EP0000770A2 - 1-Methylisoguanosin, processes and intermediates for its preparation, its pharmaceutical compositions and their preparation - Google Patents

1-Methylisoguanosin, processes and intermediates for its preparation, its pharmaceutical compositions and their preparation Download PDF

Info

Publication number
EP0000770A2
EP0000770A2 EP78100579A EP78100579A EP0000770A2 EP 0000770 A2 EP0000770 A2 EP 0000770A2 EP 78100579 A EP78100579 A EP 78100579A EP 78100579 A EP78100579 A EP 78100579A EP 0000770 A2 EP0000770 A2 EP 0000770A2
Authority
EP
European Patent Office
Prior art keywords
methyl
isoguanosine
formula
compound
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP78100579A
Other languages
German (de)
French (fr)
Other versions
EP0000770A3 (en
Inventor
Richard Peter Gregson
Ronald James Quinn
Alan Frederick Cook
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US05/876,768 external-priority patent/US4148993A/en
Priority claimed from GB7826761A external-priority patent/GB2001955A/en
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0000770A2 publication Critical patent/EP0000770A2/en
Publication of EP0000770A3 publication Critical patent/EP0000770A3/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals

Definitions

  • the present invention relates to a hitherto unknown cyclic compound, namely 1-methyl-9ßD-ribofuranosyl-isoguanine (1-methyl-isoguanosine), which can be in tautomeric forms, for example of the formula and
  • the 1-methyl-isoguanosine is contained in small amounts in marine organisms, in particular in sponges of the Tedania genus, which are found on the Australian coast.
  • the invention relates to the isolation of 1-methyl-isoguanosine from natural sources, in particular marine organisms, especially sponges of the Tedania genus.
  • the invention relates to the 1-methyl-isoguanosine itself, as well as in practically pure form, i.e. free of naturally occurring accompanying substances.
  • l-Methyl-isoguanosine can be isolated from natural sources, for example sponges, in a manner known per se, for example by extraction with dimethyl sulfoxide, water and / or an organic hydroxylic solvent, such as a lower alkanol, for example methanol or ethanol, an ethanol Water mixture is preferred, and subsequent chromatography, preferably ion exchange chromatography, for example using a cation exchange resin such as a resin containing SO 3 H groups and a mild acidic buffer such as ammonium formate.
  • a cation exchange resin such as a resin containing SO 3 H groups
  • a mild acidic buffer such as ammonium formate.
  • the invention further relates to a process for the preparation of 1-methyl-isoguanosine by reacting an imidazole derivative of the formula where R represents an easily removable acyl group, with methyl isocyanate in the presence of a strongly aprotic solvent, such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide, advantageously at a temperature between about room temperature and 150 ° C., preferably at about 100 ° C.
  • a strongly aprotic solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide
  • the new intermediate of the formula created during this reaction where R has the above meaning is then with a base, preferably a weak base, such as ammonium hydroxide, in the presence or absence of a C 1-4 alkanol, with anhydrous ammonia in the presence of a C 1-4 alkanol, or with an alkali metal hydroxide, for example sodium or Potassium hydroxide implemented.
  • a base preferably a weak base, such as ammonium hydroxide
  • anhydrous ammonia in the presence of a C 1-4 alkanol
  • an alkali metal hydroxide for example sodium or Potassium hydroxide implemented.
  • Examples of easily removable acyl groups R in the starting materials of the formula II are lower alkanoyl, such as acetyl, propionyl or butyryl, aroyl or substituted aroyl, such as benzoyl, p-tolyoyl, p-methoxybenzoyl or p-chlorobenzoyl, preferably acetyl.
  • the invention further relates to a process for the preparation of 1-methyl-isoguanosine by reaction of a compound of the formula with a methylating agent.
  • the methylation is preferably carried out using a methyl halide, for example methyl iodide or bromide, in the presence of an aprotic solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide, under basic conditions, for example in the presence of sodium or potassium hydroxide or carbonate, at a temperature between about O and 100 ° C, preferably carried out at about room temperature.
  • a methyl halide for example methyl iodide or bromide
  • an aprotic solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide
  • basic conditions for example in the presence of sodium or potassium hydroxide or carbonate
  • sodium or potassium hydroxide or carbonate sodium or potassium hydroxide or carbonate
  • the methylation in the 1-position of the Isoguanosins IV can also be prepared using diazomethane in a solvent such as an ether, for example dioxane or 1,2 imethoxyäthan to D, or a C 1-4 alkanol, be carried out, for example, ethanol.
  • Dimethyl sulfate in a polar aprotic solvent such as dioxane or in water can also be used as the methylating agent. These reactions are preferably carried out at about room temperature.
  • 1-methyl-isoguanosin develops various therapeutic activities, for example has a muscle-relaxing effect, influences the central nervous system, is anti-inflammatory, anti-allergic and hypotensive.
  • the ED 50 value for 1-methyl-isoguanosine as a muscle relaxant is 3.1 mg / kg with intraperitoneal administration and 12 mg / kg with oral administration.
  • the LD 50 in the mouse is 1000 mg / kg po after 48 hours.
  • 1-methyl-isoguanosine can be used as a muscle relaxant and / or as an agent for influencing the central nervous system and / or as an anti-inflammatory and / or anti-allergen gisch and / or hypotensive means are used. It can be used in the form of pharmaceutical preparations together with a compatible pharmaceutical carrier, for example an organic or inorganic inert carrier which is suitable for enteral, preferably oral or parenteral administration. Examples of such carriers are water, gelatin, lactose, starch, talc, magnesium stearate, rubber, vegetable oils and petroleum jelly.
  • the pharmaceutical preparations can be in solid form, for example as tablets, capsules, coated tablets or suppositories, or in liquid form, for example as solutions, emulsions or suspensions. They can be sterilized and / or contain compatible auxiliaries, such as preservatives, stabilizers, flavors, colors, emulsifiers and salts for changing the osmotic pressure or buffers.
  • a suitable pharmaceutical dosage form contains about 1-100 mg of 1-methyl-isoguanosine.
  • the dosage for oral administration is in the range of 0.1 mg per kg to 25 mg per kg per day. Dosages in the range from 0.01 mg per kg to 10 mg per kg per day are suitable for parenteral administration. However, these ranges can be varied up or down depending on individual needs.
  • the starting material was an orange sponge of the Tedania genus, which was collected on the Australian coast.
  • the frozen organism was lyophilized and ground.
  • the powder obtained (300 g) was stirred with an ethanol: water mixture (3: 7 parts by volume, 2 l) at 4 ° C. for 24 hours, then filtered and the residue was extracted again.
  • the combined extracts were concentrated at 35 ° C. and 7 Torr to a volume of 1.2 l, the aqueous suspension thus obtained was centrifuged at 13000 g for 0.3 hours and the supernatant was lyophilized. This gave 75.7 g of an orange powder A.
  • the foam is left under vacuum overnight, then dissolved in 150 ml of methanol and treated with 150 ml of concentrated ammonium hydroxide at 5 ° C. overnight.
  • the crystals formed are collected, washed with methanol and recrystallized from ethanol / water (1/1). Repeated recrystallizations remove traces of impurities. Melting point 265-266 ° C, decomposes.
  • the 20 ml fractions 100-140 are evaporated to dryness and 4-cyan-5- [bis- (methylcarbamoyl)] - amino-l- (2 ', 3', 5'-tri-O-acetyl- ß - D-ribofurano- syl) imidazole as white foam n; I R 2245 cm -1 (C ⁇ N), 1753 (ester), 1728, 1680 (urea carbonyl); UV 227 nm ( E 11.360) in methanol, 226 nm (e 9540) in 0.1N HCl.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

1-Methylisoguanosine is prepared by isolation from natural sources in a conventional manner or by a chemical process. 1-Methyl- isoguanosine can be used as muscle relaxant and/or as agent for influencing the central nervous system and/or as antiinflammatory and/or antiallergic and/or hypotensive agent.

Description

Die vorliegende Erfindung betrifft eine bisher unbekannte cyclische Verbindung, nämlich das 1-Methyl-9ßD-ribofuranosyl- isoguanin (1-Methyl-isoguanosin), welches in tautomeren Formen vorliegen kann, z.B. der Formel

Figure imgb0001
Figure imgb0002
und
Figure imgb0003
 The present invention relates to a hitherto unknown cyclic compound, namely 1-methyl-9ßD-ribofuranosyl-isoguanine (1-methyl-isoguanosine), which can be in tautomeric forms, for example of the formula
Figure imgb0001
Figure imgb0002
 and
Figure imgb0003

Erfindungsgemäss wurde gefunden, dass das 1-Methyl-isoguanosin in geringen Mengen in Meeresorganismen, insbesondere in Schwämmen der Gattung Tedania, welche sich an der australischen Küste finden, enthalten ist.It was found according to the invention that the 1-methyl-isoguanosine is contained in small amounts in marine organisms, in particular in sponges of the Tedania genus, which are found on the Australian coast.

In einer Hinsicht betrifft die Erfindung die Isolierung von 1-Methyl-isoguanosin aus natürlichen Vorkommen, insbesondere Meeresorganismen, vor allem Schwämmen der Gattung Tedania.In one aspect, the invention relates to the isolation of 1-methyl-isoguanosine from natural sources, in particular marine organisms, especially sponges of the Tedania genus.

Weiterhin betrifft die Erfindung das 1-Methyl-isoguanosin selbst, sowie in praktisch reiner Form, d.h. frei von natürlich vorkommenden Begleitstoffen.Furthermore, the invention relates to the 1-methyl-isoguanosine itself, as well as in practically pure form, i.e. free of naturally occurring accompanying substances.

l-Methyl-isoguanosin kann aus natürlichen Vorkommen, z.B. Schwämmen, in an sich bekannter Weise isoliert werden, z.B. durch Extraktion mit Dimethylsulfoxyd, Wasser und/oder einem organischen hydroxylischen Lösungsmittel, wie einem niederen Alkanol, z.B. Methanol oder Aethanol, wobei ein Aethanol-Wassergemisch bevorzugt ist, und anschliessende Chromatographie, vorzugsweise Ionenaustauscherchromatographie, z.B. mittels eines Kationenaustauscherharzes, wie einem SO3H-Gruppen enthaltenden Harz und einem milden sauren Puffer, wie Ammoniumformiat.l-Methyl-isoguanosine can be isolated from natural sources, for example sponges, in a manner known per se, for example by extraction with dimethyl sulfoxide, water and / or an organic hydroxylic solvent, such as a lower alkanol, for example methanol or ethanol, an ethanol Water mixture is preferred, and subsequent chromatography, preferably ion exchange chromatography, for example using a cation exchange resin such as a resin containing SO 3 H groups and a mild acidic buffer such as ammonium formate.

Die Erfindung betrifft ferner ein Verfahren zur Herstellung von 1-Methyl-isoguanosin durch Umsetzung eines Imidazolderivates der Formel

Figure imgb0004
worin R eine leicht abspaltbare Acylgruppe darstellt,
mit Methylisocyanat in Gegenwart eines stark aprotischen Lösungsmittels,wie Dimethylformamid, Dimethylsulfoxid oder Hexamethylphosphoramid,zweckmässiger Weise bei einer Temperatur zwischen etwa Raumtemperatur und 150°C,vorzugsweise bei etwa 100°C.The invention further relates to a process for the preparation of 1-methyl-isoguanosine by reacting an imidazole derivative of the formula
Figure imgb0004
 where R represents an easily removable acyl group,
with methyl isocyanate in the presence of a strongly aprotic solvent, such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide, advantageously at a temperature between about room temperature and 150 ° C., preferably at about 100 ° C.

Das bei dieser Reaktion entstandene neue Zwischenprodukt der Formel

Figure imgb0005
worin R obige Bedeutung hat,
wird dann mit einer Base,vorzugsweise einer schwachen Base, wie Ammoniumhydroxid,in Gegenwart oder in Abwesenheit eines C1-4-Alkanols, mit wasserfreiem Ammoniak in Gegenwart eines C1-4-Alkanols, oder mit einem Alkalimetallhydroxid, zum Beispiel Natrium- oder Kaliumhydroxid umgesetzt. Zweckmässiger Weise wird diese Reaktion bei einer Temperatur zwischen etwa 0 oder 100°C,vorzugsweise bei Raumtemperatur durchgeführt.The new intermediate of the formula created during this reaction
Figure imgb0005
 where R has the above meaning,
is then with a base, preferably a weak base, such as ammonium hydroxide, in the presence or absence of a C 1-4 alkanol, with anhydrous ammonia in the presence of a C 1-4 alkanol, or with an alkali metal hydroxide, for example sodium or Potassium hydroxide implemented. This reaction is expediently carried out at a temperature between about 0 or 100 ° C., preferably at room temperature.

Beispiele von leicht abspaltbaren Acylgruppen R in den Ausgangsmaterialien der Formel II sind Niederalkanoyl,wie Acetyl, Propionyl oder Butyryl, Aroyl oder substituiertes Aroyl,wie Benzoyl, p-Tolyoyl, p-Methoxybenzoyl oder p-Chlorbenzoyl, vorzugsweise Acetyl.Examples of easily removable acyl groups R in the starting materials of the formula II are lower alkanoyl, such as acetyl, propionyl or butyryl, aroyl or substituted aroyl, such as benzoyl, p-tolyoyl, p-methoxybenzoyl or p-chlorobenzoyl, preferably acetyl.

Ferner betrifft die Erfindung ein Verfahren zur Herstellung von 1-Methyl-isoguanosin durch Reaktion einer Verbindung der Formel

Figure imgb0006
mit einem Methylierungsmittel.The invention further relates to a process for the preparation of 1-methyl-isoguanosine by reaction of a compound of the formula
Figure imgb0006
 with a methylating agent.

Die Methylierung wird vorzugsweise unter Verwendung eines Methylhalogenids,zum Beispiel Methyliodid oder Bromid,in Gegenwart eines aprotischen Lösungsmittels,wie Dimethylformamid, Dimethylsulfoxid oder Hexamethylphosphoramid, unter basischen Bedingungen,zum Beispiel-in Gegenwart von Natrium- oder Kaliumhydroxid oder Carbonat, bei einer Temperatur zwischen etwa O und 100°C,vorzugsweise bei etwa Raumtemperatur durchgeführt. Als Nebenprodukt der obigen Methylierung wird das aus J.Org. Chem. 22, 1957, 1575 bekannte 9ß-D-ribofuranosyl-2-methoxy-adenin (2-Methoxy-adenosin) erhalten. Die Produkte können in an sich bekannter Weise,zum Beispiel durch Chromatographie, getrennt werden.The methylation is preferably carried out using a methyl halide, for example methyl iodide or bromide, in the presence of an aprotic solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide, under basic conditions, for example in the presence of sodium or potassium hydroxide or carbonate, at a temperature between about O and 100 ° C, preferably carried out at about room temperature. As a by-product of the above methylation, this is from J.Org. Chem. 22, 1957, 1575 known 9ß-D-ribofuranosyl-2-methoxy-adenine (2-methoxy-adenosine) obtained. The products can be separated in a manner known per se, for example by chromatography.

Die Methylierung in 1-Stellung des Isoguanosins IV kann auch unter Verwendung von Diazomethan in einem Lösungsmittel, wie einem Aether,zum Beispiel Dioxan oder 1,2-Dimethoxyäthan, oder einem C1-4-Alkanol, zum Beispiel Aethanol durchgeführt werden. Als Methylierungsmittel kann auch Dimethylsulfat in einem polaren aprotischen Lösungsmittel, wie Dioxan,oder in Wasser verwendet werden. Diese Reaktionen werden vorzugsweise bei etwa Raumtemperatur durchgeführt.The methylation in the 1-position of the Isoguanosins IV can also be prepared using diazomethane in a solvent such as an ether, for example dioxane or 1,2 imethoxyäthan to D, or a C 1-4 alkanol, be carried out, for example, ethanol. Dimethyl sulfate in a polar aprotic solvent such as dioxane or in water can also be used as the methylating agent. These reactions are preferably carried out at about room temperature.

Erfindungsgemäss wurde weiter gefunden, dass 1-Methyl-isoguanosin verschiedene therapeutische Aktivitäten entfaltet, z.B. muskelrelaxierend wirkt, das zentrale Nervensystem beeinflusst, anti-inflammatorisch, anti-allergisch und hypotensiv wirksam ist. Bei der Maus beträgt der ED50-Wert für 1-Methyl-isoguanosin als Muskelrelaxans bei intraperitonealer Applikation 3,1 mg/kg und bei Oraler Applikation 12 mg/kg. Die LD50 bei der Maus beträgt 1000 mg/kg p.o. nach 48 Stunden.According to the invention, it was further found that 1-methyl-isoguanosin develops various therapeutic activities, for example has a muscle-relaxing effect, influences the central nervous system, is anti-inflammatory, anti-allergic and hypotensive. In the mouse, the ED 50 value for 1-methyl-isoguanosine as a muscle relaxant is 3.1 mg / kg with intraperitoneal administration and 12 mg / kg with oral administration. The LD 50 in the mouse is 1000 mg / kg po after 48 hours.

