WO1989008109A1 - Nouveaux derives d'ergoline, leur procede de fabrication ainsi que leur emploi a titre de medicaments - Google Patents

Nouveaux derives d'ergoline, leur procede de fabrication ainsi que leur emploi a titre de medicaments Download PDF

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Publication number
WO1989008109A1
WO1989008109A1 PCT/DE1989/000119 DE8900119W WO8908109A1 WO 1989008109 A1 WO1989008109 A1 WO 1989008109A1 DE 8900119 W DE8900119 W DE 8900119W WO 8908109 A1 WO8908109 A1 WO 8908109A1
Authority
WO
WIPO (PCT)
Prior art keywords
ergolinyl
nitro
alkyl
amino
methylthio
Prior art date
Application number
PCT/DE1989/000119
Other languages
German (de)
English (en)
Inventor
Gerhard Sauer
Josef Heindl
Gertrud SCHRÖDER
Bernd Günter SCHULZ
Original Assignee
Schering Aktiengesellschaft Berlin Und Bergkamen
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 to KR1019890701809A priority Critical patent/KR950009714B1/ko
Application filed by Schering Aktiengesellschaft Berlin Und Bergkamen filed Critical Schering Aktiengesellschaft Berlin Und Bergkamen
Publication of WO1989008109A1 publication Critical patent/WO1989008109A1/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
    • C07D457/10—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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to new ergoline derivatives, processes for their preparation and medicaments based on these compounds.
  • the invention relates to substituted ergolines of the general formula I.
  • R 3 and R 4 are different and represent hydrogen, C 1 -C 4 alkyl, or acyl, or
  • R 3 and R 4 each represent the same radical C 1 -C 4 alkyl or together with
  • the acid addition salts of the compounds according to the invention are derived from physiologically acceptable acids.
  • physiologically acceptable acids are inorganic acids, such as, for example, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, or organic acids, such as, for example, aliphatic mono- or dicarboxylic acids, phenyl-substituted alkane carboxylic acid, hydroxyaromatic carboxylic acids or alkane acids aliphatic or aromatic sulfonic acids.
  • Physiologically acceptable salts of these acids are therefore, for example, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate , Isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, halate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, ethylbenzoate, dinitrobenzoate, hydroxybenzoate, phthalate, methoxyben , Benzenesulfonate.
  • alkyl radicals with up to 4 carbon atoms are those which are derived from the aliphatic hydrocarbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, is ⁇ butyl, tert-butyl and cyclopropylmethyl.
  • the substituent is, for example, an aziridine, pyrrolidine or piperidine ring system which can also be substituted with alkyl groups.
  • Acyl is to be understood as acid residues such as alkanoyl with up to 5 carbon atoms, aroyl and aralkanoyl with 7-10 carbon atoms.
  • alkanoyl radicals with 1 to 5 carbon atoms are derived from aliphatic carboxylic acids that are physiologically compatible, e.g. Acetyl, propionyl, n-butyryl and isobutyryl.
  • the aroyl residues and aralkanoyl residues with 7 to 10 carbon atoms are, for example, benzoyl, p-methylbenzoyl, 3,5-dimethylbenzoyl, phenylacetyl, phenylpropionyl and p-tolylacetyl.
  • 80o-ergolinyl urea derivatives are preferred compounds of this invention.
  • the compounds according to the invention showed a very good hypotensive activity in the dose range of 1 mg / kg body weight in SH rats.
  • the hypotensive effects shown can be attributed to DA-agonistic effects of the compounds examined, which can be demonstrated in the electrically irritated rabbit ear arteries.
  • no antihypertensive agent that is effective exclusively via the DA 2 receptor is known. The new connections of the
  • Formula I are surprisingly DA 2 agonists.
  • the ergolinyl urea derivatives according to the invention would therefore be therapeutically applicable as antihypertensives. Because of their prolactin-lowering effect, they are also suitable as a weaning agent.
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as e.g. Contains water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
  • suitable pharmaceutical, organic or inorganic inert carrier materials such as e.g. Contains water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
  • the pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. present as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure
  • the dosage of the compounds according to the invention in humans is in the range of 5-100 mg / day and a dosage form contains 1-20 mg of active ingredient.
  • the compounds according to the invention are prepared by methods known per se.
  • the starting material of formula II used is known.
  • There are ergoline-diethylurea derivatives in which the ureido side chain is ⁇ -permanent, which is saturated or unsaturated in the 9.10 position, substituted on the nitrogen atom in the 6-position with methyl and a nitro group on the aromatic in position 12, 13 or 14 are (e.g. DE-OS 33 09 493).
  • the nitrated ergolinyl-urea compounds can then be substituted in the 2-position.
  • R 2 has the meaning given above and which can be represented according to DE-OS 28 10 774, nitrided.
  • the nitration of the compounds of the formula III is optionally carried out after acetylation in the 1 position with nitric acid in the presence of sulfuric acid or acetic acid.
  • the mono-nitration essentially follows the rules of electrophilic substitution of aniline, whereby the 2,3-dihydro-ergolines in the 13-position and the 9,10-didehydro-2,3-dihydro-ergolines in the 12- and 14-positions are mainly nitrided side by side.
  • small amounts of the other positional isomers and double nitrated products can be formed.
  • the separation is carried out by chromatography or crystallization.
  • the nitro compound which is unsubstituted in the 1 position can then be oxidatively converted back into the ergoline or indole system.
  • this compound is reacted in an inert solvent, such as chlorinated hydrocarbons, with an oxidizing agent, such as manganese dioxide, nickel peroxide, derivatives of chromic acid, phenylselenetic anhydride, palladium salts, oxygen and catalysts, or with dimethyl sulfide, tert-butyl hypochlorite and base.
  • an inert solvent such as chlorinated hydrocarbons
  • an oxidizing agent such as manganese dioxide, nickel peroxide, derivatives of chromic acid, phenylselenetic anhydride, palladium salts, oxygen and catalysts, or with dimethyl sulfide, tert-butyl hypochlorite and base.
  • the ergolinylureas of the formula I can be converted into ergolinylthioureas by the process described in DE-OS 35 28 576.
  • the nitro group can be selectively reduced to the amino group at any stage, ie without reducing any 9.10 double bond which may be present with sodium borohydride in the presence of metal salts such as nickel (II) salts or tin (II) salts [(A. Nose et al ., Chem. Pharm. Bull. 29, 1155 (1981) and T. Satoh et al., Chem. Pharm. Bull. 21. 1443 (1981) j.
  • the nitro compound reduced to the amino compound can be converted to the corresponding alkyl or acyl compounds by alkylation and acylation.
  • an acylamino compound obtained in this way can be converted into the corresponding honalkylamino compounds by reduction with diisobutylaluminum hydride, with lithium aluminum hydride or with borane dimethyl sulfide.
  • the compounds thus obtained are used either as free bases or in the form of their acid addition salts, which if desired by reaction with a physiologically acceptable acid such as e.g. Tartaric acid, maleic acid or benzoic acid can be obtained, purified by recrystallization and / or chromatography.
  • a physiologically acceptable acid such as e.g. Tartaric acid, maleic acid or benzoic acid
  • the compound obtained is dissolved in a little methanol and a concentrated solution of the desired organic acid in methanol is added at room temperature.
  • the invention thus also relates to a process for the preparation of substituted ergolines of the general formula I, which is characterized in that an ergoline of the general formula II which is unsubstituted in the 2-position

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Ergolines substituées de formule générale (I) et leurs sels d'addition d'acide, où (a) et (b) représentent une liaison simple C-C ou une liaison double C=C, X représente de l'oxygène ou du soufre, R1 représente amino, nitro ou le résidu (c), R2 représente méthylthio, si (a) est une liaison double C=C, ou bien un alkyl C1-C4, R3 et R4 sont différents et représentent un hydrogène, un alkyle C1-C4 ou bien un acyl, ou encore R3 et R4 représentent chacun le même résidu alkyle C1-C4 ou forment conjointement avec l'atome N du résidu (c) un composé cyclique trigonal à nonagonal. Ces composés sont produits par des procédés connus en soi et possèdent, par exemple, une activité hypotensive.
PCT/DE1989/000119 1988-02-12 1989-02-24 Nouveaux derives d'ergoline, leur procede de fabrication ainsi que leur emploi a titre de medicaments WO1989008109A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019890701809A KR950009714B1 (ko) 1988-02-12 1989-02-09 열가소성 화합물로부터 압축 모울딩되는 재료의 제조방법 및 장치

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3806374A DE3806374A1 (de) 1988-02-25 1988-02-25 Neue ergolin-derivate, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DEP3806374.3 1988-02-25

Publications (1)

Publication Number Publication Date
WO1989008109A1 true WO1989008109A1 (fr) 1989-09-08

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PCT/DE1989/000119 WO1989008109A1 (fr) 1988-02-12 1989-02-24 Nouveaux derives d'ergoline, leur procede de fabrication ainsi que leur emploi a titre de medicaments

Country Status (4)

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EP (1) EP0401263A1 (fr)
JP (1) JPH03503886A (fr)
DE (1) DE3806374A1 (fr)
WO (1) WO1989008109A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010663A1 (fr) * 1990-01-15 1991-07-25 Schering Aktiengesellschaft Berlin Und Bergkamen Ergolins disubstitues, leur fabrication et utilisation dans des medicaments

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0118848A2 (fr) * 1983-03-14 1984-09-19 Schering Aktiengesellschaft Dérivés d'ergoline, leur procédé de préparation, et leur application comme médicaments
EP0159522A1 (fr) * 1984-03-16 1985-10-30 Schering Aktiengesellschaft 3-(6-Méthylergolin-8 alpha-yl)-1.1-diéthyl-urée comme antihypertensif
EP0220129A2 (fr) * 1985-09-19 1987-04-29 Schering Aktiengesellschaft Dérivés d'ergoline substitués dans la position 12 et 13

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0118848A2 (fr) * 1983-03-14 1984-09-19 Schering Aktiengesellschaft Dérivés d'ergoline, leur procédé de préparation, et leur application comme médicaments
EP0159522A1 (fr) * 1984-03-16 1985-10-30 Schering Aktiengesellschaft 3-(6-Méthylergolin-8 alpha-yl)-1.1-diéthyl-urée comme antihypertensif
EP0220129A2 (fr) * 1985-09-19 1987-04-29 Schering Aktiengesellschaft Dérivés d'ergoline substitués dans la position 12 et 13

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010663A1 (fr) * 1990-01-15 1991-07-25 Schering Aktiengesellschaft Berlin Und Bergkamen Ergolins disubstitues, leur fabrication et utilisation dans des medicaments

Also Published As

Publication number Publication date
DE3806374A1 (de) 1989-09-07
EP0401263A1 (fr) 1990-12-12
JPH03503886A (ja) 1991-08-29

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