NO165922B - Analogifremgangsmaate for fremstilling av terapeutisk aktive estere av hexahydro-8-hydroxy-2,6-methano-2h-kinolizin-3-(4h)-on og beslektede forbindelser. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive estere av hexahydro-8-hydroxy-2,6-methano-2h-kinolizin-3-(4h)-on og beslektede forbindelser. Download PDFInfo
- Publication number
- NO165922B NO165922B NO874550A NO874550A NO165922B NO 165922 B NO165922 B NO 165922B NO 874550 A NO874550 A NO 874550A NO 874550 A NO874550 A NO 874550A NO 165922 B NO165922 B NO 165922B
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- hexahydro
- lower alkyl
- quinolizin
- methano
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 230000001225 therapeutic effect Effects 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 5
- 150000002513 isocyanates Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- -1 methyl- Chemical group 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- VLJQDHDVZJXNQL-UHFFFAOYSA-N 4-methyl-n-(oxomethylidene)benzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N=C=O)C=C1 VLJQDHDVZJXNQL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- VGZOTUWVGXUNRC-UHFFFAOYSA-N 1-butylazepan-2-one Chemical compound CCCCN1CCCCCC1=O VGZOTUWVGXUNRC-UHFFFAOYSA-N 0.000 description 1
- CZVSOFLNEUYJRJ-UHFFFAOYSA-N 3-azabicyclo[2.2.2]octan-2-one Chemical compound C1CC2C(=O)NC1CC2 CZVSOFLNEUYJRJ-UHFFFAOYSA-N 0.000 description 1
- BXYQVGFHMYTNBX-UHFFFAOYSA-N 5-methylazepan-2-one Chemical compound CC1CCNC(=O)CC1 BXYQVGFHMYTNBX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000004679 hydroxides 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
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 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
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Analogifremgangsmåte for fremstilling av hittil ukjente N<1->substituerte N-arylsulfonylcarbamider med hypoglykemisk virkning.
Nærværende oppfinnelse vedrorer en analogifremgangsmåte for fremstilling av hittil ukjente N'-substituerte N-arylsulfonylcarbamider.
Forbindelser med den generelle formel I,
o
hvor m og n er null, 1, 2 eller 3 og sammen 1, 2 eller 3,
R-^ betyr en lavere alkylgruppe,
R2 en lavere alkylgruppe,
R~ hydrogen, en lavere alkylgruppe eller
R2 og Rg sammen, ifall m er null og n er 2
en ethylengruppe , -O^-Ch^- ,
såvel som deres salter med uorganiske eller organiske baser er hittil ikke kjent.
Som det nå ble funnet, innehar disse forbindelser og de nevnte salter interessante farmakologiske egenskaper. De viser ved peroral eller parentera.l administrasjon overraskende god hypoglykemisk virkning, som karakteriserer de som egnet for behandling av sukkersyke.
I forbindelsene med den generelle formel I kan R^ innta o-, m-eller p-stilling, R2 4-, 5-, 6- eller 7-, og R3 3-, 4-, 5-eller 6-stilling. R-^, R2 og R^ kan f.eks. som lavere alkyl-rester bety methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl, sek. butyl-, teft. butyl-, pentyl-, isopentyl-
.såvel som 1,1-dimethylpropylgruppeh.
Det^fra det franske BSM 545 tidligere kjente N-(p-tolylsul-foriyl)- N'-N'-pentametylenurinstoff bevirker ved administrasjon av 400 mg/kg per os på kaniner en senkning av blodsukkerspeilet med 25%. Videre bevirker den tilsvarende kjente N'-N' -heksa-metylen-henh. N'N'-tetrametylenforbindelse ifblge BSM 544 og 546 ved peroral administrasjon av 400 mg/kg hos kaniner en
senkning av blodsukkerspeilet med 30% henh. 37%.
Den hypoglykemiske virkning av nedenstående forbindelser er blitt undersbkt: I N-(p-tolylsulfonyl)-2-okso-5-metyl-heksahydro-l-H-
azepin-karboksamid (ifolge foreliggende oppfinnelse) II N-(p-tolylsulfonyl)-3-okso-2-azabicyklo [2.2.2] oktan-2-karboksamid
III N-(p-tolylsulfonyl)-2-okso-4-metyl-pyrrolidin-1-karboksamid.
Forsokene viser at ved peroral administrasjon av forbindelse I på kaniner kan allerede ved en dosering på 100 mg/kg, oppnås en maksimal senkning av blodsukkerspeilet med 26%. Forbindelse II bevirker under samme betingelser 22% og forbindelse III ved en dosering på 200 mg/kg 33% senkning av blodsukkerspeilet.
