JPH01250353A - 9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredient - Google Patents
9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredientInfo
- Publication number
- JPH01250353A JPH01250353A JP63283351A JP28335188A JPH01250353A JP H01250353 A JPH01250353 A JP H01250353A JP 63283351 A JP63283351 A JP 63283351A JP 28335188 A JP28335188 A JP 28335188A JP H01250353 A JPH01250353 A JP H01250353A
- Authority
- JP
- Japan
- Prior art keywords
- formulas
- formula
- tables
- mathematical
- chemical
- 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.)
- Pending
Links
- 239000004480 active ingredient Substances 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 title abstract description 81
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 239000002253 acid Substances 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 9
- 230000001713 cholinergic effect Effects 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 9
- 210000005036 nerve Anatomy 0.000 claims description 7
- 229960001231 choline Drugs 0.000 claims description 5
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- 206010027175 memory impairment Diseases 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000006872 improvement Effects 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 14
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 6
- 206010039966 Senile dementia Diseases 0.000 abstract description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 210000000653 nervous system Anatomy 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- -1 Amino- Chemical class 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 102000003914 Cholinesterases Human genes 0.000 description 4
- 108090000322 Cholinesterases Proteins 0.000 description 4
- 208000026139 Memory disease Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 229940048961 cholinesterase Drugs 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- RXBYRTSOWREATF-UHFFFAOYSA-N 1,2,3,4-tetrahydroacridine Chemical compound C1=CC=C2C=C(CCCC3)C3=NC2=C1 RXBYRTSOWREATF-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000000946 synaptic effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- LZDYZEGISBDSDP-UHFFFAOYSA-N 2-(1-ethylaziridin-1-ium-1-yl)ethanol Chemical compound OCC[N+]1(CC)CC1 LZDYZEGISBDSDP-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 230000002252 carbamoylating effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
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- 150000004820 halides Chemical class 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
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- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 2
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- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
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- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- YXYDRUPYTWHNHC-UHFFFAOYSA-N n-(1,2,3,4-tetrahydroacridin-9-yl)benzamide Chemical compound C=12CCCCC2=NC2=CC=CC=C2C=1NC(=O)C1=CC=CC=C1 YXYDRUPYTWHNHC-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001696 purinergic effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems 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 carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
- C07D219/10—Nitrogen atoms attached in position 9
- C07D219/12—Amino-alkylamino radicals attached in position 9
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、機能低下したコリン作動性神経を賦活する、
新規で有用なデーアセルアミノーテらを有効成分とする
記憶障害改善剤に関する。Detailed Description of the Invention (Industrial Field of Application) The present invention provides a method for activating cholinergic nerves with decreased function.
The present invention relates to a novel and useful memory impairment improving agent containing deaceraminote et al. as an active ingredient.
（従来技術及び発明が解決しようとする問題点）アルツ
ハイマー病（Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ
）のような、コリン作動性神経機能の低下により特徴
づけられる種々の記憶障害の治療法として、コリンエス
テラーゼ阻害剤を用いて脳内のアセチルコリン含量を高
めようという試みが有る。(Prior art and problems to be solved by the invention) Alzheimer's disease
), attempts have been made to increase the content of acetylcholine in the brain using cholinesterase inhibitors as a treatment for various memory disorders characterized by a decline in cholinergic nerve function.
たとえば、フィゾスチグミンを用いた検討がニューロロ
ジ−（Ｎｅｕｒｏｌｏｇｙ ）、 ｇ、 ｊ？？（／９
７＆）に報告されている。さらに特開昭Ａ／−／’Ｉｔ
／！；’Ｉ号、特開昭４３４３−１ｌ１１９号、特開昭
６３−／乙ｂｇｇｉ号、特開昭Ａ３−２０．３Ａ＆’１
号、特開昭４．３−２２３３！ｉｇ号、特開昭６３−２
３ｇ０１，３号、特開昭１．３−．２３９コア／号、Ｅ
Ｐ−Ａ−２４ｇｇ７／号、国際公開第１１７０２２３６
号等の公報には、特定のターアミノ−テトラヒドロアク
リジン誘導体がコリンエステラーゼ阻害作用を有し、ア
ルツハイマー病の治療に有効であると報告されている。For example, studies using physostigmine have been reported in Neurology, g, j? ? (/9
7 &). Furthermore, JP-A-A/-/'It
/! 'I No., JP-A-4343-1l119, JP-A-63-/Otsu-bggi, JP-A-3-20.3A&'1
No. 4.3-2233! ig issue, JP-A-63-2
3g01, No. 3, JP-A-1.3-. 239 cores/issue, E
P-A-24gg7/No., International Publication No. 11702236
It is reported in publications such as No. 1 that certain teramino-tetrahydroacridine derivatives have a cholinesterase inhibitory effect and are effective in treating Alzheimer's disease.
またサマーズ（Ｓｕｍｍｅｒｓ ）はザニューイングラ
ンドジャーナルオプメディシン（ＴｈｅＮｅｗ Ｅｎｇ
ｌａｎｄ Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎｅ）
、Ｊ ／ ！ｒ。Summers is also an author of The New England Journal Op Medicine.
Land Journal of Medicine)
, J/! r.
／コリン（／デｇ乙）でデーアミノ−／、 ２ 、？、
＃テトラヒドロアクリジン（タフリン）がレシチンと
の併用でヒトのアルツハイマー病に有効と報告している
。しかしながら、充分な改善が達成されなかったり、副
作用の発現が問題となっており、新しい治療法の出現が
望まれている。一方、公知の９−アシルアミノ−テトラ
ヒドロアクリジンの例としては、ジャーナルオプケミカ
ルソサイエティ（Ｊｏｕｒｎａｌ ｏｆ Ｃｈｅｍｉｃ
ａｌ ５ｏｃｉｅｔｙ）。/Colin (/Deg Otsu) de Amino-/, 2,? ,
#Tetrahydroacridine (Tafrin) has been reported to be effective in treating Alzheimer's disease in humans when used in combination with lecithin. However, sufficient improvement has not been achieved and side effects have been a problem, and new treatment methods are desired. On the other hand, as an example of known 9-acylamino-tetrahydroacridine, the Journal of Chemical Society (Journal of Chemical Society)
al 5ociety).
６ｊ４’（／９＜Ｚり）にデーアセチルアミノ−テトラ
ヒドロアクリジンが記載されており、ケミケリステ４
（Ｃｈｅｍ、 １ｉｓｔｙ）、 ｊ／、 ／９０Ａ（／
９！；７）にタークロルアセチルアミノ−テトラヒドロ
アクリジン及びタージエチルアミノアセチルアミノ−テ
トラヒドロアクリジンが記載されており、後者が局所麻
酔作用を有することが記されている。また、ジャーナル
オブメディシナルケミスト リ −（Ｊｏｕｒｎａｌ
ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ
）。Deacetylamino-tetrahydroacridine is described in 6j4'(/9<Zri), and Chemicheliste 4
(Chem, 1isty), j/, /90A(/
9! 7) describes ter-chloracetylamino-tetrahydroacridine and ter-diethylaminoacetylamino-tetrahydroacridine, and states that the latter has a local anesthetic effect. In addition, the Journal of Medicinal Chemistry
of Medicinal Chemistry
).
１ｇ、 １０！ｒ＆（／９７！；）には、デーアミノ−
テトラヒドロアクリジノ誘導体のコリンエステラーゼ阻
害作用の構造活性相関が記載されており、ターアセチル
アミノ−テトラヒドロアクリジン及び９−ベンゾイルア
ミノ−テトラヒドロアクリジンは、デーアミノ−テトラ
ヒドロアクリジンに比べ活性が／／１０００になること
が記されている。また前記の特許（特開昭Ａ１−／１，
１．ｇｇ／号、特開昭６３−コク３６６グ号、特開昭６
３−コ、２ｊＪｊｔｇ号、特開昭６３−２３ｇ０Ａ３号
及び特開昭Ａ、？−２３９２７／号）の中には、その特
許請求の範囲に９−アシルアミノ−テトラヒドロアクリ
ジン誘導体を包含するものが有るが、そのいずれにもタ
ーアシルアミノ基を有する化合物の具体的な合成例及び
薬理活性は記載されていない。1g, 10! r&(/97!;) is deamino-
The structure-activity relationship of the cholinesterase inhibitory action of tetrahydroacridino derivatives has been described, and it has been reported that teracetylamino-tetrahydroacridine and 9-benzoylamino-tetrahydroacridine have an activity of 1000 times higher than that of deamino-tetrahydroacridine. has been done. Also, the above-mentioned patent (JP-A-1-1-1,
1. gg/issue, JP-A-63-Koku-366-g, JP-A-Sho 6
3-co, 2jJjtg, JP-A-63-23g0A3 and JP-A-A, ? -23927/) includes 9-acylamino-tetrahydroacridine derivatives in its claims, but all of them include specific synthetic examples of compounds having a teracylamino group and pharmacological studies. Activity not listed.
（問題点を解決するための手段）
本発明者らは、アルツハイマー病を含む老年性痴呆の治
療薬を提供することを目的として種々の検討を重ねた結
果、特定のデーアミルアミノ−テトラヒドロアクリジン
誘導体、その光学対掌体または薬学的に許容され得るそ
の酸付加塩が、従来のコリンエステラーゼ阻害作用を有
する化合物とは異ったメカニズムで、アルツハイマー病
等の記憶障害を改善する薬剤となり得ることを見出し、
本発明を完成するに至った。(Means for Solving the Problems) As a result of various studies aimed at providing a therapeutic agent for senile dementia including Alzheimer's disease, the present inventors have discovered a specific deamylamino-tetrahydroacridine derivative. discovered that its optical antipode or its pharmaceutically acceptable acid addition salt can serve as a drug that improves memory disorders such as Alzheimer's disease through a mechanism different from that of conventional cholinesterase inhibitory compounds. ,
The present invention has now been completed.
