DK167251B1 - N-(substitueret alkyliden)-1,2,3,4-tetrahydro-9-a cridinaminer, en fremgangsmaade til deres fremstilling, en anvendelse deraf til fremstilling af et laegemiddel, og farmaceutiske praeparater deraf - Google Patents
N-(substitueret alkyliden)-1,2,3,4-tetrahydro-9-a cridinaminer, en fremgangsmaade til deres fremstilling, en anvendelse deraf til fremstilling af et laegemiddel, og farmaceutiske praeparater deraf Download PDFInfo
- Publication number
- DK167251B1 DK167251B1 DK497888A DK497888A DK167251B1 DK 167251 B1 DK167251 B1 DK 167251B1 DK 497888 A DK497888 A DK 497888A DK 497888 A DK497888 A DK 497888A DK 167251 B1 DK167251 B1 DK 167251B1
- Authority
- DK
- Denmark
- Prior art keywords
- tetrahydro
- acridinamine
- lower alkyl
- preparation
- compound according
- Prior art date
Links
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- 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
- 230000037396 body weight Effects 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
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 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
- 230000000052 comparative effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical group OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 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
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002708 enhancing effect Effects 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
- 238000002474 experimental method Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 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
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid 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
- 206010027175 memory impairment Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GDMUKNANKXDMAF-UHFFFAOYSA-N n-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)-1-phenylmethanimine Chemical compound C=12CCCCC2=NC2=CC(Cl)=CC=C2C=1N=CC1=CC=CC=C1 GDMUKNANKXDMAF-UHFFFAOYSA-N 0.000 description 1
- GHZLOFXSALULLM-UHFFFAOYSA-N n-(6-methoxy-1,2,3,4-tetrahydroacridin-9-yl)-1-phenylmethanimine Chemical compound C=12CCCCC2=NC2=CC(OC)=CC=C2C=1N=CC1=CC=CC=C1 GHZLOFXSALULLM-UHFFFAOYSA-N 0.000 description 1
- FISFSWPOJLYBHT-UHFFFAOYSA-N n-(6-methyl-1,2,3,4-tetrahydroacridin-9-yl)-1-phenylmethanimine Chemical compound C=12CCCCC2=NC2=CC(C)=CC=C2C=1N=CC1=CC=CC=C1 FISFSWPOJLYBHT-UHFFFAOYSA-N 0.000 description 1
- KJECOIPTGOVVSL-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-1,2,3,4-tetrahydroacridin-9-amine Chemical compound C1=CC(F)=CC=C1CNC1=C(CCCC2)C2=NC2=CC=CC=C12 KJECOIPTGOVVSL-UHFFFAOYSA-N 0.000 description 1
- UEJXGDKPCPJCAE-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroacridin-9-amine Chemical compound C1=CC(OC)=CC=C1CNC1=C(CCCC2)C2=NC2=CC=CC=C12 UEJXGDKPCPJCAE-UHFFFAOYSA-N 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
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 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
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 229960001416 pilocarpine Drugs 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
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent 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
- 230000011664 signaling Effects 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 235000012773 waffles Nutrition 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
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- Plural Heterocyclic Compounds (AREA)
Description
i DK 167251 B1
Den foreliggende opfindelse angår hidtil ukendte N-- C substitueret alkyliden) -1,2,3,4-tetrahydroacridinaminer med formlen I
5 H
A
hvori R1 betyder phenyl eller phenyl-lavere alkyl, hvor phenyl eventuelt er substitueret med 1-3 substituenter valgt 15 blandt lavere alkyl, lavere alkoxy, halogen, hydroxy, tri-fluormethyl, nitro og cyano, eller R1 betyder naphthyl, X er hydrogen, lavere alkyl, cycloalkyl, lavere alkoxy, halogen, hydroxy, nitro eller trifluormethyl, stereoisomere, optiske og geometriske isomere deraf, farmaceutisk acceptable syre-20 additionssalte deraf og solvater deraf, som er anvendelige til forbedring af hukommelsen.
Opfindelsen angår også et farmaceutisk præparat, der er ejendommeligt ved det i krav 6's kendetegnende del angivne.
25 Opfindelsen angår desuden en anvendelse af en for bindelse ifølge opfindelsen til fremstilling af et lægemiddel, som er effektivt ved behandling af hukommelsesdysfunktioner, som er karakteriserede ved nedsat cholinerg funktion.
Opfindelsen angår endelig også en fremgangsmåde til 30 fremstilling af forbindelser ifølge opfindelsen, hvilken fremgangsmåde er ejendommelig ved det i krav 8's kendetegnende del angivne.
I hele beskrivelsen og i kravene skal en given kemisk formel eller navn omfatte alle stereoisomere og optiske 35 isomere af forbindelserne med formlen I, hvor sådanne isomere eksisterer, samt farmaceutisk acceptable syreadditionssalte DK 167251 B1 2 deraf og solvater deraf, f.eks. hydrater.
Udtrykket alkyl betyder en ligekædet eller forgrenet alkylgruppe med 1-18 carbonatomer. Eksempler herpå omfatter methyl, n-propyl, isobutyl, heptyl, decyl, dodecyl, hexadecyl 5 og octadecyl.
Udtrykket lavere alkyl betyder en ligekædet eller forgrenet alkylgruppe med 1-6 carbonatomer. Eksempler herpå omfatter methyl, ethyl, n-propyl, isobutyl, pentyl og hexyl.
Udtrykket cycloalkyl betyder en mættet ring indehol-10 dende 3-7 carbonatomer. Eksempler herpå omfatter cyclopropyl, cyclohexyl og cycloheptyl.
Udtrykket halogen betyder fluor, chlor, brom eller iod.
Den nærmest liggende teknik er beskrevet i dansk 15 patentansøgning nr. 4888/85, hvorfra der kendes 9-amino--1,2,3,4-tetrahydroacridinderivater med acetylcholinestera-seinhiberende virkning.
Imidlertid er alle de kendte forbindelser sådanne, der i 9-stillingen indeholder en aminogruppe -NH2, som even-20 tuelt er mono- eller disubstitueret, medens forbindelserne ifølge opfindelsen i 9-stillingen indeholder en væsentlig anderledes struktur, nemlig en iminomethylengruppering:
H
/
25 -N=C
V
Ud over at være en væsentlig anderledes struktur 30 udgør grupperingen også en ikke nærliggende variation set i forhold til de kendte, eventuelt substituerede aminogrupper. Desuden kan man ikke ud fra de kendte forbindelsers virkning antage, at forbindelser med denne væsentlig anderledes struktur også har en sådan virkning. Herudover indeholder de 35 kendte forbindelser i den højre side af ringsystemet typisk en cyclohexan-l-ol-ring, dvs. cyclohexan substitueret med en hydroxygruppe, og kan yderligere indeholde en dobbeltbinding i denne ring, medens forbindelserne ifølge opfindelsen på DK 167251 B1 3 dette sted indeholder en usubstitueret cyclohexanring, dvs. en ring, som er mættet og ikke indeholder nogen polær eller funktionel gruppe. I betragtning af de nævnte forskelle må forbindelserne ifølge opfindelsen anses at adskille sig 5 væsentligt fra de kendte forbindelser.
Forbindelserne ifølge den foreliggende opfindelse fremstilles ved anvendelse af synteserækkefølgen beskrevet nedenfor.
10 Syntese
Forbindelserne med formlen I kan fremstilles ved omsætning af en forbindelse med formlen II med et aldehyd med formlen III, hvor definitionerne af X og er som tidligere angivet. Typisk gennemføres reaktionen i et egnet 15 opløsningsmiddel, såsom benzen, toluen eller xylen, ved en temperatur på ca. 80-150eC i nærværelse af en base, såsom piperidin, morpholin, diethylamin eller diisopropylamin.
20 I 2 x“f· || 1 + RicHO -► (X) 25 (ID (III)
Forbindelserne med formlen I ifølge den foreliggende opfindelse er anvendelige ved behandling af forskellige hukommelsesdysfunktioner, der er karakteriserede ved nedsat 30 cholinerg funktion, såsom Alzheimer's sygdom.
Denne anvendelighed viser sig ved disse forbindelsers evne til at inhibere enzymet acetylcholinesterase og derved forøge acetylcholin-niveauer i hjernen. Desuden er forbindelserne ifølge den foreliggende opfindelse generelt mindre 35 toksiske og har et bredere terapeutisk vindue, dvs. en større afstand mellem virksomme doser og toksiske doser, end hidtil DK 167251 B1 4 kendte forbindelser, såsom tacrin og physostigmin, hvilket gør dem mere terapeutisk acceptable.
Evnen til at inhibere acetylcholinesterase bestemmes ved den fotometriske metode ifølge Ellman et al., Biochem.
5 Pharmacol. 7, 88 (1961). Resultater af acetylcholinesterase--inhibering for nogle af forbindelserne ifølge den foreliggende opfindelse er vist i tabel I sammen med resultaterne for sammenligningsforbindelser.
10 Acetylcholinesterase-inhiberinasbesteTmnp-1
Tabel I
Forbindelse Acetylcholinesterase- inhibering 15 IC50 (molær) N-Phenylmethylen-1,2,3,4-tetra- hydro-9-acridinamin 2,3 x 10"7 20 9-Amino-N- [ (2 -hydroxyphenyl) - methylen]-1,2,3,4-tetrahydro- acridin-hemi-fumarat 5,1 x 10"6 (Sml.forbindelser) 25 Tacrin (9-amino-1,2,3,4-tetra- hydroacridin) 3,1 x 10"7
Physostigmin 6,0 x 10"® DK 167251 B1 5
Denne anvendelighed påvises yderligere ved disse forbindelsers evne til at genskabe cholinergt mangelfuld hukommelse i et mørke-undgåelsesforsøg, hvor de generelt er aktive over et bredere dosisområde end hidtil kendte for-5 bindeiser, hvilket er en udpræget terapeutisk fordel. Ved denne bestemmelse testes mus for deres evne til at huske en ubehagelig stimulus i en periode på 24 timer. En mus anbringes i et kammer, som indeholder en mørk sektion. Et stærkt glødelys driver musen til den mørke sektion, hvor 10 den modtager et elektrisk chok gennem metalplader på gulvet. Dyret fjernes fra forsøgsapparaturet og testes igen, 24 timer senere, for dets evne til at huske det elektriske chok.
Hvis scopolamin, et anticholinergt stof, som er kendt for at forårsage hukommelsessvækkelse, indgives før et dyrs 15 første udsættelse for forsøgskammeret, går dyret igen ind i den mørke sektion kort efter at være blevet anbragt i forsøgskammeret 24 timer senere. Denne virkning af scopolamin blokeres af en aktiv forsøgsforbindelse, hvilket resulterer i et større interval, før dyret igen går ind i den mørke 20 sektion.
Resultaterne for en aktiv forbindelse udtrykkes som den procentdel af en gruppe dyr, hos hvilke virkningen af scopolamin blokeres, hvilket konstateres ved et forøget interval mellem dyrenes anbringelse i forsøgskammeret og 25 deres genindtræden i den mørke del.
DK 167251 B1 6 Mørke-undgåelsesforsøg
Tabel II
% Dyr med blokering 5 Dosis (mg/kg af scopolamin- kropsvægt, fremkaldt hukcmmel-
Forbindelse s.c.) sessvækkelse 10 N-Phenylmethylen-1,2,3,4- 0,31 27% tetrahydro-9-acridinamin 5,0 60% (Sml.forbindelser)
Tacrin 0,63 13% 15 Pilocarpin 5,0 13%
Effektive mængder af forbindelserne ifølge opfindelsen kan indgives til en patient ved en hvilken som helst af 20 forskellige metoder, f.eks. oralt som i kapsler eller tabletter, parenteralt i form af sterile opløsninger eller suspensioner og i nogle tilfælde intravenøst i form af sterile opløsninger.
Slutprodukterne i form af fri base kan, selv om de 25 er effektive i sig selv, formuleres og indgives i form af deres farmaceutisk acceptable syreadditionssalte med henblik på stabilitet, krystallisationsnemhed, forøget opløselighed og lignende.
Syrer, der er anvendelige til fremstilling af de 30 farmaceutisk acceptable syreadditionssalte ifølge opfindelsen, omfatter uorganiske syrer, såsom saltsyre, hydrogen-bromidsyre, svovlsyre, salpetersyre, phosphorsyre og per-chlorsyre, samt organiske syrer, såsom vinsyre, citronsyre, eddikesyre, ravsyre, maleinsyre, fumarsyre og oxalsyre.
35 De aktive forbindelser ifølge den foreliggende opfin delse kan indgives oralt, f.eks. sammen med et indifferent fortyndingsmiddel eller et spiseligt bæremateriale, eller DK 167251 B1 7 de kan indkaples i gelatinekapsler eller komprimeres til tabletter. Til oral terapeutisk indgivelse kan de aktive forbindelser ifølge opfindelsen inkorporeres sammen med excipienser og anvendes i form af tabletter, pastiller, 5 kapsler, eliksirer, suspensioner, sirupper, vafler, tyggegummi og lignende. Disse præparater bør indeholde mindst 0,5% aktiv forbindelse, men mængden kan varieres afhængigt af den bestemte form og kan hensigtsmæssigt være på mellem 4 og ca. 70% af enhedens vægt. Mængden af aktiv forbindelse 10 i sådanne præparater er sådan, at der opnås en egnet dosis. Foretrukne materialer og præparater ifølge den foreliggende opfindelse fremstilles således, at en oral dosisenhedsform indeholder mellem 1,0 og 300 mg aktiv forbindelse.
Tabletter, piller, kapsler, pastiller og lignende 15 kan også indeholde de følgende bestanddele: et bindemiddel, såsom mikrokrystallinsk cellulose, tragantgummi eller gelatine, et excipiens, såsom stivelse eller laktose, et desintegreringsmiddel, såsom alginsyre, "Primogel" og majsstivelse, et smøremiddel, såsom magnesiumstearat eller 20 "Sterotex", et glidemiddel, såsom kolloidt siliciumdioxid, og et sødemiddel, såsom saccharose eller saccharin, eller et smagsstof, såsom pebermynte, methylsalicylat eller orangesmagsstof. Når dosisenhedsformen er en kapsel, kan den foruden materialer af den ovennævnte type indeholde et flydende 25 bæremateriale, såsom en fed olie. Andre dosisenhedsformer kan indeholde forskellige andre materialer, som modificerer dosisenhedens fysiske form, f.eks. som overtræk. Således kan tabletter eller piller være overtrukket med sukker, shellak eller andre enteriske overtræksmidler. En sirup kan 30 foruden de aktive forbindelser indeholde saccharose som et sødemiddel og visse konserveringsmidler, farvestoffer og smagsstoffer. Materialer, der anvendes ved fremstillingen af disse forskellige præparater, bør være farmaceutisk rene og ikke-giftige i de anvendte mængder.
35 Til parenteral terapeutisk indgivelse kan de aktive forbindelser ifølge opfindelsen være inkorporeret i en op- DK 167251 B1 8 løsning eller suspension. Disse præparater bør indeholde mindst 0,1% aktiv forbindelse, men mængden kan være på mellem 0,5 og ca. 30% af præparatets vægt. Mængden af aktiv forbindelse i sådanne præparater er sådan, at der opnås en egnet 5 dosis. Foretrukne materialer og præparater ifølge den foreliggende opfindelse fremstilles således, at en parenteral dosisenhed indeholder mellem 0,5 og 100 mg aktiv forbindelse.
Opløsningerne eller suspensionerne kan også indeholde de følgende bestanddele: et sterilt fortyndingsmiddel, såsom 10 vand til injektion, saltopløsning, ikke-flygtige olier, polyethylenglycoler, glycerol, propylenglycol eller andre syntetiske opløsningsmidler, antibakterielle midler, såsom benzylalkohol eller methylparabener, antioxidanter, såsom ascorbinsyre eller natriumbisulfit, chelateringsmidler, 15 såsom ethylendiamintetraeddikesyre, puffere, såsom acetater, citrater eller phosphater, eller midler til regulering af toniciteten, såsom natriumchlorid eller dextrose. De paren-terale præparater kan være indeholdt i éngangssprøjter eller flerdosisbeholdere fremstillet af glas eller plast.
20 Eksempler på forbindelserne ifølge den foreliggende opfindelse omfatter: N-(phenylmethylen)-1,2,3,4-tetrahydro-9-acridinamin, N- [ (4-fluorphenyl) me thyl en] -1,2,3,4-tetrahydro-9-acridinamin, 25 N- [ (3-fluorphenyl)methylen] -1,2,3,4-tetrahydro-9- acridinamin, N- [ (2-fluorphenyl)methylen] -1,2,3,4-tetrahydro-9-acridinamin, N- [ (2-chlorphenyl)methylen] -l, 2,3,4-tetrahydro-9-30 acridinamin, N-[(4-chlorphenyl)methylen]-1,2,3,4-tetrahydro-9-acridinamin, N- [ (2,4-dichlorphenyl) methylen] -1,2,3,4-tetrahydro-9-acridinamin, 35 N- [ (4-methoxyphenyl) methylen] -1,2,3,4-tetrahydro-9- acridinamin, DK 167251 B1 9 6- chlor-N- (phenylmethylen) -1,2,3,4-tetrahydro-9-acri-dinamin, 7- chlor-N- (phenylmethylen) -1,2,3,4-tetrahydro-9-acri- dinamin 5 7-methyl-N-(phenylmethylen)-1,2,3,4-tetrahydro-9- acridinamin, 7-methoxy-N- (phenylmethylen) -1,2,3,4-tetrahydro-9-acridinamin, N- (phenylmethylen) -6-trifluormethyl-l,2,3,4-tetra- 10 hydro-9-acridinamin, N- [ (4-nitrophenyl) methyl en] -1,2,3,4-tetrahydro-9-acridinamin, N- [ (4-cyanophenyl) methylen] -1,2,3,4-tetrahydro-9-acridinamin, 15 N-[ (2-hydroxyphenyl)methylen]-1,2,3,4-tetrahydro-9- acridinamin, N- [ (4-hydroxyphenyl) methylen] -1,2,3,4-tetrahydro-9-acridinamin, 1,2,3,4-tetrahydro-N-[(4-trifluormethylphenyl)methy- 20 len]-9-acridinamin, 6-methoxy-N- (phenylmethylen) -1,2,3,4-tetrahydro-9-acridinamin, 6-methyl-N-(phenylmethylen) -1,2,3,4-tetrahydro-9-acridinamin, 25 7-methyl-N- (phenylmethylen) -1,2,3,4-tetrahydro-9- acridinamin, 6-f luor-N- (phenylmethylen) -1,2,3,4-tetrahydro-9-acri-dinamin, N- [ (1-naphthyl) methylen ] -1,2,3,4-tetrahydro-9-acridin- 30 amin, N- [ (2-naphthyl) methylen] -1,2,3,4-tetrahydro-9-acridin- amin,
De følgende eksempler tjener til at illustrere den foreliggende opfindelse.
DK 167251 B1 10
Eksempel 1 N-Phenvlmethvlen-l.2.3.4-tetrahvdro-9-acridinamin 4.0 g l,2,3,4-tetrahydro-9-acridinamin opløses i 400 ml varm toluen, og derpå tilsættes 3,5 g morpholin og 2,65 5 g benzaldehyd (friskt vasket med vandig I^CC^-opløsning) , og reaktionsblandingen bringes til tilbagesvaling med en Dean-Stark-vandfraskiller. Efter at opløsningen er tilbage-svalet natten over tilsættes yderligere 2,65 g benzaldehyd, og tilbagesvalingen fortsættes i yderligere 5 timer. Efter 10 dette tidsrum fjernes de flygtige stoffer under formindsket tryk, og remanensen renses ved flashchromatografi (EtOAc), hvorved fås 3,18 g rent produkt efter triturering med Et20. Analytisk rent materiale fås ved omkrystallisation fra cyclohexan, smp. 168-169°C.