Sammenligningsverdiene viser at de ifolge oppfinnelsen frem-stillbare forbindelser med den generelle formel I med en 2-oksogruppe og tilsvarende substitusjon i den ved N'-nitrogenet foreliggende heterocykliske ring i sammenligning til de tilsvarende kjente N'N'-polymetylenforbindelser allerede i vesentlig mindre doser, innehar samme gode virkning.
For fremgangsmåten ifolge oppfinnelsen av forbindelser med den generelle formel I omsetter man et isocyanatderivat med den generelle formel II,
hvor R^ har den under formel I angitte betydning, med en forbindelse med den generelle formel III,
hvor m, n, R^ og R« har den under formel I
angitte betydning,
eller med et alkali- eller jordalkalimetallderivat av en slik forbindelse, eventuelt i nærvær av et kondensasjonsmiddel og fortrinnsvis i et inert opplbsningsmiddel og overforer reaksjonsproduktet hvis onsket med en uorganisk eller organisk base til et salt.
Omsetningen finner f.eks. sted i kulde eller ved oppvarmning
i et inert organisk opplosningsmiddel. Egnede inerte organiske opplosningsmidler er f.eks. hydrocarboner som benzol, toluol eller xylol, etherlignende væsker, som diethylether, dioxan eller tetrahydrofuran, klorte hydrocarboner, som methylen-klorid og lavere ketoner, som aceton eller methylethylketon.
Omsetningen av et isocyanat kan også gjennomfores i fravær
av opplosnings- eller fortynningsmidler. De trenger i almindelighet heller ingen kondensasjonsmiddel: hvis onsket kan som slikt middel f.eks. et alkalialkoholat anvendes.
Som ytterligere kondensasjonsmidler kan ved omsetningen av et isocyanat tertiere aminer finne anvendelse, men isocyanatet kan også anvendes i form av et anleiringsprodukt med et ter-tiert amin.
Fra utgartpstof f ene med den generelle formel III skal som eksempler nevnes: ifolge den foran angitte definisjon av
R2 og R3 lavere alkyl-derivater av 2-pyrrolidinon, 2-piperidon og hexahydro-2H-azepin-2-on, såvel som videre 2-azabicyclo [2.2.21octan-3-on. Lengere oppvarmning av forbindelser med den generelle formel I bevirker en omdannelse av de samme under carbondioxydutvikling og skal ved fremgangsmåten ifolge oppfinnelsen eller ved omkrystallisasjonen unngås.
De nye aktivstoffer eller ikke-toxiske salter av de samme administreres fortrinnsvis peroralt. For saltdannelse kan uorganiske eller organiske baser, som f.eks. alkali- eller jordalkalihydroxyder, carbonater eller bicarbonater, trietha-nolamin, cholin, N^-dimethyl- og N"^-((3-f enylethyl)-biguanid , anvendes. De daglige doser beveger seg mellom 100 og 2000
mg for voksne pasienter. Egnete doseenhetsformer, som dragéer,
tabletter, inneholder fortrinnsvis 100-500 mg av et aktiv-stoff ifolge oppfinnelsen, og da 20 til 80 % av en forbindelse med den generelle formel I.
De efterfolgende eksempler redegjor nærmere for fremstillingen av de nye forbindelser med den generelle formel I. Tempera-turene er angitt i Celsiusgrader.
Eksempel 1
Man tilsetter til 12,7 g 5-methyl-hexahydro-2H-azepin-2-on
i 40 ml absolutt toluol 19,7 g p-tolylsulfonylisocyanat. Reaksjonsproduktet krystalliserer fra oppløsningen. Det suges fra og omkrystalliseres fra methanol. Det erholte rene N-(p-tolylsulfonyl)-2-oxo-5-methyl-hexahydro-lH-azepin-l-carbo-xamid smelter ved 115-116°.
Eksempel 2
Analogt eksempel 1 oppnår man fra 19.7 g p-tolylsulfonylisocyanat : a) med 9,9 g 4-methyl-2-pyrrolidinon N-(p-tolylsulfonyl)-2-oxo-4-methyl-pyrrolidin-l-carboxamidet, Smp. 134-135° fra
methan ol:.
b) med 17,1 g 5-tert. butyl-hexahydro-2H-azepin-2-on N-(p-tolyl-sulfonyl)-2-oxo-5-tert. butyl-hexahydro-lH-azepin-1 carboxamidet,
som spalter seg etter omkrystallisasjon fra methanol ved 147-
149° og c) med 12,6 g 2-azabicyclo[2.2.2] octan-3-on N-(p-tolylsul-f onyl )-3-oxo-2-azabicyclo [2.2.2] octan-2-carboxamidet, Smp.
138-139° fra methanol og dets natriumsalt krystalliserer fra 2-n vandig natronlut og lar seg omkrystallisere fra for-
tynnet alkohol. Det smelter over 310°.
Claims (1)
- Analogifremgangsmåte for fremstilling av hittil ukjente N1 - substituerte N-arylsulfonylcarbamider med hypoglykemisk virkning og med den generelle formel I,hvor m og n er null, 1, 2 eller 3 og sammen 1, 2 eller 3, betyr en lavere ,alkylgruppe, R2 en lavere alkylgruppe, R^ hydrogen, en lavere alkylgruppe eller R2 og R^ sammen, ifall m er null og n 2, en ethylengruppe, såvel som deres salter med uorganiske eller organiske baser, karakterisert ved at man omsetter et isocyanatderivat med den generelle formel II, hvor R, har den under formel I angitte betydning , med en forbindelse med den generelle formel III, hvor m, n, R2 og R^ har den under formel I angitte betydning, eller med et alkali- eller jordalkalimetallderivat av en slik forbindelse, eventuelt i nærvær av et kondensasjonsmiddel og fortrinnsvis i et inert opplosningsmiddel og, hvis onsket, overforer reaksjonsproduktet med en uorganisk eller organisk base til et salt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92661986A | 1986-11-03 | 1986-11-03 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO874550D0 NO874550D0 (no) | 1987-11-02 |
| NO874550L NO874550L (no) | 1988-05-04 |
| NO165922B true NO165922B (no) | 1991-01-21 |
| NO165922C NO165922C (no) | 1991-05-02 |
Family
ID=25453460
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO874550A NO165922C (no) | 1986-11-03 | 1987-11-02 | Analogifremgangsmaate for fremstilling av terapeutisk aktive estere av hexahydro-8-hydroxy-2,6-methano-2h-kinolizin-3-(4h)-on og beslektede forbindelser. |
| NO1999020C NO1999020I1 (no) | 1986-11-03 | 1999-08-26 | Dolasetron |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1999020C NO1999020I1 (no) | 1986-11-03 | 1999-08-26 | Dolasetron |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0266730B1 (no) |
| JP (2) | JP2542225B2 (no) |
| KR (1) | KR950011737B1 (no) |
| CN (1) | CN1021654C (no) |
| AR (1) | AR246264A1 (no) |
| AT (1) | ATE109779T1 (no) |
| AU (1) | AU600318B2 (no) |
| CA (1) | CA1329203C (no) |
| DE (2) | DE19775092I2 (no) |
| DK (1) | DK171116B1 (no) |
| ES (1) | ES2061469T3 (no) |
| FI (1) | FI87786C (no) |
| HU (1) | HU197008B (no) |
| IE (1) | IE63670B1 (no) |
| IL (1) | IL84309A (no) |
| NL (1) | NL970043I2 (no) |
| NO (2) | NO165922C (no) |
| NZ (1) | NZ222349A (no) |
| PH (2) | PH24664A (no) |
| PT (1) | PT86060B (no) |
| ZA (1) | ZA878096B (no) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0329902A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizinone and quinolizine derivatives in the manufacture of medicaments for the treatment of psychosis |
| US5011846A (en) * | 1988-02-23 | 1991-04-30 | Merrell Dow Pharmaceuticals Inc. | Medicament compositions derived from quinolizine and quinolizinone and methods of use thereof |
| EP0329904A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments for the treatment of anxiety |
| EP0329903A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizinone and quinolizine derivatives in the manufacture of medicaments for the treatment of glaucoma |
| ES2080727T3 (es) * | 1988-02-23 | 1996-02-16 | Merrell Pharma Inc | Uso de quinolizina y derivados de quinolizinona en la fabricacion de medicamentos. |
| EP0329905A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments for increasing gastric motility |
| EP0330788A1 (en) * | 1988-03-01 | 1989-09-06 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments for the treatment of cardiac arrhythmia |
| ZA893008B (en) * | 1988-04-29 | 1989-12-27 | Merrell Dow Pharma | Process for preparing indole-3-carboxylic acid esters of transhexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one |
| GB8928837D0 (en) * | 1989-12-21 | 1990-02-28 | Beecham Group Plc | Pharmaceuticals |
| EP0492020A1 (en) * | 1990-12-21 | 1992-07-01 | Merrell Dow Pharmaceuticals Inc. | Use of certain esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one and related compounds for treating cognitive disorders |
| DE69840674D1 (de) * | 1997-12-17 | 2009-04-30 | Biocryst Pharm Inc | Substituierte cyclopentan- und cyclopenten-verbindungen als neuraminidase-blocker |
| CN100390172C (zh) * | 2004-09-10 | 2008-05-28 | 成都欣捷高新技术开发有限公司 | 一种甲磺酸多拉司琼晶型及其制备方法 |
| US20070299260A1 (en) * | 2004-11-25 | 2007-12-27 | Cilag Ltd. | Method for Preparing Hexahydro-8-Hydroxy-2, 6-Methano-2H-Chinolizin-3 (4H) -One Esters |
| WO2007003522A1 (en) * | 2005-07-06 | 2007-01-11 | Inke, S.A. | Method for obtaining a pharmaceutically active compound, synthesis intermediates thereof and methods for obtaining them |
| ES2264901B1 (es) | 2005-07-06 | 2007-12-01 | Inke, S.A. | Procedimiento para la obtencion de un compuesto farmaceuticamente activo, sus intermedios de sintesis y procedimiento para la obtencion de los mismos. |
| TW200734339A (en) * | 2006-01-05 | 2007-09-16 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Forms of dolasetron mesylate and processes for their preparation |
| EP2060557B1 (en) | 2007-11-13 | 2012-06-06 | Inke, S.A. | Intermediate compounds useful to prepare dolasetron |
| EP2253316B1 (en) | 2009-05-20 | 2013-08-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Serotonin 5-HT3 receptor antagonists for use in the treatment or prevention of an inner ear pathology with vestibular deficits |
| JP5955767B2 (ja) | 2009-05-20 | 2016-07-20 | インセルム（インスティチュート ナショナル デ ラ サンテ エ デ ラ リシェルシェ メディカル） | 損傷性前庭障害の処置における使用のためのセロトニン５−ｈｔ３受容体拮抗薬 |
| EP3347011A4 (en) | 2015-09-11 | 2019-06-19 | Chase Pharmaceuticals Corporation | MUSCARIN COMBINATION AND ITS USE FOR COMBATING HYPOCHOLINERGEN DISORDERS OF THE CENTRAL NERVOUS SYSTEM |
| CN108976230A (zh) * | 2018-06-18 | 2018-12-11 | 东莞市联洲知识产权运营管理有限公司 | 一种基于石墨烯活化制备甲磺酸多拉司琼关键中间体的方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI74707C (fi) * | 1982-06-29 | 1988-03-10 | Sandoz Ag | Foerfarande foer framstaellning av terapeutiskt anvaendbara alkylenoeverbryggade piperidylestrar eller -amider av bicykliska karboxylsyror. |
| CH664567A5 (de) * | 1983-08-26 | 1988-03-15 | Sandoz Ag | Aromatische carbonsaeure- und sulfonsaeureester oder -amide. |
| ATE86110T1 (de) * | 1984-12-20 | 1993-03-15 | Sandoz Ag | Behandlung von gastrointestinalkrankheiten durch anwendung von 5-ht3-antagonisten. |
-
1987
- 1987-10-28 ZA ZA878096A patent/ZA878096B/xx unknown
- 1987-10-29 NZ NZ222349A patent/NZ222349A/xx unknown
- 1987-10-29 CA CA000550612A patent/CA1329203C/en not_active Expired - Lifetime
- 1987-10-29 FI FI874768A patent/FI87786C/fi not_active IP Right Cessation
- 1987-10-29 IL IL84309A patent/IL84309A/xx not_active IP Right Cessation
- 1987-10-30 PH PH36006A patent/PH24664A/en unknown
- 1987-10-30 AR AR87309166A patent/AR246264A1/es active
- 1987-11-02 CN CN87107629A patent/CN1021654C/zh not_active Expired - Lifetime
- 1987-11-02 DE DE1997175092 patent/DE19775092I2/de active Active
- 1987-11-02 EP EP87116119A patent/EP0266730B1/en not_active Expired - Lifetime
- 1987-11-02 IE IE295587A patent/IE63670B1/en not_active IP Right Cessation
- 1987-11-02 JP JP62275894A patent/JP2542225B2/ja not_active Expired - Lifetime
- 1987-11-02 DE DE3750359T patent/DE3750359T2/de not_active Expired - Lifetime
- 1987-11-02 NO NO874550A patent/NO165922C/no not_active IP Right Cessation
- 1987-11-02 PT PT86060A patent/PT86060B/pt unknown
- 1987-11-02 HU HU874918A patent/HU197008B/hu unknown
- 1987-11-02 AT AT87116119T patent/ATE109779T1/de not_active IP Right Cessation
- 1987-11-02 ES ES87116119T patent/ES2061469T3/es not_active Expired - Lifetime
- 1987-11-02 DK DK572887A patent/DK171116B1/da not_active IP Right Cessation
- 1987-11-02 AU AU80596/87A patent/AU600318B2/en not_active Expired
- 1987-11-03 KR KR1019870012286A patent/KR950011737B1/ko not_active IP Right Cessation
-
1990
- 1990-01-02 PH PH39830A patent/PH26261A/en unknown
-
1996
- 1996-02-27 JP JP8065408A patent/JP2657267B2/ja not_active Expired - Lifetime
-
1997
- 1997-12-17 NL NL970043C patent/NL970043I2/nl unknown
-
1999
- 1999-08-26 NO NO1999020C patent/NO1999020I1/no unknown
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