SE452321B - 1-SUBSTITUTED N- (8ALFA-ERGOLINYL) -N ', N'-DIETHYL CARBAMIDS AND SET TO MAKE THEM - Google Patents
1-SUBSTITUTED N- (8ALFA-ERGOLINYL) -N ', N'-DIETHYL CARBAMIDS AND SET TO MAKE THEMInfo
- Publication number
- SE452321B SE452321B SE8301257A SE8301257A SE452321B SE 452321 B SE452321 B SE 452321B SE 8301257 A SE8301257 A SE 8301257A SE 8301257 A SE8301257 A SE 8301257A SE 452321 B SE452321 B SE 452321B
- Authority
- SE
- Sweden
- Prior art keywords
- ergolinyl
- general formula
- methyl
- diethylurea
- compound according
- Prior art date
Links
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Description
10 15 20 25 30 35 452 321 2 vilkas anordnande i rymden är detsamma som hos D-9,10-dihydro- isolysergsyran - I: väte vid CG) har ß-ställning (konfigurationen vid denna kolatom är SR), karbamidåterstod vid C(8) är i økställ- ning (konfigurationen vid denna kolatom är BS) och väte vid C är i lä-ställning (konfigurationen vid denna kolatom är 10R). (10) I enlighet med uppfinningen kan de 1-substituerade 8m~ergolinyl- karbamíderna med den allmänna formeln I framställas på så sätt, att i ställning 1 osubstituerad 8N-ergolinyl-N',N'-dietylkarbamid med den allmänna formeln II H z, NncoN (czas) 2 - R H (n) vari R1 har ovan angiven betydelse, omsättes med alkyleringsmedel med den allmänna formeln III R2 - X (III) vari R2 har den i samband med den allmänna formeln I angivna be- tydelsen och X betecknar halogenatom eller en återstod av ester- bunden, alifatisk eller aromatisk sulfonsyra eller en återstod av esterbunden svavelsyra. i Utgångsföreningar med den allmänna formeln II kan framställas med hjälp av kända förfaranden (se t.ex. ovan angivna patent- litteratur). 10 15 20 25 30 35 452 321 2 whose arrangement in space is the same as that of D-9,10-dihydro- the isolysergic acid - I: hydrogen at CG) has ß-position (configuration at this carbon atom is SR), urea residue at C (8) is in hydrogen (the configuration at this carbon atom is BS) and hydrogen at C is in the read position (the configuration at this carbon atom is 10R). (10) In accordance with the invention, the 1-substituted 8m-ergolinyl the ureas of the general formula I are prepared in this way, that in position 1 unsubstituted 8N-ergolinyl-N ', N'-diethylurea with the general formula II H z, NncoN (czas) 2 - R hrs (n) wherein R 1 has the meaning given above, is reacted with alkylating agents of general formula III R2 - X (III) wherein R 2 has the meaning given in connection with the general formula I and X represents the halogen atom or a residue of the ester bound, aliphatic or aromatic sulfonic acid or a residue of ester-bound sulfuric acid. in Starting compounds of the general formula II can be prepared using known methods (see, for example, the above-mentioned literature).
Alkylering av föreningar med den allmänna formeln II utföres i enlighet med uppfinningen genom att låta 1 till 5 molekvivalenter alkyleringsmedel med den allmänna formeln III inverka på lösning av förening med den allmänna formeln II i ett inert lösningsmedel i närvaro av en bas för bindning av frigjord syra vid en tempera- tur inom området från -40°C till +50°C. ' . 10 15 20 25 30 35 3 452 321 Som alkyleringsmedel med den allmänna formeln III kan användas alkylhalogenider, företrädesvis jodider eller alkylbromider, allylbromid, bensylbromid eller u-bromoalkansyror och estrar därav, eller alkylestrar av svavelsyra, som t.ex. dimetylsulfat eller dietylsulfat, eller estrar av alifatiska eller aromatiska sulfonsyror, t.ex. alkyl-metansulfonater eller alkyl-p-toluen~ sulfonater.Alkylation of compounds of general formula II is carried out in in accordance with the invention by allowing 1 to 5 molar equivalents alkylating agents of the general formula III act on solution of compound of general formula II in an inert solvent in the presence of a base for binding liberated acid at a temperature turn in the range from -40 ° C to + 50 ° C. '. 10 15 20 25 30 35 3 452 321 As the alkylating agent of the general formula III can be used alkyl halides, preferably iodides or alkyl bromides, allyl bromide, benzyl bromide or u-bromoalkanoic acids and esters thereof, or alkyl esters of sulfuric acid, such as e.g. dimethyl sulfate or diethyl sulfate, or esters of aliphatic or aromatic sulfonic acids, e.g. alkyl methanesulfonates or alkyl p-toluene sulfonates.
Som ett inert lösningsmedel kan användas sådana polära, aprotiska lösningsmedel som t.ex. dimetylformamid, dimetylsulfoxid, hexa- metyltriamid av fosforsyra eller aceton eller flytande ammoniak.As an inert solvent such polar, aprotic ones can be used solvents such as dimethylformamide, dimethylsulfoxide, hexa- methyltriamide of phosphoric acid or acetone or liquid ammonia.
Som en bas för bindning av frigjord syra kan användas starka baser, t.ex. natrium- eller kaliumamid,-litiumdiisopropylamid, natriummetylat eller natrium- eller kaliumhydroxid. Ett sär- skilt fördelaktigt förfarande för framställning av föreningar med den allmänna formeln I består i att man alkylerar föreningar med den allmänna formeln II med alkylhalogenider i ett medium av flytande ammoniak i närvaro av natriumamid eller kaliumamid, framställd in situ i det förelagda mediet. De bildade förening- *W arna med den allmänna formeln I kan isoleras ur reaktionsbland- ningen under tillämpning av vanliga separerings- och isolerings- metoder, t.ex. genom avdunstning av lösningsmedlet och kromato- grafering och/eller kristallisering av de erhållna râprodukterna. 1-substituerade N-(8G>ergolinyl)-N',N'-dietylkarbamider med den allmänna formeln I utgör färglösa, kristallina föreningar med basisk karaktär, vilka ger additionssalter med starka oorganiska och organiska syror. För terapeutiska ändamål är vattenlösliga salter med farmaceutiskt godtagbara, icke-toxiska syror lämpliga, och som exempel på sådana syror kan nämnas klorvätesyra, svavel- syra, metansulfonsyra, etansulfonsyra, maleinsyra, äpplesyra, vinsyra, citronsyra och liknande syror. De nämnda.salterna kan framställas genom omsättningen av minst 1 molekvivalent av syran .med 1 molekvivalent av föreningen med den allmänna formeln I i ett lämpligt, inert lösningsmedel, företrädesvis i metanol, eta- nol, aceton, vatten eller blandningar därav. 10 15 20 25 30 35 452 321 4 Föreningarna med den allmänna formeln I är viktiga inhibitorer av utsöndringen av prolaktin och tillväxthormon och stimulatorer för utsöndringen av gonadotropiner hos djur, påverkar vidare de fysiologiska och patologiska processerna som styres av de angivna hormonerna, och de utövar dessutom dopaminverkan på de fysiolo- giska och patologiska, dopaminreceptorstyrda funktionerna. De V kan därför användas inom human- och veterinärmedicinen för sänk- ning av nivåerna av prolaktin och tillväxthormon, t.ex. vid medi- cinsk behandling av hyperpropaktinemier, akromegali och Parkin- sons sjukdom eller ocksâ kan de användas för ökning av gonado- tropinhalterna, t.ex. vid framkallande av brunstperioder hos däggdjur och fåglars läggande av ägg.As a base for binding of liberated acid can be used strong bases, e.g. sodium or potassium amide, lithium diisopropylamide, sodium methylate or sodium or potassium hydroxide. A special particularly advantageous process for the preparation of compounds with the general formula I consists in alkylating compounds of the general formula II with alkyl halides in a medium of liquid ammonia in the presence of sodium amide or potassium amide, produced in situ in the presented medium. They formed compound- * W The compounds of general formula I can be isolated from the reaction mixture. using standard separation and isolation methods, e.g. by evaporation of the solvent and chromatography graphing and / or crystallization of the obtained crude products. 1-Substituted N- (8G> ergolinyl) -N ', N'-diethyl ureas with the general formula I are colorless, crystalline compounds with alkaline character, which give addition salts with strong inorganic and organic acids. For therapeutic purposes are water soluble salts with pharmaceutically acceptable, non-toxic acids suitable, and examples of such acids are hydrochloric acid, sulfuric acid acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, malic acid, tartaric acid, citric acid and similar acids. The mentioned salts can prepared by the reaction of at least 1 molar equivalent of the acid with 1 molar equivalent of the compound of general formula I i a suitable inert solvent, preferably in methanol, ethyl acetate nol, acetone, water or mixtures thereof. 10 15 20 25 30 35 452 321 4 The compounds of general formula I are important inhibitors of the secretion of prolactin and growth hormone and stimulators for the secretion of gonadotropins in animals, they further affect the physiological and pathological processes controlled by the indicated hormones, and they also exert a dopamine effect on the physiological and pathological, dopamine receptor-mediated functions. The V can therefore be used in human and veterinary medicine for levels of prolactin and growth hormone, e.g. at the medi- clinical treatment of hyperpropactinemia, acromegaly and Parkinson’s son’s disease or they can also be used to increase gonadal tropin contents, e.g. in induction of oestrus periods in mammals and birds' laying of eggs.
Förfarandet för framställning av 1-substituerade 8«-ergoliny1- karbamider med den allmänna formeln I belyses närmare med hjälp av följande exempel av utföringsformer, vilka dock icke är av- sedda att begränsa uppfinningens omfattning. Föreningarnas smälttemperaturer bestämdes under användande av en Koflerbänk och de är liksom andra temperaturdata angivna i OC. värdena på specifik vridning hänför sig till föreningar som är fria från ”W kristalliseringslösningsmedel.The process for the preparation of 1-substituted 8 ureas of the general formula I are further elucidated with the aid of of the following examples of embodiments, which, however, are not intended to limit the scope of the invention. The associations melting temperatures were determined using a Kofler bench and they are like other temperature data given in OC. the values of specific rotation refers to compounds that are free of “W crystallization solvent.
Exempel 1 N-(D-1,6-dimetyl-8a-ergolinyl)~N',N'-dietylkarbamid 0,225 g ( 4 mmol) pulvriserad kaliumhydroxid sattes till en lösning av 0,34 g (1 mmol) N-(D-6-metyl-8u-ergolinyl)-N',N'- -dietylkarbamid i 20 ml vattenfri aceton, varefter blandningen omrördes i 10 minuter vid 23 - 26°C och 0,284 g (2 mmol) metyl- jodid tillsattes sedan droppvis vid samma temperatur. Reaktions- blandningen omrördes 2 timmar vid rumstemperatur, ytterligare 0,284 g (2 mmol) metyljodid tillsattes sedan och blandningen omrördes ytterligare tre timmar. Den oorganiska fraktionen filtrerades av, lösningsmedlet destillerades från filtratet under reducerat tryck, avdunstningsåterstoden togs upp i en blandning av kloroform och vatten, den organiska“fraktionen torkades med vattenfritt natriumsulfat och lösningsmedlet de-' stillerades av under reducerat tryck. Råprodukten (0,4 g) rena- des under tillämpning av kolonnkromatografi på silikagel under 10 15 20 25 30 35 5 452 321 utnyttjande av en blandning av kloroform och etanol (95:5) för eluering av föreningarna och de förenade homogena fraktionerna omkristalliserades ur aceton efter avgivning av lösningsmed- len. Den i'rubriken angivna föreningen erhölls (I, R1 = R2 = = neryi) i form ev färglösa kristaller med snp. 136 - 13e°c, speeifik vridning ¿1u¿7g0 = +24,4° (e = 0,2, pyridin).Example 1 N- (D-1,6-dimethyl-8α-ergolinyl) -N ', N'-diethylurea 0.225 g (4 mmol) of powdered potassium hydroxide was added to one solution of 0.34 g (1 mmol) of N- (D-6-methyl-8u-ergolinyl) -N ', N'- -diethylurea in 20 ml of anhydrous acetone, then the mixture was stirred for 10 minutes at 23-26 ° C and 0.284 g (2 mmol) of methyl iodide was then added dropwise at the same temperature. Reactional the mixture was stirred for 2 hours at room temperature, further 0.284 g (2 mmol) of methyl iodide was then added and the mixture stirred for a further three hours. The inorganic fraction was filtered off, the solvent was distilled off from the filtrate under reduced pressure, the evaporation residue was taken up in a mixture of chloroform and water, the organic 'fraction dried over anhydrous sodium sulfate and the solvent de- was set off under reduced pressure. The crude product (0.4 g) is purified. was applied by column chromatography on silica gel 10 15 20 25 30 35 5,452,321 using a mixture of chloroform and ethanol (95: 5) for eluting the compounds and the combined homogeneous fractions recrystallized from acetone after release of the solvent. len. The title compound was obtained (I, R1 = R2 = = neryi) in the form of possible colorless crystals with snp. 136 - 13e ° c, specific rotation ¿1u¿7g0 = + 24.4 ° (e = 0.2, pyridine).
Exemgel 2 N-(D-1-metyl-6-n-propyl-8u-ergolinyl)-N',N'-dietylkarbamid Ungefär 10 mg järn(III)nitrat tillsattes under omröring till en lösning ev 62,4 ng (2,71s nnei) nefrium i ungefär 100 mi flytande ammoniak och efter avfärgning av lösningen tillsattes 500 mg (1,357 mmol) N-(D-6-propyl-8d-ergolinyl)-N',N'-dietyl- karbamid till den erhållna suspensionen av natriumamid. Efter upplösning av karbamiden (ungefär efter 30 minuter) tíllfördes 385 mg (2,715 mmol) metyljodid droppvis och reaktionsbland- ningen omrördes i 1 timme vid kokpunkten för ammoniak. Ammo- niaken avdrevs sedan, varefter avdunstningsåterstoden upptogs i en blandning av kloroform och vatten, kloroformfraktionen tvättades med vatten, torkades med vattenfritt natriumsulfat och sedan destillerades lösningsmedlet av under reducerat tryck. Råprodukten (0,55 g) gav efter omkristallisering ur aceton den i rubriken angivna föreningen (I, R2 = metyl, R1 = = propyl) i form av färglösa kristaller med smp. 117 - 119°C; ¿'=<_7â° = +2s,3° (e = 0,2, pyridin).Example 2 N- (D-1-methyl-6-n-propyl-8u-ergolinyl) -N ', N'-diethylurea Approximately 10 mg of ferric nitrate was added with stirring to a solution of possibly 62.4 ng (2.71s nnei) of nephrium for about 100 ml liquid ammonia and after decolorization of the solution was added 500 mg (1.357 mmol) of N- (D-6-propyl-8d-ergolinyl) -N ', N'-diethyl- urea to the resulting suspension of sodium amide. After dissolution of the urea (approximately after 30 minutes) was added 385 mg (2.715 mmol) of methyl iodide dropwise and the reaction mixture The mixture was stirred for 1 hour at the boiling point of ammonia. Ammo- the niak was then evaporated, after which the evaporation residue was taken up in a mixture of chloroform and water, the chloroform fraction washed with water, dried over anhydrous sodium sulfate and then the solvent was distilled off under reduced pressure print. The crude product (0.55 g) gave, after recrystallization, acetone the title compound (I, R2 = methyl, R1 = = propyl) in the form of colorless crystals, m.p. 117-119 ° C; ¿'= <_ 7â ° = + 2s, 3 ° (e = 0.2, pyridine).
Exemgel 3 N-(D-1-metyl-6-etyl-8a-ergolinyl)-N',N'-dietylkarbamid, smp. 103 - 1os°c, ¿"=~_7š° = +2e,3° (e = 0,2, pyridin), och N-(D-1-metyl-6-butyl-Burergolinyl)-N',N'-dietylkarbamid, smp. vs - 77°c, ¿1~¿7š° = +32,9° (e = 0,2, pyridin) framställdes med hjälp av samma förfarande som i exempel 2 med den skillnaden att ekvimolära mängder N-(D-6-etyl-Smëergolinylk eller N-(D-6- -butyl-Ba-ergolinyl)-N',N'-dietylkarbamid användes i stället för N-(D-6-propyl-8u-ergolinyl)-N',N'fdietylkarbamid. 10 15 20 25 452 621 6 Exemgel 4 N-(D-1-etyl-6-propyl-8u-ergolinyl)-N',N'-dietylkarbamid, smp- ss - se°c, ¿i57â° = +3o,4° (C = 0,2, pyriain) och N-(n-1,s- -dipropyl-Bd-ergølinyl)-N',N'-dietylkarbamid framställdes med hjälp av samma förfarande som det i exempel 2 med den skillna- den, att ekvimolära mängder av etyljodid eller propylbromid utnyttjades i stället för metyljodid.Exemgel 3 N- (D-1-methyl-6-ethyl-8α-ergolinyl) -N ', N'-diethylurea, m.p. 103 - 1 ° C, ¿ N- (D-1-methyl-6-butyl-Burergolinyl) -N ', N'-diethylurea, m.p. vs - 77 ° c, ¿1 ~ ¿7š ° = + 32.9 ° (e = 0.2, pyridine) was prepared using the same procedure as in Example 2 with that difference that equimolar amounts of N- (D-6-ethyl-Smergolinyl or N- (D-6- -butyl-Ba-ergolinyl) -N ', N'-diethylurea was used instead N- (D-6-propyl-8u-ergolinyl) -N ', N'-diethylurea. 10 15 20 25 452 621 6 Exemgel 4 N- (D-1-ethyl-6-propyl-8u-ergolinyl) -N ', N'-diethylurea, m.p. ss - se ° c, ¿i57â ° = + 30 °, 4 ° (C = 0.2, pyrene) and N- (n-1, s- -dipropyl-Bd-ergølinyl) -N ', N'-diethylurea was prepared with using the same procedure as in Example 2 with the difference that equimolar amounts of ethyl iodide or propyl bromide was used instead of methyl iodide.
Exemfiel 5 Följande föreningar: N-(D-1-etyl-6-metyl-8M-ergolinyl)-Nl,N'-dietylkarbamid, smp. 124 - - 126°c, ¿?¿7å° = +2o,s° (C = 0,2, pyriain); N-(D~1-propyl-6-metyl-ßw-ergolinyl)-N',N'-dietylkarbamid, smp. 63 - es°c, ¿E¿7š° = +21,9° (C = 0,2, pyriain); N-(D-1-butyl-6-metyl-Bm-ergolinyl)-N',N'-dietylkarbamid; N-(D-1-al1yl-6-metyl-Ba-ergolinyl)-N',N'-dietylkarbamid, smp. az - s4°c, ¿2¿7š° = +1a,o° (c = 0,2, pyriain): N-(D-1-bensyl-6-metyl-8«-ergolinyl)-N',N'-dietylkarbamid, smp. 167 - 1s9°c, ¿É¿7š° = +1s,o° (C = o,2, pyria1n): øcn N-(D-1-etoxikarbonylmetyl-6-metyl-8%-ergolinyl)-N',N'-dietyl- karbamia, smp. sv - s9°c, ¿3¿7š° = +17.o° (C = 0,2, pyriain) framställdes med hjälp av samma förfarande som det i exempel 2 beskrivna med den skillnaden, att ekvimolära mängder N-(D-6-metyl- -8w-ergolinyl)-N',N'-dietylkarbamid användes i stället för N-(D-6-propyl-8u-ergolinyl)-N',N'-dletylkarbamid och ekvimolära 'mängder alkylbromider, allylbromid, bensylbromid eller etylbromo- acetat användes.Example 5 The following compounds: N- (D-1-ethyl-6-methyl-8M-ergolinyl) -N1, N'-diethylurea, m.p. 124 - - 126 ° C, ¿? ¿7å ° = + 2o, s ° (C = 0,2, pyrene); N- (D-1-propyl-6-methyl-β-ergolinyl) -N ', N'-diethylurea, m.p. 63 - es ° c, ¿E¿7š ° = + 21,9 ° (C = 0,2, pyriain); N- (D-1-butyl-6-methyl-Bm-ergolinyl) -N ', N'-diethylurea; N- (D-1-allyl-6-methyl-Ba-ergolinyl) -N ', N'-diethylurea, m.p. az - s4 ° c, ¿2¿7š ° = + 1a, o ° (c = 0,2, pyriain): N- (D-1-benzyl-6-methyl-8 '-ergolinyl) -N', N'-diethylurea, m.p. 167 - 1s9 ° c, ¿É¿7š ° = + 1s, o ° (C = o, 2, pyria1n): øcn N- (D-1-ethoxycarbonylmethyl-6-methyl-8% -ergolinyl) -N ', N'-diethyl- carbamia, m.p. sv - s9 ° c, ¿3¿7š ° = + 17.o ° (C = 0,2, pyriain) was prepared by the same procedure as in Example 2 described with the difference that equimolar amounts of N- (D-6-methyl- -8w-ergolinyl) -N ', N'-diethylurea was used instead N- (D-6-propyl-8u-ergolinyl) -N ', N'-diethylurea and equimolar amounts of alkyl bromides, allyl bromide, benzyl bromide or ethyl bromide. acetate was used.
Claims (8)
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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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SE8301257D0 SE8301257D0 (en) | 1983-03-08 |
SE8301257L SE8301257L (en) | 1983-09-13 |
SE452321B true SE452321B (en) | 1987-11-23 |
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SE8301257A SE452321B (en) | 1982-03-12 | 1983-03-08 | 1-SUBSTITUTED N- (8ALFA-ERGOLINYL) -N ', N'-DIETHYL CARBAMIDS AND SET TO MAKE THEM |
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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) |
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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 |
US20140058108A1 (en) * | 2010-11-11 | 2014-02-27 | Sinoxa Pharma Ug | Lisuride, Terguride and Derivatives Thereof for Use in the Prophylaxis and/or Treatment of Fibrotic Changes |
BR112017015487A2 (en) | 2015-01-20 | 2018-01-30 | Xoc Pharmaceuticals Inc | COMPOUND; COMPOSITION; METHOD OF TREATMENT AND / OR PREVENTION OF MIGRAINE, ALS, ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, EXTRAPYRIMIDAL DISORDERS, DEPRESSION, NAUSEA, AEMESIS, SYNDROME OF THE WASTE LEGS, INSOMENESS, HYGERNESS, AGING , ANXIETY, DRUG DEPENDENCIES, DYSTONIA, PARASSONIA OR HYPERLACTINEMIA IN AN INDIVIDUAL; AGONIZATION METHODS OF D2, 5-HT1D, 5-HT1A AND 5-HT2C RECEPTORS, IN AN INDIVIDUAL; ANTAGONIZATION METHOD OF THE D3 RECEPTOR IN AN INDIVIDUAL; METHODS OF SELECTIVE AGONIZATION OF RECEPTORS 5 -HT1D, AND 5-HT2C, METHOD OF PROVIDING FUNCTIONAL ANTAGONIST ACTIVITY IN RECEPTOR 5 -HT2B OR IN RECEIVER 5-HT7, OR IN BOTH, IN AN INDIVIDUAL; METHOD OF PROVIDING FUNCTIONAL ANTAGONIST ACTIVITY IN ADRENERGIC RECEPTORS IN AN INDIVIDUAL |
MX2017009406A (en) | 2015-01-20 | 2018-01-18 | Xoc Pharmaceuticals Inc | Isoergoline compounds and uses thereof. |
BR112019025420A2 (en) | 2017-06-01 | 2020-06-16 | Xoc Pharmaceuticals, Inc. | POLYCYCLICAL COMPOUNDS AND USES OF THESE |
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Publication number | Priority date | Publication date | Assignee | Title |
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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 |
DE3063869D1 (en) * | 1979-06-13 | 1983-07-28 | Schering Ag | (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 GB GB08305735A patent/GB2116548B/en not_active Expired
- 1983-03-02 AT AT0072783A patent/AT383349B/en not_active IP Right Cessation
- 1983-03-07 NL NL8300829A patent/NL8300829A/en not_active Application Discontinuation
- 1983-03-07 IT IT19935/83A patent/IT1161209B/en active
- 1983-03-07 FI FI830754A patent/FI830754L/en not_active Application Discontinuation
- 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 BE BE0/210287A patent/BE896122A/en not_active IP Right Cessation
- 1983-03-10 CA CA000423264A patent/CA1203531A/en not_active Expired
- 1983-03-11 JP JP58039349A patent/JPS58180484A/en active Pending
- 1983-03-11 FR FR8304005A patent/FR2523131B1/en not_active Expired
- 1983-03-11 DE DE3308719A patent/DE3308719A1/en not_active Withdrawn
- 1983-03-11 CH CH1351/83A patent/CH652125A5/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
AU555961B2 (en) | 1986-10-16 |
AT383349B (en) | 1987-06-25 |
SE8301257L (en) | 1983-09-13 |
FI830754L (en) | 1983-09-13 |
DE3308719A1 (en) | 1983-09-22 |
IT8319935A0 (en) | 1983-03-07 |
CS231214B1 (en) | 1984-10-15 |
DK84683D0 (en) | 1983-02-24 |
CH652125A5 (en) | 1985-10-31 |
NL8300829A (en) | 1983-10-03 |
FR2523131A1 (en) | 1983-09-16 |
JPS58180484A (en) | 1983-10-21 |
ATA72783A (en) | 1986-11-15 |
BE896122A (en) | 1983-07-01 |
GB2116548A (en) | 1983-09-28 |
GB2116548B (en) | 1985-03-20 |
DK84683A (en) | 1983-09-13 |
AU1216783A (en) | 1983-09-15 |
FI830754A0 (en) | 1983-03-07 |
SE8301257D0 (en) | 1983-03-08 |
CA1203531A (en) | 1986-04-22 |
IT1161209B (en) | 1987-03-18 |
GB8305735D0 (en) | 1983-04-07 |
FR2523131B1 (en) | 1987-08-28 |
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