DK144160B - Analogifremgangsmaade til fremstilling af 8-thiomethylergoliner - Google Patents
Analogifremgangsmaade til fremstilling af 8-thiomethylergoliner Download PDFInfo
- Publication number
- DK144160B DK144160B DK249975AA DK249975A DK144160B DK 144160 B DK144160 B DK 144160B DK 249975A A DK249975A A DK 249975AA DK 249975 A DK249975 A DK 249975A DK 144160 B DK144160 B DK 144160B
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- DK
- Denmark
- Prior art keywords
- methyl
- compound
- compounds
- prolactin
- acid
- Prior art date
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- OWEUDBYTKOYTAD-MKTPKCENSA-N ergocristine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@@H]1C=C2C3=CC=CC4=NC=C([C]34)C[C@H]2N(C)C1)C(C)C)C1=CC=CC=C1 OWEUDBYTKOYTAD-MKTPKCENSA-N 0.000 description 1
- HEFIYUQVAZFDEE-UHFFFAOYSA-N ergocristinine Natural products N12C(=O)C(C(C)C)(NC(=O)C3C=C4C=5C=CC=C6NC=C(C=56)CC4N(C)C3)OC2(O)C2CCCN2C(=O)C1CC1=CC=CC=C1 HEFIYUQVAZFDEE-UHFFFAOYSA-N 0.000 description 1
- 229960001405 ergometrine Drugs 0.000 description 1
- NESVMZOPWPCFAU-ZPRCMDFASA-N ergosine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C)C2)=C3C2=CNC3=C1 NESVMZOPWPCFAU-ZPRCMDFASA-N 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000000960 hypophysis hormone Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- LRPCLTPZMUIPFK-UHFFFAOYSA-N methane;sulfuric acid Chemical compound C.OS(O)(=O)=O LRPCLTPZMUIPFK-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- HNDXKIMMSFCCFW-UHFFFAOYSA-N propane-2-sulphonic acid Chemical compound CC(C)S(O)(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- PVEFEIWVJKUCLJ-UHFFFAOYSA-N sulfuric acid;toluene Chemical compound OS(O)(=O)=O.CC1=CC=CC=C1 PVEFEIWVJKUCLJ-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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)
Description
09) DANMARK
(¾
|j| 02) FREMLÆGGELSESSKRIFT od 11+4160 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 2499/75 (51) IntCI* C 07 D A57/02 (22) Indleveringsdag 4. Jun. 1975 (24) Løbedag 4. jun. 1975 (41) Aim. tilgængelig 7* dec. 1975 (44) Fremlagt 28. dec. 1981 (86) International ansøgning nr. - (86) International indleveringsdag (85) Videreførelsesdag - (62) Stamansøgning nr. -
(30) Prioritet 6. jun. 1974, 477156, US
(71) Ansøger ELI LILLY AND COMPANY, Indianapolis, US.
(72) Opfinder Edmund Carl Kornf eld, US: Nicholas James Bach, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Bout ard.
(54) Analogifremgangsmåde til fretsstilling af 8-thiomethylergollner.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 8-thiomethylergoliner med den i kravets indledning anførte almene formel II eller farmaceutisk acceptable syreadditions- 0 salte heraf, og fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte. De omhandlede forbinet delser er nyttige som prolactininhibitorer.
±
d" Forbindelser baseret på ergolinringsystemet med formel I
t 2 144160 fe 7)
XV ^L° eJ'MH
1^18 N/
| il 11 S|N
^JLj ' T (i) H-N--3 har en overraskende varierende mængde farmaceutiske virkningsretninger. Lyserg- og isolysergsyre er f.eks. 8-carboxy-6-methyl-Å9-ergoliner (9,10-didehydroergoliner). Amider af lysergsyre, hvoraf mange har værdifulde og enestående farmakologiske egenskaber, omfatter naturligt forekommende oxytocin-alkaloider - ergocornin, ergokryptin, ergonovin, ergocristin, ergosin, ergotamin etc. - og syntetiske oxytociner, såsom methergin samt det syntetiske hallucinogen lysergsyrediethylamid eller LSD. Amider af 6-methyl-8-carboxyergolin, generisk kendt som dihydroergotalkaloider, er oxytociner med lavere styrke og også med lavere toxicitet end selve ergotalkaloiderne. Ergotamin, en A^-ergolin, har været anvendt ved behandling af migræne, og for nylig har både ergocornin og 2-brom-α-ergocryptin vist sig at være inhibitorer for prolactin og for dimethylbenzanthracen (DMBA)-inducerede svulster hos rotter, ifølge Nagasawa og Meites, Proc. Soc. Exp’tl. Biol. Med. 135, 469 (1970) og Heuson et al., Europ. J. Cancer, 353, (1970). (se også USA-patenterne nr. 3 752 888 og 3 752 814).
