Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms
  • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim

Definitions

• the invention relates to new amidino-benzylpyrimidines of the general formula I.
• R 1 , R 2 and R 3 which may be the same or different from one another, are hydrogen, methyl, methoxy or chlorine
• R 4 is alkyl having 1-6 C atoms or benzyl and R 5 and R 6 are the same or can be different from each other, hydrogen, lower alkyl with 1-4 C atoms, optionally substituted benzyl or phenyl, cyclohexyl, adamantyl or furfuryl or one of the radicals R 5 or R 6 the group -C 6 H 4 -SO 2 -NH -R 7 means, where R 7 represents the rest or a heterocyclic ring having 1 to 3 heteroatoms, which may be the same or different from one another and are nitrogen or oxygen, and which means Chlorine, methyl or methoxy can be substituted and consists of 5-6 ring members, or R 5 and R 6 together with the nitrogen to which they are connected form
• Suitable acids for the formation of pharmacologically acceptable salts are hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid and salicylic acid.
• the substituents R 1 , R2 and R 3 are preferably in the 3-, 4- and 5-position of the benzene ring.
• R 4 is a lower alkyl radical having 1-4 C atoms or the benzyl radical
• R 5 and R 6 which may be the same or different, are hydrogen, lower alkyl having 1-4 C atoms, benzyl, phenyl or, together with the nitrogen atom to which they are connected, are a polymethylene chain with 4 or 5 methylene groups which can be interrupted by an oxygen atom or the group> NY, where Y is methyl, benzyl or phenyl stands, or R 5 is hydrogen and R 6 is the group -C 6 H 4 -S0 2 NH-R 7 , where R 7 or the pyrimidin-2-yl-, 4-methyl-pyrimidin-2-yl-, 5-methyl-pyrimidin-2-yl-, 5-isopropyl-pyrimidin-2-yl-, 5-methoxy-pyrimidin- 2-yl, 6-methoxy-pyridazin-3-yl,
• R 1 , R 2 and R 3 are hydrogen, methyl or methoxy are further preferred, and of these particularly preferred are those in which R 1 , R 2 and R 3 are in the positions 3, 4 and 5 of the benzyl radical and are methoxy groups.
• the compounds of the formula I have an antimicrobial activity in diseases caused by bacteria and protozoa and, combined with sulfonamides, potentiate their antibacterial action. They can therefore be used, for example, for bacterial diseases of the respiratory organs, digestive organs and urinary tract as well as for throat, nose and ear infections and in general for systemic infectious diseases and malaria.
• the compounds of formula I and their salts can be combined with the sulfonamides mentioned by way of example in various mixing ratios, the ratio of compound formula I to sulfonamide being able to vary from 1:10 to 5: 1. However, preferred mixing ratios are 1: 1 to 1 : 5. As a rule, 20 to 550 mg of an active ingredient of the formula I are suitable as doses.
• the compounds of the formula I according to the invention are prepared by the methods customary for the preparation of amidines, as described, inter alia, in Houben-Weyl "Methods of Organic Chemistry", Volume 11/2, by an imidate of the general formula II wherein R 1 , R 2 , R3 and R 4 have the meaning given above and R 8 is lower alkyl having 1-4 C atoms or benzyl, with an amine of the general formula III in which R 5 and R 6 have the meaning given above, converted to the amidine of the general formula I. and then optionally converting the compound obtained into a pharmacologically acceptable acid addition salt with an acid customary for this.
• Amines of the formula III can be, for example:
• Ammonia methylamine, dimethylamine, diethylamine, benzylamine, 3,4,5-trimethoxybenzylamine, N-phenylpiperazine, furfurylamine, cyclohexylamine, pyrrolidine, piperidine, morpholine, aniline and sulfonamides such as 2-sulfanilamino-pyrimidine, 2-sulfanilamido-4 -pyrimidine, 2-sulfanilamido-5-methyl-pyrimidine, 2-sulfanilamido-5-isopropyl-pyrimidine, 2-sulfanilamido - 5-methoxy-pyrimidine, 3-sulfanilamido-6-methoxy-pyridazine, 2-sulfanilamido -3-methoxy-pyrazine, 3-sulfanilamido-5-methyl-isoxazole and 2-sulfanilamido-pyridine.
• 2-sulfanilamino-pyrimidine 2-
• These compounds can be prepared with or without a solvent.
• suitable solvents are pyridine, ethanol or water or mixtures of these solvents.
• the reaction temperatures are between 0 and 150 ° C, preferably between 20 and 120 ° C or at temperatures up to the boiling point of the solvent used.
• mice groups of 30 female mice each were infected with a lethal dose of Streptococcus agalactiae 7941 and treated 2 hours after the infection with a mixture of 300 mg of 2-sulfanilamido-4,5-dimethyloxazole + 60 mg of one of the substances according to the invention.
• a second group was treated with the mixture of 300 mg of 2-sulfanilamido-4,5-dimethyloxazole + 60 mg of trimethoprim, which served as reference substance. After 44 hours, the number of surviving animals was determined and this number was divided by the number of survivors from the group treated with the reference substance.
• trimethoprim The numerical value obtained in this way (trimethoprim factor) is a measure of the action of the substances according to the invention in comparison with trimethoprim.
• F 2 means that the substance is twice as effective as trimethoprim.
• the following table shows that the substances according to the invention are 5.4 times superior to trimethoprim.
• the present invention accordingly also relates to chemotherapeutic agents which, in addition to conventional carriers and diluents, contain a compound of the formula I, in particular in combination with a sulfonamide, as active ingredients, and the use of the compounds of the formula I as sulfonamide potentiators.
• chemotherapeutic agents or preparations are produced in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application.
• the preferred preparations are in a dosage form which is suitable for oral administration.
• Dosage forms of this type are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions.
• the active ingredients are mixed with corn starch and granulated with an aqueous gelatin solution.
• the dry granulate is sieved and mixed with the aggregates. Tablets are pressed from this mixture in the usual way.
• the active ingredients are granulated with aqueous gelatin solution and, after drying, mixed with corn starch, talc and magnesium stearate. Tablets are pressed from this mixture in the usual way.
• the active ingredient is mixed with corn starch and granulated with aqueous gelatin solution.
• the dry granulate is sieved and mixed with the aggregates. Tablets are pressed from this mixture in the usual way.
• the active ingredient is granulated with aqueous gelatin solution and, after drying, is mixed with corn starch, talc and magnesium stearate. Tablets are pressed from this mixture in the usual way. the finely ground active ingredients are suspended in the aqueous tylose mucus. Then all other ingredients are added in succession with stirring. Finally, make up to 100.0 with water.
• the finely ground active ingredient is suspended in the aqueous tylose mucus. Then all other ingredients are added in succession with stirring. Finally, make up to 100.0 with water.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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Citations (1)

• 1977
  • 1977-07-15 DE DE19772732029 patent/DE2732029A1/de not_active Withdrawn
• 1978
  • 1978-06-19 DE DE7878100184T patent/DE2860614D1/de not_active Expired
  • 1978-06-19 EP EP78100184A patent/EP0000336B1/fr not_active Expired
  • 1978-07-03 IL IL55063A patent/IL55063A0/xx unknown
  • 1978-07-05 IT IT25382/78A patent/IT1096976B/it active
  • 1978-07-05 IE IE1354/78A patent/IE47022B1/en unknown
  • 1978-07-10 AU AU37903/78A patent/AU520820B2/en not_active Expired
  • 1978-07-11 FI FI782221A patent/FI782221A7/fi not_active Application Discontinuation
  • 1978-07-11 AR AR272912A patent/AR227759A1/es active
  • 1978-07-13 HU HU78BA3676A patent/HU179408B/hu unknown
  • 1978-07-13 JP JP8462878A patent/JPS5419986A/ja active Pending
  • 1978-07-14 DK DK315878A patent/DK143273C/da not_active IP Right Cessation
  • 1978-07-14 AT AT513078A patent/AT360999B/de not_active IP Right Cessation
  • 1978-07-14 NO NO782455A patent/NO782455L/no unknown
  • 1978-07-14 ZA ZA00784012A patent/ZA784012B/xx unknown
  • 1978-07-14 CA CA307,427A patent/CA1129410A/fr not_active Expired

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Non-Patent Citations (1)

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