1-Methyl-isoguanosin kann als Muskelrelaxans und/oder als Mittel zur Beeinflussung des zentralen Nervensystems und/oder als anti-inflammatorisches und/oder anti-allergisches und/oder hypotensives Mittel Verwendung finden. Es kann in Form pharmazeutischer Präparate zusammen mit einem verträglichen pharmazeutischen Träger, z.B. einem organischen oder anorganischen inerten Träger, der für enterale, vorzugsweise orale, oder parenterale Administration geeignet ist, verwendet werden. Beispiele solcher Träger sind Wasser, Gelatine, Lactose, Stärke, Talkum, Magnesiumstearat, Gummi, vegetabile Oele und Vaseline. Die pharmazeutischen Präparate können in fester Form, z.B. als Tabletten, Kapseln, Dragees oder Suppositorien oder in flüssiger Form, z.B. als Lösungen, Emulsionen oder Suspensionen vorliegen. Sie können sterilisiert sein und/oder verträgliche Hilfsmittel, wie Konservierungsmittel, Stabilisierungsmittel, Geschmacksstoffe, Farbstoffe, Emulgatoren und Salze zur Veränderung des osmotischen Druckes oder Puffer enthalten.1-methyl-isoguanosine can be used as a muscle relaxant and / or as an agent for influencing the central nervous system and / or as an anti-inflammatory and / or anti-allergen gisch and / or hypotensive means are used. It can be used in the form of pharmaceutical preparations together with a compatible pharmaceutical carrier, for example an organic or inorganic inert carrier which is suitable for enteral, preferably oral or parenteral administration. Examples of such carriers are water, gelatin, lactose, starch, talc, magnesium stearate, rubber, vegetable oils and petroleum jelly. The pharmaceutical preparations can be in solid form, for example as tablets, capsules, coated tablets or suppositories, or in liquid form, for example as solutions, emulsions or suspensions. They can be sterilized and / or contain compatible auxiliaries, such as preservatives, stabilizers, flavors, colors, emulsifiers and salts for changing the osmotic pressure or buffers.

Eine geeignete pharmazeutische Dosierungsform enthält etwa 1-100 mg 1-Methyl-isoguanosin. Die Dosierung für die orale Verabreichung liegt im Bereich von O,1 mg pro kg bis 25 mg pro kg pro Tag. Für die parenterale Verabreichung kommen Dosierungen im Bereich von 0,01 mg pro kg bis lO mg pro kg pro Tag in Betracht. Diese Bereiche können jedoch nach oben oder unten in Abhängigkeit von den individuellen Erfordernissen variiert werden.A suitable pharmaceutical dosage form contains about 1-100 mg of 1-methyl-isoguanosine. The dosage for oral administration is in the range of 0.1 mg per kg to 25 mg per kg per day. Dosages in the range from 0.01 mg per kg to 10 mg per kg per day are suitable for parenteral administration. However, these ranges can be varied up or down depending on individual needs.

Die folgenden Beispiele erläutern die Erfindung.The following examples illustrate the invention.

Beispiel 1example 1

Das Ausgangsmaterial war ein orangefarbener Schwamm der Gattung Tedania, der an der australischen Küste gesammelt wurde. Der gefrorene Organismus wurde lyophilisiert und gemahlen. Das erhaltene Pulver (300 g) wurde mit einem Aethanol: Wassergemisch (3:7 Volumteile, 2 1) 24 Stunden bei 4°C gerührt, danach filtriert und der Rückstand erneut extrahiert. Die vereinigten Extrakte wurden bei 35°C und 7 Torr auf ein Volumen von 1,2 1 konzentriert, die so erhaltene wässrige Suspension 0,3 Stunden mit 13000 g zentrifugiert und der Ueberstand lyophilisiert. Man erhielt so 75,7 g eines orangefarbenen Pulvers A.The starting material was an orange sponge of the Tedania genus, which was collected on the Australian coast. The frozen organism was lyophilized and ground. The powder obtained (300 g) was stirred with an ethanol: water mixture (3: 7 parts by volume, 2 l) at 4 ° C. for 24 hours, then filtered and the residue was extracted again. The combined extracts were concentrated at 35 ° C. and 7 Torr to a volume of 1.2 l, the aqueous suspension thus obtained was centrifuged at 13000 g for 0.3 hours and the supernatant was lyophilized. This gave 75.7 g of an orange powder A.

205 g Rohextrakt A wurden in O,1 M Ammoniumformiatpuffer (pH 3,5) suspendiert, 15 Minuten beschallt und 40 Minuten auf dem siedenden Wasserbad gerührt. Die Suspension wurde auf 22°C gekühlt, das pH durch Zusatz von Ameisensäure von 4,2 auf 3,5 gebracht und sodann mit 13000 g eine halbe Stunde zentrifugiert. Der Ueberstand wurde auf eine Säule (40 x 5 cm) von Bio Rad AGSOW-X8 (Ammoniumform, 200-400 Mesh) gegeben, und mit 0,1 M Ammoniumformiat (pH 3,5) mit einer Durchflussgeschwindigkeit von 150 ml pro Stunde äquilibriert. Dabei wurde die prozentuale Durchlässigkeit des Eluats bei 254 und 280 nm überwacht. Nachdem 10 1 Puffer durchgesetzt waren, wurde 0,1 M Ammoniumformiat (pH 5,3)auf die Säule gegeben. Es wurden folgende Fraktionen gesammelt: 1,2 1 (pH 3,5-4,8) 4,5 1 (pH 4,8-5,0) und 5 1 (pH 5,0-5,2). Nur die Fraktion vom pH 4,8-5,0 war aktiv, sie wurde lyophilisiert und lieferte einen hellgelben Feststoff B (31,6 g).205 g of crude extract A were suspended in 0.1 M ammonium formate buffer (pH 3.5), sonicated for 15 minutes and stirred on the boiling water bath for 40 minutes. The suspension was cooled to 22 ° C., the pH was brought from 4.2 to 3.5 by adding formic acid and then centrifuged at 13,000 g for half an hour. The supernatant was placed on a column (40 x 5 cm) of Bio Rad AGSOW-X8 (ammonium form, 200-400 mesh) and equilibrated with 0.1 M ammonium formate (pH 3.5) at a flow rate of 150 ml per hour . The percent permeability of the eluate was monitored at 254 and 280 nm. After 10 l of buffer had passed through, 0.1 M ammonium formate (pH 5.3) was added to the column. The following fractions were collected: 1.2 l (pH 3.5-4.8), 4.5 l (pH 4.8-5.0) and 5 l (pH 5.0-5.2). Only the pH 4.8-5.0 fraction was active, it was lyophilized and gave a light yellow solid B (31.6 g).

Eine Lösung von 68,9 g B in 1,25 1 0,1 M Ammoniumformiat(pH 3,5)wurden 20 Minuten mit 13000 g zentrifugiert. Der Ueberstand wurde mit 0,1 M Ammoniumformiat (pH 3,5) auf 4 1 verdünnt und das pH wurde durch Zusatz von Ameisensäure auf 3,7 gestellt. Die Lösung wurde auf eine Säule (41,5 x 5 cm) von Bio Rad AG5OW-X8 (Ammoniumform, 200-400 Mesh) gegeben und die oben angegebene Prozedur für die Behandlung des Rohextrakts A wurde wiederholt. Nachdem 5,1 1 pH 3,5 Puffer eluiert worden waren, wurde Puffer vom pH 5,3 auf die Säule gegeben und das aktive Material zwischen 7,85 1 und 10,85 1 eluiert. Die Lyophilisierung der aktiven Fraktion lieferte 10,8 g C.A solution of 68.9 g B in 1.25 1 0.1 M ammonium formate (pH 3.5) was centrifuged at 13,000 g for 20 minutes. The supernatant was diluted to 4 l with 0.1 M ammonium formate (pH 3.5) and the pH was adjusted to 3.7 by adding formic acid. The solution was applied to a column (41.5 x 5 cm) of Bio Rad AG5OW- X 8 (ammonium form, 200-400 mesh) and the above procedure for the treatment of crude extract A was repeated. After 5.1 l of pH 3.5 buffer had been eluted, pH 5.3 buffer was added to the column and the active material was eluted between 7.85 l and 10.85 l. Lyophilization of the active fraction gave 10.8 g of C.

Umkristallisation von C aus siedendem Wasser lieferte 2,75 g 1-Methyl-isoguanosin als farblosen kristallinen Feststoff, Schmelzpunkt 262-263°C,

Figure imgb0007
- 65,4°(c = 1,0, Dimethylsulfoxid)
Figure imgb0008
- 54,6° (c = 1,0, Wasser).Recrystallization of C from boiling water gave 2.75 g of 1-methyl-isoguanosine as a colorless crystalline solid, melting point 262-263 ° C.
Figure imgb0007
 - 65.4 ° (c = 1.0, dimethyl sulfoxide)
Figure imgb0008
 - 54.6 ° (c = 1.0, water).

Beispiel 2Example 2 1-Methyl-isoguanosin1-methyl-isoguanosine

Eine Lösung von 5-Amino-4-cyan-1-(2', 3', 5'-tri-0- acetyl-ß-D-ribofuranosyl)imidazol (25,4 g, 69,3 mMol) und Methylisocyanat (40,9 ml, 693 mMol) in DMF (250 ml, getrocknet über 4A Molekularsiebe) wird unter Rühren bei 100°C erhitzt. Nach 6 Stunden wird das Gemisch abgekühlt und zu einem Oel eingedampft. Spuren von DMF werden durch Ein- , dampfen zusammen mit 250 ml Methanol entfernt. Der entstandene Schaum wird in 250 ml Methanol gelöst, filtriert und zur Trockene eingedampft. Der Schaum wird über Nacht unter Vakuum gelassen, dann in 150 ml Methanol gelöst und über Nacht bei 5°C mit 150 ml konzentriertem Ammoniumhydroxid behandelt. Die entstandenen Kristalle werden gesammelt, mit Methanol gewaschen und aus Aethanol/Wasser (1/1) umkristallisiert. Durch wiederholte Umkristallisationen werden Spuren von Verunreinigungen entfernt. Schmelzpunkt 265-266°C,Zersetzung.A solution of 5-amino-4-cyan-1- (2 ', 3', 5'-tri-0-acetyl-ß-D-ribofuranosyl) imidazole (25.4 g, 69.3 mmol) and methyl isocyanate ( 40.9 ml, 693 mmol) in DMF (250 ml, dried over 4A molecular sieves) is heated with stirring at 100 ° C. After 6 hours the mixture is cooled and evaporated to an oil. Traces of DMF are removed by evaporation, together with 250 ml of methanol. The resulting foam is dissolved in 250 ml of methanol, filtered and evaporated to dryness. The foam is left under vacuum overnight, then dissolved in 150 ml of methanol and treated with 150 ml of concentrated ammonium hydroxide at 5 ° C. overnight. The crystals formed are collected, washed with methanol and recrystallized from ethanol / water (1/1). Repeated recrystallizations remove traces of impurities. Melting point 265-266 ° C, decomposes.

Beispiel 3Example 3

Eine Lösung von 5 g 5-Amino-4-cyan-1-(2', 3', 5'-tri-O-acetyl-ß-D-ribofuranosyl) imidazol in 50 ml über 4A Molekularsiebe getrocknetem DMF wird unter Rühren 23 Stunden unter Rückfluss bei 100°C mit 8,05 ml Methylisocyanat behandelt. Die Lösung wird zur Trockene eingedampft, zusammen mit 2 x 50 ml Methanol eingedampft und über Nacht unter Vakuum gelassen. 4,76 g des erhaltenen Schaums werden in 48 ml Aethylacetat/Chloroform (3/1) gelöst und über Silicagel mit Acetat/Chloroform (3/1) als Eluierungsmittel chromatographiert. Es werden 20 ml Fraktionen gesammelt. Die Fraktionen 122-160 werden kombiniert und zu einem weissen Schaum eingedampft. Zwecks Reinigung wird dieser Schaum in 10 ml Chloroform/Methanol (50/1) gelöst und über Silicagel mit Chloroform/Methanol (50/1) als Eluierungsmittel chromatographiert. Die 20 ml Fraktionen 100-140 werden zur Trockene eingedampft und man erhält 4-Cyan-5-[bis-(methylcarbamoyl)]-amino-l-(2', 3', 5'-tri-O-acetyl-ß-D-ribofurano- syl)imidazol als weissen Schaum; IR 2245 cm-1 (C≡N) , 1753 (Ester), 1728, 1680 (Harnstoffcarbonyl); UV 227 nm (E 11,360) in Methanol, 226 nm (e 9540) in 0,1N HCl.A solution of 5 g of 5-amino-4-cyan-1- (2 ', 3', 5'-tri-O-acetyl-β-D-ribofuranosyl) imidazole in 50 ml of DMF dried over 4A molecular sieves is stirred with 23 Treated under reflux at 100 ° C with 8.05 ml of methyl isocyanate. The solution is evaporated to dryness, evaporated together with 2 x 50 ml of methanol and left under vacuum overnight. 4.76 g of the foam obtained are dissolved in 48 ml of ethyl acetate / chloroform (3/1) and chromatographed on silica gel with acetate / chloroform (3/1) as the eluent. 20 ml fractions are collected. Fractions 122-160 are combined and evaporated to a white foam. For cleaning, this foam is dissolved in 10 ml of chloroform / methanol (50/1) and chromatographed on silica gel with chloroform / methanol (50/1) as the eluent. The 20 ml fractions 100-140 are evaporated to dryness and 4-cyan-5- [bis- (methylcarbamoyl)] - amino-l- (2 ', 3', 5'-tri-O-acetyl- ß - D-ribofurano- syl) imidazole as white foam n; I R 2245 cm -1 (C≡N), 1753 (ester), 1728, 1680 (urea carbonyl); UV 227 nm ( E 11.360) in methanol, 226 nm (e 9540) in 0.1N HCl.

Eine Lösung von 480 ml 4-Cyan-5-[bis-(methylcarbamoyl)]-amino-1-(2', 3', 5-tri-O-acetyl-ß-D-ribofuranosyl)-imidazol in 5 ml Methanol und 5 ml konzentriertem Ammoniumhydroxid wird 18 Stunden bei 5°C aufbewahrt. Das Produkt wird zur Trockene eingedampft und aus Aethanol/Wasser umkristallisiert. Man erhält 1-Methyl-isoguanosin vom Schmelzpunkt 267-268°C (Zersetzung).A solution of 480 ml of 4-cyan-5- [bis- (methylcarbamoyl)] - amino-1- (2 ', 3', 5-tri-O-acetyl-β-D-ribofuranosyl) imidazole in 5 ml of methanol and 5 ml of concentrated ammonium hydroxide is stored at 5 ° C for 18 hours. The product is evaporated to dryness and recrystallized from ethanol / water. 1-Methyl-isoguanosine with a melting point of 267-268 ° C. (decomposition) is obtained.

Beispiel 4Example 4

Eine Lösung von 200 mg Isoguanosin in 6 ml über 4A Molekularsiebe getrocknetem Dimethylsulfoxid wird 18 Stunden bei Raumtemperatur mit 215 mg Kaliumcarbonat und 0,088 ml Methyljodid gerührt. Das Gemisch wird filtriert, zu einem Oel eingedampft, letzteres in Methanol/Wasser (9/1) gelöst und auf 7 g Siliciumoxid gegeben. Das Siliciumoxid wird durch Verdampfung von 3 x 100 ml Aethanol getrocknet, über Nacht im Vakuum gelassen und auf eine Siliciumoxidsäule gegeben. Die Säule wird mit 750 ml Chloroform/Methanol (5/1) und dann mit Chloroform/Methanol (3/1) eluiert. Es werden die 20 ml Fraktionen 45-60 gesammelt und eingedampft. Man erhält rohes 2-Methoxy-adenosin. Nach Umkristallisation aus Wasser erhält man reines Produkt vom Schmelzpunkt 189-192°.A solution of 200 mg of isoguanosine in 6 ml of dimethyl sulfoxide dried over 4A molecular sieves is stirred for 18 hours at room temperature with 215 mg of potassium carbonate and 0.088 ml of methyl iodide. The mixture is filtered, evaporated to an oil, the latter dissolved in methanol / water (9/1) and added to 7 g of silicon oxide. The silicon oxide is dried by evaporation of 3 × 100 ml of ethanol, left in vacuo overnight and placed on a silica column. The column is eluted with 750 ml of chloroform / methanol (5/1) and then with chloroform / methanol (3/1). The 20 ml fractions 45-60 are collected and evaporated. Crude 2-methoxy-adenosine is obtained. After recrystallization from water, pure product of melting point 189-192 ° is obtained.

Die Fraktionen 100-140 werden zur Trockene eingedampft. Man erhält rohes 1-Methyl-isoguanosin. Ein Teil davon wird durch präparative Dünnschichtchromatographie auf Siliciumoxid mit Chloroform/Methanol (2/1) gereinigt. Die geeignete Portion wird mit Wasser extrahiert, der Extrakt zur Trockene eingedampft und in heissem Wasser gelöst. Kleine Mengen von Siliciumoxid werden durch Filtrierung entfernt. Das Filtrat wird zu O,1 ml eingedampft und mit 0,2 ml Aethanol versetzt. Das Gemisch wird über Nacht bei 5°C gehalten und man erhält Kristalle vom Schmelzpunkt 265° C (Zersetzung).Fractions 100-140 are evaporated to dryness. Crude 1-methyl-isoguanosine is obtained. Part of it is purified by preparative thin layer chromatography on silica with chloroform / methanol (2/1). The appropriate portion is extracted with water, the extract is evaporated to dryness and dissolved in hot water. Small amounts of silicon oxide are removed by filtration. The filtrate is evaporated to 0.1 ml and mixed with 0.2 ml of ethanol. The mixture is kept at 5 ° C. overnight and crystals of melting point 265 ° C. (decomposition) are obtained.

Beispiel 5Example 5

Tabletten der folgenden Zusammensetzung wurden in üblicher Weise hergestellt:

Figure imgb0009
Tablets of the following composition were produced in the usual way:
Figure imgb0009

Claims (15)

1. Verfahren zur Herstellung von 1-Methyl-isoguanosin, dadurch gekennzeichnet, dass man a) es aus natürlichen Vorkommen in an sich bekannter . Weise isoliert oder b) eine Verbindung der Formel
Figure imgb0010
worin R eine leicht abspaltbare Acylgruppe darstellt, mit Methylisocyanat in Gegenwart eines stark aprotischen Lösungsmittels umsetzt und die erhaltene Verbindung der Formel
Figure imgb0011
 worin R obige Bedeutung hat,
mit einer Base umsetzt oder c) eine Verbindung der Formel
Figure imgb0012
mit einem Methylierungsmittel umsetzt. 1. A process for the preparation of 1-methyl-isoguanosine, characterized in that a) it from natural occurrences in known per se. Way isolated or b) a compound of the formula
Figure imgb0010
 wherein R represents an easily removable acyl group, reacted with methyl isocyanate in the presence of a strongly aprotic solvent and the compound of the formula obtained
Figure imgb0011
 where R has the above meaning,
with a base or c) a compound of the formula
Figure imgb0012
 reacted with a methylating agent. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man Verfahrensvariante a) durchführt.2. The method according to claim 1, characterized in that one carries out process variant a). 3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man die Verfahrensvariante b) durchführt.3. The method according to claim 1, characterized in that one carries out the process variant b). 4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man die Verfahrensvariante c) durchführt.4. The method according to claim 1, characterized in that one carries out the process variant c). 5. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass das natürliche Vorkommen ein Meeresorganismus ist und 1-Methyl-isoguanosin durch Extraktion mit einem Lösungsmittel und anschliessende Chromatographie isoliert wird.5. The method according to claim 1 or 2, characterized in that the natural occurrence is a marine organism and 1-methyl-isoguanosine is isolated by extraction with a solvent and subsequent chromatography. 6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, dass das Lösungsmittel ein Gemisch von Wasser und Aethanol ist und der Extrakt durch Ionenaustauscherchromatographie gereinigt wird.6. The method according to claim 5, characterized in that the solvent is a mixture of water and ethanol and the extract is purified by ion exchange chromatography. 7. Verfahren nach Anspruch 1 oder 3, dadurch gekennzeichnet, dass die Acylgruppe R Acetyl ist.7. The method according to claim 1 or 3, characterized records that the acyl group R is acetyl. 8. Verfahren nach Anspruch 1 oder 4, dadurch gekennzeichnet, dass die Methylierung der Verbindung der Formel IV mit Methylhalogenid in Gegenwart eines aprotischen Lösungsmittels unter basischen Bedingungen durchgeführt wird.8. The method according to claim 1 or 4, characterized in that the methylation of the compound of formula IV with methyl halide in the presence of an aprotic solvent is carried out under basic conditions. 9. Verfahren zur Herstellung von pharmazeutischen Präparaten, dadurch gekennzeichnet, dass man 1-Methyl-isoguanosin als wirksamen Bestandteil mit zur therapeutischen Verabreichung geeigneten nicht-toxischen inerten an sich in solchen Präparaten üblichen festen und flüssigen Trägern und/oder Excipientien vermischt.9. A process for the preparation of pharmaceutical preparations, characterized in that 1-methyl-isoguanosine is mixed as an effective component with non-toxic inert, solid and liquid carriers and / or excipients which are customary in such preparations and are suitable for therapeutic administration. 10. Pharmazeutische Präparate,gekennzeichnet durch einen Gehalt an 1-Methyl-isoguanosin.10. Pharmaceutical preparations, characterized by a content of 1-methyl-isoguanosine. 11 . 1-Methyl-isoguanosin11. 1-methyl-isoguanosine 12. 1-Methyl-isoguanosin in praktisch reiner Form frei von natürlich vorkommenden Begleitstoffen.12. 1-methyl-isoguanosine in practically pure form free from naturally occurring accompanying substances. 13 Verwendung von 1-Methyl-isoguanosin als Muskel- relaxants und oder als Mittel zur Beeinf lussung des zentralen Nervensystems und/oder als antiinflammatorisches und oder antiallergisches und/oder hypotensives Mittel.13 Use of 1-methyl-isoguanosine as muscle relaxants and or as an agent for influencing the central nervous system and / or as an anti-inflammatory and or anti-allergic and / or hypotensive agent. 14. Verbindungen der Formel
Figure imgb0013
worin R eine leicht abspaltbare Acylgruppe darstellt.14. Compounds of the formula
Figure imgb0013
 wherein R represents an easily removable acyl group. 15. Verbindung nach Anspruch14 worin R Acetyl darstellt.15. A compound according to claim 14 wherein R is acetyl.
EP78100579A 1977-08-03 1978-08-02 1-methylisoguanosin, processes and intermediates for its preparation, its pharmaceutical compositions and their preparation Withdrawn EP0000770A3 (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
LU77910 1977-08-03
LU77910 1977-08-03
US87676978A 1978-02-10 1978-02-10
US05/876,768 US4148993A (en) 1978-02-10 1978-02-10 Process to produce 1-methyl isoguanosine
US876769 1978-02-10
US876768 1978-02-10
GB7826761A GB2001955A (en) 1977-08-03 1978-06-13 1-Methyl-isoguanine
GB2676178 1978-06-13

Publications (2)

Publication Number Publication Date
EP0000770A2 true EP0000770A2 (en) 1979-02-21
EP0000770A3 EP0000770A3 (en) 1979-06-13

Family

ID=27449076

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100579A Withdrawn EP0000770A3 (en) 1977-08-03 1978-08-02 1-methylisoguanosin, processes and intermediates for its preparation, its pharmaceutical compositions and their preparation

Country Status (14)

Country Link
EP (1) EP0000770A3 (en)
JP (1) JPS5448794A (en)
AU (1) AU3840678A (en)
DE (1) DE2833887A1 (en)
DK (1) DK343578A (en)
ES (1) ES472297A1 (en)
FI (1) FI782298A (en)
FR (1) FR2399441A1 (en)
IL (1) IL55240A0 (en)
IT (1) IT1202760B (en)
MC (1) MC1200A1 (en)
NO (1) NO782648L (en)
PT (1) PT68377A (en)
SE (1) SE7808350L (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108864234A (en) * 2018-07-06 2018-11-23 厦门医学院 A method of the Separation of Inosine from wrinkle tumor ascidian

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 71, Eighth Collective, Formula Index, Seite 3581f, Isoguanosine, N-methyl, XP002940121; & Chemical Abstracts, 71/1969, 3612c, XP002940120; & Chemical Pharm. Bull. (Tokyo), 1968, 16(11) 2172-81, XP000989447 *
Nucleoside Antibiotics by Suhadolnik R.J. New York, 1970, Seiten 267-270, XP000990079 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108864234A (en) * 2018-07-06 2018-11-23 厦门医学院 A method of the Separation of Inosine from wrinkle tumor ascidian
CN108864234B (en) * 2018-07-06 2020-06-26 厦门医学院 Method for separating inosine from ascidians plicata

Also Published As

Publication number Publication date
FI782298A (en) 1979-02-04
IT7826445A0 (en) 1978-08-03
IL55240A0 (en) 1978-09-29
DE2833887A1 (en) 1979-02-22
FR2399441A1 (en) 1979-03-02
PT68377A (en) 1978-09-01
MC1200A1 (en) 1979-03-19
EP0000770A3 (en) 1979-06-13
SE7808350L (en) 1979-02-04
DK343578A (en) 1979-02-04
ES472297A1 (en) 1979-02-16
AU3840678A (en) 1980-01-31
IT1202760B (en) 1989-02-09
NO782648L (en) 1979-02-06
JPS5448794A (en) 1979-04-17

Similar Documents

Publication Publication Date Title
EP0316704A2 (en) Fluorocytidine derivatives, their preparation and medical preparations containing them
DE2331223C2 (en) S-substituted-2-thioadenosines, their 5'-monophosphates, processes for their preparation and pharmaceuticals containing them
DE2025624A1 (en) 5'-0 derivatives of ara-cytidine and process for their preparation
DE1962757C3 (en) Evomonoside derivatives, processes for their production and pharmaceuticals containing them
DE2310329A1 (en) ARABINOFURANOSYLCYTOSINS AND THE METHOD FOR THEIR PRODUCTION
DE1274100B (en) Process for the preparation of 1,6-dibromo-1,6-dideoxydulcite
DE68928127T2 (en) 2'-Methylidene pyrimidine nucleoside compounds, their use and process for their preparation
EP0000770A2 (en) 1-Methylisoguanosin, processes and intermediates for its preparation, its pharmaceutical compositions and their preparation
DE2404946C3 (en) Process for the preparation of 7alpha-acylthio-steroid spirolactones
DE2738498C3 (en) H2-chloroethyl) -l-nitroso-3- (2-acetamido-2deoxy- ß -D-glucopyranosyl) - ureas, process for their preparation and medicinal products containing these compounds
DE3928032A1 (en) ORGANOGERMANIUM COMPOUNDS AND METHOD FOR THEIR PRODUCTION
CH660740A5 (en) HALOGENANTHRACYCLINGLYCOSIDES.
DE2453649B2 (en) Process for the preparation of coformycin and intermediates for its preparation
DE2626792A1 (en) Adenosine-5'-phosphoric acid derivs. and their salts - prepd. by acylating adenosine-5'-phosphate and opt. desalting or salt exchanging
CH651834A5 (en) METHOD FOR PURIFYING GUANINE.
DE2601755C2 (en) Pseudoisocytidine and its salts, processes for their preparation and medicaments containing these compounds
DE3317702C2 (en)
CH667092A5 (en) METHOD FOR PRODUCING 2-BROMINE ALPHA-ERGOKRYPTIN.
DE1445873A1 (en) Process for the preparation of benzodiazepine derivatives
CH497413A (en) Proscillaridin a derivs
CH641174A5 (en) PROCESS FOR THE PREPARATION OF N-(4'-CHLORO-3'-SULFAMOYL-BENZENESULFONYL)-N-METHYL-2-AMINOMETHYL-2-METHYL-TETRAHYDROFURAN.
DE1745780C3 (en) l-Sulfonyläthyl ^ -methyl-S-nitroimidazole and process for their preparation
DE1963597C3 (en) New neriifolin derivatives, processes for producing the same and pharmaceuticals containing them
DE1620590A1 (en) Lincomycin esters and process for their preparation
DE1793690C3 (en) 1 S-Hydroxy-9-oxoprosta-5-cis-10,13-trans-trienoic acid and its salts and processes for their preparation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Designated state(s): BE CH DE FR GB LU NL SE

17P Request for examination filed
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn
RIN1 Information on inventor provided before grant (corrected)

Inventor name: GREGSON, RICHARD PETER

Inventor name: COOK, ALAN FREDERICK

Inventor name: QUINN, RONALD JAMES