EP0000336A1 - N-benzylpyrimidinyl-amidines, process for their preparation and medicines containing them - Google Patents

N-benzylpyrimidinyl-amidines, process for their preparation and medicines containing them Download PDF

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Publication number
EP0000336A1
EP0000336A1 EP78100184A EP78100184A EP0000336A1 EP 0000336 A1 EP0000336 A1 EP 0000336A1 EP 78100184 A EP78100184 A EP 78100184A EP 78100184 A EP78100184 A EP 78100184A EP 0000336 A1 EP0000336 A1 EP 0000336A1
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Prior art keywords
pyrimidin
trimethoxybenzyl
amino
acetamidine
acids
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EP78100184A
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German (de)
French (fr)
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EP0000336B1 (en
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Peter Dr. Scharwaechter
Klaus Dr. Gutsche
Wilhelm Dr. Kohlmann
Gerd Dr. Kroemer
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BASF SE
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BASF SE
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    • 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)

Abstract

1. Amidino-benzylpyrimidines of the general formula I see diagramm : EP0000336,P9,F1 where R**1 , R**2 , and R**3 , which may be identical or different, are hydrogen, methyl, methoxy or chlorine, R**4 is alkyl of 1 to 6 carbon atoms or benzyl and R**5 and R**6 , which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, trimethoxybenzyl, benzyl or phenyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R**5 and R**6 is -C6 H4 -SO2 -NH-R**7 , where R**7 is see diagramm : EP0000336,P9,F2 see diagramm : EP0000336,P9,F3 or 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, 3-methoxy-pyrazin-2-yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl, or R**5 and R**6 together with the nitrogen to which they are bonded are a saturated heterocyclic ring of 5-7 members, which may contain an oxygen atom or the N-Y group, where Y is methyl, benzyl or phenyl, and their pharmacologically acceptable salts with acids conventionally used for this purpose.

Description

Die Erfindung betrifft neue Amidino-benzylpyrimidine der allgemeinen Formel I

Figure imgb0001
in der R 1, R2 und R3, die gleich oder verschieden voneinander sein können, Wasserstoff, Methyl, Methoxy oder Chlor bedeuten, R4 Alkyl mit 1-6 C-Atomen oder Benzyl bedeutet und R 5 und R6, die gleich oder verschieden voneinander sein können, Wasserstoff, niederes Alkyl mit 1-4 C-Atomen, gegebenenfalls substituiertes Benzyl oder Phenyl, Cyclohexyl, Adamantyl oder Furfuryl oder einer der Reste R5 oder R6 die Gruppierung -C6H4-SO2-NH-R7 bedeutet, wobei R7 den Rest
Figure imgb0002
oder einen heterocyclischen Ring mit 1 bis 3 Heteroatomen, die gleich oder verschieden voneinander sein können und Stickstoff oder Sauerstoff sind, bedeutet und der durch Chlor, Methyl oder Methoxy substituiert sein kann und aus 5-6 Ringgliedern besteht, oder R5 und R6 bilden gemeinsam mit dem Stickstoff, mit dem sie verbunden sind, einen gesättigten heterocyclischen Ring mit 5-7 Gliedern, der gegebenenfalls ein Sauerstoffatom oder die >N-Y-Gruppe enthalten kann, wobei Y für Methyl, Benzyl oder Phenyl steht, sowie deren pharmakologisch verträgliche Salze mit hierfür üblichen Säuren.The invention relates to new amidino-benzylpyrimidines of the general formula I.
Figure imgb0001
 in which 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
Figure imgb0002
 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 a saturated heterocyclic ring with 5-7 members, which optionally has an oxygen atom or > NY group can contain, where Y is methyl, benzyl or phenyl, and their pharmacologically acceptable salts with customary acids.

Als übliche Säuren zur Bildung pharmakologisch verträglicher Salze kommen beispielsweise Salzsäure, Salpetersäure, Schwefelsäure, Phosphorsäure, Essigsäure, Milchsäure, Zitronensäure und Salicylsäure in Frage.Examples of 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.

Bevorzugt stehen die Substituenten R1, R2 und R3 in der 3-, 4- und 5-Stellung des Benzolringes.The substituents R 1 , R2 and R 3 are preferably in the 3-, 4- and 5-position of the benzene ring.

Unter den Verbindungen der Formel I sind dabei diejenigen bevorzugt, in denen R4 ein Niederalkylrest mit 1-4 C-Atomen oder der Benzylrest ist, und R5 und R6, die gleich oder verschieden sein können, Wasserstoff, Niederalkyl mit 1-4 C-Atomen, Benzyl, Phenyl oder, zusammen mit dem Stickstoffatom, mit dem sie verbunden sind, eine Polymethylenkette mit 4 oder 5 Methylengruppen sind, die durch ein Sauerstoffatom oder die Gruppe >N-Y unterbrochen sein können, wobei Y für Methyl, Benzyl oder Phenyl steht, oder R5 Wasserstoff und R6 die Gruppe -C6H4-S02NH-R7 ist, wobei R7

Figure imgb0003
oder der 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, 3-Methoxy-pyrazin--2-yl-, 5-Methyl-isoxazol-3-yl- oder 2-Pyridinyl-Rest ist und R1, R2 und R3 die gleiche Bedeutung wie in Formel I haben. Unter den genannten Verbindungen der Formel I sind weiter bevorzugt diejenigen, in denen R1, R2 und R3 Wasserstoff, Methyl oder Methoxy bedeuten, und davon besonders bevorzugt solche Substanzen, in denen sich R1, R2 und R3 in den Stellungen 3, 4 und 5 des Benzylrestes befinden und Methoxygruppen sind.Among the compounds of the formula I, preference is given to those in which R 4 is a lower alkyl radical having 1-4 C atoms or the benzyl radical, and 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
Figure imgb0003
 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, 3-methoxy-pyrazine - 2-yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl radical and R 1 , R2 and R 3 have the same meaning as in formula I. Among the compounds of the formula I mentioned, those in which 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.

Die Verbindungen der Formel I sind antimikrobiell wirksam bei durch Bakterien und Protozoen hervorgerufenen Krankheiten und potenzieren, kombiniert mit Sulfonamiden, deren antibakterielle Wirkung. Sie können daher beispielsweise bei bakteriellen Erkrankungen der Atmungsorgane, Verdauungsorgane und Harnwege sowie bei Hals-, Nasen-, Ohreninfektionen und allgemein bei systemischen Infektionskrankheiten und bei Malaria verwendet werden.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.

Solche Sulfonamide sind beispielsweise:Examples of such sulfonamides are:

2-Sulfanilamido-pyridin, 2-Sulfanilamido-thiazol, 2-Sulfanilamido-pyrimidin, 2-Sulfanilamido-4-methyl-pyrimidin, 2-Sulfanilamido-4,6-dimethyl-pyrimidin, 4-Sulfanilamido-2,6-dimethyl-pyrimidin, 5-Suflanilamido-3,4-dimethyl-isoxazol, 3-Sulfanilamido-6-methoxy-pyridazin, 3-Sulfanilamido-6-chlor- pyridazin, 4-Sulfanilamido-2,6-dimethoxy-pyrimidin, 3-Sulfanilamido-2-phenyl-pyrazol, 2-Sulfanilamido-5-methyl-pyrimidin, 2-Sulfanilamido-5-methoxy-pyrimidin, 2-Sulfanilamido-5-methyl-isoxazol, 2-Sulfanilamido-4,5-dimethyl-oxazol, 2-Sulfanilamido-3-methoxy-pyrazin, 4-Sulfanilamido-5,6-dimethoxy--pyrimidin, 4-Sulfanilamido-3-methoxy-1,2,5-thiadiazol, 4-Aminobenzol-sulfonyl-guanidin.2-sulfanilamido-pyridine, 2-sulfanilamido-thiazole, 2-sulfanilamido-pyrimidine, 2-sulfanilamido-4-methyl-pyrimidine, 2-sulfanilamido-4,6-dimethyl-pyrimidine, 4-sulfanilamido-2,6-dimethyl- pyrimidine, 5-suflanilamido-3,4-dimethyl-isoxazole, 3-sulfanilamido-6-methoxy-pyridazine, 3-sulfanilamido-6-chloropyridazine, 4-sulfanilamido-2,6-dimethoxy-pyrimidine, 3-sulfanilamido 2-phenyl-pyrazole, 2-sulfanilamido-5-methyl-pyrimidine, 2-sulfanilamido-5-methoxy-pyrimidine, 2-sulfanilamido-5-methyl-isoxazole, 2-sulfanilamido-4,5-dimethyl-oxazole, 2- Sulfanilamido-3-methoxy-pyrazine, 4-sulfanilamido-5,6-dimethoxy-pyrimidine, 4-sulfanilamido-3-methoxy-1,2,5-thiadiazole, 4-aminobenzene-sulfonyl-guanidine.

Die Verbindungen der Formel I und ihre Salze können mit den beispielhaft genannten Sulfonamiden in verschiedenen Mischungsverhältnissen kombiniert werden, wobei das Verhältnis Verbindung Formel I zu Sulfonamid von 1:10 bis 5:1 variieren kann. Bevorzugte Mischungsverhältnisse sind jedoch 1:1 bis 1:5. Dabei kommen in der Regel als Dosierung 20 bis 550 mg eines Wirkstoffes der Formel I in Betracht.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.

Die Herstellung der erfindungsgemäßen Verbindungen der Formel I geschieht nach den für die Herstellung von Amidinen üblichen Methoden, wie sie u.a. im Houben-Weyl "Methoden der organischen Chemie", Band 11/2 beschrieben sind, indem ein Imidsäureester der allgemeinen Formel II

Figure imgb0004
worin R 1, R2, R3 und R4 die oben angegebene Bedeutung haben und R8 niederes Alkyl mit 1-4 C-Atomen oder Benzyl bedeutet, mit einem Amin der allgemeinen Formel III
Figure imgb0005
in welcher R5 und R6 die oben angegebene Bedeutung haben, umsetzt zum Amidin der allgemeinen Formel I
Figure imgb0006
und anschließend gegebenenfalls die erhaltene Verbindung in ein pharmakologisch verträgliches Säureadditionssalz mit einer hierfür üblichen Säure überführt.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
Figure imgb0004
 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
Figure imgb0005
 in which R 5 and R 6 have the meaning given above, converted to the amidine of the general formula I.
Figure imgb0006
 and then optionally converting the compound obtained into a pharmacologically acceptable acid addition salt with an acid customary for this.

