DK151023B - METHOD OF ANALOGY FOR THE PREPARATION OF APOVINCAMINOL-3 ', 4', 5'-TRI-METHOXYBENZOATE DERIVATIVES - Google Patents
METHOD OF ANALOGY FOR THE PREPARATION OF APOVINCAMINOL-3 ', 4', 5'-TRI-METHOXYBENZOATE DERIVATIVES Download PDFInfo
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Description
i 151023in 151023
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af apovincaminol-3’,4’,5'-trimethoxybenzoatderivater med den almene formel IThe present invention relates to an analogous process for the preparation of apovincaminol-3 ', 4', 5'-trimethoxybenzoate derivatives of the general formula I
R1 r^1 0CH3 5 hvor R1 og R2 enten begge betegner hydrogen, eller hvor ét af symbolerne R1 og R2 betegner hydrogen og det andet betegner nitro, eller farmaceutisk tolerable syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved, at apovincaminol eller et syreadditionssalt deraf omsættes med 3,4,5-trimethoxybenzoesyre eller et reak-10 tivt acylerende derivat deraf, hvorefter fremstillede forbindelser med formlen la Οςψ ^H, Ia CH3°w« OCHj isoleres, eller omdannes til et farmaceutisk tolerabelt syreadditionssalt deraf, eller om ønsket nitreres, hvorefter den ved nitreringen vtindne 15 blanding af forbindelserne med formlen Ib og le Νθ2 2 151023Wherein R1 and R2 are both hydrogen or one of the symbols R1 and R2 represents hydrogen and the other represents nitro or pharmaceutically tolerable acid addition salts thereof, which process is characterized by the reaction of apovincaminol or an acid addition salt thereof. with 3,4,5-trimethoxybenzoic acid or a reactive acylating derivative thereof, whereby compounds of the formula la ΟςψψH, Ia CH3 °W «OCH₂ are isolated, or converted into a pharmaceutically tolerable acid addition salt thereof, or, if desired, nitrated, whereupon the mixture obtained by nitration mixes the compounds of formula Ib and le Νθ2 2 151023
“"VyS"" VYS
oy) ^ ^2η5 ςΐΐ°ννί lc cwV 0 CH30 adskilles i de to bestanddele, og en fremstillet forbindelse med formlen Ib eller le om ønsket omdannes til et farmaceutisk tolerabelt 5 syreadditionssalt deraf.oy) 2η5 ςΐΐ ° ννί lc cwV 0 CH30 is separated into the two constituents and a prepared compound of formula Ib or le, if desired, is converted into a pharmaceutically tolerable acid addition salt thereof.
Syreadditionssaltene af forbindelserne med formlen I kan dannes med uorganiske eller organiske syrer. Ud fra de salte, der dannes med uorganiske syrer, er hydrochloriderne, sulfaterne og phosphaterne særlig nyttige, og det samme gælder for hydrogentartraterne, succi-10 naterne, citraterne og ascorbaterne ud fra de salte, der dannes med organiske syrer.The acid addition salts of the compounds of formula I can be formed with inorganic or organic acids. From the salts formed with inorganic acids, the hydrochlorides, sulfates and phosphates are particularly useful, as are the hydrogen tartrates, succinates, citrates and ascorbates from the salts formed with organic acids.
3 1510233 151023
Det er kendt, at apovincaminolet og dets acetat har en virkning på corona rarterien (jfr. fransk patentskrift nr. 2.035.784). Det er ligeledes kendt, at apovincaminolbenzoatet besidder generelle vasodila-toriske egenskaber (jfr. ungarsk patentskrift nr. 166.476; CA 82, 129 5 279 v (1975)), og at esterne af apovincaminol, der dannes med alkan- carboxylsyre med 3-12 carbonatomer, har cerebral vasodilatorisk virkning (jfr. ungarsk patentskrift nr. 171.662, det tilsvarende USA patentskrift nr. 4.108.996 og tysk patentskrift nr. 26.32.118).It is known that the apovincaminol and its acetate have an effect on the corona artery (cf. French Patent No. 2,035,784). It is also known that the apovincaminol benzoate possesses general vasodilator properties (cf. Hungarian Patent No. 166,476; CA 82, 129 5,279 v (1975)) and that the esters of apovincaminol formed with alkanecarboxylic acid having 3-12 carbon atoms, have a cerebral vasodilatory effect (cf. Hungarian Patent No. 171,662, corresponding U.S. Patent No. 4,108,996 and German Patent No. 26,322,118).
Således har alle de kendte estere af apovincaminol vasotropisk virk-10 ning. De nye forbindelser fremstillet ifølge den foreliggende opfindelse inhiberer imidlertid phosphodiesterases enzymaktivitet og kan først og fremmest anvendes til behandling af hudsygdomme, der er forbundet med patologisk celleformering, og til forebyggelse af nye anfald af sådanne sygdomme.Thus, all the known esters of apovincaminol have vasotropic action. However, the novel compounds of the present invention inhibit the enzyme activity of phosphodiesterase and may be used primarily to treat skin diseases associated with pathological cell proliferation and to prevent new onset of such diseases.
15 Sygdomme, der er forbundet med den patologiske vækst af overhuden, er relativt hyppige og omfatter nogle få procent af befolkningen.15 Diseases associated with the pathological growth of the epidermis are relatively frequent and comprise a few percent of the population.
Disse sygdomme kan være både godartede og maligne såsom psoriasis atopias dermatitis, dermatitis forårsaget af primær kontakt, dermatitis forårsaget af allergisk kontakt, baso- og spinocellulær carcinom, 20 ichthyose, præmalign hyperkeratose, lysinduceret keratose, acne og seborrhoea dermatitis. Nogle sygdomme forekommer kun hos mennesker, hvorimod andre forekommer både hos mennesker og dyr.These diseases can be both benign and malignant such as psoriasis atopias dermatitis, primary contact dermatitis, allergic contact dermatitis, baso- and spinocellular carcinoma, ichthyosis, premalignant hyperkeratosis, light-induced keratosis, acne and seborrhoea dermatitis. Some diseases occur only in humans, while others occur in both humans and animals.
Eftersom nogle af de hudsygdomme, der er forbundet med patologisk cellevækst (fx psoriasis), ikke forekommer hos dyr, kan forbindel-25 sernes virkning mod psoriasis kun indirekte gøres sandsynlige i dyreeksperimenter.Since some of the skin diseases associated with pathological cell growth (e.g., psoriasis) do not occur in animals, the effect of the compounds against psoriasis can only be indirectly demonstrated in animal experiments.
Voorhees et al. (Arch. Derm. 704, 359-365, (1971)) har påvist, at en patologisk celleformering er ledsaget af en sænkning i niveauet af cyclisk adenozin-monophosphat (c-AMP). Det er kendt, at c-AMP 30 dannes under indvirkning af adenylcyclase og nedbrydes af phosphodiesterase. Det er lykkedes Voorhees at påvirke psoriasis ved hjælp af midler, som stimulerer adenylcyclases funktion (såsom nor-epineph-rin) eller inhiberer phosphodiesterases funktion (fx papaverin).Voorhees et al. (Arch. Derm. 704, 359-365, (1971)) have demonstrated that a pathological cell proliferation is accompanied by a decrease in the level of cyclic adenozine monophosphate (c-AMP). It is known that c-AMP 30 is formed under the action of adenyl cyclase and is degraded by phosphodiesterase. Voorhees has succeeded in affecting psoriasis by agents that stimulate the function of adenyl cyclase (such as norepinephrine) or inhibit the function of phosphodiesterase (e.g. papaverine).
4 151023 J planlægningen af en modeleksperimenttest er der gået ud fra den antagelse, at Voorhees's udsagn også er relevant i modsat retning.4 151023 J planning a model experiment test is based on the assumption that Voorhees's statements are also relevant in the opposite direction.
Hvis det således kan bevises, at en bestemt forbindelse inhiberer phosphodiesterasens funktion, er det indirekte sandsynligt, at denne 5 forbindelse egner sig til behandling af hudsygdomme, der er forbundet med patologisk celleformering.Thus, if it can be proven that a particular compound inhibits the function of phosphodiesterase, it is indirectly likely that this compound is suitable for the treatment of skin diseases associated with pathological cell proliferation.
Denne antagelse har vist sig at være sand; forbindelser, der har phosphodiesteraseinhiberende virkning i in vitro tests, har tillige vist sig at være virksomme i behandlingen af psoriasis i kliniske eksperi-10 menter.This assumption has proven to be true; compounds that have phosphodiesterase inhibitory effect in in vitro tests have also been shown to be effective in the treatment of psoriasis in clinical experiments.
Modeltestene udføres ved hjælp af phosphodiesterase, som er isoleret fra animalsk kropsvæv [rottehjerne, bovinhjerne og bovinhjerte). Enzymét isoleres ved den af J. Schroder og H.V. Richenberg (Bio-chem. Biophys. Acta 302, 50 (1973)) beskrevne metode, den isolerede 15 phosphodiesterase renses ved den af J.G. Hardman og E.W. Sutherland (J. Biol. Chem. 240, 3704 (1965)) beskrevne metode, og endelig måles det rensede enzyms aktivitet ved den af G. Poch beskrevne radioisotopmetode i nærværelse af et overskud af tritieret c-AMP (10,1 millimol c-AMP-substrat, hvoraf 3H-C-AMP er 2,59 K Bq) i et inkuba-20 tionssystem først uden en inhibitor og derefter- i nærværelse af apo-vincaminol-3r,4',5'-trimethoxybenzoatderivat som inhibitor efter en inkubationsperiode på 20 minutter (N.S. Arch. Pharmacol. 268, 272 (1979)). Ud fra testforbindelsen fremstilles en 1 millimolær stamopløs-ning, og varierende mængder tilsættes det inkuberede enzympræparat 25 ved hjælp af denne stamopløsning, således at koncentrationen af testforbindelsen i den inkuberede prøve svarer til henholdsvis 5 x 10 , 1 x 10 , 5 x 10 , 1 x 10 , 5 x 10 og 10 mol/liter. Den -- vandige opløsning af den forbindelse, der anvendes til sammenligning (papaverin) tilsættes enzymet, som er fremstillet på tilsvarende måde.The model tests are performed using phosphodiesterase, which is isolated from animal body tissue [rat brain, bovine brain and bovine heart]. The enzyme is isolated by that of J. Schroder and H.V. Richenberg (Biochem. Biophys. Acta 302, 50 (1973)) described the isolated phosphodiesterase purified by the J.G. Hardman and E.W. Sutherland (J. Biol. Chem. 240, 3704 (1965)), and finally the activity of the purified enzyme is measured by the radioisotope method described by G. Poch in the presence of an excess of tritiated c-AMP (10.1 millimoles of c. AMP substrate, of which 3H-C-AMP is 2.59 K Bq) in an incubation system first without an inhibitor and then - in the presence of apoquinaminol-3r, 4 ', 5'-trimethoxybenzoate derivative as an inhibitor after 20-minute incubation period (NS Arch. Pharmacol. 268, 272 (1979)). From the test compound, a 1 millimolar stock solution is prepared and varying amounts are added to the incubated enzyme preparation 25 using this stock solution so that the concentration of the test compound in the incubated sample corresponds to 5 x 10, 1 x 10, 5 x 10, 1, respectively. x 10, 5 x 10 and 10 mol / liter. The aqueous solution of the compound used for comparison (papaverine) is added to the enzyme which is prepared in a similar manner.
30 Kontrol prøven s virkning (enzymopløsning, som ikke indeholder nogen inhibitor) får værdien 100%, medens virkningen af de opløsninger, der indeholder forbindelserne med den almene formel I som papaverin udtrykkes som en procentdel af kontrolprøven. Resultaterne målt på det enzym, der isoleres fra rottehjerner, er vist i nedenstående 35 tabel.The effect of the control sample (enzyme solution containing no inhibitor) is given the value 100%, while the effect of the solutions containing the compounds of the general formula I as papaverine is expressed as a percentage of the control sample. The results measured on the enzyme isolated from rat brains are shown in the table below.
Tabel 5 151023Table 5
Testforbindelse Koncentration af testforbindelsen, (enzyminhibitor) mol/liter 5 -— 5 x 10 1 x 10 5 x 10Test compound Concentration of test compound, (enzyme inhibitor) mol / liter 5 - 5 x 10 1 x 10 5 x 10
Indvirkning på enzymaktivitet i procent af kontrolprøven 10 Apovincaminol-3',4',5'- trimethoxybenzoat. HCI 64,5 49,2 47,2 (-)-11 -Nitro-apovinca-minol-3',4’,5'-trimethoxy- benzoat.HCI 53,6 44,4 37,3 15 (-)-9-Nitro-apovincaminol- 3',4',5'-trimethoxybenzoat. HCI 62,9 61,6 37,7Effect on enzyme activity as a percentage of the control sample 10 Apovincaminol-3 ', 4', 5'-trimethoxybenzoate. HCl 64.5 49.2 47.2 (-) - 11-Nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate. HCl 53.6 44.4 37.3 (-) - 9-Nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate. HCl 62.9 61.6 37.7
Papaverin 91,2 89,7 60,5Papaverine 91.2 89.7 60.5
Resultaterne for det enzym, der isoleres fra bovinhjerne og bovin-20 hjerte, måles på tilsvarende måde. Ved at anvende de opnåede resultater udregnes enzymaktiviteten på baggrund af logaritmen af enzym-inhibitorkoncentrationen (udtrykt i ymol). Koncentrationen af den enzyminhibitor, som formindsker enzymaktiviteten med 50% (I^Q-værdi) aflæses af kurven. De opnåede resultater er vist i nedenstående 25 tabel.The results for the enzyme isolated from bovine brain and bovine heart are similarly measured. Using the results obtained, the enzyme activity is calculated based on the logarithm of the enzyme inhibitor concentration (expressed in ymol). The concentration of the enzyme inhibitor which reduces the enzyme activity by 50% (1Q value) is read by the curve. The results obtained are shown in the table below.
