NO830482L - PROCEDURE FOR THE MANUFACTURE OF MELDROEYE ALKALOIDS - Google Patents

PROCEDURE FOR THE MANUFACTURE OF MELDROEYE ALKALOIDS

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Publication number
NO830482L
NO830482L NO830482A NO830482A NO830482L NO 830482 L NO830482 L NO 830482L NO 830482 A NO830482 A NO 830482A NO 830482 A NO830482 A NO 830482A NO 830482 L NO830482 L NO 830482L
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stands
compounds
hydrogen
phenyl
formula
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NO830482A
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Norwegian (no)
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Georg Bollinger
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Sandoz Ag
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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
    • C07D457/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av et i 1-stillingen med en arylgruppe substituert meldrøye-alkaloid og syreaddisjonssalter derav, The present invention relates to a method for the production of an aryl alkaloid substituted in the 1-position with an aryl group and acid addition salts thereof,

og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at et tilsvarende i 1-stillingen usubstituert meldrøyealkaloid eller en forløper for en slik for- and the distinctive feature of the method according to the invention is that a corresponding in the 1-position unsubstituted melderøye alkaloid or a precursor of such a precursor

bindelse aryleres i 1-stillingen.bond is arylated in the 1-position.

Disse og andre trekk ved oppfinnelsen fremgår av patent-kravene. These and other features of the invention appear in the patent claims.

De nevnte forbindelser omfatter 1-aryl-derivatene bådeThe compounds mentioned include the 1-aryl derivatives both

av de i naturen forekommende eller fermentativt fremstillbare såvel som også syntetisk tilgjengelige meldrøyealkaloider. of the naturally occurring or fermentatively produced as well as synthetically available alkaloids.

De kan eventuelt bære de innen meldrøyealkaloid-kjemien vanlige substituenter og videre kan de foreligge som isomerer, f.eks. som 8R og 8S-isomerer. They may possibly carry the usual substituents within the alkaloid chemistry of melderøye and furthermore they may exist as isomers, e.g. as 8R and 8S isomers.

Spesielt fremstilles forbindelser med formel IIn particular, compounds of formula I are prepared

nvori nvori

Ar står for en arylgruppe,Ar stands for an aryl group,

R og står hver for hydrogen og R2betyr hydrogen eller metoksy eller R and each stand for hydrogen and R2 means hydrogen or methoxy or

R står for hydrogen og R^ og danner sammen en enkel i-binding, eller R stands for hydrogen and R^ and together form a simple i-bond, or

R og R^danner sammen en enkel binding og L står for hydrogen eller metoksy, R and R^ together form a single bond and L stands for hydrogen or methoxy,

R^. betyr hydrogen, karboksy eller en gruppe (CH2)n-XR^. means hydrogen, carboxy or a group (CH2)n-X

hvoriin which

n står for 1 eller 2, ogn stands for 1 or 2, and

X står for hydrogen, hydroksy, cyano, karboksy ellerX stands for hydrogen, hydroxy, cyano, carboxy or

Y-R', hvori R<*>står for en alkylgruppe med 1 til 4 karbonatomer, Y-R', where R<*>stands for an alkyl group with 1 to 4 carbon atoms,

fenyl eller pyridyl ogphenyl or pyridyl and

Y betyr et svovel- eller oksygenatom eller en karbonylgruppe, og Y means a sulfur or oxygen atom or a carbonyl group, and

R^betyr en alkylgruppe med 1 til 3 karbonatomer,R^ means an alkyl group with 1 to 3 carbon atoms,

idet hvis R-, står. for (CH~) -0H, karboksy, eller (CH0) -COOH since if R-, stands. for (CH~) -OH, carboxy, or (CH0) -COOH

o /. n a no /. n a n

kan forbindelsene også fremstilles i form av en fysiologisk tålbar, hydrolyserbar ester, the compounds can also be produced in the form of a physiologically tolerable, hydrolyzable ester,

i form av de fri baser eller deres syreaddisjonssalter.in the form of the free bases or their acid addition salts.

Hvis R står for hydrogen, kan R3 fremvise alfa-eller beta-konfigurasjonen og beta-konfigurasjonen foretrekkes. If R stands for hydrogen, R 3 can exhibit the alpha or beta configuration and the beta configuration is preferred.

