CH620441A5 - Process for the preparation of novel ergoline compounds - Google Patents
Process for the preparation of novel ergoline compounds Download PDFInfo
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- CH620441A5 CH620441A5 CH1668075A CH1668075A CH620441A5 CH 620441 A5 CH620441 A5 CH 620441A5 CH 1668075 A CH1668075 A CH 1668075A CH 1668075 A CH1668075 A CH 1668075A CH 620441 A5 CH620441 A5 CH 620441A5
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- formula
- acid
- addition salts
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- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- JHWDWUPYEQIICX-UFGOTCBOSA-N (6ar,9s,10ar)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-amine Chemical class C1=CC([C@@H]2[C@H](NC[C@H](C2)N)C2)=C3C2=CNC3=C1 JHWDWUPYEQIICX-UFGOTCBOSA-N 0.000 claims description 2
- ZAGRKAFMISFKIO-LNUXAPHWSA-N 6-Methyl-9,10-didehydroergoline-8-carboxylic acid Chemical compound C1=CC(C2=CC(CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-LNUXAPHWSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 238000006969 Curtius rearrangement reaction Methods 0.000 claims description 2
- 238000007126 N-alkylation reaction Methods 0.000 claims description 2
- 150000001351 alkyl iodides Chemical class 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 238000005694 sulfonylation reaction Methods 0.000 claims description 2
- 102000003946 Prolactin Human genes 0.000 abstract description 13
- 108010057464 Prolactin Proteins 0.000 abstract description 13
- 229940097325 prolactin Drugs 0.000 abstract description 13
- 230000028327 secretion Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 230000003291 dopaminomimetic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 238000011282 treatment Methods 0.000 description 3
- VJRINNMBXUKYQR-NJZAAPMLSA-N (6ar,9s,10ar)-4,7-dimethyl-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-9-amine Chemical compound C1=CC([C@H]2C[C@H](N)CN([C@@H]2C2)C)=C3C2=CN(C)C3=C1 VJRINNMBXUKYQR-NJZAAPMLSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- JHWDWUPYEQIICX-HRBVQNPCSA-N (6ar,10ar)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-amine Chemical class C1=CC([C@@H]2[C@H](NCC(C2)N)C2)=C3C2=CNC3=C1 JHWDWUPYEQIICX-HRBVQNPCSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 208000001287 Galactorrhea Diseases 0.000 description 1
- 206010017600 Galactorrhoea Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010023424 Kidney infection Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- JLVHTNZNKOSCNB-YSVLISHTSA-N Mesulergine Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CN(C)C3=C1 JLVHTNZNKOSCNB-YSVLISHTSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- -1 N -diethylsulfamoylamino Chemical group 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- NDYAAZRKZRTLQC-UHFFFAOYSA-N n,n-diethylsulfamoyl chloride Chemical compound CCN(CC)S(Cl)(=O)=O NDYAAZRKZRTLQC-UHFFFAOYSA-N 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The novel ergoline compounds correspond to the formula I <IMAGE> in which the symbols have the meaning given in the patent claim. These compounds, which can additionally be converted into their acid addition salts, are obtained by reacting an appropriate 8 alpha -(H2N)-ergoline compound with a reactive, functional derivative of an acid of the formula HO-SO2-NR2R3. The novel ergoline compounds are distinguished by pronounced dopaminergic and prolactin secretion-inhibiting properties.
Description
**WARNUNG** Anfang DESC Feld konnte Ende CLMS uberlappen **.
PATENTANSPRUCH
Verfahren zur Herstellung von neuen Ergolin-Verbindungen der Formel I,
EMI1.1
worin R1 R2 und R3 Alkyl mit 1 bis 4 Kohlenstoffatomen bedeuten und X für Wasserstoff, Chlor oder Brom steht, und ihrer Säureadditionssalze, dadurch gekennzeichnet, dass man Verbindungen der Formel II,
EMI1.2
worin Rl und X obige Bedeutung besitzen, mit einem reaktionsfähigen, funktionellen Derivat einer Säure HO - S02 - NR2R3, in der R2 und R3 obige Bedeutung besitzen, umsetzt, und die so erhaltenen Verbindungen der Formel I in Form der Basen oder von Säureadditionssalzen gewinnt.
