DK144160B - ANALOGY PROCEDURE FOR THE PREPARATION OF 8-THIOMETHYLERGOLIN - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF 8-THIOMETHYLERGOLIN Download PDFInfo
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- 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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Description
09) DANMARK09) DENMARK
(¾(¾
|j| 02) FREMLÆGGELSESSKRIFT od 11+4160 B| J | 02) PRESENTATION WRITING OR 11 + 4160 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(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. -(21) Application No. 2499/75 (51) IntCI * C 07 D A57 / 02 (22) Filing date 4 Jun. 1975 (24) Race day 4 Jun. 1975 (41) Aim. available 7 * dec. 1975 (44) Posted Dec 28 1981 (86) International application # - (86) International filing day (85) Continuation day - (62) Master application no -
(30) Prioritet 6. jun. 1974, 477156, US(30) Priority Jun 6 1974, 477156, US
(71) Ansøger ELI LILLY AND COMPANY, Indianapolis, US.(71) Applicant ELI LILLY AND COMPANY, Indianapolis, US.
(72) Opfinder Edmund Carl Kornf eld, US: Nicholas James Bach, US.(72) Inventor Edmund Carl Kornf eld, US: Nicholas James Bach, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Bout ard.(74) Associate Engineer Hofman-Bang & Bout ard.
(54) Analogifremgangsmåde til fretsstilling af 8-thiomethylergollner.(54) Analogous process for fretting of 8-thiomethylene coils.
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.The present invention relates to an analogous process for the preparation of novel 8-thiomethylergolines having the general formula II or pharmaceutically acceptable acid addition salts thereof as set forth in the preamble of claim, and the process of the invention is characterized by the characterizing part of the claim. The present compounds are useful as prolactin inhibitors.
±±
d" Forbindelser baseret på ergolinringsystemet med formel Id "Compounds Based on the Ergoline Ring System of Formula I
t 2 144160 fe 7)t 2 144160 fe 7)
XV ^L° eJ'MHXV ^ L ° eJ'MH
1^18 N/18 N /
| il 11 S|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).^ JLj 'T (i) H-N - 3 has a surprisingly varying amount of pharmaceutical action. Lysergic and isolicergic acid are e.g. 8-carboxy-6-methyl-Å9 ergolines (9,10-didehydroergolines). Lysergic acid amides, many of which have valuable and unique pharmacological properties, include naturally occurring oxytocin alkaloids - ergocornin, ergocryptin, ergonovine, ergocristine, ergosine, ergotamine etc. - and synthetic oxytocins such as methergin as well as the synthetic hallucinogenic lysergic acid LS. Amides of 6-methyl-8-carboxyergoline, generically known as dihydroergoth alkaloids, are oxytocins of lower potency and also of lower toxicity than the ergot alkaloids themselves. Ergotamine, an Aβ-ergoline, has been used in the treatment of migraine, and recently both ergocornin and 2-bromo-α-ergocryptin have been shown to be inhibitors of prolactin and of dimethylbenzanthracene (DMBA) -induced tumors in rats, according to Nagasawa and Meites, Proc. Soc. Exp'tl. Biol. With. 135, 469 (1970) and Heuson et al., Europ. J. Cancer, 353, (1970). (see also U.S. Patents Nos. 3 752 888 and 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.D-6-methyl-8-cyanomethylergoline was first prepared by Semonsky et al., Coll. Czech. Chem. Commun., 33, 577 (1968), and its use to prevent pregnancy in rats was published by the same group of researchers in Nature, 221, 666 (1969). (See also U.S. Patent No. 3,732,231). The compound is thought to interfere with the secretion of the leuteotropic pituitary hormone and the pituitary gonadotropins. It was also suggested that the compound inhibited the secretion of prolactin. [See Seda et al., Reprod. Fert. 24, 163 (1971) and 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.Comm., 36, 220 (1971), have disclosed the preparation of D-6-methyl-8-ergolinylacetamide, a compound which is reported to have antifertility and antilacterial effect on rats. The effect of these compounds in neoplastic diseases is unknown.