Som forbindelser med formel il kan f.eks. nevnes slikeAs compounds with formula 11 can e.g. such are mentioned

hvoriin which

Ar står for en arylgruppe,Ar stands for an aryl group,

R står for hydrogen,R stands for hydrogen,

R-^ og R2danner sammen en enkelt binding ellerR-^ and R 2 together form a single bond or

R-^ og R2står hver for hydrogen,R-^ and R2 each stand for hydrogen,

R^står for en rest -CP^-R^ hvoriR^ stands for a residue -CP^-R^ in which

R'^ betyr hydrogen, hydroksy, cyano, karboksy, alkoksy medR'^ means hydrogen, hydroxy, cyano, carboxy, alkoxy with

1 til 4 karbonatomer, alkoksymetyl eller alkyltiometyl med hver 2 til 5 karbonatomer, alkylkarbonyl-oksymetyl eller alkyl-karbonyl-metyl med hver 3 til 6 karbonatomer, og R^står for metyl. 1 to 4 carbon atoms, alkoxymethyl or alkylthiomethyl of each 2 to 5 carbon atoms, alkylcarbonyloxymethyl or alkylcarbonylmethyl of each 3 to 6 carbon atoms, and R 2 is methyl.

Aryiresten Ar er en eventuelt mono- eller fler-substituert 1- eller fler-kjernet, homo- eller hetero-aromatisk rest, idet som substituenter kommer på tale f.eks. halogen, hydroksy eller acyloksy, alkyl, trifluormetyl, alkoksy, aryl, nitro, alkoksykarbonyl, acylamino eller alkylamino-rester. The aryl residue Ar is an optionally mono- or poly-substituted 1- or poly-nuclear, homo- or hetero-aromatic residue, as substituents come into question e.g. halogen, hydroxy or acyloxy, alkyl, trifluoromethyl, alkoxy, aryl, nitro, alkoxycarbonyl, acylamino or alkylamino radicals.

Foretrukket står R for en eventuelt substituert fenylgruppe, spesielt for en usubstituert fenylgruppe. Fenylgruppen kan f.eks. være monosubstituert med hydroksy, alkyl eller alkoksy (med hver 1 til 4 karbonatomer) eller trifluormetyl eller kan være mono- eller di-substituert med fluor, klor eller brom. Preferably, R stands for an optionally substituted phenyl group, especially for an unsubstituted phenyl group. The phenyl group can e.g. be mono-substituted with hydroxy, alkyl or alkoxy (each having 1 to 4 carbon atoms) or trifluoromethyl or may be mono- or di-substituted with fluorine, chlorine or bromine.

R-^ og danner hensiktsmessig en enkelt binding. R-^ and conveniently forms a single bond.

Foretrukket står R^for en gruppe CH2~X. X betyr f.eks.Preferably R^ stands for a group CH2~X. X means e.g.

en hydroksy-, cyano- eller karboksy-gruppe, spesielt en hydroksygruppe. a hydroxy, cyano or carboxy group, especially a hydroxy group.

Som forbindelser med formel I, i form av fysiologisk tålbare, hydrolyserbare estere kan nevnes f.eks. forbindelser med formel I hvori R^ står for en rest As compounds with formula I, in the form of physiologically tolerable, hydrolyzable esters, e.g. compounds of formula I in which R^ represents a residue

tCH2)n-OCOR<1>tCH2)n-OCOR<1>

COOR<1>ellerCOOR<1>or

(<CH>2)n-COOR<1>, (<CH>2)n-COOR<1>,

hvori R<1>betyr alkyl med 1 til 12 karbonatomer, cykloalkyl med 3 til 7 karbonatomer eller pyridyl eller står for en eventuelt i fenylringen med alkyl med 1 til 4 karbonatomer monosubstituert eller med klor, brom eller jod mono- eller disubstituert eller med alkoksy med 1 til 4 karbonatomer monodi- eller tri substituert fenyl eller fenylalkyl rest (med 7 til 12 karbonatomer). in which R<1>means alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 7 carbon atoms or pyridyl or represents an optionally in the phenyl ring with alkyl with 1 to 4 carbon atoms monosubstituted or with chlorine, bromine or iodine mono- or disubstituted or with alkoxy with 1 to 4 carbon atoms monodi- or tri-substituted phenyl or phenylalkyl radical (with 7 to 12 carbon atoms).

R^. står foretrukket for metyl.R^. preferably stands for methyl.

Av spesiell interesse er forbindelsen i det etter-følgende eksempel 1. Of particular interest is the compound in the following example 1.

I samsvar med oppfinnelsen kommer man frem til de angjeldende forbindelser ved at et.tilsvarende, i 1-stillingen usubstituert meldrøyealkaloid eller en forløper av en slik forbindelse aryleres i 1-stillingen. Reaksjonen gjennomføres foretrukket ved omsetning med en forbindelse med formel II In accordance with the invention, the compounds in question are arrived at by arylating a corresponding, unsubstituted in the 1-position meldrøye alkaloid or a precursor of such a compound in the 1-position. The reaction is preferably carried out by reaction with a compound of formula II

hvori Ar har den ovennevnte betydning og X^står for klor, brom éller jod. Spesielt kommer man frem til forbindelsene med formel I og deres ovenfor definerte estere og salter idet forbindelser med formel III eller deres forløpere, in which Ar has the above meaning and X^ stands for chlorine, bromine or iodine. In particular, the compounds of formula I and their above-defined esters and salts are obtained as compounds of formula III or their precursors,

hvori R, R-^, R2, R^og R^har den ovennevnte betydning eller hvis R3står for (CH2)^-OH,karboksy eller (CH2)n-COOH, og også fysiologisk tålbare hydrolyserbare estere av slike forbindelser, eller deres forløpere aryleres i 1-stillingen. Reaksjonen gjennomføres foretrukket ved omsetning med forbindelser med formel II. in which R, R-^, R2, R^ and R^ have the above meaning or if R3 stands for (CH2)^-OH, carboxy or (CH2)n-COOH, and also physiologically tolerable hydrolyzable esters of such compounds, or their precursors are arylated in the 1-position. The reaction is preferably carried out by reaction with compounds of formula II.

Fremgangsmåten kan gjennomføres på i og for seg kjent måte under betingelsene for en Ullmann-reaksjon. The procedure can be carried out in a manner known per se under the conditions for an Ullmann reaction.

Som katalysator anvendes foretrukket kobberpulver.Copper powder is preferably used as a catalyst.

Reaksjonen kan enten gjennomføres uten løsningsmiddelThe reaction can either be carried out without a solvent

eller det anvendes f.eks.pyridin, kinolin, toluen, nitrobenzen, dimetylsulfoksyd eller dimetylformamid. or pyridine, quinoline, toluene, nitrobenzene, dimethylsulfoxide or dimethylformamide are used, for example.

Med anvendelse av ikke-syre-r-bindende løsningsmidler kan f.eks. kaliumkarbonat tilsettes. With the use of non-acid-binding solvents, e.g. potassium carbonate is added.

Reaksjonstemperaturen ligger vanligvis mellom 80 ogThe reaction temperature is usually between 80 and

200°C. 200°C.

Reaksjonen gjennomføres foretrukket under inert-gassThe reaction is preferably carried out under inert gas

som nitrogen eller argon.such as nitrogen or argon.

Utgangsforblndelsene med formel III såvel som de hydrolyserbare estere av forbindelser med formel III hvori R3står for (CH2)n-OH, karboksy eller (Cr^^-COOH, kan The starting compounds of formula III as well as the hydrolyzable esters of compounds of formula III in which R3 stands for (CH2)n-OH, carboxy or (Cr^^-COOH, can

også anvendes i form av en forløper, dvs. i form av en forbindelse som på i og for seg kjent måte kan overføres i utgangsforbindelsen. Etter omsetningen med forbindelsen med formel II kan det erholdte produkt ved hjelp av i og for seg kjente metoder overføres i en forbindelse med formel I. is also used in the form of a precursor, i.e. in the form of a compound which can be transferred into the starting compound in a manner known per se. After the reaction with the compound of formula II, the product obtained can be transferred into a compound of formula I by means of methods known per se.

De fri baser kan omdannes i syreaddisjonssalter og omvendt. For saltdannelsen egnede syrer er f.eks. saltsyre, svovelsyre, maleinsyre, fumarsyre og vinsyre. The free bases can be converted into acid addition salts and vice versa. Acids suitable for salt formation are e.g. hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid.

Utgangsforbindelsene med formel II og III er kjente, eller kan fremstilles ved hjelp av i og for seg kjente metoder. The starting compounds of formulas II and III are known, or can be prepared using methods known per se.

Forbindelsene med formel I og deres syreaddisjonssalter er tidligere ikke beskrevet i litteraturen. De fremviser ved dyreforsøk interessante farmakologiske egenskaper og kan følgelig anvendes som medikamenter. The compounds of formula I and their acid addition salts have not previously been described in the literature. They show interesting pharmacological properties in animal experiments and can therefore be used as drugs.

I IN

Spesielt påvirker disse substanser metabolismen av biogene aminer som Serotonin, Dopamin og Noradrenalin, i for-skjellige områder av rotte-hjerner. In particular, these substances affect the metabolism of biogenic amines such as Serotonin, Dopamine and Noradrenaline, in different areas of rat brains.

Både' i Cortex som i Hippocampus forårsaker de nye forbindelser ved 10 mg/kg s.c. en nedsettelse av 5-hydroksy indoleddiksyreinnholdet (5-HIAA). Both in the Cortex and in the Hippocampus they cause new connections at 10 mg/kg s.c. a reduction in the 5-hydroxy indole acetic acid (5-HIAA) content.

I Striatum bevirker de ved 50 mg/kg s.c. en forhøyelse avIn the striatum, they cause at 50 mg/kg s.c. an elevation of

de to Dopamin-metabolitter 3,4-dihydroksyfenyleddiksyrethe two Dopamine metabolites 3,4-dihydroxyphenylacetic acid

og homovanillinsyre (DOPAC og HVA).and homovanillic acid (DOPAC and HVA).

