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.

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

Applications Claiming Priority (8)

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Cited By (1)

• 1978
  • 1978-07-20 FI FI782298A patent/FI782298A7/fi not_active Application Discontinuation
  • 1978-07-27 AU AU38406/78A patent/AU3840678A/en active Pending
  • 1978-07-28 IL IL55240A patent/IL55240A0/xx unknown
  • 1978-07-31 MC MC781317A patent/MC1200A1/fr unknown
  • 1978-08-01 JP JP9323178A patent/JPS5448794A/ja active Pending
  • 1978-08-02 DK DK343578A patent/DK343578A/da unknown
  • 1978-08-02 SE SE7808350A patent/SE7808350L/xx unknown
  • 1978-08-02 EP EP78100579A patent/EP0000770A3/fr not_active Withdrawn
  • 1978-08-02 ES ES472297A patent/ES472297A1/es not_active Expired
  • 1978-08-02 PT PT68377A patent/PT68377A/pt unknown
  • 1978-08-02 NO NO782648A patent/NO782648L/no unknown
  • 1978-08-02 DE DE19782833887 patent/DE2833887A1/de not_active Withdrawn
  • 1978-08-03 IT IT26445/78A patent/IT1202760B/it active
  • 1978-08-03 FR FR7822976A patent/FR2399441A1/fr active Pending

Non-Patent Citations (2)

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