DK168011B1 - 4-amino-quinolinderivater, en fremgangsmaade til fremstilling deraf, farmaceutisk praeparat indeholdende disse derivater samt deres anvendelse til fremstilling af et laegemiddel - Google Patents
4-amino-quinolinderivater, en fremgangsmaade til fremstilling deraf, farmaceutisk praeparat indeholdende disse derivater samt deres anvendelse til fremstilling af et laegemiddel Download PDFInfo
- Publication number
- DK168011B1 DK168011B1 DK072388A DK72388A DK168011B1 DK 168011 B1 DK168011 B1 DK 168011B1 DK 072388 A DK072388 A DK 072388A DK 72388 A DK72388 A DK 72388A DK 168011 B1 DK168011 B1 DK 168011B1
- Authority
- DK
- Denmark
- Prior art keywords
- amino
- tetrahydro
- lower alkyl
- hydrogen
- methanoacridine
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 4
- 150000005011 4-aminoquinolines Chemical class 0.000 title claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
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- -1 loweralkyl Chemical group 0.000 claims abstract description 30
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- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 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
- 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
- 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
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 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
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- CREXVNNSNOKDHW-UHFFFAOYSA-N azaniumylideneazanide Chemical group N[N] CREXVNNSNOKDHW-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 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
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 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
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 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
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 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
- 239000000543 intermediate Substances 0.000 description 1
- 150000002496 iodine Chemical class 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
- 239000008101 lactose Substances 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
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000007074 memory dysfunction Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000003921 oil Substances 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 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
- 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
- 229940113147 shellac Drugs 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
- 235000013874 shellac Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 235000012773 waffles Nutrition 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
- 239000008096 xylene 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (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
DK 168011 B1
Den foreliggende opfindelse angår hidtil ukendte 4-amino-quinolinderivater med den almene formel 5 JL Λ—·/ 2 (i) iXAx *3 10 i hvilken R betyder hydrogen, lavere alkyl eller lavere alkylcarbonyl, betyder hydrogen, lavere alkyl, lavere alkylcarbonyl, aryl, di-lavere alkylamino-lavere alkyl, aryl-lavere alkyl, diaryl-lavere alkyl, oxygen-broholdigt aryl-lavere alkyl eller oxygen-broholdigt diaryl-lavere 15 alkyl, R2 og Rg hver for sig betyder hydrogen eller methyl, X betyder hydrogen, lavere alkyl, cycloalkyl, lavere alkoxy, halogen, hydroxy, nitro, trifluormethyl, formyl, lavere alkylcarbonyl, arylcarbonyl, -SH, lavere alkylthio, -NHCOR4 eller -NR^Rg, hvor betyder hydrogen eller lavere alkyl, 20 og Rg og Rg hver for sig betyder hydrogen, lavere alkyl eller cycloalkyl, Y og Z hver for sig betyder en direkte binding, CRyRg eller CRyRg-CRgR.^, og P og Q hver for sig betyder CRy’Rg', CRy 'Rg* -CRg 'R10 ' eller CRy'Rg'-CRg'R1Q'-“CR11R12' hvor hver af substituenterne Ry til R^ og -Ry1 25 til R10' betyder hydrogen eller methyl, samt stereoisomere, optiske og geometriske isomere eller farmaceutisk acceptable syreadditionssalte og solvater deraf, dog med undtagelse af forbindelserne 9-amino-l,2,3,4-tetrahydro-l,4-methanoacridin, 30 9-amino-7-f luor-1,2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-8-f luor-l ,2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-7-chlor-l ,2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-8-chlor-l ,2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-7-nitro-l, 2,3,4-tetrahydro-l, 4-methanoacridin, 35 9-amino-8-methyl-l ,2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-6-methoxy-l, 2,3,4-tetrahydro-l, 4-methanoacridin, 2 DK 168011 B1 9-amino-6-trifluormethyl-l, 2,3,4-tetrahydro-l,4-methano-acridin, 9-amino-7-trifluormethyl-l,2, 3,4-tetrahydro-l,4-methano-acridin, 5 9-amino-l,2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-7-fluor-1,2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-8-fluor-1,2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-8-methyl-l,2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-l,2,3,4-tetrahydro-l,4-ethanoacridin, 10 9-amino-8-fluor-1,2,3,4-tetrahydro-l,4-ethanoacridin, 9-amino-6-trifluormethyl-l, 2,3,4-tetrahydro-l, 4-ethanoacridin, 9-amino-7-fluor-1,2,3,4-tetrahydro-l,4-ethanoacridin, og 9-amino-8-methoxy-l ,2,3,4-tetrahydro-l, 4-methanoacridin, 15 hvilke forbindelser ifølge opfindelsen kan anvendes til forbedring af hukommelsen, og opfindelsen angår endvidere en fremgangsmåde til fremstilling af en gruppe af disse forbindelser med formlen (la) som angivet i krav 7's indledning, hvilken fremgangsmåde er ejendommelig ved det i krav 7's 20 kendetegnende del angivne, og farmaceutiske præparater, der er ejendommelige ved det i krav 5's kendetegnende del angivne, samt anvendelse af en forbindelse ifølge krav 1 til fremstilling af et lægemiddel med hukommelsesforøgende aktivitet.
25 Forbindelser med de almene formler jfVTTf og **3 35 DK 168011 B1 3 jr^nC - hvor R2' R3' xf Z, P og Q har den ovenfor angivne belt) tydning, betyder hydrogen eller lavere alkyl, og W betyder halogen, hydroxy eller lavere alkoxy, er nyttige som mellemprodukter til syntese, af forbindelserne med formlen I.
I den følgende beskrivelse med krav skal en given kemisk formel eller et givet kemisk navn omfatte alle ste-15 reoisomere, optiske og geometriske isomere deraf, når sådanne isomere eksisterer. Opfindelsen omfatter de farmaceutisk acceptable syreadditionssalte af forbindelserne med formlen I og solvater deraf, f.eks. hydrater.
De følgende definitioner gælder i hele den følgende 20 beskrivelse med krav:
Udtrykket "lavere alkyl" betegner en lige eller forgrenet alkylgruppe med 1-6 carbonatomer. Eksempler på sådanne lavere alkylgrupper er methyl, ethyl, n-propyl, isobutyl, pentyl og hexyl.
25 Udtrykket "cycloalkyl” betegner en mættet alicyclisk gruppe indeholdende fra 3 til 7 carbonatomer. Eksempler på sådanne cycloalkylgrupper er cyclopropyl, cyclohexyl og cycloheptyl.
Udtrykket "lavere alkoxy" betegner en ligekædet eller 30 forgrenet alkoxygruppe med 1-6 carbonatomer. Eksempler på sådanne lavere alkoxygrupper omfatter methoxy, ethoxy, iso-propoxy, sek.butoxy og ligekædet og forgrenet hexyloxy.
Udtrykket "halogen" betegner fluor, chlor, brom og iod.
35 Udtrykket "aryl" betegner en usubstitueret phenyl- gruppe eller en phenylgruppe, der er substitueret med 1, 2 DK 168011 B1 4 eller 3 substituenter, der hver for sig kan være lavere alkyl.
Udtrykket "oxygenbroholdigt" refererer til-det forhold, at et oxygenatom er til stede mellem aryl- og lavere 5 alkylgrupper og/eller, at et oxygenatom har erstattet en methylengruppe i den lavere alkylgruppe, dog således, at den nævnte methyl engruppe ikke er i α-stilling til det amino-nitrogenatom, der bærer grupperne R og R-l . Eksempler på oxygen-broholdige aryl-lavere alkylgrupper omfatter således 10 3-phenoxypropyl og 4-phenoxybutyl.
Forbindelserne ifølge opfindelsen kan fremstilles ved anvendelse af ét eller flere af de i det følgende beskrevne syntesetrin. Til forenkling af beskrivelsen af synteseskemaerne skal den følgende beskrivelse gives med 15 speciel reference til den situation, hvor R2 og R^ betegner hydrogen, Y og Z er en direkte binding, P betegner CH2, og Q betegner men det vil uden videre forstås, at synteseskemaerne også gælder for de andre situationer, idet der foretages åbenlyse modifikationer, hvor dette er 20 nødvendigt.
Gennem hele beskrivelsen af syntesetrinene har R,
Ri, R]_3 og X har den ovenfor angivne betydning, medmindre andet er angivet.
25 Trin A
Forbindelser med formlen Ila kan fremstilles ved omsætning af en forbindelse med formlen IV med 2-norbornanon. Denne omsætning kan udføres i et egnet opløsningsmiddel, f.eks. benzen, toluen eller xylen, ved en temperatur fra 30 ca. 80 til ca. 150°C i nærværelse af en sur katalysator, f.eks. p-toluensulfonsyre, benzensulfonsyre eller methan-sulfonsyre.
DK 168011 B1 5 oc ' Λ - 0¾ 5 IV Ila
Trin B
10 Forbindelser med formlen Illa kan fremstilles ved om sætning af en forbindelse med formlen Ila med phosphorpen-toxid i nærværelse af en højtkogende tertiær amin, f.eks. Ν,Ν-dimethylcyclohexylamin. Denne reaktion kan udføres uden yderligere opløsningsmiddel ved en temperatur fra ca. 170 til ca. 220°C.
15
OH
Ha —— x-f- || |7 j
20 N
Illa
Hydroxygruppen, der er bundet til den midterste ring 25 i forbindelsen med formlen Illa, kan let omdannes til en lavere alkoxygruppe på en gængs, kendt måde.
Trin C
Forbindelser med formlen Hib kan fremstilles ved omsætning af en forbindelse med formlen Ila med phosphor-30 oxychlorid og phosphorpentachlorid. Denne omsætning kan udføres ved en temperatur på fra-ca. 100 til ca. 150°C.
Cl
Hib 35 Illa -------- 0 6 DK 168011 B1
Den brom-analoge til forbindelsen Hib kan fremstilles på tilsvarende måde, nemlig f.eks. ved omsætning af en forbindelse med formlen Illa med phosphoroxybromid og phos-phorpentabromid. De fluor- og iod-analoge til forbindelsen 5 med formlen Illa kan fremstilles ved erstatning af chlor-atomet i forbindelsen med formlen Illa med fluor eller iod på gængs, kendt måde.
Trin D
10 Forbindelser med formlen VI kan fremstilles ved om sætning af en forbindelse med formlen Hib med en amin med formlen V. Denne omsætning kan udføres ved en temperatur på 120-220°C i nærværelse af en sur katalysator, f.eks.
ammoniumchlorid eller phenol.
15 R's'N/R1
Illb + HNRR^ --- 20
V VI
Trinene A til D kan kombineres til et enkelt trin.
25 Forbindelserne med formlen VI kan således fås ved opvarmning sammen af en blanding af phosphorpentoxid, N,N-dime-thylcyclohexylamin og hydrochloridet af aminen med formlen V, hvorpå der tilsættes en forbindelse med formlen IV efterfulgt af 2-norbornanon. Denne omsætning kan udføres 30 ved en temperatur på fra ca. 150 til ca. 250°C.
Forbindelserne med formlen I ifølge den foreliggende opfindelse kan anvendes til behandling af forskellige hukommelses-dysfunktioner, der er karakteriseret ved nedsat cholinergisk funktion, f.eks. Alzheimer's sygdom.
35 7 0 DK 168011 B1
Fra DK patentansøgning nr. 4888/85 kendes der forbindelser, der har en vis strukturel lighed med forbindelserne ifølge opfindelsen, og som har anti-acetylcholinesterase-aktivitet. De fra den nævnte DK ansøgning kendte forbindelser 5 har imidlertid en højre-molekyIdel, der er væsentligt forskellig fra den tilsvarende molekyldel i forbindelserne ifølge opfindelsen. Noget tilsvarende gælder de fra US patentskrift nr. 3.232.945 kendte forbindelser, der er angivet at have cholinerg virkning.
10 Anvendelsen af de her omhandlede forbindelser kan godtgøres ved bestemmelse af disse forbindelsers evne til at inhibere aktiviteten af enzymet acetylcholinesterase og dermed forøge acetylcholinniveauerne i hjernen.
Denne anvendelse kan også godtgøres ved bestemmelse 15 af disse forbindelsers evne til at afhjælpe cholinergisk deficient hukommelse ved "Dark Avoidance"-forsøget. Ved dette forsøg afprøves mus for deres evne til at huske en ubehagelig stimulans i en periode på 24 timer. En mus anbringes i et kammer, der indeholder et mørkt rum. Et kraf-20 tigt strålende lys driver musen til det mørke rum, hvor den gives et elektrisk chok gennem metalplader på gulvet. Dyret fjernes fra afprøvningsapparaturet og testes på ny 24 timer senere for evnen til at huske det elektriske chok.
Såfremt scopolamin, der er et anticholinergisk middel, 25 som vides at forårsage hukommelsesforringelse, indgives inden et dyrs indledende udsættelse for forsøgskammeret, genindtræder dyret i det mørke rum kort efter at være anbragt i forsøgskammeret 24 timer senere. Denne virkning af scopolamin blokeres af en aktiv forsøgsforbindelse, hvil-30 ket resulterer i et større interval, inden dyret genindtræder i det mørke rum.
35 DK 168011 B1 8
Forsøgsresultaterne udtrykkes som procentmængden af en gruppe dyr, hos hvilke virkningen af scopolamin blokeres, hvilket viser sig ved et forøget interval mellem anbringelsen i forsøgskammeret og genindtræden i det mørke rum. Resul-5 taterne for en række forbindelser ifølge opfindelsen er angivet i den følgende tabel tillige med resultatet for en sammenligningsforbindelse: '»Dark Avoidance"-forsøq 10
Tabel I
% dyr med reverseret Dosis (mg/kg scopolamin-induceret
Forbindelse kropsvagt, s.c.) hukommelsessvækkelse 15 _ 9 -Amino -1,4 -methano - 6 -methyl - 1.2.3.4- tetrahydroacridin 2,5 36% 20 9-Amino-6-fluor-1,4-methano- 1.2.3.4- tetrahydroacridin 0,63 9% 25 9 -Phenylamino-1,4-methano - 1.2.3.4- tetrahydroacridin 0,16 20% 30 Referenceforbindelse:
Physostigmin 0,31 20% 35
Endvidere er forbindelsernes evne til inhibering af acetylcholinesterase blevet bestemt (jf. Biochem. Pharmacol.
7, 88 (1961) med følgende resultater: DK 168011 Bl 9
Acetylcholinesterase-inhiberinq Tabel II
Acetylcholinesterase- 5 inhibering
Forbindelse IC50(molær kone.) 10 9-Amino-l,4-methano-6-methyl- 1.2.3.4- tetrahydroacridin 3,0 x 10-7 9-Amino-6-fluor-1,4-methano- 15 1,2,3,4-tetrahydroacridin 8,0 x 10“8 9-Phenylamino-l,4-methano- 1.2.3.4- tetrahydroacridin >1,0 x 10-3 20 9-Benzylamino-l^-methanols, 3, 4-tetrahydroacridin >1,0 x 10-3 25 9-Benzylamino-l,4-methano-6-me- thyl-l,2,3,4-tetrahydroacridin 3,1 x 10"5 30 9-Benzylamino-l,4-methano-l,2,3,4- tetrahydro-6-trifluormethylacridin >1,0 x 10"3 9-Benzylamino-1,4-ethano-1,2,3,4-35 tetrahydroacridin 7,8 x 10”^
Referenceforbindelser: 40
Tacrin (9-amino-l,2,3,4-tetrahydroacridin) 3,1 x 10-7 45 Physostigmin 6,0 x 10”9 10 DK 168011 B1 o
Effektive mængder af forbindelserne ifølge opfindelsen kan indgives til en patient ved hjælp af en række forskellige metoder, f.eks. oralt i form af kapsler ..eller tabletter, parenteralt i form af sterile opløsninger: eller 5 suspensioner, og i nogle tilfælde intravenøst i form af sterile opløsninger. Slutprodukterne i form af frie baser kan, omend de i sig selv er virksomme, omdannes til præparater og indgives i form af deres farmaceutisk acceptable syreadditionssalte af hensyn til stabilitet, bekvem krystal-10 lisation, forøget opløselighed og lignende forhold.
Syrer, der kan anvendes til fremstilling af de farmaceutisk acceptable syreadditionssalte ifølge opfindelsen, omfatter uorganiske syrer, såsom saltsyre, hydrogenbromid-syre, svovlsyre, salpetersyre, phosphorsyre og perchlorsyre, 15 samt organiske syrer, såsom vinsyre, citronsyre, eddikesyre, ravsyre, maleinsyre, fumarsyre og oxalsyre.
De aktive forbindelser ifølge opfindelsen kan indgives oralt, f.eks. sammen med et indifferent fortyndingsmiddel eller sammen med et spiseligt bærestof, eller de kan inde-20 sluttes i gelatinekapsler eller sammenpresses til tabletter. Til oral terapeutisk indgivelse kan de aktive forbindelser ifølge opfindelsen inkorporeres sammen med strækkemi dl er og anvendes i form af f.eks. tabletter, pastiller, kapsler, eliksirer, suspensioner, sirupper, vafler og·tygge-25 gummi. Disse præparater bør indeholde mindst 0,5% aktiv forbindelse, men mængden kan varieres afhængigt af den bestemte form, der anvendes, og kan bekvemt ligge mellem 4 og ca. 70% af vægten af enheden. Mængden af aktiv forbindelse i sådanne præparater er således, at der opnås en 30 egnet dosis. Foretrukne sammensætninger og præparater ifølge opfindelsen fremstilles således, at en oral dosisenhedsform indeholder mellem 1,0 og 300 mg aktiv forbindelse.
35 DK 168011 B1 11 o
De anvendte tabletter, piller, kapsler, pastiller og lignende præparater kan også indeholde de følgende bestanddele: et bindemiddel, f.eks. mikrokrystallinsk c.ellulose, tragacanth-gummi eller gelatine, et strækkemiddel, f.eks.
5 stivelse eller lactose, et desintegreringsmiddel, f.eks. alginsyre, Primogel, majsstivelse og lignende, et smøremiddel, f.eks. magnesiumstearat eller Sterotex, et glide-middel, f.eks. kolloidt siliciumdioxid, og der kan også tilsættes et sødemiddel, f.eks. sucrose eller saccharin, 10 eller et smagsgivende middel, f.eks. pebermynte, methyl-salicylat eller orangearoma. Når dosisenhedsformen er en kapsel, kan den udover materialer af den ovennævnte type indeholde en flydende bærer, såsom en fedtolie. Andre dosisenhedsformer kan indeholde andre forskellige materialer, 15 der modificerer dosisenhedens fysiske form, f.eks. overtræk. Tabletter eller piller kan således overtrækkes med sukker, schellak eller andre enteriske overtræksmidler.
En sirup kan udover de aktive forbindelser indeholde sucrose som et sødemiddel samt visse konserveringsmidler, 20 farvestoffer, farvemidler og aromastoffer. Materialer, der anvendes til fremstilling af disse forskellige præparater, bør være farmaceutisk rene og ikke-toksiske i de anvendte mængder.
Til parenteral terapeutisk indgivelse kan de aktive 25 forbindelser ifølge opfindelsen inkorporeres i en opløsning eller suspension. Disse præparater bør indeholde mindst 0,1% aktiv forbindelse, men mængden kan variere mellem 0,5 og ca. 30% af vægten deraf. Mængden af aktiv forbindelse i sådanne præparater er således, at der opnås en passende 30 dosis. Foretrukne sammensætninger og præparater ifølge opfindelsen fremstilles således, at en parenteral dosisenhed indeholder mellem 0,5 og 100 mg aktiv forbindelse.
Opløsningerne eller suspensionerne kan også omfatte følgende bestanddele: et sterilt fortyndingsmiddel, f.eks.
35 vand til injektionsformål, saltopløsning, fikserede olier, polyethylenglycoler, glycerol, propylenglycol eller andre syntetiske opløsningsmidler, antibakterielle midler, f.eks.
0 DK 168011 B1 12 benzylalkohol eller methylparabener, antioxidanter, f.eks. ascorbinsyre eller natriumbisulfit, chelateringsmidler, f.eks. ethylendiamintetraeddikesyre, puf fer stoffer, f.eks. acetater, citrater eller phosphater, og midler til ind-5 stilling af toniciteten, f.eks. natriumchlorid eller dextrose. De parenterale præparater kan indesluttes i éngangssprøjter eller hætteglas af glas eller plast til flere doser.
Eksempler på forbindelserne ifølge opfindelsen om- 10 fatter følgende forbindelser: 1,4-methano-9-methylamino-l, 2,3,4-tetrahydroacridin, 9-benzylamino-l, 4-methano-l ,2,3,4-tetrahydroacridin, 7-acetamido-9-benzylamino-l, 4-methano-l, 2,3,4-tetrahydroacridin, 15 9-anilino-l, 4-methano-l ,2,3,4-tetrahydroacridin, 9-anilino-6-fluor-1,4-methano-l,2,3,4-tetrahydro-acridin, 9-anilino-l, 4-methano-7-methylthio-l ,2,3,4-tetrahydroacridin, 20 9 -amino-6-chlor-l, 4-ethano-l ,2,3,4-tetrahydroacridin, 9-amino-l, 4-ethano-6-methoxy-l ,2,3,4-tetrahydroacridin, 9-acetamido-l, 4-ethano-l, 2,3,4-tetrahydroacridin, 7-acetamido-l, 4 - e thano- 9 -me thy lamino-1,2,3,4-tetrahydroacridin, 9-benzylamino-l, 4-ethano-l ,2,3,4-tetrahydroacridin, 9-benzylamino-7-chlor-l,4-ethano-l,2,3,4-tetrahydroacridin , 9-anilino-l,4-ethano-l,2,3,4-tetrahydroacridin, 30 9-anilino-8-methoxy-l,4-ethano-l,2,3,4-tetrahydroacridin , 35 0 13 DK 168011 B1 9-anilino-l,4-ethano-5-methyl-l,2,3,4-tetrahydroacridin, ll-amino-6,9-methano-7,8,9,10-tetrahydro-6H-cyclo-hepta[b]quinolin, 5 3-chlor-6,9-methano-ll-methylamino-7,8,9,10-tetra- hydro-6H-cyclohepta[b]quinolin, ll-benzylamino-6,9-methano-2-methyl-7,8,9,10-tetra-hydro-6H-cyclohepta[b]quinolin, ll-anilino-6,9-methano-3-methoxy-7,8,9,10-tetra-10 hydro-6H-cyclohepta[b]quinolin, ll-amino-7,10-methano-7,8,9,10-tetrahydro-6H-cyclo-hepta[b]quinolin og ll-amino-3-trifluormethy1-7,10-methano-7,8,9,10--tetrahydro-6H-cyclohepta[b]quinolin.
15 Det følgende eksempel tjener til nærmere belysning af opfindelsen.
Eksempel 9-Anilino-l,4-methano-l,2,3,4-tetrahydroacridin 20 28,4 g phosphorpentoxid, 25,4 g N,N-dimethylcyclo- hexylamin og 25,9 g anilin-hydrochlorid sammenblandes ved stuetemperatur og opvarmes dernæst på et oliebad ved 220°C, indtil der fås en klar, homogen blanding. Blandingen får lov til at afkøle til under 150°C, og der tilsættes dråbe-25 vis 7,58 g methylanthranilat, efterfulgt af 6,61 g 2-nor-bornanon. Blandingen opvarmes igen til 220°C under omrøring 1 20 timer. Efter afkøling til 100°C tilsættes der 450 ml 2 M NaOH, og omrøringen fortsættes ved 100°C i 30 minuttter. Reaktionsblandingen får derpå lov til at afkøle til stue- 30 temperatur og ekstraheres med ethylacetat. Ved inddampning og triturering med ethylether fås 6,28 g krystaller af 9-anilino-l,4-methano-l,2,3,4-tetrahydroacridin med smp. 223-225°C. Smeltepunktet for den analytiske prøve er uændret efter omkrystallisation fra ethylacetat.
35 Analyse:
Beregnet for C2qH^øN2: 82,88%C 6,33%H 9,78%N
Fundet: 83,67%C 6,32%H 9,99%N.
Claims (6)
10 W\a *3 i hvilken R betyder hydrogen, lavere alkyl eller lavere alkylcarbonyl, R1 betyder hydrogen, lavere alkyl, lavere 15 alkylcarbonyl, aryl, di-lavere alkylamino-lavere alkyl, aryl-lavere alkyl, di-aryl-lavere alkyl, oxygen-broholdigt aryl-lavere alkyl eller oxygen-broholdigt di-aryl-lavere alkyl, R2 og R^ hver for sig betyder hydrogen eller methyl, X betyder hydrogen, lavere alkyl, cycloalkyl, lavere al-20 koxy, halogen, hydroxy, nitro, trif luorme thyl, formyl, lavere alkylcarbonyl, arylcarbonyl, -SH, lavere alkylthio, -NHCOR^ eller -NR^Rg, hvor R^ betyder hydrogen eller lavere alkyl, og Rg og Rg hver for sig betyder hydrogen, lavere alkyl eller cycloalkyl, Y og Z hver for sig betyder en 25 direkte binding, CR^Rg eller CR^Rg-CR^R^g, og P og Q hver for sig betyder CRy1Rg' , CR^Rg'-CRg'R^g' eller CR^,Rg’“ -CRg'R-j^g ,-CR^^,R^2> / hvor hver af subs ti tuenterne R^ til R^2 0<? ' til R^g' hver for sig betyder hydrogen eller methyl, eller er stereoisomere, optiske eller geometriske 30 isomere deraf eller farmaceutisk acceptable syreadditionssalte eller solvater deraf, dog med undtagelse af forbindelserne 9-amino-l, 2,3,4-tetrahydro-l,4-methanoacridin, 9-amino-7-fluor-l, 2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-8-fluor-l, 2,3,4-tetrahydro-l, 4-methanoacridin, 35 9-amino-7-chlor-l, 2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-8-chlor-l, 2,3,4-tetrahydro-l, 4-methanoacridin, 9-amino-7-nitro-l ,2,3,4-tetrahydro-l, 4-methanoacridin, 15 DK 168011 B1 9-amino-8-methyl-l ,2,3,4-tetrahydro-l,4-methanoacridin, 9-amino-6-methoxy-l,2,3,4-tetrahydro-l,4-methanoacridin, 9-amino-6-trif luormethyl-1,2,3,4-tetrahydro-l, 4-methanoacridin, 5 9-amino-7-trifluormethyl-1,2,3,4-tetrahydro-l,4-methanoacridin, 9-amino-l,2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-7-f luor-1,2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-8-f luor-1,2,3,4-tetrahydro-2,4-ethanoacridin, 10 9-amino-8-methyl-l, 2,3,4-tetrahydro-2,4-ethanoacridin, 9-amino-l ,2,3,4-tetrahydro-l, 4-ethanoacridin, 9-amino-8-f luor-1,2,3,4-tetrahydro-l, 4-ethanoacridin, 9-amino-6-trif luormethyl-1,2,3,4-tetrahydro-l, 4-ethanoacridin, 15 9-amino-7-fluor-1,2,3,4-tetrahydro-l,4-ethanoacridin, og 9-amino-8-methoxy-l ,2,3,4-tetrahydro-l, 4-methanoacridin.
2. Forbindelse ifølge krav 1, kendetegnet ved, at Y og Z er direkte bindinger, P er CH2, og Q er ch2ch2.
3. Forbindelse ifølge krav 2, kendetegnet ved, at R betyder hydrogen, og R^ betyder hydrogen eller aryl-lavere alkyl.
4. Forbindelse ifølge krav 3, kendet egnet ved, at den er 9-anilino-l,4-methano-l,2,3,4-tetrahydroacri- 25 din.
5. Farmaceutisk præparat, kendetegnet ved, at det indeholder en forbindelse ifølge krav 1 som aktiv bestanddel i forbindelse med et farmaceutisk acceptabelt bærestof og/eller tilsætningsstof. 30 6. .Anvendelse af en forbindelse ifølge krav 1 til fremstilling af et lægemiddel med hukommelsesforøgende aktivitet. 35 DK 168011 B1 16
7. Fremgangsmåde til fremstilling af et 4-amino-qui-nolinderivat ifølge krav 1 og med den almene formel la s RySi x L '1 \ (Ia) 10 i hvilken R betyder hydrogen, lavere alkyl eller lavere alkylcarbonyl, betyder hydrogen, lavere alkyl, lavere alkylcarbonyl, aryl, di-lavere alkylamino-lavere alkyl, ary1-lavere alkyl, diary1-lavere alkyl, oxygen-broholdigt 15 aryl-lavere alkyl eller oxygen-broholdigt diary 1-lavere alkyl, X betyder hydrogen, lavere alkyl, cycloalkyl, lavere alkoxy, halogen, hydroxy, nitro, trifluormethyl, formyl, lavere alkylcarbonyl, arylcarbonyl, -SH, lavere alkylthio, -NHCOR4 eller -NRgRg, hvor R4 betyder hydrogen eller lavere 20 alkyl, og R5 og Rg hver for sig betyder hydrogen, lavere alkyl eller cycloalkyl, stereoisomere, optiske eller geometriske isomere deraf, eller farmaceutisk acceptable syreadditionssalte deraf, kendetegnet ved, at man (a) omsætter en forbindelse med den almene formel 25 Cl x iiib 30 i hvilken X har den ovenfor angivne betydning, med en amin med formlen HNRRlf hvor R og R-j_ har den ovenfor angivne betydning, hvorved der fås en forbindelse med formlen la, eller (b) til fremstilling af en forbindelse med formlen la, 35 hvor X betyder hydrogen, sammen opvarmer en blanding af phosphorpentoxid, Ν,Ν-dimethylcyclohexylamin og hydrochlori- 17 DK 168011 B1 det af aminen med formlen HNRR^, hvor R og R^ har den ovenfor angivne betydning, hvorpå der tilsættes en forbindelse med den almene formel IV aC02Ri3 i hvilken R13 betyder hydrogen eller lavere alkyl, efter-10 fulgt af 3-norbornanon med formlen X) . 15 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| US1475387 | 1987-02-13 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK72388D0 DK72388D0 (da) | 1988-02-12 |
| DK72388A DK72388A (da) | 1988-08-14 |
| DK168011B1 true DK168011B1 (da) | 1994-01-17 |
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| DK072388A DK168011B1 (da) | 1987-02-13 | 1988-02-12 | 4-amino-quinolinderivater, en fremgangsmaade til fremstilling deraf, farmaceutisk praeparat indeholdende disse derivater samt deres anvendelse til fremstilling af et laegemiddel |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US4897400A (da) |
| EP (1) | EP0278499B1 (da) |
| JP (1) | JP2736254B2 (da) |
| KR (1) | KR960012366B1 (da) |
| AT (1) | ATE112270T1 (da) |
| AU (1) | AU596887B2 (da) |
| CA (1) | CA1341335C (da) |
| DE (1) | DE3851643T2 (da) |
| DK (1) | DK168011B1 (da) |
| ES (1) | ES2061530T3 (da) |
| FI (1) | FI90416C (da) |
| HU (1) | HU205908B (da) |
| IE (1) | IE64493B1 (da) |
| IL (1) | IL85401A (da) |
| NO (1) | NO173990C (da) |
| NZ (1) | NZ223485A (da) |
| PH (1) | PH24725A (da) |
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| 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 |