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.Danish Patent Specification No. 140,986 discloses 8-substituted D-2-halogen-6-methylergolines or salts thereof, wherein the 8-substituent is either CH 2 CN or CH 2 C (= O) NH 2. These compounds are prolactin inhibitors, but have the disadvantage of being hepatotoxic to humans relative to the compounds of this invention (see 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.J. Med. Sci. 278, 65-76 (1979)). This has at least been found to be the case for the compound in which the 8-substituent is CH2-CN and the toxicity may be due to the isano group. The compounds of this invention do not contain any cyano group in the 8-position.
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,In the above Formula II, alky groups having 1-3 carbon atoms include the following groups: methyl, ethyl, n-propyl and iso-Q ΤΛ propyl. When the A 'bond of formula II is saturated, the compounds are referred to as D-6-methyl-8-thiomethyl (or mercaptomethyl) ergolines. When the 4'10 bond is unsaturated, the resulting compounds are generically referred to as D-6-methyl-8thiomethyl- or mercep-pheo-methyl-9,10-didehydroergolines. Illustrative compounds obtained by the process of the present invention are: D-2-chloro-6-methyl-8-propionylthiomethylergoline D-2-ehloro-6-methyl-8-butyrylthiomethyl-9,1O-didehydroergoline D-2 chloro-6-methyl-8-phenylmeroaptomethyl-9,1O-didehydroergoline D-2-bromo-6-methyl-8-phenylmercaptomethyl-9,1O-didehydroergoline D-2-chloro-6-methyl-8-ethylmercaptomethyl-9, 1O-didehydroergoline D-6-methyl-8-n-propylmercaptomethylergoline D-6-methyl-8-isopropylmercaptomethylergoline,
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.The compounds of the invention are prepared via nucleophilic substitution by reacting one of the following esters of a D-6-methyl-8-hydroxymethylergoline or -9,10-didehydroergoline, optionally substituted by carbon atom 2 with chlorine or bromine, with salts of thiophenol, a thioalkanecarboxylic acid (alk-COSH) or an alkyl-thiol (alk-SH). The esters used as starting materials in the above synthesis are mesyl (methanesulfonyl) and p-toluenesulfonyl (p-tosyl) esters formed with the hydroxy group in 8-hydroxy-methyl-6-methylergoline, 8-hydroxymethyl-6-roethyl 9, 10-didehydro-ergoline or of a 2-halogen derivative of both of these compounds of formula III. These mesyloxy and p-tosyloxy derivatives are either known compounds or can be prepared from corresponding hydroxy derivatives by known methods. In carrying out reactions with thiophenol or with an alkylthiol, the sodium salt of the mercap-tan group is usually formed, using sodium methylate or sodium hydroxide. The nucleophilic substitution reaction is carried out in an inert solvent such as dimethylformamide or dimethylsulfoxide. Usually the reaction is carried out at room temperature or, if desired, heated to a temperature of up to 100 ° C. The products of the reaction are usually isolated by standard technique and purified by chromatography, preferably 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.The compounds of the invention are white crystalline solids and form pharmaceutically acceptable salts with non-toxic acids. Non-toxic acids useful in the formation of these salts include such inorganic acids as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrogen bromide acid, hydrogen iodide acid, nitric acid and phosphoric acid, as well as non-toxic organic acids comprising aliphatic mono- and dicarboxylic acids. phenyl-substituted alkanecarboxylic acids, hydroxy-alkane and alkanedicarboxylic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, meta-phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, deeanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, * maleate, butyn-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate , methoxybenzoate, phthalate, terephthalate, benzenesulfonates, toluene sulfoate, chlorobenzenesulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, maleate, propane sulfate, methane sulfate and naphthalene-2-sulfonate.
