JPH03151366A - 9-aminoacetylaminotetrahydroacridine derivative - Google Patents
9-aminoacetylaminotetrahydroacridine derivativeInfo
- Publication number
- JPH03151366A JPH03151366A JP29091689A JP29091689A JPH03151366A JP H03151366 A JPH03151366 A JP H03151366A JP 29091689 A JP29091689 A JP 29091689A JP 29091689 A JP29091689 A JP 29091689A JP H03151366 A JPH03151366 A JP H03151366A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- compound
- alkyl
- formulas
- 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.)
- Granted
Links
- CGGDZVLLLYJLLW-UHFFFAOYSA-N 2-amino-n-(1,2,3,4-tetrahydroacridin-9-yl)acetamide Chemical class C1=CC=C2C(NC(=O)CN)=C(CCCC3)C3=NC2=C1 CGGDZVLLLYJLLW-UHFFFAOYSA-N 0.000 title description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 5
- 230000003287 optical effect Effects 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 abstract description 40
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 16
- -1 1,2,3,4-Tetrahydroacridin-9-yl Chemical group 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 9
- 206010039966 Senile dementia Diseases 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000004202 carbamide Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 238000000034 method Methods 0.000 description 9
- 210000005036 nerve Anatomy 0.000 description 8
- 230000001713 cholinergic effect Effects 0.000 description 7
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical class C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102000012440 Acetylcholinesterase Human genes 0.000 description 4
- 108010022752 Acetylcholinesterase Proteins 0.000 description 4
- 208000026139 Memory disease Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229940022698 acetylcholinesterase Drugs 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000011282 treatment Methods 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
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- SRBYGPZWIFFPFS-UHFFFAOYSA-N n-(1,2,3,4-tetrahydroacridin-9-yl)acetamide Chemical compound C1=CC=C2C(NC(=O)C)=C(CCCC3)C3=NC2=C1 SRBYGPZWIFFPFS-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QPAARLKPLQNQBS-UHFFFAOYSA-N 1,2,3,4-tetrahydroacridin-1-amine Chemical class C1=CC=C2C=C3C(N)CCCC3=NC2=C1 QPAARLKPLQNQBS-UHFFFAOYSA-N 0.000 description 1
- LZDYZEGISBDSDP-UHFFFAOYSA-N 2-(1-ethylaziridin-1-ium-1-yl)ethanol Chemical compound OCC[N+]1(CC)CC1 LZDYZEGISBDSDP-UHFFFAOYSA-N 0.000 description 1
- LNDLMNJYEDYDAP-UHFFFAOYSA-N 2-(diethylamino)-n-(1,2,3,4-tetrahydroacridin-9-yl)acetamide Chemical compound C1=CC=C2C(NC(=O)CN(CC)CC)=C(CCCC3)C3=NC2=C1 LNDLMNJYEDYDAP-UHFFFAOYSA-N 0.000 description 1
- ZSFTYMODTKIOCK-UHFFFAOYSA-N 2-chloro-n-(1,2,3,4-tetrahydroacridin-9-yl)acetamide Chemical compound C1=CC=C2C(NC(=O)CCl)=C(CCCC3)C3=NC2=C1 ZSFTYMODTKIOCK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000674 effect on sodium Effects 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 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
- 239000007902 hard capsule Substances 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 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
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 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
- 229960001697 physostigmine Drugs 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
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000005556 structure-activity relationship Methods 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
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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9−アミノアセチルアミノテトラヒドロア
クリジン誘導体、その先学対掌体または薬学上許容され
うるその酸付加塩に関する。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 novel and useful 9-aminoacetylaminotetrahydroacridine derivatives, their antipodes, or pharmaceutically acceptable acid addition salts thereof.
(従来の技術およ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 disea
se)のような、コリン作動性神経機能の低下によって
特徴づけられる種々の記憶障害の治療法として、アセチ
ル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ある。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ー(Neur
ology)、旦、 397 (1978)に報告され
ている。さらに特開昭61−148154号、特開昭6
3−141980号、特開昭63−225358号、特
開昭63−238063号、特開昭63−239271
号、特開昭63−284175号、特開昭63−297
367号、特開昭64−73号、特開平1−13256
6号、EP−A−268871号、国際公開88702
256号の各公報には、特定の9−アミノテトラヒドロ
アクリジン誘導体がアセチル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。また、サマーズ(Summers)はザニ
ューイングランドジャーナルオブメディシン(The
New EnglandJournal of Med
icine)、 315.1241 (1986)で9
−アミノ−1,2,3,4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。(Problems to be solved by conventional techniques and inventions) Alzheimer's disease
Attempts have been made to increase the content of acetylcholine in the brain using acetylcholinesterase inhibitors as a treatment for various memory disorders characterized by decreased cholinergic nerve function, such as se). For example, studies using physostigmine have been conducted in neurology (Neurology).
397 (1978). Furthermore, JP-A-61-148154, JP-A-6
3-141980, JP 63-225358, JP 63-238063, JP 63-239271
No., JP-A-63-284175, JP-A-63-297
No. 367, JP-A-64-73, JP-A-1-13256
No. 6, EP-A-268871, International Publication No. 88702
It is reported in each publication of No. 256 that a specific 9-aminotetrahydroacridine derivative has an acetylcholinesterase inhibitory effect and is effective in treating Alzheimer's disease. Summers also published The New England Journal of Medicine (The New England Journal of Medicine).
New England Journal of Med
icine), 315.1241 (1986) 9
-Amino-1,2,3,4 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 become a problem.
It is hoped that new treatments will emerge.
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、ジャーナルオブケミカルソサエテイ(J
ournal of Chemical 5ociet
y)、 634(1947)に9−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
ィ(Chem。On the other hand, as an example of known 9-acylaminotetrahydroacridine, the Journal of Chemical Society (J
Our own of Chemical 5ociet
y), 634 (1947) describes 9-acetylaminotetrahydroacridine, and Chem.
1isty)、 51.1907 (1957)に9−
クロロアセチルアミノテトラヒドロアクリジン及び9−
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)。1isty), 51.1907 (1957) 9-
Chloroacetylaminotetrahydroacridine and 9-
Diethylaminoacetylaminotetrahydroacridine is described, and it is noted that the latter has a local anesthetic effect. In addition, the Journal of Medicinal Chemistry
Chemistry).
坦、 1056 (1975)には、9−アミノテトラ
ヒドロアクリジン誘導体のアセチルコリンエステラーゼ
阻害活性の構造活性相関が記載されており、9−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、9−アミノテトラヒド
ロアクリジンに比べ、活性が1 / 1000になるこ
とが記されている。また前記の特許(特開昭63−16
6881号、特開昭63−203664号、特開昭63
−238063号、特開昭63 + 239271号、
特開昭63−284175号、特開昭64−73号及び
特開平1−132566号の各公報)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9−
アミノアセチ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。Tan, 1056 (1975) describes the structure-activity relationship of acetylcholinesterase inhibitory activity of 9-aminotetrahydroacridine derivatives, and 9-acetylaminotetrahydroacridine and 9-benzoylaminotetrahydroacridine are 9-aminotetrahydroacridine derivatives. It is noted that the activity is 1/1000 compared to that of Also, the above-mentioned patent (Japanese Unexamined Patent Publication No. 63-16
No. 6881, JP-A-63-203664, JP-A-63
-238063, JP-A-63 +239271,
JP-A No. 63-284175, JP-A No. 64-73, and JP-A No. 1-132566) include 9-acylaminotetrahydroacridine derivatives in their claims. However, 9-
Specific synthesis examples and pharmacological activities of compounds having an aminoacetylamino group are not described.
(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9−アミノアセチルアミノテトラヒドロアク
リジン誘導体、その先学対掌体または薬学的に許容され
得るその酸付加塩が、従来のアセチルコリンエステラー
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 discovered that a specific 9-aminoacetylaminotetrahydroacridine Derivatives, their antipodes, or pharmaceutically acceptable acid addition salts thereof can serve as drugs that improve memory disorders such as Alzheimer's disease through a mechanism different from that of conventional compounds that inhibit acetylcholinesterase. This discovery led to the completion of the present invention.
即ち、本発明の要旨は、下記一般式(I)(R3はアル
キル基を表わし、R4は水素原子またはアルキル基を表
わす。)を表わすか、またはR1とR2、R1
が、互いに連結して、(I)式における −NkR2が
原子またはハロゲン原子を表わす。)またはアミノテト
ラヒドロアクリジン誘導体、その先学対掌体または薬学
上許容されうるその酸付加塩に存する。That is, the gist of the present invention is represented by the following general formula (I) (R3 represents an alkyl group, R4 represents a hydrogen atom or an alkyl group), or R1, R2, and R1 are connected to each other, -NkR2 in formula (I) represents an atom or a halogen atom. ) or aminotetrahydroacridine derivatives, their antipodes, or pharmaceutically acceptable acid addition salts thereof.
以下本発明を説明するに、本発明の9−アミノアセチル
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。(I)式において、R3−R6、R
7及びR8で表わされるアルキル基としては、01〜C
6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、イソブチ
ル基、5ee−ブチル基、tert−ブチル基等のC1
−04のアルキル基が挙げられる。R6で表ワされるハ
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る。To explain the present invention below, the 9-aminoacetylaminotetrahydroacridine derivative of the present invention has the general formula (
I). In formula (I), R3-R6, R
As the alkyl group represented by 7 and R8, 01 to C
6 alkyl group, preferably methyl group, ethyl group, n-
C1 of propyl group, isopropyl group, n-butyl group, isobutyl group, 5ee-butyl group, tert-butyl group, etc.
-04 alkyl group is mentioned. Examples of the halogen atom represented by R6 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
前記(I)式で表わされる本発明化合物の中で、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 of the present invention represented by the above formula (I), examples of preferred substituents include the following.
(1) R1が水素原子を表わし、R2が−CH−C
0OR’3
で表わされ、R3がメチル基またはイソプロピル基であ
って、R4が水素原子、メチル基またはエチル基である
置換基。または、R1とR2が互いに連結しし、
R6が、
水素原子、
メチル基またはイソプロピ
ル基である置換基。(1) R1 represents a hydrogen atom, and R2 represents -CH-C
A substituent represented by 0OR'3, in which R3 is a methyl group or an isopropyl group, and R4 is a hydrogen atom, a methyl group, or an ethyl group. Or a substituent in which R1 and R2 are connected to each other, and R6 is a hydrogen atom, a methyl group, or an isopropyl group.
かかる好ましい置換基を有する本発明化合物の具体例を
下記表−1に示す。Specific examples of the compounds of the present invention having such preferred substituents are shown in Table 1 below.
表−1
本発明化合物の内、特に好ましいものとしては、上記衣
−1の化合物N001.3.5.10.11.12.2
1.22.24.26.27.28.31及び32が挙
げられる。Table 1 Among the compounds of the present invention, particularly preferred compounds are the above-mentioned compound No. 1.3.5.10.11.12.2
1.22.24.26.27.28.31 and 32.
(I)式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、燐酸塩等の無機酸塩、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、カンファースルホン酸塩等の有機酸塩が
挙げられる。(I)式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 organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, and camphorsulfonate. 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について説明する。Next, a 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) R1とR2が互いに連結して、前記(I)式
におけす場合を除き、特願昭63−283351号、特
願昭63−305799号及び特願平1−137645
号に記載されている方法と同様な方法により製造するこ
とができる。(1) Except for the case where R1 and R2 are connected to each other in the formula (I) above, Japanese Patent Application No. 63-283351, Japanese Patent Application No. 63-305799, and Japanese Patent Application No. 137645
It can be produced by a method similar to that described in No.
(2) R1、R2が互いに連結して、前記(I)式
にお、けで表わされる化合物を、溶媒の存在下または無
溶媒で、1から10当量の尿素とともに加熱することに
より、下記(III )式で表わされる、(I)式中の
化合物を製造できる。(2) The following ( III) A compound of formula (I) can be produced.
なお、原料の(II)式の化合物は、特願昭63−28
3351号、特願昭63−305799号及び特願平1
−137645号に記載されている方法と同様な方法で
製造できる。The compound of formula (II) as a raw material is
No. 3351, Japanese Patent Application No. 1983-305799 and Japanese Patent Application No. 1998
It can be produced by a method similar to that described in No.-137645.
反応溶媒としては、ジメチルスルホキシド、ジメチルホ
ルムアミド、ジメチルアセトアミド、N−メチルピロリ
ドンのような不活性極性溶媒が好ましい。反応温度は1
20〜190°C1好ましくは140〜170°Cの範
囲で行われる。As the reaction solvent, inert polar solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone are preferred. The reaction temperature is 1
It is carried out at a temperature of 20 to 190°C, preferably 140 to 170°C.
上記(1)、(2)の方法の基礎原料である下記(IV
)式%式%
)
(b) コレクションオブチェコスロバック ケミカ
ルコミュニケーションズ(Collect、 Czec
h、 Chem。The following (IV
) formula % formula % ) (b) Collection of Czec Chemical Communications (Collect, Czec
h, Chem.
Commun、)、盤、2802 (1977)(e)
アクタ ケミ力 スカンジナビ力(ActaChe
mica 5candinavica)、 B、 33
.313 (1979)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。Commun, ), board, 2802 (1977) (e)
Acta Chemipower Scandinavian Power (ActaChe
mica 5candinavica), B, 33
.. 313 (1979), or a method analogous thereto.
また、特開昭61−148154号、特開昭63−14
1980号、特開昭63 + 166881号、特開昭
63−203664号、特開昭63−225358号、
特開昭63−238063号、特開昭63−23927
1号、特開昭63−297367号、特開昭64−73
号、特開平1−132566号及びEP−A−2688
71号の各公報に記載されている方法に準じて合成する
ことも出来る。Also, JP-A-61-148154, JP-A-63-14
1980, JP-A-63-166881, JP-A-63-203664, JP-A-63-225358,
JP 63-238063, JP 63-23927
No. 1, JP-A-63-297367, JP-A-64-73
No., JP-A-1-132566 and EP-A-2688
It can also be synthesized according to the methods described in each publication of No. 71.
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。When the compounds of the present invention are used as therapeutic agents, they are administered alone or in combination with a pharmaceutically acceptable carrier.
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。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、懸濁剤または液剤等の剤形にして、経口投
与しても良いし、注射剤として静脈内投与、筋肉的投与
、皮下投与してもよい。Its composition depends on the compound's solubility, chemical properties, route of administration,
Determined by administration schedule, etc. For example, it may be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids, or intravenously as an injection. It may be administered internally, intramuscularly, or subcutaneously.
また、注射用の粉末にして用事調整して使用しても良い
。経口、経腸、非経口若しくは局所投与に適した医薬用
の有機または無機の、固体また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、デンプン、タルク、セルロース、デキスト
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
中に含ませても良い。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、たとえ
ば水、プロピレングリコール、ポリエチレングリコール
、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。製剤の調整方法は常法によればよい。It may also be used as a powder for injection. 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. Excipients used in producing solid preparations include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. Liquid preparations for oral administration, ie, emulsions, syrups, suspensions, solutions, etc., contain commonly used inert diluents such as water or vegetable oils. 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, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like. The formulation may be prepared by conventional methods.
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、1日量1〜10
00 mgであり、好ましくは1〜100mgであるが
、年令、病状、症状、同時投与の有無により適宜増減す
ることが更に好ましい。前記1日量の本発明化合物は、
1日に1回、または適当間隔において1日に2若しくは
3回に分けて投与しても良いし、間欠投与しても良い。Clinical dosages for a compound of the invention for adults when used by oral administration are generally 1 to 10 daily doses.
00 mg, preferably 1 to 100 mg, but it is more preferably increased or decreased as appropriate depending on age, medical condition, symptoms, and presence or absence of simultaneous administration. The daily dose of the compound of the present invention is:
It may be administered once a day, divided into two or three times a day at appropriate intervals, or administered 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、1日量0.1〜100mgでり、好ま
しくは0.1.〜50mgである。When used as an injection, the daily dose of the compound of the present invention for adults is 0.1 to 100 mg, preferably 0.1. ~50mg.
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、アセチルコリンエステラーゼ阻害作用
が公知の9−アミノテトラヒドロアクリジンの1710
0以下と弱いものの、コ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、AF64A (エチルコリンアジリジニ
ウムイオン: ethylcholineazirid
inium 1on) [ジャーナルオブファーマコロ
ジーアンドイクスペリメンタルセラボイテイクス(J、
Pharmacol、 Exp、 Ther、 )
、 222 、140 (1982):0ユーロフアー
マコロジー(Neuropharmacol、 ) 。The compound of the present invention represented by the general formula (I) obtained in this manner is a compound of 9-aminotetrahydroacridine which is known to have an acetylcholinesterase inhibitory effect.
Although it is weak (less than 0), it can activate the presynabtic side of cholinergic nerves and increase nerve transmission. Specifically, AF64A (ethylcholineaziridinium ion: ethylcholineazirid
inium 1on) [Journal of Pharmacology and Experimental Therapeutics (J,
Pharmacol, Exp, Ther, )
, 222, 140 (1982): 0 Neuropharmacol.
26 、361 (1982月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り込み
能を改善する(試験例1)。この作用は、9−アミノテ
トラヒドロアクリジンでは見られない。26, 361 (1982) improves the high-affinity choline uptake ability of the hippocampal sinusoids of rats administered intracerebroventricularly (Test Example 1). This effect is not observed with 9-aminotetrahydroacridine.
また、本発明の化合物は、9−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、副作用が少ないので、
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 9-aminotetrahydroacridine and has fewer side effects.
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)であられされる化合物は、薬理学
的に活性な価値の有る化合物である。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 damaged cholinergic nerves, 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、特にアルツハイマー病では、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 Alzheimer's 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AF64Aは、フイブリ−y −(Fisher)
[(J。On the other hand, AF64A is Fibre-y-(Fisher)
[(J.
Pharmacol、 Exp、 Ther、 ) 、
222 、140 (1982)]および]レベンダ
ー Leventer ) [(Neuropharm
acol、 ) 。Pharmacol, Exp, Ther, ),
222, 140 (1982)] and] Leventer) [(Neuropharm
acol, ).
26 、361 (1987)]が報告したように、コ
リン作動性神経を選択的にかつ長期的に障害させ、AF
64A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(Brain Res、 ) 、 3
21 、91 (1984)]、アルツハイマー病の良
いモデルである。従ってAF64A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、アルツハイマー病を含む老
年性痴呆の治療に有用と考えられる。26, 361 (1987)], selectively and long-term damage to cholinergic nerves and AF
Memory and learning deficits were observed in rats administered with 64A [
Brain Research (Brain Res), 3
21, 91 (1984)] and is a good model for Alzheimer's disease. Therefore, the compound of the present invention, which can directly activate the function of cholinergic nerves in the brain that has been decreased by administration of AF64A, is considered to be useful in the treatment of senile dementia including Alzheimer's 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、その要旨を越えない限り、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 the gist thereof is exceeded.
実施例I
N−[(1,2,3,4−テトラヒドロアクリジン−9
−イル)アミノカルボニルメチル]−L−アラニンエチ
ルエステル(表−1の化合物No、 3 )の合成9−
クロルアセチルアミノ−1,2,3,4−テトラヒドロ
アクリジン5gにL−アラニンエチルエステル22gを
加え、100°Cで30分間反応させる。室温まで冷却
後、クロロホルム100m1と水100 mlを加えて
撹拌する。クロロホルム層を無水硫酸ナトリウムで乾燥
後、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、クロロホルム−n−ヘキサ
ンから再結晶して、目的化合物5.9gを得た。Example I N-[(1,2,3,4-tetrahydroacridine-9
-yl)aminocarbonylmethyl]-L-alanine ethyl ester (Compound No. 3 in Table 1) Synthesis 9-
Add 22 g of L-alanine ethyl ester to 5 g of chloroacetylamino-1,2,3,4-tetrahydroacridine and react at 100°C for 30 minutes. After cooling to room temperature, 100 ml of chloroform and 100 ml of water are added and stirred. The chloroform layer was dried over anhydrous sodium sulfate, purified by silica gel column chromatography (chloroform-methanol), and recrystallized from chloroform-n-hexane to obtain 5.9 g of the target compound.
融点101〜102°C0
実施例2
N−[(1,2,3,4−テトラヒドロアクリジン−9
−イル)アミノカルボニルメチル]−L−アラニン(表
−1の化合物No、 1 )の合成
実施例1で得た化合物2gを、室温でIN−水酸化ナト
リウム水溶液12m1に加え、2時間反応させる。これ
に、15°C以下でIN塩酸15m1を加えると白色結
晶が析出する。これを炉取し、水10m1で洗った後乾
燥して、目的化合物1.42 gを得た。Melting point 101-102°C0 Example 2 N-[(1,2,3,4-tetrahydroacridine-9
-yl)aminocarbonylmethyl]-L-alanine (Compound No. 1 in Table 1) 2 g of the compound obtained in Example 1 was added to 12 ml of IN-sodium hydroxide aqueous solution at room temperature and reacted for 2 hours. When 15 ml of IN hydrochloric acid is added to this at 15° C. or lower, white crystals are precipitated. This was taken in a furnace, washed with 10 ml of water, and then dried to obtain 1.42 g of the target compound.
融点238〜242°C0分解。Melting point 238-242°C0 decomposition.
実施例3〜5
以下の表−2に示す化合物を実施例1または2と同様に
して合成した。Examples 3 to 5 The compounds shown in Table 2 below were synthesized in the same manner as in Example 1 or 2.
実施例6
2−((S)−5−メチル−2,4−イミダゾリジンオ
ン−1−イル)−N−(1,2,3,4−テトラヒドロ
アクリジン−9−イル)アセトアミド(表−1の化合物
No、 22 )の合成
実施例1で得た化合物3.9gをN−メチルピロリドン
9mlに溶解し、尿素2.64 gを加え、160°C
で1時間反応させる。80°Cまで冷やして、水100
m1を加え、析出する結晶を戸数する。これをメタノー
ル5ml及びクロロホルム150m1に溶かし、無水硫
酸ナトリウムで乾燥し、濃縮乾固する。エタノール−酢
酸エチルから再結晶して、目的化合物2.44gを得た
。Example 6 2-((S)-5-methyl-2,4-imidazolidinion-1-yl)-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide (Table 1 Synthesis of Compound No. 22) 3.9 g of the compound obtained in Example 1 was dissolved in 9 ml of N-methylpyrrolidone, 2.64 g of urea was added, and the mixture was heated at 160°C.
Let it react for 1 hour. Cool to 80°C and add 100% water
Add m1 and count the number of crystals to precipitate. This was dissolved in 5 ml of methanol and 150 ml of chloroform, dried over anhydrous sodium sulfate, and concentrated to dryness. Recrystallization from ethanol-ethyl acetate yielded 2.44 g of the target compound.
融点260〜263°C0
実施例7〜13
以下の表−3に示す化合物を、実施例6と同様にして合
成した。Melting point: 260-263°C0 Examples 7-13 The compounds shown in Table 3 below were synthesized in the same manner as in Example 6.
表−3
試験例I
AF64A処理ラット脳のNa+依存性高親和性コリン
取り込み(HACU)に対する作用
(方法)
AF64AはFischerからの方法(J、 Pha
rm、 Exper。Table 3 Test Example I Effect on Na+-dependent high affinity choline uptake (HACU) in AF64A-treated rat brain (method) AF64A was tested using the method from Fischer (J, Pha
rm, Expert.
Ther、 、 222 、140 (1982) )
に従ってAF64から調整した。AF64A (1,5
nmol/1.5 pl/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。0
.32 Mシュークロースでホモジェナイスし、100
0 gで10分間遠心し、その上清をさらに20000
gで20分間遠心し、粗シナプス分画を得る。粗シナ
プス分画と本発明の化合物を37°Cで30分間インキ
ュベーションし、[3H]コリン(1μM)を加え、さ
らに37°Cで10分間インキュベーションする。コン
トロールとしては、粗シナプス分画を37°010分間
インキュベーションしたものを用いた。反応はWhat
man GF / 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HACUfNと
した。タンパク量は、ブラッドフォード(Bradf’
ord )の方法[アナリティ力ルバイオケミストリー
(Anal、 Biochem、 ) 、 72 。Ther, 222, 140 (1982))
Adjusted from AF64 according to the following. AF64A (1,5
nmol/1.5 pl/5ide) is injected into bilateral rat ventricles. After -weeks, the head is decapitated and only the hippocampus is removed. 0
.. 32 Homogenized with M sucrose, 100
Centrifuge at 0 g for 10 minutes, and the supernatant is further centrifuged at 20,000 g.
Centrifuge at g for 20 minutes to obtain the crude synaptic fraction. The crude synaptic fraction and the compound of the invention are incubated at 37°C for 30 minutes, [3H]choline (1 μM) is added and further incubated at 37°C for 10 minutes. As a control, a crude synapse fraction incubated for 37°010 minutes was used. What is the reaction?
Stopped by suction filtration onto a man GF/B filter. The radioactivity on the filter was measured using a liquid scintillation counter, and this was designated as HACUfN. The protein amount is determined by Bradford's protein content.
Ord)'s method [Anal Biochem, 72.
248 (1976月に従って定量した。試験結果を表
−4に示す。248 (quantified in accordance with June 1976). The test results are shown in Table 4.
手続補正書(自発)
事件の表示
平成1年特許願第29091、
発明の名称
9−アミノアセチルアミノテトラヒドロアクリジン誘導
体
補正をする者Procedural amendment (voluntary) Case indication 1999 Patent Application No. 29091 Title of invention 9-aminoacetylaminotetrahydroacridine derivative Person making amendment
Claims (1)
化学式、表等があります▼(R^3はアルキル基を表わ
し、R^4は水素原子またはアルキル基を表わす。)を
表わすか、または、R^1とR^2が、互いに連結して
、( I )式における▲数式、化学式、表等があります
▼が▲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。)を表わす。▲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、水素原子またはハロゲン原子を
表わす。)または▲数式、化学式、表等があります▼(
R^7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^8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−アミノアセチ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) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a hydrogen atom, R^2 is a ▲mathematical formula,
There are chemical formulas, tables, etc. ▼ (R^3 represents an alkyl group, R^4 represents a hydrogen atom or an alkyl group), or R^1 and R^2 are connected to each other, In formula (I), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^5 represents a hydrogen atom or an alkyl group.) ▲There are mathematical formulas, chemical formulas, and tables.
R^7 represents a hydrogen atom or an alkyl group. ), ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ has ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (R^8 represents a hydrogen atom or an alkyl group), ▲ has mathematical formulas, chemical formulas, tables, etc. Represents ▼ or ▲, which includes mathematical formulas, chemical formulas, tables, etc. ), its optical antipode or a pharmaceutically acceptable acid addition salt thereof.
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1290916A JP2720549B2 (en) | 1989-11-08 | 1989-11-08 | 9-aminoacetylaminotetrahydroacridine derivative |
CA002029497A CA2029497C (en) | 1989-11-08 | 1990-11-07 | 4-acylaminopyridine derivative |
KR1019900018017A KR100192833B1 (en) | 1989-11-08 | 1990-11-08 | 4-acylaminotyridine derivatives |
ES90403182T ES2088998T3 (en) | 1989-11-08 | 1990-11-08 | 4-ACILAMINOPYRIDINE DERIVATIVES. |
EP90403182A EP0427636B1 (en) | 1989-11-08 | 1990-11-08 | 4-Acylaminopyridine derivatives |
AT90403182T ATE138653T1 (en) | 1989-11-08 | 1990-11-08 | 4-ACYLAMINOPYRIDINE DERIVATIVES |
DK90403182.0T DK0427636T3 (en) | 1989-11-08 | 1990-11-08 | 4-acylaminopyridin-derivatives |
DE69027180T DE69027180T2 (en) | 1989-11-08 | 1990-11-08 | 4-acylaminopyridine derivatives |
US08/115,257 US5397785A (en) | 1989-11-08 | 1993-09-02 | 4-acylaminopyridine derivative |
US08/355,181 US5536728A (en) | 1989-11-08 | 1994-12-08 | 4-acylaminopyridine derivative |
US08/629,901 US5861411A (en) | 1989-11-08 | 1996-04-10 | 4-Acylaminopyridine derivative |
GR960402226T GR3020868T3 (en) | 1989-11-08 | 1996-08-22 | 4-Acylaminopyridine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1290916A JP2720549B2 (en) | 1989-11-08 | 1989-11-08 | 9-aminoacetylaminotetrahydroacridine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH03151366A true JPH03151366A (en) | 1991-06-27 |
JP2720549B2 JP2720549B2 (en) | 1998-03-04 |
Family
ID=17762170
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1290916A Expired - Lifetime JP2720549B2 (en) | 1989-11-08 | 1989-11-08 | 9-aminoacetylaminotetrahydroacridine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2720549B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009215280A (en) * | 2008-02-14 | 2009-09-24 | Japan Health Science Foundation | New hcv entry inhibitor |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01132566A (en) * | 1987-10-05 | 1989-05-25 | Pfizer Inc | 4-aminopyridine derivative |
JPH01250353A (en) * | 1987-12-03 | 1989-10-05 | Mitsubishi Kasei Corp | 9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredient |
-
1989
- 1989-11-08 JP JP1290916A patent/JP2720549B2/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01132566A (en) * | 1987-10-05 | 1989-05-25 | Pfizer Inc | 4-aminopyridine derivative |
JPH01250353A (en) * | 1987-12-03 | 1989-10-05 | Mitsubishi Kasei Corp | 9-acylamino-tetrahydroacrydine derivative and dysmnesia improver containing the compound as an active ingredient |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009215280A (en) * | 2008-02-14 | 2009-09-24 | Japan Health Science Foundation | New hcv entry inhibitor |
Also Published As
Publication number | Publication date |
---|---|
JP2720549B2 (en) | 1998-03-04 |
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