Die Imidsäureester der allgemeinen Formel II und ihre Herstellung sind in der deutschen Patentanmeldung P 27 30 468.3 vom 6. Juli 1977 der Anmelderin beschrieben. Eine entspreqhende Patentanmeldung auf Grund dieser Priorität ist auch Im vorliegenden Land eingereicht worden.The imidic acid esters of general formula II and their preparation are described in German patent application P 27 30 468.3 dated July 6, 1977 by the applicant. A corresponding patent application based on this priority is also Has been filed in the present country.

Amine der Formel III können beispielsweise sein:Amines of the formula III can be, for example:

Ammoniak, Methylamin, Dimethylamin, Diäthylamin, Benzylamin, 3,4,5-Trimethoxybenzylamin, N-Phenyl-piperazin, Furfurylamin, Cyclohexylamin, Pyrrolidin, Piperidin, Morpholin, Anilin und Sulfonamide wie beispielsweise 2-Sulfanilamino-pyrimidin, 2-Sulfanilamido-4-pyrimidin, 2-Sulfanilamido-5-methyl-pyrimi--din, 2-Sulfanilamido-5-isopropyl-pyrimidin, 2-Sulfanilamido--5-methoxy-pyrimidin, 3-Sulfanilamido-6-methoxy-pyridazin, 2-Sulfanilamido-3-methoxy-pyrazin, 3-Sulfanilamido-5-methyl--isoxazol und 2-Sulfanilamido-pyridin.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.

Die Herstellung dieser Verbindungen kann mit oder ohne Lösungsmittel erfolgen. Als mögliche Lösungsmittel eignen sich beispielsweise Pyridin, Äthanol oder Wasser bzw. Gemische dieser Lösungsmittel. Die Reaktionstemperaturen liegen zwischen 0 und 150°C, bevorzugt zwischen 20 und 120°C bzw. bei Temperaturen bis zum Siedepunkt des verwendeten Lösungsmittels.These compounds can be prepared with or without a solvent. Examples of 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.

Verwendet man beispielsweise N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamidsäureäthylester und Anilin als Ausgangsstoffe, so kann der Reaktionsverlauf durch folgendes Formelschema wiedergegeben werden:

Figure imgb0007
2um Wirksamkeitsnachweis wurden erfindungsgemäße Substanzen im Tierversuch am Modell der sogenannten Aronson-Sepsis, wobei mit Streptococcus agalactiae infiziert wird, geprüft und mit dem bekannten Trimethoprim verglichen. Hierzu wurden Gruppen von je 30 weiblichen Mäusen mit einer tödlichen Dosis von Streptococcus agalactiae 7941 infiziert und 2 Stunden nach der Infektion mit einer Mischung von 300 mg 2-Sulfanilamido-4,5-dimethyloxazol + 60 mg einer der erfindungsgemäßen Substanzen behandelt. Außer einer nicht behandelten Kontrollgruppe wurde eine zweite Gruppe mit dem als Referenzsubstanz dienenden Gemisch von 300 mg 2-Sulfanilamido-4,5-dimethyloxazol + 60 mg Trimethoprim behandelt. Nach 44 Stunden wurde die Zahl der überlebenden Tiere bestimmt und diese Zahl durch die Zahl der überlebenden aus der mit der Referenzsubstanz behandelten Gruppe dividiert. Der so erhaltene Zahlenwert (Trimethoprimfaktor) ist ein Maß für die Wirkung der erfindungsgemäßen Substanzen im Vergleich zum Trimethoprim. F = 2 bedeutet also, daß die Substanz doppelt so wirksam ist wie Trimethoprim. Aus der folgenden Tabelle geht eine Überlegenheit der erfindungsgemäßen Substanzen gegenüber dem Trimethoprim bis zum 5,4-fachen hervor.
Figure imgb0008
 If, for example, ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetamate and aniline are used as starting materials, the course of the reaction can be represented by the following formula:
Figure imgb0007
 In order to prove their effectiveness, substances according to the invention were tested in an animal experiment on the model of the so-called Aronson's sepsis, with infection with Streptococcus agalactiae, and compared with the known trimethoprim. For this purpose, 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. In addition to an untreated control group, 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. 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.
Figure imgb0008

Gegenstand der vorliegenden Erfindung sind demnach auch chemotherapeutische Mittel, die neben üblichen Träger- und Verdünnungsmitteln eine Verbindung der Formel I, insbesondere in Kombination mit einem Sulfonamid als Wirkstoffe enthalten, sowie die Verwendung der Verbindungen der Formel I als Sulfonamidpotentiatoren.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.

Die chemotherapeutischen Mittel bzw. Zubereitungen werden mit den üblichen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutisch-technischen Hilfsstoffen entsprechend der gewünschten Applikationsart in bekannter Weise hergestellt.The 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.

Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen oder Suspensionen.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.

Beispiel 1example 1

16,2 g N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester werden in 120 ml Pyridin gelöst und mit 14 ml gesättigter äthanolischer Ammoniaklösung versetzt und 12 Stunden bei 700C gerührt. Nach Einengen im Vacuum wird der Rückstand aus Dioxan umkristallisiert. Man erhält 8,6 g (57,7 % d,Th.) N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamidin mit dem Fp.: 207°C.16.2 g of ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate are dissolved in 120 ml of pyridine and mixed with 14 ml of saturated ethanolic ammonia solution and for 12 hours stirred at 70 0 C. After concentration in vacuo, the residue is recrystallized from dioxane. 8.6 g (57.7% of theory, th.) N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetamidine are obtained with the mp: 207 ° C.

Beispiel 2Example 2

1,8 g N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester werden mit 0,93 g Anilin und 20 ml absolutem Äthanol unter Rühren 15 Stunden am Rückfluß zum Sieden erhitzt, abgekühlt und mit 80 ml Wasser versetzt. Man erhält 1,1 g (53 % d.Th.) N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidin mit dem Fp.: 189°C.1.8 g of ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate are mixed with 0.93 g of aniline and 20 ml of absolute ethanol with stirring for 15 hours Reflux heated to boiling, cooled and mixed with 80 ml of water. 1.1 g (53% of theory) of N- [4-amino-5- (3,4,5-trimeth oxybenzyl) pyrimidin-2-yl] -N'-phenyl-acetamidine with mp: 189 ° C.

Beispiel 3Example 3

1,8 g N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester werden mit 20 ml 40-prozentiger wässriger Dimethylaminlösung 10 Stunden bei 50-60°C gerührt. Der kristalline Niederschlag wird filtriert, mit Wasser gewaschen und aus Dioxan umkristallisiert. Es werden 1,24 g (69 % d.Th.) N-[4-Amino-5-(3,4,5-trimethoxybenzyl) -pyrimidin-2-yl]-N',N'-dimethyl-acetamidin mit dem Fp.: 220°C erhalten.1.8 g of ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate are mixed with 20 ml of 40 percent aqueous dimethylamine solution for 10 hours at 50-60 ° C touched. The crystalline precipitate is filtered, washed with water and recrystallized from dioxane. 1.24 g (69% of theory) of N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N'-dimethyl-acetamidine are added mp: 220 ° C obtained.

Beispiel 4Example 4

Analog Beispiel 3 wurde N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-diäthyl-acetamigin mit dem Fp.: 1540C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamidsäure-äthylester und Diäthylamin hergestellt.Analogously to Example 3 N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N ', N'-diethyl-acetamigin of mp .: 154 0 C of N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetamic acid, ethyl ester and diethylamine.

Beispiel 5Example 5

1,8 g N-[(4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester werden in 10 ml N-Phenylpiperazin suspendiert und auf 65°C erwärmt, bis alles gelöst ist, und danach 3 Stunden bei 90-100°C gerührt. Nach Abkühlung wird mit 100 ml Diäthyläther behandelt, der weißkristalline Niederschlag abfiltriert und aus Butylacetat umkristallisiert. Man erhält 1,6 g (67 % d.Th.) N-[(4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-aza-3-phenyl-pentamethylen)-acetamidin mit dem Pp.: 197°C.1.8 g of ethyl N - [(4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate are suspended in 10 ml of N-phenylpiperazine and heated to 65 ° C. until everything is dissolved and then stirred for 3 hours at 90-100 ° C. After cooling, the mixture is treated with 100 ml of diethyl ether, the white crystalline precipitate is filtered off and recrystallized from butyl acetate, giving 1.6 g (67% of theory) of N- [(4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N' - (3-aza-3-phenylpentamethylene) acetamidine with p.p .: 197 ° C.

Beispiel 6Example 6

Analog Beispiel 5 wurde N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-tetramethylen-acetamidin mit dem Fp.: 198°C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetilmidsäure-äthylester und Pyrrolidin hergestellt.Analogously to Example 5, N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N'-tetramethylene-acetamidine with the mp: 198 ° C. from N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetilmidic acid ethyl ester and pyrrolidine prepared.

Beispiel 7Example 7

5,4 g N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester und 1,6 g Benzylamin werden in 40 ml Pyridin gelöst und 2 Stunden bei 90°C gerührt. Nach Einengen im Vakuum löst man den Rückstand in der Wärme in 200 ml Essigester, klärt mit Aktivkohle und kühlt ab. Aus der Lösung kristallisieren 3,2 g (51 % d.Th.) N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidin mit dem Fp.: 1640C aus.5.4 g of ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate and 1.6 g of benzylamine are dissolved in 40 ml of pyridine and 2 hours at 90 ° C stirred. After concentration in vacuo, the residue is dissolved in 200 ml of warm ethyl acetate, clarified with activated carbon and cooled. 3.2 g (51% of theory) of N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-benzyl-acetamidine crystallize from the solution with the Mp .: 164 0 C.

Analog Beispiel 7 wurden hergestellt:The following were prepared as in Example 7:

8. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-(3,4,5-trimethoxybenzyl)-acetamidin mit dem Fp.: 143°C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 3,4,5-Trimethoxybenzylamin.8. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- (3,4,5-trimethoxybenzyl) acetamidine with mp: 143 ° C from ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate and 3,4,5-trimethoxybenzylamine.

9. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N',N'-(3-oxa-Pentamethylen)-acetamidin mit dem Fp.: 205°C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und Morpholin.9. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N' - (3-oxa-pentamethylene) acetamidine with mp: 205 ° C from ethyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidate and morpholine.

10. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-furfuryl-acetamidin mit dem Fp.: 1840C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester und Furfurylamin.10. N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-furfuryl-acetamide with mp .: 184 0 C from N- [4-amino- 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and furfurylamine.

11. N-[-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-cyclohexyl-acetamidin mit dem Fp.: 183°C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester und Cyclohexylamin.11. N - [- Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-cyclohexyl-acetamidine with mp: 183 ° C from N- [4-amino-5 - (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetimidic acid ethyl ester and cyclohexylamine.

12. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-adamantyl-acetamidin mit dem Fp.: 248°C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimidsäure-äthylester und 1-Adamantylamin.12. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-adamantyl-acetamidine with the mp .: 248 ° C. from N- [4-amino- 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and 1-adamantylamine.

Beispiel 13Example 13

10,8 g N-[4-Amirio-5-(3,4,5-trimethoxybenzyl)-pyrimidin -2-yl]-acetamidsäure-äthylester werden mit 4,2 g 2-Sulfanilamido-5-methoxy-pyrimidin (Sulfamethoxydiazin) in 80 ml Pyridin gelöst und 12 Stunden am Rückfluß gerührt und das Reaktionsgemisch sodann im Vakuum eingeengt. Nach Lösen des Rückstandes in warmem Aceton und Behandlung mit Aktivkohle kristallisieren 5,43 g (60,8 % d.Th.) N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methoxypyrimi- din-2-yl)-sulfonamido]-phenyl-acetamidin mit dem Fp.: 218°C.10.8 g of ethyl N- [4-amirio-5- (3,4,5-trimethoxybenzyl) pyrimidine -2-yl] acetamide are mixed with 4.2 g of 2-sulfanilamido-5-methoxy-pyrimidine (sulfamethoxydiazine ) dissolved in 80 ml of pyridine and stirred at reflux for 12 hours and the reaction mixture was then concentrated in vacuo. After dissolving the residue in warm acetone and treating with activated carbon, 5.43 g (60.8% of theory) of N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl crystallize ] -N '- [4- (5-methoxypyrimidine-2-yl) sulfonamido] phenyl acetamidine with mp: 218 ° C.

Analog Beispiel 13 wurden hergestellt:The following were prepared as in Example 13:

14. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl--acetamidin mit dem Fp.: 192°C aus N-[4-Amino--5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 2-Sulfanilamido-5-methyl-pyrimidin (Sulfaperin).14. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (5-methyl-pyrimidin-2-yl) sulfonamido] phenyl - Acetamidine with mp: 192 ° C from N- [4-amino - 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and 2-sulfanilamido-5-methyl -pyrimidine (sulfaperin).

15. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(pyrimidin-2-yl)-sulfonamido] -phenyl-acetamidin mit dem Fp.: 178°C (Zers.) aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 2-Sulfanilamido-pyrimidin (Sulfadiazin).15. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (pyrimidin-2-yl) sulfonamido] phenyl acetamidine with the M.p .: 178 ° C (dec.) From N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and 2-sulfanilamido-pyrimidine (sulfadiazine).

16. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl--acetamidin mit dem Fp.: 162°C aus N-[4-Amino--5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 2-Sulfanilamido-4-methyl-pyrimidin (Sulfamerazin).16. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (4-methyl-pyrimidin-2-yl) sulfonamido] phenyl - Acetamidine with mp: 162 ° C from N- [4-amino - 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and 2-sulfanilamido-4-methyl -pyrimidine (sulfamerazine).

17. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-(4-sulfonylguanidino)-phenyl-acetamidin mit dem Fp.: 246°C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 4-Aminoben olsulfonylguanidin (Sulfaguanidin).17. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- (4-sulfonylguanidino) phenyl acetamidine with the mp: 246 ° C from N. - [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] ethyl acetate and 4-aminobenzenesulfonylguanidine (sulfaguanidine).

18. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenyl--acetamidin mit dem Fp.: 155°C aus N-[4-Amino--5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 3-Sulfanilamido-5-methyl-isoxazol (Sulfamethoxazol).18. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (5-methyl-isoxazol-3-yl) sulfonamido] phenyl - Acetamidine with mp: 155 ° C from N- [4-amino - 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and 3-sulfanilamido-5-methyl -isoxazole (sulfamethoxazole).

19. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]--N'-[4-(6-methoxy-pyridazin-3-yl)-sulfonamido]-phenyl--acetamidin mit dem Fp.: 1680C aus N-[4-Amino--5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 3-Sulfanilamido-6-methoxy-pyridazin (Sulfamethoxy-pyridazin).19. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] - N '- [4- (6-methoxypyridazin-3-yl) sulfonamido] - phenyl - acetamidine; mp .: 168 0 C from N- [4-amino - 5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimidsäure acid ethyl ester and 3-sulfanilamido-6 methoxypyridazine (sulfamethoxypyridazine).

20. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(pyridin-2-yl)-sulfonamido] -phenyl-acetamidin mit dem Fp.: 2370C aus N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 2-Sulfanilamido-pyridin (Sulfapyridin).20. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (pyridin-2-yl) sulfonamido] phenyl acetamidine with the mp .: 237 0 C from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimidsäure acid ethyl ester and 2-sulfanilamido-pyridine (sulfapyridine).

21. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(4-isapropyl-pyrimidin-2-yl)-sulfonamido] -phenyl-acetamidin mit dem Fp.: 201°C aus N-[4-Amino--5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimidsäure-äthylester und 2-Sulfanilamido-4-isopropyl-pyrimidin.21. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (4-isapropyl-pyrimidin-2-yl) sulfonamido] -phenyl-acetamidine with mp: 201 ° C from N- [4-amino - 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -acetimidic acid ethyl ester and 2-sulfanilamido-4- isopropyl pyrimidine.

22. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -Nt-[4-(3-methoxy-pyrazin-2-yl)-sulfonamido]-phenyl--acetamidin mit dem Fp.: 148°C (Zers.) aus N-[4-Amino--5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl -acetimidsäure-äthylester und 2-Sulfanilamido-3-methoxypyrazin (Sulfamethoxypyrazin, Sulfalen).22. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -Nt- [4- (3-methoxypyrazin-2-yl) sulfonamido] phenyl- Acetamidine with mp: 148 ° C (dec.) from N- [4-amino - 5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl -acetimidic acid ethyl ester and 2-sulfanilamido-3 -methoxypyrazine (sulfamethoxypyrazine, sulfals).

ZusatzbeispieleAdditional examples

Beispiele für pharmazeutische ZubereitungExamples of pharmaceutical preparation

Figure imgb0009
Die Wirkstoffe werden mit Maisstärke gemischt und mit wäßriger Gelatinelösung granuliert. Das trockene Granulat wird gesiebt und mit den Zuschlägen vermischt. Aus dieser Mischung werden in üblicher Weise Tabletten gepreßt.
Figure imgb0010
Figure imgb0009
 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.
Figure imgb0010

Die Wirkstoffe werden mit wäßriger Gelatinelösung granuliert und nach dem Trocknen mit Maisstärke, Talkum und Magnesiumstearat vermischt. Aus dieser Mischung werden in üblicher Weise Tabletten gepreßt.

Figure imgb0011
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.
Figure imgb0011

Der Wirkstoff wird mit Maisstärke gemischt und mit wäßriger Gelatinelösung granuliert. Das trockene Granulat wird gesiebt und mit den Zuschlägen vermischt. Aus dieser Mischung werden in üblicher Weise Tabletten gepreßt.

Figure imgb0012
Figure imgb0013
 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.
Figure imgb0012
Figure imgb0013

Der Wirkstoff wird mit wäßriger Gelatinelösung granuliert und nach dem Trocknen mit Maisstärke, Talkum und Magnesiumstearat vermischt. Aus dieser Mischung werden in üblicher Weise Tabletten gepreßt.

Figure imgb0014
die feinst gemahlenen Wirkstoffe werden in dem wäßrigen Tylose-Schleim suspendiert. Anschließend werden alle anderen Bestandteile unter Rühren nacheinander zugegeben. Zum Schluß wird mit Wasser auf 100,0 aufgefüllt.
Figure imgb0015
Figure imgb0016
 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.
Figure imgb0014
 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.
Figure imgb0015
Figure imgb0016

Der feinst gemahlene Wirkstoff wird in dem wäßrigen Tylose--Schleim suspendiert. Anschließend werden alle anderen Bestandteile unter Rühren nacheinander zugegeben. Zum Schluß wird mit Wasser auf 100,0 aufgefüllt.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.

Claims (26)

1. Amidino-benzylpyrimidine der allgemeinen Formel I
Figure imgb0017
in der R1, R2 und R3, die gleich oder verschieden voneinander sein können, Wasserstoff, Methyl, Methoxy oder Chlor bedeuten, R Alkyl mit 1-6 C-Atomen oder Benzyl bedeutet und R5 und R6, die gleich oder verschieden voneinander sein können, Wasserstoff, niederes Alkyl mit 1-4 C-Atomen, gegebenenfalls substituiertes Benzyl oder Phenyl, oder die Gruppierung -C6H4-SO2-NH-R7 bedeutet, wobei R 7
Figure imgb0018
oder einen heterocyclischen Ring mit 1 bis 3 Heteroatomen, die gleich oder verschieden voneinander sein können und Stickstoff, Sauerstoff oder Schwefel sind, bedeutet und der durch Chlor, Methyl oder Methoxy substituiert sein kann und aus 5-6 Ringgliedern besteht, oder in der R5 und R gemeinsam mit dem Stickstoff, mit dem sie verbunden sind, einen gesättigten heterocyclischen Ring mit 5-7 Gliedern bilden, der gegebenenfalls ein Sauerstoffatom oder die )N-Y-Gruppe enthalten kann, wobei Y für Methyl, Benzyl oder Phenyl steht, sowie deren pharmakologisch verträgliche Salze mit hierfür üblichen Säuren.1. Amidino-benzylpyrimidines of the general formula I
Figure imgb0017
 in which R 1 , R 2 and R 3 , which may be the same or different from one another, are hydrogen, methyl, methoxy or chlorine, R is alkyl having 1-6 C atoms or benzyl and R 5 and R 6 are the same or can be different from one another, is hydrogen, lower alkyl having 1-4 C atoms, optionally substituted benzyl or phenyl, or the grouping —C 6 H 4 —SO 2 —NH — R 7 , where R 7
Figure imgb0018
 or a heterocyclic ring having 1 to 3 heteroatoms, which can be identical or different from one another and are nitrogen, oxygen or sulfur, and which can be substituted by chlorine, methyl or methoxy and consists of 5-6 ring members, or in which R 5 and R together with the nitrogen to which they are attached form a saturated heterocyclic ring with 5-7 members, which may optionally contain an oxygen atom or the) NY group, where Y is methyl, benzyl or phenyl, and their pharmacological compatible salts with customary acids. 2. Verbindungen der Formel I nach Anspruch 1, in denen R4 ein Niederalkylrest mit 1-4 C-Atomen oder der Benzylrest ist, und R5 und R6, die gleich oder verschieden sein können, Wasserstoff, Niederalkyl mit 1-4 C-Atomen, Benzyl, Phenyl oder, zusammen mit dem Stickstoffatom, mit dem sie verbunden sind, eine Polymethylenkette mit 4 oder 5 Methylengruppen sind, die durch ein Sauerstoffatom oder die Gruppe )N-Y unterbrochen sein können, wobei Y für Methyl, Benzyl oder Phenyl steht, oder R5 Wasserstoff und R6 die Gruppe -C6H4SO2NH-R7 ist, wobei R 7
Figure imgb0019
oder der 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, 3-Methoxy-pyrazin-2-yl-, 5-Methyl-isoxazol-3-yl- oder 2-pyridinyl-Rest ist.2. Compounds of formula I according to claim 1, in which R 4 is a lower alkyl radical having 1-4 C atoms or the benzyl radical, and R 5 and R 6 , which are the same or different may be hydrogen, lower alkyl with 1-4 C atoms, benzyl, phenyl or, together with the nitrogen atom to which they are connected, a polymethylene chain with 4 or 5 methylene groups which are interrupted by an oxygen atom or the group) NY can, where Y is methyl, benzyl or phenyl, or R 5 is hydrogen and R 6 is the group -C 6 H 4 SO 2 NH-R 7 , where R 7
Figure imgb0019
 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, 3-methoxy-pyrazin-2-yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl radical. 3. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.3. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] acetamidine and its pharmacologically acceptable salts with acids. 4. N- [-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.4. N- [-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-phenyl-acetamidine and its pharmacologically acceptable salts with acids. 5. N- [4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N',N'-dimethyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.5. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N'-dimethyl-acetamidine and its pharmacologically acceptable salts with acids. 6. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N',N'-diäthyl-acetamidin sowie seine pharmakologiach. verträglichen Salze mit Säuren.6. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N'-diethyl-acetamidine and its pharmacological. compatible salts with acids. 7. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N',N'-(3-aza-3-phenyl-pentamethylen)-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.7. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N' - (3-aza-3-phenylpentamethylene) acetamidine and its pharmacologically compatible salts with acids. 8. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N',N'-tetramethylen-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.8. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N'-tetramethylene-acetamidine and its pharmacologically acceptable salts with acids. 9. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-benzyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.9. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-benzyl-acetamidine and its pharmacologically acceptable salts with acids. 10. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-(3,4,5-trimethoxybenzyl)-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.10. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- (3,4,5-trimethoxybenzyl) acetamidine and its pharmacologically acceptable salts with acids. 11. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N',N'-(3-oxa-pentamethylen)-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.11. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N ', N' - (3-oxapentamethylene) acetamidine and its pharmacologically acceptable salts with acids . 12. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-furfuryl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.12. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-furfuryl-acetamidine and its pharmacologically acceptable salts with acids. 13. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-cyclohexyl-acetamidin sowie seine pharmakologisch. verträglichen Salze mit Säuren.13. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-cyclohexyl-acetamidine and its pharmacological. compatible salts with acids. 14. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-adamantyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.14. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N'-adamantyl-acetamidine and its pharmacologically acceptable salts with acids. 15. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] N'-[4-(5-methoxypyrimidin-2-yl)-sulfonamido] -phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.15. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] N '- [4- (5-methoxypyrimidin-2-yl) sulfonamido] phenyl acetamidine as well its pharmacologically acceptable salts with acids. 16. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido] -phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.16. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (5-methyl-pyrimidin-2-yl) sulfonamido] phenyl -acetamidine and its pharmacologically acceptable salts with acids. 17. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.17. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (pyrimidin-2-yl) sulfonamido] phenyl acetamidine and its pharmacologically acceptable salts with acids. 18. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido] -phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.18. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (4-methyl-pyrimidin-2-yl) sulfonamido] phenyl -acetamidine and its pharmacologically acceptable salts with acids. 19. N-[4-Amino-5-(3,4,,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-(4-sulfonylguanidino)-phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.19. N- [4-amino-5- (3,4,5,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- (4-sulfonylguanidino) phenyl acetamidine and its pharmacologically acceptable salts with acids. 20. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido] -phenyl-agetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.20. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (5-methyl-isoxazol-3-yl) sulfonamido] phenyl -agetamidin and its pharmacologically acceptable salts with acids. 21. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(6-methoxy-pyridazin-3-yl)-sulfonamidoj -phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.21. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (6-methoxy-pyridazin-3-yl) sulfonamidoj -phenyl- acetamidine and its pharmacologically acceptable salts with acids. 22. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(pyridin-2-yl)-sulfonamido]-phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.22. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (pyridin-2-yl) sulfonamido] phenyl acetamidine and its pharmacologically acceptable salts with acids. 23. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-[4-(4-isopropyl-pyrimidin-2-yl)-sulfonamido] -phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.23. N- [4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl] -N '- [4- (4-isopropyl-pyrimidin-2-yl) sulfonamido] -phenyl-acetamidine and its pharmacologically acceptable salts with acids. 24. N- 4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl -N'-[4-(3-methoxy-pyrazin-2-yl)-sulfonamido] -phenyl-acetamidin sowie seine pharmakologisch verträglichen Salze mit Säuren.24. N- 4-Amino-5- (3,4,5-trimethoxybenzyl) pyrimidin-2-yl -N '- [4- (3-methoxy-pyrazin-2-yl) sulfonamido] phenyl acetamidine as well as its pharmacologically acceptable salts with acids. 25. Verfahren zur Herstellung der Verbindungen gemäß Ansprüchen 1-24, dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel II
Figure imgb0020
worin R1, R2, R3 und R4 die gleiche Bedeutung wie in Formel I haben und R niederes Alkyl mit 1-4 C-Atomen oder Benzyl bedeutet, mit einem Amin der Formel III
Figure imgb0021
in welcher R5 und R6 die gleiche Bedeutung wie in Formel I haben, gegebenenfalls in Gegenwart eines Lösungsmittels umsetzt, und, falls erwünscht, die erhaltene Verbindungen in ein pharmakologisch verträgliches Salz mit einer hierfür üblichen Säure überführt.25. A process for the preparation of the compounds according to claims 1-24, characterized in that a compound of general formula II
Figure imgb0020
 wherein R 1 , R2, R3 and R 4 have the same meaning as in formula I and R is lower alkyl with 1-4 carbon atoms or benzyl, with an amine of formula III
Figure imgb0021
 in which R 5 and R 6 have the same meaning as in formula I, if appropriate in the presence of a solvent, and, if desired, convert the compounds obtained into a pharmacologically acceptable salt with a customary acid. 26. Arzneimittel, enthaltend eine Verbindung gemäß Ansprüchen 1 bis 24, gegebenenfalls zusammen mit einem antibakteriell wirksamen Sulfonamid, und nicht-toxischen, therapeutisch verträglichen festen oder flüssigen Trägerstoffen und galenischen Hilfsmitteln.26. Medicament containing a compound according to claims 1 to 24, optionally together with an antibacterial sulfonamide, and non-toxic, therapeutically acceptable solid or liquid carriers and pharmaceutical auxiliaries.
EP78100184A 1977-07-15 1978-06-19 N-benzylpyrimidinyl-amidines, process for their preparation and medicines containing them Expired EP0000336B1 (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US4315931A (en) * 1977-07-06 1982-02-16 Basf Aktiengesellschaft N-Pyrimidinyl-imidoacid esters and drugs containing the said compounds
US4333936A (en) * 1978-07-03 1982-06-08 Basf Aktiengesellschaft Novel amidino-benzylpyrimidines, processes for their manufacture and antibacterial and antiprotozoal use thereof
EP0053695A2 (en) * 1980-12-04 1982-06-16 BASF Aktiengesellschaft Esters of N-pyrimidinyl-carbamic acid, method of preparing them and pharmaceutical compositions containing them

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JPS5915110U (en) * 1982-07-22 1984-01-30 クラリオン株式会社 constant voltage circuit
JPH0618012B2 (en) * 1983-01-25 1994-03-09 セイコーエプソン株式会社 Constant voltage circuit

Citations (1)

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JPS4849791A (en) * 1971-10-26 1973-07-13

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JPS4849791A (en) * 1971-10-26 1973-07-13

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Title
CHEMICAL ABSTRACTS, Vol. 79 (1973), Nr. 19, Seite 362, Spalte 2, P115.615 c & JP-A-48 049 791 (TOKUYAMA KANJI & NISHINO TAKENORI) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4315931A (en) * 1977-07-06 1982-02-16 Basf Aktiengesellschaft N-Pyrimidinyl-imidoacid esters and drugs containing the said compounds
US4333936A (en) * 1978-07-03 1982-06-08 Basf Aktiengesellschaft Novel amidino-benzylpyrimidines, processes for their manufacture and antibacterial and antiprotozoal use thereof
EP0053695A2 (en) * 1980-12-04 1982-06-16 BASF Aktiengesellschaft Esters of N-pyrimidinyl-carbamic acid, method of preparing them and pharmaceutical compositions containing them
EP0053695A3 (en) * 1980-12-04 1982-12-15 BASF Aktiengesellschaft Esters of n-pyrimidinyl-carbamic acid, method of preparing them and pharmaceutical compositions containing them

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