DK157925B - 2,3,4,5-Tetrahydro-1H-3-benzazepine derivatives and pharmaceutical preparations comprising them - Google Patents
2,3,4,5-Tetrahydro-1H-3-benzazepine derivatives and pharmaceutical preparations comprising them Download PDFInfo
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Denne opfindelse angår hidtil ukendte 2,3,4,5-tetra-hydro-lH-3-benzazepinderivater eller salte deraf, som kan anvendes til behandlingen af sindssygdomme.This invention relates to novel 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives or salts thereof which can be used in the treatment of mental disorders.
Inden for de sidste 10 år er der foregået en intensiv 5 farmakologisk forskning vedrørende benzazepiner. Benzazepiners farmakologiske egenskaber afhænger i høj grad af karakteren af substituenterne. Der kendes f.eks. substituerede benzazepiner med neuroleptisk, antiaggresive, antiparkinson og vaskuløs virkninger.Within the last 10 years, intensive 5 pharmacological research has been conducted on benzazepines. The pharmacological properties of benzazepines depend largely on the nature of the substituents. It is known e.g. substituted benzazepines with neuroleptic, antiaggressive, antiparkinson and vascular effects.
10 I USA-patentskrift nr. 3.393.192 (Schering) er der beskrevet derivater af l-phenyl-2,3,4,5-tetrahydro-lH-3-benza-zepin med bl.a. hydroxy, lavere alkoxy eller halogen i 7-og/eller 8-stillingen. I europæiske patentansøgninger med pub-likationsnr. 5.298 og 5.299 er der beskrevet tilsvarende 15 7-hydroxyderivater. Det er anført, at disse forbindelser har antipsykotiske og antidepressive virkninger.In U.S. Patent No. 3,393,192 (Schering), derivatives of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine having been disclosed include hydroxy, lower alkoxy or halogen at the 7 and / or 8 position. In European patent applications with publication no. 5,298 and 5,299, corresponding to 15 7-hydroxy derivatives are disclosed. These compounds have been reported to have antipsychotic and antidepressant effects.
Ifølge Life Sci. 31 (1982), 637 ff, er 2,3,4,5-tetra-hydro-7,8-dihydroxy-l-phenyl-lH-3-benzazepin (betegnet SKF 38393) og 2,3,4,5-tetrahydro-9-chlor-7,8-dihydroxy-l-(4-hy-20 droxyphenyl)-lH-3-benzazepin (betegnet SKF 82526) selektive men partielle Dl-dopaminagonister, mens 2,3,4,5-tetrahydro-7,8-dihydroxy-6-thiophenyl-lH-3-benzazepin (betegnet SKF 83742) er en selektiv Dl-dopaminantagonist. Yderligere er det angivet i Eur. J. Pharmacol. 91. (1983), 153 ff, at R-8-chlor-7-hydroxy-25 2,3,4,5-tetrahydro-3-methyl-5-phenyl-lH-3-benzazepin (betegnet SCH 23390) er en selektiv Dl-dopaminantagonist (se også europæisk patentansøgning med publiceringsnr. 5300).According to Life Sci. 31 (1982), 637 ff, are 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (designated SKF 38393) and 2,3,4,5- tetrahydro-9-chloro-7,8-dihydroxy-1- (4-hydroxyphenyl) -1H-3-benzazepine (designated SKF 82526) selective but partial D1-dopamine agonists, while 2,3,4,5-tetrahydro -7,8-dihydroxy-6-thiophenyl-1H-3-benzazepine (designated SKF 83742) is a selective D1-dopamine antagonist. Further it is stated in Eur. J. Pharmacol. 91 (1983), 153 et seq. That R-8-chloro-7-hydroxy-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine (designated SCH 23390) is a selective D1 dopamine antagonist (see also European Patent Application with Publication No. 5300).
I USA-patentskrift nr. 4.187.314 (Smith Kline) er der beskrevet 1-thienyl- eller l-furyl-2,3,4,5-tetrahydro-lH-3-ben-30 zazepiner, der bl.a. indeholder hydroxy, lavere alkoxy eller lavere alkanoyloxy i 7- og 8-stillingen. I de specifikke eksempler deri på sådanne benzazepiner er de to substituenter i 7- og 8-stillingen identiske. Disse benzazepiner angives at have perifer og centraldopaminerg virkning.U.S. Patent No. 4,187,314 (Smith Kline) discloses 1-thienyl or 1-furyl-2,3,4,5-tetrahydro-1H-3-benzazepines, which include contains hydroxy, lower alkoxy or lower alkanoyloxy at the 7- and 8-positions. In the specific examples therein of such benzazepines, the two substituents at the 7- and 8-positions are identical. These benzazepines are reported to have peripheral and central dopaminergic effects.
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Det har nu vist sig, at hidtil ukendte 2,3,4,5-tetra-hydro-lH-3-benzazepiner med den almene formel IIt has now been found that novel 2,3,4,5-tetrahydro-1H-3-benzazepines of the general formula I
CHVCHV
5 2 / X^CH2"CH2x R -C Z \ „ II I n-r' (I)2 / X ^ CH2 "CH2x R -C Z \" II I n-r '(I)
r -c Sr -c S
10 |_ 2 R5 2 3 hvori R betegner halogen, R betegner hydroxy eller alkoxy med ikke over 4 kulstofatomer, R^ betegner thienyl eller ringsystemer bestående af phenyl, som er orthokondenseret med en 15 benzen-, cyclohexan-, cyclohexen-, cyclopentan- eller cyclo-pentenring, i hvilke ringe et af kulstofatomerne kan være erstattet af oxygen, og hver af disse ringsystemer kan være substitueret én gang med halogen, hydroxy eller alkoxy med ikke 7 over 4 kulstofatomer, og R betegner hydrogen eller alkyl med 20 ikke over 4 kulstofatomer, eller salte deraf, har nyttige farmakologiske egenskaber, i særdeleshed virkninger på centralnervesystemet, der overraskende er bedre end virkningerne af de kendte forbindelser. Benzazepiner med formel I kan anvendes som lægemiddel, f.eks. til behandling af skizofreni og maniodepres-25 sive forstyrrelser.R 2 represents halogen, R represents hydroxy or alkoxy having not more than 4 carbon atoms, R 2 represents thienyl or phenyl ring systems orthocondensed with a benzene, cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring, in which rings one of the carbon atoms may be replaced by oxygen, and each of these ring systems may be substituted once by halogen, hydroxy or alkoxy of not more than 7 above 4 carbon atoms, and R represents hydrogen or alkyl of 20 not above 4 carbon atoms, or salts thereof, have useful pharmacological properties, in particular effects on the central nervous system, which are surprisingly superior to the effects of the known compounds. Benzazepines of formula I can be used as a drug, e.g. for the treatment of schizophrenia and manic depressive disorders.
I denne beskrivelse angiver betegnelsen ''alkyl med ikke over 4 kulstof atomer'', både når den bruges alene eller i kombinationer, f.eks. alkoxy, en forgrenet eller ligekædet alkylgruppe, f.eks. methyl, ethyl, propyl, isopropyl og 30 tert.butyl. Med betegnelsen "alkoxy" menes fortrinsvis methoxy og ethoxy. Halogen er chlor, brom, fluor, og iod, fortrinsvis chlor og fluor.In this specification, the term "" denotes alkyl having not more than 4 carbon atoms "", when used alone or in combinations, e.g. alkoxy, a branched or straight chain alkyl group, e.g. methyl, ethyl, propyl, isopropyl and tert-butyl. The term "alkoxy" is preferably meant methoxy and ethoxy. Halogen is chlorine, bromine, fluorine, and iodine, preferably chlorine and fluorine.
I henhold til ovenstående definition kan substituen-ten betegnet R5 bl.a. være et ringsystem bestående af phenyl, 35 der er orthokondenseret med en anden ring, nemlig med en benzenring, med en cyclohexanring, med en cyclohexenring, med enAccording to the above definition, the substituent R5 be a phenyl ring system orthocondensed with another ring, namely with a benzene ring, with a cyclohexane ring, with a cyclohexene ring, with a
3 DK 157925B3 DK 157925B
cyclopentanring eller med en cyclopentenring, og i hver af disse ringe kan et af kulstofatomerne være erstattet af et oxygenatom, og hver af disse ringsystemer kan være substitueret én gang med halogen, hydroxy eller alkoxy med ikke over 4 kulstof-5 atomer. Heri betyder betegnelsen "orthokondenseret", at den pågældende phenylring har en af sine sider fælles med en anden af 5 de ovenfor anførte specifikke ringe. Substituenten R er fortrinsvis phenyl, som er er orthokondenseret med en af de oven for anførte ringe.cyclopentane ring or with a cyclopentene ring, and in each of these rings one of the carbon atoms may be replaced by an oxygen atom and each of these ring systems may be substituted once by halogen, hydroxy or alkoxy having not more than 4 carbon atoms. Herein, the term "orthocondensed" means that the phenyl ring in question has one of its sides in common with another of the 5 specific rings listed above. The substituent R is preferably phenyl which is orthocondensed with one of the rings listed above.
10 Specifikke eksempler på substituenten betegnet R~* er thienyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, chroma-nyl, chromenyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl og dihydronaphthyl, der hver kan være substitueret én gang med halogen, hydroxy eller alkoxy med ikke over 4 kulstofatomer, 15 f.eks. chlorchromanyl, methoxychromanyl, hydroxychromanyl og hydroxybenzofurany1.Specific examples of the substituent designated R 1 hydroxy or alkoxy having not more than 4 carbon atoms, e.g. chlorochromanyl, methoxychromanyl, hydroxychromanyl and hydroxybenzofurany1.
Det er aldrig før beskrevet, at der er en speciel biologisk fordel ved det specifikke substitutionsmønster i strukturerne af benzazepinerne ifølge denne opfindelse.It has never before been described that there is a particular biological benefit to the specific substitution pattern in the structures of the benzazepines of this invention.
20 Forbindelser med formel I udviser en kraftig anti- dopaminerg effekt. Således hæmmer de kraftigt stereotype bid hos mus, fremkaldt af methylphenidat (f.eks. ved at bruge 60 mg/kg legemesvægt, subkutant, en time før observationen, der blev udført analogt med den i Acta Pharmacol. Toxicol. 31.Compounds of formula I exhibit a strong anti-dopaminergic effect. Thus, they strongly inhibit stereotyped bites in mice induced by methylphenidate (eg, using 60 mg / kg body weight, subcutaneously, one hour before the observation, which was performed analogously to that of Acta Pharmacol. Toxicol. 31.
25 (1972), 488, beskrevne metode). Desuden hæmmer forbindelser med formel I det betingede afværgningsrespons og ophobningen af amphetamin i rotter.25 (1972), 488, described method). In addition, compounds of formula I inhibit the conditional aversion response and the accumulation of amphetamine in rats.
Forbindelser med formel I virker overraskende megetCompounds of formula I surprisingly work a lot
*D* D
stærkere på dopamin Dl-receptorer, der er mærket med H-SCH 30 23390 end på dopamin D2-receptorer, der er mærket med ^H-spiperon.stronger on dopamine D1 receptors labeled with H-SCH 30 23390 than on dopamine D2 receptors labeled with ^ H-spiperone.
Forbindelser med formel I er overraskende bedre end de tidligere beskrevet dopamin Dl-antagonister, især SCH 23390. Således hæmmer forbindelser med formel I bedre dopamin-stimule-35 ret adenylatcyclase i homogenater fra rottestriatum end SCH 23390, se eksempel 7.Compounds of formula I are surprisingly better than the previously described dopamine D1 antagonists, especially SCH 23390. Thus, compounds of formula I inhibit better dopamine-stimulated adenylate cyclase in rat striatum homogenates than SCH 23390, see Example 7.
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Det er endvidere rapporteret, at SCH 23390 har en ringe, peroral absorption og en kort virkning (jfr. Life Sci.Furthermore, SCH 23390 has been reported to have poor, oral absorption and a short effect (cf. Life Sci.
34 (1984), 1529). Forbindelser med formel I udviser bedre egenskaber end SCH 23390 gør, jfr. nedenstående tabel I i eksempel 5 7.34 (1984), 1529). Compounds of formula I exhibit better properties than SCH 23390 does, cf. Table I of Example 5 below.
Forbindelser med formel I blokerede desuden den dopa-minergmedierede adfærd (f.eks. stereotype bid hos gnavere, som skyldes dopaminfrigørende midler).Compounds of formula I also blocked the dopamine-mediated behavior (eg, stereotyped bites in rodents caused by dopamine releasing agents).
Forbindelserne med formel I kan være til stede som 10 enantiomere former, der kan opspaltes i R- eller S-former. Denne opspaltning kan hensigtsmæssigt opnås ved fraktioneret krystallisation fra relevante opløsninger af saltene af forbindelserne med formel I med optisk aktive syrer. Når enantiomerne opspaltes, vil den ønskede farmakologiske aktivitet være domi-15 nerende i en af de enantiomere former, for det meste i R-for-men. Derfor indbefatter denne opfindelse alle isomere, hvad enten de er opspaltede eller er blandinger deraf.The compounds of formula I may be present as 10 enantiomeric forms which can be split into R or S forms. This cleavage may conveniently be obtained by fractional crystallization from relevant solutions of the salts of the compounds of formula I with optically active acids. When the enantiomers are cleaved, the desired pharmacological activity will predominate in one of the enantiomeric forms, mostly in the R form. Therefore, this invention includes all isomers, whether they are cleaved or are mixtures thereof.
Særligt værdifulde udførelsesformer for denne opfindelse er ikke-toksiske, farmaceutisk acceptable salte af 20 benzazepiner med formel I. Sådanne salte indbefatter salte af uorganiske og organiske syrer såsom salt-, brombrinte-, svovl-, phosphor-, methansulfon-, eddike-, mælke-, malein-, phthal- og vinsyre. Disse kan fremstilles ved hjælp af standardprocedurer, såsom ved at blande en acetoneopløsning af basen med den 25 støkiometriske mængde af syren i en opløsning, såsom acetone, og afdampning af opløsningsmidlet for at udfælde det ønskede salt som remanens.Particularly valuable embodiments of this invention are nontoxic, pharmaceutically acceptable salts of 20 benzazepines of formula I. Such salts include salts of inorganic and organic acids such as salt, hydrocarbon, sulfur, phosphorus, methanesulfone, vinegar, milk. -, maleic, phthalic and tartaric acids. These can be prepared by standard procedures such as mixing an acetone solution of the base with the stoichiometric amount of the acid in a solution such as acetone and evaporation of the solvent to precipitate the desired salt as residue.
I en første gruppe af foretrukne benzazepiner med 2 formel I er R chlor eller fluor.In a first group of preferred benzazepines of Formula I, R is chlorine or fluorine.
55
30 I en anden gruppe af benzazepiner med formel I er RIn another group of benzazepines of formula I, R is
phenyl, som er orthokondenseret med en benzen-, cyclohexan-, cyclohexen-, cyclopentan- eller cyclopentenring, der kan være substitueret én gang med halogen, hydroxy eller methoxy.phenyl which is orthocondensed with a benzene, cyclohexane, cyclohexene, cyclopentane or cyclopenten ring which may be substituted once by halogen, hydroxy or methoxy.
I en tredie gruppe af foretrukne benzazepiner med 5 35 formel i er R benzofuranyl, 2,3-dihydrobenzofuranyl, thienyl eller chromanyl.In a third group of preferred benzazepines of formula I, R is benzofuranyl, 2,3-dihydrobenzofuranyl, thienyl or chromanyl.
5 DK 157925B5 DK 157925B
.1 en fjerde gruppe af foretrukne benzazepiner med 7 formel I er R hydrogen eller methyl..1 a fourth group of preferred benzazepines of formula I is R hydrogen or methyl.
Eksempler på repræsentative og foretrukne benzazepiner med formel I er følgende: 5 1) 8-chlor-7-hydroxy-3-methyl-5-(l-naphthyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, 2) 8-chlor-7-hydroxy-3-methyl-5-(2-naphthyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, 3) 8-chlor-7-hydroxy-3-methyl-5-(3-thienyl)-2,3,4,5-tetra-10 hydro-lH-3-benzazepin, 4) 8-chlor-7-hydroxy-3-methyl-5-(2,3-dihydrobenzofuran-4-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 5) 8-chlor-7-hydroxy-5-(3-thienyl)-2,3,4,5-tetrahydro-lH-3-benzazepin, 15 6) 8-chlor-7-hydroxy-5-(1-naphthyl)-2,3,4,5-tetrahydro-lH-3-benzazepin, 7) 8-chlor-7-methoxy-5-(2-naphthyl)-2,3,4,5-tetrahydro-lH-3-benzazepin, 8) 8-chlor-7-hydroxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetra- 20 hydro-lH-3-benzazepin, 9) 8-chlor-7-methoxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, 10) 8-chlor-7-hydroxy-5-(4-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-benzazepin, 25 11) 8-chlor-7-hydroxy-3-methyl-5-(5-indenyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, 12) 8-chlor-7-hydroxy-3-methyl-5-(7-chromanyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, 13) 8-chlor-7-hydroxy-5-(1,2,3,4-tetrahydronaphth-6-yl)- 30 2,3,4,5-tetrahydro-lH-3-benzazepin, 14) 8-chlor-7-hydroxy-3-methyl-5-(2,3-dihydronaphth-4-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 15) 8-chlor-7-hydroxy-3-methyl-5-(7-benzothienyl)-2,3,4,5-tetrahydro-lH-3-benzazepin.Examples of representative and preferred benzazepines of formula I are the following: 5 1) 8-Chloro-7-hydroxy-3-methyl-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3 -benzazepine, 2) 8-chloro-7-hydroxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 3) 8-chloro-7 -hydroxy-3-methyl-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 4) 8-chloro-7-hydroxy-3-methyl-5 (2,3-dihydrobenzofuran-4-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 5) 8-chloro-7-hydroxy-5- (3-thienyl) -2,3,4,5 tetrahydro-1H-3-benzazepine, 6) 8-chloro-7-hydroxy-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 7) 8-chloro-7 -methoxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 8) 8-chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2 3,4,5-tetrahydro-1H-3-benzazepine, 9) 8-chloro-7-methoxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetra hydro-1H-3-benzazepine, 10) 8-chloro-7-hydroxy-5- (4-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 11) 8-chloro-7 -hydroxy-3-methyl-5- (5-indenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 12) 8-chloro-7-hydroxy -3-methyl-5- (7-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 13) 8-chloro-7-hydroxy-5- (1,2,3, 4-tetrahydronaphth-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 14) 8-chloro-7-hydroxy-3-methyl-5- (2,3-dihydronaphth-4) -yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 15) 8-chloro-7-hydroxy-3-methyl-5- (7-benzothienyl) -2,3,4,5-tetrahydro-1H 3-benzazepine.
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16) 8-chlor-7-hydroxy-3-methyl-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-lH-3-benzazepin, 17) 8-chlor-7-hydroxy-3-methyl-5-(2,3-dihydrobenzofuran-6-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 5 18) 8-chlor-7-hydroxy-3-methyl-5-(2,3-dihydrobenzofuran-7-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 19) 8-chlor-7-hydroxy-3-methyl-5-(2,3-dihydrobenzothien-7-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 20) 8-chlor-7-hydroxy-3-methyl-5-(5-chlorchroman-8-yl)- 10 2,3,4,5-tetrahydro-lH-3-benzazepin, 21) 8-chlor-7-hydroxy-3-methyl-5-(8-chromanyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, 22) 8-chlor-7-hydroxy-3-methyl-5-(6-hydroxychroman-8-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 15 23) 8-chlor-7-hydroxy-3-methyl-5-(5-hydroxybenzofuran-7-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 24) 8-chlor-7-hydroxy-3-methyl-5-(4-hydroxybenzofuran-6-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, 25) 8-chlor-7-hydroxy-3-methyl-5-(4-hydroxybenzothien-6-yl)- 20 2,3,4,5-tetrahydro-lH-3-benzazepin, og fysiologisk acceptable salte deraf.16) 8-chloro-7-hydroxy-3-methyl-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 17) 8-chloro-7-hydroxy-3 methyl-5- (2,3-dihydrobenzofuran-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 18) 8-chloro-7-hydroxy-3-methyl-5- (2,3- dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 19) 8-chloro-7-hydroxy-3-methyl-5- (2,3-dihydrobenzothien-7-yl) - 2.3.4.5 - tetrahydro-1H-3-benzazepine, 20) 8-chloro-7-hydroxy-3-methyl-5- (5-chloro-chromoman-8-yl) -2,3,4,5-tetrahydro-1H-3 benzazepine, 21) 8-chloro-7-hydroxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 22) 8-chloro-7- hydroxy-3-methyl-5- (6-hydroxychroman-8-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 23) 8-chloro-7-hydroxy-3-methyl-5- (5- hydroxybenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 24) 8-chloro-7-hydroxy-3-methyl-5- (4-hydroxybenzofuran-6-yl) -2,3,4,5-tetrahydro -1H-3-benzazepine, 25) 8-chloro-7-hydroxy-3-methyl-5- (4-hydroxybenzothien-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, and physiologically acceptable salts thereof .
Generelt kan de omhandlede 5-substituerede 2,3,4,5-tetrahydro-lH-3-benzazepiner med formel I fremstilles ud fra 2-(phenethylamino)ethanoler med den almene formel IVIn general, the present 5-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines of formula I can be prepared from 2- (phenethylamino) ethanols of the general formula IV
25 . CH.25. CH.
2 / X2 / X
R' -C C-CH--CH_-N-CH -CH-OH (IV) 3 II I 1 I 7 I 5 R' -C CH R' R' \ /R '-C C-CH - CH_-N-CH -CH-OH (IV) 3 II I 1 I 7 I 5 R' -C CH R 'R' \ /
30 CH30 CH
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2 3 5 7 hvori R1 , R' , R' og R' hver er identiske med henholdsvis 2 3 5 72 3 5 7 wherein R1, R ', R' and R 'are each identical to 2 3 5 7 respectively
R , R , R r og R eller repræsenterer grupper, der kan omdannes dertil. Disse alkoholmellemprodukter med formel IV kan fremstilles ved at opvarme ækvimolære mængder af en oxiran med den 5 almene formel IIIR, R, R r and R or represent groups convertible thereto. These alcohol intermediates of formula IV can be prepared by heating equimolar amounts of an oxirane of the general formula III
0 /Λ 5 H2C-CH-R,J (III) 50 / Λ 5 H2C-CH-R, J (III) 5
hvori R' er som beskrevet ovenfor, med en β-phenethylamin med 10 den almene formel IIwherein R 'is as described above, with a β-phenethylamine of general formula II
2 /CH\ R' -C C-CH0-CH -NH-R' 3 II I 2 2 (II) 15 R' -C CH 1 3 7 hvori R' , R' og R' hver er som beskrevet ovenfor. Kondensationen udføres fortrinsvis ved temperaturer på ca. 100°C.2 / CH \ R '-C C-CHO-CH -NH-R' 3 II I 2 2 (II) 15 R '-C CH 1 3 7 wherein R', R 'and R' are each as described above. The condensation is preferably carried out at temperatures of approx. 100 ° C.
20 Reaktionen kan imidlertid foregå inden for intervallet mellem stuetemperatur og ca. 105°C. Alkoholmellemprodukterne med formel IV kan isoleres ved almindelige operationer såsom krystallisation eller destillation.However, the reaction can take place within the range of room temperature to approx. 105 ° C. The alcohol intermediates of formula IV can be isolated by ordinary operations such as crystallization or distillation.
2-(phenethylamino)ethanoler med formel IV omdannes 25 til de ønskede benzazepiner med formel I ved hjælp af en intra-molekylær cyklisering, som opnås ved at reagere 2-(phenethyl-amino)ethanolen med formel IV med reagenser såsom polyphosphor-syre, svovlsyre, trifluoreddikesyre eller blandinger deraf eller andre reagenser med tilsvarende virkning. Cykliseringen 30 udføres fortrinsvis i svovlsyre eller i en blanding af svovlsyre (1 - 20%) og trifluoreddikesyre ved temperaturer mellem ca. -10 og +20°C.2- (phenethylamino) ethanols of formula IV are converted to the desired benzazepines of formula I by an intra-molecular cyclization obtained by reacting the 2- (phenethylamino) ethanol of formula IV with reagents such as polyphosphoric acid, sulfuric acid, trifluoroacetic acid or mixtures thereof or other reagents having similar effect. Cyclization 30 is preferably carried out in sulfuric acid or in a mixture of sulfuric acid (1-20%) and trifluoroacetic acid at temperatures between -10 and + 20 ° C.
8 DK 157925B8 DK 157925B
Benzazepiner, der er substitueret i 3-stillingen, kan let dannes, enten ved anvendelse af egnede N-substituerede phenethylaminer eller fortrinsvis ved alkylering af benzazepi- 7 nen med formel I, x hvilken R betegner hydrogen.Benzazepines substituted at the 3-position can be readily formed, either by the use of suitable N-substituted phenethylamines or preferably by alkylation of the benzazepine of formula I, x which R represents hydrogen.
5 Ovennævnte betegnelse "gruppe, der kan omdannes der til", betegner f.eks. de tilsvarende beskyttede grupper såsom beskyttet hydroxy, f.eks. beskyttet med lavere alkyl, f.eks. methoxy eller ethoxy, eller benzyloxy. Beskyttelsesgrupperne kan fjernes på i og for sig kendt måde, f.eks. ved hydrolyse 10 eller hydrogenering.The above designation "group which can be converted there" refers, for example, to the corresponding protected groups such as protected hydroxy, e.g. lower alkyl protected, e.g. methoxy or ethoxy, or benzyloxy. The protecting groups can be removed in a manner known per se, e.g. by hydrolysis 10 or hydrogenation.
De udgangsmaterialer, for hvilke fremstillingen ikke er beskrevet heri, er enten kendte forbindelser eller forbindelser, der kan laves analogt med fremstillingen af kendte forbindelser eller analogt med kendte metoder.The starting materials for which the preparation is not described herein are either known compounds or compounds which can be made analogous to the preparation of known compounds or analogous to known methods.
15 Benzazepiner med formel I er nyttige, fordi de har farmakologisk virkning på dyr, f.eks. på mennesker. Specielt kan forbindelser med formel I være nyttige som psykofarmaka. Benzazepiner med formel I administreres i en effektiv mængde til den vært, som har brug for behandling.Benzazepines of formula I are useful because they have pharmacological effects on animals, e.g. on humans. In particular, compounds of formula I may be useful as psychopharmaceuticals. Benzazepines of formula I are administered in an effective amount to the host in need of treatment.
20 Til ovennævnte anvendelse vil doseringen variere af hængigt af, hvilket benzazepin med formel I, der anvendes, af hvordan administreringen foregår og af den ønskede terapi. I almindelighed kan der dog opnås tilfredsstillende resultater med en daglig dosis på fra 0,005 mg til ca. 2 mg pr. kg legems-25 vægt, der passende kan gives i deldoser fra 2 til 5 gange om dagen eller i retarderet form. Almindeligvis indeholder dosisformerne, der er anvendelige til oral administrering, fra ca.For the above use, the dosage will vary depending on the benzazepine of formula I used, the manner of administration and the desired therapy. In general, however, satisfactory results can be obtained with a daily dose of from 0.005 mg to approx. 2 mg per 25 kg of body weight, which may conveniently be given in sub-doses from 2 to 5 times a day or in retarded form. Generally, the dosage forms useful for oral administration contain from ca.
0,5 mg til ca. 150 mg benzazepin med formel I blandet med en farmaceutisk bærer eller et fortyndingsmiddel.0.5 mg to approx. 150 mg of benzazepine of formula I mixed with a pharmaceutical carrier or diluent.
30 Benzazepiner med formel I kan administreres i form af et farmaceutisk acceptabelt syreadditionssalt. Denne opfindelse angår også farmaceutiske præparater indeholdende et benzazepin-derivat med formel I eller et farmaceutisk acceptabelt salt deraf, og sædvanligvis indeholder sådanne præparater også en 35 farmaceutisk bærer eller et. fortyndingsmiddel. PræparaterneBenzazepines of formula I can be administered in the form of a pharmaceutically acceptable acid addition salt. This invention also relates to pharmaceutical compositions containing a benzazepine derivative of formula I or a pharmaceutically acceptable salt thereof, and usually such compositions also contain a pharmaceutical carrier or one. diluent. The compositions
9 DK 157925B9 DK 157925B
ifølge denne opfindelse kan frems'tilles ved hjælp af konventionelle metoder i konventionelle former, f.eks. kapsler eller tabletter.according to this invention can be produced by conventional methods in conventional forms, e.g. capsules or tablets.
Den anvendte farmaceutiske bærer kan være konventio-5 nelle, faste eller flydende bærere. Eksempler på faste bærere er lactose, terra alba, sucrose, talkum, gelatine, agar, pectin, acacia, magnesiumstearat og stearinsyre. Eksempler på flydende bærere er sirup, jordnøddeolie, olivenolie og vand. Ligeledes kan bæreren eller fortyndingsmidlet indeholde et 10 hvilket som helst, kendt materiale, der forsinker optagelsen, såsom glycerylmonostearat eller glyceryldistearat alene eller sammen med et voks.The pharmaceutical carrier used may be conventional, solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Likewise, the carrier or diluent may contain any known material which delays the uptake such as glyceryl monostearate or glyceryl distearate alone or together with a wax.
Hvis der bruges en fast bærer til oral administrering, kan præparatet være i tabletform, anbragt i en hårdgela-15 tinekapslen i pulverform eller som små kugler eller i form af en pastil eller et bolsje. Mængden af fast bærer kan variere betydeligt, men almindeligvis vil den være fra ca. 25 mg til ca. 1 g. Hvis der bruges en flydende bærer, kan præparatet være i form af en sirup, emulsion, blødgelatinekapsel, steril inji-20 cerbar væske såsom en ampul eller en vandig eller ikke-vandig, flydende suspension.If a solid carrier is used for oral administration, the composition may be in tablet form, placed in a hard gelatin capsule in powder form or as small beads or in the form of a lozenge or cup. The amount of solid carrier may vary considerably, but generally it will be from about 1 25 mg to approx. If a liquid carrier is used, the composition may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or an aqueous or non-aqueous liquid suspension.
De farmaceutiske præparater ifølge denne opfindelse kan fremstilles ved hjælp af konventionelle metoder af en farmaceut, hvilket indbefatter blanding, granulering og sammen-25 presning eller afvekslende blanding og opløsning af de bestanddele, der er hensigtsmæssig for at give det ønskede slutprodukt.The pharmaceutical compositions of this invention can be prepared by conventional methods by a pharmacist, which includes mixing, granulating and compressing or alternating mixing and dissolving the ingredients appropriate to provide the desired final product.
Administreringsmåden kan være enhver måde, på hvilken den aktive forbindelse effektivt transporteres til det hen-30 sigtsmæssige eller ønskede sted, såsom oral eller parenteral administration, idet oral administration foretrækkes.The mode of administration may be any manner in which the active compound is effectively transported to the appropriate or desired site, such as oral or parenteral administration, with oral administration being preferred.
Den heri anvendte nomenklatur er i overensstemmelse med IUPAC-nomenklaturen, med det forbehold, at i et forsøg på at lette læsningen af denne beskrivelse er positionen for sub- 5The nomenclature used herein is in accordance with the IUPAC nomenclature, with the proviso that in an attempt to facilitate the reading of this description, the position of sub
i° DK 157925 Bi ° DK 157925 B
stituenten betegnet R altid nummer 5. Ifølge IUPAC-nomen-klaturen er denne stilling nummer 1 eller 5, afhængigt af hvordan benzazepinet er substitueret.the stituent denoted R is always number 5. According to the IUPAC nomenclature, this position is number 1 or 5, depending on how the benzazepine is substituted.
De karakteristika, som er angivet i ovenstående be-5 skrivelse og i de følgende eksempler og krav, kan både hver for sig og i en hvilken som helst kombination deraf være af betydning for udførelsen af opfindelsen på forskellige måder.The characteristics set forth in the foregoing description and in the following Examples and Claims may be both individually and in any combination thereof relevant to the practice of the invention in various ways.
Opfindelsen belyses yderligere i de følgende eksempler. Eksempel 1 og 2 belyser fremstillingen af udgangsmateriale) ler, der kan anvendes til fremstilling af de omhandlede forbindelser med formel I, eksempel 3-6 belyser fremstillingen af de omhandlede forbindelser, eksempel 7 og 8 belyser de omhandlede forbindelsers virkning, og eksempel 9 og 10 belyser fremstillingen af farmaceutiske præparater indeholdende de omhand-15 lede forbindelser.The invention is further illustrated in the following examples. Examples 1 and 2 illustrate the preparation of starting materials which can be used to prepare the subject compounds of formula I, Examples 3-6 illustrate the preparation of the compounds of the invention, Examples 7 and 8 illustrate the effect of the compounds of the invention, and Examples 9 and 10. illustrates the preparation of pharmaceutical compositions containing the compounds of the present invention.
Eksempel 1Example 1
Til en opløsning af 4,9 g natriumhydrid i 115 ml dimethylsulfoxid blev der tilsat 26,2 g trimethyl-sulfoxonium-iodid over en periode på ca. 30 minutter. 15,0 g 5-indanyl-20 carboxaldehyd blev derefter tilsat over en periode på 5 minutter, og reaktionsblandingen blev omrørt i 15 minutter ved stuetemperatur og derefter i 30 minutter ved 50°C. Reaktionsblandingen blev hældt i isvand og ekstraheret to gange med 200 ml æter. De blandede ekstrakter blev vasket med vand og tørret 25 over Na2S0^ (vandfri).To a solution of 4.9 g of sodium hydride in 115 ml of dimethylsulfoxide was added 26.2 g of trimethylsulfoxonium iodide over a period of approx. 30 minutes. 15.0 g of 5-indanyl-20 carboxaldehyde was then added over a period of 5 minutes and the reaction mixture was stirred for 15 minutes at room temperature and then for 30 minutes at 50 ° C. The reaction mixture was poured into ice water and extracted twice with 200 ml ether. The mixed extracts were washed with water and dried over Na 2 SO 4 (anhydrous).
Afdampning af opløsningsmidlet gav en olie, der blev fraktioneret i vakuum, hvilket gav en farveløs væske, nemlig 5-indanyloxiran med kogepunkt (herefter kp.) på 66°C ved 0,3 mm Hg.Evaporation of the solvent gave an oil which was fractionated in vacuo to give a colorless liquid, namely 5-indanyloxirane with a boiling point (hereafter kp.) Of 66 ° C at 0.3 mm Hg.
30 Analogt med den ovenfor beskrevne metode blev der fremstillet følgende forbindelser:Analogous to the method described above, the following compounds were prepared:
DK 157925BDK 157925B
11 b) (5-chlorchroman-8-yl)oxiran, kp. 114°C ved 0,3 mm Hg, c) (3-thienyl)oxiran, kp. 218°C, d) (7-benzofuranyl)oxiran, kp. 76 - 78°C ved 0,1 mm Hg, e) (2,3-dihydrobenzofuran-7-yl)oxiran, kp. 78°C ved 0,4 mm Hg 5 og f) (l,2,3,4-tetrahydronaphth-6-yl)oxiran, kp. 83°C ved 0,1 mm Hg.11 b) (5-Chlorochroman-8-yl) oxirane, b.p. 114 ° C at 0.3 mm Hg, c) (3-thienyl) oxirane, b.p. 218 ° C, d) (7-benzofuranyl) oxirane, b.p. 76 - 78 ° C at 0.1 mm Hg, e) (2,3-dihydrobenzofuran-7-yl) oxirane, b.p. 78 ° C at 0.4 mm Hg 5 and f) (1,2,3,4-tetrahydronaphth-6-yl) oxirane, b.p. 83 ° C at 0.1 mm Hg.
Eksempel 2 a) En blanding af 3,0 g a-3-chlor-4-methoxyphenethyl-10 amin og 2,5 g 5-indanyloxiran blev omrørt ved 100°C i 18 timer.Example 2 a) A mixture of 3.0 g of α-3-chloro-4-methoxyphenethyl-10 amine and 2.5 g of 5-indanyloxirane was stirred at 100 ° C for 18 hours.
Der blev tilsat 20 ml acetonitril til den stadig varme reak-tionsblanding^ og krystallisation startede straks. Krystallisationen blev afsluttet ved at afkøle blandingen i isvand. Produktet blev isoleret ved filtrering, vasket med koldt 15 acetonitril og tørret. Omkrystallisation fra acetonitril gav N-(a-(3-chlor-4-methoxyphenethyl))-1-(5-indanyl)-2-aminoethanol med et smeltepunkt (herefter betegnet smp.) på 138 - 139°C.20 ml of acetonitrile was added to the still warm reaction mixture and crystallization started immediately. The crystallization was terminated by cooling the mixture in ice water. The product was isolated by filtration, washed with cold acetonitrile and dried. Recrystallization from acetonitrile afforded N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (5-indanyl) -2-aminoethanol with a melting point (hereinafter, m.p.) of 138-139 ° C.
Analogt med den ovenfor beskrevne metode blev der fremstillet følgende forbindelser: 20 b) N-(a-(3-chlor-4-methoxyphenethyl))-l-(2-naphthyl)-2-amino-ethanol, smp. 150,5 - 151°C, c) N-(a-(3-chlor-4-methoxyphenethyl))-1-(1-naphthyl)-2-amino-ethanol, smp. 121,5 - 124,5°C.Analogous to the method described above, the following compounds were prepared: b) N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (2-naphthyl) -2-amino-ethanol, m.p. 150.5 - 151 ° C, c) N- (α- (3-Chloro-4-methoxyphenethyl)) - 1- (1-naphthyl) -2-amino-ethanol, m.p. 121.5 - 124.5 ° C.
d) N-(a-(3-chlor-4-methoxyphenethyl))-1-(1,2,3,4-tetrahydro-25 naphth-6-yl)-2-aminoethanol, smp. 148 - 150°C.d) N- (α- (3-Chloro-4-methoxyphenethyl)) - 1- (1,2,3,4-tetrahydro-naphth-6-yl) -2-aminoethanol, m.p. 148 - 150 ° C.
e) N-(a-(3-chlor-4-methoxyphenethyl))-1-(3-thienyl)-2-amino-ethanol, smp. 68 - 71°C.e) N- (α- (3-Chloro-4-methoxyphenethyl)) - 1- (3-thienyl) -2-amino-ethanol, m.p. 68 - 71 ° C.
Ved en analog kondensering af N-methyl-3-chlor-4- methoxyphenethylamin og oxiran blev der fremstillet følgende forbindelser:By analogous condensation of N-methyl-3-chloro-4-methoxyphenethylamine and oxirane, the following compounds were prepared:
12 DK 157925 B12 DK 157925 B
f) N-methyl-N-(a-(3-chlor-4-methoxyphenethyl))-1-(7-benzo-5 furanyl)-2-aminoethanol, smp. 89°C, g) N-methyl-N-(a-(3-chlor-4-methoxyphenethyl))-1-(2,3-dihydro-benzofuran-7-yl)-2-aminoethanol, olie, renset ved søjle-chromatografi på silicagel, h) N-methyl-N-(a-(3-chlor-4-methoxyphenethyl))-1-(5-chlor- 10 chroman-8-yl)-2-aminoethanol, olie, renset ved søjlechroma- tografi på silicagel, j) N-(a-(3-chlor-4-methoxyphenethyl))-1-(8-chromanyl)-2-amino-ethanol, k) N-(a-(3-chlor-4-methoxyphenethyl))-1-(6-methoxychroman-8- 15 yl)-2-aminoethanol og l) N-(a-(3-chlor-4-methoxyphenethyl))-1-(5-methoxybenzofuran-7-yl)-2-aminoethanol.f) N-methyl-N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (7-benzo-furanyl) -2-aminoethanol, m.p. 89 ° C, g) N-methyl-N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (2,3-dihydro-benzofuran-7-yl) -2-aminoethanol, oil, purified by column chromatography on silica gel; h) N-methyl-N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (5-chloro-chroman-8-yl) -2-aminoethanol, oil, purified by column chromatography on silica gel; j) N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (8-chromanyl) -2-amino-ethanol, k) N- (α- (3-chloro) -4-methoxyphenethyl) -1- (6-methoxychroman-8-yl) -2-aminoethanol and l) N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (5-methoxybenzofuran-7 -yl) -2-aminoethanol.
Eksempel 3 a) 2,7 g N-(ot-(3-chlor-4-methoxyphenethyl) )-1-(5-20 indanyl)-2-aminoethanol blev opløst i en blanding af 100 ml trifluoreddikesyre (TFA) og 2,5 ml koncentreret E^SO^. Reaktionsblandingen henstod i 1 time ved stuetemperatur. Det meste TFA blev fjernet ved afdampning i vakuum (ca. 10 mm Hg), og remanensen blev blandet med et overskud af fortyndet NaOH (2 25 N). Den således opnåede basiske suspension blev ekstraheret to gange med 50 ml dichlormethan. Den organiske ekstrakt blev vasket med en mættet saltvandsopløsning og tørret over Na2S0^Example 3 a) 2.7 g of N- (ot- (3-chloro-4-methoxyphenethyl)) -1- (5-20 indanyl) -2-aminoethanol were dissolved in a mixture of 100 ml of trifluoroacetic acid (TFA) and 2 , 5 ml of concentrated E ^ SO ^. The reaction mixture was allowed to stand for 1 hour at room temperature. Most TFA was removed by evaporation in vacuo (about 10 mm Hg) and the residue was mixed with an excess of dilute NaOH (2.25 N). The basic suspension thus obtained was extracted twice with 50 ml of dichloromethane. The organic extract was washed with a saturated brine solution and dried over Na 2 SO 4
13 DK 157925B13 DK 157925B
(vandfri). Afdampning af dichlormethanet gav det ønskede produkt i form af en olie. Denne olie blev opløst i æter og udfældet som hydrochloridsalt ved tilsætning af HC1. Efter filtrering og omkrystallisering fra methanol/vand var der dannet 5 8-chlor-7-methoxy-5-(5-indanyl)-2,3,4,5-tetrahydro-lH-3-benza-zepinhydrochlorid, smp. 150 - 146°C.(Anhydrous). Evaporation of the dichloromethane gave the desired product as an oil. This oil was dissolved in ether and precipitated as hydrochloride salt by the addition of HCl. After filtration and recrystallization from methanol / water, 5 8-chloro-7-methoxy-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 150 - 146 ° C.
Analogt med den ovenfor beskrevne metode blev der fremstillet følgende forbindelser: b) 8-chlor-7-methoxy-5-(2-naphthyl)-2,3,4,5-tetrahydro-lH-3- 10 benzazepinhydrochlorid, smp. 245,5 - 248,5°C, c) 8-chlor-7-methoxy-5~(1-naphthyl)-2,3,4,5-tetrahydro-lH-3-benzazepinhydrochlorid, smp. 200°C.Analogous to the method described above, the following compounds were prepared: b) 8-chloro-7-methoxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 245.5 - 248.5 ° C; c) 8-Chloro-7-methoxy-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 200 ° C.
d) 8-chlor-7-methoxy-5-(1,2,3,4-tetrahydronaphth-6-yl)- 2.3.4.5- tetrahydro-lH-3-benzazepin, smp. 185 - 195°C (søn- 15 derdeling), e) 8-chlor-7-methoxy-5-(3-thienyl)-2,3,4,5-tetrahydro-lH-3-ben- zazepin, olie, renset ved søjlechromatografi på silicagel, NMR: CKH: 4,32; C.H: 6,42; C.H: 7,12; C_H-thienyl: 7,34; C.H j o y 2. 4 og C^H-thienyl: 6,95 ppm (CDCl^), 20 f) 8-chlor-7-methoxy-5-(7-benzofuranyl)-3-methyl-2,3,4,5-tetra-hydro-lH-3-benzazepin, smp. 141 - 142°C, g) 8-chlor-7-methoxy-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl- 2.3.4.5- tetrahydro-lH-3-benzazepin, olie, renset ved søjle-chromatografi på silicagel, NMR: C5H: 4,74; CgH: 6,32; CgH: 25 7,20; C2H-dihydrobenzofuran: 4,52; C^H-dihydrobenzofuran: 3,24 ppm (CDCl^Jr h) 8-chlor-7-methoxy-5-(5-chlorchroman-8-yl)-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepinhydrochlorid, smp. 181°C,d) 8-Chloro-7-methoxy-5- (1,2,3,4-tetrahydronaphth-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 185 - 195 ° C (dec.), E) 8-chloro-7-methoxy-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, oil, purified by column chromatography on silica gel, NMR: CKH: 4.32; C.H: 6.42; C.H: 7.12; C_H-thienyl: 7.34; CH Joy 2. 4 and C 1 H -thienyl: 6.95 ppm (CDCl 3), 20 f) 8-Chloro-7-methoxy-5- (7-benzofuranyl) -3-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepine, m.p. 141 - 142 ° C, g) 8-Chloro-7-methoxy-5- (2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, oil, purified by column chromatography on silica gel, NMR: C 5 H: 4.74; CgH: 6.32; CgH: 7.20; C2H-dihydrobenzofuran: 4.52; C ^H-dihydrobenzofuran: 3.24 ppm (CDCl ^ Jr h) 8-chloro-7-methoxy-5- (5-chlorochroman-8-yl) -3-methyl-2,3,4,5-tetrahydro-hydroxy 1H-3-benzazepine hydrochloride, m.p. 181 ° C,
14 DK 157925B14 DK 157925B
j) 8-chlor-7-methoxy-5-(3-thienyl)-3-methyl-2,3,4,5-tetra-hydro-lH-3-benzazepin, olie, og k) 8-chlor-7-methoxy-3-methyl-5-(8-chromanyl)-2,3,4,5-tetra-hydro-lH-3-benzazepinhydrochlorid, smp. 165°C.j) 8-chloro-7-methoxy-5- (3-thienyl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, oil, and k) 8-chloro-7 -methoxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 165 ° C.
5 Eksempel 4 a) Til en blanding af 40 ml myresyre og 30 ml 35% formaldehyd sættes 2,0 g 8-chlor-7-methoxy-5-(5-indanyl)- 2,3,4,5-tetrahydro-lH-3-benzazepin. Reaktionsblandingen tilbagesvales i 4 timer, og opløsningsmidlet afdampes. Til den rå 10 remanens sættes en fortyndet natriumhydroxidopløsning (2 N) i overskud, og blandingen ekstraheres med æter. Den organiske fase vaskes med vand og med saltvand og tørres over vandfrit natriumsulfat. Æteret afdampes i vacuum, hvorved det ønskede produkt fås som en sirup. Den fri base opløses i tørt æter ved 15 tilsætning af en opløsning af brombrintesyre i æter, og hydro-bromidsaltet fælder ud. Dette omkrystalliseres af trifluor-eddike-syre/æter, hvorved fås 8-chlor-7-methoxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetrahydro-lH-3-benzazepinhydrobromid med smp.Example 4 a) To a mixture of 40 ml formic acid and 30 ml 35% formaldehyde is added 2.0 g of 8-chloro-7-methoxy-5- (5-indanyl) - 2,3,4,5-tetrahydro-1H -3-benzazepine. The reaction mixture is refluxed for 4 hours and the solvent is evaporated. To the crude residue, a dilute sodium hydroxide solution (2 N) is added in excess and the mixture is extracted with ether. The organic phase is washed with water and with brine and dried over anhydrous sodium sulfate. The ether is evaporated in vacuo to give the desired product as a syrup. The free base is dissolved in dry ether by addition of a solution of hydrobromic acid in ether and the hydrobromide salt precipitates. This is recrystallized from trifluoroacetic acid / ether to give 8-chloro-7-methoxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. .
217 - 222°C (sønderdeling).217 - 222 ° C (dec.).
20 Følgende forbindelser fremstilles analogt med den ovenfor beskrevne metode: b) 8-chlor-7-methoxy-3-methyl-5-(2-naphthyl)-2,3,4,5-tetra-hydro-lH-3-benzazepinhydrobromid, smp. 251 - 253°C, og c) 8-chlor-7-methoxy-3-methyl-5-(1-naphthyl)-2,3,4,5-tetra-25 hydro-lH-3-benzazepinhydrochlorid, smp. 200°C (sønderdeling) .The following compounds are prepared analogously to the method described above: b) 8-chloro-7-methoxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide , m.p. 251 - 253 ° C; and c) 8-chloro-7-methoxy-3-methyl-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 200 ° C (dec.).
Eksempel 5Example 5
15 DK 157925 BDK 157925 B
a) 1,1 g 8-chlor-7-methoxy-3-methyl-5-(5-indanyl)- 2,3,4,5-tetrahydro-lH-3-benzazepin opløses i 10 ml dichlor-methan. Opløsningen afkøles til -10°C, og der tilsættes 5 ml 5 bortribromid. Reaktionsblandingen omrøres, mens den opvarmes til stuetemperatur. Efter henstand i 4 timer fjernes de flygtige bestanddele ved inddampning i vacuum, og remanensen fortyndes med methanol ved -10°C. Stripning med methanol giver 8-chlor-7-hydroxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetrahydro-lH-10 3-benzazepinhydrobromid, smp. 190 - 200°C (sønderdeling).a) 1.1 g of 8-chloro-7-methoxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is dissolved in 10 ml of dichloromethane. The solution is cooled to -10 ° C and 5 ml of boron tribromide is added. The reaction mixture is stirred while heated to room temperature. After standing for 4 hours, the volatiles are removed by evaporation in vacuo and the residue is diluted with methanol at -10 ° C. Striping with methanol gives 8-chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 190 DEG-200 DEG C. (decomposition).
Følgende forbindelser fremstilles analogt med den ovenfor beskrevne metode: b) 8-chlor-7-hydroxy-3-methyl-5-(1-naphthyl)-2,3,4,5-tetra-hydro-lH-3-benzazepinhydrobromid, smp. 260°C (sønderdeling).The following compounds are prepared analogously to the method described above: b) 8-chloro-7-hydroxy-3-methyl-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; mp. 260 ° C (dec.).
15 c) 8-chlor-7-hydroxy-5-(2-naphthyl)-2,3,4,5-tetrahydro-lH-3-benzazepinhydrochlorid, smp. 180°C (sønderdeling).C) 8-Chloro-7-hydroxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 180 ° C (dec.).
d) 8-chlor-7-hydroxy-3-methyl-5-(3-thienyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, smp. 200 - 209°C, e) 8-chlor-7-hydroxy-5-(3-thienyl)-2,3,4,5-tetrahydro-lH-3-ben- 20 zazepinhydrobromid, smp. 190°C (sønderdeling), f) 8-chlor-7-hydroxy-3-methyl-5-(5-chlorchroman-8-yl)-2,3,4,5-tetrahydro-lH-3-benzazepin, smp. 230 - 232°C, g) 8-chlor-7-hydroxy-3-methyl-5-(2,3-dihydrobenzofuran-7-yl)- 2,3,4,5-tetrahydro-lH-3-benzazepin, smp. 225°C (sønderde- 25 ling), h) 8-chlor-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, smp. 245°C,d) 8-chloro-7-hydroxy-3-methyl-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 200 - 209 ° C, e) 8-Chloro-7-hydroxy-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 190 ° C (dec.), F) 8-Chloro-7-hydroxy-3-methyl-5- (5-chlorochroman-8-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. . 230 - 232 ° C, g) 8-chloro-7-hydroxy-3-methyl-5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, mp. 225 ° C (dec.), H) 8-chloro-7-hydroxy-3-methyl-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, mp. 245 ° C,
16 DK 157925 B16 DK 157925 B
j) 8-chlor-7-hydroxy-5-(l,2,3,4-tetrahydronaphth-6-yl)-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepinhydrochlorid, smp.j) 8-Chloro-7-hydroxy-5- (1,2,3,4-tetrahydronaphth-6-yl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p.
195 - 200°C (sønderdeling), k) 8-chlor-7-hydroxy-3-methyl-5-(5-hydroxychroman-8-yl)- 5 2,3,4,5-tetrahydro-lH-3-benzazepinhemimaleat, l) 8-chlor-7-hydroxy-3-methyl-5-(5-hydroxybenzofuran-7-yl)- 2,3,4,5-tetrahydro-lH-3-benzazepinhemimaleat og m) 8-chlor-7-hydroxy-3-methyl-5-(8-chromanyl)-2,3,4,5-tetra-hydro-lH-3-benzazepin, smp. 190 - 200°C (sønderdeling).195 - 200 ° C (decomposition), k) 8-Chloro-7-hydroxy-3-methyl-5- (5-hydroxychroman-8-yl) - 2,3,4,5-tetrahydro-1H-3- benzazepine hemimaleate, 1) 8-chloro-7-hydroxy-3-methyl-5- (5-hydroxybenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine hemimaleate and m) 8-chloro 7-hydroxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 190 DEG-200 DEG C. (decomposition).
10 Eksempel 6 a) 0,4 g 8-chlor-7-methoxy-3-methyl-5-(2-naphthyl)- 2,3,4,5-tetrahydro-lH-3-benzazepin opløses i 20 ml 47% brom-brintesyre, og opløsningen tilbagesvales i 1 time. Reaktionsblandingen fortyndes med vand og neutraliseres til en pH-værdi 15 på 8,5 ved tilsætning af natriumhydrogencarbonat. Den vundne suspension ekstraheres med ethylacetat og tørres med vandfrit natriumsulfat. Ved afdampning af opløsningsmidlet fås produktet i form af en olie. Denne opløses i tørt æter og efter tilsætning af luftformigt brombrintesyre isoleres 8-chlor-7-hydroxy-20 3-methyl-5-(2-naphthyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-hydrobromid med smp. 260°C (sønderdeling).Example 6 a) 0.4 g of 8-chloro-7-methoxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is dissolved in 20 ml of 47% hydrochloric acid and the solution is refluxed for 1 hour. The reaction mixture is diluted with water and neutralized to a pH of 8.5 by the addition of sodium bicarbonate. The resulting suspension is extracted with ethyl acetate and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the product in the form of an oil. This is dissolved in dry ether and after the addition of gaseous hydrochloric acid, 8-chloro-7-hydroxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide is isolated. with m.p. 260 ° C (dec.).
Følgende forbindelse fremstilles analogt med den ovenfor beskrevne metode: b) 8-chlor-7-hydroxy-5-(5-indanyl)-2,3,4,5-tetrahydro-lH-3-ben-25 zazepinhydrobromid.The following compound is prepared analogously to the method described above: b) 8-chloro-7-hydroxy-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
17 DK 157925B17 DK 157925B
Eksempel 7Example 7
Forbindelser med formel I og SCH 23390 blev testet for deres evne til at hæmme dopaminstimuleret adenylatcyclase i homogenater fra rottestriatum ved brug af den i Life Sci. 37 5 (1985), 1971 f.f., beskrevne metode, og resultatet fremgår af tabel I, hvori de afprøvede forbindelser med formel I er race-miske blandinger, hvorimod SCH 23390 blev testet som den rene R-(+)-isomere. er de testede forbindelsers affinitet for dopamine Dl-receptorer, bestemt ved Schildanalysen.Compounds of formula I and SCH 23390 were tested for their ability to inhibit dopamine-stimulated adenylate cyclase in rat striatum homogenates using it in Life Sci. 37 5 (1985), 1971 et al., And the result is shown in Table I in which the tested compounds of formula I are racemic mixtures, whereas SCH 23390 was tested as the pure R - (+) - isomer. is the affinity of the tested compounds for dopamine D1 receptors, as determined by the Schild assay.
10 Tabel I _ Κ± (nM)Table I _ Κ ± (nM)
Test forbindelse_dopaminstimuleret adenylatcyclaseTest compound_dopamine-stimulated adenylate cyclase
Eksempel nr. 5j 21Example No. 5j 21
Eksempel nr. 5h 6 15 Eksempel nr. 5f 10 SCH 23390_40_Example # 5h 6 15 Example # 5f 10 SCH 23390_40_
Eksempel 8 8-chlor-7-hydroxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetrahydro-lH-3-benzazepin er atoksisk, når den gives til rot-20 ter og mus i en dosis på 100 mg/kg intraperitonealt.Example 8 8-Chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is atoxic when administered to rats and mice at a dose of 100 mg / kg intraperitoneally.
Eksempel 9Example 9
18 DK 157925 B18 DK 157925 B
Fremstilling af kapsler_Capsule Preparation_
Bestanddele_ mg pr. kapsel 8-chlor-7-hydroxy-3-methyl-5-(5-indanyl)-5 2,3,4,5-tetrahydro-lH-3-benzazepin-HBr 125Ingredients_ mg per Capsule 8-Chloro-7-hydroxy-3-methyl-5- (5-indanyl) -5 2,3,4,5-tetrahydro-1H-3-benzazepine-HBr 125
Magnesiumstearat 2Magnesium stearate 2
Lactose_ 200_Lactose_ 200_
Ovenstående bestanddele blandes grundigt og anbringes i hårdgelatinekapsler. Sådanne kapsler administreres oralt til 10 individer, som har brug for behandling, 1-5 gange daglig for at give dopaminerg aktivitet.The above ingredients are thoroughly mixed and placed in hard gelatin capsules. Such capsules are administered orally to 10 individuals in need of treatment 1-5 times daily to provide dopaminergic activity.
Eksempel 10Example 10
Fremstilling af tabletter_Preparation of Tablets_
Bestanddele_mg pr. tablet 15 8-chlor-7“hydroxy-3-methyl-5-(5-indanyl)- 2,3,4,5-tetrahydro-lH-3-benzazepin-HBr 200Ingredients_mg per tablet 15 8-chloro-7 "hydroxy-3-methyl-5- (5-indanyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine-HBr 200
Maj sstivelse 46May starch 46
Polyvinylpyrrolidon 12Polyvinylpyrrolidone 12
Magnesiumstearat_1_ 20 Benzazepinen blandes grundigt med to trediedele af majsstivelsen og granuleres. De vundne granuller tørres, blandes med de resterende bestanddele og slås til tabletter. De på denne måde fremstillede kapsler eller tabletter kan administreres oralt. På tilsvarende måde kan der anvendes andre benzaze-25 piner med formel I.Magnesium stearate_1_ 20 The benzazepine is thoroughly mixed with two thirds of the corn starch and granulated. The obtained granules are dried, mixed with the remaining ingredients and turned into tablets. The capsules or tablets thus prepared can be administered orally. Similarly, other benzazepines of formula I may be used.
Claims (7)
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