CN1481360A - 蕈毒碱拮抗剂 - Google Patents
蕈毒碱拮抗剂 Download PDFInfo
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- CN1481360A CN1481360A CNA018209718A CN01820971A CN1481360A CN 1481360 A CN1481360 A CN 1481360A CN A018209718 A CNA018209718 A CN A018209718A CN 01820971 A CN01820971 A CN 01820971A CN 1481360 A CN1481360 A CN 1481360A
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- Prior art keywords
- compound
- alkyl
- cycloalkyl
- milliliters
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- 229940121948 Muscarinic receptor antagonist Drugs 0.000 title abstract 2
- 239000003149 muscarinic antagonist Substances 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- -1 1,4 di-substituted piperidine compounds Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 208000010877 cognitive disease Diseases 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 84
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 102100033639 Acetylcholinesterase Human genes 0.000 claims description 9
- 108010022752 Acetylcholinesterase Proteins 0.000 claims description 9
- 230000001149 cognitive effect Effects 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 229940022698 acetylcholinesterase Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 208000012902 Nervous system disease Diseases 0.000 claims description 6
- 239000002532 enzyme inhibitor Substances 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 230000019771 cognition Effects 0.000 claims 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 25
- 238000000034 method Methods 0.000 abstract description 13
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 4
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000011347 resin Substances 0.000 description 15
- 229920005989 resin Polymers 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 238000001690 micro-dialysis Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 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 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 3
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 229960001231 choline Drugs 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
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000010408 film Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- 229940122041 Cholinesterase inhibitor Drugs 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RRGMXBQMCUKRLH-CTNGQTDRSA-N [(3ar,8bs)-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indol-7-yl] n-heptylcarbamate Chemical compound C12=CC(OC(=O)NCCCCCCC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C RRGMXBQMCUKRLH-CTNGQTDRSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 239000000872 buffer Substances 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 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
- 238000012545 processing Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 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
- 238000001291 vacuum drying Methods 0.000 description 2
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- ZZYYOHPHSYCHQG-UHFFFAOYSA-N 2-bromo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(Br)=C1 ZZYYOHPHSYCHQG-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QYYMDNHUJFIDDQ-UHFFFAOYSA-N 5-chloro-2-methyl-1,2-thiazol-3-one;2-methyl-1,2-thiazol-3-one Chemical compound CN1SC=CC1=O.CN1SC(Cl)=CC1=O QYYMDNHUJFIDDQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102000017926 CHRM2 Human genes 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical class CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
- 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
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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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
本发明涉及一种下式的1,4二-取代哌啶化合物的酰胺衍生物或其药学上可接受的盐、酯或溶剂化物,其中R1为视情况取代的环烷基、环烷基烷基、芳基、芳烷基或杂芳基;R2为H、烷基、或视情况取代环烷基、环烷基烷基、杂环烷基、桥环烷基、或桥杂环烷基;R3为烷基或-CH2OH;且R4为H或烷基;该化合物是用于治疗认知失调如阿兹海默症的蕈毒碱拮抗剂。本发明也公开了药物组合物及制备方法。
Description
发明背景
本发明涉及治疗认知失调用的1,4二-取代哌啶的酰胺衍生物,含该化合物的药物组合物,使用该化合物的治疗方法,及该化合物与乙酰基胆碱酯酶抑制剂并用的用途。
治疗认知失调如阿兹海默症中所用的哌啶衍生的蕈毒碱拮抗剂公开于美国专利第6,037,352号中,尤其是美国专利第6,037,352号公开了一种下列一般式的化合物其中尤其Y为CH;Z为N;X为-NHCO-;R为取代的苄基;R1及R21各为H;R3、R4、R27及R28为氢;且R2为环烷基。美国专利第6,066,636号中也公开了其中的苯环以吡啶基环取代的类似化合物。本发明的化合物是美国专利第6,037,352号及6,066,636号的选择发明。
发明概要
R1为R5-(C3-C8)环烷基、R5-(C3-C8)环烷基(C1-C6)烷基、R5-芳基,R5-芳基-(C1-C6)烷基或R5-杂芳基;
R2为H、(C1-C6)烷基、R6-(C3-C8)环烷基、R6-(C3-C8)-环烷基-(C1-C6)-烷基、R6-杂环烷基、R6-(C6-C10)桥环烷基、或R6-桥杂环烷基;
R3为C1-C6烷基或-CH2OH;
R4为H或C1-C6烷基;
R5为独立选自包含H、C1-C6烷基、卤素、-OH、C1-C6-烷氧基、-CF3、-CN、-CO2R4、-CONHR4、-SO2NHR4、-NHSO2R4及-NHC(O)R4中的1-4个取代基;且
R6为独立选自包含H、C1-C6烷基、卤素、-OH、C1-C6-烷氧基、-CF3、-NH2、(C1-C6)烷基氨基、苯基、C1-C2亚烷基二氧基、及(C1-C6)烷氧基羰基的1-4个取代基。
本发明另一方面涉及一种药物组合物,包括在药学上可接受的载体中的治疗有效量的式I化合物。本发明也涉及使用式I的化合物及包括式I化合物的药物组合物治疗认知失调或神经性疾病的方法,包括将有效量的本发明化合物或组合物对需要该治疗的哺乳动物给药。
