EP0000533B1 - N-Substituierte 9,10-Dihydrolysergsäureester sowie ein Verfahren zu deren Herstellung - Google Patents

N-Substituierte 9,10-Dihydrolysergsäureester sowie ein Verfahren zu deren Herstellung Download PDF

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Publication number
EP0000533B1
EP0000533B1 EP78100419A EP78100419A EP0000533B1 EP 0000533 B1 EP0000533 B1 EP 0000533B1 EP 78100419 A EP78100419 A EP 78100419A EP 78100419 A EP78100419 A EP 78100419A EP 0000533 B1 EP0000533 B1 EP 0000533B1
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EP
European Patent Office
Prior art keywords
radical
denotes
mmol
general formula
dihydrolysergic acid
Prior art date
Legal status (The legal status 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 status listed.)
Expired
Application number
EP78100419A
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German (de)
English (en)
French (fr)
Other versions
EP0000533A1 (de
Inventor
Rudolf Rucman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals and Chemical Co dd
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Filing date
Publication date
Application filed by Lek Pharmaceuticals and Chemical Co dd filed Critical Lek Pharmaceuticals and Chemical Co dd
Publication of EP0000533A1 publication Critical patent/EP0000533A1/de
Application granted granted Critical
Publication of EP0000533B1 publication Critical patent/EP0000533B1/de
Expired legal-status Critical Current

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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
    • C07D457/04—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

Definitions

  • the invention relates to N-substituted 9,10-dihydrolysergic acid esters and a process for their preparation.
  • X represents a hydrogen or halogen atom
  • the alkyl group is simultaneously introduced into the 1-position of the compound of the general formula II and the group in the 8-position is esterified or transesterified by the same alkyl group which was introduced into the 1-position.
  • R represents a hydrogen atom or an organic radical which can be hydrolyzed in an alkaline medium. Therefore, those 9,10-dihydrolysergic acid esters in which R represents any organic radical of higher molecular weight can also be used for the process according to the invention than the introduced group R is.
  • This organic radical R is the intermediate alkaline Hy drolysis replaced by a lower group R.
  • the compounds of the general formulas 11 and 111 are known and described or can be prepared by processes known per se.
  • Tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, triethylbenzylammonium chloride, tricaprylmethylammonium chloride or tetrabutylphosphonium bromide, for example, can be used as the catalyst for phase transfer.
  • the phase transfer catalyst is used in an amount of 0.1 to 3 moles to 1 mole of 9,10-dihydrolysergic acid.
  • the amount of catalyst within these limits greatly affects the rate of the reaction. Since 9,10-dihydrolysergic acid and its derivatives are very sensitive compounds, a rapid course of the reaction is desirable. Therefore, the use of the catalyst in an amount close to the above upper limit is advantageous.
  • the water-immiscible inert organic solvent can e.g. Benzene, toluene, xylene or a saturated hydrocarbon such as pentane, hexane, heptane or cyclohexane.
  • the alkaline aqueous phase is a 20-50% aqueous alkali hydroxide solution, e.g. Caustic soda.
  • the inventive method is carried out at room temperature or moderately elevated temperature.
  • the substitution of the 9,10-dihydrolysergic acid derivatives in the 8-position is faster than in the 1-position. Therefore, the esters and the N-substituted esters can be isolated from the reaction mixture at the beginning of the reaction. By continuing the reaction, the concentration of the ester is reduced until it completely disappears at the end of the reaction and only the N-substituted ester is obtained.
  • alkyl, alkenyl or cycloalkyl group is introduced into a 9,10-dihydrolysergic acid alkyl, alkenyl or cycloalkyl ester according to the invention, a 1- (alkyl or alkenyl or cycloalkyl) - 9,10-dihydrolysergic acid alkyl, alkenyl or cycloalkyl esters can be obtained.
  • the compounds according to the invention are important intermediate compounds for the synthesis of therapeutically highly effective compounds with an N-substituted group in the 1-position.
  • the further reactions of the synthesis proceed primarily in the direction of reducing the ester group in the 8-position to the primary alcohol group, into which a suitable acid residue, e.g. the 5-bromnicotinic acid residue is introduced. Therefore, the simultaneous introduction of the R group in the 1-position and the esterification of the carboxy group in the 8-position, which are thereby for the reduction in. the alcohol group becomes more accessible, very advantageous.
  • the toluene extract is separated from the aqueous phase and then the aqueous phase is extracted twice with 200 ml of toluene and 0.63 g (5 mmol) of dimethyl sulfate.
  • the combined toluene extracts are washed with water and evaporated to dryness in vacuo. There will be 2.14 g or 71.8% of theory Th. Crystalline 1-methyl-9,10-dihydrolysergic acid methyl ester obtained.
  • the compound has the properties given in Example 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP78100419A 1977-07-21 1978-07-18 N-Substituierte 9,10-Dihydrolysergsäureester sowie ein Verfahren zu deren Herstellung Expired EP0000533B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
YU1819/77A YU40004B (en) 1977-07-21 1977-07-21 Praocess for preparing n-substituted esters of 9,10-dihydrlysergic acid
YU1819/77 1977-07-21

Publications (2)

Publication Number Publication Date
EP0000533A1 EP0000533A1 (de) 1979-02-07
EP0000533B1 true EP0000533B1 (de) 1981-08-05

Family

ID=25555705

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100419A Expired EP0000533B1 (de) 1977-07-21 1978-07-18 N-Substituierte 9,10-Dihydrolysergsäureester sowie ein Verfahren zu deren Herstellung

Country Status (11)

Country Link
US (1) US4230859A (enrdf_load_stackoverflow)
EP (1) EP0000533B1 (enrdf_load_stackoverflow)
JP (1) JPS5436296A (enrdf_load_stackoverflow)
AT (1) AT363195B (enrdf_load_stackoverflow)
CS (1) CS216231B2 (enrdf_load_stackoverflow)
DE (1) DE2860896D1 (enrdf_load_stackoverflow)
ES (1) ES471716A1 (enrdf_load_stackoverflow)
FI (1) FI64369C (enrdf_load_stackoverflow)
PT (1) PT68278A (enrdf_load_stackoverflow)
SU (1) SU784775A3 (enrdf_load_stackoverflow)
YU (1) YU40004B (enrdf_load_stackoverflow)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4563461A (en) * 1983-03-10 1986-01-07 Eli Lilly And Company Selective method for blocking 5HT2 receptors
FR2584721B1 (fr) * 1985-07-11 1987-10-02 Rhone Poulenc Sante Procede de preparation des derives n-methyles du dihydrolysergate de methyle ou du methoxylumilysergate de methyle
FR2584720B1 (fr) * 1985-07-11 1987-10-02 Rhone Poulenc Sante Procede de preparation de derives n-methyles de l'ergoline
US4714704A (en) * 1985-10-01 1987-12-22 Eli Lilly And Company Alkoxy cycloalkanol esters of dihydrolysergic acid useful as 5HT receptor antagonists
US4845224A (en) * 1985-10-01 1989-07-04 Eli Lilly And Company Cycloalkanol esters of dihydrolysergic acid having peripheral serotonin antagonist properties
US4939258A (en) * 1985-10-01 1990-07-03 Eli Lilly And Company Cycloalkanol esters of dihydrolysergic acid
US4772709A (en) * 1985-10-01 1988-09-20 Eli Lilly And Company Process of making ketoalkanol esters of dihydrolysergic acid
US4847261A (en) * 1985-10-01 1989-07-11 Eli Lilly And Company Alkoxy cycloalkanol esters of dihydrolysergic acid having peripheral serotonin antagonists properties
US4713384A (en) * 1985-10-01 1987-12-15 Eli Lilly And Company Selective method for blocking 5HT2 receptors
US4820713A (en) * 1985-10-01 1989-04-11 Eli Lilly And Company Ketoalkanol esters of dihydrolysergic acid useful as 5HT receptor antagonists
US4762842A (en) * 1985-10-01 1988-08-09 Eli Lilly And Company Selective method for blocking 5HT2 receptors
US4906639A (en) * 1985-10-01 1990-03-06 Eli Lilly And Company Cycloalkanol esters of dihydrolysergic acid
US4968802A (en) * 1985-10-01 1990-11-06 Eli Lilly And Company Process of making alkoxy cycloalkanol esters of dihydrolysergic acid
US4713385A (en) * 1985-10-01 1987-12-15 Eli Lilly And Company Alkoxy and dialkoxyalkyl esters of dihydrolysergic acid and related compounds useful as 5HT receptor antagonists
US4810710A (en) * 1985-10-01 1989-03-07 Eli Lilly And Company 4-hydroxycyclohexyl 1-isopropyl-9,10-dihydro-lysergate for the treatment of migraine
US4734501A (en) * 1985-10-01 1988-03-29 Eli Lilly And Company N-alkylation of dihydrolysergic acid
US4683236A (en) * 1985-10-01 1987-07-28 Eli Lilly And Company Cycloalkanol esters of dihydrolysergic acid useful as 5Ht2 receptor antagonists
US4704395A (en) * 1985-12-20 1987-11-03 Eli Lilly And Company Cyclic ether esters of 2-substituted-6-(substituted and unsubstituted) dihydrolysergic acid useful as 5HT receptor antagonists
US4704396A (en) * 1985-12-20 1987-11-03 Eli Lilly And Company Phenacyl esters of 1-substituted-6-(substituted and unsubstituted) dihydrolysergic acids useful as 5HT receptor antagonists
US4683237A (en) * 1985-12-20 1987-07-28 Eli Lilly And Company Fluoroalkyl esters of dihydrolysergic acid useful as 5HT2 receptor antagonists
US4835159A (en) * 1987-05-11 1989-05-30 Eli Lilly And Company Ergoline esters useful as serotonin antagonists
US4782063A (en) * 1987-05-11 1988-11-01 Eli Lilly And Company Ergoline esters useful as serotonin antagonists
US4931447A (en) * 1987-06-15 1990-06-05 Eli Lilly And Company Cycloalkylamides of (8β)-1-alkyl-6-(substituted) ergolines
US4981859A (en) * 1987-06-15 1991-01-01 Cycloalkylamides of (8 beta )-1-alkyl-6-(substituted)ergolines
JPH01106511U (enrdf_load_stackoverflow) * 1988-01-02 1989-07-18
JPH02125915U (enrdf_load_stackoverflow) * 1989-03-29 1990-10-17

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA631701A (en) * 1961-11-28 Sandoz A.G. Compounds of the lysergic acid series alkylated at the indol nitrogen atom
FR1175276A (fr) * 1956-05-18 1959-03-23 Sandoz Ag Nouveaux dérivés de la série de l'acide lysergique et leur préparation
CH344731A (de) * 1956-05-18 1960-02-29 Sandoz Ag Verfahren zur Herstellung von neuen, am Indolstickstoff alkylierten Derivaten der Lysergsäure-Reihe
US3228943A (en) * 1962-06-11 1966-01-11 Lumilysergol derivatives
US3232942A (en) * 1964-06-02 1966-02-01 Sandoz Ltd 1-substituted (+)-lysergol
GB1298277A (en) * 1969-04-18 1972-11-29 Sandoz Ltd Preparation of ergot peptide alkaloids
US3879554A (en) * 1970-03-20 1975-04-22 Farmaceutici Italia Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders
NL159384B (nl) * 1971-03-13 1979-02-15 Farmaceutici Italia Werkwijze voor het bereiden van een geneesmiddel met een adrenolytische activiteit, alsmede werkwijze voor het bereiden van een ester van 1-methyl-10-methoxylumilysergol.
GB1413068A (en) * 1972-06-22 1975-11-05 Farmaceutici Italia Bromoergolines

Also Published As

Publication number Publication date
JPS5436296A (en) 1979-03-16
JPS5648512B2 (enrdf_load_stackoverflow) 1981-11-16
SU784775A3 (ru) 1980-11-30
YU40004B (en) 1985-06-30
DE2860896D1 (en) 1981-11-05
CS216231B2 (en) 1982-10-29
FI782081A7 (fi) 1979-01-22
ATA490078A (de) 1980-12-15
AT363195B (de) 1981-07-10
FI64369C (fi) 1983-11-10
PT68278A (en) 1978-08-01
FI64369B (fi) 1983-07-29
YU181977A (en) 1983-01-21
US4230859A (en) 1980-10-28
EP0000533A1 (de) 1979-02-07
ES471716A1 (es) 1979-10-01

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