DK157923B - METHOD OF ANALOGUE FOR THE PREPARATION OF NAE-CYANO-N- (1-OXIDO-4-PYRIDYL) -N'-1,2,2-TRIMETHYLPROPYLGUANIDINE OR SALTS THEREOF WITH PHARMACEUTICAL ACCEPTABLE ACIDS - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF NAE-CYANO-N- (1-OXIDO-4-PYRIDYL) -N'-1,2,2-TRIMETHYLPROPYLGUANIDINE OR SALTS THEREOF WITH PHARMACEUTICAL ACCEPTABLE ACIDS Download PDFInfo
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- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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Description
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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse N"-cyano-N-(l-oxido-4-pyridyl)-N'-1,2,2-trimethylpropylguan-idin eller salte deraf med farmaceutisk acceptable syrer.The present invention relates to an analogous process for the preparation of the novel compound N "-cyano-N- (1-oxido-4-pyridyl) -N'-1,2,2-trimethylpropylguanidine or salts thereof with pharmaceutically acceptable acids.
5 Den ifølge opfindelsen fremstillede forbindelse inde holder ét asymmetrisk C-atom og findes derfor i to isomere former. Den foreliggende opfindelse omfatter fremstilling af begge isomerer og blandinger heraf.The compound of the invention contains one asymmetric C atom and is therefore available in two isomeric forms. The present invention comprises the preparation of both isomers and mixtures thereof.
Forbindelsen fremstillet ifølge opfindelsen er en svag 10 base, som danner salte med stærke organiske eller uorganiske syrer, blandt hvilke de ugiftige, farmaceutisk acceptable syrer er velegnede, såsom fx hydrohalider, svovlsyre, salpetersyre eller methansulfonsyrer.The compound of the invention is a weak base which forms salts with strong organic or inorganic acids, among which the non-toxic, pharmaceutically acceptable acids are suitable, such as, for example, hydrohalides, sulfuric acid, nitric acid or methanesulfonic acids.
I dansk patentansøgning nr. 5729/75 er beskrevet den 15 antihypertensive virkning af visse 2-, 3- eller 4-pyridyl-cyanoguanidiner. Yderligere studier af forbindelser omfattet af denne ansøgning er offentliggjort i J. Med. Chem. 21, 773 (1978).Danish Patent Application No. 5729/75 discloses the antihypertensive effect of certain 2-, 3- or 4-pyridyl-cyanoguanidines. Further studies of compounds covered by this application are published in J. Med. Chem. 21, 773 (1978).
Skønt de nævnte, kendte forbindelser generelt har en 20 bemærkelsesværdig kraftig virkning har forbindelsen fremstillet ifølge den foreliggende opfindelse vist sig at besidde visse fordele fremfor disse kendte stoffer. Den er på tilsvarende måde antihypertensivt virkende, men er overlegen som følge af dens farmakokinetiske egenskaber. For 25 eksempel er den antihypertensive aktivitet lettere at kontrollere, fordi blodtryksfaldet indsætter mere gradvist end tilfældet er med de ovennævnte forbindelser, og virkningen er af længere varighed.Although said known compounds generally have a remarkably potent effect, the compound of the present invention has been found to possess certain advantages over these known substances. It is similarly antihypertensive but superior in its pharmacokinetic properties. For example, the antihypertensive activity is easier to control because the drop in blood pressure is more gradual than is the case with the above compounds and the effect is of longer duration.
Grunden til dette kan i hvert fald i nogle tilfælde 30 være, at den foreliggende forbindelse under indflydelse af oxidoreduktaser omdannes delvis.til den tilsvarende stærkere N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidin (generisk navn pinacidil) og kan således i disse tilfælde også betragtes som pro-drug for denne.The reason for this, at least in some cases, may be that the present compound under the influence of oxidoreductases is partially converted to the correspondingly stronger N "-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine ( generic name pinacidil) and can thus also be considered as pro-drug for this.
35: Denne omdannelse ses af den følgende tabel, som viser serumkoncentrationen af hhv. N"-cyano-N-(l-oxido-4-pyridyl)--N'-1,2,2-trimethylpropylguanidin (P 1368) (i det følgende35: This conversion is seen in the following table which shows the serum concentration of N "-cyano-N- (1-oxido-4-pyridyl) - N'-1,2,2-trimethylpropylguanidine (P 1368) (hereinafter:
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2 også betegnet pinacidil-N-oxid) og N'^cyano-N^-pyridyl-N'--1,2,2-trimethylpropylguanidin (P 1134) (pinacidil), efter oral indgift af 3 mg/kg P 1368 til hunde.2 also referred to as pinacidil-N-oxide) and N'-cyano-N'-pyridyl-N '- 1,2,2-trimethylpropylguanidine (P 1134) (pinacidil), after oral administration of 3 mg / kg P 1368 to dogs.
5 Tabel5 Table
Hund nr. 1 Hund nr. 2Dog # 1 Dog # 2
Timer efter ---- indgift P 1368 P 1134 P 1368 P 1134 ng/ml ng/ml ng/ml ng/ml 10 1 65 <5 52 <5 2 330 £5 297 238 3 224 15 457 1070 4 201 348 579 1000 5 245 851 512 1015 15 6 288 816 460 748 7 279 747 357 630 8 271 659 281 438 24 126 96 10.4 <5 20 En lignende in vivo omdannelse af P 1368 til P 1134 er observeret hos humane forsøgspersoner.Hours after ---- administration P 1368 P 1134 P 1368 P 1134 ng / ml ng / ml ng / ml ng / ml 10 1 65 <5 52 <5 2 330 £ 5 297 238 3 224 15 457 1070 4 201 348 579 1000 5 245 851 512 1015 15 6 288 816 460 748 7 279 747 357 630 8 271 659 281 438 24 126 96 10.4 <5 20 A similar in vivo conversion of P 1368 to P 1134 has been observed in human subjects.
Ved et andet forsøg foretoges oral indgift af 2 til 4 mg pinacidil-N-oxid pr. kg legemsvægt til hunde, som var blevet operativt behandlet ved sammensnøring af den renale 25 arterie til frembringelse af en hypertensionstilstand.In another experiment, oral administration of 2 to 4 mg of pinacidil N-oxide was administered per day. kg of body weight for dogs which had been operatively treated by constriction of the renal artery to produce a hypertension state.
Ca. 2 til 4 timer efter dosering iagttoges en kraftig blodtrykssænkende effekt, som nåede sit maksimum, svarende til et fald i det gennemsnitlige arterielle blodtryk på ca.Ca. Two to four hours after dosing, a strong blood pressure lowering effect was observed, which reached its maximum, corresponding to a decrease in the mean arterial blood pressure of approx.
30 mmHg, 4 til 7 timer efter doseringstidspunktet. Den 30 blodtrykssænkende virkning var stadig signifikant 10 til 12 timer efter en enkelt dosis på 2 mg pinacidil-N-oxid pr. kg legemsvægt.30 mmHg, 4 to 7 hours after dosing time. The 30 antihypertensive effect was still significant 10 to 12 hours after a single dose of 2 mg pinacidil N-oxide per day. kg body weight.
Da det samtidig er kendt, at N-oxider er mere polæreSince at the same time it is known that N-oxides are more polar
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3 og derfor udskilles meget hurtigere af organismen end de tilsvarende N-forbindelser, kan man ikke forklare den konstaterede effekt af pinacidil-N-oxid med, at dette løbende bliver omdannet i organismen til pinacidil, således at den 5 konstaterede, forlængede blodtrykssænkende effekt blot er et resultat heraf. Pinacidil-N-oxid ville simpelthen være udskilt længe inden, der kunne skabes de massive doser af pinacidil, som ville kunne forklare det konstaterede forløb i blodtryksvariationerne.3 and therefore secreted much faster by the organism than the corresponding N-compounds, the observed effect of pinacidil N-oxide cannot be explained by the fact that this is continuously converted in the organism to pinacidil, so that the 5 prolonged blood pressure lowering effect is merely is a result of that. Pinacidil N-oxide would simply have been excreted long before the massive doses of pinacidil could be created, which would explain the observed course of blood pressure variations.
10 Det er derfor helt uventet, at man opnår den ønskede, gunstige, forsinkede frigivelse af pinacidil, som resulterer i den ovennævnte lettere kontrollerbare blodtrykssæn-kende effekt.Therefore, it is quite unexpected that the desired, favorable, delayed release of pinacidil is obtained, which results in the above easily controllable blood pressure lowering effect.
Den foreliggende forbindelse har en lav toksicitet og 15 har som nævnt vist sig efter indgift at udøve en stærk og forlænget antihypertensiv virkning i forskellige dyrearter, når de indgives enteralt eller parenteralt uden at give anledning til andre farmakodynamiske virkninger. Det formodes, at forbindelsen udøver sin antihypertensive virkning 20 ved at påvirke de perifere blodkar, enten som sådan eller som nævnt efter en omdannelse i organismen til den tilsvarende pyridylanalog.The present compound has a low toxicity and, as mentioned, has been shown to exert a strong and prolonged antihypertensive effect in various animal species when administered enterally or parenterally without giving rise to other pharmacodynamic effects. It is believed that the compound exerts its antihypertensive effect 20 by affecting the peripheral blood vessels, either as such or as mentioned after a conversion in the organism to the corresponding pyridyl analog.
Det har således overraskende vist sig, at den foreliggende forbindelse har et gunstigt terapeutisk indeks ved 25 såvel enteral som parenteral indgift, idet den lindrer hypertensive tilstande samtidig med, at den tåles godt og ikke har udvist nogen bivirkninger i de indledende eksperimenter.Thus, it has surprisingly been found that the present compound has a favorable therapeutic index at both enteral and parenteral administration, alleviating hypertensive conditions while being well tolerated and exhibiting no side effects in the initial experiments.
Opfindelsen angår som nævnt en analogimetode til 30 fremstilling af den ovenfor beskrevne forbindelse, hvilken fremgangsmåde er ejendommelig ved det i krav l's kendetegnende del angivne. Den består således i en oxidering af en forbindelse af formel II til en forbindelse af formel I ifølge reaktionsskemaet: 35The invention relates, as mentioned, to an analogy method for the preparation of the above-described compound, which is characterized by the characterizing part of claim 1. It thus consists in the oxidation of a compound of formula II to a compound of formula I according to the reaction scheme:
Pinacidil -> pinacidil-N-oxidPinacidil -> pinacidil N-oxide
II III I
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44
Oxydationsprocessen kan gennemføres ved hjælp af velkendte metoder. Således kan fx uorganiske og organiske persyrer, såsom perborsyre, pereddikesyre, perbenzoesyre, m-chlor-perbenzoesyre, perchlorsyre, peroxymonosvovlsyre 5 eller persulfater, nævnes som forslag til oxydationsmidler.The oxidation process can be carried out by well known methods. Thus, for example, inorganic and organic peracids such as perboric acid, peracetic acid, perbenzoic acid, m-chloro perbenzoic acid, perchloric acid, peroxymonosulphuric acid or persulfates may be mentioned as suggestions for oxidizing agents.
Også molybdæn, wolfram, vanadium, mangan, chrom og lignende grundstoffer fra disse grupper i det periodiske system i et højt eller højeste iltningstrin er anvendelige som oxydationsmidler eller katalysatorer i form af deres tilsvarende 10 oxider eller syrer eller salte af sådanne syrer.Also molybdenum, tungsten, vanadium, manganese, chromium and similar elements of these groups in the periodic system in a high or high oxygenation stage are useful as oxidizing agents or catalysts in the form of their corresponding oxides or acids or salts of such acids.
Reaktionen kan gennemføres i et passende opløsningsmiddel eller reaktionsmedium, fx et inert medium såsom chloroform i den nødvendige tid og ved en temperatur, som er tilstrækkelig for at opnå den ønskede omdannelse, sæd-15 vanligvis ved en temperatur på 0-30°C. Ved en velegnet udførelsesform anvendes persyrer i overskud som opløsningsmiddel. Under andre omstændigheder anvendes oxydationsmid-let i ækvimolære mængder eller i det væsentlige ækvimolære mængder, som kan tilsættes gradvist under processen.The reaction may be carried out in a suitable solvent or reaction medium, for example an inert medium such as chloroform for the required time and at a temperature sufficient to achieve the desired conversion, usually at a temperature of 0-30 ° C. In a suitable embodiment, peracids are used in excess as solvent. In other circumstances, the oxidizing agent is used in equimolar amounts or substantially equimolar amounts which may be added gradually during the process.
20 En velegnet udførelsesform er oxydation ved hjælp af perhydrol (hydrogenperoxid 30%) i isopropanol som reaktionsmedium under anvendelse af natriumwolframat som katalysator. Ved en anden udførelsesform anvendes m-chlor-per-benzoesyre som oxidationsmiddel med fx chloroform, ethanol 25 eller isopropanol som reaktionsmedium. Endvidere kan en blanding af perhydrol og iseddikesyre anvendes som såvel oxydationsmiddel som reaktionsmedium. Endelig kan iltningen foregå ved elektrolytisk oxydation.A suitable embodiment is oxidation by means of perhydrol (hydrogen peroxide 30%) in isopropanol as reaction medium using sodium tungstate as catalyst. In another embodiment, m-chloro-per-benzoic acid is used as the oxidizing agent with, for example, chloroform, ethanol or isopropanol as the reaction medium. Furthermore, a mixture of perhydrol and glacial acetic acid can be used as both oxidant and reaction medium. Finally, the oxidation can take place by electrolytic oxidation.
