DK156649B - Analogifremgangsmaade til fremstilling af 2-oe2-oe2-oe(4-methoxybenzoyl)aminoaaphenylaaethylaa-1-methyl-1-alkylpiperidiniumhalogenider eller 2-oe2-oe2-oe(4-methoxybenzoyl)aminoaaphenylaaethylaa-1-methyl-1-benzylpiperidiniumhalogenider - Google Patents
Analogifremgangsmaade til fremstilling af 2-oe2-oe2-oe(4-methoxybenzoyl)aminoaaphenylaaethylaa-1-methyl-1-alkylpiperidiniumhalogenider eller 2-oe2-oe2-oe(4-methoxybenzoyl)aminoaaphenylaaethylaa-1-methyl-1-benzylpiperidiniumhalogenider Download PDFInfo
- Publication number
- DK156649B DK156649B DK429382A DK429382A DK156649B DK 156649 B DK156649 B DK 156649B DK 429382 A DK429382 A DK 429382A DK 429382 A DK429382 A DK 429382A DK 156649 B DK156649 B DK 156649B
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- methoxybenzoyl
- aminoaaphenylaaethylaa
- formula
- benzylpiperidiniumhalogenider
- Prior art date
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- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- PJWPNDMDCLXCOM-UHFFFAOYSA-N encainide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1CCC1N(C)CCCC1 PJWPNDMDCLXCOM-UHFFFAOYSA-N 0.000 description 8
- 229960001142 encainide Drugs 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- -1 2- [2- [2- [ (4-methoxybenzoyl) amino] phenyl] ethyl] -1-methyl-1-benzylpiperidinium halides Chemical class 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000003288 anthiarrhythmic effect Effects 0.000 description 3
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
DK 156649 B
Den foreliggende opfindelse angâr en analogifremgangsmâde til fremsti11i ng af 2-[2-[2-[(4-methoxybenzoyl)ami no]phenyl]ethyl]-1-methyl- 1-alkylpiperidini umhalogenîder eller 2-[2-[2-[(4-methoxybenzoyl)ami no]-phenyl]ethyl]-l-methyl-l-benzylpiperidiniumhalogenider med den i krav 1 5 angivne formel II, og fremgangsmâden er ejendommelig ved det i krav l's kendetegnende del angivne.
Den tilsvarende piperidinforbindelse, encainid, er en antiar-rhythmisk forbindelse, der i litteraturen ogsâ henvises til som MJ 9067 (USAN And The USP Dictionary of Drug Names 1980, side 122, United States 10 Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockwille, MD 20852, Library of Congress Catalog Card No. 72-88571). Encainid har strukturformel (I) 15 <j¥H2-\N/ ,—, ch3 (i)
HjCO—C0NH_CJ/) 20
De folgende publikationer beskriver den kemiske syntese af encainid og dets antiarrhythmiske egenskaber i dyr.
25 Dykstra, S. J., et al., J. Med. Chem., 16, 1015-1020 (1973).
Stanley J. Dykstra og Joseph L. Minielli, U.S.A. Patent nr.
3,931,195 patenteret 6. januar 1976.
Byrne, J. E„, et al., J. Pharmacology and Experimental Thera-peutics, 200, 147-154 (1977).
30 N-oxid-derivatet af encainid som et antiarrhythmisk middel er genstand for DK-ans0gning nr. 2664/81, nu DK-B 152.671.
Den foreliggende opfindelse vedrdrer kvaternære piperidinium-halogenider, som har strukturformel (II), hvori R er alkyl med 1-4 carbonatomer eller benzyl og X er halogen, sâsom chlor, brom eller iod.
35 2
DK 156649 B
5 CV|2-C©) q (II)
H3C0 -^Q)- «-Q “3 R
10
Disse forbindelser er forbedrede antiarrhythmiske midler. Ved den chloroform-inducerede arrhythmi-test i musen er de omhandlede forbindelser adskillige gange mere aktive end kinidin og kun en smule mindre aktive end encainid. Ved toksicitetstestning i mus er disse kvaternære 15 forbindelser flere gange mindre toksiske end encainid. De er derfor antiarrhythmiske midler af væsentlig styrke og de frembyder fordelen ved formindsket toksicitet i forhold til encainid. De kan administreres ,pâ samme mâde soin encainid. Hojere doser kan, om nodvendigt, i relation til deres komparative toksiciteter, anvendes til behandling af cardial 20 arrhythmi-
De omhandlede forbindelser, fremgangsmâden til fremstilling deraf og deres biologiske virkninger vil fremgâ nærmere af de fplgende eksempler.