| DE3889302T2 (de) | 1987-12-03 | 1994-10-20 | Mitsubishi Chem Ind | 9-(Acylamino)tetrahydroacridinderivate und wahrnehmungssteigernde Mittel davon als aktiver Wirkstoff. |
| 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 |
| US3318895A (en) * | 1963-12-05 | 1967-05-09 | Squibb & Sons Inc | Production of 12-substituted-6, 7, 8, 9, 10, 11-hexahydrocycloocta[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 |
| BE658695A (da) * | 1964-02-03 | 1965-07-22 | ||
| US3580915A (en) * | 1968-09-16 | 1971-05-25 | American Home Prod | 1,2,3,4-tetrahydrobenzol(b)(1,6)naphthyridine derivatives |
| US3541066A (en) * | 1968-09-16 | 1970-11-17 | American Home Prod | 2,3-dihydro-1,4-ethanobenzo(b)(1,5)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 |
| US3657233A (en) * | 1970-04-30 | 1972-04-18 | American Home Prod | 10-morpholino-1 2 3 4-tetrahydrobenzo(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 |
| 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 |
| EP0179383B1 (en) * | 1984-10-25 | 1991-05-29 | Hoechst-Roussel Pharmaceuticals Incorporated | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds, a process for their preparation and their use as medicaments |
| US4695573A (en) * | 1984-10-25 | 1987-09-22 | Hoechst-Roussel Pharmaceuticals Inc. | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds |
| US4631286A (en) * | 1984-10-25 | 1986-12-23 | 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 |
| JPS6473A (en) * | 1986-10-31 | 1989-01-05 | Sumitomo Pharmaceut Co Ltd | Novel aminoacridine derivative |
| 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 |
| DE3889302T2 (de) * | 1987-12-03 | 1994-10-20 | Mitsubishi Chem Ind | 9-(Acylamino)tetrahydroacridinderivate und wahrnehmungssteigernde Mittel davon als aktiver Wirkstoff. |
-
1987
- 1987-02-13 US US07/014,753 patent/US4897400A/en not_active Expired - Lifetime
-
1988
- 1988-02-11 IL IL85401A patent/IL85401A/xx not_active IP Right Cessation
- 1988-02-11 EP EP88101973A patent/EP0278499B1/en not_active Expired - Lifetime
- 1988-02-11 DE DE3851643T patent/DE3851643T2/de not_active Expired - Fee Related
- 1988-02-11 NZ NZ223485A patent/NZ223485A/en unknown
- 1988-02-11 ES ES88101973T patent/ES2061530T3/es not_active Expired - Lifetime
- 1988-02-11 PH PH36487A patent/PH24725A/en unknown
- 1988-02-11 AT AT88101973T patent/ATE112270T1/de not_active IP Right Cessation
- 1988-02-11 FI FI880634A patent/FI90416C/fi not_active IP Right Cessation
- 1988-02-11 PT PT86749A patent/PT86749B/pt not_active IP Right Cessation
- 1988-02-12 ZA ZA88989A patent/ZA88989B/xx unknown
- 1988-02-12 JP JP63029044A patent/JP2736254B2/ja not_active Expired - Fee Related
- 1988-02-12 CA CA000558816A patent/CA1341335C/en not_active Expired - Fee Related
- 1988-02-12 KR KR1019880001341A patent/KR960012366B1/ko not_active Expired - Fee Related
- 1988-02-12 AU AU11670/88A patent/AU596887B2/en not_active Ceased
- 1988-02-12 IE IE39188A patent/IE64493B1/en not_active IP Right Cessation
- 1988-02-12 DK DK072388A patent/DK168011B1/da not_active IP Right Cessation
- 1988-02-12 HU HU88686A patent/HU205908B/hu not_active IP Right Cessation
- 1988-02-12 NO NO880627A patent/NO173990C/no unknown
- 1988-07-08 US US07/218,755 patent/US5401749A/en not_active Expired - Fee Related
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| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |
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