本发明另一方面涉及治疗认知失调或神经性疾病的方法,包括依该治疗的需求将有效量的式I化合物与乙酰胆碱酯酶抑制剂的结合物对哺乳动物给药。
本发明最后一方面涉及治疗认知失调或神经性疾病的药盒,包括将结合使用的单包装药物组合物放在分开的容器中,其一个容器中为在药学上可接受载体中的式I化合物,第二容器中为在药学上可接受载体中的乙酰基胆碱酯酶抑制剂,其合并量为有效量。
发明详细叙述
参考上述式I,一组优选的化合物为其中的R1为R5-苯基或R5-环己基。R5优选为H、卤素或C1-C6烷基,更优选为H、F、或-CH3。
另一组优选化合物为其中的R2为R6-C3-C8环烷基,尤其是R6-C5-C7环烷基,R6优选为H或C1-C6烷基。
R3优选为-CH3,且R4优选为H。
与尤其是美国专利第6,037,352号或6,066,636号中公开的化合物比较,其中没有任一个含R3部分,本发明化合物的选择性超过m2。
本文中所用的术语“烷基”代表具有规定的碳原子数的直链或支链饱和烃链。若并未列出碳原子数,例如使用术语低级烷基,则可能为1-6个碳。
“环烷基”代表具有3至8个碳原子的饱和碳环状环。桥环烷基指其中二不相邻构环成员的环烷基以C1-C2烷基链连接。
“杂环烷基”一词指包括1至3个独立选自包含-O-、-S-、及-NR7-的杂原子的4-至7-员饱和环,其中R7为H或C1-C6烷基,且其中其余环成员为碳。当杂环包括超过一个杂原子时,在有相邻的氧原子、相邻的硫原子、或三个连续杂原子时不会形成环。杂环的实例为四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、吗啉基、硫吗啉基、及哌嗪基。桥杂环烷基指其中二不相邻的羰环成员以C1-C2烷基连接。
卤素代表氟、氯、溴或碘。
芳基代表苯基或萘基。
杂芳基指包括1至3个独立的选自包含-O-、-S-及-N=的杂原子的5或6-员芳环,其条件为环并不包含相邻的氧和/或硫原子。杂芳基的实例为吡啶基、异噁唑基、噁二唑基、呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、四唑基、三唑基、噻二唑基、吡嗪基、嘧啶基、哒嗪基、及三唑基。包含所有位置的异构物,如2-吡啶基、3-吡啶基及4-吡啶基。
当结构式中的变数超过一种时,例如R5,则超过一种的变化可独立的选自变化的定义。
本发明化合物具有至少一个不对称碳原子,即连接R3的碳原子。所有异构体包含非对映体、对映体及旋转异构体均为本发明的一部份。本发明包含纯形式及消旋混合物的预混合物形式的d及1异构体。异构体也可使用使旋光纯的或富旋光的原料反应制备,或使式I化合物的异构体分离的一般技术制备。本发明化合物优选立体化学如式IA所示:
式I的化合物可以依非溶剂化物或溶剂化物形式存在,包含水合物形式。通常,溶剂化物形式(包含药学上可接受的溶剂,如水、乙醇等)对于本发明的目的和非溶剂化形式相当。
式I化合物可以与有机及无机酸形成药学上可接受的盐。形成盐的适当酸的实例为盐酸、硫酸、磷酸、乙酸、柠檬酸、丙二酸、水杨酸、苹果酸、富马酸、丁二酸、抗坏血酸、马来酸、甲烷磺酸、及本领域技术人员已知的其他无机酸与羧酸。上述盐是使游离碱形式与足量的期望酸接触,以一般方式产生盐。游离碱形式可使用适用的稀碱性水溶液处理盐再生,如氢氧化钠、碳酸钾、氨水或碳酸氢钠的烯水溶液。游离碱形式与其个别的盐形式在某些物理性质(如在极性溶剂中的溶解性)上稍不同,但对于本发明的目的,盐为其个别游离碱形式的另一对等物。
本领域技术人员可利用公知方法制备式I化合物,例如利用US6,037,352所公开的步骤,作为本发明的参考文献,或利用平行合成或组合化学方法。本领域技术人员应该了解也可以使用其它方法,并且这些方法可经适当的修改以制备式I化合物范围中的其他化合物。
上述的式I化合物使用如下列反应流程1中所示的固相合成程序制备,其中Me为甲基,且FMOC为9-芴基甲氧基羰基。反应流程1
反应流程1的合成可使9-BBN与烯烃如2反应,接着与芳基卤化物如1进行Suzuki偶合完成,得到化合物3。水解酯3接着移除N-Boc,得到胺基酸中间物5,后者以FmocOSU处理保护。此产物接着以试剂如POCl3或草酰氯处理后转化成酰氯6。
胺(R1CHR3NH2)与树脂结合的醛类如Argopore-MB-CHO树脂(Argonaut Corporation,San Carlos,CA),通过与三乙酰氧基硼氢化钠的还原性烷化反应。接着使树脂结合的胺(树脂1)用活化的酸如酰氯7酰化,得到树脂2。使N-Fmoc基去保护,接着用醛类或酮类还原性烷化,或与醛类反应,接着以Grignard试剂处理,或与适当的甲烷磺酸酯或烷基卤化物反应,得到树脂结合的中间物,再用TFA处理,得到式I化合物。
式I化合物也可以通过一般合成化学方法制备。例如,式Ia化合物(其中R1为R5-苯基,R3为-CH3,且R4为氢)可以如反应流程2中所述制备:
反应流程2
胺如8用活化羧酸如酰氯9在碱如吡啶或三乙胺存在下反应得到类型10的酰胺。使用酸如TFA或盐酸处理,得到化合物11。化合物11的哌啶氮使用醛或酮在还原剂如三乙酰氧基硼氢化钠存在下通过还原性烷化,或另外与醛反应接着以Grignard试剂处理衍生,得到类型Ia的化合物。又另一方法包含胺11与适当的甲烷磺酸酯或烷基卤化物在碱存在下反应。
式7、8及9的原料是本领域公知的,或由本领域公知的方法制备,如使用酮及醛经由与烷基卤化物或甲苯磺酸酯还原性烷化或烷化导入R2。
上述反应后若需要或希望可再进行一或多种下列步骤:(a)从制备的化合物中移除任何保护基;(b)将制成的化合物转化成药学上可接受的盐、酯和/或溶剂化物;(c)将制备的式I化合物转化成式I的另一化合物;及(d)分离式I化合物,包含分离式I的立体异构体。
依上述的反应顺序,本领域技术人员将可选择制备式I的任一化合物所需的原料。
式I的化合物呈现选择性m2蕈毒碱拮抗剂活性,其已经用药物活性校正,以治疗认知失调和/或其症状。认知失调的实例为阿兹海默症及老化症,治疗后可改善记忆力及学习能力。
式I化合物在显现m1及m2蕈毒碱拮抗剂活性的试验程序中具有药物活性,以下描述试验方法。蕈毒碱结合活性
本发明化合物针对其抑制与克隆人类m1、m2、m3、m4、及m5蕈毒碱受体亚型结合的能力进行试验。此研究中的受体源为稳定转移的CHO细胞系的薄膜,它表达各受体亚型。生长后,将细胞制成颗粒,接着使用Polytron在50倍体积的冷却的10mM Na/K磷酸盐缓冲剂(pH7.4)(缓冲剂B)中均质化。使均质也在4℃下于40,000xg下离心20分钟。丢弃所得悬浮液,且使颗粒再悬浮于缓冲液B中,使最终浓度为20毫克湿润组织/毫升。将薄膜储存在-80℃下,直到用于下述的结合分析中为止。
与克隆人蕈毒碱受体结合是使用3H-奎宁环基二苯乙醇酸酯(QNB)(Watson et al.,1986)进行。简言的,薄膜(针对含m1、m2及m4的薄膜分别进行约8、20及14微克的蛋白质分析)以3H-QNB(最终浓度为100-200PM)培养,且在25℃下90分钟内使未标记药物浓度达到最终体积为2毫升。非特异的结合在1微升阿拖品存在下分析。培养在GF/B玻纤过滤器中,使用Skatron过滤装置通过抽真空过滤终止,且过滤器用冷却的10mM Na/K磷酸盐缓冲剂(pH7.4)洗涤。将Scintillation合剂添加于过滤器中,且将该瓶培养过夜。结合的放射性配位体在液态scintillation计数器(效率50%)定量。所得数据使用EBDA电脑程序(McPherson,1985)针对IC50值进行分析(即抑制50%结合所需化合物的浓度)。接着使用下式(Cheng and Prusoff,1973)进行亲合力值(Ki)测定:
因此,Ki愈低显示结合亲合力愈大。
为测定化合物对结合m2受体的选择性程度,将m1受体的Ki值除以m2受体的Ki值。该值愈高显示与m2蕈毒碱受体结合的选择性愈大。微渗析方法
使用下列方法显示化合物具有作为m2拮抗剂的功能。
手术:就三个研究而言,以戊巴比妥钠(54毫克/公斤ip.)麻醉雄性史帕谷-达利(Spraque-Dawley)大鼠(250-350克)及置于KopfSlerotaxic装置上。暴露头颅及在通过硬膜前面0.2毫米及前囱侧边3.0毫米处凿洞。在协调下,经由凿洞开孔在硬膜外边缘放置导引套管,垂直降低至深度2.5毫米,及以齿科石膏永久固定至骨螺钉上。手术后,对大鼠用氨苄青霉素给药(40毫克/公斤ip),分别关进改进的笼中。在进行微渗析程序之前使恢复约3至7天。
微渗析:用于体内微渗析的所有设备及仪器得自BioanalyticalSystem公司(BAS)。微渗析程序包含经由细导引插管插入针状可灌注探针(CMA/12.3毫米×0.5毫米)至超出插管端条纹3毫米深。探针预先以管子连接至微注射泵(CMA/100)。捕捉大鼠、栓住及接着插入探针,放入大的透明塑胶玻璃盆中,铺有草窝及有取用食物及饮水的入口。探针已用含5.5mM葡萄糖、0.2mM L-抗坏血酸酯及1μM溴化新斯的明(neostigmine bromide,pH7.4)的林格氏缓冲液(NaCl 147mM;KCl3.0mM;CaCl2 1.2mM;MgCl2 1.0mM)灌注2μl/min。为了达到稳定基线读数,使微渗析在收集各级份前运行90分钟。于3小时期间内每间隔10分钟使用冷冻收集器(CMA/170或200)获得级份(20微升)。收集4至5个基线级份,接着对动物投与试验药物或组合药物。完成收集后,对各大鼠进行尸体解剖以测定探针置放的精确性。
乙酰胆碱(ACh)分析:使用HPLC/电化学探测/测定微渗析所收集的样品中ACh浓度。样品自动注射(Waters712冷冻样品处理器)到聚合物分析HPLC柱(BAS,MF-6150),并且用50mM Na2HPO4(pH8.5)洗脱。为了避免细菌生长,于移动相内含有Kathon CG试剂(0.005%)(BAS)。来自分析柱的洗脱液含有被分离的ACh及胆碱,立即通过连接到柱出口处的固定酶素反应器匣(BAS,MF-6151)。反应器含有乙酰胆碱酯酶及胆碱氧化酶,其以共价键结合到聚合物主链。上述酶素对ACh及胆碱的反应导致过氧化氢的化学计量产率,其使用配备有铂电极且在500毫瓦特电位操作的Waters 460探测器用电化学方法探测。使用配备有微通道IEEE板的IBM型70的电脑获取数据。使用“Maxima”层析软件(Waters公司)完成峰的积分及定量。每个样品的总保留时间在流速1毫升/分钟时为11分钟。乙酰胆碱及胆碱的保留时间分别为6.5及7.8分钟。为了追踪及校正层析期间探测器敏感度的可能变化,在各样品测试的开始、中间及最后时加入ACh标准品。
ACh的增加与突触前的m2受体拮抗机制相符。微粒体稳定性
最终底物浓度0.5毫克/毫升的式I化合物溶液、及最终P450浓度分别为0.18、0.175及0.25nmol/ml的人类、猕猴或大鼠肝微粒体的溶液于pH7.4的0.1M磷酸钾缓冲液中于96-穴微培养皿中,在37℃于振荡水浴中培育3分钟。于各样品中添加含MgCl2、葡萄糖-6-磷酸酯、NADPH及葡萄糖-6-磷酸酯脱氢酶的辅因子溶液(总培育体积的一半/样品),将整个培育混合物培育0及30分钟(对各化合物培育n=3个样品)。各时间点后,添加等体积的CH3CN。样品通过振荡混合且将培养皿在3000rpm离心20分钟。悬浮液使用适当分析方法,通过液相层析质谱仪(LCMS)分析母体化合物和/或代谢产物。
对于本发明的化合物,发现下列范围的蕈毒碱拮抗剂活性:
m1:20-2000nM,优选的化合物在200-1000nM之前。
m2:1-500nM,优选的化合物<50nM,更优选<10nM。
依微粒体稳定性分析,实施例2化合物结果如下(30分钟后残留%):大鼠-79%,猴子-80%,人类-80%。
在本发明关于结合式I的化合物与乙酰基胆碱脂酶抑制剂方面,乙酰基胆碱脂酶抑制剂的实例为杜平齐(donepezil),庚基毒扁豆碱(heptylphysostigmine),塔克林(tacrine),理伐替民(rivastigmine)及加拉塔民(galantamine)。
对于自本发明所述化合物制备制药组合物,惰性的药学上可接受的载体可以是固体或液体。固体形式的制剂包含粉末、片剂、可分散颗粒、胶囊、扁胶囊及栓剂。粉末及片剂可包括约5至约95%的活性成分。适当的固体载体是本领域公知的,例如碳酸镁、硬脂酸镁、滑石、糖或乳糖。片剂、粉末、扁胶囊及胶囊均可用作适于口服给药用的固态剂形。药学上可接受载体及各种组合物的制法的实例可见于Easton,PA,A.Gennaro(ed.),Remington′s Pharmaceutical Sciences,18th Edition,(1990),Mack Publishing Co.中。
液体形式的制剂包含溶液、悬浮液及乳液。实例为非肠胃注射用水或水-丙二醇的溶液,或对于口服溶液、悬浮液或乳液可以添加增甜剂或不透明剂。液态制剂也包括鼻内给药用的溶液。
适于吸入的气溶胶制剂可包含溶液及粉末态的固体,其可以与药学上可接受的载体并用,如惰性压缩气体例如氮气。
也包括固态制剂,其可在使用前临时转化成口服或非肠胃给药用的液体。该液体包括溶液、悬浮液及乳液。
本发明化合物也可经皮传递。透皮组合物可为霜剂、涂剂、气溶胶和/或乳液,且可包括于基质或载体上的透皮贴片,是本领域一般常见的。
优选化合物为经口服给药。
优选的药物制剂为单位剂量形式。该形式中,制剂再分为含适量活性成分(例如有效量)的适当尺寸的单位剂量,以达到所需的目的。
制剂单位剂量中活性成分的数量依据其特定的应用,可自约1毫克改变或调节成约100毫克,优选约1毫克至约50毫克,更优选约1毫克至约25毫克。
所用实际的剂量可依患者的需求及被处理症状的严重程度改变。特殊状况的适当剂量决定于本领域的技术人员。为便利起见,可将每日总剂量分开,且依需求在一天中逐份给药。
本发明化合物和/或其药学上可接受的盐的给药量及频度会依据临床情况如患者年龄、症状及体型以及欲治疗的症状的严重程度调整。一般建议的每日剂量,口服给药为约1毫克/日至约300毫克/日,优选为1毫克/日至约50毫克/日,且分为二或四次剂量给药。
当使用式I化合物与乙酰基胆碱酯酶抑制剂并用,以治疗认知失调时,此二种活性成分可同时或依次给药,或以在药学上可接受载体中含有式I化合物和乙酰基胆碱酯酶抑制剂的单一药物组合物给药。结合物的成分可个别给药或依任一种一般口服或非肠胃制剂形式一起给药,如胶囊、片剂、粉末、扁胶囊、悬浮液、溶液、栓剂、鼻内喷剂等。乙酰基胆碱酯酶抑制剂的剂量可为0.001至100毫克/公斤体重。
本文中公开的本发明用下列装置及实施例列举,但不应限制本发明的范围。其它机制的路径及类似结构对本领域技术人员是明显的。下列术语为简写:室温(rt);9-溴二环[3.3.1]并壬烷(9-BBN);乙酸乙酯(EtOAc);四氟乙酸(TFA);四氢呋喃(THF);二甲基甲酰胺(DMF);N-(9-芴基甲氧羰基)羟基琥珀酰亚胺(FMOC-OSuc);1-(3-二甲基胺基丙基)-3-乙基碳化二亚胺一氢氯化物(EDCI);4-二甲基胺基吡啶(DMAP);二乙基偶氮二羧酸酯(DEAD);及二氯乙烷(EDC)。
使原料(2)(1克)与9-BBN(10.2毫升的0.5M THF溶液)混合,在氮气下静置且加热至回流1小时。将4-溴苯甲酸甲酯(1.09克)、碳酸钾(0.84克)、PdCl2(dppf)(0.21克)、Ph3As(0.155克)、DMF(7毫升)及水(1.1毫升)添加于冷却的上述溶液中,且在65℃下加热3小时。将反应的混合物倒入冰水中,以乙酸乙酯萃取,有机层以快速层析(己烷∶乙酸乙酯(90∶10))纯化,得到化合物(3)(1.1克)。将化合物(3)(1.1克)溶于甲醇(20毫升)中,且添加氢氧化锂(0.2克)及水(7.5毫升)。加热至回流1小时后,使反应混合物冷却,抽真空移除甲醇,且以盐酸使混合物酸化。以过滤收集固体,抽真空乾燥,得到化合物(4)。将(4)溶于含4M盐酸的二噁烷(35毫升)中,且搅拌1.5小时。添加乙醚且以过滤收集化合物(5)(0.67克)。将化合物(5)(0.66克)加于含碳酸钠(0.6克)的水(120毫升)及二噁烷(40毫升)溶液中,接着在0℃下滴加于由FMOC-OSuc(0.87克)及二噁烷(10毫升)制备的溶液中。室温下2小时后,抽真空移除二噁烷,且以盐酸使混合物酸化。以过滤收集固体,且抽真空乾燥,得到化合物(6)(0.93克,LCMS442.1[M+H])。
制备例2见上述反应流程1步骤1:树脂1的制备
合并Argopore-MB-CHO树脂(Argonaut Technologies,SanCarlos,CA 94070)(10克,8.1毫摩尔)及EDC(45毫升),振荡5分钟,接着添加4-氟-α-甲基苄基胺(5克)。振荡15分钟后,添加NaBH(OAc)3(7.5克),且在室温下持续振荡20小时。将反应混合物转移到250毫升烧瓶中,且小心添加甲醇(50毫升)。气体停止释出后,倾析掉溶剂,依次以含2N氢氧化铵的甲醇(50毫升)、二氯甲烷(100毫升)、甲醇(100毫升)及二氯甲烷(2×100毫升)洗涤树脂。以过滤收集树脂,且在40℃真空烘箱中乾燥。步骤2:树脂2的制备
将在二氯甲烷(10毫升)中的步骤1的悬浮树脂1(2克)添加DIPEA(1.5毫升)及酰氯(7)的二氯甲烷溶液(10毫升,0.27M,由相应的酸(6)与草酰氯在二氯甲烷中,室温下反应制备)。在室温下振荡24小时,接着过滤,且以二氯甲烷、甲醇、THF、甲醇及二氯甲烷洗涤,接着在40℃的真空烘箱中乾燥过夜。步骤3:树脂3的制备
步骤2的树脂2以20%在DMF中的哌啶处理20分钟。使反应混合物过滤且重复该程序数次,接着过滤且以THF、二氯甲烷、甲醇及二氯甲烷依次洗涤树脂,将树脂再悬浮于二氯甲烷中,再添加环己酮(20当量)及NaBH(OAc)3(5当量)。在室温下振荡48小时,接着过滤且以甲醇、二氯甲烷、THF及二氯甲烷洗涤,得到树脂3。
实施例1
一般方法:
用二氯甲烷中10%的TFA处理制备例2、步骤3中的树脂31小时。过滤且重复该步骤。合并有机层且浓缩得到式I化合物。
使用该方法,自适当的R1-CH(R3)-NHR4胺及含R2-的醛类、酮、烷基卤化物或甲烷磺酸烷酯制备表1中所示的化合物。表1中所示的化合物以液体层析-质谱仪,使用Sciex 100设备鉴定。流速为1毫升/分钟,使用C18柱(3.3厘米×4.6毫米,直径3微米,购自Supelco),且梯度为在水中5%至95%CH3CN(含0.05%TFA)10分钟。保留时间(Rt)和及测定的质量(相当于M+H)均列于表1中。
在氮气下,将硼烷二甲基硫醚(14毫升,0.14摩尔)添加于含对-氟苯乙酮(13.8克,0.1摩尔)及(S)-3,3-二苯基-1-甲基四氢-3H-吡咯并-[1,2-c][1.3.2]oxazaborole(30毫升的2M甲苯溶液)的无水四氢呋喃(400毫升)的冷却溶液(0℃)中。使溶液在0℃下搅拌30分钟,接着添加甲醇(50毫升),再以1M盐酸、水、饱和碳酸氢钠洗涤,以无水硫酸钠干燥。蒸发溶剂得到13.5克(R)-对-氟-α-甲基苄基醇。
分析数据:1H NMR(CDCl3),δ7.35(d,2H),δ7.1(t,2H),δ4.9(q,1H),δ1.45(d,3H)。
HPLC:(Chiralpak AS柱,10%异丙醇/己烷,流速1毫升/分钟),5.68分钟R异构体98%;6.10分钟S异构体2%。步骤2:(S)-对-氟-α-甲基苄基叠氮化物
将二苯基磷酰基叠氮化物(55.4克,0.395摩尔)添加于含步骤1的产物(23.5克,0.168摩尔)的甲苯(300ml)冷却溶液(-15℃)中,接着添加DBU(30.4毫升,0.2摩尔)。搅拌过夜后,将所得两相溶液倒入500毫升1N盐酸中。水层以甲苯萃取,且合并的有机层以水、1N盐酸洗涤且以硫酸钠干燥。移除溶剂后,得到25克粗产物,且不需经纯化用于下一步骤中。步骤3:(S)-对-氟-α-甲基苄基胺
在60PSi下使步骤2的粗产物(1.2克,7.3毫摩尔)、浓盐酸(在50毫升甲醇中1毫升)及Pd/C(10%w/w)(140毫克)的混合物氢化4小时。移除溶剂后,使残留物再溶于20毫升水中且以乙醚洗涤。接着使水层碱化至pH11,且以乙醚萃取。乙醚溶液经干燥且蒸发溶剂,得到1.1克(S)-对-氟-α-甲基苄基胺。
分析数据:1H NMR(CDCl3),δ7.3(dd 2H),δ7.05(t,2H),δ4.8(q,1H),δ1.5(d,3H)。
HPLC:(Chiralpak CR(+)柱,含过氯酸的水,pH1.5,流速1毫升/分钟),31.8分钟S异构体97.5%,43.2分钟R异构体2.5%。步骤4:N-[1-(S)-对-氟苯乙基]-4-(4′-哌啶基甲基)苯甲酰胺
将EDCI盐酸盐(6.1克,34.4毫摩尔)添加于含步骤3的产物(4.8克,34.5毫摩尔)、4-(N-Boc-哌啶基甲基)苯甲酸(10克,31.3毫摩尔)及DMAP(0.38克,3.1毫摩尔)的二氯甲烷溶液中,且使最终溶液搅拌2小时,接着以0.5N盐酸终止反应。混合物以二氯甲烷萃取,且以水洗涤。移除溶剂后,将残留物溶于TFA(10毫升)中30分钟。移除酸后,使残留物进行层析,得到10.2克所需产物。
分析数据:1H NMR(CD3OD),δ7.76(d,2H),δ7.40(dd,2H),δ7.25(dd,2H),δ7.05(t,2H),δ5.2(q,1H),δ2.95(m,2H),δ2.59(m,2H),δ2.5(m,2H),δ1.65(m,1H),δ1.6(m,2H),δ1.55(d,3H),δ1.95(m,2H)步骤5:
将环己酮(3.24克,33毫摩尔)及三乙酰氧基硼氢化钠(7.01克,33毫摩尔)添加于含步骤4的产物(7.5克,22毫摩尔)的DCE(250毫升)溶液中。最终的混合物搅拌过夜后,将其倒入1N盐酸中,且以乙醚洗涤溶液。水层以氢氧化钠碱化至pH11,且以二氯甲烷萃取。有机层经干燥且蒸发溶剂,且使残留物进行层析,得到8.5克标题化合物。
分析数据:1H NMR(CD3OD):δ7.668(d,2H),δ7.354(q,2H),
δ7.186(d,2H),δ7.028(t,2H),δ5.309(m,1H),δ2.858(d,2H),δ2.565(d,2H),δ2.231(m,1H),δ2.105(td,2H),δ1.86-1.75(m,4H),δ1.614(m,2H),δ1.58(d,3H),δ1.56-1.42(m,3H),δ1.32-1.02(m,6H)。
[α]D/20甲醇中19.8。
C13(CDC13)δ167.4,164.2,161.7,145.9,140.0,132.9,130.3,128.9,128.8,127.8,116.6,116.4,65.1,50.4,49.7,44.4,39.5,33.9,30.1,27.6,27.4,23.1
ES-LCMS,6.36min,LC面积100%,M+1,423。
熔点(盐酸盐):234-235℃。
将实例2、步骤4中的产物(0.522克,1.537毫摩尔)及碳酸钠(3.26克,30.74毫摩尔)添加于含t,t-3,5-二甲基环己基-对-甲苯磺酸酯(1.35克,4.61毫摩尔)于4-甲基-2-戊酮(5毫升)的溶液中,且使混合物回流过夜。过滤最终的反应混合物,且以二氯甲烷洗涤固体。浓缩合并的有机层,且使用在甲醇及二氯甲烷中5%v/v2M氨的混合物层析残留物,得到420毫克标题化合物。
分析数据:1H NMR(CDCl3):δ7.75(d,2H),δ7.40(q,2H),δ7.248(d,2H),δ7.04 6(t,2H),δ5.217(q,1H),δ2.918(d,2H),2.597(d,2H),δ2.408(tt,1H),δ2.241(t,2H),δ1.835(d,2H),δ1.7-1.57(m,3H),δ1.542(d,3H),δ1.5-1.22(m,6H),δ0.92(d,6H),δ0.835(q,1H),δ0.498(q,1H)。
将三苯基膦(0.33克,1.27毫摩尔)添加于含c,c-3,5-双-三氟甲基环己醇(0.2克,0.85毫摩尔)的无水苯(8毫升)溶液中,接着添加DEAD(0.22克,1.27毫摩尔)。溶液在室温下搅拌5分钟,接着添加甲苯磺酸甲酯(0.236克,1.27亳摩尔)。反应在室温下搅拌72小时后,以乙醚(80毫升)稀释,以水、1N盐酸、水及饱和碳酸氢钠、食盐水洗涤,以硫酸镁干燥。蒸发有机溶剂,且使残留物在硅胶柱上以10%乙酸乙酯/己烷溶离层析,得到0.28克所需的甲苯磺酸酯(85%产率)。H1NMR(CDCl3):δ7.8(d,2H),δ7.4(d,2H),δ5.0(b,1H),δ2.5(m,2H),δ2.45(s,3H),δ2.18(m,3H),δ1.45(m,2H),δ1.35(m,1H)。步骤2:
重复实例3相同的程序,且使用步骤1的甲苯磺酸酯,制备标题化合物。
H1NMR(CDCl3):δ7.65(d,2H),δ7.35(m,2H),δ7.2(d,2H),δ7.0(m,2H),δ5.3(m,1H),δ2.8(m,2H),δ2.6(d,2H),δ2.45(m,1H),δ2.05-2.25(m,6H),δ1.45-1.8(m,4H),δ1.6(d,3H),δ1.2-1.4(m,5H).ES-LCMS,Rt 6.11分钟,测定质量559(M+H)。
实施例5
将双环[3.3.1]壬烷-9-酮(1.0克,7.2毫摩尔)及三乙酰氧基硼氢化钠(3.24克,14毫摩尔)添加于含实例2,步骤4的产物(2.46克,7.2毫摩尔)的DCE(75毫升)溶液中。最终的混合物搅拌过夜后,蒸发溶剂且使残留物进行层析,得到0.640克的标题化合物。
分析数据:1H NMR(CD3OD):δ7.6 75(d,2H),δ7.360(q,2H),
δ7.194(d,2H),δ7.027(t,2H),δ5.309(m,1H),δ3.07(d,2H),δ2.56(d,2H),δ2.00-1.66(m,11H),δ1.58(d,3H),δ1.54-1.43(m,7H),δ1.33-1.23(m,4H)。
在氮气下,将氢化钠(57.6毫克,2.4毫摩尔)悬浮在DMF中,接着在搅拌下添加实例2中制备的化合物(100毫克,0.24毫摩尔)的DMF溶液。30分钟后,添加CH3l(0.017毫升,0.264毫摩尔)且使混合物搅拌40小时。将混合物倒入冰-水浴中,以过滤收集沉淀物,以水洗涤固体且抽真空乾燥,得到100毫克标题化合物。LCMS:Rt 6.81分钟,测定的质量437(M+H)。
实施例7
在剧烈搅拌下将在二氯甲烷(2毫升)中的13(2毫摩尔)添加于含12(0.91毫摩尔)的1∶1水/饱和碳酸氢钠(10毫升)混合物的溶液中。1小时后,分离有机层,且以二氯甲烷洗涤水层三次。合并有机层以饱和碳酸氢钠及食盐水洗涤,接着以硫酸钠干燥。移除溶剂后,残留物经半制备用HPLC柱,以在甲醇及二氯甲烷中的2%(v/v)7N NH3溶离层析,得到140毫克所需产物。
H1NMR(CDCl3)δ8.55,d,2H,δ7.7,d 2H,δ7.26d,2H,δ7.20d,2H;δ6.45d,1H;δ5.3,m,1H;δ2.85,m 2H;δ2.58,d,2H;δ2.25,m,1H;δ2.1,m,2H;δ1.7-1.9,m,4H;δ1.4-1.65,m,7H;δ1.0-1.35,m;6H。
LCMS:C18逆相柱,10分钟内5%-95%梯度的CH3CN/水,保留时间,3.58分钟,质谱数据M+1 406。
Claims (10)
R1为R5-(C3-C8)环烷基、R5-(C3-C8)环烷基(C1-C6)烷基、R5-芳基、R5-芳基-(C1-C6)烷基或R5-杂芳基;
R2为H、(C1-C6)烷基、R6(C3-C8)环烷基、R6-(C3-C8)环烷基-(C1-C6)烷基、R6-杂环烷基、R6-(C6-C10)桥环烷基、或R6-桥杂环烷基;
R3为C1-C6烷基或-CH2OH;
R4为H或C1-C6烷基;
R5为独立选自包含H、C1-C6烷基、卤素、-OH、C1-C6烷氧基、-CF3、-CN、-CO2R4、-CONHR4、-SO2NHR4、-NHSO2R4、及-NHC(O)R4的1-4个取代基;且
R6为独立选自包含H、C1-C6烷基、卤素、-OH、C1-C6烷氧基、-CF3、-NH2、(C1-C6)烷基氨基、苯基、C1-C2亚烷基二氧基、及(C1-C6)烷氧基羰基的1-4个取代基。
2.如权利要求1的化合物,其中的R1为R5-苯基或R5-环己基。
3.如权利要求2的化合物,其中的R5为H、卤素或C1-C6烷基。
4.如权利要求1的化合物,其中的R2为R6-C3-C8环烷基。
5.如权利要求4的化合物,其中的R6为H或C1-C6烷基。
7.一种药物组合物,包括治疗有效量的如权利要求1的化合物与药学上可接受载体结合。
8.如权利要求1的化合物用于制备治疗认知或神经性疾病的医药的用途。
9.如权利要求1的化合物与乙酰基胆碱酯酶并用,用于制备治疗认知或神经性疾病的医药的用途。
10.一种用于治疗认知失调或神经性疾病的药盒,包括将结合使用的单包装药物化合物放在分开的容器中,其一个容器中为权利要求1的化合物,第二容器中为乙酰基胆碱酯酶抑制剂,它们都在药学上可接受载体中,其结合量为有效量。
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AU2007332750A1 (en) * | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors containing a tricyclic ring system |
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JP2011503002A (ja) | 2007-11-05 | 2011-01-27 | シェーリング コーポレイション | γセクレターゼ調節剤 |
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JPH04312572A (ja) * | 1991-04-12 | 1992-11-04 | Takeda Chem Ind Ltd | 環状アミン化合物 |
IL117149A0 (en) | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
TW542822B (en) * | 1997-01-17 | 2003-07-21 | Ajinomoto Kk | Benzamidine derivatives |
US6066636A (en) | 1998-06-30 | 2000-05-23 | Schering Corporation | Muscarinic antagonists |
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2001
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- 2001-12-17 MX MXPA03005743A patent/MXPA03005743A/es active IP Right Grant
- 2001-12-17 WO PCT/US2001/049063 patent/WO2002051808A2/en active Application Filing
- 2001-12-17 DE DE60139571T patent/DE60139571D1/de not_active Expired - Lifetime
- 2001-12-17 AR ARP010105838A patent/AR035612A1/es unknown
- 2001-12-17 US US10/023,277 patent/US6458812B1/en not_active Expired - Fee Related
- 2001-12-17 EP EP01985584A patent/EP1343760B1/en not_active Expired - Lifetime
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US6458812B1 (en) | 2002-10-01 |
AU2002235224A1 (en) | 2002-07-08 |
JP2007297410A (ja) | 2007-11-15 |
AR035612A1 (es) | 2004-06-16 |
CA2431952A1 (en) | 2002-07-04 |
JP4012068B2 (ja) | 2007-11-21 |
CA2431952C (en) | 2010-03-09 |
ATE439344T1 (de) | 2009-08-15 |
WO2002051808A3 (en) | 2003-01-23 |
PE20020657A1 (es) | 2002-07-23 |
MXPA03005743A (es) | 2003-09-05 |
JP2004516313A (ja) | 2004-06-03 |
ES2329975T3 (es) | 2009-12-03 |
EP1343760B1 (en) | 2009-08-12 |
EP1343760A2 (en) | 2003-09-17 |
WO2002051808A2 (en) | 2002-07-04 |
DE60139571D1 (de) | 2009-09-24 |
HK1054391A1 (zh) | 2003-11-28 |
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