Tabel 6 151023 _\_ l^Q-Værdier, i ymol på phospho-Testforbindelse diesteraseenzym isoleret fra 5 bovinhjerte rottehjerneTable 6 151023 values in ymoles of phospho-Test compound diesterase enzyme isolated from 5 bovine heart rat brain
Apovincaminol-3',4',5'-tri- méthoxybenzoat . HCI 1,5 10 (-)-ll-Nitro-apovincaminoI- 10 3',4',5'-trimethoxybenzoat . HCI 1 8 -(-)-9-Nitro-apovincaminol- 3',4',5’-trimethoxybenzoat . HCI 1 15Apovincaminol-3 ', 4', 5'-trimethoxybenzoate. HCl 1.5 (-) - 11-Nitro-apovincamino-3 ', 4', 5'-trimethoxybenzoate. HCl 18 - (-) - 9-Nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate. HCl 1 15
Papaverin . HCI 50 70 15 Af ovenstående tabel fremgår det, at de nye forbindelser fremstillet ifølge opfindelsen er henholdsvis 33-50 og 4,5-9 gange mere virksomme på det enzym, der er isoleret fra bovinhjerte og rottehjerne, end papaverinet anvendt som referenceforbindelse.Papaverin. HCl 50 70 15 The above table shows that the novel compounds of the invention are 33-50 and 4.5-9 times more effective, respectively, on the enzyme isolated from bovine heart and rat brain than the papaverine used as a reference compound.
De .første kliniske tests blev udført med topiske præparater, som 20 indeholder den aktive bestanddel (salve, creme, opløsning, tinktur, pasta og aerosol). Der blev anvendt cremer, som indeholder 2%, 1%, 0,5%, 0,25% og 0,1% af henholdsvis (-)-9-nitro- eller (-)-ll-nitro-apo-vi n caminol -3' ,4', 5-' -trimethoxybenzoat .-The first clinical tests were performed with topical preparations containing the active ingredient (ointment, cream, solution, tincture, paste and aerosol). Creams containing 2%, 1%, 0.5%, 0.25% and 0.1% of (-) - 9-nitro- or (-) - 11-nitro-apo-vi respectively were used. caminol -3 ', 4', 5- 'trimethoxybenzoate.
Der behandles patienter, der lider af psoriasis. Et grundlæggende 25 udvælgelseskriterium er, at patienterne ikke samtidig modtager systemisk behandling af deres grundlæggende sygdom (fx immunosuppres-siv, cytostatisk eller glucocorticoid behandling).Patients suffering from psoriasis are treated. A basic selection criterion is that patients do not simultaneously receive systemic treatment of their basic disease (e.g., immunosuppressive, cytostatic or glucocorticoid therapy).
Grupper, som hver består af fem patienter, undersøges ved den såkaldte piaquemetode. Én side af de symmetriske hudlæsioner behand-30 les med cremen, som indeholder den aktive bestanddel, medens den 7 151023 anden side behandles med et placebo. Patientens øvrige angrebne hudflader behandles ved andre topiske metoder, blandt andet med en salve, der sædvanligvis anvendes til behandling af psoriasis, og som indeholder flumethasonpivalat og salicylsyre, hvilken salve anvendes 5 som referencepræparat.Groups, each consisting of five patients, are investigated by the so-called piaque method. One side of the symmetrical skin lesions is treated with the cream containing the active ingredient, while the other side is treated with a placebo. The other affected skin surfaces of the patient are treated by other topical methods, including an ointment usually used for the treatment of psoriasis and containing flumethasone pivalate and salicylic acid, which ointment is used as a reference preparation.
Testen indledes med cremer, der har et højt indhold af aktiv bestanddel, og yderligere patienter behandles med en creme med det laveste indhold af aktiv bestanddel, men som stadig er virksom. Behandlingen fortsætter i to uger, to gange om dagen, i en åben 10 forbinding.The test begins with creams that have a high active ingredient content, and additional patients are treated with a cream with the lowest active ingredient content but still effective. Treatment continues for two weeks, twice a day, in an open dressing.
Virkningen vurderes ved at iagttage tre forskellige symptomer, nemlig inflammation, infiltration og deskvamation (afskalning). Symptomernes styrke udtrykkes ved den nedenstående skala mellem 0 og 3 0 = ingen symptomer 15 1 = moderat symptom 2 = kraftigt symptom 3 = meget kraftigt symptom.The effect is assessed by observing three different symptoms, namely inflammation, infiltration and desquamation (peeling). The strength of the symptoms is expressed on the scale below between 0 and 30 0 = no symptoms 15 1 = moderate symptom 2 = severe symptom 3 = very severe symptom.
Symptomerne vurderes før behandling (I), efter behandling i syv dage (II) og efter behandling i fjorten dage (III). I nedenstående 20 tabel vises det gennemsnitlige antal point (det samlede antal point divideret med antallet af patienter). Der anvendes en creme, som indeholder 2% aktiv bestanddel.Symptoms are assessed before treatment (I), after treatment for seven days (II) and after treatment for fourteen days (III). The following table shows the average number of points (the total number of points divided by the number of patients). A cream containing 2% active ingredient is used.
Tabel 8 151023Table 8 151023
Gennemsnitligt antal pointAverage number of points
Testforbindelse Infiltration Inflammation DeskvamationTest compound Infiltration Inflammation Desquamation
I II III I II III I li IIII II III I II III I li III
5 ----5 ----
Forbindelse med formlen la 1,8 0,6 0,5 1,8 1,3 0,75 1,2 0,4 0Compound of formula Ia 1.8 0.6 0.5 1.8 1.3 0.75 1.2 0.4 0
Forbindelse med formlen Ib 2,2 1 0,7 2,5 2,5 1,3 1,5 0,5 0 10 Forbindelse med formlen le 2,4 1,8 1,3 2,2 1,3 1,3 1,6 1,2 0,8Compound of Formula Ib 2.2 1 0.7 2.5 2.5 1.3 1.5 0.5 0 10 Compound of Formula Le 2.4 1.8 1.3 2.2 1.3 1.3 1.6 1.2 0.8
Fremgangsmåden ifølge opfindelsen udføres fortrinsvis i nærværelse af et organisk opløsningsmiddel, især et chloreret carbonhydrid eller en 15 aliphatisk keton eller pyridin, især methylenchlorid, chloroform eller acetone. Hvis der som acyleringsmiddel anvendes et 3,4,5-trimethoxy-benzoylhalogenid, udføres omsætningen i nærværelse af en ækvimolær mængde eller et lille overskud af et syrebindemiddel. Til dette formål kan anvendes fx et alkalimetalcarbonat, alkalimetalhydrogencarbonat 20 eller en organisk amin. Hvis der som acyleringsmiddel anvendes 3,4,5-trimethoxybenzoesyre, udføres omsætningen i nærværelse af en katalytisk mængde af en syre, fortrinsvis saltsyre eller svovlsyre, eller en aktivator af carboxygruppen og/eller et dehydreringsmiddel. Carboxygruppen kan aktiveres af en halogeneret phenol, fortrinsvis 25 pentachiorphenol. Som dehydreringsmiddel kan anvendes fx N,N'-di-cyclohexyl-carbodimid. Acyleringen kan udføres ved en temperatur på mellem -20°C og reaktionsblandingens kogepunkt, fortrinsvis 20-60°C.The process of the invention is preferably carried out in the presence of an organic solvent, in particular a chlorinated hydrocarbon or an aliphatic ketone or pyridine, in particular methylene chloride, chloroform or acetone. If an 3,4,5-trimethoxy-benzoyl halide is used as the acylating agent, the reaction is carried out in the presence of an equimolar amount or a small excess of an acid binder. For this purpose, for example, an alkali metal carbonate, alkali metal hydrogen carbonate 20 or an organic amine may be used. If 3,4,5-trimethoxybenzoic acid is used as the acylating agent, the reaction is carried out in the presence of a catalytic amount of an acid, preferably hydrochloric or sulfuric acid, or an activator of the carboxy group and / or a dehydrating agent. The carboxy group may be activated by a halogenated phenol, preferably pentachiorphenol. As dehydrating agent, for example, N, N'-di-cyclohexylcarbodimide may be used. The acylation may be carried out at a temperature between -20 ° C and the boiling point of the reaction mixture, preferably 20-60 ° C.
Forbindelsen med formlen la kan isoleres fra reaktionsblandingen ved ekstraktion og/eller inddampning.The compound of formula Ia can be isolated from the reaction mixture by extraction and / or evaporation.
9 1510239 151023
Det således vundne produkt kan som anført omdannes til et farmaceutisk tolerabelt syreadditionssalt. Saltdannelse kan udføres ved at anvende en uorganisk eller organisk syre (fx saltsyre, svovlsyre eller phosphorsyre eller vinsyre, ravsyre, citronsyre eller ascorbinsyre).The product thus obtained can be converted into a pharmaceutically tolerable acid addition salt as indicated. Salt formation can be carried out by using an inorganic or organic acid (e.g. hydrochloric, sulfuric or phosphoric or tartaric, succinic, citric or ascorbic).
5 Saltdannelsen udføres på i og for sig kendt måde. Der kan fortrinsvis gås frem ved at sætte en opløsning af syren i ethylether eller acetone til opløsningen af basen. Saltdannelse opnås ved en pH-værdi på 3-6.5 Salt formation is carried out in a manner known per se. It is preferable to proceed by adding a solution of the acid in ethyl ether or acetone to the solution of the base. Salt formation is achieved at a pH of 3-6.
Den således vundne forbindelse med formlen la kan som anført om ønsket nitreres. Nitrering kan fortrinsvis udføres ved hjælp af kon-10 centreret salpetersyre. Omsætningen udføres fortrinsvis i iseddike som medium. Nitreringen udføres fortrinsvis under afkøling ved en temperatur på ca. 0°C. Når reaktionen er løbet til ende, neutraliseres overskuddet af syre, og den således vundne blanding af forbindelserne med formlen Ib og le isoleres fra reaktionsblandingen ved ekstrak-15 tion og/eller inddampnmg.The compound thus obtained of formula Ia may be nitrated as indicated if desired. Nitration can preferably be carried out by means of concentrated nitric acid. The reaction is preferably carried out in glacial acetic acid as a medium. The nitration is preferably carried out under cooling at a temperature of approx. 0 ° C. When the reaction is complete, the excess acid is neutralized and the thus obtained mixture of the compounds of formula Ib and le is isolated from the reaction mixture by extraction and / or evaporation.
Den således vundne isomerblanding adskilles i de to bestanddele. Adskillelsen af isomererne kan fortrinsvis udføres ved chromatografi.The isomer mixture thus obtained is separated into the two components. The separation of the isomers can preferably be carried out by chromatography.
Forbindelserne med formlen Ib og le kan om ønsket omdannes til farmaceutisk tolerable syreadditionssalte deraf ved de i forbindelse 20 med fremstillingen af syreadditionssaltene af forbindelsen med formlen la beskrevne metoder.The compounds of formula Ib and le may, if desired, be converted into pharmaceutically tolerable acid addition salts thereof by the methods described in connection 20 with the preparation of the acid addition salts of the compound of formula la.
Fremgangsmåden ifølge opfindelsen muliggør tilvejebringelse af farmaceutiske præparater med phosphodiesteraseinhiberende virkning, der hovedsagelig kan anvendes til behandling af hudsygdomme, som er 25 forbundet med patologisk celleformering, og forebyggelsen af nye anfald af disse sygdomme, idet disse præparater som den aktive bestanddel omfatter en forbindelse med den almene formel I eller et farmaceutisk tolerabelt syreadditionssalt deraf og eventuelt yderligere terapeutisk virksomme forbindelser i en blanding med sædvanlige 30 farmaceutiske bærere og/eller fortyndingsmidler.The method of the invention allows for the provision of pharmaceutical compositions with phosphodiesterase inhibitory effect which can be used mainly for the treatment of skin diseases associated with pathological cell proliferation, and the prevention of new attacks of these diseases, these compositions comprising the compound of the active ingredient. general formula I or a pharmaceutically tolerable acid addition salt thereof and optionally additional therapeutically effective compounds in a mixture with conventional pharmaceutical carriers and / or diluents.
Indholdet af aktiv bestanddel i de farmaceutiske præparater ifølge opfindelsen er fortrinsvis 0,1-8,0%, især 0,2-2,0%. Præparaterne kan 151023 ίο eventuelt yderligere indeholde farmaceutisk og terapeutisk virksomme forbindelser såsom antibiotika, cytostatiske midler, prostaglandiner, ditranol, salicylsyre, tjære, antiinflammationsmidler, immunosuppressive midler, glucocorticoid og - hvad angår præparater, der egner sig 5 til parenteral administration - lokalbedøvende midler. Som glucocorticoid kan der fortrinsvis anvendes triamcinolon-acetonid. Den aktive bestanddel kan færdigbehandles fortrinsvis i form af præparater til topisk anvendelse såsom cremer, salver, opløsninger, geléer, aerosoler, aerosolskum eller adhæsive plastre.The active ingredient content of the pharmaceutical compositions of the invention is preferably 0.1-8.0%, especially 0.2-2.0%. The compositions may optionally further contain pharmaceutically and therapeutically active compounds such as antibiotics, cytostatic agents, prostaglandins, ditranol, salicylic acid, tar, anti-inflammatory agents, immunosuppressants, glucocorticoids and - in the case of preparations suitable for parenteral administration - topical drugs. As a glucocorticoid, triamcinolone-acetonide can preferably be used. The active ingredient may preferably be pre-treated in the form of topical preparations such as creams, ointments, solutions, jellies, aerosols, aerosol foams or adhesive patches.
10 Den aktive bestanddel kan fortrinsvis anvendes i form af basen, men også syreadditionssalte kan anvendes.The active ingredient may preferably be used in the form of the base, but acid addition salts may also be used.
. Det foretrækkes at inkorporere den aktive bestanddel i en creme, der , kan afvaskes.. It is preferred to incorporate the active ingredient into a cream which can be washed.
Cremer kan fremstilles ved at opløse den aktive bestanddel i et opløs-15 ningsmiddel af alkoholtypen, fortrinsvis i propylenglycol eller ethy-lenglycol eller en blanding deraf, der er dannet med en ringe mængde vand, og blande den således vundne opløsning med en fedtfase, der let kan påsmøres, og som er hud kompatibel.Creams can be prepared by dissolving the active ingredient in an alcohol-type solvent, preferably in propylene glycol or ethylene glycol or a mixture thereof formed with a small amount of water, and mixing the thus obtained solution with a fat phase which can be easily applied and is skin compatible.
Fedtfasen kan omfatte cetylalkohol, stearylalkohol, cetostearylalkohol, 20 paraffinolie eller glycerin-monostearat.The fat phase may include cetyl alcohol, stearyl alcohol, cetostearyl alcohol, paraffin oil or glycerine monostearate.
Cremen kan også indeholde et emulgeringsmiddel, fortrinsvis polyoxy-ethylensorbitan-monooieat eller -monostearat, og et konserveringsmiddel såsom benzoesyrederivater, fortrinsvis methyl-p-hydroxybenzoat.The cream may also contain an emulsifier, preferably polyoxyethylene sorbitan monoosteate or monostearate, and a preservative such as benzoic acid derivatives, preferably methyl p-hydroxybenzoate.
Cremerne kan fortrinsvis indeholde 0,25-2,0% aktiv bestanddel, 45-50% 25 glycol, 23-27% paraffinolie, 11-15% stearylalkohol og eventuelt andre hjælpestoffer i op til 100%.The creams may preferably contain 0.25-2.0% active ingredient, 45-50% glycol, 23-27% paraffin oil, 11-15% stearyl alcohol and optionally other adjuvants up to 100%.
Den aktive bestanddel kan også formuleres i form af en salve, der ikke kan vaskes af med vand, ved at inkorporere den aktive bestanddel direkte i fedtfasen.The active ingredient may also be formulated in the form of an ointment which cannot be washed off with water by incorporating the active ingredient directly into the fat phase.
11 15102311 151023
Den aktive bestanddel kan også formuleres i form af en opløsning eller tinktur, der kan indeholde fx 20-40% propylenglycol eller di-propylenglycol, 40-55% 96%'s ethanol og destilleret vand i op til 100%.The active ingredient may also be formulated in the form of a solution or tincture which may contain, for example, 20-40% propylene glycol or dipropylene glycol, 40-55% 96% ethanol and distilled water in up to 100%.
Aerosolformuleringerne kan fremstilles ved til opløsningen af den 5 aktive bestanddel i propylenglycol at sætte et fedtstof, fx isopropyl-myristat, og et drivmiddel, fx freon.The aerosol formulations can be prepared by adding to the solution of the active ingredient in propylene glycol a fat, e.g., isopropyl myristate, and a propellant, e.g., Freon.
Injicerbare opløsninger, der egner sig til parenteral administration og fortrinsvis er anvendelige ad subcutan eller intracutan vej, kan fremstilles ved at opløse et salt af den aktive bestanddel i en 0,72%’s 10 opløsning af vandigt natriumchlorid og indstille opløsningens pH-værdi til 5.Injectable solutions suitable for parenteral administration and preferably useful by subcutaneous or intracutaneous route can be prepared by dissolving a salt of the active ingredient in a 0.72% 10 aqueous sodium chloride solution and adjusting the pH of the solution to 5th
De farmaceutiske præparater kan fremstilles ved metoder, der er kendt i lægemiddelindustrien. Der kan gås frem ved at blande den aktive bestanddel og eventuelt yderligere terapeutisk virksomme 15 forbindelser med egnede inerte ikke-toxiske kendte farmaceutiske bærere og/eller tilsætningsstoffer og færdigbehandle en således vunden blanding, til den har en form, der egner sig til medicinsk anvendelse.The pharmaceutical compositions can be prepared by methods known in the pharmaceutical industry. It can be proceeded by mixing the active ingredient and optionally additional therapeutically active compounds with suitable inert non-toxic known pharmaceutical carriers and / or additives and finalizing a thus obtained mixture until it has a form suitable for medical use.
Opfindelsen er nærmere belyst ved nedenstående eksempler.The invention is further illustrated by the following examples.
20 EKSEMPEL 1EXAMPLE 1
Fremstilling af (-j-apovincaminol-S'^'^'-trimethoxybenzoat 3,10 g (10,1 millimol) (-)-apovincaminol opløses i 60 ml vandfrit dichlormethan, hvorefter der tilsættes 3,10 g vandfrit natriumcarbonat og 2,50 g (10,9 millimol) 3,4,5-trimethoxybenzoylchlorid, og reakti-25 onsblandingen omrøres ved stuetemperatur i 24 timer. Reaktionsblandingen fortyndes med 100 ml vand, den organiske fase fraskilles, og den vandige fase ekstraheres to gange med hver gang 20 ml dichlormethan. De samlede dichlormethanfaser tørres over magnesiumsulfat, filtreres, og filtratet inddampes i vakuum. Derved fås 4,50 g af 30 titelforbindelsen, udbytte 89,1%.Preparation of (-j-apovincaminol-5 '' - trimethoxybenzoate 3.10 g (10.1 millimoles) (-) - apovincaminol is dissolved in 60 ml of anhydrous dichloromethane, then 3.10 g of anhydrous sodium carbonate and 2, 50 g (10.9 millimoles) of 3,4,5-trimethoxybenzoyl chloride and the reaction mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with 100 ml of water, the organic phase is separated and the aqueous phase is extracted twice with each time. The combined dichloromethane phases are dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give 4.50 g of the title compound, yield 89.1%.
12 15102312 151023
Bruttoformel ^39^34^2^5- Molekylvægt 502,61.Gross formula ^ 39 ^ 34 ^ 2 ^ 5- Molecular weight 502.61.
IR-Spektrum (film): v = 1725 (-C=0) og 1620 (=C=C=) cm 1.IR Spectrum (film): v = 1725 (-C = O) and 1620 (= C = C =) cm
max NMR-Spektrum (CDCI^): δ (ppm) = 1,01 (t, 3H, CA/gCh^-); 3,72 (s, 6H, 2 x -OCHg); 3,85 (s, 3H, -OCHg); 4,25 (s, 1H, anellering); 5 5,29 (s, 1H, -CH=); 5,4 (m, 2H, -OCl·^); 7,0-7,8 (m, 6H, aroma tisk) .max NMR Spectrum (CDCl3): δ (ppm) = 1.01 (t, 3H, CA / g 3.72 (s, 6H, 2 x -OCH 3); 3.85 (s, 3H, -OCHg); 4.25 (s, 1H, annealing); 5.29 (s, 1H, -CH =); 5.4 (m, 2H, -OCl · +); 7.0-7.8 (m, 6H, aromatic).
Massespektrum: m/e = 502(53), 432(100), 290(17), 261(41), 220(19), 216(23), 212(18), 195(35).Mass spectrum: m / e = 502 (53), 432 (100), 290 (17), 261 (41), 220 (19), 216 (23), 212 (18), 195 (35).
[oi]q1 = -22,0° (c = 0,7; CH2CI2).[α] D = -22.0 ° (c = 0.7; CH 2 Cl 2).
10 EKSEMPEL 2EXAMPLE 2
Fremstilling af (-)-apovincaminol-3',4',5'-trimethoxybenzoat-hydrogen-tartratPreparation of (-) - apovincaminol-3 ', 4', 5'-trimethoxybenzoate hydrogen tartrate
En i eksempel 1 fremstillet forbindelse opløses i diethylether. Til opløsningen sættes en mættet opløsning af D-vinsyre i diethylether, 15 indtil udfældningen af hydrogentartratsaltet er fuldført. Saltet fra-filtreres og tørres. Smeltepunkt, 120-121°C.A compound prepared in Example 1 is dissolved in diethyl ether. To the solution is added a saturated solution of D-tartaric acid in diethyl ether until the precipitation of the hydrogen tartrate salt is complete. The salt is filtered off and dried. Melting point, 120-121 ° C.
IR-Spektrum (KBr): v = 1730 (-C=0) og 1640-1665 (=C=C=) cm"1.IR Spectrum (KBr): v = 1730 (-C = 0) and 1640-1665 (= C = C =) cm
ΓΠ3Χ [a]^ = -8,5° (c = 1 i pyridin)ΓΠ3Χ [a] + = -8.5 ° (c = 1 in pyridine)
Molekylvægt 652,7.Molecular Weight 652.7.
20 EKSEMPEL 3EXAMPLE 3
Fremstilling af (-l-O-nitro-apovincaminol-S'^'^S'-trimethoxybenzoat og (-)-11-nitro-apovincaminol-3',4’,5'-trimethoxybenzoat g (-)-apovincaminol-3',4',5'-trimethoxybenzoat opløses i 50 ml iseddike. Til den vundne opløsning sættes en blanding af 20 ml iseddike 25 og 10 ml koncentreret salpetersyre (d - 1,52) ved 0°C under omrøring. Reaktionsblandingen hældes i 350 mg iskoldt vand, og pH-vær-dien indstilles på 9 ved tilsætning af en 25%'s opløsning af vandigt 13 151023 ammoniumhydroxid. Den alkaliske opløsning ekstraheres først med 250 ml og derefter to gange med hver gang 200 ml dichlormethan. Den samlede organiske opløsning tørres over vandfrit natriumsulfat og filtreres, og filtratet inddampes, til tørhed i vakuum.Preparation of (-10-nitro-apovincaminol-5'-5'-trimethoxybenzoate and (-) - 11-nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate g (-) - apovincaminol-3 ', Dissolve 4 ', 5'-trimethoxybenzoate in 50 ml of glacial acetic acid. To the solution obtained, add a mixture of 20 ml glacial acetic acid 25 and 10 ml of concentrated nitric acid (d - 1.52) at 0 ° C with stirring. water and the pH is adjusted to 9 by adding a 25% solution of aqueous ammonium hydroxide. The alkaline solution is first extracted with 250 ml and then twice with 200 ml of dichloromethane each time. The total organic solution is dried. over anhydrous sodium sulfate and filtered and the filtrate evaporated to dryness in vacuo.
5 En således vunden isomerblanding adskilles i de to bestanddele ved chromatografi under anvendelse af silicagel 60 som adsorbent og en 10:2-blanding af benzen og acetone som udviklingsmiddel. Under disse betingelser er 9-nitroforbindelsens R^-værdi større end 11-nitroderi-vatets R^-værdi. Således fås 1,7 g af 9-nitroforbindelsen og 1,8 g af 10 11-nitroderivatet.An isomer mixture thus obtained is separated into the two components by chromatography using silica gel 60 as adsorbent and a 10: 2 mixture of benzene and acetone as the developing agent. Under these conditions, the R ^ value of the 9-nitro compound is greater than the R ^ value of the 11-nitroderate. Thus, 1.7 g of the 9-nitro compound and 1.8 g of the 10-11 nitro derivative are obtained.
(-J-O-Nitro-apovincaminol-S'^'/S'-trimethoxybenzoatets fysiske konstanter er følgende, smeltepunkt 77-78°C.The physical constants of the (-J-O-Nitro-apovincaminol-S '^' / S 'trimethoxybenzoate are as follows, m.p. 77-78 ° C.
[a]D = -78,5° (c = 1 i CHClg).[α] D = -78.5 ° (c = 1 in CHCl 3).
15 ^H-NMR-Spektrum (CDCIg): 6 (ppm) = 3,8 (s, 6H, 2 x CH30-); 3,91 (s, 3H, 1 x CH3O-); 7,3 (d, IH, H12); 7,96 (d, IH, Hn); 8,1 (d, 1H, H10).1 H-NMR Spectrum (CDCl 3): δ (ppm) = 3.8 (s, 6H, 2 x CH 3 O); 3.91 (s, 3H, 1 x CH 3 O-); 7.3 (d, 1H, H12); 7.96 (d, 1H, Hn); 8.1 (d, 1H, H10).
(-)-11-Nitro-apovincaminol-3',4',5'-trimethoxybenzoatets fysiske konstanter er følgende, 20 smeltepunkt 72-73°C.The physical constants of the (-) - 11-Nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate are as follows, m.p. 72-73 ° C.
[a]D = -134,3° (c = 1 i CHCI3).[α] D = -134.3 ° (c = 1 in CHCl 3).
1 H-NMR-Spektrum (CDCLj): 5 (ppm) = 3,8 (s, 6H, 2 x CH3<>); 3,9 (s, 3H, 1 x CH30-); 7,56 (d, IH, Hg); 8,1 (d, IH, H1()); 8,9 (d, IH, H12).1 H NMR Spectrum (CDCL 3): δ (ppm) = 3.8 (s, 6H, 2 x CH 3 <>); 3.9 (s, 3H, 1 x CH 3 O); 7.56 (d, 1H, Hg); 8.1 (d, 1H, H1 ()); 8.9 (d, 1H, H12).
14 151023 EKSEMPEL 4EXAMPLE 4
Fremstilling af Ø-nitro-apovincaminol-S’^^S'-trimethoxybenzoat-hydro-chlorid og 11-nitro-apovincaminol-3’,4’,5’-trimethoxybenzoat-hydrochlo-rid 5 Det i eksempel 3 fremstillede 9-nitro- eller 11-nitro-apovincaminol-S'^'jS'-trimethoxybenzoat opløses i methanol, og opløsningens pH-værdi indstilles ved tilsætning af en opløsning af hydrogenchlorid og methanol. Det dannede hydrochloridsalt udfældes ved tilsætning af diethylether. Saltet frafiltreres, vaskes og tørres. 9-Nitroderivatets 10 hydrochlorid har et smeltepunkt på 144-150°C, medens 11-nitroderiva-tets hydrochlorid har et smeltepunkt på 141-144°C.Preparation of O-Nitro-Apovincaminol-S '^^ S'-trimethoxybenzoate hydrochloride and 11-nitro-apovincaminol-3', 4 ', 5'-trimethoxybenzoate hydrochloride 5 The 9-nitro prepared in Example 3 - or 11-nitro-apovincaminol-S '^ jSS trimethoxybenzoate is dissolved in methanol and the pH of the solution is adjusted by adding a solution of hydrogen chloride and methanol. The hydrochloride salt formed is precipitated by the addition of diethyl ether. The salt is filtered off, washed and dried. The 9-nitro derivative hydrochloride has a melting point of 144-150 ° C, while the 11-nitro derivative hydrochloride has a melting point of 141-144 ° C.
EKSEMPEL 5EXAMPLE 5
Der fremstilles en creme med følgende sammensætningA cream of the following composition is prepared
Bestanddel Mængde (g) 15 - -Ingredient Quantity (g) 15 - -
Apovincaminol-3',4',5'-trimethoxybenzoat 2Apovincaminol-3 ', 4', 5'-trimethoxybenzoate 2
Propylenglycol 50Propylene Glycol 50
Paraffinolie 26Paraffin Oil 26
Polyethylenglycol 5 20 S tea ry lal kohol 15Polyethylene glycol 5 20 S tea ry lal carbon 15
Glycerol-monostearat 2Glycerol Monostearate 2
Den aktive bestanddel opløses i propylenglycol i vandbad (idet badets temperatur ikke overstiger 50°C). De øvrige bestanddele opvarmes, indtil de smelter, og afkøles derefter til 40-45°C under konstant 25 omrøring. Til de smeltede bestanddele sættes under omrøring opløsningen af den aktive bestanddel, og den således vundne creme afkøles under omrøring.The active ingredient is dissolved in propylene glycol in a water bath (since the temperature of the bath does not exceed 50 ° C). The other ingredients are heated until melted and then cooled to 40-45 ° C with constant stirring. To the melted ingredients, the solution of the active ingredient is added, with stirring, and the cream thus obtained is cooled with stirring.
På tilsvarende måde fremstilles cremer, der indeholder henholdsvis 0,25%, 0,5%, 1,0% og 1,5% af den aktive bestanddel.Similarly, creams containing 0.25%, 0.5%, 1.0% and 1.5% of the active ingredient are prepared, respectively.
i 15 151023in 151023
Den aktive bestanddel 9-nitro- eller H-nitro-apovincaminol-3’,4',5'-trimethoxybenzoat kan også anvendes.The active ingredient 9-nitro- or H-nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate can also be used.
EKSEMPEL 6EXAMPLE 6
Der fremstilles en creme med følgende sammensætning 5 Bestanddel Mængde (g) 9-Nitro-apovincaminol-3',4’,5'-trimethoxy-benzoat 2A cream of the following composition is prepared. Component Amount (g) 9-Nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate 2
Triamcinolonacetonid 0,1 10 Glycerol-monostearat 3,0Triamcinolone Acetonide 0.1 Glycerol Monostearate 3.0
Polyethylenglycol 400 5,0Polyethylene Glycol 400 5.0
Stearylalkohol 13,0Stearyl alcohol 13.0
Paraffinolie 24,9Paraffin Oil 24.9
Propylenglycol 53,0 15 Der gås frem på tilsvarende måde som i eksempel 5 med undtagelse af, at der opløses to aktive bestanddele i propylenglycol. 11-Nitrode-rivatet eller apovincaminol-3',4',5'-trimethoxybenzoatet kan ligeledes anvendes som aktiv bestanddel.Propylene Glycol 53.0 15 Proceed in the same manner as in Example 5 except that two active ingredients are dissolved in propylene glycol. The 11-nitrode derivative or apovincaminol-3 ', 4', 5'-trimethoxybenzoate can also be used as active ingredient.
EKSEMPEL 7 20 Fremstilling af en tinkturopløsning med følgende sammensætningExample 7 20 Preparation of a tincture solution of the following composition
Bestanddel Mængde (g) 9-Nitro-apovincaminol-3,,4,,5'-trimeth-oxybenzoat 1 25 Propylenglycol 30 96%'s methanol 69 16 151023Ingredient Amount (g) 9-Nitro-apovincaminol-3,4,4,5'-trimethoxybenzoate 1 25 Propylene glycol 30 96% methanol 69 16 151023
Den ovennævnte fremgangsmåde kan også udføres under anvendelse af 11-nitroderivaterne som de aktive bestanddele.The above process can also be carried out using the 11-nitro derivatives as the active ingredients.
EKSEMPEL 8EXAMPLE 8
Der fremstilles en tinkturopløsning med følgende sammensætning 5 Bestanddel Mængde (%)A tincture solution of the following composition is prepared 5 Component Amount (%)
Apovincaminol-S'^^S'-trimethoxybenzoat-hydrogentartrat 1Apovincaminol-S '^^ S'-trimethoxybenzoate hydrogen tartrate 1
Propylenglycol 30 10 96%'s ethanol 47Propylene Glycol 30 10 96% Ethanol 47
Destilleret vand 22 EKSEMPEL 9Distilled water 22 EXAMPLE 9
Der fremstilles en aerosol med følgende sammensætningAn aerosol of the following composition is prepared
Bestanddel Mængde (%) 15 - -Ingredient Quantity (%) 15 - -
Apovincaminol-3',4,/5,-trimethoxybenzoat-hydrogentartrat 0,5Apovincaminol-3 ', 4, 5, -trimethoxybenzoate hydrogen tartrate 0.5
Propylenglycol 30 I sopropylmy ristat 4,5 20 Freon 65 9-Nitro- eller 11-nitroderivatet kan også anvendes som aktiv bestanddel.Propylene glycol 30 in sopropyl myristate 4.5 20 Freon 65 9-Nitro or 11-nitro derivative may also be used as active ingredient.
Claims (8)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU81322A HU183324B (en) | 1981-02-11 | 1981-02-11 | Process for preparing new apovincaminol-3',4',5'-trimethoxy-benzoate and acid addition salts thereof |
| HU81323A HU183325B (en) | 1981-02-11 | 1981-02-11 | Process for preparing new apovincaminol-3',4',5'-trimethoxy-benzoates substituted with a nitro group |
| HU32281 | 1981-02-11 | ||
| HU32381 | 1981-02-11 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK57782A DK57782A (en) | 1982-08-12 |
| DK151023B true DK151023B (en) | 1987-10-12 |
| DK151023C DK151023C (en) | 1988-06-27 |
Family
ID=26317194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK057782A DK151023C (en) | 1981-02-11 | 1982-02-10 | METHOD OF ANALOGY FOR THE PREPARATION OF APOVINCAMINOL-3 ', 4', 5'-TRI-METHOXYBENZOATE DERIVATIVES |
Country Status (19)
| Country | Link |
|---|---|
| AR (1) | AR227574A1 (en) |
| AT (1) | AT386203B (en) |
| AU (1) | AU544455B2 (en) |
| CA (1) | CA1202028A (en) |
| CH (1) | CH651038A5 (en) |
| DD (1) | DD202570A5 (en) |
| DE (1) | DE3204509A1 (en) |
| DK (1) | DK151023C (en) |
| ES (1) | ES509419A0 (en) |
| FI (1) | FI70215C (en) |
| FR (1) | FR2499571B1 (en) |
| GB (1) | GB2094787B (en) |
| GR (1) | GR75857B (en) |
| IL (1) | IL64808A (en) |
| IT (1) | IT1157301B (en) |
| NL (1) | NL8200490A (en) |
| NO (1) | NO820394L (en) |
| SE (1) | SE449863B (en) |
| SU (1) | SU1093249A3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU192013B (en) * | 1984-04-25 | 1987-04-28 | Richter Gedeon Vegyeszet | Process for production of new aporincavinol esther derivatives |
| HU193772B (en) * | 1985-06-12 | 1987-11-30 | Richter Gedeon Vegyeszet | Process for producing new nitro-bis-indole derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2035784A1 (en) * | 1969-03-27 | 1970-12-24 | Olivier Louisette | Vincamine derivs with therapeutic propert- - ies |
| HU170888B (en) * | 1975-06-10 | 1977-09-28 | Richter Gedeon Vegyeszet | Process for producing new, optically active eburnamenine derivatives |
| HU171662B (en) * | 1975-07-18 | 1978-02-28 | Richter Gedeon Vegyeszet | Process for preparing new optically active derivatives of apovincaminol and acid addition salts thereof |
| HU177370B (en) * | 1977-07-27 | 1981-09-28 | Richter Gedeon Vegyeszet | Process for producing new bracket-cross-bracket-vincaminol-esters |
-
1982
- 1982-01-18 SE SE8200248A patent/SE449863B/en not_active IP Right Cessation
- 1982-01-19 IL IL64808A patent/IL64808A/en unknown
- 1982-01-25 CA CA000394857A patent/CA1202028A/en not_active Expired
- 1982-01-26 AT AT0026082A patent/AT386203B/en not_active IP Right Cessation
- 1982-01-29 CH CH565/82A patent/CH651038A5/en not_active IP Right Cessation
- 1982-02-03 FI FI820339A patent/FI70215C/en not_active IP Right Cessation
- 1982-02-08 GR GR67242A patent/GR75857B/el unknown
- 1982-02-08 ES ES509419A patent/ES509419A0/en active Granted
- 1982-02-09 NL NL8200490A patent/NL8200490A/en not_active Application Discontinuation
- 1982-02-09 FR FR8202044A patent/FR2499571B1/en not_active Expired
- 1982-02-10 DK DK057782A patent/DK151023C/en not_active IP Right Cessation
- 1982-02-10 NO NO820394A patent/NO820394L/en unknown
- 1982-02-10 IT IT19587/82A patent/IT1157301B/en active
- 1982-02-10 SU SU823390301A patent/SU1093249A3/en active
- 1982-02-10 DE DE19823204509 patent/DE3204509A1/en active Granted
- 1982-02-10 DD DD82237319A patent/DD202570A5/en not_active IP Right Cessation
- 1982-02-10 AU AU80338/82A patent/AU544455B2/en not_active Ceased
- 1982-02-11 GB GB8204018A patent/GB2094787B/en not_active Expired
- 1982-02-11 AR AR288399A patent/AR227574A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IL64808A0 (en) | 1982-03-31 |
| AU544455B2 (en) | 1985-05-30 |
| ATA26082A (en) | 1987-12-15 |
| ES8307006A1 (en) | 1983-07-01 |
| SE449863B (en) | 1987-05-25 |
| FR2499571B1 (en) | 1986-03-28 |
| FI820339L (en) | 1982-08-12 |
| ES509419A0 (en) | 1983-07-01 |
| CH651038A5 (en) | 1985-08-30 |
| SE8200248L (en) | 1982-08-12 |
| DD202570A5 (en) | 1983-09-21 |
| IT8219587A0 (en) | 1982-02-10 |
| GB2094787A (en) | 1982-09-22 |
| IL64808A (en) | 1984-12-31 |
| AR227574A1 (en) | 1982-11-15 |
| CA1202028A (en) | 1986-03-18 |
| DK57782A (en) | 1982-08-12 |
| SU1093249A3 (en) | 1984-05-15 |
| DK151023C (en) | 1988-06-27 |
| IT1157301B (en) | 1987-02-11 |
| AU8033882A (en) | 1982-08-19 |
| GR75857B (en) | 1984-08-02 |
| GB2094787B (en) | 1984-10-24 |
| DE3204509A1 (en) | 1982-08-26 |
| NL8200490A (en) | 1982-09-01 |
| FI70215C (en) | 1986-09-15 |
| AT386203B (en) | 1988-07-25 |
| NO820394L (en) | 1982-08-12 |
| DE3204509C2 (en) | 1990-10-04 |
| FR2499571A1 (en) | 1982-08-13 |
| FI70215B (en) | 1986-02-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |