NO119798B - - Google Patents
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- Publication number
- NO119798B NO119798B NO156721A NO15672165A NO119798B NO 119798 B NO119798 B NO 119798B NO 156721 A NO156721 A NO 156721A NO 15672165 A NO15672165 A NO 15672165A NO 119798 B NO119798 B NO 119798B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- acid
- nitro
- formula
- benzodiazepine
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- -1 analgesic Substances 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- XIKCEAKJIODSMP-UHFFFAOYSA-N 2-(7-chloro-5-phenyl-2,3-dihydro-1,4-benzodiazepin-1-yl)-n,n-diethylethanamine Chemical compound C12=CC(Cl)=CC=C2N(CCN(CC)CC)CCN=C1C1=CC=CC=C1 XIKCEAKJIODSMP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YMDNODNLFSHHCV-UHFFFAOYSA-N 2-chloro-n,n-diethylethanamine Chemical compound CCN(CC)CCCl YMDNODNLFSHHCV-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YNHGHPCGMBEGEU-UHFFFAOYSA-N 5-phenyl-1h-1,4-benzodiazepine Chemical compound C12=CC=CC=C2NC=CN=C1C1=CC=CC=C1 YNHGHPCGMBEGEU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate 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
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Description
Fremgangsmåte for fremstilling av terapeutisk virksomme benzodiazepin-derivater.
Nærværende oppfinnelse vedrorer en fremgangsmåte for fremstilling av 7-klor-l-(2-dietylaminoetyl)-2,3-dihydro-5-fenyl-1,4-benzodiazepin med formel
og salter av denne forbindelse.
Fremgangsmåten ifolge nærværende oppfinnelse karakteriseres ved at man omsetter en forbindelse med den generelle formel
hvor R betyr klor eller nitro, med en forbindelse med den generelle formel
hvor X betyr halogen,
og i en oppnådd forbindelse, hvor R betyr nitro, reduserer nitrogruppen og erstatter den erholdte aminogruppe med et halogenatom og, hvis onsket, overforer det oppnådde produkt i et salt.
Eksempler på halogener i forbindelser med formel III er klor, brom og jod.
For substitusjonen i 1-stilling omdanner man hensiktsmessig det tilsvarende 5-fenyl-1,4-benzodiazepin med formel II forst til 1-natriumderivatet, f.eks. ved behandling med natriummet-oksyd, natriumhydrid eller lignende for man bringer forbindelsen til omsetning med en forbindelse med formel III.
Reaksjonen av utgangsmaterialet med formel II med en forbindelse med formel III gjennomfores hensiktsmessig i et inert organisk opplosningsmiddel under anvendelse av et eller flere av de folgende opplosningsmidler: metanol, etanol, dimetyl-formamid, benzen, toluen, N-metylpyrrolidon eller lignende. Temperaturene og trykkene som anvendes, er ikke kritiske. Reaksjonen kan gjennomfores ved romtemperatur eller forhoyet temperatur, ved normaltrykk eller forhoyet trykk.
Forbindelsen med foranstående formel I danner syreaddisjonssalter f.eks. med uorganiske eller organiske syrer, som saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, salpetersyre, vinsyre, salicylsyre, toluensulfosyre, askorbinsyre, malein-syre, ravsyre, maursyre, eddiksyre og lignende.
Forbindelsen med foranstående formel I og deres farmasoytisk anvendbare syreaddisjonssalter har antikonvulsive, analgetiske, sedative, muskelrelakserende, hypotensive og antidepressive egenskaper.
Det foreliggende eksempel anskueliggjør fremgangsmåten ifolge oppfinnelsen. Alle temperaturer er angitt i °C og smelte-punktene er korrigerte.
EKSEMPEL
Til en oppløsning av 2,3-dihydro-7-nitro-5-fenyl-lH-1,4-benzodiazepin (26,7 g 0,100 mol) i vannfri N,N-dimetylformamid (300 ml) tilsettes natriummetylat (5,00 g 0,110 mol) og blandingen rores 1 time ved romtemperatur. Over et tidsrom av 2 timer tildryppes en opplosning av 2-klor-N,N-dietyletylamin. . Blandingen oppvarmes under roring på vannbad ved 60° 1 time, konsentreres i vakuum til et lite volum, fortynnes med vann og ekstraheres med metylenklorid. Ekstraktet vaskes Iried vann, torkes (natriumsulfat) og konsentreres. Det blir tilbake en morkt farget viskos olje. Den sistnevnte opploses i benzen og kromatrograferes på noytralt aluminiumoksyd med aktivitetstrinn I. Konsentrering av benzenfraksjonene gir 1-(2-dietylamino-etyl)- 2,3-dihydro-7-nitro-5-fenyl-1,4-benzodiazepin i form av en olje. Oljen opploses i den beregnede mengde metanolisk 1,5-n saltsyre, og man oppnår ved tilsetning av eter l-(2-di-etylaminoetyl)- 2,3-dihydro-7-nitro-5-fenyl-1,4-benzodiazepin-dihydroklorid som gule små plater med et smeltepunkt 232 - 236°C.
