CH652125A5 - 1-SUBSTITUTED N- (8ALPHA-ERGOLINYL) -N ', N'-DIAETHYL UREAS AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents
1-SUBSTITUTED N- (8ALPHA-ERGOLINYL) -N ', N'-DIAETHYL UREAS AND METHOD FOR THE PRODUCTION THEREOF. Download PDFInfo
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- CH652125A5 CH652125A5 CH1351/83A CH135183A CH652125A5 CH 652125 A5 CH652125 A5 CH 652125A5 CH 1351/83 A CH1351/83 A CH 1351/83A CH 135183 A CH135183 A CH 135183A CH 652125 A5 CH652125 A5 CH 652125A5
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- 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
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Description
Die Erfindung betrifft 1-substituierte N-[8a-Ergolinyl]-N',N'-diäthylharnstoffe der allgemeinen Formel I The invention relates to 1-substituted N- [8a-ergolinyl] -N ', N'-diethylureas of the general formula I.
/I/, / I /,
worin bedeutet: in which means:
R1 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, R1 is an alkyl group with 1 to 4 carbon atoms,
R2 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine Benzylgruppe, eine Allylgruppe oder eine Gruppe der Formel -[CH2]nCOOR3, worin R3 für ein Wasserstoffatom oder eine Alkylgruppe mit 1 bis 2 Kohlenstoffatomen steht, und n eine ganze Zahl von 1 bis 4; die Erfindung betrifft auch Verfahren zur Herstellung dieser Verbindungen. R2 is an alkyl group having 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of the formula - [CH2] nCOOR3, in which R3 represents a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer from 1 to 4; the invention also relates to processes for the preparation of these compounds.
Es ist bekannt, dass in 1-Stellung nicht substituierte 8a-Ergolinyl-N',N'-diäthylharnstoffe, d.h. Verbindungen der unten angeführten allgemeinen Formel II, beispielsweise N-[D-6-Methyl-8a-ergolinyl]-N',N'-diäthylharnstoff (tschechslowakische Autorenbescheinigung Nr. 152 153) und dessen 6-Propylanalog bei Tieren eine starke Hemmwirkung auf die Sekretion des Prolaktins und des Wachstumshormons und eine stimulierende Wirkung auf die Sekretion der Gonadotropine aufweisen. Die Autoren der Erfindung haben nun gefunden, dass auch die 1-substituierten Derivate der Harnstoffe der allgemeinen Formel I starke Inhibitoren der Prolaktinsekretion bei Versuchstieren darstellen. It is known that 8a-ergolinyl-N ', N'-diethylureas unsubstituted in the 1-position, i.e. Compounds of the general formula II listed below, for example N- [D-6-methyl-8a-ergolinyl] -N ', N'-diethylurea (Czech Slovak Author's Certificate No. 152 153) and its 6-propyl analogue have a strong inhibitory effect on animals Secretion of prolactin and growth hormone and have a stimulating effect on the secretion of the gonadotropins. The authors of the invention have now found that the 1-substituted derivatives of the ureas of the general formula I are also strong inhibitors of prolactin secretion in experimental animals.
Die 8a-Ergolinylharnstoffe der allgemeinen Formel I enthalten im Molekül 3 asymmetrische Kohlenstoffatome in 5-, 8- und 10-Stellung, deren räumliche Anordnung dieselbe ist wie bei der D-9,10-Dihydroisolysergsäure-I: das C(5)-Wasserstoffatom ist in ß-Stellung (die Konfiguration an diesem Kohlenstoffatom ist 5R), der Harnstoffrest am C(8) ist in a-Stellung (die Konfiguration an diesem Kohlenstoffatom ist 8S) und das C(10)-Wasserstoffatom ist in a-Stellung (die Konfiguration an diesem Kohlenstoffatom ist 10R). The 8a-ergolinylureas of the general formula I contain 3 asymmetric carbon atoms in the 5-, 8- and 10-position in the molecule, the spatial arrangement of which is the same as for the D-9,10-dihydroisolysergic acid I: the C (5) hydrogen atom is in the β position (the configuration on this carbon atom is 5R), the urea residue on C (8) is in the a position (the configuration on this carbon atom is 8S) and the C (10) hydrogen atom is in the a position ( the configuration on this carbon atom is 10R).
Gemäss der Erfindung lassen sich die 1-substituierten 8a-Ergolinylharnstoffe der Formel I so herstellen, dass man einen in 1-Stellung nicht substituierten 8a-Ergolinyl-N',N'-diäthylharnstoff der allgemeinen Formel II According to the invention, the 1-substituted 8a-ergolinylureas of the formula I can be prepared in such a way that an 8a-ergolinyl-N ', N'-diethylurea of the general formula II which is not substituted in the 1-position
-R -R
/II/, / II /,
HN HN
worin R1 die oben angeführte Bedeutung besitzt, mit einem where R1 has the meaning given above, with a
Organylierungsmittel der Formel III Organizing agents of the formula III
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R2-X (III), R2-X (III),
worin R2 die in Formel I angeführte Bedeutung besitzt und X ein Halogenatom oder den Rest einer esterartig gebundenen aliphatischen oder aromatischen Sulfonsäure oder den Rest von esterartig gebundener Schwefelsäure bedeutet, umsetzt. wherein R2 has the meaning given in formula I and X denotes a halogen atom or the residue of an ester-like aliphatic or aromatic sulfonic acid or the residue of ester-like sulfuric acid.
Die Ausgangsverbindungen der allgemeinen Formel II lassen sich in an sich bekannter Weise herstellen (siehe oben). The starting compounds of the general formula II can be prepared in a manner known per se (see above).
Die Alkylierung der Verbindungen der allgemeinen Formel II führt man gemäss der Erfindung durch Einwirkung von 1 bis 5 Moläquivalenten des Alkylierungsmittels der allgemeinen Formel III auf die Lösung der Verbindung der allgemeinen Formel II in einem inerten Lösungsmittel, in Gegenwart einer Base zur Bindung der in Freiheit gesetzten Säure, in einem Temperaturbereich von —40 bis +50 °C, durch. The alkylation of the compounds of the general formula II is carried out according to the invention by the action of 1 to 5 molar equivalents of the alkylating agent of the general formula III on the solution of the compound of the general formula II in an inert solvent, in the presence of a base to bind those released Acid, in a temperature range of -40 to +50 ° C.
Als Alkylierungsmittel der allgemeinen Formel III lassen sich Alkylhalogenide, vorzugsweise Alkyljodide oder Al-kylbromide, Allylbromid, Benzylbromid oder ©-Bromalkan-säuren und deren Ester, oder Schwefelsäurealkylester, wie Dimethylsulfat oder Diäthylsulfat, oder aliphatische oder aromatische Sulfonsäureester, beispielsweise Alkylmethan-sulfonate oder Alkyl-p-toluolsulfonate, verwenden. Suitable alkylating agents of the general formula III are alkyl halides, preferably alkyl iodides or alkyl bromides, allyl bromide, benzyl bromide or © bromoalkanoic acids and their esters, or alkyl sulfuric acid, such as dimethyl sulfate or diethyl sulfate, or aliphatic or aromatic sulfonic acid esters, for example alkyl methane sulfonates -p-toluenesulfonate.
Als inerte Lösungsmittel kann man polare aprotische Lösungsmittel, wie Dimethylformamid, Dimethylsulfoxid, Phosphorsäurehexamethyltriamid, Aceton oder flüssiges Ammoniak, verwenden. Polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, phosphoric acid hexamethyltriamide, acetone or liquid ammonia can be used as the inert solvent.
Als eine Base zur Bindung der freigesetzten Säure lässt sich eine starke Base, beispielsweise Natrium- oder Kalium-amid, Lithiumdiisopropylamid, Natriummethylat oder Na-trium- oder Kaliumhydroxid verwenden. Ein besonders vorteilhaftes Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I liegt in der Alkylierung der Verbindungen der allgemeinen Formel II mit Alkylhalogeniden in flüssigem Ammoniak in Gegenwart von Natrium- oder Ka-liumamid, das in genanntem Medium (in situ) hergestellt wird. Die entstandenen Verbindungen der allgemeinen Formel I lassen sich aus dem Reaktionsgemisch mit gewöhnlichen Separations- und Isolierungsmethoden isolieren, beispielsweise durch Abdampfen des Lösungsmittels und Chromatographie und/oder durch Kristallisation der erhaltenen Rohprodukte. A strong base, for example sodium or potassium amide, lithium diisopropylamide, sodium methylate or sodium or potassium hydroxide, can be used as a base for binding the released acid. A particularly advantageous process for the preparation of the compounds of the general formula I is the alkylation of the compounds of the general formula II with alkyl halides in liquid ammonia in the presence of sodium or potassium amide, which is prepared in the medium mentioned (in situ). The resulting compounds of general formula I can be isolated from the reaction mixture using conventional separation and isolation methods, for example by evaporating off the solvent and chromatography and / or by crystallizing the crude products obtained.
1 -substituierte N-[8a-Ergolinyl]-N',N'-diäthylharnstoffe der allgemeinen Formel I stellen farblose kristalline Substanzen vom basischen Charakter dar, welche mit starken anorganischen oder organischen Säuren Additionssalze bilden. Zu therapeutischen Zwecken eignen sich wasserlösliche Salze mit pharmazeutisch unbedenklichen, nicht toxischen Säuren, wie beispielsweise Chlorwasserstoff-, Schwefel-, Methansul-fon-, Äthansulfon-, Malein-, Äpfel-, Wein, Zitronensäure u.ähnl. Die genannten Salze erhält man durch Einwirkung von mindestens 1 Moläquivalenten der Säure auf 1 Moläquivalent der Verbindung der allgemeinen Formel I in einem geeigneten inerten Lösungsmittel, vorzugsweise in Methanol, Äthanol, Aceton, Wasser oder in deren Gemischen. 1-Substituted N- [8a-ergolinyl] -N ', N'-diethylureas of the general formula I are colorless crystalline substances of basic character, which form addition salts with strong inorganic or organic acids. For therapeutic purposes, water-soluble salts with pharmaceutically acceptable, non-toxic acids, such as, for example, hydrochloric acid, sulfuric acid, methane sulfonic acid, ethane sulfonic acid, maleic acid, apple acid, wine, citric acid and the like are suitable. The salts mentioned are obtained by the action of at least 1 molar equivalent of the acid per 1 molar equivalent of the compound of the general formula I in a suitable inert solvent, preferably in methanol, ethanol, acetone, water or in mixtures thereof.
Die Verbindungen der allgemeinen Formel I sind bedeutsame Inhibitoren der Sekretion des Prolaktins und des Wachstumshormons bei Lebewesen. Sie können deshalb in der Human- und Veterinärtherapie zur Senkung des Prolaktins- und Wachstumshormonspiegels eingesetzt werden, beispielsweise bei der Behandlung der Hyperprolaktinämie, Akromegalie und des Parkinsonismus, oder zur Erhöhung des Spiegels der Gonadotropine, beispielsweise zum Hervorrufen der Brunst bei Säugetieren und zum Hervorrufen des Eierlegens bei Vögeln. The compounds of general formula I are important inhibitors of the secretion of prolactin and growth hormone in living beings. They can therefore be used in human and veterinary therapy to lower the level of prolactin and growth hormone, for example in the treatment of hyperprolactinemia, acromegaly and Parkinsonism, or to increase the level of gonadotropins, for example to induce the heat in mammals and to cause the Eggs laying in birds.
Das Verfahren zur Herstellung von 1-substituierten 8a-Ergolinylharnstoffen der allgemeinen Formel I ist in den nachfolgenden Beispielen näher erläutert, welche allerdings den Umfang der Erfindung keineswegs begrenzen. Die Schmelztemperaturen der Verbindungen wurden am Kofler-Block bestimmt und sind, wie auch die übrigen Temperaturangaben, in 'C angeführt. Die Werte der spezifischen Drehungsvermögen beziehen sich auf kristallösungsmittelfreie Substanzen. The process for the preparation of 1-substituted 8a-ergolinylureas of the general formula I is explained in more detail in the following examples, which, however, in no way limit the scope of the invention. The melting temperatures of the compounds were determined on the Kofler block and, like the other temperature data, are given in ° C. The values of the specific rotatory power refer to substances free of crystal solvents.
Beispiel 1 example 1
N-[D-l,6-Dimethyl-8a-ergolinyl]-N',N'-diäthylharnstoff Zu einer Lösung von 0,34 g (1 mMol) N-[D-6-Methyl-8a-ergolinyl]-N',N'-diäthylharnstoff in 20 ml wasserfreiem Aceton gibt man 0,225 g (4 mMol) pulveriges Kaliumhydroxid zu, rührt das Gemisch 10 Minuten bei 23 bis 26 °C und hiernach tropft, bei derselben Temperatur, 0,284 g (2 mMol) Methyljodid zu. Man rührt das Reaktionsgemisch 2 Stunden bei Zimmertemperatur, dann gibt man weitere 0,284 g (2 mMol) Methyljodid zu und rührt das Gemisch noch 3 Stunden. Den anorganischen Anteil filtriert man ab, aus dem Filtrat destilliert man das Lösungsmittel unter vermindertem Druck ab, nimmt den Rückstand in ein Chloroform-Wasser-Gemisch auf, trocknet den organischen Anteil mit wasserfreiem Natriumsulfat und destilliert das Lösungsmittel unter vermindertem Druck ab. Das Rohprodukt (0,4 g) reinigt man durch Kieselgel-Säulenchromatographie, unter Verwendung eines Chloroform-Äthanol-Gemisches (95 : 5) zur Eluierung der Stoffe, und die vereinigten einheitlichen Fraktionen kristallisiert man nach Abdampfen der Lösungsmittel aus Aceton um. Man erhält die Titelverbindung (Formel I, R1 = R2 = Methyl) in Form von farblosen Kristallen mit Fp. 136 bis 138 °C; spezifisches Drehvermögen [a]D20 = +26,3° (c = 0,2, Pyridin). N- [Dl, 6-dimethyl-8a-ergolinyl] -N ', N'-diethylurea To a solution of 0.34 g (1 mmol) of N- [D-6-methyl-8a-ergolinyl] -N', N'-diethylurea in 20 ml of anhydrous acetone is added 0.225 g (4 mmol) of powdery potassium hydroxide, the mixture is stirred for 10 minutes at 23 to 26 ° C and then drops, at the same temperature, 0.284 g (2 mmol) of methyl iodide. The reaction mixture is stirred for 2 hours at room temperature, then a further 0.284 g (2 mmol) of methyl iodide are added and the mixture is stirred for a further 3 hours. The inorganic portion is filtered off, the solvent is distilled off from the filtrate under reduced pressure, the residue is taken up in a chloroform-water mixture, the organic portion is dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The crude product (0.4 g) is purified by silica gel column chromatography, using a chloroform / ethanol mixture (95: 5) to elute the substances, and the combined uniform fractions are recrystallized from acetone after evaporation of the solvents. The title compound (formula I, R1 = R2 = methyl) is obtained in the form of colorless crystals with mp. 136 to 138 ° C; specific turning capacity [a] D20 = + 26.3 ° (c = 0.2, pyridine).
Beispiel 2 Example 2
N-[D-1 -Methyl-6-n-propyl-8a-ergolinyl]-N',N'-diäthylharnstoff Zu einer Lösung von 62,4mg (2,715 mMol) Natrium in etwa 100 ml flüssigem Ammoniak gibt man unter Rühren etwa 10 mg Eisen/III/-nitrat zu und nach Entfärbung der Lösung fügt man zu der entstandenen Natriumamidsuspen-sion 500 mg (1,357 mMol) N-[D-6-Propyl-8a-ergolinyl]-N',N'-diäthylharnstoff hinzu. Nach Auflösen dieser Verbindung (etwa nach 30 Minuten) tropft man 385 mg (2,715 mMol) Methyljodid zu und rührt das Reaktionsgemisch 1 Stunde bei Siedetemperatur des Ammoniaks. Danach dampft man Ammoniak ab, nimmt den Rückstand in ein Chloroform-Wasser-Gemisch auf, wäscht den Chloroformanteil mit Wasser, trocknet ihn mit wasserfreiem Natriumsulfat und destilliert das Lösungsmittel unter vermindertem Druck ab. Das Rohprodukt liefert nach Umkristallisieren aus Aceton die Titelverbindung (Formel I, R2 = Methyl, R1 = Propyl) in Form von farblosen Kristallen mit Fp. 117 bis 119 °c; [a]D20 = +26,3° (c = 0,2, Pyridin). N- [D-1-Methyl-6-n-propyl-8a-ergolinyl] -N ', N'-diethylurea. To a solution of 62.4 mg (2.715 mmol) of sodium in about 100 ml of liquid ammonia is added with stirring 10 mg of iron / III / nitrate and after decolorization of the solution, 500 mg (1.357 mmol) of N- [D-6-propyl-8a-ergolinyl] -N ', N'-diethyl urea are added to the resulting sodium amide suspension . After this compound has been dissolved (approximately after 30 minutes), 385 mg (2.715 mmol) of methyl iodide are added dropwise and the reaction mixture is stirred for 1 hour at the boiling point of the ammonia. Then ammonia is evaporated off, the residue is taken up in a chloroform-water mixture, the chloroform portion is washed with water, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. After recrystallization from acetone, the crude product gives the title compound (formula I, R2 = methyl, R1 = propyl) in the form of colorless crystals with mp. 117 to 119 ° c .; [a] D20 = + 26.3 ° (c = 0.2, pyridine).
Beispiel 3 Example 3
Auf dieselbe Weise wie im Beispiel 2, jedoch unter Verwendung von äquimolaren Mengen N-[D-6-Äthyl-8a-ergoli-nyl]- oder N-[D-6-Butyl-8a-ergolinyl]-N',N'-diäthylharn-stoff anstatt N-[D-6-Propyl-8a-ergolinyl]-N',N'-diäthyl-harnstoff erhält man: N-[D-l-Methyl-6-äthyl-8a-ergolinyl]-N',N'-diäthylharnstoff, Fp. 103 bis 105°C, [a]D20 = +26,3" (c = 0,2, Pyridin) und N-[D-1 -Methyl-6-butyl-8a-ergolinyl]-N',N'-diäthylharnstoff, Fp. 75 bis 77 "C, [a]D20 = +32,9" (c = 0,2, Pyridin). In the same manner as in Example 2, but using equimolar amounts of N- [D-6-ethyl-8a-ergolinyl] - or N- [D-6-butyl-8a-ergolinyl] -N ', N' -Diethylurea instead of N- [D-6-propyl-8a-ergolinyl] -N ', N'-diethylurea gives: N- [Dl-methyl-6-ethyl-8a-ergolinyl] -N', N'-diethylurea, mp 103-105 ° C, [a] D20 = +26.3 "(c = 0.2, pyridine) and N- [D-1-methyl-6-butyl-8a-ergolinyl] -N ', N'-diethylurea, mp 75-77 "C, [a] D20 = +32.9" (c = 0.2, pyridine).
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Beispiel 4 Example 4
Auf dieselbe Weise wie in Beispiel 2, jedoch unter Verwendung von einer äquimolekularen Menge Äthyljodid oder Propylbromid anstatt Methyljodid erhält man: N-[D-1-Äthyl-6-propyl-8a-ergolinyl]-N',N'-diäthylharnstoff, Fp. 85 bis 86 C, [a]D20 = + 30,4" (c = 0,2, Pyridin) und N-[D-1,6-Dipropyl-8a-ergolinyl]-N',N'-diäthylharnstoff. In the same manner as in Example 2, but using an equimolecular amount of ethyl iodide or propyl bromide instead of methyl iodide, one obtains: N- [D-1-ethyl-6-propyl-8a-ergolinyl] -N ', N'-diethylurea, mp 85 to 86 C, [a] D20 = + 30.4 "(c = 0.2, pyridine) and N- [D-1,6-dipropyl-8a-ergolinyl] -N ', N'-diethylurea.
Beispiel 5 Example 5
Auf dieselbe Weise wie im Beispiel 2, jedoch unter Verwendung von einer äquimolaren Menge N-[D-6-Methyl-8a-ergolinyl]-N',N'-diäthylharnstoff anstatt N-[D-6-Propyl-8a-ergolinly]-N',N'-diäthylharnstoff, und von äquimolaren Mengen der Alkylbromide, Allylbromid, Benzylbromid oder In the same manner as in Example 2, but using an equimolar amount of N- [D-6-methyl-8a-ergolinyl] -N ', N'-diethylurea instead of N- [D-6-propyl-8a-ergolinly] -N ', N'-diethylurea, and of equimolar amounts of the alkyl bromides, allyl bromide, benzyl bromide or
Äthylbromacetat stellt man folgende Verbindungen her: N-[D-1 -Äthyl-6-methyl-8a-ergolinyl]-N',N',diäthylharnstoff, Fp. 124 bis 126'C, [<z]D20 = +20,5" (c = 0,2, Pyridin); N-[D-l-Propyl-6-methyl-8a-ergolinyl]-N',N'-diäthylhamstoff, Fp. 63 bis 66 °C, [a]D20 = +21,9° (c = 0,2, Pyridin); N-[D-1 -Butyl-6-methyl-8a-ergolinyl]-N'N'-diäthylharnstoff; N-[D-1 -Allyl-6-methyl-8a-ergolinyl]-N',N'-diäthylharnstoff, Fp. 82 bis 84 °C, [a]D20 = +18,0° (c = 0,2, Pyridin); N-[D-1 -Benzyl-6-methyl-8a-ergolinyl]-N',N'-diäthylharnstoff, Fp. 167 bis 169 °C, [a]D20 = +15,0° (c = 0,2, Pyridin); N-[D-1-Äthoxykarbonylmethyl-6-methyl-8a-ergolinyl]-N',N'-diäthylharnstoff, Fp. 57 bis 59 °C, [a]D20 = +17,0° (c = 0,2, Pyridin). The following compounds are prepared from ethyl bromoacetate: N- [D-1-ethyl-6-methyl-8a-ergolinyl] -N ', N', diethyl urea, mp. 124 to 126'C, [<z] D20 = +20, 5 "(c = 0.2, pyridine); N- [Dl-propyl-6-methyl-8a-ergolinyl] -N ', N'-diethyl urea, mp 63 to 66 ° C, [a] D20 = + 21.9 ° (c = 0.2, pyridine); N- [D-1-butyl-6-methyl-8a-ergolinyl] -N'N'-diethylurea; N- [D-1-allyl-6- methyl-8a-ergolinyl] -N ', N'-diethylurea, mp. 82 to 84 ° C, [a] D20 = + 18.0 ° (c = 0.2, pyridine); N- [D-1 - Benzyl-6-methyl-8a-ergolinyl] -N ', N'-diethylurea, mp. 167 to 169 ° C, [a] D20 = + 15.0 ° (c = 0.2, pyridine); N- [ D-1-ethoxycarbonylmethyl-6-methyl-8a-ergolinyl] -N ', N'-diethylurea, mp 57 to 59 ° C, [a] D20 = + 17.0 ° (c = 0.2, pyridine) .
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Claims (8)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS821734A CS231214B1 (en) | 1982-03-12 | 1982-03-12 | Processing method of 1-substituted n+l8alpha-ergoline+p-n,diethyl urea |
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| Publication Number | Publication Date |
|---|---|
| CH652125A5 true CH652125A5 (en) | 1985-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CH1351/83A CH652125A5 (en) | 1982-03-12 | 1983-03-11 | 1-SUBSTITUTED N- (8ALPHA-ERGOLINYL) -N ', N'-DIAETHYL UREAS AND METHOD FOR THE PRODUCTION THEREOF. |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS58180484A (en) |
| AT (1) | AT383349B (en) |
| AU (1) | AU555961B2 (en) |
| BE (1) | BE896122A (en) |
| CA (1) | CA1203531A (en) |
| CH (1) | CH652125A5 (en) |
| CS (1) | CS231214B1 (en) |
| DE (1) | DE3308719A1 (en) |
| DK (1) | DK84683A (en) |
| FI (1) | FI830754L (en) |
| FR (1) | FR2523131B1 (en) |
| GB (1) | GB2116548B (en) |
| IT (1) | IT1161209B (en) |
| NL (1) | NL8300829A (en) |
| SE (1) | SE452321B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3309493A1 (en) * | 1983-03-14 | 1984-09-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW ERGOLIN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT |
| EP0208417A3 (en) * | 1985-06-12 | 1989-09-06 | SPOFA Spojené Podniky Pro Zdravotnickou Vyrobu | Use of 1-(8-alpha-ergolinyl)-3,3-diethyl urea derivatives in the treatment of endometritis |
| DE3522894A1 (en) * | 1985-06-24 | 1987-01-02 | Schering Ag | USE OF TERGURID AS GERIATRIC |
| FR2584720B1 (en) * | 1985-07-11 | 1987-10-02 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF ERGOLINE |
| DE3620293A1 (en) * | 1986-06-16 | 1987-12-17 | Schering Ag | 1 AND / OR 2 SUBSTITUTED ERGOL DERIVATIVES |
| DE3623503A1 (en) * | 1986-07-09 | 1988-01-21 | Schering Ag | 1-ARYL-ERGOLINYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE OF THESE COMPOUNDS AS A MEDICINAL PRODUCT |
| DE10212564B4 (en) * | 2002-03-12 | 2007-04-19 | Neurobiotec Gmbh | 1-Allyl ergot alkaloid derivatives and their use for the prophylaxis and treatment of migraine |
| WO2012062676A1 (en) * | 2010-11-11 | 2012-05-18 | Sinoxa Pharma Ug | Lisuride, terguride and derivatives thereof for use in the prophylaxis and/or treatment of fibrotic changes |
| US9657020B2 (en) | 2015-01-20 | 2017-05-23 | Xoc Pharmaceuticals, Inc. | Ergoline compounds and uses thereof |
| BR112017015510A2 (en) | 2015-01-20 | 2018-01-30 | Xoc Pharmaceuticals Inc | compound of formula (i), method of treatment and / or prevention, d2 receptor agonizing method in one individual, d3 receptor antagonizing method in one individual, 5-ht1d receptor agonizing method in one individual, 5-ht1a receptor agonization in one individual, selective 5-ht1d receptor agonizing method instead of 5-ht1b receptor in one individual, 5-ht2c re-receptor selective agonizing method instead of 5-ht2a or 5 receptor -ht2b in one individual, method of 5-ht2c receptor agonization in one individual, method of providing functional antagonist activity at 5-ht2b receptor or 5-ht7 receptor, and, method of providing functional antagonist activity at adrenergic receptors in one individual |
| CA3064274A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH344731A (en) * | 1956-05-18 | 1960-02-29 | Sandoz Ag | Process for the production of new derivatives of the lysergic acid series alkylated on the indole nitrogen |
| AT231082B (en) * | 1960-10-12 | 1964-01-10 | Sandoz Ag | Process for the production of new urea derivatives |
| EP0021206B1 (en) * | 1979-06-13 | 1983-06-22 | Schering Aktiengesellschaft | (ergolin-yl)-n', n'-diethyl urea derivatives, their preparation and pharmaceutical compositions containing them |
-
1982
- 1982-03-12 CS CS821734A patent/CS231214B1/en unknown
-
1983
- 1983-02-24 DK DK84683A patent/DK84683A/en not_active Application Discontinuation
- 1983-03-02 AT AT0072783A patent/AT383349B/en not_active IP Right Cessation
- 1983-03-02 GB GB08305735A patent/GB2116548B/en not_active Expired
- 1983-03-07 FI FI830754A patent/FI830754L/en not_active Application Discontinuation
- 1983-03-07 NL NL8300829A patent/NL8300829A/en not_active Application Discontinuation
- 1983-03-07 IT IT19935/83A patent/IT1161209B/en active
- 1983-03-08 SE SE8301257A patent/SE452321B/en not_active IP Right Cessation
- 1983-03-08 AU AU12167/83A patent/AU555961B2/en not_active Ceased
- 1983-03-10 CA CA000423264A patent/CA1203531A/en not_active Expired
- 1983-03-10 BE BE0/210287A patent/BE896122A/en not_active IP Right Cessation
- 1983-03-11 JP JP58039349A patent/JPS58180484A/en active Pending
- 1983-03-11 CH CH1351/83A patent/CH652125A5/en not_active IP Right Cessation
- 1983-03-11 DE DE3308719A patent/DE3308719A1/en not_active Withdrawn
- 1983-03-11 FR FR8304005A patent/FR2523131B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2116548B (en) | 1985-03-20 |
| AU1216783A (en) | 1983-09-15 |
| NL8300829A (en) | 1983-10-03 |
| BE896122A (en) | 1983-07-01 |
| IT1161209B (en) | 1987-03-18 |
| GB2116548A (en) | 1983-09-28 |
| FI830754L (en) | 1983-09-13 |
| SE452321B (en) | 1987-11-23 |
| IT8319935A0 (en) | 1983-03-07 |
| CA1203531A (en) | 1986-04-22 |
| AT383349B (en) | 1987-06-25 |
| AU555961B2 (en) | 1986-10-16 |
| GB8305735D0 (en) | 1983-04-07 |
| JPS58180484A (en) | 1983-10-21 |
| DK84683D0 (en) | 1983-02-24 |
| SE8301257D0 (en) | 1983-03-08 |
| ATA72783A (en) | 1986-11-15 |
| FR2523131B1 (en) | 1987-08-28 |
| CS231214B1 (en) | 1984-10-15 |
| DK84683A (en) | 1983-09-13 |
| FI830754A0 (en) | 1983-03-07 |
| SE8301257L (en) | 1983-09-13 |
| DE3308719A1 (en) | 1983-09-22 |
| FR2523131A1 (en) | 1983-09-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |