-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶马来酸盐;1-[3-[4-[(4-氟苯基)(苯并噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷马来酸盐;1-[3-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]哌啶富马酸盐;1-[3-[4-[(4-氟苯基)(4-乙基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]吡咯烷二盐酸盐;4,4-二甲基-1-[3-[4-[(4-氟苯基)(4-甲基噻吩-2-基)亚甲基]哌啶-1-基甲基]苯甲酰基]氮杂环丁烷马来酸盐;和它们的可药用盐和溶剂化物。
8.用于治疗的如权利要求1-5任一项所述的式(I)化合物或其可药用盐或溶剂化物。
9.药物制剂,其中含有如权利要求1-7任一项所述的式(I)化合物或其可药用盐或溶剂化物,以及可药用载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP97203107.4 | 1997-10-07 | ||
EP97203107 | 1997-10-07 |
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CN1274357A true CN1274357A (zh) | 2000-11-22 |
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CN98809976A Pending CN1274357A (zh) | 1997-10-07 | 1998-10-07 | 抗精神病的取代哌啶衍生物 |
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US (4) | US6365604B1 (zh) |
EP (1) | EP1021440A2 (zh) |
JP (1) | JP2001519430A (zh) |
KR (1) | KR20010024441A (zh) |
CN (1) | CN1274357A (zh) |
AU (1) | AU747393B2 (zh) |
BR (1) | BR9812862A (zh) |
CA (1) | CA2305277A1 (zh) |
HU (1) | HUP0004796A3 (zh) |
IL (1) | IL135195A0 (zh) |
NO (1) | NO20001778L (zh) |
NZ (1) | NZ503711A (zh) |
PL (1) | PL340294A1 (zh) |
RU (1) | RU2198172C2 (zh) |
TR (1) | TR200000916T2 (zh) |
WO (1) | WO1999019324A2 (zh) |
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US6770659B2 (en) * | 2002-08-26 | 2004-08-03 | Sk Corporation | Benzoyl piperidine compounds |
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NL88063C (zh) | 1950-12-05 | |||
US4640925A (en) * | 1983-06-02 | 1987-02-03 | Warner-Lambert Company | Diphenylmethylene piperidines, compositions and use |
US4540780A (en) | 1983-06-02 | 1985-09-10 | Warner-Lambert Company | Diphenylmethylene piperidines |
NO912475L (no) * | 1990-06-27 | 1991-12-30 | Sankyo Co | Tiazolidinkarboksylsyreamidderivater med antiallergisk aktivitet, og fremgangsmaate til fremstilling derav. |
IL118768A (en) * | 1995-07-12 | 2000-10-31 | Akzo Nobel Nv | Diphenylmethane piperidine derivatives pharmaceutical compositions containing them and a method for their preparation |
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1998
- 1998-10-07 WO PCT/EP1998/006521 patent/WO1999019324A2/en not_active Application Discontinuation
- 1998-10-07 CA CA002305277A patent/CA2305277A1/en not_active Abandoned
- 1998-10-07 HU HU0004796A patent/HUP0004796A3/hu unknown
- 1998-10-07 KR KR1020007003722A patent/KR20010024441A/ko not_active Application Discontinuation
- 1998-10-07 IL IL13519598A patent/IL135195A0/xx unknown
- 1998-10-07 US US09/529,204 patent/US6365604B1/en not_active Expired - Fee Related
- 1998-10-07 RU RU2000111489/04A patent/RU2198172C2/ru not_active IP Right Cessation
- 1998-10-07 TR TR2000/00916T patent/TR200000916T2/xx unknown
- 1998-10-07 PL PL98340294A patent/PL340294A1/xx not_active Application Discontinuation
- 1998-10-07 JP JP2000515896A patent/JP2001519430A/ja not_active Withdrawn
- 1998-10-07 NZ NZ503711A patent/NZ503711A/en unknown
- 1998-10-07 BR BR9812862-0A patent/BR9812862A/pt not_active IP Right Cessation
- 1998-10-07 EP EP98965629A patent/EP1021440A2/en not_active Withdrawn
- 1998-10-07 AU AU21506/99A patent/AU747393B2/en not_active Ceased
- 1998-10-07 CN CN98809976A patent/CN1274357A/zh active Pending
-
2000
- 2000-04-06 NO NO20001778A patent/NO20001778L/no not_active Application Discontinuation
-
2002
- 2002-01-11 US US10/045,726 patent/US20020087001A1/en not_active Abandoned
- 2002-04-25 US US10/131,867 patent/US20020165395A1/en not_active Abandoned
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2003
- 2003-01-28 US US10/353,131 patent/US20030149269A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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AU747393B2 (en) | 2002-05-16 |
BR9812862A (pt) | 2000-08-08 |
WO1999019324A2 (en) | 1999-04-22 |
US6365604B1 (en) | 2002-04-02 |
US20020165395A1 (en) | 2002-11-07 |
US20030149269A1 (en) | 2003-08-07 |
US20020087001A1 (en) | 2002-07-04 |
PL340294A1 (en) | 2001-01-29 |
JP2001519430A (ja) | 2001-10-23 |
NO20001778D0 (no) | 2000-04-06 |
KR20010024441A (ko) | 2001-03-26 |
IL135195A0 (en) | 2001-05-20 |
CA2305277A1 (en) | 1999-04-22 |
HUP0004796A3 (en) | 2002-05-28 |
WO1999019324A3 (en) | 1999-07-01 |
NZ503711A (en) | 2002-05-31 |
HUP0004796A2 (hu) | 2002-04-29 |
NO20001778L (no) | 2000-05-25 |
EP1021440A2 (en) | 2000-07-26 |
RU2198172C2 (ru) | 2003-02-10 |
AU2150699A (en) | 1999-05-03 |
TR200000916T2 (tr) | 2000-07-21 |
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