WO1982002892A1 - Nouveaux derives d'ergoline, leur preparation et leurs compositions pharmaceutiques - Google Patents

Nouveaux derives d'ergoline, leur preparation et leurs compositions pharmaceutiques Download PDF

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Publication number
WO1982002892A1
WO1982002892A1 PCT/CH1982/000025 CH8200025W WO8202892A1 WO 1982002892 A1 WO1982002892 A1 WO 1982002892A1 CH 8200025 W CH8200025 W CH 8200025W WO 8202892 A1 WO8202892 A1 WO 8202892A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
formula
acid addition
addition salts
Prior art date
Application number
PCT/CH1982/000025
Other languages
German (de)
English (en)
Inventor
Ag Sandoz
Peter Gull
Original Assignee
Ag Sandoz
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CH121181A external-priority patent/CH645895A5/de
Priority claimed from CH121081A external-priority patent/CH645894A5/de
Application filed by Ag Sandoz filed Critical Ag Sandoz
Publication of WO1982002892A1 publication Critical patent/WO1982002892A1/fr

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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
    • C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8

Definitions

  • the invention relates to ergoline derivatives, their preparation and their pharmaceutical compositions.
  • German Offenlegungsschrift No. 1,910,930 describes a broad class of N-acyl-N- (12-hydroxy-1,6-dimethylergolin-8-yl-methyl) amino derivatives which are said to be particularly useful in the treatment of Migraines, trigeminal neuralgia, general allergy and inflammatory diseases, which is demonstrated by antagonism of serotonin,
  • acyl derivatives A wide variety of acyl derivatives is specifically mentioned. One of these compounds is a derivative of diethyl carbamic acid. No other carbamic acid derivatives are mentioned. The five examples described do not relate on carbaric acid derivatives,
  • the invention relates to compounds of the formula I.
  • Such precursors in position 1 are such substituents. means which are converted under physiological conditions into other meanings of R 1 , preferably H, mentioned.
  • substituents are, for example, CH 2 0H, (C 1-22 ) alkanoyloxymethyl or acetyl.
  • R 5 when it is alkyl, preferably has 1 to 20, especially 1 to 4, carbon atoms.
  • R 1 H, (C 1-4 ) alkyl, CH 2 OH or (C 1-4 ) alkanoyloxymethyl
  • R 3 H or (C 1-4 ) alkyl
  • R 4 (C 1-4 ) alkyl and / or
  • a group of compounds includes those of the formula Ia
  • Another group of compounds of formula I includes those wherein R 1 and R 2 are both CH 3 , R 3 and R 4 are both (C 1- 4 ) alkyl, A and B are both H and R 5 alkyl.
  • the invention also relates to a process for the preparation of the compounds according to the invention, thereby characterized that
  • R 1 to R 4 and A and B have the meanings mentioned above and R 6 represents H or OH, or their precursors are oxidized and a compound of the formula I in which R 5 is hydrogen is obtained, or
  • R 1 , R 3 , R 4 and R 5 is hydrogen, or a precursor, alkylated and a corresponding compound in which at least R 1 (C 1- 4 ) alkyl, CH 2 is OH or (C 1-22 ) alkanoyloxymethyl and / or at least R 3 , R 4 or R 5 is alkyl,
  • the oxidation according to process a) can be carried out in a manner known per se
  • 2,3-position is suitable, and when R 6 is hydrogen, is suitable for introducing a hydroxyl group into the 12-position of the ergoline core.
  • R 6 is hydrogen
  • the oxidation can be carried out in one step or in two steps, one step the introduction of the hydroxyl group and the other stage the
  • Manner as is customary for the conversion of indolines into corresponding indoles, e.g. by passing an air stream through a solution of the compound.
  • Oxidizing agents such as a nitrosodisulfonate, e.g. in the form of the potassium salt.
  • a nitrosodisulfonate e.g. in the form of the potassium salt.
  • the reaction is preferably carried out with the nitrosodisulfonate in an aqueous medium at a pH between about 3 and 9, preferably at a pH. of about 7.
  • the ergon compound can be in an organic solvent, e.g. Chloroform, dissolved and the system stirred vigorously.
  • organic solvent e.g. Chloroform
  • the reaction temperature can be, for example, between about 0 ° and 50 ° C. If a group, for example, CH 2 OH, is present in position 1 of the ergoline core, R 6 is preferably hydroxy.
  • Such groups are preferably introduced after the oxidation reaction.
  • the alkylation process b) can be carried out in a conventional manner, using suitable alkylating agents to alkylate the appropriate group.
  • alkylation includes not only the introduction of an unsubstituted alkyl group, but also the introduction of CH 2 OH and alkanoyloxymethyl. Where selective alkylation is required, other reactive groups can be temporarily blocked if desired.
  • the etherification of the hydroxyl group can be carried out with a diazoalkane, for example diazomethane.
  • the CH 2 OH group in position 1 can be introduced with formaldehyde. If desired, the CH 2 OH group can then be acylated afterwards with, for example, an acid halide.
  • the compounds of formula II in which R 6 is hydrogen are either known or can be prepared by known methods.
  • Some compounds of the formula II, in which R 6 is hydroxy, hereinafter referred to as compounds of the formula III, are generally new and can be prepared, for example, as described in the reaction scheme below and for a product unsubstituted in position 1.
  • the compounds of the formula I in which R 5 is hydrogen can be converted in a conventional manner into other compounds of the formula I, for example they can be alkylated or, for the preparation of the abovementioned precursor groups in position 1, acetylated or formylated and the formylated products preferably be acylated.
  • the compounds can optionally also be alkylated in the urea methyl radical and hydrogenated in the 9.10 position.
  • the etherification of the 12-hydroxylated product can be carried out according to methods known for the synthesis of analogous phenol ethers.
  • the alkylation can be carried out in a conventional manner.
  • the acetylation and the formylation can also be carried out in a conventional manner by reaction with ketene or with formaldehyde and an acid.
  • the rest in position 1 can also be carried out using known methods, e.g. can be carried out with an acid halide.
  • Other precursor groups in position 1 can be introduced in a conventional manner.
  • the hydrogenation can also be carried out by known methods, in particular by catalytic hydrogenation, e.g. with Pd-C as a catalyst.
  • the compounds of formula I can be isolated in free base form or in acid addition salt form.
  • the acid addition salts of a compound of formula I can be formed in a conventional manner from the free bases and vice versa. Suitable acids are fumaric acid and hydrochloric acid. If compounds of the formula I are to be prepared in which one or more of the substituents (C 1- 4) alkyl or A and Al are BH, the required hydrogenation alkylation or 10 may in position 9, either before. or after the formation of the 12-hydroxy group. R 1 precursors are preferably introduced after the hydroxyl group.
  • the temperatures are in degrees Celsius. They are uncorrected.
  • the evaporation residue consists of 1, 1-Dimethyl-3- (12-hydroxy-6-methyl-2,3 ⁇ -dihydro-9,10-di-dehydro-ergolin-8 ⁇ -ylmethyl) urea, is dissolved in 10 ml of ethanol, after adding 1 ml of concentrated ammonia solution is blown air through the solution for 1 hour. After evaporation, the crude product is chromatographed on 100 g of silica gel with methylene chloride containing 10% methanol and 0.2% ammonia solution. The pure title compound results as a beige residue.
  • the compounds according to the invention have pharmacological activity and can therefore be used as medicines. In particular, they cause a reduction in blood pressure in standard experiments with the awake spontaneously hypertensive rat after administration of 0.001 to 0.1 mg / kg s.c.
  • the compounds according to the invention are therefore in the treatment of high blood pressure and of heart failure usable.
  • the daily dose for the above-mentioned application is between about 0.2 and about 300 mg and is expediently administered orally 2 to 4 times a day in portions from about 0.05 to about
  • a compound of formula I can be administered as a free base or as a pharmaceutically acceptable acid addition salt.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention and a pharmaceutical carrier or diluent.
  • Such compositions can be made into conventional forms e.g. Capsules or tablets.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Les composes repondent a la formule I (FORMULE) dans laquelle R1 represente H, alkyl en C1-4 ou leurs precurseurs, R2 est alkyl en C1-4, R3 et R4 independamment l'un de l'autre sont H, alkyl en C1-4 ou ensemble sont alkylene en C2-5 R5 est H ou alkyl et A et B sont chacun H ou ensemble representent une liaison a la condition que lorsque R1 et R2 = CH3, R3 et R4 = C2H5, A et B = H, R5 est alkyl. Sont concernes egalement les sels d'addition d'acide de ces composes. Les composes sont utilises pour le traitement de l'hypertonie et des insuffisances cardiaques.
PCT/CH1982/000025 1981-02-24 1982-02-19 Nouveaux derives d'ergoline, leur preparation et leurs compositions pharmaceutiques WO1982002892A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH1211/81810224 1981-02-24
CH121181A CH645895A5 (en) 1981-02-24 1981-02-24 Ergoline derivatives, their preparation and use
CH1210/81 1981-02-24
CH121081A CH645894A5 (en) 1981-02-24 1981-02-24 Ergoline derivatives, their preparation and use

Publications (1)

Publication Number Publication Date
WO1982002892A1 true WO1982002892A1 (fr) 1982-09-02

Family

ID=25687002

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CH1982/000025 WO1982002892A1 (fr) 1981-02-24 1982-02-19 Nouveaux derives d'ergoline, leur preparation et leurs compositions pharmaceutiques

Country Status (16)

Country Link
AU (1) AU8068282A (fr)
CA (1) CA1178582A (fr)
DE (1) DE3205169A1 (fr)
DK (1) DK77082A (fr)
ES (1) ES509825A0 (fr)
FI (1) FI820526L (fr)
FR (1) FR2500454A1 (fr)
GB (1) GB2093452B (fr)
HU (1) HU187650B (fr)
IL (1) IL65074A0 (fr)
NL (1) NL8200694A (fr)
NZ (1) NZ199795A (fr)
PH (1) PH17494A (fr)
PT (1) PT74468B (fr)
SE (1) SE8201098L (fr)
WO (1) WO1982002892A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190534A1 (fr) * 1984-12-13 1986-08-13 Schering Aktiengesellschaft Procédé pour la préparation de dérivés d'ergoline
EP0220129A2 (fr) * 1985-09-19 1987-04-29 Schering Aktiengesellschaft Dérivés d'ergoline substitués dans la position 12 et 13

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3309493A1 (de) * 1983-03-14 1984-09-20 Schering AG, 1000 Berlin und 4709 Bergkamen Neue ergolin-derivate, verfahren zu ihrer herstellung sowie verwendung als arzneimittel
DE3402392A1 (de) * 1984-01-25 1985-08-01 Sandoz-Patent-GmbH, 7850 Lörrach Neue ergolinderivate, deren herstellung und deren verwendung
DE3528576A1 (de) * 1985-08-06 1987-02-19 Schering Ag Verfahren zur herstellung von ergolin-thioharnstoffen
DE3528584A1 (de) * 1985-08-06 1987-02-19 Schering Ag Neue 1-alkyl-ergolin-thioharnstoffderivate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1910930A1 (de) * 1968-03-07 1969-10-16 Farmaceutici Italia Verfahren zur Herstellung von neuen 1,6-Dimethyl-10alpha-ergolinderivaten
DE2223681A1 (de) * 1971-05-19 1972-11-30 Sandoz Ag Neue heterocyclische Verbindungen und Verfahren zu ihrer Herstellung
DE2810774A1 (de) * 1977-03-25 1978-10-05 Sandoz Ag Ergotderivate, ihre verwendung und herstellung

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2421176A1 (fr) * 1978-03-29 1979-10-26 Sandoz Sa Nouveaux derives de l'ergot de seigle, leur preparation et leur application comme medicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1910930A1 (de) * 1968-03-07 1969-10-16 Farmaceutici Italia Verfahren zur Herstellung von neuen 1,6-Dimethyl-10alpha-ergolinderivaten
DE2223681A1 (de) * 1971-05-19 1972-11-30 Sandoz Ag Neue heterocyclische Verbindungen und Verfahren zu ihrer Herstellung
DE2810774A1 (de) * 1977-03-25 1978-10-05 Sandoz Ag Ergotderivate, ihre verwendung und herstellung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
European Journal of Medicinal Chemistry - Chemica Therapeutica, Band 9, Nr. 6, November-Dezember 1974, (Chatenay-Malabry, FR), T. Fehr u.a: "Antihypertensiv wirksame Harnstoffderivate des 8beta-Aminomethyl-6-methyl-ergolens", Seiten 597-601 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190534A1 (fr) * 1984-12-13 1986-08-13 Schering Aktiengesellschaft Procédé pour la préparation de dérivés d'ergoline
EP0220129A2 (fr) * 1985-09-19 1987-04-29 Schering Aktiengesellschaft Dérivés d'ergoline substitués dans la position 12 et 13
EP0220129A3 (en) * 1985-09-19 1987-08-05 Schering Aktiengesellschaft Berlin Und Bergkamen 12- and 13-substituted ergoline derivatives
US4863929A (en) * 1985-09-19 1989-09-05 Schering Aktiengesellschaft 12- and 13-substituted ergoline derivatives having alpha2 -receptor-blocking effect

Also Published As

Publication number Publication date
PH17494A (en) 1984-09-04
DK77082A (da) 1982-08-25
AU8068282A (en) 1982-09-02
GB2093452A (en) 1982-09-02
NZ199795A (en) 1985-08-30
DE3205169A1 (de) 1982-10-14
GB2093452B (en) 1984-11-07
ES8304578A1 (es) 1983-03-01
ES509825A0 (es) 1983-03-01
FR2500454B1 (fr) 1984-11-09
HU187650B (en) 1986-02-28
NL8200694A (nl) 1982-09-16
SE8201098L (sv) 1982-08-25
PT74468B (en) 1984-08-01
FR2500454A1 (fr) 1982-08-27
CA1178582A (fr) 1984-11-27
IL65074A0 (en) 1982-04-30
PT74468A (en) 1982-03-01
FI820526L (fi) 1982-08-25

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