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Ergolin-Verbindungen der Formel I,
EMI1.3
worin R1, R2 und R3 Alkyl mit 1 bis 4 Kohlenstoffatomen bedeuten und X für Wasserstoff, Chlor oder Brom steht, und ihrer Säureadditionssalze, dadurch gekennzeichnet, dass man Verbindungen der Formel II,
EMI1.4
worin R1 und X obige Bedeutung besitzen, mit einem reaktionsfähigen, funktionellen Derivat einer Säure HO - S02- NRzR3, in der R2 und R3 obige Bedeutung besitzen, umsetzt und die so erhaltenen Verbindungen der Formel I in Form der Basen oder von Säureadditionssalzen gewinnt.
Das Verfahren ist ein N-Sulfonylierungsverfahren. Es kann analog zu bekannten Verfahren zur Verknüpfung von Sulfonsäureamidbindungen durchgeführt werden. Als reaktionsfähiges, funktionelles Derivat einer Säure HOSO2-NR2R3 wählt man z. B. ein Halogenid dieser Säure, beispielsweise das Säurechlorid davon.
Man arbeitet zweckmässig in Gegenwart einer tertiären Base, vorzugsweise von Pyridin oder Homologen davon.
Die Verbindungen der Formel I können in freier Form als Base, oder in Form ihrer Additionssalze mit Säuren vorliegen.
Aus den freien Basen lassen sich in bekannter Weise Säureadditionssalze herstellen und umgekehrt.
Die Verbindungen der Formel II sind neu. Man kann sie durch Alkylierung der entsprechenden, am Indolstickstoff unsubstituierten 8a-Aminoergoline I der Formel III,
EMI1.5
worin X obige Bedeutung besitzt, erhalten. Diese N-Alkylierung kann nach an sich bekannten Methoden, z. B. mittels Alkyljodid in dem System flüssigem Ammoniak/Natriumamid durchgeführt werden.
Verbindungen der Formel III erhält man beispielsweise ausgehend von A7.8-Lysergsäuremethylester, durch Hydrierung in Gegenwart von Platin, allfällige Halogenierung in 2 Stellung des so erhaltenen 9,10-Dihydro-isolysergsäure I- methylesters, Überführung dieses Esters in das entsprechende Hydrazid und anschliessende Curtius-Umlagerung dieses Hydrazids. Unter Verwendung eines in 1-Stellung alkylierten A7-3-Lysergsäuremethylesters gelangt man analog zu diesem Verfahren direkt zu Verbindungen der Formel II.
Die Verbindungen der Formel I in freier Form oder in Form
von physiologisch verträglichen Additionssalzen mit Säuren (erfindungsgemässe Verbindungen) zeichnen sich durch interessante pharmakodynamische Eigenschaften aus. Sie können als Heilmittel verwendet werden.
Aus der schweizerischen Patentschrift Nr. 416.660 sind ähnliche 8-Amino-ergoline bekannt, welche in Stellung 8 eine Carbamidsäurealkylestergruppe aufweisen und serotoninantagonistische und analeptische Wirkungen zeigen. Von diesen vorbekannten Verbindungen unterscheiden sich die erfindungsgemäss hergestellten Verbindungen durch den verschiedenartigen Substituenten in Stellung 8 sowie durch ihre andersartige pharmakodynamische Wirkung.
So zeichnen sie sich durch eine ausgeprägte prolactinsekretionshemmende Wirkung aus. Sie sind daher geeignet zur Prophylaxe oder Behandlung von prolactinabhängigen Funktionsstörungen wie z. B. physiologischer Lactation und Galactorrhoe, von Prostatahypertrophie, von Prostata- und Mammacarcionomen; des weiteren können sie bei Nephropathien und chronischen Nierenentzündungen, zur Regulierung des Wasser- und Elektrolythaushaltes, bei Oedemen, zur Behandlung von essentiellen und renalen Hypertonieformen sowie bei akuten Zuständen wie vor Migräneattacken und beim praemenstruellen Syndrom Anwendung finden.
Die Prolactin-Sekretionshemmung konnte an Ratten deutlich gemacht werden. Bei lactierenden Ratten, die zeitweilig von ihren Jungen getrennt waren, kommt es bei erneuter Kontaktaufnahme zu einer massiven Prolactin-Ausschüttung, die z. B. als Depletion des hypophysären Prolactin-Gehaltes erfasst werden kann. Dieses Phänomen (beschrieben von Grosvenor und Mena in J. Endocr. 52, 11 [1972]) ergibt eine reproduzierbare Versuchsanordnung, um die Prolactin-Sekretionshemmung pharmakologisch zu erfassen. Es zeigte sich, dass 1 bis 5 mg/kg s.c. einer Verbindung der Formel I nicht nur signifikant die durch sensorische Reize ausgelöste Prolactin-Freisetzung hemmen, sondern gleichzeitig zu einem leichten Anstieg des Prolactin-Gehaltes führen, wodurch deutlich gemacht wird, dass die Verbindungen die physiologisch stimulierte Prolactin-Sekretion zu hemmen vermögen.
Auch an männlichen Ratten konnte eine Wirkung auf den Prolactin-Spiegel festgestellt werden; die Verbindungen der Formel I hemmen die tonische Prolactin-Sekretion mit ED5o- Werten zwischen 0,005 und 1,0 mg/kg s.c. (durch Prolactin Bestimmungen der Rattenseren mittels Radioimmuno-assay).
Für oben genannte Anwendung variiert die zu verwendende Dosis selbstverständlich je nach verwendeter Substanz, Art der Administration und der gewünschten Behandlung. Im allgemeinen werden aber befriedigende Resultate mit Dosen von ungefähr 0,005 bis 1,0 mg/kg Körpergewicht erreicht; die Administration kann mit einer Dosis täglich vorgenommen werden oder nötigenfalls in mehreren beispielsweise 2 bis 4 Teildosen erfolgen. Für grössere Säugetiere liegt die Tagesdosis im Bereich von etwa 0,5 bis 50 mg der Substanz, geeignete Dosierungsformen für z. B. orale Anwendung enthalten im allgemeinen ungefähr 0,1 bis 100 mg wirksame Substanz neben festen oder flüssigen Trägersubstanzen oder Verdünnungsmitteln.
Die Erfindung ist im experimentellen Teil erläutert.
Beispiel I 1,6-Dimethyl-8 a-(N,N-dimethylsulfamoylamino)ergolin I
2,55 g (10 mMol) 1,6-Dimethyl-8a-aminoergolin I werden in 20 ml 2,6-Lutidin gelöst und innert 10 Minuten in ein gerührtes Gemisch von 3,58 g (25 mMol) N,N-Dimethylsulfa minsäurechlorid, 40 ml Methylenchlorid und 10 ml 2,6 Lutidin eingetropft. Nach 1 Stunde Rühren bei Raumtemperatur trägt man noch 1,5 ml N,N-Dimethylsulfaminsäurechlorid ein und rührt noch 2 Stunden bei Raumtemperatur. Zur Aufarbeitung versetzt man bei 00 mit 2N Ammoniak bis zur basischen Reaktion und extrahiert mit einem Gemisch von 10% Methanol in Methylenchlorid. Nach Trocknen über Natriumsulfat hellt man die organische Phase mit Aktivkohle auf und dampft am Rotationsverdampfer ein.
Der so erhaltene, grünliche Schaum wird an 150 g Kieselgel chromatographiert, wobei die Titelverbindung mit 2% Methanol in Methylenchlorid als gelbliches Harz eluiert wird. Das Hydrochlorid der Titelverbindung kristalli siert aus Äthanol, Smp. 226-2280. [a]20 = -23' (c = 0,3 in Pyridin).
Zu dem als Ausgangsverbindung benötigten 1,6-Dimethyl8a-amino-ergolin I gelangt man durch Hydrierung von 1 Methyl- A7,84ysergsäuremethylester nach Zugabe von Platinoxyd, Umsetzung des so erhaltenen 1-Methyl-9,10-dihydroisolysergsäure I-methylesters (Smp. 150-151 ) mit einem Gemisch von Hydrazinhydrat und Hydrazin-dihydrochlorid und Umwandlung des so entstandenen 1-Methyl-9,10-dihydroisolysergsäure I-hydrazids (Smp. 208-211") nach Curtius.
Beispiel 2 1 ,6-Dimethyl-8a-(N,N-diäthylsulfamoylamino)-ergolin I
Analog Beispiel 1 wird 1,6-Dimethyl-8a-aminoergolin I mit N,N-Diäthylsulfaminsäurechlorid umgesetzt. Das Methansul fonat schmilzt bei 199-201"; [ot]D0 = -25' (c = 0,3 in Dime- thylsulfoxid).
** WARNING ** beginning of DESC field could overlap end of CLMS **.
PATENT CLAIM
Process for the preparation of new ergoline compounds of formula I,
EMI1.1
in which R1 R2 and R3 are alkyl having 1 to 4 carbon atoms and X is hydrogen, chlorine or bromine, and their acid addition salts, characterized in that compounds of the formula II,
EMI1.2
wherein Rl and X have the meaning given above, with a reactive, functional derivative of an acid HO - S02 - NR2R3, in which R2 and R3 have the meaning given above, and the compounds of the formula I thus obtained in the form of the bases or of acid addition salts.
The invention relates to a process for the preparation of new ergoline compounds of the formula I,
EMI1.3
in which R1, R2 and R3 are alkyl having 1 to 4 carbon atoms and X is hydrogen, chlorine or bromine, and their acid addition salts, characterized in that compounds of the formula II,
EMI1.4
in which R1 and X have the above meaning, with a reactive, functional derivative of an acid HO - S02 - NRzR3, in which R2 and R3 have the above meaning, and the compounds of the formula I thus obtained are obtained in the form of the bases or of acid addition salts.
The process is an N-sulfonylation process. It can be carried out analogously to known processes for linking sulfonic acid amide bonds. As a reactive, functional derivative of an acid HOSO2-NR2R3 one chooses e.g. B. a halide of this acid, for example the acid chloride thereof.
It is convenient to work in the presence of a tertiary base, preferably pyridine or homologues thereof.
The compounds of the formula I can be in free form as a base or in the form of their addition salts with acids.
Acid addition salts can be prepared from the free bases in a known manner and vice versa.
The compounds of formula II are new. They can be obtained by alkylating the corresponding 8a-aminoergolines I of the formula III which are unsubstituted on the indole nitrogen,
EMI1.5
where X has the above meaning. This N-alkylation can by known methods, for. B. by means of alkyl iodide in the liquid ammonia / sodium amide system.
Compounds of the formula III are obtained, for example, starting from methyl A7.8 lysergate, by hydrogenation in the presence of platinum, any halogenation in the 2 position of the 9,10-dihydro-isolysergic acid I-methyl ester thus obtained, conversion of this ester into the corresponding hydrazide and subsequent Curtius rearrangement of this hydrazide. Using an A7-3-lysergic acid methyl ester alkylated in the 1-position, compounds of the formula II are obtained analogously to this process.
The compounds of formula I in free form or in form
Physiologically compatible addition salts with acids (compounds according to the invention) are distinguished by interesting pharmacodynamic properties. They can be used as a remedy.
Similar 8-amino-ergolines are known from Swiss Patent No. 416,660, which have a carbamic acid alkyl ester group in position 8 and show serotonin-antagonistic and analeptic effects. The compounds prepared according to the invention differ from these previously known compounds by the different substituents in position 8 and by their different pharmacodynamic action.
They are characterized by a pronounced prolactin secretion-inhibiting effect. They are therefore suitable for the prophylaxis or treatment of prolactin-dependent functional disorders such. B. Physiological lactation and galactorrhea, prostate hypertrophy, prostate and breast carcionomas; Furthermore, they can be used for nephropathies and chronic kidney infections, for regulating the water and electrolyte balance, for edema, for the treatment of essential and renal forms of hypertension as well as for acute conditions such as before migraine attacks and premenstrual syndrome.
The inhibition of prolactin secretion could be demonstrated in rats. In lactating rats, which were temporarily separated from their young, there is a massive prolactin release when contacting them again. B. can be detected as a depletion of the pituitary prolactin content. This phenomenon (described by Grosvenor and Mena in J. Endocr. 52, 11 [1972]) results in a reproducible experimental set-up for pharmacologically recording the prolactin secretion inhibition. It was found that 1 to 5 mg / kg s.c. a compound of formula I not only significantly inhibit the prolactin release triggered by sensory stimuli, but at the same time lead to a slight increase in the prolactin content, which makes it clear that the compounds are able to inhibit the physiologically stimulated prolactin secretion.
An effect on the prolactin level was also found in male rats; the compounds of the formula I inhibit the tonic prolactin secretion with ED5o values between 0.005 and 1.0 mg / kg s.c. (by prolactin determinations of rat sera using radioimmunoassay).
For the above-mentioned application, the dose to be used naturally varies depending on the substance used, the type of administration and the desired treatment. In general, however, satisfactory results are achieved with doses of approximately 0.005 to 1.0 mg / kg body weight; administration can be carried out with one dose daily or, if necessary, in several, for example 2 to 4, partial doses. For larger mammals, the daily dose is in the range of about 0.5 to 50 mg of the substance. Suitable dosage forms for e.g. B. oral application generally contain about 0.1 to 100 mg of active substance in addition to solid or liquid carriers or diluents.
The invention is explained in the experimental part.
Example I 1,6-dimethyl-8 a- (N, N-dimethylsulfamoylamino) ergoline I
2.55 g (10 mmol) of 1,6-dimethyl-8a-aminoergoline I are dissolved in 20 ml of 2,6-lutidine and within 10 minutes in a stirred mixture of 3.58 g (25 mmol) of N, N-dimethylsulfa minic acid chloride, 40 ml methylene chloride and 10 ml 2.6 lutidine added dropwise. After stirring for 1 hour at room temperature, 1.5 ml of N, N-dimethylsulfamic acid chloride are added and stirring is continued for 2 hours at room temperature. For working up, 2N ammonia is added at 00 until the reaction is basic and extracted with a mixture of 10% methanol in methylene chloride. After drying over sodium sulfate, the organic phase is lightened with activated carbon and evaporated on a rotary evaporator.
The greenish foam thus obtained is chromatographed on 150 g of silica gel, the title compound being eluted with 2% methanol in methylene chloride as a yellowish resin. The hydrochloride of the title compound crystallizes from ethanol, mp. 226-2280. [a] 20 = -23 '(c = 0.3 in pyridine).
The 1,6-dimethyl8a-amino-ergoline I required as the starting compound is obtained by hydrogenation of 1 methyl A7,84ysergic acid methyl ester after addition of platinum oxide, reaction of the 1-methyl-9,10-dihydroisolysergic acid methyl ester obtained in this way (mp. 150-151) with a mixture of hydrazine hydrate and hydrazine dihydrochloride and conversion of the resulting 1-methyl-9,10-dihydroisolysergic acid I-hydrazide (mp. 208-211 ") according to Curtius.
Example 2 1, 6-Dimethyl-8a- (N, N -diethylsulfamoylamino) -ergoline I
Analogously to Example 1, 1,6-dimethyl-8a-aminoergoline I is reacted with N, N-diethylsulfamic acid chloride. The methanesulfonate melts at 199-201 "; [ot] D0 = -25 '(c = 0.3 in dimethyl sulfoxide).
Claims (1)
Priority Applications (28)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1668075A CH620441A5 (en) | 1975-12-23 | 1975-12-23 | Process for the preparation of novel ergoline compounds |
| DE19762656344 DE2656344A1 (en) | 1975-12-23 | 1976-12-13 | ERGOLIN DERIVATIVES, THEIR USE AND MANUFACTURING |
| DK562376A DK146205C (en) | 1975-12-23 | 1976-12-14 | ANALOGY PROCEDURE FOR THE PREPARATION OF 8ALFA ERGOLIN-I DERIVATIVES |
| FI763587A FI763587A (en) | 1975-12-23 | 1976-12-14 | |
| SE7614085A SE432253B (en) | 1975-12-23 | 1976-12-15 | ANALOGY PROCEDURE FOR PREPARING 8ALFA-ERGOLIN-I DERIVATIVES |
| NL7614018A NL7614018A (en) | 1975-12-23 | 1976-12-17 | METHODS FOR PREPARING AND USING CYCLIC COMPOUNDS. |
| IL51133A IL51133A (en) | 1975-12-23 | 1976-12-21 | 1-alkyl-6,8 alpha-disubstituted ergoline derivatives,their production and pharmaceutical compositions containing them |
| GB53303/76A GB1567484A (en) | 1975-12-23 | 1976-12-21 | Ergoline i derivatives |
| CA268,415A CA1092100A (en) | 1975-12-23 | 1976-12-21 | Ergoline i derivatives |
| PH19276A PH14035A (en) | 1975-12-23 | 1976-12-21 | Ergoline derivatives |
| ES454442A ES454442A1 (en) | 1975-12-23 | 1976-12-21 | Sulfonamido and sulfamoylamino-ergoline-I derivatives |
| IE2803/76A IE44242B1 (en) | 1975-12-23 | 1976-12-21 | Ergoline i derivatives |
| NZ182934A NZ182934A (en) | 1975-12-23 | 1976-12-21 | 80c-(cyanomethyl or substituted amino)-1,6-disubstituted-ergoline i derivatives |
| AU20793/76A AU514288B2 (en) | 1975-12-23 | 1976-12-21 | Ergoline derivatives |
| JP51153514A JPS5278900A (en) | 1975-12-23 | 1976-12-22 | Improvement in organic compound |
| BE173545A BE849745A (en) | 1975-12-23 | 1976-12-22 | NEW ERGOLINE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| FR7638697A FR2336135A1 (en) | 1975-12-23 | 1976-12-22 | NEW ERGOLINE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| PT66006A PT66006B (en) | 1975-12-23 | 1976-12-22 | PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION CONTAINING NEW ORGANIC COMPOUNDS |
| ZA00767640A ZA767640B (en) | 1975-12-23 | 1976-12-23 | Improvements in or relating to organic compounds |
| AT759579A AT376221B (en) | 1975-12-23 | 1979-11-30 | METHOD FOR PRODUCING NEW ERGOL DERIVATIVES |
| AT759479A AT370102B (en) | 1975-12-23 | 1979-11-30 | METHOD FOR PRODUCING NEW ERGOL DERIVATIVES |
| DK554179A DK554179A (en) | 1975-12-23 | 1979-12-21 | PROCEDURE FOR THE PRODUCTION OF ERGOLIN DERIVATIVES |
| US06/189,068 US4348391A (en) | 1975-12-23 | 1980-09-22 | Sulfonamido and sulfamoylamino-ergoline-I derivatives |
| FI812150A FI65430C (en) | 1975-12-23 | 1981-07-08 | FOERFARANDE FOER FRAMSTAELLNING AV NYA 8ALFA-ERGOLIN I-DERIVATVILKA HAR DOPAMINERGISKA OCH PROLAKTINSEKRETIONSHAEMMANDE EENSKAPER |
| FI812151A FI812151L (en) | 1975-12-23 | 1981-07-08 | NYA ORGANIC FOERENINGAR OCH FRAMSTAELLNING OCH ANVAENDNING AV DEM |
| SG633/82A SG63382G (en) | 1975-12-23 | 1982-12-23 | Ergoline l derivatives |
| HK34/83A HK3483A (en) | 1975-12-23 | 1983-01-20 | Ergoline 1 derivatives |
| MY60/84A MY8400060A (en) | 1975-12-23 | 1984-12-30 | Ergoline derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1668075A CH620441A5 (en) | 1975-12-23 | 1975-12-23 | Process for the preparation of novel ergoline compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH620441A5 true CH620441A5 (en) | 1980-11-28 |
Family
ID=4419329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1668075A CH620441A5 (en) | 1975-12-23 | 1975-12-23 | Process for the preparation of novel ergoline compounds |
Country Status (3)
| Country | Link |
|---|---|
| BE (1) | BE849745A (en) |
| CH (1) | CH620441A5 (en) |
| ZA (1) | ZA767640B (en) |
-
1975
- 1975-12-23 CH CH1668075A patent/CH620441A5/en not_active IP Right Cessation
-
1976
- 1976-12-22 BE BE173545A patent/BE849745A/en not_active IP Right Cessation
- 1976-12-23 ZA ZA00767640A patent/ZA767640B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE849745A (en) | 1977-06-22 |
| ZA767640B (en) | 1978-07-26 |
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