DK154833B - Analogifremgangsmaade til fremstilling af 3-allyl-7,8-dihydroxy-6-halogen-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepin-derivater - Google Patents
Analogifremgangsmaade til fremstilling af 3-allyl-7,8-dihydroxy-6-halogen-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepin-derivater Download PDFInfo
- Publication number
- DK154833B DK154833B DK217380AA DK217380A DK154833B DK 154833 B DK154833 B DK 154833B DK 217380A A DK217380A A DK 217380AA DK 217380 A DK217380 A DK 217380A DK 154833 B DK154833 B DK 154833B
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- Prior art keywords
- acid
- compounds
- allyl
- halogen
- tetrahydro
- Prior art date
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- PYIHTIJNCRKDBV-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCCCCC[N+](C)(C)C PYIHTIJNCRKDBV-UHFFFAOYSA-L 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- H—ELECTRICITY
- H04—ELECTRIC COMMUNICATION TECHNIQUE
- H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
- H04N3/00—Scanning details of television systems; Combination thereof with generation of supply voltages
- H04N3/10—Scanning details of television systems; Combination thereof with generation of supply voltages by means not exclusively optical-mechanical
- H04N3/16—Scanning details of television systems; Combination thereof with generation of supply voltages by means not exclusively optical-mechanical by deflecting electron beam in cathode-ray tube, e.g. scanning corrections
- H04N3/26—Modifications of scanning arrangements to improve focusing
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Multimedia (AREA)
- Signal Processing (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
DK 154833 B
Den foreliggende opfindelse angår en analogifremgangsmade til fremstilling af en gruppe forbindelser, hvis strukturer har et l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepin-skelet, der specielt har en 6-halogen-7,8-dihydroxy-substitution i benz- 5 ringen, et allyl bundet til N-ringen i 3-stilling og en hydroxy-substituent på 1-phenylet. Disse forbindelser er nyrevasodilatorer med en hidtil ukendt bradykardisk virkning. Som sådanne har de særlig interesse til behandling af angina pectoris.
10 Schweizisk patent nr. 555.831 og belgisk patent nr. 860.774 beskriver grupper af forbindelser beslægtet med de ifølge den foreliggende ansøgning, men uden nogen special beskrivelse af disse fire stamforbindelser og deres enestående biologiske virkning.
15 Slutprodukterne fremstillet ifølge opfindelsen repræsenteres ved følgende strukturformel:
X
3 n-ch9ch=ch9 20 (I)
Oh hvor X er halogen, d.v.s. fluor, chlor, brom eller jod.
25 De farmaceutisk anvendelige syreadditionssalte, der har anvendelighed som de frie baser af formlen I, fremstillet på i og for sig kendte måder, dannes med både uorganiske og organiske syrer, for eksempel maleinsyre, fumarsyre, benzoesyre, ascorbinsyre, pamoinsyre, ravsyre, bismethylensali= 30 cylsyre, methansulfonsyre, ethandisulfonsyre, eddikesyre, oxalsyre, propionsyre, vinsyre, salicylsyre, citronsyre, gluconsyre, asparaginsyre, stearinsyre, palmitinsyre, ita= consyre, glycolsyre, p-aminobenzoesyre, glutaminsyre, benzen= sulfonsvre, saltsyre, brombrintesyre, svovlsyre, cyklohexyl= 2
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sulfaminsyre, phosphorsyre og salpetersyre. Basen bringes til at reagere med et ækvivalent eller et overskud af den valgte syre i et organisk opløsningsmiddel. Saltet isoleres ved filtrering eller afdampning af opløsningsmid-5 let. Hydrohalogensyresaltene og især methansulfonsyresal-tene har særlig anvendelighed på grund af god opløselighed og oral aktivitet.
Opfindelsen indbefatter fremstilling af også O-lavere alkanoylestere af forbindelserne' af formlen I, der har fra 2 til 8 carbonato-10 mer i hver alkanoylgruppe såsom acetyl, isobutyryl, propi= onyl, isovaleryl, n-heptanoyl og andre. Triester-deriva-terne eksemplificeres, men en eller flere hydroxygrupper kan forestres trinvis under anvendelse af i og for sig kendte syntetiske metoder. Ester-derivaterne fremstilles ved at 15 behandle trihydroxy-stamforbindelsen af formlen I med enten en støkiometrisk mængde eller et overskud af et syrebromid eller -anhydrid i nærværelse af en organisk base, eventuelt i et organisk opløsningsmiddel. Acetonitril er et foretrukket opløsningsmiddel.
20 Det er klart for fagfolk, at forbindelserne af formlen I kan eksistere som diastereoisomere, der kan opspaltes til d,l-optiske isomere. Opspaltningen af de optiske isomere kan bekvemt udføres ved fraktioneret krystallisation af deres salte med optisk aktive syrer af passende opløsningsmid-25 ler. Med mindre andet er anført i den foreliggende bekri-velse med krav, er det meningen at indbefatte alle isomere, hvadenten de er adskilt, eller det drejer sig om blandinger deraf. Hvor isomere adskilles, vil den ønskede farmaka-logiske virkning i regelen være dominerende 'hos en af de 30 isomere, men i regelen anvendes imidlertid blandingen af isomere til opfindelsens formål.
Udgangsmaterialerne til forbindelserne af formlen I fremstilles ved N-allylering af en forbindelse af formlen:
X
3
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RO-fi^S/ \
I F-H
R0-\X_/ I (IX)
V
OR
5 hvor X er halogen, og hvert R er et lavere alkyl, især med 1-6 carbonatomer såsom methyl, benzyl eller, når to tages sammen i benzringen, methylen eller ethylen. N-allylerin-gen til fremstilling af de umiddelbare forstadier af formlen: X
RO-r^Y/ \ I N-CH2CH=CH2 RO-icv. / 10 a: (ud
OR
hvor R har den ovennævnte betydning, udføres ved anvendelse af allylbromid, -chlorid eller -jodid i et indifferent or-15 ganisk opløsningsmiddel, især acetonitril, i nærværelse af en tertiær organisk base såsom pyridin, triethylamin eller dimethylanilin.
De beskyttende R-grupper i forbindelserne af formlen III fjernes så ved reaktion af de O-beskyttede forbindelser 20 med etherspaltningsmidler såsom bortribromid eller -tri= chlorid, fortrinsvis i et halogeneret organisk opløsningsmiddel såsom methylenchlorid, tetrachlorkulstof eller chlor= oform, pyridinhydrochlorid, vandig hydrogenbromid, alumi= niumchlorid eller -bromid i et egnet opløsningsmiddel så-25 som benzen eller svovlkulstof, jodbrintesyre, flussyre- antimonpentafluorid eller trifluormethylsulfonsyre i thio= anisol til dannelse af de ønskede forbindelser af formlen
T ν' v· η i>1r AW/3a Λν O— λ! 1 Λν· "NT hS 1 1 T71 rfVI 1Λ1 C
4
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aktionsdygtig, men det foretrækkes at holde reaktionsbetingelserne så milde som muligt for at formindske reaktion ved dobbeltbindingen i allylgruppen.
Den foretrukne fremgangsmåde ifølge opfindelsen omfatter 5 reaktion af trietheren af strukturenIII med bortribromid i et halogeneret organisk opløsningsmiddel såsom methylen= chlorid, chloroform'eller tetrachlorkulstof ved temperaturer fra -15°C til stuetemperatur, indtil reaktionen er fuldendt. Overskud af bortribromid ødelægges ved anven-10 delse af en alkohol. Afdampning af de flygtige stoffer giver det ønskede slutprodukt ifølge opfindelsen (I).
BIOLOGISK SPEKTRUM AF FORBINDELSERNE
Forbindelserne af formlen I har uventet vist sig at have en enestående hæmodynamisk profil, som er karakteriseret 15 ved reduceret arterieblodtryk, reduceret hjertefrekvens og reduceret myokardialt arbejde med et forøget hjerteslagsrumfang og forøget nyreperfusion.
Forbindelserne er derfor særligt nyttige som anti-angina-midler.
20 Aktivitetsspektret af disse hidtil ukendte forbindelser demonstreres ved tre farmakologiske metoder: (1) Prøvemeto den med normotensiv anæstetiseret hund, hvor middel-arterie-blodtryk (MAP), nyreblodstrøm (EBF), nyrevaskulær modstand (RVR) og hjertefrekvens (HR) styres efter infusion i pg/kg/ 25 min.-doser under anvendelse af den kendte farmakodynamiske fremgangsmåde til bestemmelse af perifere dopaminergiske virkninger, især på nyren, (2) anti-Parkinsonisme-prøven for centrale dopaminergiske virkninger med vendende rotte og (3) metoden med spontant hypertensiv rotte.
30 De følgende data illustrerer det ønskelige aktivitetsspektrum af forbindelserne fremstillet ifølge opfindelsen sammenlignet med 5
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beslægtede forbindelser, hvis strukturer anses for at være nærmere de af forbindelserne fremstillet ifølge opfindelsen end de strukturer, der er specielt beskrevet i den kendte tekriik.
PRØVE 1 - normotensiv anæstetiseret hund.
5 (A) 3-allyl-6-chlor-7,8-dihydroxy-l (4-hydroxyphenyl) - 2.3.4.5- tetrahydro-lH-3-benzazepinhydrobromid.
μ g/kg/min MAP RBF RVR HR
0,3 - 3,5 + 8,7 x) -11,4 x) 0,0 3.0 -14,4 x) +18,1 x) -27,8 x) + 0,5 30.0 -16,9 x) +20,0 x) -30,7 x) - 8,7 x) 10 (B) 3-allyl-6-chlor-7,8-dihydroxy-l-phenyl-2,3,4,5- tetrahydro-lH-3-benzazepinhydrobromidhydrat.
μ g/kg/min MAP RBF RVR HR
0,3 - 1,8 +13,0 x) -13,1 + 6,8 x) 3.0 - 8,5 x) +32,5 x) -30,7 x) + 7,4 x) 30.0 -22,3 x) + 6,6 x) -22,3 x) - 1,0 300.0 + 3,4 -12,5 x) +18,3 x) -13,5 x) 15 (C) 6-chlor-7,8-dihydroxy-3-methyl-l(4-hydroxyphenyl)- 2.3.4.5- tetrahydro-lH-e-benzazepinhydrobromid.
μ g/kg/min MAP RBF RVR HR
3.0 - 3,3 0,0 - 3,0 0,0 30.0 + 4,5 + 7,1 - 2,4 0,0 300.0 +11,1 x) +17,4 x) - 5,1 0,0 20 (d) 6-chlor-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5- tetrahydro-lH-3-benzazapin.
μg/kg/min MAP RBF RVR HR
3.0 - 6,7 +29,4 -26,2 x) + 6,7 30.0 - 6,8 +18,7 x) -21,1 x) +14,2 x) 300.0 -18,3 x) - 9,8 x) -10,4 x) +18,2 x) 25 Tallene med "kryds" betragtes som signifikante.
Disse data viser, at med 30 mikrogram udviste 6-chlorpro-totypeforbindelserne fremstillet ifølge opfindelsen '(forbindelse A) renale dopaminergiske virkninger, som forøgede nyreblodstrøm-
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e
Forbindelse B, hvis struktur mangler den phenoliske hydroxy-gruppe, udviser ingen bradykardia ved 30 mikrogram og udviser bradykardia ved 300 mikrogram, men ingen renal dopa-minergisk virkning. Forbindelse C, hvis struktur har en 5 3-methylgruppe i stedet for 3-allylgruppen, viser ingen renal dopaminergisk virkning eller bradykardisk virkning. Forbindelse D, hvis struktur mangler N-allylgruppen, udviser forøget hjertefrekvens i alle doser. Sidsnævnte er den forventede reaktion på generel perifer vasodilation.
10 PRØVE 2 - rotte-rotation (i.p.).
(A) 10 mg/kg 647 - 84 (B) RD5qo °»03 mg/kg 10 631 - 152 2,0 297 - 64
Signifikant men svag virkning.
15 (C) 10 mg/kg 762 - 253 (D) 10 mg/kg 14-7
Svag aktivitet. Inaktiv.
PRØVE 3 - spontant hypertensiv rotte.
Forsøgsmetode:
Voksne spontant hypertensive hanrotter, der vejer ca. 350 -20 500 g, anæstetiseres med natriumpentobarbital (65 mg/kg, i.p.). Luftrørene forsynes med kanyle, og rotterne får lov at ånde spontant. Det pulserende arterieblodtryk måles fra en med kanyle forsynet carotid arterie’under anvendelse af en transducer. Middelarterieblodtrykket be-25 regnes som diastolisk blodtryk +1/3 pulstryk. Hjertefrekvensen styres af et kardiotachometer, der igangsættes af den systotiske blodtrykspuls. Lægemiddelopløsninger administreres gennem en halevene med kanyle. Efter kirurgien lader man ca. 10 minutter hengå til ligevægt. For-30 søgsforbindelserne administreres i 0,9% saltopløsning. Resultaterne noteres som mcg/kg fri base. Kontroloptegnelser foretages, og der aflæses med 5-10 minutters mellem- 7
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rum med stigende doser fra 1 til 1,000 mcg/kg.
Forbindelse A fremstillet ifølge opfindelsen nedsatte arterieblodtrykket og hjertefrekvensen på en måde, der stod i relation til dosen, i intervallet 1 - 1,000 mcg/kg (i.v.). I samme 5 dosisinterval frembragte dopamin fremtrædende tachykardia og arteriehypertension. Bradykardiaen og hypotensionen, som forbindelse A udviste, blev modvirket af en ganglie-blokker (hexamethonium) og en dopamin-antagonist (metoclopromid)„ Prototypeforbindelsen fremstillet ifølge opfindelsen (A) frembragte i 10 en intraduodenal dosis på 10 mg/kg på anæstetiseret hund bradykardia og arteriehypotension af en varighed på 30 -45 minutter.Ved en dosis på 5 mg/kg oral til normal hund blev ikke iagttaget nogen bivirkninger.
Forbindelse B, den tilsvarende deshydroxyforbindelse, frem-15 bragte også bradykardia og hypotension i SH-rotte, men virkningen var ikke specifik, da den var et meget kraftigt centralt dopaminergisk. middel.
Forbindelse C i en dosis på 1 - 1.000 mg/kg (i.v.) udviste kun trivielle blodtryksvirkninger og nedsatte kun hjerte-20 frekvensen i den højest afprøvede dosis (1.000 mcg/kg).
Foruden de ovenfor beskrevne prøver viste detaljeret undersøgelse af forbindelsen A, prototypen fremstillet ifølge opfindelsen, på anæstetiseret hund en nedsat perifer modstandsevne i den systemiske vaskulaturog forøget slagrumfang af hjertet 25 til trods for en langsommere og muligvis en nedsat adrener-gisk tonus for hjertet og vaskulaturen.
De farmaceutiske midler indeholdende en forbindelse fremstillet ifølge opfindelsen, som har en enestående anti-hypertensiv virkning, og især virkning mod angina 30 pectoris, fremstilles i sædvanlige enhedsdosisformer ved at inkorporere en forbindelse af formlen I, en isomer el 1 O-n Ω *f“ f QT»mQPQIlf 1 el· oni/anrlol n n-f- ev/noarlrN-l-i λ n o <?· ο Ί + Ί Ί q -r> 8
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} esterderivat deraf i en ikke-giftig farmaceutisk bærer på velkendte måder i en ugiftig mængde, der er tilstrækkelig til at frembringe den ønskede farmakodynamiske virkning i et individ, dyr eller menneske. Fortrinsvis indeholder midlerne den aktive bestanddel i en aktiv, men ugiftig 5 mængde, der ligger fra ca. 25 mg til ca. 500 mg, fortrinsvis ca. 15 - 75 mg aktiv bestanddel pr. enhedsdosis, men denne mængde afhænger af den relative styrke af grundforbindelsen, den særlige biologiske virkning, som ønskes, administrationsvejen, oral eller parenteral, og patientens til-10 stand. Den foretrukne forbindelse (A) fremstillet ifølge opfindelsen, især som methylsulfonatsaltet, har vist sig at have god absorberbarhed fra det gastrointestinale område, således at orale doseringsformer her har særlig betydning fortrinsvis valgt inden for det enhedsdosis-interval, der er anført 15 ovenfor. Intravenøse eller subkutane doser kunne være lavere .
De farmaceutiske præparater fremstilles ved at følge sædvanlig teknik, der indebærer blanding, granulering og sammentrykning, når dette er nødvendigt, eller blanding og op-20 løsning af bestanddelene efter behov til dannelse af det ønskede slutprodukt.
De følgende eksempler er beregnet alene til at illustrere fremstillingen og brugen af forbindelserne ifølge opfindelsen. Temperaturerne er grader Celsius. Andre vari-25 tioner af disse eksempler vil være indlysende for fagfolk.
EKSEMPEL 1 6-chlor-7,8-dimethoxy-l-(4-methoxyphenyl)-2,3,4,5-tetrahydro-ΙΗ-3-benzazepin (smeltepunkt 140 - 142,5°C, 3,47 g, 0,01 m) i 50 ml acetonitril blev blandet med 2,8 ml (0,02 m) tri= 30 ethylamin og 1,4 ml (0,011 m) allylbromid. Blandingen blev opvarmet til 85 - 95°C i 2 1/2 time. Reaktionsblandingen blev inddampet. Remanensen blev suspenderet i vand nrt c+T> nsnrre τπωι·1 Ω-t-VnT·! λι'Ό-Ηλ-Η _ Πω nrrrarii aVo
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9 ekstrakter blev vasket med vand, saltvand og inddampet til dannelse af 2,6 g (67,2%) af en gul olie, 3-allyl-6-chlor-7,8-dimethoxy-l-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzaz epin.
5 Dette materiale (2,6 g, 0,0067 m) blev opløst i 55 ml methylenchlorid og afkølet til -15°C, på hvilket tidspunkt 6,0 ml (0,064 m) bortribromid i 40 ml methylenchlorid blev tilsat langsomt i løbet af 1/2 time. Reaktionsblandingen blev omrørt ved stuetemperatur i 3 timer, afkølet og be-10 handlet med et overskud af methanol, langsomtog under afkøling. Methanolen blev afdampet til dannelse af et skum. Dette blev opløst i en minimal mængde methanol og afkølet. Noget ethylacetat blev tilsat for at inducere udskillelse af 1,85 g (65%) 3-allyl~6-chlor-7,8-dihydroxy-l-(4-hydroxy= 15 phenyl)-2,3,4,5-tetrahydro-lH-3-benzazepinhydrobromid (smeltepunkt 195 - 199°C under dekomponering).
EKSEMPEL 2
Bestanddele Mg pr. kapsel 20 3-allyl-6-chlor-7,8-dihydroxy-l- (4-hydroxyphenyl)-2,3,4,5-tetra= 50 hydro-lH-3-benzazepinhydrobromid (fri base)
Magniumstearat 2
Laktose 150 25 Ovennævnte bestanddele blandes grundigt og anbringes i hårde gelatinekapsler. Sådanne kapsler administreres oralt til individer, der har behov for behandling fra 1 til 5 gange daglig,for at induce en specifik dopaminer-gisk virkning til behandling af angina-symptomer.
30
Claims (5)
1. Analogifremgangsmåde til fremstilling af 3-allyl-7,8-dihydroxy- 6-halogen-l-(4-hydroxyphenyl)-2,3,4,5-:tetrahydro-lH-3-benzazepinderi vater med den almene formel X KD-t^V \ N-CH0CH=CH0 RoVw v
5 OH hvor X er halogen, eller et farmaceutisk anvendeligt syreadditionssalt eller O-lavere alkanoylester med 2-8 carbonatomer deraf, kendetegnet ved'reaktion af en forbindelse af formlen X
10 N-CH0CH=CH0 ίίΊ OR 15 hvor X er halogen, og R er et lavere alkyl med 1-6 carbonatomer, benzyl eller, taget sammen ved 7,8-stillingerne på kernens benzring, methylen eller ethylen, med et dealky-leringsmiddel, eventuelt dannelse af et syreadditionssalt ved reaktion af basen med mindst ét ækvivalent syre eller 20 eventuelt dannelse af en O-lavere alkanoylester ved reaktion af basen med et lavere alkansyreanhydrid eller syre= chlorid i nærværelse af base.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at X er chlor. o ™____________ ·,______ ·, DK 154833 B n ved, at X er chlor, og demethyleringsmidlet er bortribromid.
4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at X er chlor, demethyleringsmidlet er bortribromid, og basen yderligere bringes til at reagere med en ugiftig 5 syre til dannelse af et salt. 10 15
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/042,680 US4251525A (en) | 1979-05-25 | 1979-05-25 | 3-Allyl-7,8-dihydroxy-6-halo-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives |
| US4268079 | 1979-05-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK217380A DK217380A (da) | 1980-11-26 |
| DK154833B true DK154833B (da) | 1988-12-27 |
| DK154833C DK154833C (da) | 1989-05-16 |
Family
ID=21923200
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK217380A DK154833C (da) | 1979-05-25 | 1980-05-19 | Analogifremgangsmaade til fremstilling af 3-allyl-7,8-dihydroxy-6-halogen-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepin-derivater |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4251525A (da) |
| EP (1) | EP0020107B1 (da) |
| JP (1) | JPS55157569A (da) |
| KR (1) | KR840001212B1 (da) |
| AT (1) | ATE1448T1 (da) |
| AU (1) | AU534783B2 (da) |
| CS (1) | CS216929B2 (da) |
| DD (1) | DD151162A5 (da) |
| DE (1) | DE3060753D1 (da) |
| DK (1) | DK154833C (da) |
| ES (1) | ES491620A0 (da) |
| FI (1) | FI66599C (da) |
| GR (1) | GR68523B (da) |
| HU (1) | HU180582B (da) |
| IE (1) | IE49815B1 (da) |
| IL (1) | IL60144A (da) |
| IN (1) | IN154373B (da) |
| MX (1) | MX6526E (da) |
| NO (1) | NO146025C (da) |
| NZ (1) | NZ193767A (da) |
| PH (1) | PH15922A (da) |
| PL (1) | PL124374B1 (da) |
| PT (1) | PT71262A (da) |
| SU (1) | SU982539A3 (da) |
| YU (1) | YU140580A (da) |
| ZA (1) | ZA802325B (da) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4340601A (en) * | 1980-07-08 | 1982-07-20 | Smithkline Corporation | Dopaminergic isoquinolines |
| US4328153A (en) * | 1980-07-17 | 1982-05-04 | Smith Kline Corporation | Dopaminergic benzazepines |
| CA2098446A1 (en) * | 1992-09-30 | 1994-03-31 | Eckard Weber | 2,5-dihydro-2,5-dioxo-1h-azepines and 2,5-dihydro-2-oxo-1h-azepines and the use thereof as excitatory amino acid and glycine receptor antagonists |
| US7458374B2 (en) * | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| US7585493B2 (en) | 2001-05-24 | 2009-09-08 | Alexza Pharmaceuticals, Inc. | Thin-film drug delivery article and method of use |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US7766013B2 (en) | 2001-06-05 | 2010-08-03 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
| US7090830B2 (en) * | 2001-05-24 | 2006-08-15 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| US20040105818A1 (en) * | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
| US7913688B2 (en) * | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
| EP1625333A1 (en) | 2003-05-21 | 2006-02-15 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
| US7540286B2 (en) * | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| EP2246086A3 (en) * | 2004-08-12 | 2012-11-21 | Alexza Pharmaceuticals, Inc. | Aerosol drug delivery device incorporating percussively activated heating unit |
| US20100006092A1 (en) * | 2004-08-12 | 2010-01-14 | Alexza Pharmaceuticals, Inc. | Aerosol Drug Delivery Device Incorporating Percussively Activated Heat Packages |
| EP2121088B1 (en) | 2007-03-09 | 2016-07-13 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
| EP3746138B1 (en) | 2018-02-02 | 2025-12-10 | Alexza Pharmaceuticals, Inc. | Electrical condensation aerosol device |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4160765A (en) * | 1976-11-17 | 1979-07-10 | Smithkline Corporation | Method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds |
| ZA777444B (en) * | 1977-01-19 | 1978-10-25 | Smithkline Corp | Alkylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepines having dopaminergic activity |
| US4104379A (en) * | 1977-01-19 | 1978-08-01 | Smithkline Corporation | Substituted 1-alkylthiophenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds |
| US4108989A (en) * | 1977-04-01 | 1978-08-22 | Smithkline Corporation | 2,3,4,5-tetrahydro-1h-3-benzazepine-7,8-diones |
| US4171359A (en) * | 1978-04-12 | 1979-10-16 | Smithkline Corporation | Benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines |
-
1979
- 1979-05-25 US US06/042,680 patent/US4251525A/en not_active Expired - Lifetime
-
1980
- 1980-04-18 ZA ZA00802325A patent/ZA802325B/xx unknown
- 1980-05-16 IN IN359/DEL/80A patent/IN154373B/en unknown
- 1980-05-16 JP JP6585780A patent/JPS55157569A/ja active Pending
- 1980-05-19 DK DK217380A patent/DK154833C/da not_active IP Right Cessation
- 1980-05-19 PT PT71262A patent/PT71262A/pt unknown
- 1980-05-19 AU AU58520/80A patent/AU534783B2/en not_active Expired
- 1980-05-19 PH PH24043A patent/PH15922A/en unknown
- 1980-05-19 HU HU80801241A patent/HU180582B/hu not_active IP Right Cessation
- 1980-05-19 FI FI801612A patent/FI66599C/fi not_active IP Right Cessation
- 1980-05-19 NZ NZ193767A patent/NZ193767A/xx unknown
- 1980-05-20 NO NO801497A patent/NO146025C/no unknown
- 1980-05-20 ES ES491620A patent/ES491620A0/es active Granted
- 1980-05-21 IE IE1063/80A patent/IE49815B1/en not_active IP Right Cessation
- 1980-05-22 IL IL60144A patent/IL60144A/xx unknown
- 1980-05-22 GR GR62031A patent/GR68523B/el unknown
- 1980-05-22 PL PL1980224415A patent/PL124374B1/pl unknown
- 1980-05-23 DE DE8080301716T patent/DE3060753D1/de not_active Expired
- 1980-05-23 DD DD80221356A patent/DD151162A5/de not_active IP Right Cessation
- 1980-05-23 MX MX808838U patent/MX6526E/es unknown
- 1980-05-23 AT AT80301716T patent/ATE1448T1/de not_active IP Right Cessation
- 1980-05-23 YU YU01405/80A patent/YU140580A/xx unknown
- 1980-05-23 CS CS803658A patent/CS216929B2/cs unknown
- 1980-05-23 EP EP80301716A patent/EP0020107B1/en not_active Expired
- 1980-05-23 SU SU802927002A patent/SU982539A3/ru active
- 1980-05-24 KR KR1019800002048A patent/KR840001212B1/ko not_active Expired
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| PUP | Patent expired |