15 Analyse for C% H% N%
Beregnet: 83,88 6,33 9,78
Fundet: 83,99 6,34 9,64 20 Eksempel 2 Ν-Γ (2-Methvlphenvl) methvlenl -1,2,3.4-tetrahvdro-9-acridinamin 4.0 g l,2,3,4-tetrahydro-9-acridinamin suspenderes i 400 ml toluen, hvortil der successivt sættes 3,5 g morpholin og 3,0 g o-tolualdehyd. Reaktionsblandingen tilbagesvales 25 natten over, og derpå tilsættes yderligere 1,5 g aldehyd. Tilbagesvalingen fortsættes i yderligere 6 timer, hvorpå reaktionsblandingen koncentreres og renses ved flashchromatografi (CH2C12, derpå 20% EtOAc/CH2Cl2). Fraktioner indeholdende det rene produkt koncentreres og omkrystalliseres 30 fra benzen/pentan, hvorved fås 3,32 g analytisk rent produkt, smp. 160-162 ° C.
Analyse for C2iH2gN2: C% H% N%
Beregnet: 83,96 6,71 9,33 35 Fundet: 83,77 6,78 9,24 DK 167251 B1 11
Eksempel 3 N-Γ(4-Fluorphenyl)methvlen]-1.2.3.4-tetrahvdro-9-acridinamin 4.0 g l,2,3,4-tetrahydro-9-acridinamin tilbagesvales i 400 ml toluen indeholdende 3,5 g morpholin og 3,10 g 4- 5 fluorbenzaldehyd, der er frisk vasket i K2CO3. Reaktionsblandingen tilbagesvales over 2 nætter og koncentreres derpå, renses ved flashchromatografi (20% EtOAc/CH2Cl2) og omkrystalliseres fra dichlormethan/pentan, hvorved fås 2,20 g analytisk rent produkt, smp. 161-163'C.
10 Analyse for C20Hi7FN2: C% H% N%
Beregnet: 78,91 5,63 9,20
Fundet: 79,06 5,66 9,19 15 Eksempel 4 Ν-Γ(2-Chlorphenvl^methvlen|-l.2.3.4-tetrahvdro-9-acridinamin 4.0 g l,2,3,4-tetrahydro-9-acridinamin suspenderes i 400 ml toluen, hvortil der successivt sættes 3,5 g morpholin og 3,5 g 2-chlorbenzaldehyd. Reaktionsblandingen tilbage- 20 svales natten over, og derpå tilsættes yderligere 1,7 g aldehyd. Tilbagesvalingen fortsættes i yderligere 16 timer, hvorpå reaktionsblandingen koncentreres og renses ved flash-chromatografi (CH2C12, derpå 20% EtOAc/CH2Cl2). Fraktioner indeholdende produktet koncentreres og omkrystalliseres fra 25 Et20/pentan, hvorved fås 2,10 g analytisk rent produkt, smp. 165-166°C.
Analyse for C2qH17C1N2: C% H% N%
Beregnet: 74,87 5,34 8,73 30 Fundet: 74,75 5,34 8,57
Eksempel 5 N-r 4-Chlorphenvl)methvlenl-1.2.3.4-tetrahvdro-9-acridinamin 4.0 g l,2,3,4-tetrahydro-9-acridinamin tilbagesvales 35 i 400 ml toluen indeholdende 3,5 g morpholin og 3,5 g 4- chlorbenzaldehyd, der er nyvasket i K2C03. Reaktionsblandin- DK 167251 B1 12 gen tilbagesvales i 2 nætter, hvorpå den koncentreres, renses ved flashchromatografi (20% EtOAc/CH2Cl2) og omkrystalliseres fra dichlormethan/pentan, hvorved fås 1,95 g analytisk rent produkt, smp. 169-170°C.
5 Analyse for ¢20^17^^^ C% H% N%
Beregnet: 74,87 5,34 8,73
Fundet: 74,78 5,37 8,65 10 Eksempel 6 N-Γ(2.6-Dichlorphenvl)methvlenl-1,2,3,4-tetrahvdro-9-acridinamin 3,23 g l,2,3,4-tetrahydro-9-acridinamin suspenderes i 400 ml toluen, hvortil der successivt sættes 2,8 g mor-pholin og 3,5 g 2,6-dichlorbenzaldehyd. Reaktionsblandingen 15 tilbagesvales natten over, og derefter tilsættes yderligere 1,7 g aldehyd. Tilbagesvalingen fortsættes i yderligere 16 timer, hvorpå reaktionsblandingen koncentreres og renses ved flashchromatografi (CH2C12, derpå 20% EtOAc/CH2Cl2). Fraktioner indeholdende produktet koncentreres og omkrystal-20 liseres fra benzen/hexan, hvorved fås 2,18 g analytisk rent produkt, smp. 200-202°C.
Analyse for C20H16cl2N2: C% H% N%
Beregnet: 67,61 4,54 7,89 25 Fundet: 67,47 4,47 7,73
Eksempel 7 N-Γ(4-Methoxvphenvl)methvlen]-1,2.3,4-tetrahvdro-9-acridinamin 4,0 g l,2,3,4-tetrahydro-9-acridinamin tilbagesvales 30 natten over i 400 ml toluen indeholdende 3,5 g morpholin og 3,4 g 4-methoxybenzaldehyd. Ved denne tids ophør tilsættes yderligere 1,7 g aldehyd, og opvarmningen fortsættes i 6 timer til. Reaktionsblandingen koncentreres derpå og renses ved flashchromatografi (CH2Cl2, derpå 10% EtOAc/CH2Cl2).
35 Fraktioner indeholdende produktet koncentreres og omkrystalliseres fra benzen/pentan, hvorved fås 3,37 g analytisk DK 167251 B1 13 rent materiale, smp. 160-162°C.
Analyse for ¢21^201^05 C% H% N%
Beregnet: 79,72 6,37 8,85 5 Fundet: 79,78 6,43 8,82
Eksempel 8 N- Γ M-Trif luormethvlphenvllmethvlenl -1.2.3,4-tetrahydro-9-acridinamin 10 4,00 g 1,2,3,4-tetrahydro-9-acridinamin tilbagesvales i 24 timer i 400 ml toluen indeholdende 3,50 g morpholin og 4,35 g 4-trifluormethylbenzaldehyd. Derefter tilsættes yderligere 2,0 g aldehyd, og tilbagesvalingen fortsættes i yderligere 16 timer. Derefter koncentreres reaktionsblandingen, 15 og remanensen renses ved flashchromatografi (CH2CI2, derpå 20% EtOAc/CH2Cl2). Fraktioner indeholdende produktet koncentreres og omkrystalliseres fra benzen/pentan, hvorved fås 3,46 g analytisk rent produkt, smp. 203-205°C.
Analyse for C21H27F3N2: 20 C% H% N%
Beregnet: 71,18 4,84 7,90
Fundet: 71,57 4,88 7,94
Eksempel 9 25 9-Amino-N- Γ (2-hvdroxvphenvl)methvlen1 -1,2.3.4-tetrahydro-acridin-hemifumarat
En blanding af 4,1 g tacrin, 3,3 ml salicylaldehyd og 3,6 ml morpholin i 200 ml toluen tilbagesvales med fjernelse af vand i 2 timer. Opløsningsmidlerne afdampes derpå, 30 og forbindelsen passeres gennem en søjle af "Florisil" (DCM), hvorved fås 2,7 g gult fast stof, smp. 173-183°c.
Fumarsyreadditionssaltet dannes i isopropanol og omkrystalliseres fra isopropylether/methanol, hvorved fås 1,2 g gult pulver, smp. 217-219°c.
14 DK 167251 B1
Analyse for C20H18N2°* 0,50411404: C% H% N%
Beregnet; 73,31 5,59 7,77
Fundet; 73,03 5,77 7,76 5
Eksempel 10 N- Γ (4-NitrophenvH methylenl -1.2,3,4-tetrahvdro-9-acridinamin 4,0 g l,2,3,4-tetrahydro-9-acridinamin tilbagesvales i 400 ml toluen indeholdende 3,5 g morpholin og 3,78 g 10 4-nitrobenzaldehyd. Efter 48 timer tilsættes yderligere 3,78 g aldehyd, og tilbagesvalingen fortsættes i yderligere 24 timer. Derefter koncentreres og renses reaktionsblandingen ved flashchromatografi. Fraktioner indeholdende produktet koncentreres og omkrystalliseres fra CH2Cl2/pentan, hvorved 15 fås 3,38 g produkt, smp. 237-238°C.
Analyse for C2oHi7N3°2: C% H% N%
Beregnet; 72,49 5,17 12,68
Fundet: 72,60 5,12 12,44 20
Eksempel 11 N- Γ (4-CvanophenvH methvlenl -1,2.3.4-tetrahvdro-9-acridinamin 3,2 g l,2,3,4-tetrahydro-9-acridinamin tilbagesvales i 300 ml toluen indeholdende 2,8 g morpholin og 2,60 g 4-25 cyanobenzaldehyd. Efter 24 timer koncentreres og renses reaktionsblandingen ved flashchromatografi. Fraktioner indeholdende produktet koncentreres og omkrystalliseres fra CH2Cl2/pentan, hvorved fås 2,30 g produkt, smp. 204-205*C. Analyse for C21H17N3: 30 C% H% N%
Beregnet: 81,00 5,50 13,49
Fundet: 81,00 5,48 13,53 35 DK 167251 B1 15
Eksempel 12 N-Γ(1-naphthvl)methvlen]-1.2,3,4-tetrahvdro-9-acridinamin 4,0 g l,2,3,4-tetrahydro-9-acridinamin tilbagesvales i 400 ml toluen indeholdende 3,5 g morpholin og 3,10 g 5 1-naphthaldehyd. Reaktionsblandingen tilbagesvales over 2 nætter, hvorpå den koncentreres og renses ved flashchroma-tografi (20% EtOAc/CH2Cl2), hvorved fås 2,30 g analytisk rent produkt efter krystallisation fra benzen/pentan, smp. 229-231eC.
10 Analyse for C24H20N2: C% H% N%
Beregnet: 85,70 6,00 8,30
Fundet: 85,59 5,88 8,35 15 20
Claims (8)
1. N-(Substitueret alkyliden)-1,2,3,4-tetrahydro-9--acridinaminer, kendetegnet ved, at de har formlen I 5 H ^v.Ri R CCO hvori R1 betyder phenyl eller phenyl-lavere alkyl, hvor 15 phenyl eventuelt er substitueret med 1-3 substituenter valgt blandt lavere alkyl, lavere alkoxy, halogen, hydroxy, tri-fluormethyl, nitro og cyano, eller R1 betyder naphthyl, X er hydrogen, lavere alkyl, cycloalkyl, lavere alkoxy, halogen, hydroxy, nitro eller trifluormethyl, stereoisomere, optiske 20 eller geometriske isomere deraf, farmaceutisk acceptable syreadditionssalte deraf og solvater deraf.
2. Forbindelser ifølge krav 1, kendetegnet ved, at Ri er phenyl, der eventuelt er substitueret med 1-3 substituenter valgt blandt lavere alkyl, lavere alkoxy, 25 halogen, hydroxy, trifluormethyl, nitro og cyano.
3. Forbindelser ifølge krav 2, kendetegnet ved, at X er hydrogen, lavere alkyl eller trifluormethyl.
4. Forbindelse ifølge krav 1, kendetegnet ved, at den er N-(phenylmethylen)-1,2,3,4-tetrahydro-9-acri- 30 dinamin eller et farmaceutisk acceptabelt syreadditionssalt deraf.
5. Forbindelse ifølge krav 1, kendetegnet ved, at den er 9-amino-N-(2-hydroxyphenyl)-methylen-l,2,3,4--tetrahydroacridin eller et farmaceutisk acceptabelt syre- 35 additionssalt deraf. DK 167251 B1 17
6. Farmaceutisk præparat, kendetegnet ved, at det som aktiv bestanddel indeholder en forbindelse ifølge krav 1 og et egnet bæremateriale hertil.
7. Anvendelse af en forbindelse ifølge krav 1 til 5 fremstilling af et lægemiddel, som er effektivt ved behandlingen af hukommelsesdysfunktioner, som er karakteriserede ved nedsat cholinerg funktion.
8. Fremgangsmåde til fremstilling af en forbindelse ifølge krav 1, kendetegnet ved, at en forbindelse 10 med formlen II nh2 'j IJ (11) 15 hvori X har den i krav 1 angivne betydning, omsættes med et aldehyd med formlen R1CHO, hvori R1 har den i krav 1 angivne 20 betydning. 25 30 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9393587A | 1987-09-08 | 1987-09-08 | |
| US9393587 | 1987-09-08 | ||
| US07/223,846 US5013741A (en) | 1987-09-08 | 1988-07-25 | N-[substituted alkylidene]-1,2,3,4-tetrahydro-9-acridinamines useful for enhancing the cholinergic function in a mammal |
| US22384688 | 1988-07-25 |
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| Publication Number | Publication Date |
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| DK497888D0 DK497888D0 (da) | 1988-09-07 |
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| US (1) | US5013741A (da) |
| EP (1) | EP0306825B1 (da) |
| JP (1) | JP2641915B2 (da) |
| KR (1) | KR890005058A (da) |
| AU (1) | AU620043B2 (da) |
| CA (1) | CA1334669C (da) |
| DE (1) | DE3889043T2 (da) |
| DK (1) | DK167251B1 (da) |
| ES (1) | ES2053652T3 (da) |
| FI (1) | FI89478C (da) |
| HU (1) | HU201017B (da) |
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| US4868177A (en) * | 1988-11-09 | 1989-09-19 | Hoechst-Roussel Pharmaceuticals, Inc. | 1,2,3,4-tetrahydro-1,9-acridinediamines, pharmaceutical compositions and use |
| AU621416B2 (en) * | 1988-11-16 | 1992-03-12 | Hoechst Marion Roussel, Inc. | Hydroxy-1,2,3,4-tetrahydroaminoacridines, a process for their preparation and their use as medicaments |
| FR2640508B1 (fr) * | 1988-12-19 | 1994-07-01 | Dietlin Francois | Nouvelles compositions et nouveaux produits pharmaceutiques assurant la regeneration de leucocytes et leur emploi pour le traitement du syndrome immuno-deficitaire |
| US5175172A (en) * | 1988-12-19 | 1992-12-29 | Francois Dietlin | Method of alleviating AIDS symptoms and compositions therefor |
| US5149813A (en) * | 1989-06-26 | 1992-09-22 | Hoechst-Roussel Pharmaceuticals Incorporated | Process for (1,2,3,4-tetrahydro-9-acridinimino)cyclohexane carboxylic acid and related compounds |
| JPH09500645A (ja) * | 1993-07-22 | 1997-01-21 | ワーナー−ランバート・コンパニー | 制御放出タクリン薬物送達システムおよびその製造方法 |
| CN108047202B (zh) * | 2017-12-20 | 2021-06-11 | 东南大学 | 一种铝离子响应型化合物及其制备方法与应用 |
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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 | ||
| 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 |
| 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 |
| 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 |
| US4575553A (en) * | 1984-06-18 | 1986-03-11 | Bristol-Myers Company | Antitumor m-AMSA analog |
| US4631286A (en) * | 1984-10-25 | 1986-12-23 | Hoechst-Roussel Pharmaceuticals Inc. | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds |
| 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. |
| 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 |
| US4762841A (en) * | 1987-03-30 | 1988-08-09 | Hoechst-Roussel Pharmaceuticals Inc. | Substituted 9-amino-spiro(cycloalkyl(b)quinoline-2,1'cycloalkanes) |
| US4851536A (en) * | 1987-05-07 | 1989-07-25 | American Home Products Corporation | Cyclohexylquinolines as inhibitors of interleukin 1 |
| WO1989002739A1 (en) * | 1987-10-05 | 1989-04-06 | Pfizer Inc. | 4-aminopyridine derivatives |
| IL87861A0 (en) * | 1987-10-05 | 1989-03-31 | Pfizer | 4-aminopyridine derivatives |
| DE3889302T2 (de) * | 1987-12-03 | 1994-10-20 | Mitsubishi Chem Ind | 9-(Acylamino)tetrahydroacridinderivate und wahrnehmungssteigernde Mittel davon als aktiver Wirkstoff. |
-
1988
- 1988-07-25 US US07/223,846 patent/US5013741A/en not_active Expired - Lifetime
- 1988-09-01 EP EP88114248A patent/EP0306825B1/en not_active Expired - Lifetime
- 1988-09-01 ES ES88114248T patent/ES2053652T3/es not_active Expired - Lifetime
- 1988-09-01 DE DE3889043T patent/DE3889043T2/de not_active Expired - Fee Related
- 1988-09-06 FI FI884104A patent/FI89478C/fi not_active IP Right Cessation
- 1988-09-06 IL IL87679A patent/IL87679A0/xx not_active IP Right Cessation
- 1988-09-06 NZ NZ226054A patent/NZ226054A/xx unknown
- 1988-09-07 AU AU21936/88A patent/AU620043B2/en not_active Ceased
- 1988-09-07 CA CA000576693A patent/CA1334669C/en not_active Expired - Fee Related
- 1988-09-07 KR KR1019880011521A patent/KR890005058A/ko not_active Withdrawn
- 1988-09-07 DK DK497888A patent/DK167251B1/da not_active IP Right Cessation
- 1988-09-07 IE IE270388A patent/IE63027B1/en not_active IP Right Cessation
- 1988-09-07 PT PT88444A patent/PT88444B/pt not_active IP Right Cessation
- 1988-09-07 NO NO88883986A patent/NO883986L/no unknown
- 1988-09-07 JP JP63222590A patent/JP2641915B2/ja not_active Expired - Fee Related
- 1988-09-08 HU HU884630A patent/HU201017B/hu not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI884104A0 (fi) | 1988-09-06 |
| DK497888A (da) | 1989-03-09 |
| HU201017B (en) | 1990-09-28 |
| FI89478B (fi) | 1993-06-30 |
| NO883986D0 (no) | 1988-09-07 |
| FI884104A7 (fi) | 1989-03-09 |
| ES2053652T3 (es) | 1994-08-01 |
| JPH01131160A (ja) | 1989-05-24 |
| EP0306825A1 (en) | 1989-03-15 |
| PT88444A (pt) | 1989-07-31 |
| PT88444B (pt) | 1992-10-30 |
| NZ226054A (en) | 1991-08-27 |
| KR890005058A (ko) | 1989-05-11 |
| IE882703L (en) | 1989-03-08 |
| AU2193688A (en) | 1989-03-09 |
| IL87679A0 (en) | 1989-02-28 |
| DE3889043T2 (de) | 1994-10-06 |
| FI89478C (fi) | 1993-10-11 |
| JP2641915B2 (ja) | 1997-08-20 |
| HUT49332A (en) | 1989-09-28 |
| US5013741A (en) | 1991-05-07 |
| NO883986L (no) | 1989-03-09 |
| IE63027B1 (en) | 1995-03-22 |
| DK497888D0 (da) | 1988-09-07 |
| AU620043B2 (en) | 1992-02-13 |
| EP0306825B1 (en) | 1994-04-13 |
| DE3889043D1 (de) | 1994-05-19 |
| CA1334669C (en) | 1995-03-07 |
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| Date | Code | Title | Description |
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| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |
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