Fremgangsmâden, som anvendes til fremstilling af de omhandlede 25 forbindelser med formel (II) involverer opvarmning af omtrentlig stpchiometriske mængder encainid (I) og R-X (hvor R er alkyl med 1-4 carbonatomer eller benzyl, og X er halogen sâsom chlor, brom eller iod) i et passende organisk oplpsningsmiddel ved tilbagesvaling i et tidsrum varierende fra 6 til 24 timer. Acetone er et foretrukkent oplpsnings-30 middel til udfprelse af processen, selv om andre oplosningsmidler, som har været anvendt til dannelse af kvaternære ammoniumsal te, sâsom acetonitril, benzen, chloroform, methanol, dichlorethan og andre, i almindelighed kan anvendes. Oplosningsmidlet afdampes og reaktions-remanensen fordeles mellem HgO og benzen. Det vandige lag fraskilles, 35 vaskes to gange med benzen og inddampes i vakuum til opnâelse af et fast produkt med formel (II).
En sammenligning af nogle biologiske egenskaber af encainid (I) og to repræsentative eksempler pâ formel (II) (Ha: R=CHj, X=I; Ilb: 3
DK 156649 B
R-CHgPh, X=Br) er givet i folgende tabel.
5
Eaenskab I lia_ Ilb
Toksicitet ALDgQ^^ 50-100 mg/kg >2000 mg/kg >1000 mg/kg ΑΤ°5ο^^ 5-10 m9A9 250 m9/k9 125-250 mg/kg 10 Antiarrhythmisk aktivitet
Mus^2jED50 7-15 mgkg 30,5 mg/kg 19 mg/kg (1) Forskellige orale doser fra 5 mg/kg til 2000 mg/kg gives til 2 mus hver; ALDgg er den omtrentlige léthale dosis for halvdelen af 15 dyrene; ATDgg er den omtrentlige laveste dosis, hvor tegn pâ fysiologisk eller neurologisk déficit forékommer.
(2) Ventrikulær arrhythmî fremkatldt i mus ved chloroform-inhalation, 10 .dyr pn. dosis (Lawson, J. W., J. Pharmacol. Exp. Therap. 160, 22 (1968).
20 Med henvisning til de i ekserçiplerne nedenfor givne spectraldata: iQe kernemagnetiske resonansværdier (NMR) refererer til kemiske dkifter ($) udtrÿkt som dele pr. million (ppm) ,i forhold til tetra-methylsilan som referencestandard. Det for de forskellige skifter rapporterede relative areal svarer til antallét af hydrogenatomer i den 25 individuelle substituent og skiftets art med hensyn til multiplicitet er rapporteret som bred singlet (bs), singlet (s) eller multiplet (m).
Formatet er NMR (oplpsningsmiddel): 8 (relativt areal, multiplicitet).
De infrarpde (IR) mal tes pâ en dispersion af det faste materiale i krystallinsk kaliumbromid. Bplgetallene for signifikante absorptions-30 maksima er anfort.
Eksempel 1 2-r2-r2-rf4-methoxvbenzov1laminolphenvllethyll-l.1-dimethvloiDeridinium-iodid filai 35 En oplpsning af 7.,04 g (0,020 mol) ©icalfliid (I) og 5,68 g (0,040 mol) methyliodid i 100 ml acetone opvamedes ved tilbagesvalings-temperatur i 24 timer. OpTpsnlngsmidlet afdampedes og remanensen for-deltes mellem HgO og benzen. Det vandige lag fraskiltes, vaskedes to 4
DK 156649 B
gange med benzen og inddampedes i vakuum til opnâelse af et fast stof, smeltepunkt 75-80°C.
Analyse for ^HgjNgOgl:
Beregnet: C, 55,88; H, 6,32; N, 5,67.
5 Fundet: C, 55,74; H, 6,48; N, 5,58.
NMR: DMSO-dgj 1,65 (8,m); 2,87 (3,s); 2,90 (5,m); 3,01 (3,s); 3,84 (3,s); 7,22 (6,m); 7,98 (2,m); 9,75 (l,bs).
IR: 768, 1175, 1255, 1310, 1490, 1500, 1608, 1650, 2940, 3240 cm"1.
10 Eksemoel 2 2-Γ2-Γ2-Γ(4-methoxvbenzovl)ami nolphenvllethvl1-1-methvl-1-phenvlmethvl1-piperidiniumbromidhydrat fllb)
En opl0sning af 3,52 g (0,010 mol) encainid (I) og 1,71 g (0,010 mol) benzylbromid opvarmedes ved tilbagesvalingstemperatur i 24 timer.
15 Reaktionsblandingen oparbejdedes dernæst som beskrevet i eksempel 1. Der opnâedes 2,80 g, smeltepunkt 135-140°C.
Analyse for ^gHjg^OgBr.O^ HgO:
Beregnet: C, 65,97; H, 6,78; N, 5,31; HgO, 0,85.
Fundet: C, 65,68; H, 6,79; N, 5,23; HgO, 1,16.
20 NMR: DMS0-dg: 1,70 (8,m) 2,86 (3,s); 3,00 (5,m); 3,79, 3,82 [3,2s (2:1)]*; 4,50 (2,m); 7,00 (2,m); 7,40 (9,m); 9,01 (2,m)* 9,89 (l,bs).
IR: 770, 1170, 1255, 1312, 1500, 1610, 1655, 2950, 3220 cm"1.
* 25 Disse mdnstre indikerer en 2:1 isomerblanding i DMS0-dg oplesning af stereoisomere pâ grund af dissymmetri indftfrt i dette molekyle af den kvaternære nitrogenkonfiguration.
30
Claims (2)
1. Analogifremgangsmâde til fremstilliig af eiï farbindelse med formel (II) CH,CH,—L Θ J Λ I2 /\ p (Π) hvori R er alkyl med 1-4 carbonatomer eller benzyl og X er halogen,
15 KENDETEGNET ved, AT man opvarmer en forbindelse med formlen 20 -- .. - J-, CHj - H3C°—/ CONH—/ \ 25. nærværelse af en forbindelse med formlen R-X, hvori R er en Cj-C^ alkyl- eller benzyl-gruppe og X er halogen, sasom chlor, brom eller iod, i et organisk oplpsningsmiddel under tilbagesvaling og derefter udvinder slutproduktet. 30 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/229,244 US4321386A (en) | 1981-01-28 | 1981-01-28 | Quaternary piperidinium halides |
| US22924481 | 1981-01-28 | ||
| PCT/US1982/000108 WO1982002551A1 (en) | 1981-01-28 | 1982-01-27 | Quaternary piperidinium halides |
| US8200108 | 1982-01-27 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK429382A DK429382A (da) | 1982-09-27 |
| DK156649B true DK156649B (da) | 1989-09-18 |
| DK156649C DK156649C (da) | 1990-02-05 |
Family
ID=22860396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK429382A DK156649C (da) | 1981-01-28 | 1982-09-27 | Analogifremgangsmaade til fremstilling af 2-oe2-oe2-oe(4-methoxybenzoyl)aminoaaphenylaaethylaa-1-methyl-1-alkylpiperidiniumhalogenider eller 2-oe2-oe2-oe(4-methoxybenzoyl)aminoaaphenylaaethylaa-1-methyl-1-benzylpiperidiniumhalogenider |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US4321386A (da) |
| JP (1) | JPH0348904B2 (da) |
| AR (1) | AR230266A1 (da) |
| AT (1) | AT378183B (da) |
| AU (1) | AU551523B2 (da) |
| BE (1) | BE891938A (da) |
| CA (1) | CA1184917A (da) |
| CH (1) | CH651021A5 (da) |
| DE (1) | DE3223499T1 (da) |
| DK (1) | DK156649C (da) |
| FI (1) | FI65239C (da) |
| GB (1) | GB2100736B (da) |
| GR (1) | GR74720B (da) |
| IE (1) | IE52420B1 (da) |
| IT (1) | IT1147809B (da) |
| NL (1) | NL8220049A (da) |
| SE (1) | SE435057B (da) |
| WO (1) | WO1982002551A1 (da) |
| YU (1) | YU43063B (da) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2010234518A1 (en) * | 2009-04-09 | 2012-02-02 | Cognition Therapeutics, Inc. | Inhibitors of cognitive decline |
| JP2013501006A (ja) | 2009-07-31 | 2013-01-10 | コグニション セラピューティクス インク． | 認知機能低下の阻害剤 |
| SG192596A1 (en) | 2011-02-02 | 2013-09-30 | Cognition Therapeutics Inc | Isolated compounds from turmeric oil and methods of use |
| BR112016017808B1 (pt) | 2014-01-31 | 2022-07-12 | Cognition Therapeutics, Inc | Composto ou sal farmaceuticamente aceitável, uso de um composto e composição para a inibição de um efeito betaamilóide numa célula neuronal |
| KR102614814B1 (ko) | 2017-05-15 | 2023-12-20 | 카그니션 테라퓨틱스, 인코퍼레이티드 | 신경변성 질환 치료용 조성물 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3037910A (en) * | 1958-04-18 | 1962-06-05 | Burroughs Wellcome Co | Process for treatment of hypertension |
| US3931195A (en) * | 1971-03-03 | 1976-01-06 | Mead Johnson & Company | Substituted piperidines |
| US3917679A (en) * | 1974-04-12 | 1975-11-04 | Lilly Co Eli | Quaternary ammonium salts of N-dialkylaminoalkyl-N-(2-indanyl)anilines |
-
1981
- 1981-01-28 US US06/229,244 patent/US4321386A/en not_active Expired - Lifetime
-
1982
- 1982-01-27 JP JP57500784A patent/JPH0348904B2/ja not_active Expired - Lifetime
- 1982-01-27 DE DE823223499T patent/DE3223499T1/de active Granted
- 1982-01-27 WO PCT/US1982/000108 patent/WO1982002551A1/en active IP Right Grant
- 1982-01-27 GB GB08220076A patent/GB2100736B/en not_active Expired
- 1982-01-27 AU AU81485/82A patent/AU551523B2/en not_active Ceased
- 1982-01-27 CH CH5828/82A patent/CH651021A5/de not_active IP Right Cessation
- 1982-01-27 AT AT0900782A patent/AT378183B/de active
- 1982-01-28 CA CA000395068A patent/CA1184917A/en not_active Expired
- 1982-01-28 GR GR67146A patent/GR74720B/el unknown
- 1982-01-28 NL NL8220049A patent/NL8220049A/nl unknown
- 1982-01-28 IT IT47667/82A patent/IT1147809B/it active
- 1982-01-28 YU YU197/82A patent/YU43063B/xx unknown
- 1982-01-28 BE BE0/207171A patent/BE891938A/fr not_active IP Right Cessation
- 1982-01-28 AR AR288281A patent/AR230266A1/es active
- 1982-01-28 IE IE191/82A patent/IE52420B1/en unknown
- 1982-07-08 FI FI822443A patent/FI65239C/fi not_active IP Right Cessation
- 1982-09-27 DK DK429382A patent/DK156649C/da not_active IP Right Cessation
- 1982-09-28 SE SE8205535A patent/SE435057B/sv not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IT1147809B (it) | 1986-11-26 |
| FI65239B (fi) | 1983-12-30 |
| FI65239C (fi) | 1984-04-10 |
| FI822443A0 (fi) | 1982-07-08 |
| CH651021A5 (de) | 1985-08-30 |
| DE3223499C2 (da) | 1989-11-23 |
| WO1982002551A1 (en) | 1982-08-05 |
| IT8247667A0 (it) | 1982-01-28 |
| DE3223499T1 (de) | 1983-01-13 |
| DK429382A (da) | 1982-09-27 |
| NL8220049A (nl) | 1982-11-01 |
| YU19782A (en) | 1985-04-30 |
| GR74720B (da) | 1984-07-10 |
| JPH0348904B2 (da) | 1991-07-25 |
| FI822443L (fi) | 1982-07-08 |
| AR230266A1 (es) | 1984-03-01 |
| AU551523B2 (en) | 1986-05-01 |
| CA1184917A (en) | 1985-04-02 |
| SE8205535D0 (sv) | 1982-09-28 |
| IE820191L (en) | 1982-07-28 |
| BE891938A (fr) | 1982-07-28 |
| YU43063B (en) | 1989-02-28 |
| SE8205535L (sv) | 1982-09-28 |
| IE52420B1 (en) | 1987-10-28 |
| US4321386A (en) | 1982-03-23 |
| GB2100736A (en) | 1983-01-06 |
| SE435057B (sv) | 1984-09-03 |
| GB2100736B (en) | 1985-01-30 |
| DK156649C (da) | 1990-02-05 |
| ATA900782A (de) | 1984-11-15 |
| AU8148582A (en) | 1982-08-16 |
| JPS57502216A (da) | 1982-12-16 |
| AT378183B (de) | 1985-06-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |