CN1142910C - 酰胺化合物 - Google Patents
酰胺化合物 Download PDFInfo
- Publication number
- CN1142910C CN1142910C CNB008027455A CN00802745A CN1142910C CN 1142910 C CN1142910 C CN 1142910C CN B008027455 A CNB008027455 A CN B008027455A CN 00802745 A CN00802745 A CN 00802745A CN 1142910 C CN1142910 C CN 1142910C
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- China
- Prior art keywords
- compound
- salt
- group
- rudimentary
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- -1 Amide compounds Chemical class 0.000 title abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 103
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 10
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 39
- 238000002360 preparation method Methods 0.000 abstract description 16
- 125000002252 acyl group Chemical group 0.000 abstract description 9
- 125000002947 alkylene group Chemical group 0.000 abstract description 5
- 230000001713 cholinergic effect Effects 0.000 abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 229910052727 yttrium Inorganic materials 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 62
- 239000000203 mixture Substances 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 45
- 239000000243 solution Substances 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 238000005406 washing Methods 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000002585 base Substances 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 125000003545 alkoxy group Chemical group 0.000 description 20
- 239000012266 salt solution Substances 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 206010012289 Dementia Diseases 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000006722 reduction reaction Methods 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 125000001118 alkylidene group Chemical group 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 125000003282 alkyl amino group Chemical group 0.000 description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 238000009834 vaporization Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000003435 aroyl group Chemical group 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 125000001769 aryl amino group Chemical group 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 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 7
- 230000008016 vaporization Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- IQRBPUVIUQDULO-UHFFFAOYSA-N 4-fluoro-n-piperidin-4-ylbenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1CCNCC1 IQRBPUVIUQDULO-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- 238000007430 reference method Methods 0.000 description 5
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 150000001342 alkaline earth metals Chemical class 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 125000005133 alkynyloxy group Chemical group 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- VCAONUYLBSXAIA-UHFFFAOYSA-N 1-(4-fluorophenyl)-3-piperidin-4-ylurea Chemical compound C1=CC(F)=CC=C1NC(=O)NC1CCNCC1 VCAONUYLBSXAIA-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 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
- VNDHYTGVCGVETQ-UHFFFAOYSA-N 4-fluorobenzamide Chemical compound NC(=O)C1=CC=C(F)C=C1 VNDHYTGVCGVETQ-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
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- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
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- 239000007788 liquid Substances 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- FKSXRCPGQMOMBI-UHFFFAOYSA-N pyridin-4-ylcarbamic acid Chemical compound OC(=O)NC1=CC=NC=C1 FKSXRCPGQMOMBI-UHFFFAOYSA-N 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
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- 229910000104 sodium hydride Inorganic materials 0.000 description 3
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- 238000001228 spectrum Methods 0.000 description 3
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 3
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- ZXKKOFJYPRJFIE-UHFFFAOYSA-N 4-(trifluoromethoxy)benzoyl chloride Chemical compound FC(F)(F)OC1=CC=C(C(Cl)=O)C=C1 ZXKKOFJYPRJFIE-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
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- 206010036018 Pollakiuria Diseases 0.000 description 2
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- 208000037132 Subdural Chronic Hematoma Diseases 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000006986 amnesia Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- QDTJPFNETGKJFK-UHFFFAOYSA-N methyl 4-[(4-fluorobenzoyl)amino]piperidine-1-carboxylate Chemical class C1CN(C(=O)OC)CCC1NC(=O)C1=CC=C(F)C=C1 QDTJPFNETGKJFK-UHFFFAOYSA-N 0.000 description 1
- HQVBFABRLFZLFH-UHFFFAOYSA-N methyl 4-[(4-fluorophenyl)carbamoylamino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC)CCC1NC(=O)NC1=CC=C(F)C=C1 HQVBFABRLFZLFH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- SXAUCEJUZQMIGN-UHFFFAOYSA-N n-(1-acetylpiperidin-4-yl)-4-fluoro-n-methylbenzamide Chemical compound C=1C=C(F)C=CC=1C(=O)N(C)C1CCN(C(C)=O)CC1 SXAUCEJUZQMIGN-UHFFFAOYSA-N 0.000 description 1
- JHHLEHRNFSMQNP-UHFFFAOYSA-N n-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide Chemical compound C1CN(C(=O)C)CCC1NS(=O)(=O)C1=CC=C(F)C=C1 JHHLEHRNFSMQNP-UHFFFAOYSA-N 0.000 description 1
- MVSVNQXAAMBQBO-UHFFFAOYSA-N n-(1-benzoylpiperidin-4-yl)-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1CCN(C(=O)C=2C=CC=CC=2)CC1 MVSVNQXAAMBQBO-UHFFFAOYSA-N 0.000 description 1
- FYHNUDJASFUMBF-UHFFFAOYSA-N n-[1-(cyclopropanecarbonyl)piperidin-4-yl]-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1CCN(C(=O)C2CC2)CC1 FYHNUDJASFUMBF-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- BOTNYLSAWDQNEX-UHFFFAOYSA-N phenoxymethylbenzene Chemical compound C=1C=CC=CC=1COC1=CC=CC=C1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- IYPZRUYMFDWKSS-UHFFFAOYSA-N piperazin-1-amine Chemical class NN1CCNCC1 IYPZRUYMFDWKSS-UHFFFAOYSA-N 0.000 description 1
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 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
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
-
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- 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及具有胆碱能活性潜力的新的酰胺化合物及其药物上可接受的盐,涉及其制备方法、含有这类化合物的药物组合物,所述化合物可用通式〔I〕表示,其中R1是酰基,R2是低级烷基等,A是单键(1)或-SO2-,E是低级亚烷基等,X是CH或N,Y是单键等,Q是-CH2-等,以及R3和R4合在一起形成低级亚烷基等。
Description
技术领域
本发明涉及可用作药物的新的酰胺化合物及其药物上可接受的盐。
背景技术
已经知道可用作抗记忆遗忘剂或抗痴呆剂的某些氨基哌嗪衍生物,例如可参见PCT国际申请公开号WO 91/01979和WO 98/35951。
发明公开
本发明涉及新的酰胺化合物及其药物上可接受的盐。
更具体说,本发明涉及具有胆碱能活性潜力的新的酰胺化合物及其药物上可接受的盐,涉及其制备方法、含有这类化合物的药物组合物,并涉及哺乳动物中枢神经系统中各种疾病的治疗和/或预防方法,更具体说,涉及记忆遗忘症、痴呆(例如老年性痴呆、阿耳茨海默氏痴呆、与各种疾病有关的痴呆如大脑血管痴呆、大脑外伤后痴呆、脑肿瘤引起的痴呆、慢性硬膜下血肿引起的痴呆、常压脑积水引起的痴呆、脑膜炎后痴呆、帕金森氏疾病类型的痴呆等)以及类似疾病的治疗和/或预防方法。此外,该目的化合物预期可用作神经分裂症、抑郁症、发作、头损伤、尼古丁脱瘾、脊髓损伤、焦虑、频尿、尿失禁、肌强直性营养不良、注意短缺机能亢进疾病、过长日间睡眠(发作性睡眠)、帕金森氏疾病或孤独癖等疾病的治疗剂和/或预防剂。
本发明的一个目的是提供一类具有胆碱能活性潜力的新的和有用的酰胺化合物及其药物上可接受的盐。
本发明的另一个目的是提供制备所述酰胺化合物及其盐的方法。
本发明的再一个目的是提供一种含有所述酰胺化合物及其药物上可接受的盐作为有效成分的药物组合物。
本发明的又一个目的是提供一种用所述酰胺化合物及其药物上可接受的盐来治疗和/或预防上述哺乳动物疾病的治疗方法。
本发明的酰胺化合物是新的,可用如下通式〔I〕及其药物上可接受的盐表示:
其中R1是酰基,
R2是低级烷基、低级烷氧基、低级烷基氨基、低级链烯基、低级链烯氧基、低级链烯氨基、低级炔基、低级炔氧基、低级炔氨基、环(低级)烷基、环(低级)烷氧基、环(低级)烷基氨基、芳基、芳氧基、芳基氨基、杂环基或氨基取代的杂环基,各基团可被适当的取代基取代;或酰基;
A是1个单键、
或-SO2-,
E是低级亚烷基,可任选地被适当取代基取代,
X是CH或N,
Y是1个单健、低级亚烷基或
(其中R5是氢、低级烷基、取代的低级烷基、N-保护基、芳基、酰基或杂环基),
R3和R4各是氢或低级烷基,或合在一起形成低级亚烷基,可任选地与环烃或杂环稠合,
其条件是如果X是N,则1)Y是单键、Q是-CH2-、
-SO2-,或者2)Y是低级亚烷基。
目的化合物〔I〕或其盐可通过下列反应方案所示的方法制备。
方法1
方法2
方法3
方法4
方法5
方法6
方法7
方法8
方法9
方法10
其中
R1、R2、R3、R4、A、E、Q、X和Y各自的定义如上所述,
R6是芳基,可被适当的取代基取代,或吡啶基,
R7是低级烷基、低级链烯基、低级炔基、环(低级)烷基、芳基或杂环基,各个基团可被适当的取代基取代,
Ra 5是N-保护基,
Ra 2是低级烷基、低级链烯基、低级炔基、环(低级)烷基、芳基或杂环基,各个基团可被适当的取代基取代,
Qb是-CH2-、
或-SO2-,
Za是酸基,
Rb 5是低级烷基,
Zh是酸基,
Zc是酸基,以及
Ya是低级亚烷基。
在本说明书的上面和随后的描述中,打算包括在本发明范围内的各个定义的适当例子详细说明如下。
术语“低级”是指含1-6个碳原子的基团,但另有说明除外。
术语“低级链烯基”、“低级链烯氧基”、“低级链烯氨基”、“低级炔基”、“低级炔氧基”和“低级炔氨基”中的低级部分是指含2-6个碳原子的基团。
术语“环(低级)烷基”、“环(低级)烷氧基”和“环(低级)烷基氨基”中的低级部分是指含3-6个碳原子的基团。
适当的“低级烷基”和术语“取代的低级烷基”、“芳(低级)烷基”、“卤(低级)烷基”、“低级烷基氨基”、“低级烷基甲硅烷基”、“低级烷硫基”和“低级烷磺酰基”中的低级烷基部分可以是一个直链或支化的C1-C6烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、乙基丙基、己基等,其中优选的是甲基。
适当的“低级链烯基”和术语“低级链烯氧基”和“低级链烯氨基”中的低级链烯基部分可以是一个直链或支化的C2-C6链烯基,例如乙烯基、丙烯基、丁烯基、戊烯基、已烯基、异丙烯基、丁二烯基、戊二烯基、己二烯基等,其中优选的是乙烯基、丙烯基或丁二烯基。
适当的“低级炔基”和术语“低级炔氧基”和“低级炔氨基”中的低级炔基部分可以是一个直链或支化的C2-C6炔基,例如乙炔基、炔丙基、丁炔基等,其中优选的是乙炔基。
适当的“环(低级)烷基”和术语“环(低级)烷氧基”及“环(低级)烷基氨基”中的环(低级)烷基部分可以是环(C3-C6)烷基,例如环丙基、环丁基、环戊基或环己基,其中优选的是环丙基。
适当的“芳基”和术语“芳(低级)烷氧基”、“芳氧基”、“芳基氨基”、“芳基磺酰基”、“芳酰基”和“芳(低级)烷基”中的芳基或芳基部分可以是苯基、萘基、被低级烷基取代的苯基〔例如甲苯基、二甲苯基、基、枯烯基、二(叔丁基)苯基等〕等,其中优选的是苯基或甲苯基。
适当的“芳(低级)烷基”可以是苄基、苯乙基、苯丙基、二苯甲基、三苯甲基等,其中优选的是苄基。
适当的“低级亚烷基”和术语“低级亚烷二氧基”中的低级亚烷基部分可以是直链或支化的C1-C6亚烷基,例如亚甲基、亚乙基、三亚甲基、亚丙基、四亚甲基、五亚甲基、六亚甲基、乙基亚乙基等,其中优选的是亚甲基、亚乙基或三亚甲基。
适当的“低级烷氧基”和术语“芳(低级)烷氧基”及“卤(低级)烷氧基”中的低级烷氧基部分可以是直链或支化的C1-C6烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、甲基丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基等,其中优选的是甲氧基或叔丁氧基。
适当的“芳(低级)烷氧基”可以是苄氧基、苯乙氧基、苯丙氧基、二苯甲氧基、三苯甲氧基等。
适当的“卤素”和术语“卤(低级)烷基”中的卤部分可以是氟、氯、溴和碘,其中优选的是氟、氯或碘。
适当的“卤(低级)烷基”可以是被1个或多个卤素取代的低级烷基,例如氯甲基、二氯甲基、氟甲基、二氟甲基、三氟甲基、五氯乙基等,其中优选的是三氟甲基。
适当的“卤(低级)烷氧基”可以是被1个或多个卤素取代的低级烷氧基,例如氯甲氧基、二氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、五氟甲氧基等,其中优选的是三氟甲氧基。
适当的“低级烷基氨基”可以是一或二(低级烷基氨基),例如甲基氨基、乙基氨基、丙基氨基、异丙基氨基、丁基氨基、叔丁基氨基、异丁基氨基、戊基氨基、己基氨基、二甲基氨基、二乙基氨基、二丙基氨基、二丁基氨基、二异丙基氨基、二戊基氨基、二己基氨基、N-甲基乙基氨基等,其中优选的是二甲基氨基。
适当的“低级烷基甲硅烷基”可以是一、二或三(低级)烷基甲硅烷基,例如三甲基甲硅烷基、二甲基甲硅烷基、三乙基甲硅烷基等,其中优选的是三甲基甲硅烷基。
适当的“低级亚烷二氧基”可以是亚甲二氧基、亚乙二氧基等,其中优选的是亚甲二氧基。
适当的“杂环基”可以是含有至少1个选自氮、硫和氧原子的杂原子、并可包括饱和或不饱和单环式或多环式的杂环基,优选的杂环基可以是含N杂环基,如含1-4个氮原子的不饱和3-6元杂单环基,例如吡咯基、吡咯啉基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基〔例如4H-1,2,4-三唑基、1H-1,2,3-三唑基、2H-1,2,3-三唑基等〕、四唑基〔例如1H-四唑基、2H-四唑基等〕等;
含1-4个氮原子的饱和3-7元杂单环基〔例如吡咯烷基、咪唑烷基、哌啶基、哌嗪基、高哌嗪基等〕;
含1-5个氮原子的不饱和稠合杂环基,例如吲哚基、异吲哚基、中氮茚基、苯并咪唑基、喹啉基、异喹啉基、咪唑并吡啶基、吲唑基、苯并三唑基、四唑并哒嗪〔例如四唑并[1,5-b]哒嗪基等〕、喹喔啉基等;
含1个氧原子的不饱和3-6元杂单环基,例如吡喃基、呋喃基等;
含1个氧原子的饱和3-6元杂单环基,例如1H-四氢吡喃基、四氢呋喃基等。
含1-2个硫原子的不饱和3-6元杂单环基,例如噻吩基等;
含1-2个氧原子和1-3个氮原子的不饱和3-6元杂单环基,例如噁唑基、异噁唑基、噁二唑基〔例如1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基等〕,噁唑啉基〔例如2-噁唑啉基等〕等;
含1-2个氧原子和1-3个氮原子的饱和3-6元杂单环基〔例如吗啉基等〕;
含1-2个氧原子和1-3个氮原子的不饱和稠合杂环基〔例如苯并呋咱基、苯并噁唑基、苯并噁二唑基等〕;
含1-2个硫原子和1-3个氮原子的不饱和3-6元杂单环基,例如噻唑基、噻二唑基〔例如1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基等〕等;
含1-2个硫原子和1-3个氮原子的饱和3-6元杂单环基〔例如噻唑烷基等〕;
含1-2个硫原子和1-3个氮原子的不饱和稠合杂环基〔例如苯并噻唑基、苯并噻二唑基等〕;
含1-2个氧原子的不饱和稠合杂环基〔例如苯并呋喃基、苯并间二氧杂环戊烯基、苯并二氢吡喃基等〕等。
所述“杂环基”可以被上面例示的低级烷基取代,其中优选的是噻吩基、吡啶基、甲基吡啶基、喹啉基、吲哚基、喹喔啉基、苯并呋喃基或四甲基苯并二氢吡喃基,更优选的是吡啶基。
适当的“酰基”可以是羧基;酯化羧基;被低级烷基、芳基、芳(低级)烷基、芳基磺酰基、低级烷基磺酰基或杂环基取代的氨基甲酰基;有取代或无取代的芳基磺酰基;低级烷基磺酰基;环(低级)烷基羰基;低级链烷酰基;有取代或无取代的芳酰基;杂环羰基等。
酯化羧基可以是有取代或无取代的低级烷氧羰基〔例如甲氧羰基、乙氧羰基、丙氧羰基、丁氧羰基、叔丁氧羰基、已氧羰基、2-碘乙氧羰基、2,2,2-三氯乙氧羰基等〕、有取代或无取代的芳氧羰基〔例如苯氧羰基、4-硝基苯氧羰基、2-萘氧羰基等〕、有取代或无取代的芳(低级)烷氧羰基〔例如苄氧羰基、苯乙氧羰基、二苯甲氧羰基、4-硝基苄氧羰基等〕等,其中优选的是无取代的低级烷氧羰基,更优选的是甲氧羰基或叔丁氧羰基。
被低级烷基取代的氨基甲酰基可以是甲基氨基甲酰基、乙基氨基甲酰基、丙基氨基甲酰基、二甲基氨基甲酰基、二乙基氨基甲酰基、N-甲基-N-乙基氨基甲酰基等。
被芳基取代的氨基甲酰基可以是苯基氨基甲酰基、萘基氨基甲酰基、低级烷基取代的苯基氨基甲酰基〔例如甲苯基氨基甲酰基、二甲苯基氨基甲酰基等〕等。
被芳(低级)烷基取代的氨基甲酰基可以是苄基氨基甲酰基、苯乙基氨基甲酰基、苯丙基氨基甲酰基等,其中优选的是苄基氨基甲酰基。
被芳基磺酰基取代的氨基甲酰基可以是苯磺酰基氨基甲酰基、甲苯磺酰基氨基甲酰基等。
被低级烷基磺酰基取代的氨基甲酰基可以是甲磺酰基氨基甲酰基、乙磺酰基氨基甲酰基等。
被杂环基取代的氨基甲酰基可以是被上面提到的杂环基取代的氨基甲酰基。
低级链烷酰基可以是甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基等,其中优选的是乙酰基或新戊酰基。
有取代或无取代的芳酰基可以是苯甲酰基、萘甲酰基、甲基苯甲酰基、二(叔丁基)苯甲酰基、卤(低级)烷氧基苯甲酰基〔例如三氟甲氧基苯甲酰基等〕等,其中优选的是苯甲酰基或三氟甲氧基苯甲酰基。
有取代或无取代的芳基磺酰基可以是苯磺酰基、甲苯磺酰基、卤苯磺酰基〔例如氟苯磺酰基等〕等,其中优选的是氟苯磺酰基。
低级烷基磺酰基可以是甲磺酰基、乙磺酰基等,其中优选的是甲磺酰基。
环(低级)烷基羰基可以是环(C3-C6)烷基羰基,例如环丙基羰基、环丁基羰基、环戊基羰基或环己基羰基,其中优选的是环丙基羰基。
术语“杂环羰基”中的杂环部分可以是在上面作为杂环基提到的那些。
适当的“酸基”可以是卤素〔例如氟、氯、溴、碘〕、芳烃磺酰氧基〔例如苯磺酰氧基、甲苯磺酰氧基等〕、烷磺酰氧基〔例如甲磺酰氧基、乙磺酰氧基等〕等,其中优选的是卤素。
适当的“N-保护基”可以是通常的N-保护基,例如有取代或无取代的低级链烷酰基〔例如甲酰基、乙酰基、丙酰基、三氟乙酰基等〕、低级烷氧羰基〔例如叔丁氧羰基、叔戊氧羰基等〕、有取代或无取代的芳烷氧羰基〔例如苄氧碳基、对硝基苄氧羰基等〕、9-芴基甲氧羰基、有取代或无取代的芳烃磺酰基〔例如苯磺酰基、甲苯磺酰基等〕、硝基苯亚磺酰基、芳烷基〔例如三苯甲基、苄基等〕等,其中优选的是低级烷氧羰基,更优选的是叔丁氧羰基。
适当的“环烃”可以是饱和或不饱和的环烃,例如环戊烃、环己烷、苯、萘、1,2-二氢化茚、茚等。
适当的“取代的低级烷基”可以是被卤素、芳基、酰基、低级烷氧基、芳氧基等取代的低级烷基,其中优选的是苄基。
适当的“杂环”可以是上面提到的杂环基加了氢原子而形成的杂环。
对于R1,优选的“酰基”可以是低级链烷酰基;低级烷氧羰基;任选地被卤(低级)烷氧基取代的芳酰基;任选地被卤素取代的芳基磺酰基;低级烷基磺酰基;或环(低级)烷基羰基,其中优选的是乙酰基、新戊酰基、甲氧羰基、叔丁氧羰基、苯甲酰基、三氟甲氧基苯甲酰基、氟苯磺酰基、甲磺酰基或环丙基羰基。
对于R2,作为低级烷基、低级烷氧基、低级烷基氨基、低级链烯基、低级链烯氧基、低级链烯氨基、低级炔基、低级炔氧基、低级炔氨基、环(低级)烷基、环(低级)烷氧基、环(低级)烷基氨基、芳基、芳氧基、芳基氨基、杂环基或氨基取代的杂环基的取代基,优选的“适当的取代基”可以是卤(低级)烷基、卤(低级)烷氧基、低级链烯基、低级炔基、低级烷基氨基、酰氨基、酰基、低级烷基甲硅烷基、低级烷氧基、芳基、低级亚烷二氧基、酰氧基、羟基、硝基、氨基、氰基、卤素、芳氧基、低级烷硫基等。
对于R2,优选的“可被适当的取代基取代的芳基”可以是任选地被卤素取代的芳基,其中更优选的是氟苯基。
对于R2,优选的“可被适当的取代基取代的芳基氨基”可以是任选地被卤素取代的芳基氨基,其中优选的是苯基氨基或氟苯基氨基。
对于R2,优选的“可被适当的取代基取代的芳氧基”可以是任选地被卤素取代的芳氧基,其中优选的是氟苯氧基。
对于Y,优选的“低级亚烷基”可以是亚甲基。
对于Y中的R5,优选的“低级烷基”可以是甲基,
对于Y中的R5,优选的“N-保护基”可以是叔丁氧羰基。
对于E,作为低级亚烷基的取代基,优选的“适当的取代基”可以是氧代、低级烷基、羧基(低级)烷基或酰基,其中更优选的是氧代、二氧代、甲基、二甲基、羟甲基或苄基氨基甲酰基。
对于E,优选的“低级亚烷基”可以是亚甲基、亚乙基或三亚甲基,更优选的是亚乙基。
对于R3和R4,优选的“低级烷基”可以是甲基。
优选的“ R3和R4合在一起形成的低级亚烷基”可以是亚乙基或三亚甲基。
优选的“与低级亚烷基稠合的环烃”可以是苯。
优选的化合物〔I〕是如下定义的化合物,其中R1是低级链烷酰基、低级烷氧羰基、芳酰基、被卤(低级)烷氧基取代的芳酰基、低级烷基磺酰基、芳基磺酰基、被卤素取代的芳基磺酰基或环(低级)烷基羰基,R2是芳基、芳氧基或芳基氨基,各基团中的芳基可被卤素取代;吡啶基;或吡啶基氨基,A是单键,E是亚乙基,X是CH,Y是-NH-,Q是
以及R3和R4合在一起形成亚乙基,或者其中R1是低级链烷酰基、低级烷氧羰基、芳酰基、被卤(低级)烷氧基取代的芳酰基、低级烷基磺酰基、芳基磺酰基、被卤素取代的芳基磺酰基或环(低级)烷基羰基,R2是芳基、芳氧基或芳基氨基,各基团中的芳基可被卤素取代;吡啶基;或吡啶基氨基,A是单键,E是亚乙基,X是N,Y是单键,Q是
以及R3和R4合在一起形成亚乙基。
目的化合物〔I〕的合适的药物上可接受的盐是通常的无毒盐,包括酸加成盐,例如无机酸加成盐〔例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等〕、有机酸加成盐〔例如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐等〕、与氨基酸形成的盐〔例如天冬氨酸盐、谷氨酸盐等〕、金属盐,例如碱金属盐〔例如钠盐、钾盐等〕以及碱土金属盐〔例如钙盐、镁盐等〕等。
下面详细说明目的化合物〔I〕的制备方法。
方法1
化合物〔Ia〕或其盐可通过使化合物〔II〕或其盐与化合物〔III〕或其羧基或磺基上的活性衍生物或其盐反应来制备。
化合物〔Ia〕和〔II〕的合适的盐可以是与对化合物〔I〕所列举的那些盐相同。
化合物〔III〕及其羧基或磺基上的活性衍生物的合适的盐可以是如对化合物〔I〕所列举的金属盐或碱土金属盐。
合适的羧基或磺基上的活性衍生物或化合物〔III〕可包括酯、酰卤、酸酐等。活性衍生物的合适例子可以是酰卤〔例如酰氯、酰溴等〕;对称酸酐;与酸,例如脂肪族羧酸〔例如乙酸、戊酸等〕、取代的磷酸〔例如二烷基磷酸、二苯基磷酸等〕形成的混合酸酐;酯,例如有取代或无取代的低级烷基酯〔例如甲酯、乙酯、丙酯、己酯、三氯甲基酯等〕、有取代或无取代的芳〔低级)烷基酯〔例如苄酯、二苯甲基酯、对氯苄酯等〕、有取代或无取代的芳基酯〔例如苯酯、甲苯酯、4-硝基苯酯、2,4-二硝基苯酯、五氯苯酯、萘酯等〕,或与N,N-二甲基羟基胺、N-羟基琥珀酰亚胺、N-羟基邻苯二甲酰亚胺或1-羟基苯并三唑、1-羟基-6-氯-1H-苯并三唑形成的酯,等。这些活性衍生物可任选地根据要使用的化合物〔III〕的种类进行选择。
该反应一般在通常的溶剂中进行,例如在水、丙酮、二噁烷、氯仿、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、N,N-二甲基甲酰胺、吡啶或任何其它对该反应不会产生不利影响的有机溶剂中进行。在这些溶剂中,亲水性溶剂可以与水混合使用。
该反应也优选地在通常的碱如三乙胺、二异丙基乙基胺、吡啶、N,N-二甲基氨基吡啶等,或其混合物的存在下进行。
当化合物〔III〕以游离酸形式或其盐形式用于反应中时,该反应优选在常用的缩合剂的存在下进行,例如在N,N′-二环己基碳化二亚胺、N-环己基-N′-吗啉代乙基碳化二亚胺、N-乙基-N′-(3-二甲基氨基丙基)碳化二亚胺、亚硫酰氯、草酰氯、低级烷氧碳酰卤〔例如氯甲酸乙酯、氯甲酸异丁酯等〕、1-(对氯苯磺酰氧基)-6-氯-1H-苯并三唑,等存在下进行。
反应温度不是关键,因此该反应可在冷却至加热的条件下进行。
方法2
化合物〔Ib〕或其盐可通过使化合物〔II〕或其盐与化合物〔IV〕反应来制备。
化合物〔Ib〕和〔II〕的合适的盐与对化合物〔I〕所列举的那些盐相同。
该反应通常在诸如二噁烷、四氢呋喃、苯甲苯、氯仿、二氯甲烷或任选其它对反应不会产生不利影响的有机溶剂之类的溶剂中进行。
反应温度不是美键,因此该反应可在冷却至加热的条件下进行。
方法3
化合物〔Ic〕或其盐可通过使化合物〔V〕或其盐与化合物〔III〕或其羧基或磺基上的活性衍生物或其盐反应来制备。
化合物〔Ic〕和〔V〕的合适的盐与对化合物〔I〕所列举的那些盐相同。
化合物〔III〕及其羧基或磺基上的活性衍生物的合适的盐可以是如对化合物〔I〕所列举的金属盐或碱土金属盐。
该反应可按基本上与
方法1相同的方式进行,因此该反应的反应方式与反应条件〔例如溶剂、反应温度等〕可参考
方法1中所述的那些。
方法4
化合物〔Id〕或其盐可通过使化合物〔V〕或其盐与化合物〔IV〕反应来制备。
化合物〔Id〕和〔V〕的合适的盐与对化合物〔I〕所列举的那些盐相同。
该反应可按基本上与
方法2相同的方式进行,因此该反应的反应方式与反应条件〔例如溶剂、反应温度等〕可参考
方法2中所述的那些。
方法5
化合物〔I〕或其盐可通过使化合物〔IV〕或其盐与化合物〔VII〕或其羧基或磺基上的活性衍生物或其盐反应来制备。
化合物〔VI〕的合适的盐可以是对化合物〔I〕所列举的那些酸加成盐。
化合物〔VII〕及其羧基或磺基上的活性衍生物的合适的盐可以是如对化合物〔I〕所列举的金属盐或碱土金属盐。
该反应可按基本上与
方法1相同的方式进行,因此该反应的反应方式与反应条件〔例如溶剂、反应温度等〕可参考
方法1中所述的那些。
方法6
化合物〔Ie〕或其盐可通过便化合物〔VIII〕或其羧基或磺基上的活性衍生物或其盐与化合物〔IX〕或其盐反应来制备。
化合物〔Ie〕、〔VIII〕及其羧基或磺基上的活性衍生物的合适的盐与对化合物〔I〕所列举的那些盐相同。
化合物〔IX〕的合适的盐可以是对化合物〔I〕所列举的那些酸加成盐。
该反应可按基本上与
方法1相同的方式进行,因此该反应的反应方式与反应条件〔例如溶剂、反应温度等〕可参者
方法1中所述的那些。
方法7
化合物〔If〕可通过使化合物〔X〕或其盐与化合物〔XI〕反应来制备。
化合物〔If〕和〔X〕的合适的盐与对化合物〔I〕所列举的那些盐相同。
该反应优选在碱的存在下进行,例如在碱金属〔例如锂、钠、钾等〕、碱土金属〔例如钙等〕、碱金属氢化物〔例如氢化钠等〕、碱土金属氢化物〔例如氢化钙等〕、碱金属或碱土金属的氢氧化物或碳酸盐或碳酸氢盐〔例如碳酸氢钾等〕,等的存在下进行。
该反应通常在溶剂中进行,例如在N,N-二甲基甲酰胺、乙醚、四氢呋喃、二噁烷、苯、甲苯、乙腈或任何其它对反应不会产生不利影响的溶剂中进行。
反应温度不是关键,因此该反应可在冷却至加热的条件下进行。
方法8
目的化合物〔Ig〕或其盐可通过使化合物〔If〕或其盐进行N-保护基的消除反应来制备。
化合物〔If〕和〔Ig〕的合适的盐可以是对化合物〔I〕所列举的那些酸加成盐。
该反应按照通常的方法,例如水解、还原等进行。
水解反应优选在碱或包括路易斯酸的酸的存在下进行。
适用的碱包括无机碱和有机碱,例如碱金属〔如钠、钾等〕、碱土金属〔如镁、钙等〕、其氢氧化物或碳酸盐或碳酸氢盐、肼、烷基胺〔如甲胺、三甲胺、三乙胺等〕、甲基吡啶、1,5-二氮杂双环[4.3.0]壬-5-烯、1,4-二氮杂双环[2.2.2]辛烷、1,8-二氮杂双环[5.4.0]十一碳-7-烯等。
适用的酸包括有机酸〔例如甲酸、乙酸、丙酸、三氯乙酸、三氟乙酸等〕、无机酸〔例如盐酸、氢溴酸、硫酸、氯化氢、溴化氢、氟化氢等〕以及酸加成盐化合物〔例如盐酸吡啶等〕。
用三卤乙酸〔例如三氯乙酸、三氟乙酸等〕等进行的消除反应优选在阳离子捕集剂〔例如茴香醚、苯酚等〕的存在下进行。
该反应通常在溶剂中进行,例如在水、醇〔如甲醇、乙醇等〕、二氯甲烷、氯仿、四氯甲烷、二噁烷、四氢呋喃、这些溶剂的混合物或任何其它对反应不会产生不利影响的溶剂中进行。液体的碱或酸也可以用作溶剂。反应温度不是关键,因此该反应通常在冷却至加热的条件下进行。
适用于消除反应的还原方法包括化学还原和催化还原。
适用于化学还原的还原剂是金属〔例如锡、锌、铁等〕或金属化合物〔例如氯化铬、乙酸铬等〕与有机酸或无机酸〔例如甲酸、乙酸、丙酸、三氟乙酸、对甲苯磺酸、盐酸、氢溴酸等〕的组合。
适用于催化还原的催化剂是一些常用的催化剂,例如铂催化剂〔如铂板、海绵铂、铂黑、胶体铂、氧化铂、铂丝等〕、钯催化剂〔如海绵钯、钯黑、氧化钯、披钯炭、胶体钯、披钯硫酸钡、披钯碳酸钡等〕、镍催化剂〔如还原镍、氧化镍、阮内镍等〕、钴催化剂〔如还原钴、阮内钴等〕、铁催化剂〔如还原铁、阮内铁等〕、铜催化剂〔如还原铜、阮内铜、Ullman铜等〕,等。
在N-保护基是苄基的情况下,该还原反应优选在钯催化剂〔例如钯黑、披钯炭等〕和甲酸或其盐〔例如甲酸铵等〕的组合的存在下进行。
该还原反应通常在对反应不会产生不利影响的常用溶剂中进行,例如在水、甲醇、乙醇、丙醇、N,N-二甲基甲酰胺或其混合物中进行。另外,在要用于化学还原反应中的上述酸是液体的情况下,这些酸也可用作溶剂。此外,适用于催化还原的溶剂可以是上述溶剂,以及其它常用溶剂,例如乙醚、二噁烷、四氢呋喃等,或其混合物。
该还原反应的反应温度不是关键,因此该反应通常在冷却至加热的条件下进行。
方法9
化合物〔Ii〕或其盐可通过使化合物〔Ih〕或其盐与化合物〔XII〕反应来制备。
化合物〔Ih〕和〔Ii〕的合适的盐与对化合物〔I〕所列举的那些盐相同。
该反应可按基本上与
方法7相同的方式进行,因此该反应的反应方式与反应条件〔例如溶剂、反应温度等〕可参考
方法7中所述的那些。
方法10
化合物〔Ij〕或其盐可通过使化合物〔II〕或其盐与化合物〔XIII〕反应来制备。
化合物〔Ij〕和〔II〕的合适的盐与对化合物〔I〕所列举的那些盐相同。
该反应可按基本上与
方法7相同的方式进行,因此该反应的反应方式与反应条件〔例如溶剂、反应温度等〕可参考
方法7中所述的那些。
由上述各种方法制得的化合物可采用传统方法,例如粉化、重结晶、柱色谱、再沉淀等进行分离和精制。
要注意的是,化合物〔I〕和其它化合物可包括一种或多种立体异构体,例如由于不对称碳原子和双键而产生的旋光异构体或几何异构体,因此所有这类异构体及其混合物均应包括在本发明的范围内。
此外,还应该注意的是,化合物〔I〕或其药物上可接受的盐的任何溶剂合物〔例如包封化合物(如水合物等)〕也应该包括在本发明的范围内。
目的化合物〔I〕及其药物上可接受的盐具有强的胆碱活性潜力,因而可用于治疗和/或预防哺乳动物中枢神经系统中的各种疾病,更具体说,可用于治疗和预防记忆遗忘症、痴呆(例如老年性痴呆、阿耳茨海默氏痴呆、与各种疾病有关的痴呆如大脑血管痴呆、大脑外伤后痴呆、脑肿瘤引起的痴呆、慢性硬膜下血肿引起的痴呆、常压脑积水引起的痴呆、脑膜炎后痴呆、帕金森氏疾病类型的痴呆等)以及类似疾病。此外,该目的化合物预期可用作神经分裂症、抑郁症、发作、头损伤、尼古丁脱瘾、脊髓损伤、焦虑、频尿、尿失禁、肌强直性营养不良、注意短缺机能亢进疾病、过长日间睡眠(发作性睡眠)、帕金森氏疾病或孤独癖等疾病的治疗剂和/或预防剂。
为了说明目的化合物〔I〕的效果,下面给出化合物〔I〕的药理学数据。
试验
鼠阴茎勃起
(本实验按Jpn.J.Pharmacol.(日本药理学杂志),64卷,147-153页(1994)中所述类似方法进行)。
(i)方法
使用8周龄雌性费希尔(Fischer)344鼠(n=7)进行试验。所有鼠在试验前连续3天每天处理3分钟。这些鼠以7只一组进行试验,并以半随机次序给药不同剂量的试验化合物。使用前将实验化合物悬浮于0.5%甲基纤维素中,试验刚开始前以1ml/kg的体积剂量通过腹膜内注射给药。注射之后立即将每只鼠关在一个有机玻璃盒(25×25×35cm)内,并对其行为进行观察60分钟,在此期间记录阴茎勃起次数。在每个盒子后面安放一个镜子,以便于观察鼠。数据以平均数表示。
(ii)试验结果
试验化合物(实施例号) | 剂量(mg/kg) | 阴茎勃起(次数/小时) |
2 | 1 | 1.14 |
19 | 0.32 | 0.75 |
很明显,具有上述活性的化合物改善了Journal of Pharmacologyand Experimental Therapeutics(药理学和实验治疗学杂志),279卷,No.3,1157-1173页(1996)中所述的记忆短缺(即记忆遗忘、痴呆等),此外,可以预期,具有上述活性的化合物作为上述各种疾病的治疗和/或预防剂是有效的,这可参阅某些专利申请(例如PCT国际公开号WO 98/27930等)。
对于治疗目的,本发明的化合物〔I〕及其药物上可接受的盐可以以由含有一种所述化合物作为活性成分,并掺混了一种药物上可接受的载体,例如一种适用于经口或非经肠给药的有机或无机固体、半固体或液体赋形剂,而制成的药物制剂形式使用。这种药物制剂可以是胶囊剂、片剂、糖农丸、颗粒剂、栓剂、溶液、悬浮液、乳剂等。如果希望的话,这些制剂中还可以包含辅助物质、稳定剂、润湿剂或乳化剂、缓冲剂以及其它常用的添加剂。
虽然化合物〔I〕的剂量将随患者的年龄和状况而改变,但约0.1mg、1mg、10mg、50mg、100mg、250mg、500mg和1000mg化合物〔I〕的平均单剂量对于治疗上述疾病是有效的。通常每天的给药量可为0.1mg/人体~约1000mg/人体。
下面的制备例和实施例是为了说明本发明而给出的。
制备1
在冰-水浴冷却下往1-苄基-4-氨基哌啶(50g)在水(360ml)中的溶液中滴加二叔丁基二碳酸酯(61g)在丙酮(360ml)中的溶液。搅拌2.5小时后,过滤收集沉淀物,用水洗涤,然后干燥。将该粗产物倒入到二异丙醚(200ml)和正己烷(200ml)的混合物中,进行搅拌。过滤后得到N-(1-苄基哌啶-4-基)氨基甲酸O-叔丁酯(66.9g)。
NMR(DMSO-d6,δ):1.2-1.5(2H,m),1.37(9H,s),1.66
(2H,br d,J=9.9Hz),1.91(2H,br t,J=10.7Hz),
2.73(2H,失真 d,J=11.8Hz),3.2(1H,m),3.41
(2H,s),6.75(1H,d,J=7.8Hz),7.1-7.4(5H,m)
MASS(APCI)(m/z):291
制备例2
在搅拌下在室温下往N-(1-苄基哌啶-4-基)氨基甲酸O-叔丁酯(45g)和10%披钯炭(50%含湿,9g)在甲醇(1升)中的混合物中鼓入氢气。用玻璃过滤器滤除催化剂,然后在减压下除去溶剂。用二异丙醚淋洗后得到N-(哌啶-4-基)氨基甲酸O-叔丁酯(28.35g)。在减压下除去洗涤的溶剂,残留物用二异丙醚淋洗。得到N-(哌啶-4-基)氨基甲酸O-叔丁酯的第二级分(344mg)。
NMR(DMSO-d6,δ):1.18(2H,ddd,J=3.8,11.8,11.8Hz),
1.37(9H,s),1.62(2H,distorted d,J=10.8Hz),
1.85(1H,m),2.38(2H,dt,J=2.2,12.0Hz),2.86
(2H,失真 d,J=12.3Hz),3.2(1H,m),6.72(1H,
br d)
MASS(APCI)(m/z):201
制备3
在室温下往N-(哌啶-4-基)氨基甲酸O-叔丁酯(4.0g)在二氯甲烷(40ml)中的悬浮液中加入哌啶(1.94ml)、二氯甲烷(40ml)、乙酸酐(20.8ml),然后再加入N,N-二甲基氨基吡啶(0.1g)。搅拌3小时后,混合物依次用0.1 N盐酸、水和食盐水洗涤。用硫酸镁干燥后,在减压下除去溶剂。用二异丙醚淋洗后得到N-(1-乙酰基哌啶-4-基)氨基甲酸O-叔丁酯(4.01g)。
NMR(DMSO-d6,δ):1.23(2H,m),1.38(9H,s),1.70
(2H,失真 t,J=11.4Hz),1.97(3H,s),2.64(1H,
br t,J=11.1Hz),3.04(1H,dt,J=2.8,11.5Hz),3.42
(1H,m),3.72(1H,br d,J=15.0Hz),4.19(1H,br d,
J=13.1Hz),6.86(1H,d,J=7.5Hz)
MASS(APCI)(m/z):243
制备4
往N-(1-乙酰基哌啶-4-基)氨基甲酸O-叔丁酯(2.42g)在二氯甲烷(24ml)中的溶液中加入4N氯化氢的二噁烷溶液(24ml)。在减压下除去溶剂。用二异丙醚淋洗后得到1-乙酰基-4-氨基哌啶盐酸盐(2.02g)。
NMR(DMSO-d6,δ):1.41(2H,m),1.93(2H,失真
t),2.00(3H,s),2.60(1H,brt,J=10.4Hz),3.06
(1H,br t,J=11.3Hz),3.12(1H,m),3.84(1H,br d,
J=14.0Hz),4.34(1H,br d,J=13.0Hz),8.32(3H,br
s)
MASS(APCI)(m/z):143
制备5
在冰-水浴冷却下往氯甲酸苯酯(5.64g)的二氮甲烷(70ml)溶液中滴加4-氨基吡啶(2.84g)和三乙胺(5.02ml)在二氯甲烷(100ml)中的溶液。搅拌1小时后,在减压下除去溶剂。残留物用二氮甲烷(200ml)和水(200ml)稀释。分离出有机相,用水和食盐水洗涤。用硫酸镁干燥后,在减压下除去溶剂。反应混合物用二异丙醚稀释,然后滤出沉淀物。用乙醚淋洗后得到N-(4-吡啶基)氨基甲酸O-苯酯(5.07g)。
NMR(CDCl3,δ):7.17(2H,m),7.27(1H,m),7.3-7.5
(4H,m),8.50(2H,dd,J=1.4,5.0Hz),8.06(1H,s)
MASS(APCI)(m/z):215
制备6
在冰-水浴冷却下往硫酰氮(3.55ml)的氯仿(45ml)溶液中滴加1-乙酰基哌嗪(5.66mg)和三乙胺(6.16ml)在氯仿(15ml)中的溶液。搅拌6小时后,过滤收集沉淀物。用氢氧化钠干燥后得到1-乙酰基哌嗪-4-磺酰氯(2.43g)。
NMR(CDCl3,δ):2.15(3H,s),3.35(4H,m),3.69(2H,
t,J=5.1Hz),3.83(2H,br s)
MASS(APCI)(m/z):227
制备7
在冰-水浴冷却下往1-苄基-4-氨基哌啶(1.13g)的二氯甲烷(10ml)溶液中加入4-氟苯甲酰氯(0.99g)在二氯甲烷(1ml)和二异丙基乙基胺(1.09ml)中的溶液。在搅拌下使混合物慢慢温热至室温。混合物用二氯甲烷稀释,然后依次用水、饱和碳酸氢钠水溶液、水和食盐水洗涤。用硫酸镁干燥后,在减压下除去溶剂。残留物用柱色谱法精制(硅胶100ml,二氯甲烷∶甲醇=15∶1)。用二异丙醚/正己烷(1∶1)淋洗后得到N-(1-苄基哌啶-4-基)-4-氟苯甲酰胺(1.31g)。
NMR(DMSO-d6,δ):1.4-1.7(2H,m),1.7-1.9(2H,m),
2.01(2H,br t,J=10.7Hz),2.81(2H,br d,
J=11.6Hz),3.46(2H,s),3.73(1H,m),7.2-7.4(7H,
m),7.90(2H,dd,J=5.6,8.9Hz),8.26(1H,br d,
J=7.7Hz)
MASS(APCI)(m/z):313
制备8
按照与实施例2相似的方法,用4-氨基-1-苄基哌啶作为起始化合物,制得了下面的化合物。
N-(1-苄基哌啶-4-基)-N′-(4-氟苯基)脲
NMR(DMSO-d6,δ):1.25-1.5(2H,m),1.7-1.9(2H,m),
2.0-2.2(2H,m),2.65-2.8(2H,m),3.4-3.6(3H,m),
6.07(1H,d,J=7.6Hz),7.05(2H,t,J=9Hz),7.2-
7.45(2H,m),8.35(1H,s)
MASS(APCI)(m/z):328
制备9
往N-(1-苄基哌啶-4-基)-N′-(4-氟苯基)脲(3.0g)在甲醇(15ml)和四氢呋喃(15ml)的混合物中的溶液中加入披钯炭(10% w/w,50%含湿,0.6g),所得混合物在1大气压的氢压下进行加氢8小时。滤出催化剂,在减压下使溶液蒸发,所得残留物用二异丙醚研制,得到N-(哌啶-4-基)-N′-(4-氟苯基)脲(1.97g)。
NMR(DMSO-d6,δ):1.1-1.4(2H,m),1.65-1.85(2H,m),
2.3-2.65(2H,m),2.8-3.0(2H,m),3.3-3.7(1H,m),
6.08(1H,d,J=8Hz),7.04(2H,t,J=9Hz),7.25-7.5
(2H,m),8.33(1H,s)
MASS(APCI)(m/z):238
制备10
在室温下将N-(1-苄基哌啶-4-基)-4-氟苯甲酰胺(937mg)和10%披钯炭(50%含湿,0.2g)的混合物在甲醇(20ml)中在氢气氛围中搅拌7.5小时。用玻璃过滤器滤除催化剂,然后在减压下除去溶剂。用二异丙醚淋洗后得到N-(哌啶-4-基)-4-氟苯甲酰胺(653mg)。
NMR(DMSO-d6,δ):1.40(2H,ddd ,J=4.0,11.9,23.8Hz),
1.72(2H,br d,J=9.5Hz),2.3-2.7(2H,m),2.8-3.2
(2H,m),3.80(1H,m),7.27(2H,t,J=8.9Hz),7.92
(2H,dd,J=5.6,8.9Hz),8.26(1H,d,J=7.7Hz)
MASS(APCI)(m/z):223
实施例1
在室温下往N-(4-吡啶基)氨基甲酸O-苯酯(446mg)的1,2-二氯乙烷(5ml)溶液中加入1-乙酰基哌嗪(1.12g)在1,2-二氯乙烷(20ml)中的悬浮液。混合物在搅拌下在60℃加热9小时。使混合物冷却至室温,然后用二氯甲烷和水稀释。分离出水相,用氢氧化钠溶液调节至pH 11.5。往该水溶液中加入过量氯化钠。该混合物用二氯甲烷和甲醇(约10∶1)的混合液萃取,有机相用食盐水洗涤。用硫酸镁干燥后,在减压下除去溶剂。残留物用柱色谱法精制(硅胶100ml,二氯甲烷∶甲醇∶氨水=10∶1∶0.1)。用二异丙醚淋洗后得到1-乙酰基-4-(4-吡啶基氨基羰基)哌嗪(398mg)。
NMR(DMSO-d6,δ):2.03(3H,s),3.3-3.6(8H,m),7.47
(2H,dd,J=1.5,4.8Hz),8.31(2H,dd,J=1.5,
4.8Hz),9.01(1H,s)
MASS(APCI)(m/z):271
实施例2
在室温下往搅拌着的1-乙酰基哌嗪(0.64gg)的四氢呋喃(10ml)溶液中加入异氰酸4-氟苯酯(0.574g)。在室温下搅拌1小时后在减压下蒸发除去溶剂,所得残留物用二异丙醚研制后得到1-乙酰基-4-(4-氟苯基氨基甲酰基)哌嗪(1.25g)。
NMR(DMSO-d6,δ):2.03(3H,s),3.3-3.6(8H,m),7.07
(2H,t,J=9Hz),7.46(2H,dd,J=5,9Hz),8.61(1H,
s)
MASS(APCI)(m/z):266
实施例3
按照与实施例2相似的方法,用1-叔丁氧羰基哌嗪作为起始化合物,制得了下面的化合物。
1-叔丁氧羰基-4-(4-氟苯基氨基甲酰基)哌嗪
NMR(DMSO-d6,δ):1.42(9H,s),3.25-3.5(8H,m),7.07
(2H,t,J=9Hz),7.45(2H,dd,J=5,9Hz),8.60(1H,
s)
MASS(LD)(m/z):346.2
实施例4
在室温下往吡啶-4-羧酸(1.0g)和三乙胺(1.2ml)在甲苯(20ml)中的溶液中加入二苯基磷酰叠氮(1.75ml)。将所得混合物加热至回流,保持30分钟,然后使其冷却至0℃。往该混合物中加入1-叔丁氧羰基哌嗪(1.51g),然后让混合物热至90℃,保持1小时。冷却至室温后,将反应混合物转移到乙酸乙酯中,依次用水和食盐水洗涤,用硫酸镁干燥,然后减压蒸发。残留物在硅胶(150ml)上进行色谱精制,用0-7%甲醇在二氯甲烷中的混合液洗脱。用二异丙醚和乙醇的混合物研制后得到1-叔丁氧羰基-4-(吡啶-4-基氨基甲酰基)哌嗪(0.66g)。
NMR(DMSO-d6,δ):1.42(9H,s),3.25-3.5(8H,m),7.46
(2H,d,J=1.5,5Hz),8.30(2H,d,J=1.5,5Hz),
9.00(1H,s)
MASS(LD)(m/z):307.2
实施例5
在0℃往1-乙酰基-4-氨基哌啶盐酸盐(0.4g)在二氯甲烷(5ml)中的悬浮液中依次加入吡啶(0.54ml)和氯甲酸4-氟苯酯(0.29ml)。让混合物温热至室温,搅拌1小时,然后转移到水和乙酸乙酯的混合物中。分离出的有机层依次用盐酸(1N)、碳酸氢钠水溶液和食盐水洗涤,用硫酸镁干燥。减压蒸发后所得残留物用二异丙醚研制,得到1-乙酰基-4-(4-氟苯氧羰基氨基)哌啶(347mg)。
NMR(DMSO-d6,δ):1.15-1.55(2H,m),1.7-1.95(2H,m),
2.00(3H,s),2.65-2.85(1H,m),3.0-3.25(1H,m),
3.5-3.7(1H,m),3.7-3.9(1H,m),4.15-4.3(1H,m),
7.05-7.3(4H,m),7.86(1H,d,J=8Hz)
MASS(APCI)(m/z):281
实施例6
在室温下往1-乙酰基-4-氨基哌啶盐酸盐(715mg)在二氯甲烷(7ml)中的悬浮液中加入二异丙基乙基胺(1.83ml)和4-氟苯甲酰氯(0.83mg)的二氯甲烷(2ml)溶液。搅拌6.5小时后,反应混合物用二氯甲烷稀释,再依次用水、饱和碳酸氢钠水溶液和食盐水洗涤。用硫酸镁干燥后,在减压下除去溶剂。残留物用柱色谱法精制(硅胶50ml,二氯甲烷∶甲醇=50∶1~10∶1)。用二异丙醚淋洗后得到N-(1-乙酰基哌啶-4-基)-4-氟苯甲酰胺(738mg)。
NMR(DMSO-d6,δ):1.40(2H,m),1.81(2H,失真 t,
J=12.4Hz),2.01(3H,s),2.68(1H,br t,J=11.4Hz),
3.13(1H,br t,J=11.6Hz),3.83(1H,br t,
J=13.9Hz),4.01(1H,m),4.33(1H,br d,J=13.7Hz),
7.29(2H,t,J=8.9Hz),7.92(2H,dd,J=5.5,8.8Hz),
8.31(1H,d,J=7.7Hz)
MASS(APCI)(m/z):265
实施例7
在室温下往1-乙酰基-4-氨基哌啶盐酸盐(536mg)在二氯甲烷(5ml)中的悬浮液中加入异烟酰氯盐酸盐(534mg)和二异丙基乙基胺(1.05ml)。搅拌8小时后将反应混合物倒入水中,然后用二氯甲烷稀释。用1N氢氧化钠溶液将混合物的pH值调节至8.5,往混合物中加入氯化钠,分离出有机相。水相用二氯甲烷萃取,合并的有机相用硫酸镁干燥后,在减压下除去溶剂。残留物用柱色谱法精制(硅胶50ml,二氯甲烷∶甲醇=10∶1)。用二异丙醚/正己烷重结晶后得到N-(1-乙酰基哌啶-4-基)-N-异烟酰胺(477mg)。
NMR(DMSO-d6,δ):1.4(2H,m),1.83(2H,失真 t,
J=11Hz),2.01(3H,s),2.69(1H,br t,J=11Hz),
3.14(1H,br t,J=12Hz),3.83(1H,br d,J=14.1Hz),
4.03(1H,m),4.33(1H,br d,J=13.1Hz),7.75(2H,
dd,J=1.7,4.4Hz),8.62(1H,d,J=7.5Hz),8.72(2H,
dd,J=1.6,4.4Hz)
MASS(APCI)(m/z):248
实施例8
在室温下往1-乙酰基-4-氨基哌啶盐酸盐(715mg)在二氯甲烷(7ml)中的悬浮液中加入二异丙基乙基胺(1.83ml)和4-氟苯磺酰氯(0.83mg)的二氯甲烷(2ml)溶液。搅拌6.5小时后,反应混合物用二氯甲烷稀释,再依次用水、饱和碳酸氢钠水溶液和食盐水洗涤。用硫酸镁干燥后,在减压下除去溶剂。残留物用柱色谱法精制(硅胶50ml,二氯甲烷∶甲醇=50∶1~20∶1)。用二异丙醚淋洗后得到N-(1-乙酰基哌啶-4-基)-4-氟苯磺酰胺(859mg)。
NMR(DMSO-d6,δ):1.21(2H,m),1.54(2H,m),1.94
(3H,s),2.66(1H,br t,J=10.8Hz),3.02(1H,dt,
J=2.9,12.0Hz),3.22(1H,m),3.64(1H,br d,
J=14.0Hz),4.05(1H,br d,J=13.2Hz),7.44(2H,t,
J=8.9Hz),7.8-8.0(3H,m)
MASS(APCI)(m/z):301
实施例9
在室温下往N-(4-吡啶基)氨基甲酸O-苯酯(0.81g)的氯仿(10ml)溶液中加入1-乙酰基-4-氨基哌啶盐酸盐(0.68g)和三乙胺(1.06ml)。搅拌1天后,混合物转变为溶液。在减压下除去溶剂。残留物用柱色谱法精制(硅胶100ml,二氯甲烷∶甲醇=10∶1~5∶1,和硅胶50ml,二氯甲烷∶甲醇∶氨水=10∶1∶0.1)。在减压下除去所需级分中的溶剂。残留物用甲醇(5ml)和二氯甲烷(5ml)溶解,然后往该溶液中加入4N氯化氢在二噁烷中的溶液(1.5ml)。在减压下除去溶剂,残留物用甲醇共沸蒸发。用二异丙醚和正己烷重结晶后得到N-(1-乙酰基哌啶-4-基)-N′-(4-吡啶基)脲(343mg)。
NMR(DMSO-d6,δ):1.1-1.6(2H,m),1.77(2H,m),2.01
(3H,s),2.94(1H,brt,J=10.4Hz),3.22(1H,br t,
J=10.1Hz),3.76(2H,m),4.05(1H,d,J=13.6Hz),
7.60(1H,d,J=7.8Hz),7.83(2H,d,J=6.8Hz),8.52
(2H,d,J=7.1Hz),11.21(1H,s),14.66(1H,br s)
MASS(APCI)(m/z):263
实施例10
在室温下往1-乙酰基-4-氨基哌啶盐酸盐(536mg)在二氯甲烷(5ml)中的悬浮液中加入异氰酸4-氟苯酯(375μl)和二异丙基乙基胺(575μl)。搅拌3小时后,用二氯甲烷将反应混合物稀释。分离出有机相,水相用二氯甲烷萃取。合并的有机相用硫酸镁干燥,然后在减压下除去溶剂。用二异丙醚和正己烷重结晶后得到N-(1-乙酰基哌啶-4-基)-N′-(4-氟苯基)脲(448mg)。
NMR(DMSO-d6,δ):1.1-1.5(2H,m),1.80(2H,失真
t,J=10Hz),2.00(3H,s),2.77(1H,br d,
J=10.8Hz),3.14(1H,br d,J=11.1Hz),3.5-3.9(2H,
m),4.16(1H,br d,J=13.2Hz),6.15(1H,d,
J=7.6Hz),7.05(2H,t,J=8.9Hz),7.40(2H,dd,
J=5.0,9.2Hz),8.37(1H,s)
MASS(APCI)(m/z):280
实施例11
在0℃往4-(4-氟苯甲酰氨基)哌啶(0.25g)和二氯甲烷(5ml)溶液中依次加入吡啶(0.14ml)和氯甲酸甲酯(87μl)。让混合物温热至室温,然后搅拌1小时。往该混合物中加入N,N-二甲基氨基吡啶(0.13g),再搅拌1小时后。将反应混合物转移到水和乙酸乙酯的混合物中。分离出的有机层依次用盐酸(1N)、碳酸氢钠水溶液和食盐水洗涤,然后用硫酸镁干燥。减压蒸发得到的残留物用二异丙醚研制后得到4-(4-氟苯甲酰氨基)-1-甲氧羰基哌啶(0.265g)。
NMR(DMSO-d6,δ):1.3-1.6(2H,m),1.75-1.9(2H,m),
2.8-3.05(2H,m),3.60(3H,s),3.85-4.1(2H,m),
7.29(2H,t,J=9Hz),7.90(2H,dd,J=6,9Hz),8.30
(1H,d,J=8Hz)
MASS(APCI)(m/z):281
实施例12
在0℃往4-(4-氟苯甲酰氨基)哌啶(0.25g)的吡啶(5ml)溶液中依次加入4-三氟苯磺酰氯(0.219g)和催化量的N,N-二甲基氨基吡啶。让混合物温热至室温,然后搅拌1小时,将其转移到水和二氯甲烷的混合物中。分离出的有机层依次用盐酸(1N)、碳酸氢钠水溶液和食盐水洗涤,然后用硫酸镁干燥。减压蒸发得到的残留物用二异丙醚研制后得到4-(4-氟苯甲酰氨基)-1-(4-三氟苯磺酰基)哌啶(0.38g)。
NMR(DMSO-d6,δ):1.45-1.7(2H,m),1.8-1.95(2H,m),
2.35-2.55(2H,m),3.5-3.85(3H,m),7.28(2H,t,
J=9Hz),7.50(2H,t,J=9Hz),7.75-7.95(4H,m),
8.31(1H,d,J=8Hz)
MASS(APCI)(m/z):381
实施例13
在0℃往4-(4-氟苯甲酰氨基)哌啶(0.15g)的二氯甲烷(5ml)溶液中依次加入吡啶(82μl)和4-三氟甲氧基苯甲酰氯(106μl)。让混合物温热至室温,搅拌4小时后将其转移到水和二氯甲烷的混合物中。分离出的有机层依次用盐酸(1N)、碳酸氢钠水溶液和食盐水洗涤,然后用硫酸镁干燥。在减压下蒸出溶剂后得到4-(4-氟苯甲酰氨基)-1-(4-三氟甲氧基苯甲酰基)哌啶(205mg)。
NMR(DMSO-d6,δ):1.3-1.7(2H,m),1.7-2.0(2H,m),
2.7-3.4(2H,m),3.4-3.8(1H,m),3.9-4.2(1H,m),
4.2-4.6(1H,m),7.30(2H,t,J=9Hz),7.35-7.6(4H,
m),7.91(2H,dd,J=6,9Hz),8.35(1H,d,J=8Hz)
MASS (LD)(m/z):433.2
实施例14
在0℃往4-(4-氟苯甲酰氨基)哌啶(0.15g)的二氯甲烷(5ml)溶液中依次加入吡啶(0.14ml)和甲磺酰氯(96μl)。让混合物温热至室温,然后搅拌1小时。往该混合物中加入N,N-二甲基氨基吡啶(0.13g),再搅拌1小时。将反应混合物转移到水和二氯甲烷的混合物中。分离出的有机层依次用盐酸(1N)、碳酸氢钠水溶液和食盐水洗涤,然后用硫酸镁干燥。减压蒸发得到的残留物用二异丙醚研制后得到4-(4-氟苯甲酰氨基)-1-甲磺酰基哌啶(0.30g)。
NMR(DMSO-d6,δ):1.45-1.7(2H,m),1.8-2.05(2H,m),
2.7-2.95(2H,m),2.88(3H,s),3.5-3.65(2H,m),
3.8-4.05(1H,m),7.30(2H,t,J=9Hz),7.91(2H,
dd,J=6,9Hz),8.36(1H,d,J=8Hz)
MASS(APCI)(m/z):301
实施例15
在0℃往N-(哌啶-4-基)-N′-(4-氟苯基)脲(0.3g)的四氢呋喃(4ml)溶液中依次加入吡啶(0.28ml)、氯甲酸甲酯(98μl)和催化量的N,N-二甲基氨基吡啶。让混合物温热至室温后搅拌2小时。将反应混合物转移到水和乙酸乙酯的混合物中。分离出的有机层依次用盐酸(1 N)、碳酸氢钠水溶液和食盐水洗涤,然后用硫酸镁干燥。减压蒸发得到的残留物用二异丙醚研制后得到N-(1-甲氧羰基哌啶-4-基)-N′-(4-氟苯基)脲(0.312g)。
NMR(DMSO-d6,δ):1.1-1.4(2H,m),1.7-1.9(2H,m),
2.8-3.1(2H,m),3.5-3.75(1H,m),3.59(3H,s),
3.75-3.95(2H,m),6.15(1H,d,J=7.6Hz),7.05(2H,
t,J=9Hz),7.37(2H,dd,J=5,9Hz),8.37(1H,s)
MASS(APCI)(m/z):296
实施例16
在0℃往N-(哌啶-4-基)-N′-(4-氟苯基)脲(0.3g)的四氢呋喃(4ml)溶液中依次加入N,N-二甲基氨基吡啶(0.23g)和4-氟苯磺酰氯(0.25g)。让混合物温热至室温后搅拌1小时。将反应混合物转移到水和二氮甲烷的混合物中。分离出的有机层依次用盐酸(1 N)、碳酸氢钠水溶液和食盐水洗涤,然后用硫酸镁干燥。减压蒸发得到的残留物用二异丙醚研制后得到N-(1-(4-氟苯磺酰基)-哌啶-4-基)-N′-(4-氟苯基)脲(0.468g)。
NMR(DMSO-d6,δ):1.3-1.6(2H,m),1.75-1.95(2H,m),
2.45-2.7(2H,m),3.35-3.6(3H,m),6.14(1H,d,
J=7.5Hz),7.03(2H,t,J=9Hz),7.34(2H,dd,J=5,
9Hz),7.50(2H,t,J=9Hz),7.75-7.95(2H,m),8.31
(1H,s)
MASS(APCI)(m/z):396
实施例17
在室温下往N-(哌啶-4-基)-4-氟苯甲酰胺(0.5g)在二氯甲烷(5ml)中的悬浮液中加入吡啶(218μl)、二氯甲烷(5ml)和苯甲酰氯(290μl)。搅拌3.5小时后往混合物中倒入水(5ml)。分离出有机层,用水和食盐水洗涤。用硫酸镁干燥后在减压下除去溶剂。残留物用柱色谱法精制(硅胶,甲苯∶乙酸乙酯=1∶1~乙酸乙酯)。用二异丙醚淋洗后得到N-(1-苯甲酰基哌啶-4-基)-4-氟苯甲酰胺(515mg)。
NMR(DMSO-d6,δ):1.50(2H,br s),1.85(2H,br s),
2.8-3.3(2H,m),3.61(1H,m),4.1(1H,m),4.35
(1H,m),7.29(2H,t,J=8.9Hz),7.3-7.5(5H,m),
7.92(2H,dd,J=5.6,8.9Hz),8.34(1H,d,J=7.9Hz)
MASS(APCI)(m/z):327
实施例18
在室温下往N-(哌啶-4-基)-4-氟苯甲酰胺(556mg)在二氯甲烷(5ml)中的悬浮液中加入戊酰氯(0.37ml)、吡啶(0.24ml)和N,N-二甲基氨基吡啶(25mg)。搅拌1天后,混合物用二氯甲烷稀释,然后用水和食盐水洗涤。用硫酸镁干燥后在减压下除去溶剂。用二异丙醚研制后得到N-(1-戊酰基哌啶-4-基)-4-氟苯甲酰胺(305mg)。
NMR(DMSO-d6,δ):1.20(9H,s),1.41(2H,m),1.7-1.9
(2H,m),2.91(2H,br t,J=11.9Hz),4.07(1H,m),
4.27(2H,br d,J=13.3Hz),7.29(2H,t,J=8.9Hz),
7.92(2H,dd,J=5.5,8.9Hz),8.30(1H,d,J=7.8Hz)
MASS(APCI)(m/z):329
实施例19
在室温下往N-(哌啶-4-基)-4-氟苯甲酰胺(556mg)在二氯甲烷(6ml)中的悬浮液中加入环丙烷羧酸(0.20ml)、1-羟基苯并三唑(338mg)和1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(480mg)。搅拌21小时后,混合物用二氯甲烷稀释,然后用水、饱和碳酸氢钠水溶液和盐水洗涤。用硫酸镁干燥后在减压下除去溶剂。从二异丙醚中重结晶后得到N-(1-环丙羰基哌啶-4-基)-4-氟苯甲酰胺(627g)。
NMR(DMSO-d6,δ):0.6-0.8(4H,m),1.2-1.6(2H,m),
1.7-2.0(2H,m),1.85(1H,m),2.72(1H,m),3.21
(1H,m),4.04(1H,m),4.30(2H,m),7.29(2H,t,
J=8.9Hz),7.92(2H,dd,J=5.6,8.9Hz),8.31(1H,d,
J=7.7Hz)
MASS(APCI)(m/z):313
实施例20
将1-叔丁氧羰基-4-(4-氟苯基氨基甲酰基)哌嗪(0.30g)溶解在氯化氢的乙酸乙酯溶液(4N,2ml)中,然后在室温下将该溶液搅拌1小时。减压蒸发除去溶剂后得到白色粉末状的1-(4-氟苯基氨基甲酰基)哌嗪。将其溶解在二氯甲烷(3ml)中,然后往该混合物中依次加入吡啶(0.25ml)、4-三氟甲氧基苯甲酰氯(0.146ml)和催化量的N,N-二甲基氨基吡啶。在室温下搅拌12小时后,混合物依次用盐酸(0.5N)、碳酸氢钠水溶液和食盐水洗涤,用硫酸镁干燥,然后在减压下蒸发。残留物在硅胶(50ml)上进行色谱精制,用0%-3%甲醇在二氯甲烷中的混合液洗脱,得到1-(4-氟苯基氨基甲酰基)-4-(4-三氟甲氧基苯甲酰基)哌嗪(0.19g)。
NMR(DMSO-d6,δ):3.2-3.8(8H,m),7.08(2H,t,
J=9Hz),7.35-7.5(4H,m),7.5-7.65(2H,m)
MASS(LD)(m/z):434.1
实施例21
按照类似于实施例20的方式,用氯甲酸甲酯作为羧基上的活性衍生物,制得了下面的化合物。
1-甲氧羰基-4-(4-氟苯基氨基甲酰基)哌嗪
NMR(DMSO-d6,δ):3.3-3.5(8H,m),3.62(3H,s),7.07
(2H,t,J=9Hz),7.44(2H,dd,J=5,9Hz),8.62(1H,
s)
MASS(APCI)(m/z):282
实施例22
N-乙酰基哌啶-4-羧酸(514mg)、1-羟基苯并三唑(405mg)、1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(575mg)和4-氟苯胺(284.2ml)在二氯甲烷(5ml)中的混合物在室温下搅拌18小时。然后用二氯甲烷将混合物稀释,并依次用水、饱和碳酸氢钠水溶液、水和食盐水洗涤。用硫酸镁干燥后在减压下除去溶剂。残留物用柱色谱法精制(硅胶40ml,二氯甲烷∶甲醇=15∶1)。用二异丙醚研制后得到1-乙酰基-4-(4-氟苯基)-氨基甲酰基哌啶(532mg)。
NMR(DMSO-d6,δ):1.3-1.7(2H,m),1.8(2H,m),2.01
(3H,s),2.5(2H,m),3.05(1H,br t,J=10.6Hz),
3.87(1H,br d,J=14.1Hz),4.40(1H,br d,
J=13.1Hz),7.12(2H,t,J=8.9Hz),7.61(2H,dd,
J=5.1,9.1Hz),9.96(1H,s)
MASS(APCI)(m/z):265
实施例23
在室温下往1-乙酰基哌嗪-4-磺酰氯(0.90g)的氯仿(10ml)溶液中加入4-氟苯胺(0.38ml)和三乙胺(0.56ml)。搅拌6天后在减压下除去溶剂。残留物用柱色谱法精制(硅胶100ml,二氯甲烷∶甲醇=19∶1)。用二异丙醚淋洗后得到1-乙酰基-4-(4-氟苯基)-氨磺酰哌嗪(716mg)。
NMR(CDCl3,δ):1.97(3H,s),3.09(4H,m),3.37(4H,
m),7.20(4H,m),10.00(1H,s)
MASS(APCI)(m/z):302
实施例24
在室温下往(1-乙酰基哌啶-4-基)氨基甲酸O-叔丁酯(0.97g)的N,N-二甲基甲酰胺(10ml)溶液中加入60%氢化钠(0.18g)。搅拌40分钟后,将4-氟苄基溴(0.6ml)加入到反应混合物中。再搅拌4小时后,将反应混合物倒入到乙酸乙酯(50ml)和水(10ml)的混合物中。分离出有机相,用水和食盐水洗涤。用硫酸镁干燥后在减压下除去溶剂。残留物用柱色谱法精制(硅胶100ml,甲苯∶乙酸乙酯=1∶1~1∶2)。从二异丙醚中重结晶后得到N-(4-氟苄基)-N-(1-乙酰基哌啶-4-基)氨基甲酸O-叔丁酯(922mg)。
NMR(DMSO-d6,δ):1.35(9H,br s),1.3-1.8(4H,m),
1.95(3H,s),2.3-2.6(1H,m),2.97(1H,m),3.80
(1H,br d,J=15.2Hz),4.0(1H,m),4.32(2H,s),
4.2-4.6(1H,m),7.0-7.4(4H,m)
MASS(APCI)(m/z):295
实施例25
往N-(4-氟苄基)-N-(1-乙酰基哌啶-4-基)氨基甲酸O-叔丁酯(0.5g)的二氯甲烷(5ml)溶液中加入4N氯化氢在二噁烷中的溶液(5ml)。反应混合物用二异丙醚稀释,过滤收集沉淀物。减压干燥后得到1-乙酰基-4-(4-氟苄基)氨基哌啶盐酸盐(409mg)。
NMR(DMSO-d6+D2O,δ):1.54(2H,m),2.02(3H,s),
2.0-2.3(2H,m),2.4-2.7(1H,m),3.04(1H,br t,
J=12.1Hz),3.29(1H,m),3.9(1H,m),4.17(2H,s),
4.44(1H,br d,J=13.6Hz),7.27(2H,t,J=8.9Hz),
7.66(2H,br t,J=6.8Hz)
MASS(APCI)(m/z):251
实施例26
往N-(1-乙酰基哌啶-4-基)-4-氟苯甲酰胺(529mg)的N,N-二甲基甲酰胺(5ml)溶液中加入氢化钠(0.1g)。搅拌45分钟后,往该溶液中加入甲基碘(623ml)。再搅拌45分钟后,用乙酸乙酯(100ml)和水(50ml)将混合物稀释。分离出有机相,用水和食盐水洗涤。用硫酸镁干燥后在减压下除去溶剂。用二异丙醚研制后得到N-(1-乙酰基哌啶-4-基)-N-甲基-4-氟苯甲酰胺(248mg)。
NMR(DMSO-d6,δ):1.65(4H,m),2.00(3H,s),2.78
(3H,s),3.8(1H,m),4.4(1H,m),2.0-4.6(3H,br
m),7.26(2H,t,J=8.9Hz),7.46(2H,dd,J=5.6,
8.7Hz)
MASS(APCI)(m/z):301
实施例27
1-乙酰基哌嗪(0.627g)、2-氯-4′-氟乙酰苯(0.844g)和碳酸氢钾(0.735g)在乙腈(12ml)中的悬浮液在室温下搅拌3天。过滤除去固体物后,滤液在减压下蒸发,所得残留物在硅胶(100ml)上进行色谱精制,用0%-5%甲醇在二氯甲烷中的混合液洗脱。将所得游离形式的目的化合物溶解在乙酸乙酯(2ml)中,然后往该溶液中加入氯化氢的乙酸乙酯溶液(4N,2ml)。过滤收集所形成的沉淀物,用二异丙醚洗涤,经真空干燥后得到1-乙酰基-4-(4-氟苯基羰基甲基)哌嗪盐酸盐(1.47g)。
NMR(DMSO-d6,δ):2.06(3H,s),2.95-3.8(6H,m),3.9-
4.15(1H,m),4.2-4.45(1H,m),5.13(2H,s),7.48
(2H,t,J=9Hz),8.09(2H,dd,J=5,9Hz)
MASS(APCI)(m/z):265
Claims (6)
2.按照权利要求1的化合物,其中
R1是C1-C6链烷酰基、C1-C6烷氧羰基、苯甲酰基、被卤(C1-C6)烷氧基取代的苯甲酰基或环(C3-C6)烷基羰基。
3.按照权利要求2的化合物,其中R1是C1-C6链烷酰基。
4.一种制备通式〔I〕化合物或其药物上可接受的盐的方法,
其中R1、R2、R3、R4、A、E、Q、X和Y各自的定义如权利要求1中所述,
该方法包含:
1)使式〔V〕的化合物:
或其盐与式〔III〕的化合物:
HO-Qa-R2 〔III〕
或其羧基上的活性衍生物或其盐反应,以提供式〔Ic〕的化合物或其盐:
2)使式〔VI〕的化合物:
或其盐与式〔VII〕的化合物:
R1-A-OH 〔VII〕或其羧基或磺基上的活性衍生物或其盐反应,以提供式〔I〕的化合物或其盐:
在上述通式中,R1、R2、R3、R4、A、E、X、Y和Q各自的定义如权利要求1中所述。
5.一种用于制造治疗和/或预防哺乳动物中记忆遗忘或痴呆的药物组合物,其中含有权利要求1的化合物作为有效成分,并结合了一种药物上可接受的实际上无毒的载体或赋形剂。
6.权利要求1的化合物用于制造治疗和/或预防哺乳动物中记忆遗忘或痴呆的药物的用途。
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1999
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