FI90416C - Menetelmä terapeuttisesti aktiivisen 9-anilino-1,4-metano-1,2,3,4-tetrahydroakridiinin valmistamiseksi - Google Patents
Menetelmä terapeuttisesti aktiivisen 9-anilino-1,4-metano-1,2,3,4-tetrahydroakridiinin valmistamiseksi Download PDFInfo
- Publication number
- FI90416C FI90416C FI880634A FI880634A FI90416C FI 90416 C FI90416 C FI 90416C FI 880634 A FI880634 A FI 880634A FI 880634 A FI880634 A FI 880634A FI 90416 C FI90416 C FI 90416C
- Authority
- FI
- Finland
- Prior art keywords
- formula
- tetrahydroacridine
- anilino
- methano
- loweralkyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 10
- SOBWNQMTUWBVNJ-UHFFFAOYSA-N N-phenyl-3-azatetracyclo[10.2.1.02,11.04,9]pentadeca-2,4,6,8,10-pentaen-10-amine Chemical compound C1CC(C=23)CC1C3=NC1=CC=CC=C1C=2NC1=CC=CC=C1 SOBWNQMTUWBVNJ-UHFFFAOYSA-N 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 6
- 239000000203 mixture Substances 0.000 claims description 9
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 7
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 claims description 6
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 claims description 4
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 claims description 4
- 229940102398 methyl anthranilate Drugs 0.000 claims description 3
- KPMKEVXVVHNIEY-UHFFFAOYSA-N norcamphor Chemical compound C1CC2C(=O)CC1C2 KPMKEVXVVHNIEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- -1 loweralkyl Chemical group 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract 5
- 150000002431 hydrogen Chemical group 0.000 abstract 4
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 125000005129 aryl carbonyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 5
- 102000012440 Acetylcholinesterase Human genes 0.000 description 4
- 108010022752 Acetylcholinesterase Proteins 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 229960001685 tacrine Drugs 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940022698 acetylcholinesterase Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229960001697 physostigmine Drugs 0.000 description 3
- 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 3
- RXBYRTSOWREATF-UHFFFAOYSA-N 1,2,3,4-tetrahydroacridine Chemical compound C1=CC=C2C=C(CCCC3)C3=NC2=C1 RXBYRTSOWREATF-UHFFFAOYSA-N 0.000 description 2
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 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
- 230000037396 body weight Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 206010027175 memory impairment Diseases 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 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
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 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
- 208000026139 Memory disease Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- ZEUUMNAWFTVOOL-UHFFFAOYSA-N [P].N(C1=CC=CC=C1)C=1C2=CC=CC=C2N=C2C3CCC(C12)C3 Chemical compound [P].N(C1=CC=CC=C1)C=1C2=CC=CC=C2N=C2C3CCC(C12)C3 ZEUUMNAWFTVOOL-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 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
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000011976 maleic acid Substances 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000012453 solvate 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
- 239000000126 substance Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
- 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
- C07D221/22—Bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
1 90416
MenetelmS terapeuttlsesti aktiivisen 9-anilino-l,4-metano- 1,2,3,4-tetrahydroakridiinin valmistamiseksi
Tama keksintd koskee menetelmaa kaava (I)
: · Q
Nil I
mukaisen yhdisteen valmistamiseksi.
Koko tassa selityksessa ja oheisissa patenttivaati-muksissa annettu kemiallinen kaava tai nimi kasittaa kaik-15 ki sen stereoisomeerit, optiset ja geometriset isomeerit, silloin, kun tailaisia isomeereja esiintyy, samoin kuin sen farmaseuttisesti hyvSksyttavåt happoadditiosuolat ja sen solvaatit kuten esimerkiksi hydraatit.
Kaavan I mukainen 9-anilino-l,4-metano-l,2,3,4-20 tetrahydroakridiini valmistetaan keksinnon mukaisesti siten, etta lammitetaan seosta, jossa on fosforipentoksidia, N,N-dimetyylisykloheksyyliamiinia ja aniliinihydroklori-dia, ja lisStSSn sitten metyyliantranilaattia, jolla on kaava (IV) 25 a-COOCH3
IV
nh2 30 ja sen jålkeen 2-norbornanonia, jolla on kaava
ID
35 2 90416
Tama menetelma voidaan toteuttaa lampOtilassa noin 150-250eC.
Kaavan I mukaista yhdistetta voidaan kayttaa hoi-dettaessa erilaisia muistihairiOita, joille on tunnus-5 omaista alentunut kolinerginen toiminta, kuten Alzheimerin tautia.
Yhdisteiden kayttOkelpoisuus tahan tarkoitukseen voidaan todeta maarittamaiia niiden kyky estaa asetyyliko-liiniesteraasientsyymin vaikutusta ja siten asetyylikolii-10 nitason nousua aivoissa.
Tamå kayttOkelpoisuus voidaan todeta myOs maarittamaiia yhdisteiden kyky palauttaa kolinergisesti heiken-tynyt muisti "pimean vaittamiskokeessa". TOssa maaritysme-netelmåssa testataan hiirien kykya muistaa epamiellyttava 15 arsyke 24 tunnin ajan. Hiiri laitetaan kammioon, jossa on pimea osasto, jolloin voimakas hehkuvalo ajaa sen pimeaan osastoon, jossa annetaan sahkOshokki laittialla olevien metallilevyjen kautta. Elain poistetaan testauslaitteesta ja testataan uudelleen 24 tuntia myOhemmin sen kykya muis-20 taa sahkOshokki.
Jos annostellaan skopolamiinia, antikolinergista ainetta, jonka tiedetaan aiheuttavan muistin heikentymis-ta, ennen eiaimen ensimmaista vientia testikammioon, elain astuu uudelleen pimeaan osastoon pian sen jaikeen, kun se 25 on laitettu testikammioon 24 tuntia myOhemmin. Tama sko-polamiinin vaikutus estyy aktiivisella testattavalla yh-disteelia, jolloin saavutetaan pitempi aikavOli ennen uudelleen astumista pimeaan osastoon.
KeksinnOn mukaisesti valmistetulla 9-anilino-l,4-30 metano-l,2,3,4-tetrahydroakridiinilia ja vertailuyhdis- teilia saatiin edelia esitetyissa asetyylikoliiniesteraa-si-inhibitiokokeessa ja pimeanvaittamiskokeessa seuraavas-sa esitetyt tulokset. Ensin mainitussa kokeessa saadut tulokset annetaan lC50-arvona, joka on 50-prosenttisen in-35 hibition aiheuttava pitoisuus (molaarisuutena), ja pimean vaittamiskokeessa niiden elainten prosentuaalisena osuute- 3 90416 na, joilla skopolamiinin vaikutuksesta huonotunut muisti on palautunut.
Asetyylikoli iniesteraasi-inhibitiokoe:
Yhdiste ICS0 (M) « 5 9-anilino-l,4-metano-l,2,3,4- tetrahydroakridiini >1,0 x 10~3
Vertailuyhdisteet:
Takriini (9-amino-l,2,3,4- tetrahydroakridiini) 3,1 x 10~7 10 Fysostigmiini 6,0 x 10'9
Pimeånvålttåmiskoe:
Yhdiste Annos % elåimista (mg/kg, s.c.) 15 9-anilino-l,4-metano- 1,2,3,4-tetrahydroakridiini 0,16 20 %
Vertailuyhdiste:
Fysostigmiini 0,31 20 % 20 Vaikka koetulosten perusteella 9-anilino-l,4-meta no-l , 2, 3 , 4- tetrahydroakridiinilla on heikompi asetyyliko-liiniesteraasi-inhibitio kuin låheistå rakennetta olevalla 9-amino-l,2,3,4-tetrahydroakridiinilla eli takriinilla, on se noin kaksi kertaa aktiivisempi kuin fysostigmiini sko-25 polamiinin indusoimassa muistinhuonontumisen palautumista mittaavassa testisså ja våhemmån myrkyllinen kuin takriini primåårisiå avoimia vaikutuksia mittaavassa kokeessa (primary overt effect assay) rotilla. KeksinnOn mukaisesti valmistetun 9-anilinoyhdisteen LD50-annos on yli 80 mg/kg 30 kehon painoa, kun taas takriinin LD50-annos on 10 - 20 * mg/kg kehon painoa.
Yhdisteitå, jotka rakenteeltaan jossakin måårin muistuttavat keksinnOn mukaisesti valmistettua yhdistettå, tunnetaan my6s FI-patenttihakemuksesta 854156, US-patent-35 tijulkaisusta 4 631 286 ja julkaisusta J. Med. Chem., vol 18 (1975) s. 1056 - 1061. Kaavan I mukainen yhdiste eroaa 4 90416 nåistå tunnetuista yhdisteista rakenteeltaan kuitenkin olennaisesti 1,4-metanosillan osalta.
Vaikuttavat maarat kaavan I mukaista yhdistetta voidaan annostella potilaalle milla tahansa eri menetel-5 mista, eslmerkiksl suun kautta kapseleina tai tabletteina, parenteraalisesti steriileina liuoksina tai suspen-sioina, ja joissakin tapauksissa suonen sisaisesti steriileina liuoksina. Lopullinen tuote, joka on vapaa emas, joka on vaikuttava sellaisenaan, voidaan myOs formuloida 10 ja annostella sen farmaseuttisesti hyvaksyttavina happoad-ditiosuoloina sen kaltaisten tarkoitusten vuoksi kuin sta-biilisuus, kiteytymisen helppous, kasvanut liukoisuus ja muut sellaiset.
Farmaseuttisesti hyvaksyttavien happoadditiosuo-15 lojen valmistuksessa kayttdkelpoisiin happoihin kuuluvat epaorgaaniset hapot kuten vetykloridi-, vetybromidi-, rik-ki-, typpi-, fosfori- ja perkloorihappo samoin kuin orgaa-niset hapot kuten viini-, sitruuna-, etikka-, meripih-ka-, maleiini-, fumaari- ja oksaalihappo.
20 Keksinndn mukaisesti valmistettu vaikuttava yhdiste voidaan annostella suun kautta esimerkiksi inertin lai-mentimen tai sydtavaksi kelpaavan kantaja-aineen kanssa, tai ne voidaan sulkea gelatiinikapseleihin, tai se voidaan puristaa tableteiksi. Terapeuttista oraalista annos-25 telua vårten vaikuttava yhdiste voidaan yhdistaa lisSai-neiden kanssa ja kayttaa tabletteina, laakenappeina, kapseleina, eliksiireina, suspensioina, siirappeina, imeske-lytabletteina, purukumina ja muina sellaisina. Naiden val-misteiden tulisi sisaitaa ainakin 0,5 % vaikuttavaa yhdis-30 tetta, mutta se voi vaihdella kyseisesta muodosta riip-puen, ja se voi olla edullisesti vaiilia noin 4-70 % yksi-kOn painosta. Vaikuttavan yhdisteen maara tailaisissa koostumuksissa on sellainen, etta saadaan aikaan sopiva annostus. Edulliset koostumukset ja valmisteet valmiste-35 taan niin, etta oraalinen annostusyksikkSmuoto sisaitaa 1,0-300 milligrammaa vaikuttavaa yhdistetta.
5 90416
Tabletit, pillerit, kapselit, lSSkenapit ja muut sellaiset voivat myiis sisaitaa seuraavia lisaaineita: sideainetta kuten mikrokiteista selluloosaa, tragantti-kumia tai gelatiinia: tayteainetta kuten tarkkelysta tai * 5 laktoosia, paakkuuntumisenestoainetta kuten algiinihappoa,
Primogelia, maissitarkkelystå ja muita sellaisia; voitelu-ainetta kuten magnesiumstearaattia tai Steroteksia; liu-kastinainetta kuten kolloidista piidioksidia, ja voidaan lisåta makeutusainetta kuten sakkaroosia tai sakkariinia 10 tai makuainetta kuten piparminttua, metyylisalisylaattia tai appelsiininmakua. Kun annosyksikkdmuoto on kapseli, se voi sisaitaa edelia esitetyn tyyppisten aineiden lisaksi nestemaista kantajaa kuten rasvaGljya. Muut annostusyksik-kbmuodot voivat sisaitaa erilaisia muita aineita, jotka 15 modifioivat annostusyksikOn fysikaalista muotoa kuten esi-merkiksi paallysteet. Siten tabletit tai pillerit voidaan paailystaa sokerilla, sellakalla tai muilla enteraalisilla paailystysaineilla. Siirappi voi sisaitaa vaikuttavien yhdisteiden lisaksi sakkaroosia makeutusaineena ja tietty-20 ja sailGntåaineita, variaineita, pigmentteja ja makuainei-ta. Naiden erilaisten koostumusten valmistuksessa kaytet-tyjen aineiden tulisi olla farmaseuttisesti puhtaita ja myrkyttGmia kaytetyilia maarilia.
Parenteraalista terapeuttista annostelua vårten 25 keksinnGn mukaisesti valmistettu vaikuttava yhdiste voidaan yhdistaa liuokseen tai suspensioon. Naiden valmistei-den tulisi sisaitaa ainakin 0,1 % vaikuttavaa yhdistetta, mutta se voi vaihdella vaiilia noin 0,5-30 % valmisteen painosta. Vaikuttavan yhdisteen maara naissa koostumuk-30 sissa on sellainen, etta saadaan aikaan sopiva annostus.
Edulliset koostumukset ja valmisteet valmistetaan niin, etta parenteraalinen annostusyksikkG sisaitaa 0,5-100 mil- * ligrammaa vaikuttavaa yhdistetta. Liuokset tai suspensiot voivat sisaitaa myGs seuraavia komponentteja: steriilia 35 laimenninta kuten vetta injektiota vårten, suolaliuosta, rasvaGljyS, polyetyleeniglykoleja, lyseriinia, propyleeni- 6 90416 glykolia tai muita synteettisia liuottimia; bakteerinvas-taisia aineita kuten bentsyylialkoholia tai metyyliparaok-sibentsoaattia: hapettumisenestoaineita kuten askorbiini-happoa tai natriumvetysulfiittia; kelatoivia aineita kuten 5 etyleenidiamiinitetraetikkahappoa; puskureita kuten ase- taatteja, sitraatteja tai fosfaatteja ja aineita toonisuu-den saatelemiseksi kuten natriumkloridia tai dekstroosia. Parenteraaliset valmisteet voidaan sulkea kayttaviin ruis-kuihin tai monen annoksen laakepulloihin, jotka on tehty 10 lasista tai muovista.
Seuraavan esimerkin tarkoitus on kuvata tata kek- sintoa.
Esimerkki 9-anilino-l,4-metano-l,2,3,4-tetrahydroakridiini 15 Fosforipentoksidia (28,4 g) N,N-dimetyylisyklohek- syyliamiinia (25,4 g) ja aniliinihydrokloridia (25,9 g) sekoitettiin keskenåan huoneen lampOtilassa ja sen jaikeen lammitettiin 01jyhauteessa lampOtilassa 220°C, kunnes saa-tiin kirkas homogeeninen seos. Seoksen annettiin jaahtya 20 lampOtilaan alle 150°C, ja lisattiin pisaroittain metyyli-antranilaattia (7,58 g) ja sen jaikeen 2-norbornanonia (6,61 g). Seosta lammitettiin uudelleen lampOtilassa 220°C sekoittaen 20 tuntia. Sen jaikeen, kun se oli jaahdytetty lampOtilaan 100°C, lisattiin 450 ml 2-M NaOH ja sekoitusta 25 jatkettiin lampOtilassa 100°C 30 minuuttia. Sitten reaktio-seoksen annettiin jaahtya huoneen lampOtilaan, ja sita uutettiin etyyliasetaatilla. Haihdutuksen ja etyyliasetaa-tin kanssa suoritetun hiertamisen jaikeen saatiin 6,28 g 9-anilino-l, 4-metano-l, 2,3,4-tetrahydroakridiinikiteita, 30 sp. 223-225°C. Analyysinaytteen sulamispiste oli muuttuma-ton etyyliasetaatista suoritetun uudelleenkiteytyksen jaikeen.
Analyysi: C20HieN2:lle laskettu 82,88 % C 6,33 % H 9,78 % N 35 Havaittu 83,67 % C 6,32 % H 9,99 % N.
Claims (3)
- 7 90416 Patenttivaatimus MenetelmS terapeuttisesti aktiivisen 9-anilino- 1,4-metano-l,2,3,4-tetrahydroakridiinin valmistamiseksi, * 5 jolla on kaava (I) 9
- 10 NH I 15 tunnettu siita, ettå låmmitetaan seosta, jossa on fosforipentoksidia, N,N-dimetyylisykloheksyyliamiinia ja aniliinihydrokloridia, ja lisåtSån sitten metyyliantrani-laattia, jolla on kaava (IV) 20 a- C00CH3 25 ja sen jålkeen 2-norbornanonia, jolla on kaava JO- 30 m 8 90416 Fdrfarande fOr framstållning av terapeutiskt aktivt 9-anilino-l,4-metano-l,2,3,4-tetrahydroakridin med 5 formeln (I) 10 "H I QpD 15 kdnnetecknat dSrav, att en blandning innehål-lande fosforpentoxid, N,N-dimetylcyklohexylamin och ani-linhydroklorid uppv&rms och tillsåtts sedan metylantrani-lat med formeln (IV)
- 20 COOCH o ΓΤ paNH2 och dSrefter 2-norbornanon med formeln 25 9) · 30
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1475387 | 1987-02-13 | ||
| US07/014,753 US4897400A (en) | 1987-02-13 | 1987-02-13 | 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI880634A0 FI880634A0 (fi) | 1988-02-11 |
| FI880634A FI880634A (fi) | 1988-08-14 |
| FI90416B FI90416B (fi) | 1993-10-29 |
| FI90416C true FI90416C (fi) | 1994-02-10 |
Family
ID=21767514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI880634A FI90416C (fi) | 1987-02-13 | 1988-02-11 | Menetelmä terapeuttisesti aktiivisen 9-anilino-1,4-metano-1,2,3,4-tetrahydroakridiinin valmistamiseksi |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US4897400A (fi) |
| EP (1) | EP0278499B1 (fi) |
| JP (1) | JP2736254B2 (fi) |
| KR (1) | KR960012366B1 (fi) |
| AT (1) | ATE112270T1 (fi) |
| AU (1) | AU596887B2 (fi) |
| CA (1) | CA1341335C (fi) |
| DE (1) | DE3851643T2 (fi) |
| DK (1) | DK168011B1 (fi) |
| ES (1) | ES2061530T3 (fi) |
| FI (1) | FI90416C (fi) |
| HU (1) | HU205908B (fi) |
| IE (1) | IE64493B1 (fi) |
| IL (1) | IL85401A (fi) |
| NO (1) | NO173990C (fi) |
| NZ (1) | NZ223485A (fi) |
| PH (1) | PH24725A (fi) |
| PT (1) | PT86749B (fi) |
| ZA (1) | ZA88989B (fi) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4897400A (en) * | 1987-02-13 | 1990-01-30 | Hoeschst-Roussel Pharmaceuticals, Inc. | 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal |
| US5037833A (en) * | 1988-07-25 | 1991-08-06 | Hoechst-Roussel Pharmaceuticals Inc. | N-[substituted alkylidene]fused-bicycloalkylidene quinolinamines useful for enhancing the cholinergic function in a mammal |
| US5202440A (en) * | 1987-10-05 | 1993-04-13 | Pfizer Inc. | Certain 9-amino-2-(or 4)-oxa 1,2,3,4-tetrahydro- or 1,2,3,4,5,6,7,8-octahydro-acridines |
| IL87861A0 (en) * | 1987-10-05 | 1989-03-31 | Pfizer | 4-aminopyridine derivatives |
| US5008853A (en) | 1987-12-02 | 1991-04-16 | Xerox Corporation | Representation of collaborative multi-user activities relative to shared structured data objects in a networked workstation environment |
| US4985430A (en) | 1987-12-03 | 1991-01-15 | Mitsubishi Kasei Corporation | 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| JP2720517B2 (ja) * | 1989-05-31 | 1998-03-04 | 三菱化学株式会社 | ９―アシルアミノーテトラヒドロアクリジン誘導体および該誘導体を有効成分とする記憶障害改善剤 |
| ES2100129B1 (es) * | 1995-10-11 | 1998-02-16 | Medichem Sa | Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion. |
| KR101953366B1 (ko) | 2018-12-26 | 2019-02-28 | 정종문 | 침향을 포함하는 기억력 및 인지능력을 향상시키는 기능성 건강식품 및 이의 제조방법 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3232945A (en) * | 1962-08-13 | 1966-02-01 | S E Massengill Company | 7,8,9,10-tetrahalo-6h-cyclohepta-(b)-quinolines |
| US3318896A (en) * | 1963-12-05 | 1967-05-09 | Squibb & Sons Inc | Production of 12-substituted-6, 7, 8, 9, 10, 11-hexahydrocycloocta[b]quinolines |
| US3318895A (en) * | 1963-12-05 | 1967-05-09 | Squibb & Sons Inc | Production of 12-substituted-6, 7, 8, 9, 10, 11-hexahydrocycloocta[b]quinolines |
| BE658695A (fi) * | 1964-02-03 | 1965-07-22 | ||
| US3541066A (en) * | 1968-09-16 | 1970-11-17 | American Home Prod | 2,3-dihydro-1,4-ethanobenzo(b)(1,5)naphthyridine derivatives |
| US3580915A (en) * | 1968-09-16 | 1971-05-25 | American Home Prod | 1,2,3,4-tetrahydrobenzol(b)(1,6)naphthyridine derivatives |
| US3637706A (en) * | 1970-04-30 | 1972-01-25 | American Home Prod | 10-(4 - (lower)alkylpiperazino) - 1 2 3 4-tetrahydrobenzo(b)(1 6) naphthyridine derivatives useful as cns depressants |
| US3657233A (en) * | 1970-04-30 | 1972-04-18 | American Home Prod | 10-morpholino-1 2 3 4-tetrahydrobenzo(b)(1 6)naphthyridine derivatives |
| US3647800A (en) * | 1970-04-30 | 1972-03-07 | American Home Prod | 10-substituted - 1 2 3 4 - tetrahydrobenzo(b)(1 6)naphthyridines useful as cns depressants |
| US3674790A (en) * | 1970-05-01 | 1972-07-04 | American Home Prod | 2,10-disubstituted-1,2,3,4-tetrahydrobenzo(bhq (1,6)naphthyridines useful as cns depressants |
| ES431307A1 (es) * | 1973-11-16 | 1976-09-01 | Thomae Gmbh Dr K | Procedimiento para la preparacion de nuevos derivados de quinoleina. |
| US4108998A (en) * | 1976-11-08 | 1978-08-22 | American Home Products Corp. | Furo[3,4-b]quinoline derivatives and pharmaceutical compositions and methods employing them |
| DE3582995D1 (de) * | 1984-10-25 | 1991-07-04 | Hoechst Roussel Pharma | 9-amino-1,2,3,4-tetrahydroacridin-1-ol und verwandte verbindungen, verfahren zu ihrer herstellung und verwendung als arzneimittel. |
| US4631286A (en) * | 1984-10-25 | 1986-12-23 | Hoechst-Roussel Pharmaceuticals Inc. | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds |
| US4695573A (en) * | 1984-10-25 | 1987-09-22 | Hoechst-Roussel Pharmaceuticals Inc. | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds |
| US4816456A (en) * | 1986-10-01 | 1989-03-28 | Summers William K | Administration of monoamine acridines in cholinergic neuronal deficit states |
| EP0268871A1 (en) * | 1986-10-31 | 1988-06-01 | Sumitomo Pharmaceuticals Company, Limited | Quinoline derivatives |
| US4897400A (en) * | 1987-02-13 | 1990-01-30 | Hoeschst-Roussel Pharmaceuticals, Inc. | 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal |
| US4851536A (en) * | 1987-05-07 | 1989-07-25 | American Home Products Corporation | Cyclohexylquinolines as inhibitors of interleukin 1 |
| MX13270A (es) * | 1987-10-05 | 1993-06-01 | Pfizer | Procedimiento para la preparacion de derivados de 4-aminopiridina |
| US4985430A (en) * | 1987-12-03 | 1991-01-15 | Mitsubishi Kasei Corporation | 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
-
1987
- 1987-02-13 US US07/014,753 patent/US4897400A/en not_active Expired - Lifetime
-
1988
- 1988-02-11 DE DE3851643T patent/DE3851643T2/de not_active Expired - Fee Related
- 1988-02-11 IL IL85401A patent/IL85401A/xx not_active IP Right Cessation
- 1988-02-11 AT AT88101973T patent/ATE112270T1/de not_active IP Right Cessation
- 1988-02-11 NZ NZ223485A patent/NZ223485A/en unknown
- 1988-02-11 ES ES88101973T patent/ES2061530T3/es not_active Expired - Lifetime
- 1988-02-11 PT PT86749A patent/PT86749B/pt not_active IP Right Cessation
- 1988-02-11 PH PH36487A patent/PH24725A/en unknown
- 1988-02-11 EP EP88101973A patent/EP0278499B1/en not_active Expired - Lifetime
- 1988-02-11 FI FI880634A patent/FI90416C/fi not_active IP Right Cessation
- 1988-02-12 DK DK072388A patent/DK168011B1/da not_active IP Right Cessation
- 1988-02-12 NO NO880627A patent/NO173990C/no unknown
- 1988-02-12 ZA ZA88989A patent/ZA88989B/xx unknown
- 1988-02-12 HU HU88686A patent/HU205908B/hu not_active IP Right Cessation
- 1988-02-12 IE IE39188A patent/IE64493B1/en not_active IP Right Cessation
- 1988-02-12 AU AU11670/88A patent/AU596887B2/en not_active Ceased
- 1988-02-12 KR KR1019880001341A patent/KR960012366B1/ko not_active IP Right Cessation
- 1988-02-12 CA CA000558816A patent/CA1341335C/en not_active Expired - Fee Related
- 1988-02-12 JP JP63029044A patent/JP2736254B2/ja not_active Expired - Fee Related
- 1988-07-08 US US07/218,755 patent/US5401749A/en not_active Expired - Fee Related
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Legal Events
| Date | Code | Title | Description |
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| BB | Publication of examined application | ||
| PC | Transfer of assignment of patent |
Owner name: HOECHST MARION ROUSSEL, INC. |
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| MM | Patent lapsed |
Owner name: HOECHST MARION ROUSSEL INC., INC. |