D-6-methyl-8-cyanomethylergolin fremstilledes først af Semonsky et al., Coll. Czech. Chem. Commun., 33, 577 (1968), og dets anvendelse til at forhindre graviditet hos rotter blev publiceret af den samme gruppe forskere i Nature, 221, 666 (1969). (Se også USA-patent nr. 3 732 231). Forbindelsen mentes at interferere med udskillelsen af leuteotropisk hypofyse-hormon og hypofyse-gonadotro-pinerne. Det blev også foreslået, at forbindelsen hindrede udskillelse af prolactin. [Se Seda et al., Reprod. Fert. 24, 163 (1971) og Mantle and Finn, id. 441)]. Semonsky et al.,· Coll. Czech. Chem.
Comm., 36, 220 (1971), har beskrevet fremstillingen af D-6-methyl- 8-ergolinylacetamid, en forbindelse, som angives at have antifer-tilitetsvirkning og antilacterende virkning på rotter. Virkningen af disse forbindelser i forbindelse med neoplastiske sygdomme er 3 144160 ukendt.
Fra dansk fremlæggelsesskrift nr. 140 986 kendes 8-substituerede D-2-halogen-6-methylergoliner eller salte heraf, hvori 8-substitu-enten er CH2CN eller CH2C(=0)NH2. Disse forbindelser er prolactin-inhibitorer, men har i forhold til de her omhandlede forbindelser den ulempe, at de kan være hepatotoxiske over for mennesker (se Amer.
J. Med. Sci. 278, 65-76 (1979)). Dette har i det mindste vist sig at være tilfældet for den forbindelse, hvori 8-substituenten er CH2-CN, og toxiciteten skyldes muligvis eyanogruppen. De her omhandlede forbindelser indeholder ikke nogen cyanogruppe i 8-stillingen.
I den ovennævnte formel II betyder alk alkyigrupper med 1-3 carbon-atomer omfattende følgende grupper: methyl, ethyl, n-propyl og iso- Q ΤΛ propyl. Når A ’ -bindingen i formel II er mættet, benævnes forbindelserne som D-6-methyl-8-thiomethyl- (eller mercaptomethyl)-ergoliner. Når 4.^»10-bindingen er umættet, er de fremkomne forbindelser generisk benævnt som D-6-methyl-8.thiomethyl- eller merc^pfeo-methyl-9,10-didehydroergoliner. Illustrative forbindelser, der fås ved fremgangsmåden ifølge den foreliggende opfindelse, er: D-2-chlor-6-methyl-8-propionylthiomethylérgolin D-2-ehlor-6-methyl-8-butyrylthiomethyl-9,1O-didehydroergolin D-2-chlor-6-methyl-8-phenylmeroaptomethyl-9,1O-didehydroergolin D-2-brom-6-methyl-8-phenylmercaptomethy1-9,1O-didehydroergolin D-2-chlor-6-methyl-8-ethylmercaptomethyl-9,1O-didehydroergolin D-6-methyl-8-n-propylmercaptomethylergolin D-6-methyl-8-isopropylmercaptomethylergolin,
Forbindelserne fremstilles ifølge opfindelsen via nucleophil substitution ved at omsætte en af nedennævnte estere af en D-6-methyl- 8-hydroxymethylergolin eller -9,10-didehydroergolin, eventuelt substitueret ved carbonatom 2 med chlor eller brom, med salte af thiophenol, en thioalkancarboxylsyre (alk-COSH) eller en alkyl-thiol (alk-SH). Esterne, der anvendes som udgangsmaterialer ved ovennævnte syntese er mesyl-(methansulfonyl) og p-toluen-sulfonyl-(p-tosyl) estere dannet med hydroxygruppen i 8-hydroxy-methyl-6-methylergolin, 8-hydroxymethyl-6-roethyl-9,lO-didehydro- 4 144160 ergolin eller af et 2-halogenderivat af begge disse forbindelser med formel III. Disse mesyloxy- og p-tosyloxyderivater er enten kendte forbindelser eller kan fremstilles ud fra tilsvarende hydroxy-derivater ved kendte metoder. Yed udførelse af reaktioner med thiophenol eller med en alkylthiol dannes natriumsaltet af mercap-tangruppen sædvanligvis, idet der anvendes natriummethylat eller natriumhydroxid. Den nucleophile substitutionsreaktion udføres i et inert opløsningsmiddel, såsom dimethylformamid eller dimethyl-sulfoxid. Sædvanligvis udføres reaktionen ved stuetemperatur, eller om ønsket opvarmes til en temperatur på op til 100°C. Produkterne fra reaktionen isoleres sædvanligvis ved standard-teknik og oprenses ved kromatografi, fortrinsvis over florisil.
Forbindelserne fremstillet ifølge opfindelsen er hvide, krystallinske, faste stoffer og danner farmaceutisk acceptable salte med ikke-toxiske syrer. Ikke-toxiske syrer, der er anvendelige ved dannelsen af disse salte, omfatter sådanne uorganiske syrer som saltsyre, salpetersyre, phosphorsyre, svovlsyre, hydrogen-bromidsyre, hydrogeniodidsyre, salpetersyrling og phosphorsyrling .samt ikke-toxiske organiske syrer omfattende alifatiske mono- og dicarboxylsyrer, phenylsubstituerede alkancarboxylsyrer, hydroxy-alkan- og alkandicarboxylsyre, aromatiske syrer og alifatiske og aromatiske sulfonsyrer. Sådanne farmaceutisk acceptable salte omfatter således sulfat, pyrosulfat, bisulfat, sulfit, bisulfit, nitrat, phosphat, monohydrogenphosphat, dihydrogenphosphat, meta-phosphat, pyrophosphat, chlorid, bromid, iodid, fluorid, acetat, pr.opionat, deeanoat, caprylat, acrylat, formiat, isobutyrat, caprat, heptanoat, propionat, oxalat, malonat, succinat, suberat, sebacat, fumarat,*maleat, butyn-l,4-dioat, hexyn-l,6-dioat, benzoat, chlorbenzoat, methylbenzoat, dinitrobenzoat, hydroxybenzoat, methoxybenzoat, phthalat, terephthalat, benzensulfonater, toluen-sulfohat, chlorbenzensulfonat, xylensulfonat, phenylacetat, phenyl-propionat, phenylbutyrat, citrat, lactat, β-hydroxybutyrat, gly-collat, maleat, tartrat, methansulfonat, propansulfonat, naphthalen-1-sulfonat og naphthalen-2-sulfonat.
Forbindelserne fremstillet ifølge opfindelsen er nyttige som pro-lactininhibitorer. Hæmning af prolactinudskillelsen ved hjælp af forbindelserne ses af følgende eksperiment. Voksne hanrotter af 5 mieo
Spraque-Dawley-stammen, der vejede ea. 200 g, blev anvendt. Alle rotter blev anbragt i et luftkonditioneret rum med lys fra 6 morgen til 8 aften, og de blev indgivet foder og vand ad libitum.
I hvert forsøg blev hver hanrotte indgivet en intraperitoneal injektion af 2,0 mg reserpin i en vandig suspension 18 timer før indgivelsen af ergolinderivatet. Formålet med resperpinindgivel-sen var at holde prolactinniveuaet ensartet højt. Derivaterne blev opløst i 10 pet. ethanol i en koncentration på 10 jag/m! og blev injiceret intraperitonealt i en standarddosis på 50 yig/kg.
Hver forbindelse blev indgivet til en gruppe på ti rotter og en kontrolgruppe på ti raske hanrotter modtog en lignende mængde 10 pet. ethanol. En time efter behandlingen blev alle rotter dræbt ved halshugning, og 150 μΐ serum blev opsamlet og undersøgt for prolactin. Resultaterne blev vurderet statistisk, idet der anvendtes Student’s "t" test (en matematisk sammenligning mellem middelværdier) for at beregne signifikansniveauet udtrykt ved "p”.
Forskellen mellem prolactinkoncentrationen i de behandlede rotter og prolactinkoncentrationen i kontrolrotterne divideret med prolactinkoncentrationen i kontrolrotterne angiver den procentvise hæmning af prolactinsekretionen, der kan tilskrives indgivelsen af de omhandlede forbindelser. I følgende tabel er angivet prolactinhæmningen for en række forbindelse med formel II fremstillet ifølge opfindelsen. I tabellen giver kolonne 1 navnet på forbindelsen, kolonne 2 dosis af den indgivne forbindelse, kolonne 3 procent prolactinhæmning og kolonne 4 signifikansniveauet .
Da de omhandlede forbindelser er prolactininhlbitorer, er de også potentielt nyttige til at undertrykke væksten af brystadenocar-cinoma i hunlige pattedyr.
6 144160
TABEL
$> prolactin "p"
Eorbindelse Dosis hæmning værdi D-6-methyl-8-phenylmercapto- methyl-9,10-didehydroergolin 10 pg 50 <0,05 D_ 6-me t hy 1-8-me thylmer c apt o- methyl-9,10-didehydroergolin 10 ug 62 <0,01 D-6-methyl-8-acetylthiomethyl- ergolin 10 ug 40 <0,01 D-6-methyl-8-methylmercapto- methylergolin 10 μg 49 <0,001 D-2-chlor-6-methyl-8-methyl- mercaptomethylergolin 10 pg 46 <0,001 D-6-methyl-8-acetylthiornethy1- 9,10-didehydroergolin 10 pg 44 <0,01 Følgende eksempler illustrerer nærmere fremgangsmåden ifølge opfindelsen: EKSEMPEL 1
En suspension af 10 g D-6-methyl-8-hydroxymethylergolin i 200 ml pyridin "blev fremstillet. Til denne suspension sattes langsomt en opløsning indeholdende 6,0 ml methansulfonylchlorid og 200 ml pyridin. Den fremkomne blanding omrørtes ved stuetemperatur under en nitrogenatmosfære i en halv time og hældtes i 2,5 liter mættet vandig natriumbicarbonat. Den vandige basiske fase fortyndedes til 6 liter med vand, og den fortyndede fase henstod ved stuetemperatur. D-6-methyl-8-mesyloxymethylergolin dannet ved ovennævnte reaktion krystalliserede langsomt ud. Opløsningen afkøledes til cirka 0° C for at få mere af forbindelsen til at udfælde. Opløsningen filtreredes, og filterkagen omkrystalliseredes fra ethanol. En yderligere mængde D-6-methyl-8-mesyloxymethylergolin opnåedes ved at ekstrahere filtratet med ethylacetat, fraseparere ethylacetatfa- 7 144160 sen og fjerne ethylacetatet derfra ved inddampning i vakuum. Om-krystallisation fra ethanol af D-6-methyl-8-mesyloxymethylergo-lin fremstillet som ovenfor gav et stof, der smeltede ved 192 -194° C under dekomponering.
Analyse: Beregnet: 061,05 - H6,63 - N 8,38 - S 9,59
Pundet : C 60,85 - N 6,46 - N 8,45 - S 9,30.
En opløsning af 2,5 ml thiophenol i 25 ml dimethylsulfoxid blev fremstillet. 1,1 g natriummethylat tilsattes. Herefter tilsattes en opløsning af 700 mg af ovennævnte produkt i 50 ml dimethylsulfoxid, idet tilsætningen blev udført dråheviB. Efter endt tilsætning omrørtes reaktionshlandingen.ved stuetemperatur under en nitrogenatmosfære i 2 timer og hældtes ud i en mættet vandig vinsyre-opløsning. Ben sure fase ekstraheredes med chloroform. Chloroform-ekstrakten separeredes fra og borthældtes. Den sure fase blev gjort basisk med overskud af 14N ammoniumhydroxid, og den fremkomne basiske fase ekstraheredes med chloroform. Chloroformekstrakten frasepareredes og tørredes. Afdampning af chloroformen gav en remanens, der blev opløst i ethylacetat. Ethylacetatopløsningen vaskedes grundigt med vand, hvorefter der blev vasket med en mættet natriumchloridopløsning. Ethylacetatfasen tørredes. Fjernelse af ethylacetat ved afdampning i vakuum gav en remanens bestående af D-6-methyl-8-phenylmereaptomethylergolin, der omkrystalliseredes fra ethanol og smeltede ved 194 - 195° C under dekomponering. Forbindelsen blev opløst i chloroform og kromatograferet over florisil (25 g). Kromatogrammet blev udviklet med en chloroform-methanol-opløsningsmiddelblanding (19:1). Praktioner indeholdende D-6-methyl-8-phenylmercaptomethylergolin bestemt ved tyndtlagskroma-tografi blev samlet. Afdampning af opløsningsmidlet fra de samlede fraktioner og omkrystallisation af den fremkomne remanens fra en ether-hexan-opløsningsmiddelblanding gav D-6-methyl-8-phenylmer-captomethylergolin, smeltepunkt 195 - 196° C under dekomponering.
Analyse: Beregnet: C 75,82 - H 6,95 - N 8,04 - S 9,20
Pundet : C 75,85 - H 6,69 - N 7,97 - S 9,19.
144160 8
Ved at følge ovennævnte metode omsattes D-6-methyl-8-mesyloxymethyl-9,1O-didehydroergolin med thiophenol til opnåelse af D-6-methyl-8-phenylmereaptomethyl-9,1O-didehydroergolin, der smeltede ved cirka 200 - 203° C under dekomponering efter omkrystallisation fra methanol.
.Analyse: Beregnet: C 76,26 - H 6,40 - N 8,08 - S 9»25
Bundet : 0 76,02 - H 6,42 - N 7,99 - S 9,02.
Det tilsvarende 9,1O-didehydromaleatsalt fremstilledes ved at opløse forbindelsen i tetrahydrofuran og tilsætte en ækvivalent mængde maleinsyre, også opløst i tetrahydrofuran. Maleatsaltet smeltede ved 188 - 189° C efter omkrystallisation fra methanol.
Analyse: Beregnet: 0 67,51 - H 5,67 - N 6,06 - S 6,93
Bundet: C 67,29 - H 5,89 - N 5,79 - S 6,71.
EKSEMPEL 2
Ti milliliter dimethylformamid afkøledes til 0° C. Der tilsattes 1 ml methanthiol efterfulgt af 1 g natriumhydrid som en 50 pct. suspension i mineralolie i små portioner. Den fremkomne blanding omrørtes i 1 time og opvarmedes herefter til stuetemperatur. Ved at følge metoden i eksempel 1 sattes en opløsning af 1 g D-6-methyl-8-mesyl-oxymethylergolin i 50 ml dimethylformamid dråbevis til natriumsaltet af methanthiolen. Det fremkomne produkt isoleredes og oprensedes ved metoiden i eksempel 1 til opnåelse af D-6-methyl-8-methylmercap- tomethylergolin, der smeltede ved 153 - 155° C. Omkrystallisation » af forbindelsen (idet den kromatografiske oprensning i eksempel 1 blev undladt) fra en ether-hexan-opløsningsmiddelblanding gav D-6-methyl-8-methylmercaptomethylergolin, smeltepunkt 153 - 154° C.
Analyse: Beregnet: 071,28 - H7,74 - N 9,78 - S 11,19
Bundet : 071,08 - H 7,59 - N 9,83 - S 10,99.
Ved at følge ovennævnte metode fremstilledes D-6-methyl-8-methyl-mercaptomethyl-9,1O-didehydroergolin fra den tilsvarende 8-mesyloxy-methylforbindelse ved at omsætte med methylmercaptan. Borbindelsen smeltede ved 181 - 183° 0 under dekomponering efter omkrystallisation fra en ether-hexan-opløsningsmiddelblanding.
9 144160
Analyse: Beregnet: 071,79 - H7,09 - N 9,85 - S 11,27
Pundet : C 72,01 - H 6,84 — N 9,62 - S 11,27·
Det tilsvarende 9,10-didehydromaleatsalt fremstilledes ved at opløse forbindelsen i ether og tilsætte en ækvivalent mængde maleinsyre, også opløst i ether. Maleatsaltet smeltede ved 159 - 160° C under dekomponering.
Analyse: Beregnet: C 62,98 - H 6,07 - N 6,99 - S 8,01
Pundet : C 62,99 - H 6,15 - N 6,78 - S 7,86.
EKSEMPEL 5
Ved at følge metoden i eksempel 1 omsattes thioeddikesyre (som natriumsalt) med D-6-methyl-8-mesyloxymethylergolin i dimethylformamid-opløsning til opnåelse af D-6-methyl--8-acetylmercaptomethylergolin, der isoleredes og oprensedes ved metoden i eksempel 1. Kromatografi af det rå produkt over florisil under anvendelse af chloroform indeholdende 2 pet. ethanol som elueringsmiddel gav det oprensedé. D-6-methyl-8-acetylmercaptomethylergolin, smeltepunkt: 155 - 155° C under dekomponering.
Analyse: Beregnet: C 68,75 - H 7,05 - N 8,91 - S 10,20
Pundet : C 68,70 - H 7,22 - N 8,62 - S 10,47.
Ved at følge ovennævnte metode fremstilledes D-6-methyl-8-acetylmer-captomethyl-9,10-didehydroergolin ud fra den tilsvarende 8-mesyloxy-methylforbindelse. Den rensede forbindelse smeltede ved 165 - 167° C under dekomponering efter omkrystallisation fra ether-hexan.
Analyse: Beregnet: 0 69,20 - H 6,45 - N 8,97 - S 10,26
Pundet : C 69,48 - H 6,71 - N 9,00 - S 10,56.
Det tilsvarende 9,1O-didehydromaleatsalt fremstilledes ved at opløse basen i ether og tilsætte en ækvivalent mængde maleinsyre i ether. Maleatsaltet smeltede ved 178 - 179° C under dekomponering.
Analyse: Beregnet: C 61,67 - H 5,65 - N 6,54 - S 7,48
Pundet : C 61,95 - H 5,50 - N 6,84 - S 7,65.
U4160 ίο D-2-chlor-6-methyl-8-acetylmercaptomethylergolin fremstilledes også ved ovennævnte metode. Omkrystallisation af remanensen, der blev tilovers efter at kombinere fraktionerne fra kromatografi viste sig at indeholde D-2-chlor-6-methyl-8-acetylmereaptomethylergolin ved tyndtlagskromatografi, idet der anvendtes en opløsningsmiddelblan-ding af ether og hexan til omkrystallisation, hvilket gav et oprenset materiale med et smeltepunkt på 140 - 141° C.
Analyse: Beregnet: C 61,97 - H 6,07 - N 8,03 - S 9,19 -
Cl 10,16
Pundet : C 61,75 - H 5,78 - N 7,75 - S 9,41 -
Cl 10,32.
Ovennævnte metode "blev gentaget, idet dog der anvendtes methylmer-captan i stedet for thioeddikesyre til omsætning med D-2-chlor-6T methyl-8-mesyloxymethylergolin til dannelse af D-2-chlor-6-methyl- 8-methylmercaptomethylergolin. Kromatografi over florisil af remanensen opnået ved at blande de kromatografiske fraktioner viste sig^ at denne remanens indeholdt det ønskede materiale, idet der anvendtes en ether-hexan-blanding til omkrystallisation, og der opnåedes et oprenset D-2-chlor-6-methyl-8-methylmercaptomethyler-golin med et smeltepunkt på 194 - 195° C.
Analyse: Beregnet:C 63,63 - H 6,60 - N 8,73 - S 9,99 - Cl 11,05 Fundet :C 63,42 - H 6,55 - N 8,47 - S 10,12 - Cl 11,35.
Claims (1)
11 1U160 Analogifremgangsmåde til fremstilling af 8-thiomethylergoliner med den almene formel II: (II) o II hvori R er C-alk, phenyl eller alk; R er hydrogen, ehlor eller hrom; alk er alkyl med 1-3 carbonatomer, og hvor den punkterede linie repræsenterer en eventuel tilstedeværende dobbeltbinding, eller ikke-toxiské, farmaceutisk acceptable syreadditionssalte heraf, kendetegnet ved, at man omsætter en forbindelse med den almene formel III ch2or2 .øpv Jf U-C Hg HN-, ^"•R1 (III)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US477136A US3901894A (en) | 1974-06-06 | 1974-06-06 | 8-thiomethylergolines |
| US47713674 | 1974-06-06 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK249975A DK249975A (da) | 1975-12-07 |
| DK144160B true DK144160B (da) | 1981-12-28 |
| DK144160C DK144160C (da) | 1982-06-07 |
Family
ID=23894677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK249975A DK144160C (da) | 1974-06-06 | 1975-06-04 | Analogifremgangsmaade til fremstilling af 8-thiomethylergoliner |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US3901894A (da) |
| JP (1) | JPS582946B2 (da) |
| AR (1) | AR210736A1 (da) |
| AT (1) | AT344333B (da) |
| AU (1) | AU507574B2 (da) |
| BE (1) | BE829887A (da) |
| BG (1) | BG24812A3 (da) |
| CA (1) | CA1071623A (da) |
| CH (1) | CH617196A5 (da) |
| CS (1) | CS199591B2 (da) |
| DD (1) | DD120438A5 (da) |
| DE (1) | DE2524575A1 (da) |
| DK (1) | DK144160C (da) |
| ES (1) | ES438313A1 (da) |
| FR (1) | FR2273542A1 (da) |
| GB (1) | GB1505296A (da) |
| HU (1) | HU173590B (da) |
| IE (1) | IE41474B1 (da) |
| IL (1) | IL47424A (da) |
| NL (1) | NL180911C (da) |
| PH (1) | PH10992A (da) |
| PL (1) | PL95738B1 (da) |
| RO (1) | RO77543A (da) |
| SE (1) | SE420095B (da) |
| SU (1) | SU613724A3 (da) |
| YU (1) | YU145575A (da) |
| ZA (1) | ZA753638B (da) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4147789A (en) * | 1974-03-14 | 1979-04-03 | Sandoz Ltd. | 6-Methyl-8-thiomethyl-ergolene derivatives |
| US3959288A (en) * | 1974-12-13 | 1976-05-25 | Eli Lilly And Company | 8-Oxymethylergolines and process therefor |
| JPS5283894A (en) * | 1976-01-01 | 1977-07-13 | Lilly Co Eli | 88thiomethyl ergoline |
| GB1549829A (en) * | 1976-05-26 | 1979-08-08 | Farmaceutici Italia | 10'-methoxy-1',6'-dimethylergoline-8'-beta-methyl-amino(or thio)-pyrazines |
| IT1192260B (it) * | 1977-07-05 | 1988-03-31 | Simes | Derivati di ergoline-2-tioeteri e loro solfossidi |
| US4180582A (en) * | 1978-02-08 | 1979-12-25 | Eli Lilly And Company | 6-n-Propyl-8-methoxy-methyl or methylmercaptomethylergolines and related compounds as prolactin inhibitors and to treat Parkinson's syndrome |
| US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4202979A (en) * | 1979-01-11 | 1980-05-13 | Eli Lilly And Company | 6-Ethyl(or allyl)-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4246265A (en) * | 1979-10-01 | 1981-01-20 | Eli Lilly And Company | 6-n-Propyl-8α-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4382940A (en) * | 1979-12-06 | 1983-05-10 | Farmitalia Carlo Erba S.P.A. | Ercoline derivatives and therapeutic compositions having CNS affecting activity |
| DE3216870A1 (de) * | 1982-05-03 | 1983-11-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | Pharmazeutische zubereitungen mit zytostatischer wirkung |
| FR2526797A1 (fr) * | 1982-05-12 | 1983-11-18 | Roussel Uclaf | Nouveaux derives de l'acide 9-oxalysergique, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant |
| CH649998A5 (de) * | 1982-08-09 | 1985-06-28 | Sandoz Ag | Ergolinderivate, ein verfahren zu ihrer herstellung und heilmittel, enthaltend diese ergolinderivate als wirkstoff. |
| GB8427536D0 (en) * | 1984-10-31 | 1984-12-05 | Lilly Industries Ltd | Ergoline derivatives |
| US4675322A (en) * | 1984-12-10 | 1987-06-23 | Eli Lilly And Company | 1-Substituted-6-n-propyl-8β-methylthio-methylergolines |
| US4801712A (en) * | 1985-06-24 | 1989-01-31 | Eli Lilly And Company | 2-Alkyl(or phenyl)thio-6-n-alkylergolines are dopamine D-1 antagonists without D-2 agonist activity |
| FR2589734B1 (fr) * | 1985-11-13 | 1988-09-02 | Roussel Uclaf | Utilisation de derives de l'ergoline a l'obtention d'un medicament a visee geriatrique |
| HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
| ATE424414T1 (de) | 2001-06-08 | 2009-03-15 | Sod Conseils Rech Applic | Chimere somatostatin-dopamin-analoga |
| US7019140B2 (en) * | 2002-03-15 | 2006-03-28 | Antibioticos S.P.A. | Process for the synthesis of pergolide |
| TWI523863B (zh) | 2012-11-01 | 2016-03-01 | 艾普森藥品公司 | 體抑素－多巴胺嵌合體類似物 |
| HK1213486A1 (zh) | 2012-11-01 | 2016-07-08 | Ipsen Pharma S.A.S. | 促生长素抑制素类似物及其二聚体 |
| EP3197429B1 (en) | 2014-09-25 | 2024-05-22 | Boehringer Ingelheim Vetmedica GmbH | Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals |
| US20190374534A1 (en) | 2018-06-08 | 2019-12-12 | Boehringer Ingelheim Vetmedica Gmbh | Liquid pharmaceutical compositions comprising pergolide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH507248A (de) * | 1967-03-16 | 1971-05-15 | Spofa Vereinigte Pharma Werke | Verfahren zur Herstellung von D-6-Methylergolin(I)ylessigsäure |
| DE1935556A1 (de) * | 1969-07-12 | 1971-01-21 | Hoechst Ag | Verfahren zur Herstellung von Lysergol |
| JPS5012398A (da) * | 1973-06-08 | 1975-02-07 |
-
1974
- 1974-06-06 US US477136A patent/US3901894A/en not_active Expired - Lifetime
-
1975
- 1975-05-16 JP JP50059191A patent/JPS582946B2/ja not_active Expired
- 1975-06-03 DE DE19752524575 patent/DE2524575A1/de not_active Ceased
- 1975-06-03 HU HU75EI623A patent/HU173590B/hu unknown
- 1975-06-03 NL NLAANVRAGE7506584,A patent/NL180911C/xx not_active IP Right Cessation
- 1975-06-03 PH PH17225A patent/PH10992A/en unknown
- 1975-06-03 GB GB23869/75A patent/GB1505296A/en not_active Expired
- 1975-06-03 CA CA228,332A patent/CA1071623A/en not_active Expired
- 1975-06-03 CS CS753882A patent/CS199591B2/cs unknown
- 1975-06-03 IE IE1221/75A patent/IE41474B1/en unknown
- 1975-06-03 SE SE7506327A patent/SE420095B/xx not_active IP Right Cessation
- 1975-06-04 BG BG030188A patent/BG24812A3/xx unknown
- 1975-06-04 AU AU81827/75A patent/AU507574B2/en not_active Expired
- 1975-06-04 PL PL1975180897A patent/PL95738B1/pl unknown
- 1975-06-04 DK DK249975A patent/DK144160C/da not_active IP Right Cessation
- 1975-06-04 IL IL47424A patent/IL47424A/xx unknown
- 1975-06-05 BE BE1006709A patent/BE829887A/xx not_active IP Right Cessation
- 1975-06-05 FR FR7517652A patent/FR2273542A1/fr active Granted
- 1975-06-05 YU YU01455/75A patent/YU145575A/xx unknown
- 1975-06-05 ZA ZA3638A patent/ZA753638B/xx unknown
- 1975-06-05 RO RO7582445A patent/RO77543A/ro unknown
- 1975-06-05 AT AT427975A patent/AT344333B/de not_active IP Right Cessation
- 1975-06-05 SU SU752140862A patent/SU613724A3/ru active
- 1975-06-06 CH CH731075A patent/CH617196A5/de not_active IP Right Cessation
- 1975-06-06 AR AR259118A patent/AR210736A1/es active
- 1975-06-06 ES ES438313A patent/ES438313A1/es not_active Expired
-
1976
- 1976-06-05 DD DD186472A patent/DD120438A5/xx unknown
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