Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/10—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• 3,6-Dihydro-l,3,5-triazine derivatives show pharmacological properties in the treatment of pathological conditions associated with the insulin-resistance syndrome.
• Several patents describe the preparation of 3,6-dihydro-l,3,5-triazine derivatives.
• US3287366 the synthesis of dihydro-triazine bearing the following structure is described:
• the synthesis involves the reaction of a mono-substituted bisguanidine and an aldehyde or ketone in presence of an acid at elevated temperatures.
• Patent JP48064088 describes the synthesis of dihydro-triazines bearing the following structure:
• the analogous synthesis also involves heating under acidic condition.
• Patent JP54014986 describes the synthesis of dihydro-triazines bearing the following structure:
• Patent application WO 01/55122 describes the synthesis of dihydro-triazines of the following structure:
• the synthesis is directed to the reaction of mono-substituted bisguanidines and an acetal, hemiacetal, ketal, hemiketal, aldehyde, or ketone in presence of an acid at elevated temperatures.
• compounds of formula I can be prepared either in absence of a base or in presence of a base selected from the group K 2 CO 3 , NaHCO 3 , NaOMe, Na 2 CO 3 , piperidine, morpholine, preferably at temperatures between -5 ° and 80 0 C under ambient pressure.
• reaction is carried out at temperatures between -5 ° and 60 0 C under ambient pressure.
• the invention relates to a process for the preparation of compounds of the formula I
• R is methyl, phenyl, 4-hydroxy-phenyl or 4-methoxyphenyl and pharmaceutically salts, tautomers and stereoisomers thereof, characterised in that a compound of the formula II and the salts thereof is reacted with a compound of the formula III
• R is as defined above, in a polar solvent or solvant mixture in presence or absence of an anorganic and/or organic base, wherein the base is selected from the group
• the solvent may be chosen from water, methanol, ethanol, isopropanol, n-butanol, 2-butanol, i-butanol, t-butanol, N,N-dimethyl formamide or any combination of solvents.
• the base particularly preferred is NaOMe or piperidine.
• the solvent particularly preferred is methanol, isopropanol or a mixture of water and methanol.
• the concentration of the compound of formula II ranges from 0.1 mol/L to 4 mol/L.
• the concentration of the compound of formula III ranges from 1 equivalent to 10 equivalents to the compound of formula II.
• the base ranges from 0.5 equivalents to 10 equivalents to the compound of formula II.
• the compounds of formula I also mean their solvates and their pharmaceutically usable derivatives.
• solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force.
• Solvates are, for example, mono- or dihydrates or alcoholates.
• pharmaceutically usable derivatives is taken to mean, for example, the salts of the compounds according to the invention and so-called prodrug compounds.
• prodrug derivatives is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds according to the invention.
• biodegradable polymer derivatives of the compounds according to the invention as described, for example, in Int. J. Pharm. 115, 61-67 (1995).
• Formula I also embraces the tautomeric forms of the compounds.
• a preferred process for the preparation of compounds of formula I is related to compounds in which
• R is methyl or 4-hydroxyphenyl; most preferably R is methyl.
• N,N-dimethylbiguanide hydrochloride is used as educt the process is carried out in presence of a base.
• N,N-dimethylbiguanide base
• the process is carried out in absence of a base.
• Most preferably the reaction is carried with NaOMe as base in methanol at temperatures between -5 ° and 2O 0 C.
• R is methyl and pharmaceutically salts, tautomers and stereoisomers thereof, characterised in that a compound of the formula II
• R-CHO III in which R is as defined above, in a polar solvent or solvant mixture in presence of an anorganic and/or organic base, wherein the base is selected from the group K 2 CO 3 , NaHCO 3 , NaOMe, Na 2 CO 3 , piperidine, morpholine.
• the base is selected from the group K 2 CO 3 , NaHCO 3 , NaOMe, Na 2 CO 3 , piperidine, morpholine.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Emergency Medicine (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Endocrinology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (18)

Applications Claiming Priority (2)

Publications (2)

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Cited By (4)

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• 2009
  • 2009-04-24 KR KR1020107028733A patent/KR101618198B1/ko not_active Expired - Fee Related
  • 2009-04-24 PL PL09749530T patent/PL2300444T3/pl unknown
  • 2009-04-24 ES ES09749530T patent/ES2571793T3/es active Active
  • 2009-04-24 RS RS20160296A patent/RS54736B1/sr unknown
  • 2009-04-24 WO PCT/EP2009/002997 patent/WO2009141040A2/en not_active Ceased
  • 2009-04-24 JP JP2011509869A patent/JP5458093B2/ja not_active Expired - Fee Related
  • 2009-04-24 EA EA201001828A patent/EA018921B1/ru not_active IP Right Cessation
  • 2009-04-24 AU AU2009250149A patent/AU2009250149B2/en not_active Ceased
  • 2009-04-24 HR HRP20160414TT patent/HRP20160414T1/hr unknown
  • 2009-04-24 SI SI200931424A patent/SI2300444T1/sl unknown
  • 2009-04-24 EP EP09749530.3A patent/EP2300444B1/en active Active
  • 2009-04-24 US US12/736,856 patent/US20110124860A1/en not_active Abandoned
  • 2009-04-24 MX MX2010012741A patent/MX2010012741A/es active IP Right Grant
  • 2009-04-24 DK DK09749530.3T patent/DK2300444T3/en active
  • 2009-04-24 CA CA2725011A patent/CA2725011A1/en not_active Abandoned
  • 2009-04-24 CN CN2009801188956A patent/CN102036970A/zh active Pending
  • 2009-04-24 HU HUE09749530A patent/HUE027532T2/en unknown
  • 2009-04-24 BR BRPI0912512A patent/BRPI0912512B1/pt not_active IP Right Cessation
• 2010
  • 2010-11-08 IL IL209198A patent/IL209198A/en active IP Right Grant
  • 2010-12-21 ZA ZA2010/09160A patent/ZA201009160B/en unknown
• 2016
  • 2016-05-11 CY CY20161100394T patent/CY1117855T1/el unknown

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