1-(2-dietylaminoetyl)- 2,3-dihydro-7-nitro-5-fenyl-1,4-benzodiazepin-dihydroklorid (30 g) opploses i vann, oppløsningen innstilles alkalisk ved tilsetning av 3-n natronlut, ekstraheres med metylenklorid og overfores så til den frie base. Ekstraktet vaskes med vann, torkes (magnesiumsulfat) og konsentreres. Man oppnår den frie base i form av en gul viskos olje. Den sistnevnte opploses i metanol (800 ml) og hydreres i nærvær av Raney-nikkel (3 fulle teskjeer Raney-nikkel kreves omtrentlig). Etter absorpsjon av 3 mol hydrogen (3 timer) opptas intet ytterligere hydrogen mer. Katalysatoren filtreres fra under anvendelse av filterslim, vaskes med vann og kastes.Konsentrering av filtratet i vakuum gir 7-amino-l-(2-dietyl-aminoetyl) -2, 3-dihydro- 5- f enyl-1 , 4-benzodiazepin i form av en olje.
For rensning opploses produktet i metylenklorid og helles på en soyle som er beskikket med noytralt aluminiumoksyd med aktivitetstrinn III. Eluatet inndampes og tilsettes under roring til 3-n saltsyre (72 ml, 6 ekvivalenter). Den således erholdte opplosning avkjoles til -10°C og tilsettes dråpevis sålenge en opplosning av natriumnitrit (2,76 g) i vann (8 ml) inntil jod-stivelse-reaksjonen forblir positiv. Den således erholdte opplosning tildryppes over et tidsrom av 35 minutter under roring til en opplosning av kobber(I)klorid (7 g) i en blan-ding av konsentrert saltsyre (40 ml) og vann (20 ml). Reaksjonsblandingen oppvarmes på et vannbad 3 timer ved 35 - 40°C og tilslutt enda 10 minutter ved 60°C inntil utviklingen av nitrogen kommer til stillstand. Reaksjonsblandingen fortynnes med vann, gjores alkalisk med 3-n vandig ammoniak og ekstraheres med metylenklorid. Ekstraktet vaskes med vann, torkes (natriumsulfat) og konsentreres. Man oppnår 7-klor-l-(2-dietylaminoetyl)- 2,3-dihydro-5-fenyl-1,4-benzodiazepin, som overfores som ovenfor beskrevet til dihydroklorid. Orange prismer av 7-klor-l-(2-dietylaminoetyl)- 2,3-dihydro-5-fenyl-1,4-benzodiazepin, smeltepunkt 234 - 236°C.
Claims (1)
- Fremgangsmåte for fremstilling av terapeutisk virksomme benzodiazepin-derivater med formelog salter av denne forbindelse,karakterisertved at man omsetter en forbindelse med den generelle formelhvor R betyr klor eller nitro, med en forbindelse med den generelle formelhvor X betyr halogen, og reduserer nitrogruppen i en erholdt forbindelse, hvor R betyr nitro, og erstatter den erholdte aminogruppe med et halogenatom og, hvis onsket, overforer det erholdte produkt til et salt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US343941A US3299053A (en) | 1964-02-11 | 1964-02-11 | Novel 1-and/or 4-substituted alkyl 5-aromatic-3h-1, 4-benzodiazepines and benzodiazepine-2-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO119798B true NO119798B (no) | 1970-07-06 |
Family
ID=23348328
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO156707A NO117367B (no) | 1964-02-11 | 1965-02-09 | |
| NO156722A NO118273B (no) | 1964-02-11 | 1965-02-10 | |
| NO156721A NO119798B (no) | 1964-02-11 | 1965-02-10 |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO156707A NO117367B (no) | 1964-02-11 | 1965-02-09 | |
| NO156722A NO118273B (no) | 1964-02-11 | 1965-02-10 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US3299053A (no) |
| BE (4) | BE659442A (no) |
| BR (4) | BR6567051D0 (no) |
| CH (4) | CH460030A (no) |
| DE (4) | DE1545933A1 (no) |
| DK (3) | DK118249B (no) |
| ES (4) | ES309167A2 (no) |
| FR (6) | FR4123M (no) |
| GB (4) | GB1077358A (no) |
| IL (4) | IL22869A (no) |
| NL (4) | NL6501578A (no) |
| NO (3) | NO117367B (no) |
| SE (4) | SE307952B (no) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO120269B (no) * | 1965-11-02 | 1970-09-28 | Hoffmann La Roche | |
| US3464978A (en) * | 1967-04-21 | 1969-09-02 | Hoffmann La Roche | 1-substituted urea alkyl 1,2-dihydro-1,4-benzodiazepines and benzodiazepin - 2-ones |
| US3523939A (en) * | 1967-07-03 | 1970-08-11 | Hoffmann La Roche | 5-(2,6-disubstituted phenyl)-1,4-benzodiazepines and methods for their preparation |
| US3506404A (en) * | 1967-12-19 | 1970-04-14 | Hoffmann La Roche | Colorimetric method for determining iron in blood |
| US3506403A (en) * | 1967-12-19 | 1970-04-14 | Hoffmann La Roche | Colorimetric method for determining iron in fluids |
| US3609146A (en) * | 1968-11-01 | 1971-09-28 | Sandoz Ag | Substituted benzodiazepinone derivatives |
| IL33961A (en) * | 1969-03-13 | 1973-03-30 | Sparamedica Ag | Benzodiazepine aminoalkyl carboxylates,their preparation and pharmaceutical compositions containing them |
| US3691157A (en) * | 1970-08-12 | 1972-09-12 | Rodney Ian Fryer | Preparation of 7-substituted-1-(2-diethylaminoethyl)-5-(2-halophenyl)-1,3-dihydro-2h-1,4-benzodiazepin-2-ones |
| AT314541B (de) * | 1970-10-19 | 1974-04-10 | Sumitomo Chemical Co | Verfahren zur Herstellung von neuen Benzodiazepinen und ihren Salzen |
| US3678038A (en) * | 1971-04-01 | 1972-07-18 | Hoffmann La Roche | 1,4-benzodiazepin-5-ones and methods for the preparation thereof |
| US3856802A (en) * | 1971-05-10 | 1974-12-24 | Upjohn Co | 1,6-DISUBSTITUTED-4H-5-{8 4,3-a{9 BENZODIAZEPINES |
| US3872089A (en) * | 1971-05-14 | 1975-03-18 | Hoffmann La Roche | Substituted thienodiazepines |
| USRE31071E (en) * | 1971-12-09 | 1982-11-02 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | 6-Aza-3H-1,4-benzodiazepines |
| US4008223A (en) * | 1971-12-09 | 1977-02-15 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | 6-Aza-3H-1,4-benzodiazepines |
| US3859276A (en) * | 1972-12-13 | 1975-01-07 | Merck & Co Inc | 7-chloro-1,3-dihydro-5-2-polyfluoroalkoxyphenyl)-2h-1,4-benzodiazepin-2-ones |
| GB1414370A (en) * | 1973-08-24 | 1975-11-19 | Grindstedvaerket As | Benzodiazepines and their production |
| US4232016A (en) * | 1974-12-20 | 1980-11-04 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | 3-Fluorobenzodiazepines |
| US4246270A (en) * | 1976-05-26 | 1981-01-20 | E. I. Du Pont De Nemours And Company | 3-Fluorobenzodiazepines and compositions and uses thereof |
| FI783743A (fi) * | 1977-12-14 | 1979-06-15 | Gerot Pharmazeutika | Foerfarande foer framstaellning av 3-di-n-propyl-acetoxi-benzodiazepin-2-oner |
| AT361492B (de) * | 1978-12-18 | 1981-03-10 | Gerot Pharmazeutika | Verfahren zur herstellung von neuen 3-hydroxy- 1,4-benzodiazepin-2-onen |
| US8530463B2 (en) * | 2007-05-07 | 2013-09-10 | Hale Biopharma Ventures Llc | Multimodal particulate formulations |
| JP2010526825A (ja) | 2007-05-10 | 2010-08-05 | エーエムアール テクノロジー インコーポレイテッド | アリール置換およびヘテロアリール置換テトラヒドロベンゾ−１，４−ジアゼピンならびにノルエピネフリン、ドーパミンおよびセロトニンの再取り込みを遮断するためのその使用 |
| JP5613657B2 (ja) | 2008-03-28 | 2014-10-29 | ヘイル バイオファーマ ベンチャーズ，エルエルシー | ベンゾジアゼピン組成物の投与 |
| CN107737100A (zh) | 2011-06-14 | 2018-02-27 | 哈尔生物药投资有限责任公司 | 苯二氮卓组合物的投与 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3109843A (en) * | 1963-11-05 | Process for preparing | ||
| US3121076A (en) * | 1964-02-11 | Benzodiazepinones and processes | ||
| US2461038A (en) * | 1947-05-15 | 1949-02-08 | Searle & Co | Chemical compositions and the preparation thereof |
| US2532292A (en) * | 1947-12-12 | 1950-12-05 | Searle & Co | Diarylmethyl ethers of amino alkanols |
| US2576106A (en) * | 1948-07-13 | 1951-11-27 | Searle & Co | N-dicyclohexyl, dialkylaminoalkanamides |
| US2687414A (en) * | 1948-11-26 | 1954-08-24 | Searle & Co | Method for producing aromatic aminoalkyl amines |
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0
- GB GB1052144D patent/GB1052144A/en active Active
- GB GB1051795D patent/GB1051795A/en active Active
-
1964
- 1964-02-11 US US343941A patent/US3299053A/en not_active Expired - Lifetime
-
1965
- 1965-01-25 CH CH102465A patent/CH460030A/de unknown
- 1965-01-25 CH CH332768A patent/CH460793A/de unknown
- 1965-01-28 CH CH118165A patent/CH467787A/de unknown
- 1965-01-28 CH CH118265A patent/CH458372A/de unknown
- 1965-01-28 DE DE19651545933 patent/DE1545933A1/de active Pending
- 1965-01-29 IL IL22869A patent/IL22869A/en unknown
- 1965-01-30 DE DE19651545934 patent/DE1545934A1/de active Pending
- 1965-02-01 DE DE19651545935 patent/DE1545935A1/de active Pending
- 1965-02-01 DE DE1545936A patent/DE1545936B2/de active Pending
- 1965-02-02 FR FR4021A patent/FR4123M/fr not_active Expired
- 1965-02-03 IL IL22902A patent/IL22902A/en unknown
- 1965-02-03 IL IL22903A patent/IL22903A/xx unknown
- 1965-02-05 SE SE1508/65A patent/SE307952B/xx unknown
- 1965-02-05 SE SE1507/65A patent/SE309597B/xx unknown
- 1965-02-06 FR FR4639A patent/FR1455059A/fr not_active Expired
- 1965-02-08 GB GB5288/65A patent/GB1077358A/en not_active Expired
- 1965-02-08 GB GB5289/65A patent/GB1098242A/en not_active Expired
- 1965-02-08 IL IL22935A patent/IL22935A/xx unknown
- 1965-02-09 FR FR4801A patent/FR1443116A/fr not_active Expired
- 1965-02-09 NL NL6501578A patent/NL6501578A/xx unknown
- 1965-02-09 BE BE659442D patent/BE659442A/xx unknown
- 1965-02-09 NO NO156707A patent/NO117367B/no unknown
- 1965-02-09 BE BE659445D patent/BE659445A/xx unknown
- 1965-02-09 NL NL6501579A patent/NL6501579A/xx unknown
- 1965-02-09 FR FR4800A patent/FR4138M/fr not_active Expired
- 1965-02-09 SE SE1617/65A patent/SE307953B/xx unknown
- 1965-02-09 BE BE659443D patent/BE659443A/xx unknown
- 1965-02-09 BE BE659444D patent/BE659444A/xx unknown
- 1965-02-09 DK DK65465AA patent/DK118249B/da unknown
- 1965-02-10 ES ES0309167A patent/ES309167A2/es not_active Expired
- 1965-02-10 ES ES0309170A patent/ES309170A1/es not_active Expired
- 1965-02-10 DK DK69265AA patent/DK105984C/da active
- 1965-02-10 DK DK69165AA patent/DK107032C/da active
- 1965-02-10 NL NL656501632A patent/NL141781B/xx unknown
- 1965-02-10 NL NL6501631A patent/NL6501631A/xx unknown
- 1965-02-10 BR BR167051/65A patent/BR6567051D0/pt unknown
- 1965-02-10 NO NO156722A patent/NO118273B/no unknown
- 1965-02-10 BR BR167055/65A patent/BR6567055D0/pt unknown
- 1965-02-10 ES ES0309169A patent/ES309169A1/es not_active Expired
- 1965-02-10 SE SE1688/65A patent/SE321477B/xx unknown
- 1965-02-10 NO NO156721A patent/NO119798B/no unknown
- 1965-02-10 ES ES0309168A patent/ES309168A1/es not_active Expired
- 1965-02-10 BR BR167053/65A patent/BR6567053D0/pt unknown
- 1965-02-10 BR BR167054/65A patent/BR6567054D0/pt unknown
- 1965-04-06 FR FR12017A patent/FR4772M/fr not_active Expired
- 1965-04-07 FR FR12188A patent/FR4609M/fr not_active Expired
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