Pinacidil kendes som nævnt fra den tidligere omtalte 30 danske ansøgning nr. 5729/75.As mentioned, Pinacidil is known from the previously mentioned 30 Danish application no. 5729/75.
Pinacidil-N-oxid kan ved konventionelle metoder omdannes til sine syreadditionssalte.Pinacidil N-oxide can be converted to its acid addition salts by conventional methods.
Ved de ovenfor beskrevne fremgangsmåder kan en ønsket stereoisomer fås ved at anvende den tilsvarende isomer af 35 udgangsstoffet i den pågældende fremgangsmåde.In the methods described above, a desired stereoisomer can be obtained by using the corresponding isomer of the starting substance in the process in question.
Alternativt kan racematet anvendes som udgangsmateriale, hvorefter den resulterende blanding underkastes en racematspaltning, fx ved krystallisation af et passendeAlternatively, the racemate may be used as starting material, after which the resulting mixture is subjected to a racemate cleavage, e.g., by crystallization of a suitable
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salt med en optisk aktiv, stærk syre på i og for sig kendt måde.salt with an optically active, strong acid in a manner known per se.
Den foreliggende forbindelse er tænkt anvendt i farmaceutiske præparater til behandling af for højt blodtryk 5 og lignende tilstande.The present compound is intended to be used in pharmaceutical compositions for the treatment of hypertension 5 and similar conditions.
Præparaterne kan indeholde fra 0,1 til 99% af forbindelsen blandet med organiske eller uorganiske, faste eller flydende bærere og/eller hjælpestoffer, som er egnede til fremstilling af forskellige farmaceutiske indgivelsesformer 10 til oral eller anden enteral indgift, herunder præparater med forsinket afgivelse.The compositions may contain from 0.1 to 99% of the compound mixed with organic or inorganic solid or liquid carriers and / or excipients suitable for the preparation of various pharmaceutical administration forms 10 for oral or other enteral administration, including delayed-release preparations.
Præparaterne kan yderligere indeholde andre terapeutisk aktive forbindelser, der anvendes ved behandlingen af for højt blodtryk og lignende tilstande, fx diuretika, 15 reserpin, a-methyldopa, og i særdeleshed β-adrenergiske blokkere.The compositions may further contain other therapeutically active compounds used in the treatment of hypertension and similar conditions, e.g., diuretics, reserpine, α-methyldopa, and in particular β-adrenergic blockers.
Præparaterne kan oparbejdes til forskellige farmaceutiske indgivelsesformer, såsom tabletter, piller, drageer, kapsler, tabletter med forsinket afgivelse, suspensioner, 20 suppositorier og injektionsmedicin, som indeholder forbindelsen fremstillet ifølge opfindelsen eller dens ugiftige salte.The compositions may be processed into various pharmaceutical forms of administration, such as tablets, pills, drags, capsules, delayed-release tablets, suspensions, suppositories and injection drugs containing the compound of the invention or its non-toxic salts.
I den humane terapi kan den omhandlede forbindelse og dens salte med fordel indgives (til voksne) i dosisenheder 25 indeholdende forbindelsen i en mængde på mindst 0,5 mg og op til 500 mg, fortrinsvis fra 5 til 250 mg.In human therapy, the subject compound and its salts may advantageously be administered (to adults) in dosage units containing the compound in an amount of at least 0.5 mg and up to 500 mg, preferably from 5 to 250 mg.
Ved betegnelsen "doseringsenhed" forstås en enhedsdosis, dvs. en enkelt dosis, der kan indgives til en patient, og som under håndtering og pakning forbliver fysisk 30 stabil, hvilken dosis enten består af det aktive materiale som sådant eller af en blanding heraf med faste eller flydende farmaceutiske fortyndingsmidler eller bærestoffer.The term "dosage unit" means a unit dose, i.e. a single dose which may be administered to a patient and which remains physically stable during handling and packaging, which dose either consists of the active material as such or of a mixture thereof with solid or liquid pharmaceutical diluents or carriers.
I form af doseringsenheder kan forbindelsen fremstillet ifølge opfindelsen indgives én eller flere gange dag-35 ligt med passende intervaller, dog altid afhængig af patientens tilstand og i overensstemmelse med de anvisninger, som gives af den behandlende læge.In the form of dosage units, the compound of the invention may be administered once or several times daily at appropriate intervals, however, always depending on the patient's condition and in accordance with the instructions given by the attending physician.
De foreliggende forbindelser skal indgives i sådanneThe present compounds are to be administered in such
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6 doser, at den ønskede virkning opnås uden samtidige bivirkninger.6 doses that the desired effect is achieved without simultaneous side effects.
I patientbehandlingen indgives den foreliggende forbindelse og dens salte passende (til voksne) i en daglig 5 dosis fra 5 mg og op til 1000 mg, fortrinsvis fra 20 til 500 mg, beregnet som den fri base, og i den veterinære praksis i mængder svarende til daglige doser på fra 0,07 til 14 mg/kg legemsvægt.In the patient treatment, the present compound and its salts are suitably administered (for adults) in a daily dose of 5 mg and up to 1000 mg, preferably from 20 to 500 mg, calculated as the free base, and in veterinary practice in amounts corresponding to daily doses of 0.07 to 14 mg / kg body weight.
Opfindelsen skal i det følgende beskrives nærmere ved 10 hjælp af en række eksempler.The invention will now be described in more detail by means of a number of examples.
Eksempel 1 N"-Cyano-N-(l-oxido-4-pyridyl)-N,-1,2,2-trimethylpropyl-15 guanidinExample 1 N "-Cyano-N- (1-oxido-4-pyridyl) -N, -1,2,2-trimethylpropyl-guanidine
En suspension af 10,0 g vandfri N"-cyano-N-4-pyridyl-N'-l,2,2-trimethylpropylguanidin (40 mmol) i 60 ml iso-propanol omrørtes ved 0°C, medens 31 g m-chlorperbenzoe-syre (160 mmol, 90% renhed) tilsattes, hvilket resulterede 20 i en klar opløsning indenfor 5 minutter. Efter henstand ved 0°C i tre dage dannedes et bundfald, som fjernedes ved filtrering. Filtratet inddampedes forsigtigt i vakuum ved 0°C. Bundfaldet omrørtes med 200 ml ether, og blandingen filtreredes og vaskedes med ether, hvorved man fik det rå pro-25 dukt. Yderligere rensning skete ved omrøring med 75 ml acetone og filtrering.A suspension of 10.0 g of anhydrous N "-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine (40 mmol) in 60 ml of isopropanol was stirred at 0 ° C, while 31 g of m.p. chlorperbenzoic acid (160 mmol, 90% purity) was added, resulting in a clear solution within 5 minutes. After standing at 0 ° C for three days, a precipitate formed which was removed by filtration. The filtrate was gently evaporated in vacuo at 0 °. C. The precipitate was stirred with 200 ml of ether and the mixture filtered and washed with ether to give the crude product, further purification by stirring with 75 ml of acetone and filtration.
Det faste bundfald underkastedes selektiv udfældning ved opløsning i overskud af 1 N vandig saltsyre og indstilling af pH til 1,3 ved tilsætning af fast natriumacetat.The solid precipitate was subjected to selective precipitation by dissolving in excess of 1 N aqueous hydrochloric acid and adjusting the pH to 1.3 by addition of solid sodium acetate.
30 Det rene krystallinske produkt opsamledes ved filtre ring, vaskedes med vand og lufttørredes.The pure crystalline product was collected by filter ring, washed with water and air dried.
Smeltepunkt: 242-243°C (under sønderdeling). IR(KBr) udviste kraftige bånd ved 2180 cm ^ og 1620-1560 cm "*.Melting point: 242-243 ° C (with decomposition). IR (KBr) exhibited strong bands at 2180 cm -1 and 1620-1560 cm -1.
NMR-spektret ((CDg^SO) udviste signaler ved δ = 0,93 35 (s, 9H), 1,10 (d, 3=7 Hz, 3H), 3,93 (q, 3=7 Hz, IH), 7,28 (bd, 2H), 7,40 (bs, IH), 8,15 (bd, 2H), 9,50 (bs, IH), ppm. Tetramethylsilan anvendtes som intern reference.The NMR spectrum ((CDg ^ SO) showed signals at δ = 0.93 (s, 9H), 1.10 (d, 3 = 7 Hz, 3H), 3.93 (q, 3 = 7 Hz, 1H) ), 7.28 (bd, 2H), 7.40 (bs, 1H), 8.15 (bd, 2H), 9.50 (bs, 1H), ppm. Tetramethylsilane was used as internal reference.
Ubedøvede hunde, som er gjort hypertensive ved Gold-Anesthetized dogs made hypertensive by Gold-
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7 blatt et al' s metode (J.Exp.Med. J59, 347 (1934)) fik indgivet orale doser på 3,0 og 10,0 mg/kg. Et fald i blodtrykket på henholdsvis 42 + 12 mmHg og 79 ± 16 mmHg (middelværdi ± SEM, tre dyr pr. dose) observeres. Den højeste 5 virkning sås 3-4 timer efter dosering, og en hypotensiv virkning var stadig til stede 8 timer efter dosering.7 Blatt et al's method (J.Exp. Med. J59, 347 (1934)) was given oral doses of 3.0 and 10.0 mg / kg. A decrease in blood pressure of 42 + 12 mmHg and 79 ± 16 mmHg (mean ± SEM, three animals per dose, respectively) is observed. The highest effect was seen 3-4 hours after dosing, and a hypotensive effect was still present 8 hours after dosing.
I hunde med normalt blodtryk bevirkede en intravenøs indgift på 1,0 og 3,0 mg/kg af ovennævnte forbindelse et blodtryksfald på henholdsvis 15 ± 7 mmHg og 28 ± 9 mmHg 10 (middelværdi ± SEM, tre dyr/dose). Det højeste blodtryksfald indtraf ca. 10 minutter efter dosering. Den hypotensive virkning forsvandt to timer senere.In dogs with normal blood pressure, intravenous administration of 1.0 and 3.0 mg / kg of the above compound caused a drop in blood pressure of 15 ± 7 mmHg and 28 ± 9 mmHg 10, respectively (mean ± SEM, three animals / dose). The highest drop in blood pressure occurred approx. 10 minutes after dosing. The hypotensive effect disappeared two hours later.
Eksempel 2 15 N"-Cyano-N-(l-oxido-4-pyridyl)-N *-1,2,2-trimethylpropyl-guanidin 2,45 g vandfri iT-cyano-N^-pyridyl-N'-1,2,2-tri-methylpropylguanidin (10 mmol) suspenderedes i 25 ml chloroform. Under omrøring ved 0°C tilsattes 6 portioner (i 20 alt 2,50 g) m-chlorperbenzoesyre (90%, 13 mmol) i løbet af en time. Blandingen holdtes ved 0eC natten over og inddampedes i vakuum ved 0°C. Remanensen behandledes med tre portioner ether (25 ml) - og med mellemliggende dekanteringer - og man fik det rå produkt ved filtrering og adskillige 25 vaskninger med ether. Råproduktet opløstes i 8 dele iseddikesyre ved forsigtig opvarmning, og det udfældedes ved tilsætning af 32 dele vand.Example 2 N "-Cyano-N- (1-oxido-4-pyridyl) -N * -1,2,2-trimethylpropyl-guanidine 2.45g of anhydrous iT-cyano-N4-pyridyl-N'-1 , 2,2-Trimethylpropylguanidine (10 mmol) was suspended in 25 ml of chloroform, while stirring at 0 ° C, 6 portions (20.50 g total) of m-chloroperbenzoic acid (90%, 13 mmol) were added over one The mixture was kept at 0 ° C overnight and evaporated in vacuo at 0 ° C. The residue was treated with three portions of ether (25 ml) - and with intermediate decantations - to give the crude product by filtration and several 25 washes with ether. in 8 parts glacial acetic acid by gentle heating, and it precipitated by the addition of 32 parts water.
Den rene forbindelse frafiltreredes, vaskedes med vand og lufttørredes.The pure compound was filtered off, washed with water and air dried.
30 Smeltepunkt: 242-243°C (sønderdeling).Melting point: 242-243 ° C (dec.).
35 835 8
DK 157923BDK 157923B
Eksempel 3 KapselExample 3 Capsule
Fremstilling af 100.000 kapsler 5 _ ( P 1368 ...................... 1,000 kg ( Laktose ..................... 10,000 kg __ ( Polyvinylpyrrolidon......... 0,200 kg ( Vand, afjoniseret ........... 1,000 kg 10 ( Siliciumdioxid, kolloidal ... 0,050 kg ( Magnesiumstearat ............ 0,100 kg 15 I blandes i en planetblandemaskine. I vådgranuleres med II. Den våde blanding sigtes gennem en sigte med 1,5 mm åbninger og tørres i en "fluid bed" ved 60°C. Det tørrede granulat sigtes gennem en sigte med 0,8 mm åbninger, og det sigtede granulat smøres med III.Preparation of 100,000 capsules 5 _ (P 1368 ...................... 1,000 kg (Lactose ............... ...... 10,000 kg __ (Polyvinylpyrrolidone ......... 0.200 kg (Water, Deionized ........... 1,000 kg 10 (Silica, Colloidal ... 0.050 kg) Magnesium stearate ............ 0,100 kg 15 I is mixed in a planetary mixer I wet granulated with II The wet mixture is sieved through a 1.5 mm sieve and dried in a fluid bed at 60 ° C. The dried granules are sieved through a sieve with 0.8 mm openings and the sieved granules are lubricated with III.
20 Granulatet fyldes i kapsler af størrelse 4 i en mængde på 113,5 mg granulat pr. kapsel, svarende til 10 mg P 1368 pr. kapsel.The granulate is filled into size 4 capsules in an amount of 113.5 mg granules per day. capsule, equivalent to 10 mg of P 1368 per ml. capsule.
Eksempel 4 25 TabletExample 4 Tablet
Fremstilling af 100.000 tabletter ( P 1368 ...................... 1,000 kg I ( Majstivelse ................. 2,250 kg 30 ( Laktose ..................... 10,825 kg __ ( Polyvinylpyrrolidon ......... 0,300 kg ( Vand, afjoniseret ........... 1,500 kg 30 ( Talkum...................... 0,500 kg III ( Magnesiumstearat ............ 0,075 kg ( Siliciumdioxid, kolloidal ... 0,050 kg 35 I blandes i en planetblandemaskine. I vådgranuleres med II. Den våde blanding sigtes gennem sigtevæv med 1,5 mm åbninger. Det sigtede granulat tørres i en "fluid bed" ved 60°C. Det tørre granulat sigtes gennem en sigtevæv med 0,8 mm åbninger og det sigtede granulat smøres med III.Preparation of 100,000 tablets (P 1368 ...................... 1,000 kg I (Maize Starch ................ 2,250 kg 30 (Lactose ..................... 10,825 kg __ (Polyvinylpyrrolidone ......... 0.300 kg (Water, Deionized ... ........ 1,500 kg 30 (Talc ...................... 0.500 kg III (Magnesium stearate .......... .. 0.075 kg (Silicon dioxide, colloidal ... 0.050 kg 35 I is mixed in a planetary mixing machine. I is wet granulated with II. The wet mixture is sieved through sieve tissue with 1.5 mm openings. The sieved granulate is dried in a "fluid bed" at 60 The dry granules are sieved through a sieve of 0.8 mm openings and the sieved granules are lubricated with III.
DK 157923 BDK 157923 B
99
Granulatet slås til tabletter med en vægt på 0,150 g·The granules are beaten into tablets weighing 0.150 g ·
Stempelstørrelse: 7 mm, rund, flade tabletter med affaset kant.Stamp size: 7 mm, round, flat tablets with bevelled edge.
5 Tablethårdhed: 4-5 kp.5 Tablet Hardness: 4-5 kp.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8127367 | 1981-09-10 | ||
| GB8127367 | 1981-09-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK398882A DK398882A (en) | 1983-03-11 |
| DK157923B true DK157923B (en) | 1990-03-05 |
| DK157923C DK157923C (en) | 1990-08-06 |
Family
ID=10524416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK398882A DK157923C (en) | 1981-09-10 | 1982-09-07 | METHOD OF ANALOGUE FOR THE PREPARATION OF NAE-CYANO-N- (1-OXIDO-4-PYRIDYL) -N'-1,2,2-TRIMETHYLPROPYLGUANIDINE OR SALTS THEREOF WITH PHARMACEUTICAL ACCEPTABLE ACIDS |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5857363A (en) |
| BE (1) | BE894350A (en) |
| CA (1) | CA1177080A (en) |
| CH (1) | CH655500B (en) |
| DE (1) | DE3233380A1 (en) |
| DK (1) | DK157923C (en) |
| FR (1) | FR2512447B1 (en) |
| GB (1) | GB2105331B (en) |
| GR (1) | GR77009B (en) |
| IE (1) | IE54196B1 (en) |
| IT (1) | IT1156515B (en) |
| LU (1) | LU84375A1 (en) |
| NL (1) | NL8203214A (en) |
| PH (1) | PH18596A (en) |
| SE (1) | SE441357B (en) |
| ZA (1) | ZA825997B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05294935A (en) * | 1991-03-15 | 1993-11-09 | Green Cross Corp:The | Aminopyridine-based compound |
| US5371086A (en) * | 1991-03-15 | 1994-12-06 | The Green Cross Corporation | Aminopyridine compounds |
| WO2007022946A1 (en) | 2005-08-21 | 2007-03-01 | Abbott Gmbh & Co. Kg | Heterocyclic compounds and their use as binding partners for 5-ht5 receptors |
| WO2007022964A2 (en) | 2005-08-24 | 2007-03-01 | Abbott Gmbh & Co. Kg | Hetaryl-substituted guanidine compounds and use thereof as binding partners for 5-ht5-receptors |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3074955A (en) * | 1960-11-30 | 1963-01-22 | Us Vitamin Pharm Corp | Pyridylalkyl dicyandiamides and guanylureas |
| US3329569A (en) * | 1962-07-31 | 1967-07-04 | Smith Kline French Lab | Hypotensive compositions and methods of producing hypotension |
| FR2043491A1 (en) * | 1969-05-30 | 1971-02-19 | Ugine Kuhlmann | Alpha-pyrid-4'-yl-benzylidene-aminoguani- - dines useful as hypotensives and spasmoly-tics |
| GB1489879A (en) * | 1974-12-20 | 1977-10-26 | Leo Pharm Prod Ltd | N'-cyano-n'-3-pyridylguanidines |
| US4287346A (en) * | 1979-02-16 | 1981-09-01 | Eisai Co., Ltd. | Cyanoguanidine derivatives |
-
1982
- 1982-08-09 IE IE1918/82A patent/IE54196B1/en unknown
- 1982-08-16 NL NL8203214A patent/NL8203214A/en not_active Application Discontinuation
- 1982-08-16 PH PH27732A patent/PH18596A/en unknown
- 1982-08-18 ZA ZA825997A patent/ZA825997B/en unknown
- 1982-08-31 GB GB08224808A patent/GB2105331B/en not_active Expired
- 1982-08-31 CH CH517782A patent/CH655500B/de unknown
- 1982-09-07 DK DK398882A patent/DK157923C/en not_active IP Right Cessation
- 1982-09-07 CA CA000410917A patent/CA1177080A/en not_active Expired
- 1982-09-08 SE SE8205107A patent/SE441357B/en not_active IP Right Cessation
- 1982-09-08 DE DE19823233380 patent/DE3233380A1/en not_active Withdrawn
- 1982-09-08 GR GR69232A patent/GR77009B/el unknown
- 1982-09-09 IT IT68075/82A patent/IT1156515B/en active
- 1982-09-09 BE BE0/208978A patent/BE894350A/en not_active IP Right Cessation
- 1982-09-09 JP JP57157939A patent/JPS5857363A/en active Pending
- 1982-09-09 FR FR8215312A patent/FR2512447B1/en not_active Expired
- 1982-09-09 LU LU84375A patent/LU84375A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL8203214A (en) | 1983-04-05 |
| GB2105331B (en) | 1985-05-01 |
| JPS5857363A (en) | 1983-04-05 |
| DE3233380A1 (en) | 1983-03-17 |
| SE8205107L (en) | 1983-03-11 |
| GR77009B (en) | 1984-09-04 |
| FR2512447A1 (en) | 1983-03-11 |
| BE894350A (en) | 1983-03-09 |
| IT8268075A0 (en) | 1982-09-09 |
| DK157923C (en) | 1990-08-06 |
| FR2512447B1 (en) | 1985-11-22 |
| SE8205107D0 (en) | 1982-09-08 |
| IE54196B1 (en) | 1989-07-19 |
| LU84375A1 (en) | 1983-06-07 |
| IE821918L (en) | 1983-03-10 |
| IT1156515B (en) | 1987-02-04 |
| ZA825997B (en) | 1983-07-27 |
| DK398882A (en) | 1983-03-11 |
| CH655500B (en) | 1986-04-30 |
| CA1177080A (en) | 1984-10-30 |
| GB2105331A (en) | 1983-03-23 |
| PH18596A (en) | 1985-08-15 |
| SE441357B (en) | 1985-09-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |