DK160047B - Analogifremgangsmaade til fremstilling af 3-imino-dibenzooec,faaimidazooe1,5-aaaazepiner og -dibenzooeb,faaimidazooe1,5-daaoe1,4aaoxazepiner og -thiazepiner - Google Patents
Analogifremgangsmaade til fremstilling af 3-imino-dibenzooec,faaimidazooe1,5-aaaazepiner og -dibenzooeb,faaimidazooe1,5-daaoe1,4aaoxazepiner og -thiazepiner Download PDFInfo
- Publication number
- DK160047B DK160047B DK391182A DK391182A DK160047B DK 160047 B DK160047 B DK 160047B DK 391182 A DK391182 A DK 391182A DK 391182 A DK391182 A DK 391182A DK 160047 B DK160047 B DK 160047B
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- DK
- Denmark
- Prior art keywords
- compounds
- imino
- imidazo
- carbon atoms
- formula
- Prior art date
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Description
DK 16C047B
i
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 3-imino-di-benzo[c,fJimidazo[1,5-a]azepiner og -dibenzo[b,fJimida-zo[1,5—d][1,4Joxazepiner og -thiazepiner, der kan anven-5 des som aktive bestanddele i lægemidler.
De hidtil ukendte forbindelser har den almene formel I
r3 --0O3 10 -V 1 —C >
^ N X
I
R6 15 hvori betegner hydrogen eller methyl, betegner hydrogen, methyl eller chlor,
Rg betegner alkyl med 1 til 6 C-atomer eller allyl, X betegner O, S eller C^, og den punkterede linie betyder at der foreligger enten en 20 enkeltbinding eller en^ dobbeltbinding.
Forbindelser der har et asymmetrisk C-atom kan optræde som racemat eller som rene enantiomere eller som blandinger med forskellige andele af de enantiomere.
Alle forbindelserne kan foreligge i form af de fri baser eller farmaceutisk acceptable syreadditionssalte.
Betegnelsen af stillingerne er angivet i nedenstående skelet-formel.
8 9 10 30 X w :CCiO: 5 / \ 13 A 2 l\ - \ N / 35
DK 16 O C 4 7 B
2
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del angivne.
Til fremstilling af forbindelserne med formlen I kan således benyttes følgende fremgangsmåde: 5 Omsætning af en diamin med den i krav 1 angivne almene formel II, hvori den punkterede linie, grupperne Rj, og Rg samt X har den ovenfor angivne betydning, med en halogencyan såsom bromcyan.
Omsætningen sker fortrinsvis ved stuetemperatur 10 i en blanding af ethanol og tetrahydrofuran, men kan også udføres i andre opløsningsmidler såsom alkoholer, chloroform eller carbonhydrider såsom toluen, xylen osv., eventuelt også under tilsætning af en hjælpebase som f.eks. kaliumcarbonat. Reaktionstemperaturerne kan vari-15 ere vidtgående og kan andrage indtil reaktionsblandingens kogetemperatur.
Ved omsætningen mellem en forbindelse med formlen II med f.eks. bromcyan dannes intermediært en forbindelse med den i krav 1 angivne formel Ila, hvori den punkterede 20 linie, grupperne R^, R^ og Rg samt X har den ovenfor angivne betydning, og denne forbindelse er således det egentlige udgangsstof for ringslutningsreaktionen. Det er imidlertid ikke nødvendigt at isolere denne forbindelse, da den viderereagerer glat til det ønskede slutprodukt.
25 Diaminerne med formlen II er til dels kendte [se J. Med. Chem. J_3, 35-39 ( 1970); eller GB-PS 1 229 252] eller kan fremstilles på hermed analog måde.
En hensigtsmæssig udførelsesform for fremgangsmåden ifølge opfindelsen er angivet i krav 2.
30 De ved de forskellige fremgangsmåder opnåede reaktionsprodukter isoleres ved hjælp af kendte arbejdsmetoder. Eventuelt kan de således opnåede råprodukter renses yderligere under anvendelse af særlige metoder,f.eks. ved søjlechromatografi, før man kry-35 stalliserer dem i form af baserne eller egnede salte.
DK 16GO47 B
3
Om ønsket adskilles opnåede racemater i de enantiomere ved sædvanlige metoder.
Af primært opnåede salte vindes om ønsket fri baser, og af primært opnåede fri baser om ønsket syre-5 additionssalte ved kendte metoder.
Til fremstilling af syreadditionssalte anvendes især sådanne syrer, der er egnede til fremstilling af terapeutisk anvendelige salte.
Som sådanne syrer kan eksempelvis nævnes: hydro-10 genhalogenidsyrer; alifatiske, alicycliske, aromatiske eller heterocycliske carboxylsyrer eller sulfonsyrer, såsom eddikesyre, vinsyre, malonsyre, citronsyre, fumar-syre, salicylsyre, urethansulfonsyre, toluensulfonsyre og endvidere svovlsyre og phosphorsyre.
15 De ifølge opfindelsen fremstillede forbindelser er terapeutisk anvendelige. De udmærker sig ved relativt ringe toxicitet fremfor alt ved deres langvarige anti-allergiske, antihistaminerge og antiserotoninerge virkning; endvidere hammer de blodpladeaggregationen. Terapeutiske anven-20 delsesmuligheder for disse forbindelser er f.eks. behandlingen af reaktioner fremkaldt ved frigørelse af histamin eller serotonin, Asthma bronchiale, allergisk bronchitis, allergisk rhinitis, allergisk konjunc-tivitis samt allergiske diateser. Af særlig betydning 25 for terapeutiske formål er forbindelsernes gode orale virkning. Den orale virkning er også en væsentlig fordel i forhold til dinatriumsaltet af cromoglicinsyre, et stærkt benyttet handelsprodukt til behandling af Asthma bronchiale og allergisk bronchitis.
30 For anvendelsen forarbejdes de her omhandlede forbindelser til sædvanlige galeniske tilberedninger på sædvanlig måde med hjælpe- og bærestoffer, f.eks. til kapsler, tabletter, drageer, opløsninger, suspensioner for oral anvendelse, til aerosoler for pulmo-35 nal indgift, til sterile isotoniske vandige opløsninger for parenteral anvendelse og til cremer, salver, lo-
DK Ί 60047 B
4 tioner, emulsioner eller sprays for lokal applikation.
Enkeltdosis ved oral anvendelse andrager for voksne ca. 0,2 til 40, fortrinsvis ca. 0,5 til 10 mg. Til inhalation anvendes enkeltdoser mellem 0,05 til 20, 5 fortrinsvis 0,2 til 5 mg, hvorved der benyttes sæd- « vanlige tilberedninger især doseringsaerosoler og kapsler til pulverinhalation. De angivne doser kan eventuelt indgives flere gange pr. dag.
Til konstatering af forbindelsernes virkning 10 blev disse underkastet talrige farmakologiske prøver.
(a) Der blev udført forsøg på allergiserede rotter efter passiv sensibilisering af dyrene med IgE-antistoffer og efterfølgende antigenprovokation. På denne måde kunne frembringes en 15 passiv, kutan anafylaxi (GOOSE et al. (1969);
Immunology 16, 749) (PCA).
(b) Antih'istaminvirkning;
Forbindelserne hæmmer indgivet peroralt og intravenøst i rotter, hunde og aber den 20 ved intrakutan injektion af histamin fremkaldte histaminhævelse. Bedømmelsen skete efter extravasation af Evans blå-farvestof i huden ved måling af hævelsen.
Angivelserne i nedenstående tabel tjener som 25 eksempel på virkningen af en vigtig forbindelse ifølge opfindelsen; PCA ED,-n Histamin- LDcn au . , 50 [mg/kg] fritte) tmgAg]
Forbindelse (rotte p.o.) . K * (mus p.o.) x·V· p»o· 30 ----------------
Eksempel 2 1,1 0,07 2,7 280
DK 16 C C 4 7 B
5 I DE-offentliggørelsesskrift nr. 2.311.019 er der beskrevet oxazepiner og diazepiner, som er strukturelt beslægtede med de ifølge opfindelsen fremstillede forbindelser. Disse kendte forbindelser er imidlertid angivet 5 at være antidepressive, medens de ifølge opfindelsen fremstillede forbindelser udmærker sig ved deres antial-lergiske, antihistaminerge og antiserotoniske virkning.
I forbindelserne ifølge DE-offentliggørelsesskrift nr. 2.248.477 indeholder ringsystemet, i lighed med de ifølge 10 opfindelsen fremstillede forbindelser, en femring med to nitrogenatomer som ring-led. De ifølge opfindelsen fremstillede forbindelser udviser imidlertid et yderligere nitrogenatom, således at der i alt foreligger en guani-dingruppering som del-element. Guanidinstrukturen findes 15 ganske vist i enkelte I^-antihistaminika, men også i talrige lægemidler med andre virkningsgrupper. I overensstemmelse hermed hedder det i "Burger's Medicinal Chemistry", 4. oplag, del III, side 509, som resumé af forsøg med talrige guanidinderivater, "at evnen til at 20 antagonisere histamin var ikke en egenskab hos guanidiner som sådanne".
Af en anden angivelse i dette værk (side 518-519) fremgår det, at tautomerievnen for guanidingrupperingen må foreligge for at den for antihistamin ønskede flade 25 komformation af guanidinstrukturenheden skal opstå. For de ifølge opfindelsen fremstillede forbindelser er tauto-meri ikke mulig, da ringnitrogenatomerne repræsenterer tertiære aminogrupper. Desuden har disse forbindelser overraskende en stærk antisterminerg virkning.
30 Forbindelserne ifølge DE-offentliggørelsesskrift nr. 2.548.045 indeholder i deres ringsystem en pyrroli-dinring, hvor gruppen -NRg, som er et ringled i de ifølge opfindelsen fremstillede forbindelser, er erstattet med en gruppe =CH-NR^Rg. Endvidere mangler gruppen =NH, som 35 er dobbeltbundet til ringen, og i stedet indeholder de kendte forbindelser på samme sted et oxygenatom eller to hydrogenatomer. De ifølge opfindelsen fremstillede forbindelser er således væsentligt forskellige fra forbin-
DK 160047 B
6 delserne ifølge DE-offentliggørelsesskrift nr. 2.548.045.
I det> følgende er angivet nogle eksempler på farmaceutiske præparater indeholdende de her omhandlede forbindelser som virksomme stoffer:
Tabletter Sammensætning:
Virksomt stof ifølge formel I 0,005 g
Stearinsyre 0,001 g
Druesukker 0,194 g
Inhalationsaerosol Sammensætning:
Virksomt stof ifølge formel I 1,00 dele 15
Sojalecitin 0,20 dele
Drivgasblanding (Frigen 11, 12 og 14) ad 100,00 dele
Tilberedningen fyldes fortrinsvis i aerosol-beholdere med doseringsventil; den enkelte løftning afmåles således, at der afgives en dosis på 0,5 mg.
For andre doseringer indenfor det angivne område anvender man hensigtsmæssigt tilberedninger med højere eller lavere indhold af virksomt stof.
Kapsler for inhalation.
25
Et virksomt stof med formlen I fyldes i mikro-niseret form (partikelstørrelse i det væsentlige mellem 2 og 6 ym) i hårdgelatinekapsler, eventuelt under tilsætning af mikroniserede bærestoffer, f.eks. lacto-2Q se. Til inhalationen tjener almindelige apparater for pulverinhalation. I hver kapsel indfyldes f.eks. mellem 0,2 og 20 mg virksomt stof og 0 til 40 mg lactose.
DK 16 Π C 4 7 B
7
Salve
Sammensætning: g/100 g salve
Virksomt stof ifølge opfindelsen 2,000
Rygende saltsyre 0,011 5 Natriumpyrosulfit 0,050
Blanding af lige dele cetyl- alkohol og stearylalkohol 20,000
Hvid vaseline 5,000
Kunstig Bergamotteolie 0,075 jq destill. vand ad 100,000
Bestanddelene forarbejdes på sædvanlig måde til en salve.
Fremgangsmåden ifølge opfindelsen belyses nær-^ mere gennem nedenstående eksempler. Alle temperaturangivelser er i °C.
Fremstillingseksempler 20 Eksempel 1 2-Methyl-3-imino-l,2,9,13b-tetrahydro-3H—dibenz[c,f] imidazo-[1,5-a]-azepinhydrobromid.
8 9 10 25 7 Λ^Λ 11 6 L I 13a v I J 12 X/\M 13b/\/ 5 /* \ 13 HNa<3 1\ 30 I X HBr cn.
DK 16G047 B
8
Under omrøring sættes der til en suspension af 7,15 g (0,03 mol) 6-methylaminomethyl-6,ll-dihydro-5H-dibenz-[b,e]-azepin [formel II, R^ og = H; Rg = -CH^» X = -CHpunkterede linie - der foreligger 5 enkeltbinding] i 70 ml absolut ethanol en opløsning af 3,2 g (0,03 mol) bromcyan i 8 ml absolut tetrahydro-furan. Herved dannes under let exoterm reaktion en opløsning, der omrøres i yderligere 4 timer ved stuetemperatur. Derefter tilsættes ether til reaktions-10 opløsningen. De opnåede krystaller frasuges og tørres. Udbyttes 8,6 g (83% af det teoretiske); smp. 247-249°C.
Efter omkrystallisation af methanol/ethylacetat smelter det analyserene stof ved 247-250°C.
Eksempel 2 15 2-Methyl-3-imino-2,3-dihydro-9H-dibenz-[c,f]-imidazo-[1,5-a]-azepinhydrobromid.
8 9 10 - :fV"xv 5 /k \ 13 HN^=^3 2 1> 25 I X HBr ch3
Til en opløsning af 44,4 g (0,188 mol) 6-methyl-aminomethyl-morphanthridin [formel II: punkteret 3Q linie = dobbeltbinding; R^ og. R3 = H; Rg = ~CH3; X = CH2^ tildryppes under omrøring og isafkøling en opløsning af 19,93 g (0,188 mol) bromcyan i 140 ml absolut tetrahydrofuran. Reaktionsblandingen omrøres yderligere i 4 timer ved stuetemperatur, hvorpå der 35 tilsættes ethylacetat. De opnåede krystaller frasuges og tørres.
Udbyttes 49,5 g (77% af det teoretiske); smp. 287-289°C.
DK 160047B
9 Déb analyserene hydrobromid har efter omkrystallisation af ethanol/ethylacetat et smeltepunkt på 291-393°.
På analog måde (se eksempel 1 og 2) kan man ud 5 fra de tilsvarende diaminer med formlen II opnå nedenstående forbindelser: A. Tetrahydro-forbindelser med X = CI^, dvs. med formlen la 15
H
a) 2-Ethyl-3-imino-l/2,9,13b-tetrahydro-3H-dibenz-[c,f]-imidazo-[1,5-a]-azepinhydrobromid 20 og R3 = H; Rg = C^) smp. 213-216° (acetonitril).
b) 2-Isopropyl-3-imino-l,2,9,13b-tetrahydro-3H-dibenz-[c,f]-imidazo-(1,5-a]-azepinhydrobromid (R, og R, = H; R, = -Cli^CH3 ) X j O \ 25 smp. 230-233° (acetonitlil/ether).
B. Tetrahydro-forbindelse med X = O, dvs. med formlen HN=-C. ^ r6 35
DK 160047 B
ίο 2-Methyl-3-imino-l,2,3,13b-tetrahydrodibenz-[b,f]-imidazo-[l,5-d][l,4)-oxazepinhydro-chlorid smp. 297-300° (alkohol/ethylacetat) 5 (R^ og R3 =H; Rg = CH3) .
C. Tetrahydro-forbindelse med X = S, dvs. med formel " ' OCXf - 15 2-Methyl-3-imino-l,2,3,13b-tetrahydrodibenz-[b,f]-imidazo-[1,5-d][l,4]-thiazepin-hydro-bromid 20 smp. 204-206-° (alkohol/ethylacetat) ;(RX og R3 = H; R6 = -CH3).
D. Dihydro-forbindelser med X = CHj, dvs. med formel Id 25 30 HN=\^ i *6 a) 2-Ethyl-3-imino-2,3-dihydro-9H-dibenz-[c,f]-^ imidazo-[1,5-a]-azepin-hydrobromid (Rx og R3 = H; Rg = “C2H5) smp. 279-282° (methanol/ether) (sønderdeling).
DK 16 f: G i 7 B
11 b) 2-Allyl-3-imino-2,3-dihydro-9H-dibenz-[c, f ] -imidazo-[1,5-a]-azepin-hydrobromid (Rxog R3 = H? R6 = -CH2-CH=CH2) smp. 244-246° (methanol/ether).
5 c) 2-Isopropyl-37imino-2,3-dihydro-9H- dibenz-[cf f]-imidazo-[1,5-a]-azepin-hydrobromid (Rj^ og R3 = H; Rg = -CH ) ^ CH, 10 o 6 smp. 291-294 C; (acetonitril) (sønderdeling) .
E. Dihydro-forbindelse med X = O, dvs. med formel le 20 .
% 2-Methyl-3-imino-2,3-dihydro-dibenz- [b,f]-imidazo-[1,5-d][l#4]-oxazepin- 25 hydrobromid (R-^og R3 = H;R6 = CH3) smp. 296-299°; (methanol/ethylacetat).
F. Dihydro-forbindelse med X = S, dvs. med formel If 30 r6
DK 16 O C 7 B
12 2-Methyl-3-imino-2,3-dihydro-dibenz-[b,f]-imidazo-[1,5-d][1,4]-thiazepin-hydrobromid (Rl0g R3 = H; R6 = CH3) 5 smp. 314-317°C (methanol/ethylacetat) (sønderdeling).
De i nedenstående tabeller opførte forbindelser kan ligeledes opnås ved de ovenfor beskrevne fremgangs-10 måder.
Tabel I
Forbindelser med formlen I med en dobbeltbinding i l/13b- stilling 15 X Rj R3 Rg Fysiske data
-O- 6"CH3 -H -CH3 Smp. 303-305°C
(hydrobromid) 20 --—--
-S- 6-CH3 -H -CH3 Smp. 327-328°C
(hydrobromid)
25 Tabel II
Forbindelse med formlen I med en enkeltbinding i 1/13b-stilling 30 x R.j ^3 Rg Fysiske data
-O- 6~CH3 -H -CH3 Smp. 257-259°C
(hydrobromid)
Claims (2)
1 II (H) \ H-N 30 i R6 hvori den punkterede linie, grupperne R1, R3, Rg og X har den ovenfor angivne betydning, med et halogencyan, eller ved intramolekylær omsætning af den intermediært dannede 35 forbindelse med den almene formel DK 160047B v / ^3 Ila (H) \ NC—ΙΓ ! R6 hvori den punkterede linie, grupperne R1, R^, Rg og X har den ovenfor angivne betydning, og om ønsket opspalter opnåede racemater i de enantiomere og/eller ud fra primært opnåede fri baser fremstiller syreadditionssalte eller ud fra primært opnåede syreadditionssalte fremstiller fri baser.
1. Analogifremgangsmåde til fremstilling af 3-imi-no-dibenzo[c,f]imidazo[1,5-a]azepiner og -dibenzo[b,f]-imidazo[1,5—d][1,4Joxazepiner og -thiazepiner med den 5 almene formel / 1. hn==<C i'y ^ N ' R6 hvori R1 betegner hydrogen eller methyl, R3 betegner hydrogen, methyl eller chlor, Rg betegner alkyl med 1 til 6 C-atomer eller allyl, X betegner O, S eller CH2, og den punkterede linie betyder, at der foreligger enten en 2Φ enkeltbinding eller en dobbeltbinding, i form af frie baser eller farmaceutisk acceptable syreadditionssalte, kendetegnet ved, at man udfører en ringslutning ved omsætning af en diamin med den almene formel
2. Fremgangsmåde ifølge krav 1 til fremstilling af 2-methyl-3-imino-2,3-dihydro-9H-dibenzo[c,f]imidazo-[1,5-a ]azepin, Især hydrobromidet deraf, kendetegnet ved, at man anvender tilsvarende udgangsmaterialer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3134672 | 1981-09-02 | ||
| DE19813134672 DE3134672A1 (de) | 1981-09-02 | 1981-09-02 | Heterocyclische verbindungen, ihre herstellung und verwendung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK391182A DK391182A (da) | 1983-03-03 |
| DK160047B true DK160047B (da) | 1991-01-21 |
| DK160047C DK160047C (da) | 1991-06-10 |
Family
ID=6140652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK391182A DK160047C (da) | 1981-09-02 | 1982-09-01 | Analogifremgangsmaade til fremstilling af 3-imino-dibenzooec,faaimidazooe1,5-aaaazepiner og -dibenzooeb,faaimidazooe1,5-daaoe1,4aaoxazepiner og -thiazepiner |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4503060A (da) |
| EP (1) | EP0073506B1 (da) |
| JP (1) | JPS5846089A (da) |
| KR (1) | KR880001988B1 (da) |
| AT (1) | ATE18049T1 (da) |
| AU (1) | AU550340B2 (da) |
| CA (1) | CA1169858A (da) |
| CS (1) | CS236680B2 (da) |
| DD (1) | DD204255A5 (da) |
| DE (2) | DE3134672A1 (da) |
| DK (1) | DK160047C (da) |
| ES (3) | ES8308330A1 (da) |
| FI (1) | FI76089C (da) |
| GB (1) | GB2108112B (da) |
| GR (1) | GR77274B (da) |
| HU (1) | HU185110B (da) |
| IE (1) | IE54261B1 (da) |
| IL (1) | IL66694A0 (da) |
| NO (1) | NO160445C (da) |
| NZ (1) | NZ201780A (da) |
| PH (1) | PH19377A (da) |
| PL (1) | PL135812B1 (da) |
| PT (1) | PT75494B (da) |
| SU (1) | SU1155158A3 (da) |
| YU (1) | YU43089B (da) |
| ZA (1) | ZA826380B (da) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020091850A1 (en) | 1992-10-23 | 2002-07-11 | Cybex Corporation | System and method for remote monitoring and operation of personal computers |
| DE69428546T2 (de) * | 1993-11-22 | 2002-04-11 | Merck & Co., Inc. | 3-acylaminobenzazepine |
| ES2139933T3 (es) * | 1994-08-18 | 2000-02-16 | Merck & Co Inc | 2,3-dihidro-1-(2,2,2-trifluoroetil)-2-oxo-5-fenil-1h-1,4-benzodiacepinas. |
| US5478934A (en) * | 1994-11-23 | 1995-12-26 | Yuan; Jun | Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands |
| US5691331A (en) * | 1995-06-07 | 1997-11-25 | Merck & Co., Inc. | N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3yl) -3- amides |
| US5726171A (en) * | 1995-06-07 | 1998-03-10 | Merck & Co Inc | N-(1-alkyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo B! 1,4!diazepin-3yl)-acetamides |
| CA2222491A1 (en) * | 1995-06-07 | 1996-12-19 | Merck & Co., Inc. | Novel n-(2,4-dioxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3yl)-3-amides |
| US5631251A (en) * | 1995-06-07 | 1997-05-20 | Merck & Co., Inc. | 5-cyclopropyl-1,4 benzodiazepine-2-ones |
| US5700797A (en) * | 1995-06-07 | 1997-12-23 | Merck & Co, Inc. | N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-3-amides |
| PL3150209T3 (pl) * | 2006-03-31 | 2020-03-31 | Vistakon Pharmaceuticals, Llc | Leczenie alergii oczu |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE789410A (fr) * | 1971-10-05 | 1973-01-15 | Akzo Nv | Nieuwe imidazolidine derivaten |
| NL7202963A (da) * | 1972-03-07 | 1973-09-11 | ||
| NL7414038A (nl) * | 1974-10-28 | 1976-05-03 | Akzo Nv | Nieuwe tetracyclische pyrrolidino derivaten. |
| DE3008944A1 (de) * | 1980-03-08 | 1981-09-24 | C.H. Boehringer Sohn, 6507 Ingelheim | Dibenzimidazoazepine, ihre herstellung und verwendung |
-
1981
- 1981-09-02 DE DE19813134672 patent/DE3134672A1/de not_active Withdrawn
-
1982
- 1982-08-20 US US06/410,006 patent/US4503060A/en not_active Expired - Fee Related
- 1982-08-23 PH PH27765A patent/PH19377A/en unknown
- 1982-08-27 JP JP57149040A patent/JPS5846089A/ja active Granted
- 1982-08-28 EP EP82107929A patent/EP0073506B1/de not_active Expired
- 1982-08-28 AT AT82107929T patent/ATE18049T1/de not_active IP Right Cessation
- 1982-08-28 DE DE8282107929T patent/DE3269187D1/de not_active Expired
- 1982-08-30 DD DD82242882A patent/DD204255A5/de unknown
- 1982-08-30 CA CA000410412A patent/CA1169858A/en not_active Expired
- 1982-08-31 YU YU1960/82A patent/YU43089B/xx unknown
- 1982-08-31 PL PL1982238090A patent/PL135812B1/pl unknown
- 1982-08-31 GR GR69167A patent/GR77274B/el unknown
- 1982-08-31 FI FI823001A patent/FI76089C/fi not_active IP Right Cessation
- 1982-08-31 SU SU823484887A patent/SU1155158A3/ru active
- 1982-09-01 GB GB08224915A patent/GB2108112B/en not_active Expired
- 1982-09-01 PT PT75494A patent/PT75494B/pt not_active IP Right Cessation
- 1982-09-01 CS CS826355A patent/CS236680B2/cs unknown
- 1982-09-01 IE IE2131/82A patent/IE54261B1/en not_active IP Right Cessation
- 1982-09-01 NO NO822948A patent/NO160445C/no unknown
- 1982-09-01 DK DK391182A patent/DK160047C/da not_active IP Right Cessation
- 1982-09-01 AU AU87926/82A patent/AU550340B2/en not_active Ceased
- 1982-09-01 IL IL66694A patent/IL66694A0/xx not_active IP Right Cessation
- 1982-09-01 ZA ZA826380A patent/ZA826380B/xx unknown
- 1982-09-01 HU HU822808A patent/HU185110B/hu not_active IP Right Cessation
- 1982-09-01 NZ NZ201780A patent/NZ201780A/en unknown
- 1982-09-01 ES ES515413A patent/ES8308330A1/es not_active Expired
- 1982-09-02 KR KR8203956A patent/KR880001988B1/ko not_active Expired
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1983
- 1983-04-19 ES ES521604A patent/ES521604A0/es active Granted
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| PBP | Patent lapsed |