Forbindelserne fremstillet ifølge opfindelsen er nyttige som pro-lactininhibitorer. Hæmning af prolactinudskillelsen ved hjælp af forbindelserne ses af følgende eksperiment. Voksne hanrotter af 5 mieoThe compounds of the invention are useful as prolactin inhibitors. Inhibition of prolactin secretion by the compounds is seen in the following experiment. Adult male rats of 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.The Spraque-Dawley tribe that weighed ea. 200 g, was used. All rats were placed in an air-conditioned room with light from 6 am to 8 pm and were fed feed and water 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.In each experiment, each male rat was given an intraperitoneal injection of 2.0 mg of reserpine in an aqueous suspension 18 hours prior to the administration of the ergoline derivative. The purpose of the resperpine administration was to keep the prolactin level uniformly high. The derivatives were dissolved in 10 pet. ethanol at a concentration of 10 µm / m! and was injected intraperitoneally at a standard dose of 50 µg / 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”.Each compound was administered to a group of ten rats and a control group of ten healthy rats received a similar amount of 10 pet. ethanol. One hour after treatment, all rats were killed by decapitation and 150 μΐ serum were collected and examined for prolactin. The results were statistically assessed using Student's "t" test (a mathematical comparison of mean values) to calculate the significance level expressed by "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 .The difference between the prolactin concentration in the treated rats and the prolactin concentration in the control rats divided by the prolactin concentration in the control rats indicates the percentage inhibition of prolactin secretion attributable to the administration of the compounds of the invention. The following table lists the prolactin inhibition for a variety of compounds of formula II prepared according to the invention. In the table, column 1 gives the name of the compound, column 2 dose of the compound administered, column 3 percent prolactin inhibition, and column 4 the significance level.
Da de omhandlede forbindelser er prolactininhlbitorer, er de også potentielt nyttige til at undertrykke væksten af brystadenocar-cinoma i hunlige pattedyr.Since the compounds of the present invention are prolactin inhibitors, they are also potentially useful in suppressing the growth of breast adenocarcinoma in female mammals.
6 1441606 144160
TABELTABLE
$> prolactin "p"$> 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 1Compound Dose inhibition value D-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline 10 pg 50 <0.05 D_6-me t hy 1-8-me thylmer c apt o -methyl-9,10- dide hydroergoline 10 µg 62 <0.01 D-6-methyl-8-acetylthiomethylergoline 10 µg 40 <0.01 D-6-methyl-8-methylmercaptomethylergoline 10 µg 49 <0.001 D-2-chloro-6- methyl 8-methylmercaptomethylergoline 10 pg 46 <0.001 D-6-methyl-8-acetylthiornethyl1,9,10-didehydroergoline 10 pg 44 <0.01 The following examples further illustrate the process of the invention: EXAMPLE 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.A suspension of 10 g of D-6-methyl-8-hydroxymethylergoline in 200 ml of pyridine "was prepared. To this suspension was slowly added a solution containing 6.0 ml of methanesulfonyl chloride and 200 ml of pyridine. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for one hour. half an hour and poured into 2.5 liters of saturated aqueous sodium bicarbonate, the aqueous basic phase was diluted to 6 liters with water and the diluted phase was allowed to stand at room temperature D-6-methyl-8-mesyloxymethylergoline formed by the above reaction slowly crystallized out. The solution was cooled to about 0 ° C to precipitate more of the compound, the solution was filtered and the filter cake was recrystallized from ethanol An additional amount of D-6-methyl-8-mesyloxymethylergoline was obtained by extracting the filtrate with ethyl acetate, 144160 and remove the ethyl acetate from it by evaporation in vacuo. Recrystallization from ethanol of D-6-methyl-8-mesyloxymethylergoline to prepare t as above gave a substance which melted at 192 -194 ° C during decomposition.
Analyse: Beregnet: 061,05 - H6,63 - N 8,38 - S 9,59Analysis: Calculated: 061.05 - H6.63 - N 8.38 - S 9.59
Pundet : C 60,85 - N 6,46 - N 8,45 - S 9,30.Pound: 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.A solution of 2.5 ml of thiophenol in 25 ml of dimethyl sulfoxide was prepared. 1.1 g of sodium methylate was added. Then, a solution of 700 mg of the above product was added in 50 ml of dimethyl sulfoxide, the addition being carried out dropwise. Upon completion of the addition, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and poured into a saturated aqueous tartaric acid solution. Bone acidic phase was extracted with chloroform. The chloroform extract was separated and poured off. The acidic phase was made basic with excess 14N ammonium hydroxide and the resulting basic phase extracted with chloroform. The chloroform extract was separated and dried. Evaporation of the chloroform gave a residue which was dissolved in ethyl acetate. The ethyl acetate solution was thoroughly washed with water and then washed with a saturated sodium chloride solution. The ethyl acetate phase was dried. Removal of ethyl acetate by evaporation in vacuo gave a residue consisting of D-6-methyl-8-phenylmereaptomethylergoline, which was recrystallized from ethanol and melted at 194 - 195 ° C under decomposition. The compound was dissolved in chloroform and chromatographed over florisil (25 g). The chromatogram was developed with a chloroform-methanol-solvent mixture (19: 1). Operations containing D-6-methyl-8-phenylmercaptomethylergoline as determined by thin layer chromatography were pooled. Evaporation of the solvent from the combined fractions and recrystallization of the resulting residue from an ether-hexane-solvent mixture gave D-6-methyl-8-phenylmer-captomethylergoline, m.p. 195 - 196 ° C during decomposition.
Analyse: Beregnet: C 75,82 - H 6,95 - N 8,04 - S 9,20Analysis: Calculated: 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.Pound: C 75.85 - H 6.69 - N 7.97 - S 9.19.
144160 8144160 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.Following the above method, D-6-methyl-8-mesyloxymethyl-9,1O-didehydroergoline was reacted with thiophenol to give D-6-methyl-8-phenylmereaptomethyl-9,1O-didehydroergoline, which melted at about 200-203 ° C under decomposition after recrystallization from methanol.
.Analyse: Beregnet: C 76,26 - H 6,40 - N 8,08 - S 9»25Analysis: Calculated: 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.Bound: 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.The corresponding 9,1O-didehydromaleate salt was prepared by dissolving the compound in tetrahydrofuran and adding an equivalent amount of maleic acid, also dissolved in tetrahydrofuran. The maleate salt melted at 188 - 189 ° C after recrystallization from methanol.
Analyse: Beregnet: 0 67,51 - H 5,67 - N 6,06 - S 6,93Analysis: Calculated: 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.Found: C 67.29 - H 5.89 - N 5.79 - S 6.71.
EKSEMPEL 2EXAMPLE 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.Ten milliliters of dimethylformamide was cooled to 0 ° C. 1 ml of methanethiol was added followed by 1 g of sodium hydride as a 50 per cent. suspension in mineral oil in small portions. The resulting mixture was stirred for 1 hour and then warmed to room temperature. Following the method of Example 1, a solution of 1 g of D-6-methyl-8-mesyl-oxymethylergoline in 50 ml of dimethylformamide was added dropwise to the sodium salt of the methanethiol. The resulting product was isolated and purified by the method of Example 1 to give D-6-methyl-8-methylmercaptomethylergoline melting at 153 - 155 ° C. Recrystallization of the compound (omitting the chromatographic purification of Example 1) from an ether-hexane-solvent mixture gave D-6-methyl-8-methylmercaptomethylergoline, m.p. 153 - 154 ° C.
Analyse: Beregnet: 071,28 - H7,74 - N 9,78 - S 11,19Analysis: Calculated: 071.28 - H7.74 - N 9.78 - S 11.19
Bundet : 071,08 - H 7,59 - N 9,83 - S 10,99.Bound: 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.Following the above method, D-6-methyl-8-methyl-mercaptomethyl-9,1O-didehydroergoline was prepared from the corresponding 8-mesyloxy-methyl compound by reacting with methylmercaptan. The boron compound melted at 181 - 183 ° C with decomposition after recrystallization from an ether-hexane solvent mixture.
9 1441609 144160
Analyse: Beregnet: 071,79 - H7,09 - N 9,85 - S 11,27Analysis: Calculated: 071.79 - H7.09 - N 9.85 - S 11.27
Pundet : C 72,01 - H 6,84 — N 9,62 - S 11,27·Pound: 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.The corresponding 9,10-didehydromaleate salt was prepared by dissolving the compound in ether and adding an equivalent amount of maleic acid, also dissolved in ether. The maleate salt melted at 159 - 160 ° C during decomposition.
Analyse: Beregnet: C 62,98 - H 6,07 - N 6,99 - S 8,01Analysis: Calculated: 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.Pound: C 62.99 - H 6.15 - N 6.78 - S 7.86.
EKSEMPEL 5EXAMPLE 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.Following the method of Example 1, thioacetic acid (as sodium salt) was reacted with D-6-methyl-8-mesyloxymethylergoline in dimethylformamide solution to give D-6-methyl-8-acetylmercaptomethylergoline, which was isolated and purified by the method of Example 1 Chromatography of the crude product over florisil using chloroform containing 2 pet. ethanol as eluent gave it purification. D-6-methyl-8-acetylmercaptomethylergoline, m.p .: 155 - 155 ° C during decomposition.
Analyse: Beregnet: C 68,75 - H 7,05 - N 8,91 - S 10,20Analysis: Calculated: 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.Pound: 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.Following the above method, D-6-methyl-8-acetylmer-captomethyl-9,10-didehydroergoline was prepared from the corresponding 8-mesyloxy-methyl compound. The purified compound melted at 165 - 167 ° C during decomposition after recrystallization from ether-hexane.
Analyse: Beregnet: 0 69,20 - H 6,45 - N 8,97 - S 10,26Analysis: Calculated: 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.Pound: 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.The corresponding 9,1O-didehydromaleate salt was prepared by dissolving the base in ether and adding an equivalent amount of maleic acid in ether. The maleate salt melted at 178 - 179 ° C during decomposition.
Analyse: Beregnet: C 61,67 - H 5,65 - N 6,54 - S 7,48Analysis: Calculated: 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.Pound: 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.U4160 of D-2-chloro-6-methyl-8-acetylmercaptomethylergoline was also prepared by the above method. Recrystallization of the residue remaining after combining the fractions from chromatography was found to contain D-2-chloro-6-methyl-8-acetylmereaptomethylergoline by thin layer chromatography, using a solvent mixture of ether and hexane to recrystallize. purified material with a melting point of 140 - 141 ° C.
Analyse: Beregnet: C 61,97 - H 6,07 - N 8,03 - S 9,19 -Analysis: Calculated: C 61.97 - H 6.07 - N 8.03 - S 9.19 -
Cl 10,16Cl 10.16
Pundet : C 61,75 - H 5,78 - N 7,75 - S 9,41 -Pound: C 61.75 - H 5.78 - N 7.75 - S 9.41 -
Cl 10,32.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.The above method "was repeated, however, using methylmercaptan instead of thioacetic acid for reaction with D-2-chloro-6T methyl-8-mesyloxymethylergoline to give D-2-chloro-6-methyl-8-methylmercaptomethylergoline. of florisil of the residue obtained by mixing the chromatographic fractions showed that this residue contained the desired material, using an ether-hexane mixture for recrystallization, and a purified D-2-chloro-6-methyl-8 was obtained. -methylmercaptomethylergoline with a melting point of 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.Analysis: Calculated: C 63.63 - H 6.60 - N 8.73 - S 9.99 - Cl 11.05 Found: C 63.42 - H 6.55 - N 8.47 - S 10.12 - Cl 11.35.
Claims (1)
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Application Number | Priority Date | Filing Date | Title |
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US477136A US3901894A (en) | 1974-06-06 | 1974-06-06 | 8-thiomethylergolines |
US47713674 | 1974-06-06 |
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Publication Number | Publication Date |
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DK249975A DK249975A (en) | 1975-12-07 |
DK144160B true DK144160B (en) | 1981-12-28 |
DK144160C DK144160C (en) | 1982-06-07 |
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US (1) | US3901894A (en) |
JP (1) | JPS582946B2 (en) |
AR (1) | AR210736A1 (en) |
AT (1) | AT344333B (en) |
AU (1) | AU507574B2 (en) |
BE (1) | BE829887A (en) |
BG (1) | BG24812A3 (en) |
CA (1) | CA1071623A (en) |
CH (1) | CH617196A5 (en) |
CS (1) | CS199591B2 (en) |
DD (1) | DD120438A5 (en) |
DE (1) | DE2524575A1 (en) |
DK (1) | DK144160C (en) |
ES (1) | ES438313A1 (en) |
FR (1) | FR2273542A1 (en) |
GB (1) | GB1505296A (en) |
HU (1) | HU173590B (en) |
IE (1) | IE41474B1 (en) |
IL (1) | IL47424A (en) |
NL (1) | NL180911C (en) |
PH (1) | PH10992A (en) |
PL (1) | PL95738B1 (en) |
RO (1) | RO77543A (en) |
SE (1) | SE420095B (en) |
SU (1) | SU613724A3 (en) |
YU (1) | YU145575A (en) |
ZA (1) | ZA753638B (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
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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 (en) * | 1977-07-05 | 1988-03-31 | Simes | ERGOLINE-2-THIOETHERS AND THEIR SULPHOXIDES DERIVATIVES |
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 (en) * | 1982-05-03 | 1983-11-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | PHARMACEUTICAL PREPARATIONS WITH A CYTOSTATIC EFFECT |
FR2526797A1 (en) * | 1982-05-12 | 1983-11-18 | Roussel Uclaf | NOVEL 9-OXALYSERGIC ACID DERIVATIVES, THEIR SALTS, PREPARATION METHOD, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
CH649998A5 (en) * | 1982-08-09 | 1985-06-28 | Sandoz Ag | ERGOL DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND HEALING AGENTS, CONTAINING THESE ERGOL DERIVATIVES AS AN ACTIVE SUBSTANCE. |
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 (en) * | 1985-11-13 | 1988-09-02 | Roussel Uclaf | USE OF ERGOLIN DERIVATIVES FOR OBTAINING A GERIATRIC MEDICINE |
HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
NZ530007A (en) * | 2001-06-08 | 2006-02-24 | Sod Conseils Rech Applic | Somatostatin-dopamine chimeric analogues that retain both somatostatin and dopamine activity in vivo and display enhanced biological activity |
AU2003221494A1 (en) * | 2002-03-15 | 2003-09-29 | Antibioticos S.P.A. | Process for the synthesis of pergolide |
CN104768565B (en) | 2012-11-01 | 2017-04-26 | 益普生制药股份有限公司 | Somatostatin analogs and dimers thereof |
TWI523863B (en) | 2012-11-01 | 2016-03-01 | 艾普森藥品公司 | Somatostatin-dopamine chimeric analogs |
AU2015320975B2 (en) | 2014-09-25 | 2020-10-08 | Boehringer Ingelheim Vetmedica Gmbh | Combination treatment of SGLT2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals |
WO2019234069A1 (en) | 2018-06-08 | 2019-12-12 | Boehringer Ingelheim Vetmedica Gmbh | Liquid pharmaceutical compositions comprising pergolide |
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CH507248A (en) * | 1967-03-16 | 1971-05-15 | Spofa Vereinigte Pharma Werke | Process for the preparation of D-6-methylergolin (I) ylacetic acid |
DE1935556A1 (en) * | 1969-07-12 | 1971-01-21 | Hoechst Ag | Process for the production of lysergol |
JPS5012398A (en) * | 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/en not_active Expired
- 1975-06-03 SE SE7506327A patent/SE420095B/en not_active IP Right Cessation
- 1975-06-03 HU HU75EI623A patent/HU173590B/en unknown
- 1975-06-03 NL NLAANVRAGE7506584,A patent/NL180911C/en not_active IP Right Cessation
- 1975-06-03 CS CS753882A patent/CS199591B2/en unknown
- 1975-06-03 PH PH17225A patent/PH10992A/en unknown
- 1975-06-03 IE IE1221/75A patent/IE41474B1/en unknown
- 1975-06-03 DE DE19752524575 patent/DE2524575A1/en not_active Ceased
- 1975-06-03 GB GB23869/75A patent/GB1505296A/en not_active Expired
- 1975-06-03 CA CA228,332A patent/CA1071623A/en not_active Expired
- 1975-06-04 AU AU81827/75A patent/AU507574B2/en not_active Expired
- 1975-06-04 BG BG7500030188A patent/BG24812A3/en unknown
- 1975-06-04 PL PL1975180897A patent/PL95738B1/en unknown
- 1975-06-04 IL IL47424A patent/IL47424A/en unknown
- 1975-06-04 DK DK249975A patent/DK144160C/en not_active IP Right Cessation
- 1975-06-05 RO RO7582445A patent/RO77543A/en unknown
- 1975-06-05 ZA ZA3638A patent/ZA753638B/en unknown
- 1975-06-05 FR FR7517652A patent/FR2273542A1/en active Granted
- 1975-06-05 AT AT427975A patent/AT344333B/en not_active IP Right Cessation
- 1975-06-05 YU YU01455/75A patent/YU145575A/en unknown
- 1975-06-05 BE BE1006709A patent/BE829887A/en not_active IP Right Cessation
- 1975-06-05 SU SU752140862A patent/SU613724A3/en active
- 1975-06-06 CH CH731075A patent/CH617196A5/de not_active IP Right Cessation
- 1975-06-06 ES ES438313A patent/ES438313A1/en not_active Expired
- 1975-06-06 AR AR259118A patent/AR210736A1/en active
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1976
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