I Hypothalamus og i Pons-Medulla-regionen forhøyesIn the Hypothalamus and in the Pons-Medulla region is elevated

sterkt Noradrenalin-metabolitten 4-hydroksy-3-metoksy-fenyl-etylenglykol (MHPG-S04) ved 5 0 mg/kg s.c. strongly The norepinephrine metabolite 4-hydroxy-3-methoxy-phenyl-ethylene glycol (MHPG-SO4) at 5 0 mg/kg s.c.

For den kvantitative bestemmelse av de ovennevnte biokjemiske parametere, se F. Karoum et al, Europ. J. Pharmacol. 44, 311 - 318 (1977); For the quantitative determination of the above biochemical parameters, see F. Karoum et al, Europ. J. Pharmacol. 44, 311-318 (1977);

B.H.C. Westrink et al., Europ. J. Pharmacol. 42, 179 - 190 B.H.C. Westrink et al., Europ. J. Pharmacol. 42, 179 - 190

(1977) og H.R. BUrki et al, Psycopharmacology 57, 227 - 237 (1977) and H.R. Burki et al, Psychopharmacology 57, 227-237

(1978) . (1978).

Videre bevirker de nye substanser ved søvn/våkesyklusenFurthermore, they affect new substances during the sleep/wake cycle

i katter ved 3-10 mg/kg p.o. en reduksjon av varigheten av den paradoksale søvn uten påvirkning av den klassiske søvn eller en forlengelse av våkentilstanden. in cats at 3-10 mg/kg p.o. a reduction of the duration of the paradoxical sleep without affecting the classical sleep or an extension of the waking state.

Videre forårsaker de nye substanser ved Ungerstedt-rotter (metode etter U. Ungerstedt, Acta physiol. scand. Suppl. 387, 69 - 93 (1971)) dreininger kontralateralt til de nigrostriatalt satte lesjoner, med doser på 1 til 3 mg/ kg i.p. Furthermore, the new substances in Ungerstedt rats (method according to U. Ungerstedt, Acta physiol. scand. Suppl. 387, 69 - 93 (1971)) cause turns contralateral to the nigrostriatal lesions, with doses of 1 to 3 mg/kg i.p.

I de ovennevnte forsøk har 83-hydroksymetyl-6-metyl-l-fenyl-9,10-didehydro-ergolin utmerket seg ved en spesielt interessant virkningsprofil. I søvn/våkensyklus i katter, reduserte f.eks. denne forbindelse etter 3 mg/kg p.o. varigheten av den paradoksale søvn med omtrent 30%. På' grunn av de biokjemiske in vivo undersøkelser i rotter, over Serotonin- og Noradrenalin-stoffski ftet og resultatene ved Ungerstedt-modellen kan de nye substanser finne anvendelse som anti-depressiva fremfor alt ved eldre mennesker. In the above-mentioned experiments, 83-hydroxymethyl-6-methyl-1-phenyl-9,10-didehydro-ergoline has distinguished itself by a particularly interesting action profile. In the sleep/wake cycle in cats, reduced e.g. this compound after 3 mg/kg p.o. the duration of the paradoxical sleep by about 30%. Because of the biochemical in vivo investigations in rats, on Serotonin and Noradrenaline metabolism and the results of the Ungerstedt model, the new substances can find use as anti-depressants above all in older people.

På grunn av de biokjemiske in vivo undersøkelser i rotter over Serotonin-, Dopamin- og Noradrenalin-stoffskiftet og resultatene ved Ungerstedtmodellen og ved søvn-våken-syklusen i katter, er de nye substanser egnet for behandling av senil demens, spesielt i tidlig stadium. Due to the biochemical in vivo investigations in rats on Serotonin, Dopamine and Noradrenaline metabolism and the results of the Ungerstedt model and of the sleep-wake cycle in cats, the new substances are suitable for the treatment of senile dementia, especially in the early stages.

På grunn av resultatene ved søvn-våkensyklusen i katterDue to the results of the sleep-wake cycle in cats

kan substansene også finne anvendelse for vigilansforhøyelse. the substances can also be used to increase vigilance.

På grunn av de biokjemiske in, vivo undersøkelser i rotter over Dopamin-stoffskiftet er forbindelsene utover dette egnet for neuroleptika. Due to the biochemical in vivo studies in rats on Dopamine metabolism, the compounds are furthermore suitable for neuroleptics.

De nye forbindelser kan overføres i preparatform og for deres fremstilling kan de innenfor farmasien vanlige hjelpe- og bærerstoffer anvendes. The new compounds can be transferred in the form of preparations and for their preparation the auxiliary and carrier substances common in pharmacy can be used.

I de etterfølgende eksempler som skal illustrere oppfinnelsen, er alle temperaturangivelser i °C og er ukorri-gert . In the following examples to illustrate the invention, all temperature indications are in °C and are uncorrected.

EKSEMPEL 1: 8B- hydroksymetyl- 6- metyl- l- fenyl- 9, 10-didehydro- ergolin ( 1- fenyl- lyserqol) EXAMPLE 1: 8B-hydroxymethyl-6-methyl-1-phenyl-9,10-didehydro-ergoline (1-phenyl-lyserqol)

5,7 g kobberpulver og 3,3 g kaliumkarbonat anordnes i en sulfideringskolbe og tilsettes så med en løsning av 5,1 g lysergol i 60 ml dimetylformamid og 4,5 ml jodbenzen. 5.7 g of copper powder and 3.3 g of potassium carbonate are placed in a sulphiding flask and then added with a solution of 5.1 g of lysergol in 60 ml of dimethylformamide and 4.5 ml of iodobenzene.

Den kobberbrune suspensjon omrøres i 5 timer ved 170°C under nitrogen. Etter avkjøling fortynnes den brune blanding med metylenklorid og filtreres over "Hyflo". Filtratet ekstraheres 3 ganger med 2N-sodaløsning. De forente organiske faser vaskes med vann, behandles med aktiv kull, tørkes over natriumsulfat og inndampes. The copper-brown suspension is stirred for 5 hours at 170°C under nitrogen. After cooling, the brown mixture is diluted with methylene chloride and filtered over "Hyflo". The filtrate is extracted 3 times with 2N soda solution. The combined organic phases are washed with water, treated with activated carbon, dried over sodium sulfate and evaporated.

Man erholder 5,5 g råprodukt som krystalliseres fra eter/ petroleter. Etter 2 gangers omkrystallisering fra metylenklorid/heksan erholdes hvite krystaller med smp: 133-136°C; £"a_7<20>= + 19 ,1° (c = 0, 74 i kloroform) 5.5 g of crude product is obtained which is crystallized from ether/petroleum ether. After 2 times recrystallization from methylene chloride/hexane, white crystals are obtained with mp: 133-136°C; £"a_7<20>= + 19.1° (c = 0.74 in chloroform)

D D

Hydrogenmaleinat: Smp.: 199 - 201°C (spaltning); Hydrogen maleate: mp: 199 - 201°C (decomposition);

/~ a_ 7<20>= +88,0° (c = 0,7 i dimetyl-/~ a_ 7<20>= +88.0° (c = 0.7 in dimethyl-

D D

formamid) .formamide).

De følgende forbindelser fremstilles analogt med den i eksempel 1 beskrevne metode. The following compounds are prepared analogously to the method described in example 1.

EKSEMPEL 2: 8B- hvdroksvmetyl- 6- metyl- l- fenyl- erqolin ( l- fenyl- 9, 10- dihydrolyserqol) EXAMPLE 2: 8B-hydroxymethyl-6-methyl-1-phenyl-erqoline (1-phenyl-9, 10-dihydrolyserqol)

20 20

Smp.: 200 - 202°C ; /~a_7 = -93,5° (c = 0,73 i kloroform) Melting point: 200 - 202°C; /~a_7 = -93.5° (c = 0.73 in chloroform)

D D

EKSEMPEL 3: 8B- cyanometyl- 6- metyl- l- fenyl- 9, 10- didehydro-erqolin EXAMPLE 3: 8B- cyanomethyl- 6- methyl- 1- phenyl- 9, 10- didehydro-erqoline

20 20

Smp.: 164 - 167°C ; J = +41,7° (c =0,63 i kloroform)Melting point: 164 - 167°C; J = +41.7° (c =0.63 in chloroform)

D D

EKSEMPEL 4: 1- fenyl- 6- metyl- 9, 10- didehydro- erqolin-8B- eddiksyre ( 1- fenyl- homo- lyserqsyre) EXAMPLE 4: 1-phenyl-6-methyl-9, 10-didehydro-erqolin-8B-acetic acid (1-phenyl-homolyserq acid)

Smp: 270°C (spaltning).Mp: 270°C (decomposition).

EKSEMPEL 5:8- hydroksymetyl- 6- metyl- l- fenyl- 8, 9- didehydro-erqolin ( 1- fenyl- elymoclavin) EXAMPLE 5: 8- hydroxymethyl- 6- methyl- 1- phenyl- 8, 9- didehydro-erqoline ( 1- phenyl- elymoclavine)

20 20

Smp: 140 - 143°C; /"a J = -118,0 (c = 0,58 i kloroform)Mp: 140 - 143°C; /"a J = -118.0 (c = 0.58 in chloroform)

D D

EKSEMPEL 6: 9, 10- didehydro- 8B- hydroksymetyl- 6- metyl- l-( 4- klorfenyl)- erqolin EXAMPLE 6: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(4-chlorophenyl)-erqoline

Smp: 201 - 202°C (spaltning); /~ct_7<20>= + 12,8° (c = 0,5 i Mp: 201 - 202°C (decomposition); /~ct_7<20>= + 12.8° (c = 0.5 in

kloroform). Dchloroform). D

I IN

EKSEMPEL 7: 9, 10- didehvdro- 88- hvdroksvmetyl- 6- metvl- l-( 3, 4- diklorfenyl)- ergolin EXAMPLE 7: 9,10-didehydro-88-hydroxymethyl-6-methyl-1-(3,4-dichlorophenyl)-ergoline

Smp: 107°C (spaltning) ;£~aJ<20>=-10,3° (c=0,5i Mp: 107°C (decomposition) ;£~aJ<20>=-10.3° (c=0.5i

dimetylformamid) Ddimethylformamide) D

EKSEMPEL 8: 9, 10- didehvdro- 8B- hydroksymetvl- 6- metyl- l-( 4- metoksyfenyl)- ergolin EXAMPLE 8: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(4-methoxyphenyl)-ergoline

Smp: 160 - 161°C (spaltning); /~ a_ J<20>= +41,5°. (c = 0,7 Mp: 160 - 161°C (decomposition); /~ a_ J<20>= +41.5°. (c = 0.7

i kloroform) Din chloroform) D

EKSEMPEL 9: 9, 10- didehvdro- 8B- hvdroksymetvl- 6- metvl- l-( 4- fluorofenvl) - ergolin EXAMPLE 9: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(4-fluorophenyl)-ergoline

20 20

Smp: 200 - 201°o C (spaltning): / _ a_7 = -5,5° (c = 0,5 i Mp: 200 - 201°o C (decomposition): / _ a_7 = -5.5° (c = 0.5 in

dimetylformamid) Ddimethylformamide) D

EKSEMPEL 10: 9, 10- didehvdro- 88- hvdroksvmetvl- 6- metvl- l-( 2- metoksyfenyl) - ergolin EXAMPLE 10: 9,10-didehydro-88-hydroxymethyl-6-methyl-1-(2-methoxyphenyl)-ergoline

Smp: 155 - 157°C (spaltning):<20>=+18,2° (cMp: 155 - 157°C (decomposition):<20>=+18.2° (c

D D

0,5 i dimetylformamid)0.5 in dimethylformamide)

EKSEMPEL 11: 9, lO- didehvdro- 8B- hydroksvmetvl- 6- metvl- l-( 2- fluorofenyl) ergolin EXAMPLE 11: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(2-fluorophenyl)ergoline

Smp: 141 - 144°C (spaltning): /~a J<20>= +13° (c =0,5Mp: 141 - 144°C (decomposition): /~a J<20>= +13° (c =0.5

i dimetylformamid) Din dimethylformamide) D

EKSEMPEL 12: 9, 10- didehydro- 8B- hydroksymetyl- 6- metyl- l-( 4- metvlfenvl) ergolin) EXAMPLE 12: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(4-methylphenyl)ergoline)

Smp: 202 - 203°C (spaltning) ; Z~ <x_ 7<2>° = -1,2° (c=Mp: 202 - 203°C (decomposition); Z~ <x_ 7<2>° = -1.2° (c=

• 0,5 i dimetylformamid) D• 0.5 in dimethylformamide) D

EKSEMPEL 13: 9, 10- didehydro- 8B- hydroksymetyl- 6- metyl- l-( 4- trifluormetylfenyl) - ergolin' EXAMPLE 13: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(4-trifluoromethylphenyl)-ergoline'

Smp: 151 - 152°C (spaltning); /"a_</><20>= -7,3° (c = 0,5Mp: 151 - 152°C (decomposition); /"a_</><20>= -7.3° (c = 0.5

i dimetylformamid) Din dimethylformamide) D

EKSEMPEL 14: 9, 10- didehydro- 8B- hydroksymetyl- 6- metyl- l-_ EXAMPLE 14: 9, 10- didehydro- 8B- hydroxymethyl- 6- methyl- l-_

( 3- klorfenyl) ergolin(3-chlorophenyl)ergoline

20 20

Smp: 170 - 172°C; Z~ct J = -6,0° (c = 0,45 i dimetylformamid) M.p.: 170 - 172°C; Z~ct J = -6.0° (c = 0.45 in dimethylformamide)

D D

EKSEMPEL 15: 9, 10- didehydro- 8B- hydroksymetyl- 6- metyl- l-( 3- metoksyfenyl) ergolin EXAMPLE 15: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(3-methoxyphenyl)ergoline

Smp: 160 - 16 2°C ; C^- J<20>= 2,8° (c = 0,5 i dimetylf ormamid) Melting point: 160 - 162°C; C^- J<20>= 2.8° (c = 0.5 in dimethylformamide)

D D

EKSEMPEL 16: 8B- acetoksymetyl- 9, 10- didehydro- 6- metyl- l-fenyl- ergolin- hydrogenfumarat EXAMPLE 16: 8B- acetoxymethyl- 9, 10- didehydro- 6- methyl- l-phenyl- ergoline- hydrogen fumarate

i- - 20 Qi- - 20 Q

Smp: 190 - 194UC (spaltning); [_ aj = +9,0U (c = 0,5Mp: 190 - 194UC (decomposition); [_ aj = +9.0U (c = 0.5

i dimetylformamid) Din dimethylformamide) D

EKSEMPEL 17: 9, 10- didehydro- 6- metyl- 8B- nikotinoyloksymetyl-1- fenyl- ergolin EXAMPLE 17: 9, 10- didehydro- 6- methyl- 8B- nicotinoyloxymethyl-1- phenyl- ergoline

Smp: 135 - 138°C (spaltning); Z"V_7<2>° = +20,0° (c = 0,5Mp: 135 - 138°C (decomposition); Z"V_7<2>° = +20.0° (c = 0.5

i dimetylformamid) Din dimethylformamide) D

E KSEMPEL 18: 9, 10- didehvdro- 6- metyl- l- fenyl- 8B- trimetyl-acetoksymetyl- ergolin EXAMPLE 18: 9, 10- didehydro- 6- methyl- 1- phenyl- 8B- trimethyl- acetoxymethyl- ergoline

Smp: 130 - 133°C : £~ aJ<20>= +14,0° (c = 0,7 i dimetylformamid) Mp: 130 - 133°C : £~ aJ<20>= +14.0° (c = 0.7 in dimethylformamide)

D D

EKSEMPEL 19: 9, 10- didehydro- 6- 8B- dimetyl- l- fenyl- ergolin-hydroklorid EXAMPLE 19: 9,10-didehydro-6-8B-dimethyl-1-phenyl-ergoline hydrochloride

Smp: 282 - 285°C (spaltning): /f~a J<20>= +109° (c = 0,5Mp: 282 - 285°C (decomposition): /f~a J<20>= +109° (c = 0.5

. i dimetylformamid). D. in dimethylformamide). D

EKSEMPEL 20: 9, 10- didehydro- 8B- hydroksymetyl- 6- propyl-1- fenyl- ergolin- hydroklorid EXAMPLE 20: 9, 10- didehydro- 8B- hydroxymethyl- 6- propyl-1- phenyl- ergoline hydrochloride

Smp: 270 - 273°C (spaltning); /~ a_ f<20>= + 68° (c = 0,1Mp: 270 - 273°C (decomposition); /~ a_ f<20>= + 68° (c = 0.1

i dimetylformamid) ^in dimethylformamide) ^

EKSEMPEL 21: 9, 10- dihydro- l- fenyl- lysergsyre- metylester EXAMPLE 21: 9, 10-dihydro-l-phenyl-lysergic acid methyl ester

Smp: 155 - 157°C : _f~ct J<20>= -91,8° (c = 0,55 i kloroform) Mp: 155 - 157°C : _f~ct J<20>= -91.8° (c = 0.55 in chloroform)

D D

EKSEMPEL 22: 1- fenyl- 6- metyl- ergolinEXAMPLE 22: 1-phenyl-6-methyl-ergoline

Smp: 242 - 243°C; faj<2>°= -46,8° (c = 0,77 i dimetylformamid) D Mp: 242 - 243°C; faj<2>°= -46.8° (c = 0.77 in dimethylformamide) D

EKSEMPEL 23: 9, 10- didehydro- 6- metyl- l- fenyl- 86- 2- pyridvl-tiometyl- ergolin EXAMPLE 23: 9,10-didehydro-6-methyl-1-phenyl-86-2-pyridyl-thiomethyl-ergoline

Smp: 107 - 109°C ; _f~c_7<20>= -20,0° (c = 0,4 i kloroform)Mp: 107 - 109°C; _f~c_7<20>= -20.0° (c = 0.4 in chloroform)

D D

EKSEMPEL 24: 9, 10- didehydro- 8B- hydroksymetyl- 6- metyl- l-( 3- hydroksyfenyl) ergolin EXAMPLE 24: 9,10-didehydro-8B-hydroxymethyl-6-methyl-1-(3-hydroxyphenyl)ergoline

Smp: 201 - 203°C (spaltning); /~a_7<20>= +1,0° ( c = 0,5Mp: 201 - 203°C (decomposition); /~a_7<20>= +1.0° ( c = 0.5

i dimetylformamid) Din dimethylformamide) D

EKSEMPEL 25: 9, 10- didehydro- 8g- hydroksymetv1- 6- metyl-1-( 4- hydroksyfenyl) ergolin EXAMPLE 25: 9, 10- didehydro- 8g- hydroxymethyl- 6- methyl-1-(4- hydroxyphenyl) ergoline

20 20

Smp: 186 - 190°C (spaltning); _Ta_7 = +5,0° (c = 0,55 i Mp: 186 - 190°C (decomposition); _Ta_7 = +5.0° (c = 0.55 in

dimetylformamid) Ddimethylformamide) D

EKSEMPEL 26: 8a- cyanonrety1- 6- mety1- 1- fenyl- ergolinEXAMPLE 26: 8a-cyanonerety1-6-methyl1-1-phenyl-ergoline

Smp: 147 - 149°C; /~ a_/<20>= -99,0° (c = 0,94 i kloroform) Mp: 147 - 149°C; /~ a_/<20>= -99.0° (c = 0.94 in chloroform)

D D

i in

Claims (4)

1. Fremgangsmåte for fremstilling av et i 1-stillingen ved en arylgruppe substituert meldrøyealkaloid og dets syreaddisj onssalter, karakterisert ved at et tilsvarende i 1-stillingen usubstituert meldrøyealkaloid eller en forløper av en slik forbindelse aryleres i 1-stillingen.1. Process for the preparation of a sorghum alkaloid substituted in the 1-position by an aryl group and its acid addition salts, characterized in that a corresponding in the 1-position unsubstituted meldrøye alkaloid or a precursor of such a compound is arylated in the 1-position. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at reaksjonen gjennom-føres ved omsetning med en forbindelse med formel II 2. Method as stated in claim 1, characterized in that the reaction is carried out by reaction with a compound of formula II hvori Ar står for en arylgruppe og X1 står for klor, brom eller jod.in which Ar represents an aryl group and X1 represents chlorine, bromine or iodine. 3. Fremgangsmåte som angitt i krav 1, for fremstilling av forbindelser med formel I 3. Method as stated in claim 1, for the preparation of compounds of formula I hvori Ar står for en arylgruppe, R og R-^ står hver for hydrogen og R2 betyr hydrogen eller metoksy eller R står for hydrogen og R^ og R2 danner sammen en enkelt bl inding eller, R og R-^ danner sammen en enkelt binding og R2 står for hydrogen eller metoksy, R-, betyr hydrogen, karboksy eller en gruppe (CF^ ) -X hvori n står for 1 eller 2 og X betyr hydrogen, hydroksy, cyano, karboksy eller Y-R <*> hvori R' står for en alkylgruppe med 1 til 4 karbonatomer, fenyl eller pyridyl og Y betyr et svovel- eller oksygenatom eller en karbonylgruppe, og R^ betyr en alkylgruppe med 1 til 3 karbonatomer, idet hvis R-, står for (CH0) -0H, karboksy eller (CH0) -COOH 3 2' n 1 2 n forbindelsen også kan foreligge i form av en fysiologisk tålbar, hydrolyserbar ester, samt forbindelsenes ester og salter, karakterisert ved at forbindelser med formel III eller deres forløpere in which Ar stands for an aryl group, R and R-^ each stand for hydrogen and R 2 means hydrogen or methoxy or R stands for hydrogen and R^ and R2 together form a single bond or, R and R-^ together form a single bond and R2 stands for hydrogen or methoxy, R-, means hydrogen, carboxy or a group (CF^ ) -X in which n stands for 1 or 2 and X means hydrogen, hydroxy, cyano, carboxy or Y-R <*> in which R' stands for an alkyl group with 1 to 4 carbon atoms, phenyl or pyridyl and Y means a sulfur or oxygen atom or a carbonyl group, and R^ means an alkyl group with 1 to 3 carbon atoms, whereas if R-, stands for (CH0) -OH, carboxy or (CH0) -COOH 3 2' n 1 2 n the compound can also exist in the form of a physiologically tolerable, hydrolyzable ester, as well as the compounds' esters and salts, characterized in that compounds with formula III or their precursors hvori R, R^ , R2 , R^ og R 4 har den ovennevnte betydning, eller hvis R^ står for (CH2 )n -OH, karboksy eller (CH2 )n -COOH, også fysiologisk tålbare hydrolyserbare estere av. slike forbindelser, eller deres forløpere i 1-stillingen aryleres:in which R, R^ , R2 , R^ and R 4 have the above meaning, or if R^ stands for (CH2 )n -OH, carboxy or (CH2 )n -COOH, also physiologically tolerable hydrolyzable esters of. such compounds, or their precursors in the 1-position, are arylated: 4. Fremgangsmåte som angitt i krav 3, karakterisert ved at reaksjonen gjennom-føres ved omsetning med forbindelser med formel II Ar-Xx II hvori Ar og X-^ har den ovennevnte betydning.4. Method as stated in claim 3, characterized in that the reaction is carried out by reaction with compounds of formula II Ar-Xx II wherein Ar and X-^ have the above meaning.
NO830482A 1982-02-17 1983-02-14 PROCEDURE FOR THE MANUFACTURE OF MELDROEYE ALKALOIDS NO830482L (en)

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FI830462A7 (en) 1983-08-18
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