即ち、本発明の要旨は、下記一般式（Ｉ）Ｃ＝Ｏ
〔式中、Ｒはアルキル基、アルアルキル基または（ｎ）
式
（式中、Ｒ１は水素原子またはアルキル基を表ゎ−ＣＨ
２Ｃ−０Ｒ３（Ｒ３は水素原子またはアルキル基、アル
コキシ基またはヒドロキシル基を表わ（Ｒ６は水素原子
、アルキル基またはヒドロキシ（Ｒ７は水素原子、アル
キル基、アルアルキル基原子またはアルキル基を表わす
）を表わす。）、で表わされる９−アシルアミノ−テト
ラヒドロアクリジン誘導体、その光学対掌体または薬学
上許容されつるその酸付加塩に存する。That is, the gist of the present invention is the following general formula (I) C=O [wherein R is an alkyl group, an aralkyl group, or (n)
Formula (wherein R1 represents a hydrogen atom or an alkyl group -CH
2C-0R3 (R3 represents a hydrogen atom, an alkyl group, an alkoxy group, or a hydroxyl group (R6 represents a hydrogen atom, an alkyl group, or hydroxy (R7 represents a hydrogen atom, an alkyl group, an aralkyl group atom, or an alkyl group)) 9-acylamino-tetrahydroacridine derivatives represented by the following formulas, their optical antipodes, or pharmaceutically acceptable acid addition salts thereof.
以下本発明を説明するに、本発明の９−アシルアミノ−
テトラヒドロアクリジン誘導体は前記一般式（Ｉ）で表
わされる。In order to explain the present invention, the 9-acylamino-
The tetrahydroacridine derivative is represented by the above general formula (I).
（Ｉ）式において、Ｒは０２〜Ｃ８のアルキル基等のア
ルキル基、好ましくはエチル基、ｎ−プロピル基、イソ
プロピル基、ｎ−ブチル基、５ｅｃ−ブチル基、 ｔ
ｅｒｔ−ブチル基等の０２〜Ｃ４のアルキル基；または
、Ｃ，％ Ｃ３のアルキル基で置換されたフェニル基等
のアルアルキル基：または、前記（ＩＩ）式で表わされ
る基を表わす。In formula (I), R is an alkyl group such as a 02-C8 alkyl group, preferably an ethyl group, n-propyl group, isopropyl group, n-butyl group, 5ec-butyl group, t
An alkyl group of 02 to C4 such as ert-butyl group; or an aralkyl group such as a phenyl group substituted with an alkyl group of C, % C3; or a group represented by the above formula (II).
（ｎ）式において、Ｒ１及びＲ３で表わされるアルキル
基としては、Ｃ１〜ｃ６のアルキル基、好ましくは、メ
チル基、エチル基、ｎ−プロピル基、イソプロピル基、
ｎ−ブチル基、５ｅｃ−ブチル基等のＣ１” Ｃ４のア
ルキル基が挙げられる。In formula (n), the alkyl group represented by R1 and R3 is a C1 to C6 alkyl group, preferably a methyl group, ethyl group, n-propyl group, isopropyl group,
Examples include C1''C4 alkyl groups such as n-butyl group and 5ec-butyl group.
また、（Ｉ）式において、Ｒ４−Ｒ９で表わされるハロ
ケン原子、アルキル基、アルコキシ基またはアルアルキ
ル基としては、各々次の様なものが挙げられる。ハロゲ
ン原子としては、フッ素原子、塩素原子、臭素原子、ヨ
ウ素原子が挙げられ、アルキル基としては、メチル基、
エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチ
ル基、５ｅｃ−ブチル基等の０１〜Ｃ４のアルキル基が
挙げられ、アルコキシ基としては、メトキシ基、エトキ
シ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブト
キシ基、 ５ｅｃ−ブトキシ基等のＣｌ−０４のアルコ
キシ基が挙げられ、アルアルキル基としては、ベンジル
基、フェネチル基等が挙げられる。Further, in formula (I), examples of the halokene atom, alkyl group, alkoxy group or aralkyl group represented by R4 to R9 include the following. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, and iodine atom, and examples of the alkyl group include methyl group,
Examples include 01 to C4 alkyl groups such as ethyl group, n-propyl group, isopropyl group, n-butyl group, and 5ec-butyl group. Examples of alkoxy groups include methoxy group, ethoxy group, n-propoxy group, and isopropoxy group. Examples of the aralkyl group include a benzyl group, a phenethyl group, and the like.
本発明の（Ｉ）式で表わされる化合物の中で、好ましい
化合物の置換基の例としては以下のものが挙げられる。Among the compounds represented by formula (I) of the present invention, examples of preferred substituents include the following.
（１）Ｒとしては、ｎ−プロピル基、イソプロピル基ま
たは（ｎ）式で表わされる化合物。特に好ましくは、Ｒ
が（ＩＩ）式で表わされ、しかもし、かつｎが／である
化合物。(1) R is an n-propyl group, an isopropyl group, or a compound represented by formula (n). Particularly preferably, R
A compound represented by formula (II), and n is /.
化合物。Compound.
−２に示す。-2.
本発明化合物の特に好ましいものとして、上記衣−／及
び表−コの化合物層コ、３、ｌ／、／ｑ、２０Ｓ２３．
２６．２ｇ、３０．３２．３ダ、３７．３９、グ／、グ
リ１弘！、タグ、ＡＩ、４３．６１Ｉ、６６〜＆ｑ、
クコ、り３．７ ７〜 ざ θ 、 ｒ ３ 、
ｇ グ 、 ｇ ざ 、 ざ タ 、
９ ２〜ｑダが挙げられる。Particularly preferable compounds of the present invention include compound layer 3, l/, /q, 20S23.
26.2 g, 30.32.3 da, 37.39, g/, Guri 1 Hiro! ,tag,AI,43.61I,66~&q,
Wolfberry, ri 3.7 7~za θ, r 3,
g gu, g za, za ta,
9 2 to q da.
式（Ｉ）で表わされる化合物の塩類としては、生理的に
許容される塩類が好ましく、例えば塩酸塩、臭化水素酸
塩、ヨウ化水素酸塩、硫酸塩、リン酸塩等の無機酸塩、
及びシュウ酸塩、マレイン酸塩、フマル酸塩、乳酸塩、
リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、メタ
ンスルホン酸塩等の有機酸塩が挙げられる。式（Ｉ）の
化合物及びその塩は水和物又は溶媒和物の形で存在する
こともあるので、これらの水和物及び溶媒和物も又本発
明の化合物に含まれる。The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate. ,
and oxalates, maleates, fumarates, lactates,
Examples include organic acid salts such as malate, citrate, tartrate, benzoate, and methanesulfonate. Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.
次に本発明化合物の製造法たついて説明する。Next, the method for producing the compound of the present invention will be explained.
本発明化合物は、例えば以下のいずれかの方法により製
造することができる。The compound of the present invention can be produced, for example, by any of the following methods.
（１）下記（ＴＩｌＦ）式
における定義と同義である。）で表わされる化合物と、
下記（ＩＶ）式
％式％（）
（式中、Ｒ”は一般式（Ｉ）においてＲで表わされるア
ルキル基またはアルアルキル基を表わす。）で表わされ
る化合物の反応性誘導体とを反応させることにより、（
Ｉ）式で表わされる化合物を得ることができる。(1) It has the same meaning as the definition in the following formula (TIIF). ) and a compound represented by
Reacting with a reactive derivative of a compound represented by the following formula (IV) % formula % (in the formula, R'' represents an alkyl group or an aralkyl group represented by R in general formula (I)). By (
I) A compound represented by the formula can be obtained.
（ＩＶ）式の化合物の反応性誘導体としては、対称酸無
水物または酸ハライド（特に酸クロライド）が好ましい
。反応はベンゼン、トルエン、キシレン、／、、２−ジ
クロロエタン、／、 ／、 ２ ｕ−テトラクロロエタ
ン等の不活性す溶媒の存在下、または過剰の対称酸無水
物あるいは酸ハライドを溶媒として行われる。対称酸無
水物を用いる場合、ピリジン等の３級アミンを用いるこ
ともある。反応温度は３０〜１３０℃、好ましくはり０
〜７２０℃の範囲で行われる。As the reactive derivative of the compound of formula (IV), symmetrical acid anhydrides or acid halides (especially acid chlorides) are preferred. The reaction is carried out in the presence of an inert solvent such as benzene, toluene, xylene, /, 2-dichloroethane, /, /, 2 u-tetrachloroethane, or using an excess of symmetrical acid anhydride or acid halide as a solvent. When using a symmetrical acid anhydride, a tertiary amine such as pyridine may be used. The reaction temperature is 30 to 130°C, preferably 0
The temperature range is 720°C.
（２）前記＠）式の化合物を、／当量以上の水素化ナト
リウムで処理してナトリウム塩とし、下記（Ｖ）式
％式％（）
はエチル基を表わす。）
で表わされるエステル化合物と反応し、（Ｉ）式で表わ
される化合物を得ることができる。(2) The compound of the above formula @) is treated with at least an equivalent amount of sodium hydride to form a sodium salt, and the formula (V) below represents an ethyl group. ) can be reacted with an ester compound represented by formula (I) to obtain a compound represented by formula (I).
溶媒としては、テトラヒドロフラン、ジオキサン、アセ
トニトリル、ジメチルホルムアミド、Ｎ−メチルピロリ
ドン、ジメチルスルホキシドが好ましい。反応温度は７
０〜ｇ。Preferred solvents include tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide. The reaction temperature is 7
0~g.
℃、好ましくは３０〜６０℃の範囲で行われる。The temperature is preferably 30 to 60°C.
（３）Ｘ ■ （ＣＨ２）ｒｒｌ Ｃ＝。(3)X ■ (CH2)rrl C=.
暮
Ｃ＝Ｏ
上記ａ工程の反応式で一般式（Ｉ）の化合物を合成でき
る。C=O The compound of general formula (I) can be synthesized using the reaction formula in step a above.
（反応式中、Ｘは塩素原子または臭素原子を（Ｖ’ｌｌ
）中のＲ１３は、Ｃ１〜Ｃ４の直鎖状または分枝状のア
ルキル基を表わす。（ＩＸ）式中のＲ１４は、を表わす
。）
すなわち、まず（ＩＩＩ）式の化合物Ｋ （Ｖｌ）式の
アシルハライド化合物を反応させ、（Ｖｌｌ）式の化合
物を得る（ （−ａ）工程）。次いで、（ｖＩ）式の化
合物あるいはイミダゾールを反応させるか、または（Ｉ
Ｘ）式の化合物を水素化す） ＩＪウムでナトリウム塩
とした化合物を反応させ（（ｂ）工程）、対応する（Ｉ
）式の化合物が得られる。(In the reaction formula, X is a chlorine atom or a bromine atom (V'll
R13 in ) represents a C1 to C4 linear or branched alkyl group. R14 in formula (IX) represents. ) That is, first, compound K of formula (III) is reacted with an acyl halide compound of formula (Vl) to obtain a compound of formula (Vll) (step (-a)). Then, a compound of formula (vI) or imidazole is reacted, or (I
(Hydrogenation of the compound of the formula
) is obtained.
（ａ）工程は、過剰のアシルハライドを溶媒兼用として
、またはベンゼン、トルエン、キシレン、ｌ、２−ジク
ロロエタン、’ｔ’ｔ２コーチトラクロロエタンのよう
な不活性な溶媒を用いて、５０〜ｉｓｏ℃、好ましくは
７０〜／２０℃の温度範囲で行われる。Step (a) is carried out at 50 to isoC using an excess of acyl halide as a solvent or an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 't't2-cochtrachloroethane. , preferably at a temperature range of 70 to 20°C.
（ｂ）工程は、（ｖＩｌｌ）式のアミンあるいはイミダ
ゾールを反応させる場合、過剰のアミンを溶媒兼用とし
て、またはメタノール、エタノール、ｎ−プロパツール
、インプロパツール、ｎ−ブタノールのようなアルコー
ル系溶媒、テトラヒドロフラン、ジオキサン、アセトニ
トリル、ジメチルホルムアミド、ジメチルスルホキシド
等の溶媒を用いて、０〜７５０℃、好ましくは、２０〜
１００℃の温度範囲で行われる。ＧＸ）式の化合物のす
） ＩＪウム塩を反応させる場合には、テトラヒドロフ
ラン、ジオキサン、アセトニトリル、ジメチルホルムア
ミド、ジメチルスルホキシド等の溶媒を用いて、０〜７
２０℃、好しくはコＯ〜ｇｏ℃の温度範囲で行われる。In the step (b), when reacting an amine or imidazole of the formula (vIll), use an excess of the amine as a solvent or an alcoholic solvent such as methanol, ethanol, n-propanol, impropanol, or n-butanol. , using a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc., at 0 to 750°C, preferably from 20 to
It is carried out in a temperature range of 100°C. When reacting a compound of the formula GX) with a salt of 0 to 7
It is carried out at a temperature range of 20°C, preferably 0 to 0°C.
（ｖｎ）
＜ｘンαＤ
前記（ｖｌ）式の化合物を用い、上記３工程の反応によ
り、一般式（Ｉ）の化合物を得ることすなわち、（至）
）式の化合物にアジ化ナトリウムを反応させ（（Ｃ）工
程）、（Ｘ）式のアジド化合物を得、これを、例えばパ
ラジウムを触媒として水素化分解する方法で還元して（
（ｄ）工程）（１））式の一級アミン化合物とし、これ
をアシル化（（ｅ）工程）あるいはカルバモイル化する
（（ｆ）工程）ことにより、（Ｉ）式の化合物が得られ
る。(vn)
<xn αD Using the compound of formula (vl) above, obtaining the compound of general formula (I) by the reaction of the above three steps, that is, (to)
) is reacted with sodium azide (step (C)) to obtain an azide compound of formula (X), which is reduced by, for example, hydrogenolysis using palladium as a catalyst (
(d) Step) A compound of formula (I) is obtained by preparing a primary amine compound of formula (1) and acylating it (step (e)) or carbamoylating it (step (f)).
（Ｃ）工程は、ジメチルホルムアミド、ジメチルスルホ
キシド、アセトニトリル、メタノール、エタノール、ｎ
−プロパツール、イソプロパツール等の溶媒を単独か、
あるいはそれらの溶媒と水との混合溶媒中で、ｏ−ｇｏ
℃、好ましくは１０−！；０℃の温度範囲で行われる。Step (C) includes dimethylformamide, dimethylsulfoxide, acetonitrile, methanol, ethanol, n
-Using a solvent such as propatool or isopropatool alone,
Or in a mixed solvent of those solvents and water, o-go
℃, preferably 10-! ; carried out in a temperature range of 0°C.
（ｄ）工程は、メタノール、エタノール、ｎ−プロパノ
ール、イソプロパツール、テトラヒドロフラン、ジオキ
サン、アセトニトリル等の溶媒中で、Ｏ〜ｇｏ℃、好ま
しくはｌＯ〜ｔｉｏ℃の温度範囲で行われる。Step (d) is carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, etc. at a temperature range of O to goC, preferably lO to tioC.
Ｃｅ）工程は、通常のアシル化条件、例えば三級アミン
の存在下、アシルハライド化合物または対称酸無水物と
反応させる方法等によって行うことができる。Step Ce) can be carried out under conventional acylation conditions, such as a method of reacting with an acyl halide compound or a symmetrical acid anhydride in the presence of a tertiary amine.
（ｆ）工程も通常のカルバモイル化の条件で行えば良い
。例えば、（ＸＩ）式の化合物とアルキルイソシアナー
トを反応させて、アルキル置換ウレアが得られ、酢酸中
でイソシアン酸ナトリウムを反応させて、ウレア体が得
られる。Step (f) may also be carried out under normal carbamoylation conditions. For example, an alkyl-substituted urea is obtained by reacting the compound of formula (XI) with an alkyl isocyanate, and a urea compound is obtained by reacting with sodium isocyanate in acetic acid.
（５）一般式（Ｉ）の化合物の７つを変換させて、一般
式Ｃｒ）に含まれる他の化合物を合成する方法として、
例えば下記のような方法が有る。(5) A method for synthesizing other compounds included in general formula Cr) by converting seven of the compounds of general formula (I),
For example, there are the following methods.
（■）
Ｒ
■
（Ｘｌｌｌｌ）
式（Ｉ）における定義と同義）
すなわち、蕩）式で表わされるＮ−ベンジルアミンを、
パラジウムを触媒とする水素化分解で脱ベンジル化しく
（ｇ）工程）、得られる（ＸＩｆｆ）式の２級アミンを
アシル化（（ｈ）工程）またはカルバモイル化（（ｉ）
工程）する方法である。(■) R ■ (Xllll) Same as the definition in formula (I)) That is, N-benzylamine represented by the formula,
The resulting secondary amine of the formula (XIff) is debenzylated by hydrogenolysis using palladium as a catalyst (step (g)), and the resulting secondary amine of formula (XIff) is acylated (step (h)) or carbamoylated ((i)
process).
（ｇ）工程は、通常の方法、例えばエタノール中でパラ
ジウムカーボンを触媒とし、塩酸を加えて水素化分解す
る方法で行える。（ｈ）及び（ｉ）工程は、それぞれ前
記（４）項の（ｅ）工程及び（ｆ）工程と同様の通常法
で行なえる。Step (g) can be carried out by a conventional method, for example, by hydrogenolysis in ethanol using palladium carbon as a catalyst and adding hydrochloric acid. Steps (h) and (i) can be carried out by the same conventional methods as steps (e) and (f) in section (4) above, respectively.
上記（１）〜（３）の製造方法の出発原料である皿）式
の化合物は、例えば
（ａ） テトラヘドロンレターズ（Ｔｅｔｒａｈｅｄ
ｒｏｎＬｅｔｔｅｒｓ ）、 ／２７り（／９Ａ、、
７）（ｂ） コレクションオプチェコスロバックケミ
カル コミュニケーションズ（Ｃｏ１１ｅｃｔ。The compound of the formula D, which is the starting material for the production methods of (1) to (3) above, is, for example, (a) Tetrahedron Letters (Tetrahedron Letters).
ronLetters), /27ri(/9A,,
7) (b) Collection Opcheko Slobak Chemical Communications (Co11ect.
Ｃｚｅｃｈ、Ｃｈｅｍ、Ｃｏｍｍｕｎ、）、’１２．．
２ｇ０２（／９７り）オ
（Ｃ） アクタ ケミ力 スカンジナビＦ （Ａｃｔ
ａＣｈｅｍｉｃａ ５ｃａｎｄｉｎａｖｉｃａ ）、
Ｂ、 ３ 、？、 ３ ／ 、？（／９７？）
等に記載の方法、またはこれに準する方法によって容易
に合成できる。Czech, Chem, Commun, ), '12. ．．
2g02(/97ri)o(C) Acta Chemi-Riki Scandinavi F (Act
aChemica 5candinavica),
B, 3,? , 3 / ,? (/97?) etc., or a method analogous thereto.
また、特開昭４／−／’Ｉｇ／！；’Ｉ号、特開昭６３
−１１１１９１０号、特開昭４３−１１６１１１１号、
特開昭４．７−２０３１，４９号、特開昭Ａ３−２２！
３３；１号、特開昭Ａ３−２３ｇ０Ａ３号、特開昭Ａ３
−２３９２７／号及びＥＰ−Ａ−２４ｇｇ７／号の各公
報に記載されている方法に準じて合成することもできる
。Also, Tokukai Showa 4/-/'Ig/! ;'I, JP-A-63
-1111910, JP-A-43-1161111,
JP-A-4.7-2031,49, JP-A-A3-22!
33; No. 1, JP-A-A3-23g0A3, JP-A-A3
It can also be synthesized according to the methods described in Publications No. -23927/ and EP-A-24gg7/.
本発明化合物を治療剤として用いる場合、単独または薬
学的に可能な担体と複合して投与する。その組成は、化
合物の溶解度、化学的性質、投与経路、投与計画等によ
って決定される。When the compounds of the present invention are used as therapeutic agents, they are administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the compound's solubility, chemical properties, route of administration, regimen, etc.
例えば、顆粒剤、細粒剤、散剤、錠剤、硬カプセル剤、
軟カプセル剤、シロップ剤、乳剤、懸濁剤又は液剤等の
剤形にして、経口投与してもよいし、注射剤として静脈
内投与、筋肉内投与又は皮下投与してもよい。For example, granules, fine granules, powders, tablets, hard capsules,
It may be administered orally in the form of soft capsules, syrups, emulsions, suspensions, or liquids, or it may be administered intravenously, intramuscularly, or subcutaneously as an injection.
また、注射用の粉末にして用時調製して使用してもよい
。経口、経腸、非経口若しくは局所投与に適した医薬用
の有機又は無機の、固体又は液体の担体若しくは希釈剤
を本発明化合物と共に用いることができる。固形製剤を
製造する際に用いられる賦形剤としては、例えば乳糖、
ショ糖、テンプン、タルク、セルロース、テキストリン
、カオリン、炭酸カルシウム等が用いられる。経口投与
のための液体製剤、即ち、乳剤、シロップ剤、懸濁剤、
液剤等は、一般的に用いられる不活性な希釈剤、例えば
水又は植物油等を含む。この製剤は、不活性な希釈剤以
外に補助剤、例えば湿潤剤、懸濁補助剤、甘味剤、芳香
剤、着色剤又は保存剤等を含むことができる。液体製剤
にしてゼラチンのような吸収されうる物質のカプセル中
に含ませてもよい。非経口投与の製剤、即ち、注射剤等
の製造に用いられる溶剤又は懸濁化剤としては、例えば
水、プロピレングリコール、ポリエチレン！＋）！−ル
、ベンジルアルコール、オレイン酸エチル、レシチン等
が挙げられる。製剤の調製方法は常法によればよい。Alternatively, it may be prepared as a powder for injection before use. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used with the compounds of this invention. Examples of excipients used in manufacturing solid preparations include lactose,
Sucrose, starch, talc, cellulose, texturin, kaolin, calcium carbonate, etc. are used. Liquid preparations for oral administration, i.e. emulsions, syrups, suspensions,
Solutions include commonly used inert diluents such as water or vegetable oil. In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents, or preservatives. Liquid preparations may be enclosed in capsules of absorbable material such as gelatin. Examples of solvents or suspending agents used in the production of parenteral preparations, ie, injections, etc. include water, propylene glycol, and polyethylene. +)! -ol, benzyl alcohol, ethyl oleate, lecithin, and the like. The preparation method may be any conventional method.
臨床投与量は、経口投与により用いる場合には、成人に
対し本発明の化合物として、一般には、／日量ｌ〜１０
００ｍ９であり、好ましくは７〜１００ｍ９であるが、
年令、病状、症状、同時投与の有無等により適宜増減す
ることが更に好ましい。前記７日量の本発明化合物は、
／日に１回、又は適当間隔をおいて７日にコ若しくは３
回に分けて投与してもよいし、間欠投与してもよい。Clinical dosages for a compound of the invention for adults when used by oral administration are generally between 1 and 10 liters per day.
00 m9, preferably 7 to 100 m9,
It is more preferable to increase or decrease the amount as appropriate depending on age, medical condition, symptoms, presence or absence of simultaneous administration, etc. The 7-day dose of the compound of the present invention is:
/ Once a day, or at appropriate intervals every 7 days or 3 days
It may be administered in divided doses or intermittently.
また、注射剤として用いる場合には、成人に対し本発明
の化合物として、／日量０．／〜１００■であり好まし
くは０． ／〜りＯ■である。When used as an injection, the compound of the present invention may be administered to adults at a dosage of 0. /~100■, preferably 0. /～riO■.
このようにして得られた一般式（Ｉ）にて表わされる本
発明の化合物は、コリンエステラーゼ阻害作用が公知の
デーアミノ−テトラヒドロアクリジンの／／／ ００以
下と弱いものの、プリン作動性神経のプレシナブチイッ
ク側を活性化して、神経伝達を高めることができる。具
体的には、ＡＦ−４４’Ａ（エチルコリン アジリジニ
ウムイオン： ｅｔｈｙｌｃｈｏｌｉｎｅ ａｚｉｒｉ
ｄｉｎｉｕｍ ｉｏｎ ）ジャーナルオプファーマコロ
ノーアンドイクスベリメンタル セラボイティクス（Ｊ
。Although the compound of the present invention represented by the general formula (I) thus obtained has a weak cholinesterase inhibitory effect of less than ///00 of the known deamino-tetrahydroacridine, it has a presynaptic effect on purinergic nerves. It can activate the ick side and increase nerve transmission. Specifically, AF-44'A (ethylcholine aziridinium ion: ethylcholine aziridinium ion)
dinium ion) Journal op Pharmacorono and Experimental Therapeutics (J
.
Ｐｈａｒｍａｃｏｌ、 Ｅｘｐ、 Ｔｈｅｒ、 ）、
２２２． ／ダ０（／りｔｒｔ）；ニューロファーマコ
ロジー（Ｎｅｕｒｏｐｈａｒｍａｃｏｌ、 ）ｙ２６、
３１．／ （／９ざコ）〕 を脳室内に投与されたラ
ットの、海馬シナブトシームの高親和性コリン取込み能
を改善する（試験例／）。この作用は、ターアミノーテ
トラヒドロアクリジンでは見られない。Pharmacol, Exp, Ther, ),
222. /da0(/ritrt); Neuropharmacology (Neuropharmacol, )y26,
31. / (/9zako)] improves the high-affinity choline uptake ability of the hippocampal synapse of rats administered intracerebroventricularly (Test Example/). This effect is not seen with teraminotetrahydroacridine.
また、本発明の化合物は、デーアミノ−テトラヒドロア
クリジンに比べ非常に毒性が弱く、副作用も少ないので
、アルツハイマー病等の記憶障害に対し有用な治療薬と
なり得る。In addition, the compound of the present invention is much less toxic than deamino-tetrahydroacridine and has fewer side effects, so it can be a useful therapeutic agent for memory disorders such as Alzheimer's disease.
（発明の効果）
本発明の一般式（Ｉ）で表わされる化合物は、薬理学的
に活性な価値ある化合物である。特にこれらの化合物は
、障害されたコリン作動性神経系を直接活性化する作用
を有するので、老年性痴呆、アルツハイマー病等の記憶
障害の治療のために、使用しうる医薬品として有用であ
る。(Effects of the Invention) The compound represented by the general formula (I) of the present invention is a valuable pharmacologically active compound. In particular, these compounds have the effect of directly activating the impaired cholinergic nervous system, and therefore are useful as pharmaceuticals that can be used to treat memory disorders such as senile dementia and Alzheimer's disease.
老年性痴呆、特にアルツノ・イブ−病では、脳内コリン
作動性神経の機能が低下しており、この低下と記憶障害
の程度とは良い相関性がある。In senile dementia, especially Arzno-Yves disease, the function of cholinergic nerves in the brain decreases, and there is a good correlation between this decrease and the degree of memory impairment.
一方ＡＦＡ４’Ａは、フイシン＋ −（Ｆｉｓｈｅｒ
）（（Ｊ、 Ｐｈａｒｍａｃｏｌ、 Ｅｘｐ、 Ｔｈｅ
ｒ、 ）、 ２２２． ／ ａＯ（／ｑｇａ）］および
レベンター（Ｌｅｖｅｎｔｅｒ ）（（Ｎｅｕｒｏｐｈ
ａｒｍａｃｏｌ、）ｔ ＋２ Ａ、Ｊ ６／ （／
９ざ７）〕が報告したように、コリン作動性神経を選択
的かつ長期的に障害させ、ＡＦＡＩＩＡを投与したラッ
トでは記憶学習障害が認められ〔プレインリサーチ（Ｂ
ｒａｉｎ Ｒｅｓ、 ）、 、？ ２ ／、 タ／（／
りざ４’））、アルツハイマー病の良いモデルである。On the other hand, AFA4'A is a ficin + - (Fisher
) ((J, Pharmacol, Exp, The
r, ), 222. / aO (/qga)] and Leventer ((Neuroph
armacol, )t +2 A, J 6/ (/
As reported by [Plain Research (B.
rain Res, ), ,? 2 /, ta/(/
It is a good model for Alzheimer's disease.
従ってＡＦＡＩＩＡの投与により低下した脳内コリン作
動性神経の機能を直接活性化させることのできる本発明
の化合物は、アルツノ・イブ−病を含む老年痴呆の治療
に有用と考えられる。Therefore, the compound of the present invention, which can directly activate the function of cholinergic nerves in the brain that has been decreased by the administration of AFAIIA, is considered to be useful in the treatment of senile dementia including Arzno-Yves disease.
（実施例）
以下、実施例により本発明をさらに具体的に説明するが
、本発明は、その要旨を超えない限り、以下の実施例に
限定されるものではない。(Examples) Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.
実施例１
Ｎ−（／、、２．．７．ｌ−テトラヒドロアクリジン−
ターイル）ブタナミド（表−／の化合物／Ｊ６２）の合
成
ピリジンＩＩ ｍｌに９−アミノ−／、 ２３． ’Ｉ
−テトラヒドロアクリジンｓｇを添加した。この混合物
に無水−ｎ−酪酸３．３ ｍｌを加え、３時間還流した
。次いで減圧下溶媒を留去し得られた残渣にメタノール
１０ｒＦＬｌを加えた。この混合物に濃アンモニア水を
加え７時間還流した。減圧下溶媒を留去した後、水を加
えクロロホルムで抽出した。クロロホルム層を無水硫酸
ナトリウムで乾燥し、減圧下溶媒を留去した。得られた
残渣をシリカゲルカラムクロマトグラフィーで精製し、
クロロホルム／エーテルから再結晶し、Ｎ−（’ｐ 、
２，３ｙ ”−テトラヒドロアクリジン−ターイル）ブ
タナミド／、 ！； ７ ｇを得た。融点２０１〜λθ
グ℃。Example 1 N-(/, 2..7.l-tetrahydroacridine-
9-amino-/, 23. Synthesis of (Table-/Compound/J62) 9-amino-/, in ml of pyridine II. 'I
-Tetrahydroacridine sg was added. 3.3 ml of anhydrous n-butyric acid was added to this mixture, and the mixture was refluxed for 3 hours. Next, the solvent was distilled off under reduced pressure, and 10 rFLl of methanol was added to the resulting residue. Concentrated ammonia water was added to this mixture and the mixture was refluxed for 7 hours. After distilling off the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography,
Recrystallized from chloroform/ether to give N-('p,
7 g of 2,3y ”-tetrahydroacridine-teryl)butanamide/, ! was obtained. Melting point: 201-λθ
Gu℃.
以下の表−３に示す化合物を実施例１と同様にして合成
した。The compounds shown in Table 3 below were synthesized in the same manner as in Example 1.
実施例／ダ
Ｘ−（２−オキソピロリジン−７−イル）−Ｎ−（／、
、２．．７．ｌＩ−テトラヒドロアクリジン−９−イル
）アセトアミド（表−／の化合物層２６）塩酸塩の合成
水素化ナトリウム（６０％含量） ｐ、 ｌＩｇをＮ−
メチルピロリドン！；Ｏｍｇに懸濁し、９−アミノ−／
、 ２ 、、？、 ＩＩ−ｆ トラヒドロアクリジン１
０．ｌＩｇを加え、室温で７時間撹拌する。次いで夕０
°に加温し、コーオキソー／−ピロリジン酢酸メチルエ
ステル１７．ｌＩｇを３０分かげて滴下する。Example/DaX-(2-oxopyrrolidin-7-yl)-N-(/,
, 2. ．． 7. Synthesis of lI-tetrahydroacridin-9-yl)acetamide (Table-/Compound Layer 26) Hydrochloride Sodium hydride (60% content) p, lIgN-
Methylpyrrolidone! ;suspended in Omg, 9-amino-/
, 2,,? , II-f trahydroacridine 1
0. Add lIg and stir at room temperature for 7 hours. Then evening 0
Warm to 17°C. Add lIg dropwise over 30 minutes.
１０℃まで冷やした後、塩化アンモニウム１１０Ｉの水
溶液ＪＯＯｍｌに注ぎ、クロロホルム、３００ＷＬｌで
抽出する。クロロホルム溶液を減圧乾固し、イソプロパ
ツールから再結晶すると、／１１．デｙの結晶が得られ
る。融点２３３〜２３ｂ℃。これをイソプロパツール／
２０ ｍｌに懸濁し、塩化水素２６％イライングノー
ル溶液１０ｒｎｌを加え、室温で７時間撹拌した後濾過
すると、表題の化合物／ ｔ、 ２ ｇを得た。融点２
３０〜２．３ｊ℃分解。After cooling to 10° C., it is poured into JOOml of an aqueous solution of 110I ammonium chloride, and extracted with chloroform and 300WLl. When the chloroform solution was dried under reduced pressure and recrystallized from isopropanol, /11. Crystals of Dey are obtained. Melting point 233-23b°C. Run this in isopropatools/
The mixture was suspended in 20 ml, added with 10 rnl of a 26% hydrogen chloride solution in iraignol, stirred at room temperature for 7 hours, and then filtered to obtain 2 g of the title compound/t. Melting point 2
Decomposed at 30-2.3j℃.
以下の表−ダに示す化合物を実施例／４’と同様にして
合成した。The compounds shown in Table D below were synthesized in the same manner as in Example 4'.
表−ダ
Ｈ２
Ｃ＝０
実施例３ｌ
−−（２４’−イミダゾリジンジオン−３−イル）−Ｎ
−Ｃｉｓ占３． ’Ｉ−テトラヒドロアクリジンー９−
イル）アセトアミド（表−／の化合物／１６３り）の合
成
水素化ナトリウム（６０％含ｔ ） ０． ｇ Ｉをジ
メチルホルムアミド２０ｍ１に懸濁し、コツクーイミダ
ゾリジンジオン３ｇを加え、室温で３０分纜拌した後、
タークロロアセチルアミノー／、 ！。Table-Da H2 C=0 Example 3l --(24'-imidazolidinedione-3-yl)-N
-Cis fortune telling 3. 'I-tetrahydroacridine-9-
Synthesis of acetamide (Compound/163 in Table-/) Sodium hydride (60% content) 0. g I was suspended in 20 ml of dimethylformamide, 3 g of Kokku imidazolidinedione was added, and after stirring at room temperature for 30 minutes,
Terchloroacetylamino/,! .
３、弘−テトラヒドロアクリジン（Ｃｈｅｍ、 ｌ １
ｓｔｙ。3. Hiro-tetrahydroacridine (Chem, l 1
sty.
土ｚ、 １ｑｏｔ、（ｌｑｓｑ）に記載）２．７りＩを
加える。これをｇθ℃に加温してＪＯ分反応させ、１０
℃まで冷やした後、・塩化アンモニウムｇｇの水溶液１
００Ｒ１３に注ぐ。析出した固体を戸数し、水洗して乾
燥する。これをメタノール−クロロホルムから再結晶し
て、２，３ｇの表題の化合物を得た。融点、３０２〜隻
℃分解。2.7 Add I. This was heated to gθ℃ and reacted for JO minutes, and
After cooling to ℃, an aqueous solution of ammonium chloride gg
Pour into 00R13. Separate the precipitated solid, wash with water, and dry. This was recrystallized from methanol-chloroform to yield 2.3 g of the title compound. Melting point, 302°C decomposed.
以下の表−３に示す化合物を実施例３／と同様にして合
成した。The compounds shown in Table 3 below were synthesized in the same manner as in Example 3/.
表−Ｉ
ＣＨ２
Ｃ＝Ｏ
実施例３５
ｑ−（（２−メチルアミン）アセチル−アミノ］ ’
＋ユ、３．ｑ−テトラヒドロアクリジン（表−／の化合
物層／／）の合成
ダＯ％メチルアミンメタノールＨ液３ｏｍｌＦｃ。Table-I CH2 C=O Example 35 q-((2-methylamine)acetyl-amino]'
+ Yu, 3. Synthesis of q-tetrahydroacridine (Table-/Compound layer//) O% methylamine methanol H solution 3 omlFc.
デークロロアセチルアミノー／、 ！ 、？、 ！−テ
トラヒドロアクリジン／、 ９ ／／を加え、室温で２
時間、ＳＯ℃で３０分反応させた後、水ｂｏａｔ及びク
ロロホルムｇＯｍｌを加えて抽出する。クロロホルム溶
液を濃縮し、シリカゲルカラムクロマトグラフィー（ク
ロロホルム−メタノール〕で精製し、イングロパノール
ージエチルエーテルから再結晶して、ｏ、ｇ ｑ ｇの
表題の化合物を得た。Dechloroacetylamino/, ! ,? , ! -Tetrahydroacridine/, 9// was added, and 2
After reacting at SO 0 C for 30 minutes, water boat and chloroform (gOml) were added for extraction. The chloroform solution was concentrated, purified by silica gel column chromatography (chloroform-methanol), and recrystallized from ingropanol-diethyl ether to obtain the title compound o, g q g.
融点／３コ〜１５５０ｃ。Melting point/3c to 1550c.
実施例３ｊと同様にして、下記実施例３Ａ、３７の化合
物を合成した。また実施例３ｓの化合物を常法により無
水酢酸−ピリジンでアセチル化し、下記実施例３ｇの化
合物を合成した。Compounds of Examples 3A and 37 below were synthesized in the same manner as in Example 3j. Further, the compound of Example 3s was acetylated with acetic anhydride-pyridine in a conventional manner to synthesize the compound of Example 3g below.
これらの化合物の融点を、表−６に示す。The melting points of these compounds are shown in Table-6.
表−６
Ｃ＝Ｏ
蓋
実施例３ｑ
デー〔（コーアミノ）アセチル−アミノ〕−／、 ２３
．’Ｉ−テトラヒドロアクリジン（表−７の化合物層１
０）の合成
アジ化ナトリウムＪ、 ｇ ｅ ｇをジメチルホルムア
ミドｌＩｏｗｔｔに懸濁し、９−クロロアセチルアミノ
−／、 ２３． ’ｌ−テトラヒドロアクリジン１０Ｉ
を加え、室温で２時間反応させる。水を３２ｍ１加えて
析出する結晶を濾過すると、９−アジドアセチルアミノ
−／、 ２．．７． Ｑ−テトラヒドロアクリジンデ、
７ｇが得られる。融点／りＯ℃分解。Table-6 C=O Lid Example 3q D[(Co-amino)acetyl-amino]-/, 23
．． 'I-tetrahydroacridine (compound layer 1 of Table 7)
0) Synthesis Sodium azide J, g eg was suspended in dimethylformamide lIowtt, 9-chloroacetylamino-/, 23. 'l-tetrahydroacridine 10I
and react at room temperature for 2 hours. When 32 ml of water was added and the precipitated crystals were filtered, 9-azidoacetylamino-/2. ．． 7. Q-tetrahydroacridine,
7g is obtained. Melting point/℃ decomposition.
これをメタノールｚ ｏ ｏ ｍｔに懸濁し、パラジウ
ムブラック１１を加え、室温で１時間、水素化分解反応
を行う。、触媒を戸去し、濃縮してメタノールーイソグ
ロパノールから結晶化して濾過すると、７．ｆ ｆｌの
表題の化合物を得た。融点−一！〜２３０℃。This is suspended in methanol z o mt, palladium black 11 is added, and a hydrogenolysis reaction is carried out at room temperature for 1 hour. 7. Remove the catalyst, concentrate, crystallize from methanol-isoglopanol and filter. The title compound of ffl was obtained. Melting point - one! ~230℃.
実施例Ｊ９の化合物を常法によりアシル化またはカルバ
モイル化することにより、下記の表−７に示す化合物を
合成した。The compounds shown in Table 7 below were synthesized by acylating or carbamoylating the compound of Example J9 by a conventional method.
表−７ ■ Ｃ＝。Table-7 ■ C=.
■
実施例ｑグ
； −（２−オキソピロリジン−／−イル）−Ｎ （
’＋ ２３＋グーテトラヒドロ−ベンゾ（ｂ）〔ｉ、
Ａ ）ナフチリジン−１０−イル）アセトアミド（表−
２の化合物／１６＆？）マレイン酸塩（／：／）の合成
実施例／４’の化合物の遊離塩基１０．２ｇをエタノ−
＃ ２００ ｍｌと酢酸ｉｏｏｍｔ；にとかし、３０％
塩化水素エタノール溶液６ｍｌと、３％パラジウムカー
ボン／、５ ｊｊを加え、常圧５０℃で乙時間水素化分
解を行う。触媒を戸去後、溶媒を戸去し、残った固体を
エタノールから再結晶すると、ｇ、７ ｊｉの粗結晶が
得られる。これを、飽和炭酸水素ナトリウム水溶液１０
０ｍ１とクロロホルム／！ｒ０７ｎｌに加えて攪拌する
。クロロホルム溶液を硫酸ナトリウムで乾燥後、クロロ
ホルムを留去しメタノールＡＯｍｌにとかし、マレイン
酸２． Ａ ９のメタノール溶液ＡＯＷＬｌを加え析出
する結晶を濾過すると、７．５ ｇの表題の化合物を得
た。融点／ｑコ〜／９ｇ℃分解。■ Example q; -(2-oxopyrrolidin-/-yl)-N (
'+ 23+ gutetrahydro-benzo (b) [i,
A) Naphthyridin-10-yl)acetamide (Table-
Compound 2/16&? ) Maleate salt (/:/) Synthesis Example/10.2 g of the free base of compound 4' was dissolved in ethanol.
# 200 ml and acetic acid ioomt; dissolved in 30%
Add 6 ml of hydrogen chloride ethanol solution and 3% palladium on carbon, and perform hydrogenolysis at normal pressure of 50° C. for two hours. After the catalyst is removed, the solvent is removed and the remaining solid is recrystallized from ethanol to obtain crude crystals of g, 7 ji. Add this to 10% of a saturated aqueous sodium hydrogen carbonate solution.
0ml and chloroform/! Add to r07nl and stir. After drying the chloroform solution with sodium sulfate, the chloroform was distilled off and dissolved in AO ml of methanol. A methanol solution of A9, AOWLl, was added and the precipitated crystals were filtered to obtain 7.5 g of the title compound. Melting point/qco~/9g℃ decomposition.
実施例１ＩＩＩの化合物の遊離塩基を、常法によってア
シル化またはカルバモイル化することにより、下記の表
−ｇに示す化合物を合成した。The free base of the compound of Example 1III was acylated or carbamoylated by a conventional method to synthesize the compounds shown in Table-g below.
表−ｇ
Ｈ２
Ｃ＝０
実施例ｙｇ
Ｎ （３ｒ ”−ジヒドロアクリジンーー（／Ｈ）オ
ンーデーイル）ブタナミド（表−コの化合物置７Ａ）の
合成
参考例／の化合物３．６ｇをアセトン３０ｍ１にとかし
、２Ｎ−塩酸７ ｒｕｌを加えて５０℃で３時間反応さ
せる。溶媒を減圧留去し、クロロホルム１００ｍ１と１
０％炭酸カリ水溶液３０ｒｎｌを加えて攪拌する。クロ
ロホルム層をとり、硫酸ナトリウムで乾燥し、濃縮して
クロロホルム−ジエチルエーテルから結晶化させると、
表題の化合物２．１ｌｆｊを得た。融点２７３〜．２７
７℃分解。Table-g H2C=0 Example yg Synthesis of N (3r ''-dihydroacridine-(/H)on-dale)butanamide (Compound 7A in Table-C) Reference Example 3.6g of the compound in / was dissolved in 30ml of acetone. , 7 rul of 2N-hydrochloric acid was added and reacted at 50°C for 3 hours. The solvent was distilled off under reduced pressure, and 100 ml of chloroform and 1 ml of chloroform were added.
Add 30 rnl of 0% potassium carbonate aqueous solution and stir. The chloroform layer was taken, dried over sodium sulfate, concentrated and crystallized from chloroform-diethyl ether.
The title compound 2.1lfj was obtained. Melting point: 273~. 27
Decomposed at 7℃.
実施例１Ｉ９
Ｎ −（／、２，３．ＩＩ−テトラヒドロアクリジンー
コオール−９−イル）ブタナミドの合成実施例３？の化
合物／ｇをメタノールλＯｍ１３にとかし、水素化ホウ
素ナトリウム０． ／ ４Ｚ 、！９を加え、室温で／
２時間反応させる。溶媒を減圧留去し、クロロホルム３
０ｍ１と水３０ｍ１を加え攪拌する。クロロホルム層を
とり、硫酸ナトリラムで乾燥後、濃縮してクロロホルム
−酢酸エチルから結晶化させると、表題の化合物０．７
７Ｉを得た。融点２４０−２４！ｒ℃分解。Example 1 I9 Synthesis of N-(/,2,3.II-tetrahydroacridine-chool-9-yl)butanamide Example 3? of compound/g was dissolved in methanol λOm13 and sodium borohydride 0. / 4Z,! 9 and at room temperature/
Let react for 2 hours. The solvent was distilled off under reduced pressure, and chloroform
Add 0ml and 30ml of water and stir. The chloroform layer was taken, dried over sodium sulfate, concentrated, and crystallized from chloroform-ethyl acetate to yield the title compound (0.7
I got 7I. Melting point 240-24! r℃ decomposition.
参考例コ
ｑ−アミノ−，５−、Ａ、 ７． ｇ−テトラヒドロ〔
コ、３−ｂ）チェノキノリンの合成
シクロヘキサノンｔｉｓｍｉに塩化亜鉛り、ｓｌＩｇト
コ−アミノ−３−シアノチオフェンｓ、 ｒ ｂ ｇを
加えて１００〜／１０℃でコ時間反応させる。Reference example coq-amino-,5-,A, 7. g-tetrahydro [
3-b) Synthesis of chenoquinoline Zinc chloride, slIg toco-amino-3-cyanothiophenes, and rbg are added to cyclohexanone tism, and the mixture is reacted at 100 to 10°C for several hours.
２０℃まで冷して酢酸エチルｓｏｍｅを加え、結晶を濾
過する。結晶をクロロホルム／ ００ ｍｌに懸濁し、
濃アンモニア水／７ｍｌを加えて攪拌する。クロロホル
ム溶液を硫酸ナトリウムで乾燥し、濃縮してクロロホル
ム−ｎ−へブタンから結晶化して、表題の化合物Ａ、
／ ／ ｇを得た。融点７５９〜１６１℃。Cool to 20°C, add some ethyl acetate, and filter the crystals. Suspend the crystals in chloroform/00 ml,
Add 7 ml of concentrated ammonia water and stir. The chloroform solution was dried over sodium sulfate, concentrated and crystallized from chloroform-n-hebutane to yield the title compound A,
/ / g was obtained. Melting point: 759-161°C.
参考例３
ＩＯ−アミノ−／ Ｈ−３，’Ｉ−ジヒドローピラノ〔
グ、３−ｂ）キノリンの合成
テトラヒドロ−１ＩＨ−ビラン−グーオン５、 ｏ ｑ
ｇ、塩化亜鉛ｆｆ、 ９２ ｇとλ−アミンベンゾニ
トリル友？ ｊ ９を混ぜ、ｑｏ℃で７時間反応させる
。室温まで冷やすと固体になるので、トルエン２ｏｍｌ
を加えて砕き、濾過する。この固体をクロロホルム／ざ
Ｏｍｌに懸濁し、濃アンモニア水、２２ＦＩＬｌを加え
て攪拌する。クロロホルム溶液をとり、硫酸ナトリウム
で乾燥後濃縮し、クロロホルム−〇−へブタンから結晶
化して、表題の化合初成ざｌＩｙを得た。融点／９デ〜
−０１℃。Reference example 3 IO-amino-/H-3,'I-dihydropyrano [
3-b) Synthesis of quinoline Tetrahydro-1IH-biran-guone 5, o q
g, zinc chloride ff, 92 g and λ-amine benzonitrile friend? Mix j 9 and react at qo℃ for 7 hours. It becomes solid when cooled to room temperature, so add 2 oml of toluene.
Add, crush, and filter. This solid was suspended in chloroform/oml, and concentrated aqueous ammonia and 22 FIL were added and stirred. The chloroform solution was taken, dried over sodium sulfate, concentrated, and crystallized from chloroform-〇-hebutane to obtain the title compound, IIy. Melting point/9 de~
-01℃.
参考例ダ
ｑ−アミノ−３Ｈ−り、ざ−ジヒドロ−ピラノ〔弘、、
？−ｂ〕チェノ［３，２−ｅ］ピリジンの合成
参考例３と同様の方法で表題の化合物を合成した。融点
ｌ？ｔ〜２０２℃。Reference example Daq-amino-3H-dihydro-pyrano [Hiroshi, .
? -b] Synthesis of Cheno[3,2-e]pyridine The title compound was synthesized in the same manner as in Reference Example 3. Melting point l? t~202°C.
参考例！
ＩＯ−アミノーコーベンジルー／、占３． ’Ｉ−テト
ラヒドローベンゾ（ｂ）（／、Ａ）ナフチリジンの合成
イサチン！；！ｒｊｊ、Ｎ−ベンジル−ｑ−ピペリトン
ク＆、 、ｌ ｉと酢酸アンモンｇ ｂ、 ｑ ｊｉを
ジメチルホルムアミド９００ ｍｌに加え、１２０℃で
３時間反応させる。溶媒を減圧留去した後、アセトンｓ
ｏｏｍｔ、水コｏｏｍｔを加えて、不溶物を戸数する。Reference example! IO-amino cobenziru/, 3. 'Synthesis of I-tetrahydrobenzo(b) (/, A) naphthyridine isatin! ;! rjj, N-benzyl-q-piperitonk &, , l i and ammonium acetate g b, qji were added to 900 ml of dimethylformamide and reacted at 120°C for 3 hours. After distilling off the solvent under reduced pressure, acetone s
Add water and water to count the insoluble matter.
これをエタノール’ｌ００ｍ１で懸濁洗浄し、濾過する
と、６り、ざＩのλ−ベンジルー１０−カルバモイル−
／、 ２．３．ダ→トラヒドロ−ベンゾ（ｂ）（／１４
）ナフチリジンを得る。融点２３ｑ〜２３７℃０
水酸化ナトリウム２０．２ ｇを水２ ！ｒ Ｏｍｌに
溶かし、−Ｓ℃で臭素コ２．２９を滴下し、上記化合物
のカルボキサミドｑｏｇを加え、激しく撹拌して、弘時
間かけて１０℃まで昇温する。−０℃まで冷却し、結晶
を濾過し、水洗する。メタノールから再結晶して表題の
化合物／３９を得た。融点７９３〜７９６℃。This was suspended and washed with 100 ml of ethanol and filtered.
/, 2.3. da → trahydro-benzo (b) (/14
) to obtain naphthyridine. Melting point: 23q~237°C 0 20.2 g of sodium hydroxide 2 parts water! 2.29 ml of bromine was added dropwise to the mixture at -S°C, qog of the carboxamide of the above compound was added, the mixture was vigorously stirred, and the temperature was raised to 10°C over a period of time. Cool to -0°C, filter the crystals and wash with water. Recrystallization from methanol gave the title compound/39. Melting point 793-796°C.
参考例６
ＩＯ−アミノーコーメチルー／、 ２ Ｊ、 ｔＩ−テ
トラヒドロ−ベンゾ（ｂ）（／、Ａ）ナフチリジンの合
成
参考例１と同様の方法で合成した。融点／６９〜／７／
℃。Reference Example 6 Synthesis of IO-amino-comethyl-/, 2 J, tI-tetrahydro-benzo(b) (/, A) naphthyridine Synthesis was performed in the same manner as in Reference Example 1. Melting point /69~/7/
℃.
参考例７
１０−アミノーコーメチルーｌ、３−プロパノ−／２．
２，３．弘−テトラヒドロ−ベンゾ［ｂ）（／、Ａ）ナ
フチリジンの合成
コーアミノベンゾニトリルＩＩ、 ３ Ａ ９ 、プソ
イドペレチェリン塩酸塩７ｙと塩化亜鉛！、ｊ ３ 、
ｌｉｔを混ぜ７５０℃で２．５時間反応させる。室温ま
で冷やすと固化する。これに酢酸エチル１０ｍ１とイソ
プロパツール１０ｍ１を加えて砕き、濾過する。この固
体をクロロホルム１００ｍ１に懸濁し、濃アンモニア水
２０ｍ１を加えて撹拌する。Reference example 7 10-amino-comethyl-1, 3-propano-/2.
2,3. Synthesis of Hiro-tetrahydro-benzo[b) (/, A) naphthyridine co-aminobenzonitrile II, 3 A 9 , pseudopellecherine hydrochloride 7y and zinc chloride! ,j3,
Lit was mixed and reacted at 750°C for 2.5 hours. It solidifies when cooled to room temperature. Add 10 ml of ethyl acetate and 10 ml of isopropanol to the mixture, crush it, and filter. This solid was suspended in 100 ml of chloroform, 20 ml of concentrated aqueous ammonia was added, and the mixture was stirred.
クロロホルム溶液をとり、濃縮してシリカゲルカラムク
ロマトグラフィー（クロロホルム−メタノール）で精製
し、酢酸エチルから再結晶して、表題の化合物／、 Ｊ
／ｌを得た。融点コ２０〜２’ｌＯ℃分解。The chloroform solution was taken, concentrated, purified by silica gel column chromatography (chloroform-methanol), and recrystallized from ethyl acetate to obtain the title compound/, J
/l was obtained. Melting point: 20-2'10°C decomposed.
参考例ざ
ダーアミノー！１ｇ−エタノ−ｔ、 ｇ、 ７． ｔ−
テトラヒドローチエノ（２，７−ｂ）（／を左〕ナフチ
リジンの合成
λ−アミノー３−シアノチオフェン５ｇ、３−キヌクリ
ジノン塩酸塩ｂｒｉｇと塩化亜鉛１、、 ｏ ａ ｇを
混ぜ、７１０℃で７時間反応させる。Reference example: Daamino! 1g-ethanol-t, g, 7. t-
Tetrahydrothieno(2,7-b) (/ on left) Synthesis of naphthyridine 5 g of λ-amino-3-cyanothiophene, 3-quinuclidinone hydrochloride brig and 1,0 a g of zinc chloride were mixed and heated at 710°C for 7 hours. Make it react.
室温まで冷やすと固化する。これにクロロホルム１００
ｍ１を加えて砕き、濃アンモニア水３０ｍ１とメタノー
ル１０ｍｇを加えて攪拌する。不溶物を戸去して、クロ
ロホルム層をとり、濃縮してシリカゲルカラムクロマト
グラフィーで精製し、酢酸エチルから再結晶して表題の
化合物０、３９ ｇを得た。融点２６５〜．２Ａｔ℃分
解。It solidifies when cooled to room temperature. Add 100 chloroform to this
ml and crush it, add 30 ml of concentrated ammonia water and 10 mg of methanol, and stir. Insoluble matter was removed, the chloroform layer was taken, concentrated, purified by silica gel column chromatography, and recrystallized from ethyl acetate to obtain 0.39 g of the title compound. Melting point: 265~. 2At℃ decomposition.
試験例／
ＡＦ Ａ ’ＩＡ処理ラッう脳のＮａ依存性高親和性コ
リン取り込み（ＨＡＣＵ）に対する作用（方 法）
八Ｆ６１ＩＡはＦ １ｓｃｈｅｒらの方法（Ｊ、 Ｐｈ
ａｒｍ。Test Example / Effect on Na-dependent high affinity choline uptake (HACU) in rat brain treated with AF A 'IA (Method)
arm.
Ｅｘｐｅｒ、 Ｔｈｅｒ、、 ｓｘｓ、 ／ｌａｏ
（ｉｑｔ２））に従ってＡＦｘＩＩから調製した。ＡＦ
ｂ １ＩＡ（／、ｊｍｍｏｌ／／、ｊμｌ／５ｉｄｅ
）をラット両側脳室に注入する。−週間後に断頭し海馬
のみを取り出す。Expert, Ther,, sxs, /lao
(iqt2)) from AFxII. AF
b 1IA(/, jmmol//, jμl/5ide
) is injected into both rat ventricles. After -weeks, the head is decapitated and only the hippocampus is removed.
０、 、？ ｊ Ｍシェフロースでホモジナイズし、／
θｏｏｇで１０分間遠心し、その上清をさらに２０．０
００ ｇで２０分間遠心し、粗シナプス分画を得る。粗
シナプス分画と薬物を３７℃で３０分間インキュベーシ
ョンし、［’Ｈ）コリン（ｌＩｉＭ）を加え、更に３７
℃で７０分間インキュベーションする。0, ,? j Homogenize with M chef's roast, /
Centrifuge at θoog for 10 minutes, and the supernatant is further centrifuged at 20.0
Centrifuge at 00 g for 20 minutes to obtain the crude synaptic fraction. The crude synaptic fraction and drug were incubated at 37°C for 30 min, and ['H)choline (lIiM) was added and further incubated at 37°C.
Incubate for 70 minutes at °C.
コントロールとしては、粗シナプス分画を３７℃で３０
分間インキュベーションし、〔３Ｈ〕コリン（／μＭ）
を加えさらに３７℃ｌＯ分間インキュベーションしたも
のを用いた。As a control, the crude synaptic fraction was incubated at 37°C for 30 min.
Incubate for [3H]choline (/μM)
was added and further incubated for 37° C. 10 minutes.
反応はＷｈａｔｍａｎ Ｇ Ｆ／ Ｂフィルター上に吸
引濾過することにより停止した。フィルター上の放射活
性を液体シンチレーションカウンターで測定し、これを
ＨＡＣＵ量とした。タンパク量はブラッドフォード（Ｂ
ｒａｄｆｏｒｄ ）の方法〔アナリティカルバイオケミ
ストリ−（Ａｎａｌ、 Ｂｉｏｃｈｅｍ、入クコ、 ２
ａｇ （／ｖ７Ａ））に従って定量した。試験結果を表
−９に示す。The reaction was stopped by suction filtration onto a Whatman GF/B filter. The radioactivity on the filter was measured using a liquid scintillation counter, and this was taken as the amount of HACU. The amount of protein is Bradford (B
radford) method [Analytical Biochemistry (Anal, Biochem, Entericus, 2
ag (/v7A)). The test results are shown in Table-9.
試験例コ
急性毒性試験
ラットに本発明の化合物を経口投与し、急性毒性値を測
定して結果を表−１０に示した。Test Example Acute Toxicity Test The compound of the present invention was orally administered to rats, and the acute toxicity values were measured and the results are shown in Table 10.
表−１０Table-10
Claims (3)
式 ▲数式、化学式、表等があります▼（II） ｛式中、Ｒ＾１は水素原子またはアルキル基を表わし、
Ｒ＾２は水素原子、▲数式、化学式、表等があります▼
、▲数式、化学式、表等があります▼、▲数式、化学式
、表等があります▼（Ｒ＾３は水素原子またはアルキ ル基を表わす）、または▲数式、化学式、表等がありま
す▼を表 わす。また、（II）式中、▲数式、化学式、表等があり
ます▼はＲ＾１とＲ＾２とが互いに連結して、▲数式、
化学式、表等があります▼、▲数式、化学式、表等があ
ります▼、▲数式、化学式、表等があります▼、▲数式
、化学式、表等があります▼、▲数式、化学式、表等が
あります▼、▲数式、化学式、表等があります▼、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼または▲数式、化学式、表等がありま
す▼を形成して もよい。ｎは１または２を表わす。｝を表わし、▲数式
、化学式、表等があります▼は▲数式、化学式、表等が
あります▼（Ｒ＾４は水素原子、ハロゲン原子、アルキ
ル基、アルコキシ基またはヒドロキシル基を表わす）ま
たは▲数式、化学式、表等があります▼（Ｒ＾５は水素
原子またはアルキル基を表わす）を表わし、▲数式、化
学式、表等があります▼は▲数式、化学式、表等があり
ます▼（Ｒ＾６は水素原子、アルキル基またはヒドロキ
シル基を表わす）、▲数式、化学式、表等があります▼
、▲数式、化学式、表等があります▼、▲数式、化学式
、表等があります▼｛Ｒ＾７は水素原子、アルキル基、
アルアルキル基または▲数式、化学式、表等があります
▼あるいは ▲数式、化学式、表等があります▼（Ｒ＾８は水素原子
またはアルキル基を表わす）を表わす。｝、▲数式、化
学式、表等があります▼、▲数式、化学式、表等があり
ます▼ （Ｒ＾９は水素原子またはアルキル基を表わす）、▲数
式、化学式、表等があります▼または▲数式、化学式、
表等があります▼を表わす。〕 で表わされる９−アシルアミノ−テトラヒドロアクリジ
ン誘導体、その光学対掌体または薬学上許容されうるそ
の酸付加塩。(1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is an alkyl group, an aralkyl group, or (II)
Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) {In the formula, R^1 represents a hydrogen atom or an alkyl group,
R^2 is a hydrogen atom, ▲There are mathematical formulas, chemical formulas, tables, etc.▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^3 represents a hydrogen atom or an alkyl group), or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. In addition, in formula (II), ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ means that R^1 and R^2 are connected to each other, ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
You may form ▼ or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼. n represents 1 or 2. } and ▲ has a mathematical formula, chemical formula, table, etc.▼ means ▲ has a mathematical formula, chemical formula, table, etc. ▼ (R^4 represents a hydrogen atom, halogen atom, alkyl group, alkoxy group, or hydroxyl group) or ▲ a mathematical formula , there are chemical formulas, tables, etc. ▼ (R^5 represents a hydrogen atom or an alkyl group), ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (R^6 is (represents a hydrogen atom, alkyl group, or hydroxyl group), ▲Mathematical formula, chemical formula, table, etc.▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {R^7 is a hydrogen atom, an alkyl group,
Represents an aralkyl group or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^8 represents a hydrogen atom or an alkyl group). }, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^9 represents a hydrogen atom or an alkyl group), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Mathematical formulas ,Chemical formula,
There are tables etc. Represents ▼. ] A 9-acylamino-tetrahydroacridine derivative represented by the following, its optical antipode or a pharmaceutically acceptable acid addition salt thereof.
能を増加させる９−アシルアミノ−テトラヒドロアクリ
ジン誘導体、その光学対掌体または薬学上許容されうる
その酸付加塩を有効成分とする記憶障害改善剤。(2) Memory impairment improvement using a 9-acylamino-tetrahydroacridine derivative, its optical antipode, or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, which increases the ability of high-affinity choline uptake into cholinergic nerves. agent.
アシルアミノ−テトラヒドロアクリジン誘導体、その光
学対掌体または薬学上許容されうるその酸付加塩を有効
成分とする記憶障害改善剤。(3) 9- represented by general formula (I) according to claim 1
A memory impairment improving agent containing an acylamino-tetrahydroacridine derivative, an optical antipode thereof, or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63283351A JPH01250353A (en) | 1987-12-03 | 1988-11-09 | 9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredient |
| AT8888403058T ATE104966T1 (en) | 1987-12-03 | 1988-12-02 | 9-(ACYLAMINO)TETRAHYDROACRIDIN DERIVATIVES AND Cognition ENHANCERS THEREOF AS THE ACTIVE INGREDIENTS. |
| DE3889302T DE3889302T2 (en) | 1987-12-03 | 1988-12-02 | 9- (Acylamino) tetrahydroacridine derivatives and perceptual agents thereof as an active ingredient. |
| EP88403058A EP0319429B1 (en) | 1987-12-03 | 1988-12-02 | 9-Acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| HU886151A HU202499B (en) | 1987-12-03 | 1988-12-02 | Process for producing 9-(acylamino)-tetrahydroacridine derivatives and pharmaceutical compositions containing them as active components |
| US07/279,051 US4985430A (en) | 1987-12-03 | 1988-12-02 | 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| KR1019880016146A KR0128975B1 (en) | 1987-12-03 | 1988-12-03 | 9-acylamino-tetrahydroacridine derivatives and memory euhancing agent containing said derivative as active ingredient |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30675387 | 1987-12-03 | ||
| JP62-306753 | 1987-12-03 | ||
| JP63283351A JPH01250353A (en) | 1987-12-03 | 1988-11-09 | 9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01250353A true JPH01250353A (en) | 1989-10-05 |
Family
ID=26555006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63283351A Pending JPH01250353A (en) | 1987-12-03 | 1988-11-09 | 9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredient |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPH01250353A (en) |
| KR (1) | KR0128975B1 (en) |
| HU (1) | HU202499B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03151366A (en) * | 1989-11-08 | 1991-06-27 | Mitsubishi Kasei Corp | 9-aminoacetylaminotetrahydroacridine derivative |
| JPH03218361A (en) * | 1989-11-08 | 1991-09-25 | Mitsubishi Kasei Corp | 9-acylaminotetrahydroacridine derivative |
| JP2013523607A (en) * | 2010-03-26 | 2013-06-17 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Benzonaphthyridineamine as an autotaxin inhibitor |
-
1988
- 1988-11-09 JP JP63283351A patent/JPH01250353A/en active Pending
- 1988-12-02 HU HU886151A patent/HU202499B/en not_active IP Right Cessation
- 1988-12-03 KR KR1019880016146A patent/KR0128975B1/en not_active IP Right Cessation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03151366A (en) * | 1989-11-08 | 1991-06-27 | Mitsubishi Kasei Corp | 9-aminoacetylaminotetrahydroacridine derivative |
| JPH03218361A (en) * | 1989-11-08 | 1991-09-25 | Mitsubishi Kasei Corp | 9-acylaminotetrahydroacridine derivative |
| JP2013523607A (en) * | 2010-03-26 | 2013-06-17 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Benzonaphthyridineamine as an autotaxin inhibitor |
| US9029387B2 (en) | 2010-03-26 | 2015-05-12 | Merck Patent Gmbh | Benzonaphthyridinamines as autotaxin inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| KR890009876A (en) | 1989-08-04 |
| KR0128975B1 (en) | 1998-04-09 |
| HUT50460A (en) | 1990-02-28 |
| HU202499B (en) | 1991-03-28 |
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