EP0000334B1 - 2,4-Diamino-5-benzylpyrimidines, procédé pour leur préparation et médicaments les contenant - Google Patents

2,4-Diamino-5-benzylpyrimidines, procédé pour leur préparation et médicaments les contenant Download PDF

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Publication number
EP0000334B1
EP0000334B1 EP78100180A EP78100180A EP0000334B1 EP 0000334 B1 EP0000334 B1 EP 0000334B1 EP 78100180 A EP78100180 A EP 78100180A EP 78100180 A EP78100180 A EP 78100180A EP 0000334 B1 EP0000334 B1 EP 0000334B1
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EP
European Patent Office
Prior art keywords
trimethoxybenzyl
general formula
amino
pyrimidine
compound
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.)
Expired
Application number
EP78100180A
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German (de)
English (en)
Other versions
EP0000334A1 (fr
Inventor
Klaus Dr. Gutsche
Peter Dr. Scharwaechter
Wilhelm Dr. Kohlmann
Gerd Dr. Kroemer
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.)
BASF SE
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BASF SE
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Publication date
Application filed by BASF SE filed Critical BASF SE
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • the invention relates to 2,4-diamino-5-benzylpyrimidines of the general formula I.
  • R 1 , R 2 and R 3 which may be the same or different from one another, denote hydrogen, methyl, methoxy or chlorine and R 4 is a methyl radical which is substituted by an alkoxy radical having 1 to 6 carbon atoms
  • the alkyl radical of which may be used is additionally substituted by a chlorine atom or an alkoxy group having 1 to 2 carbon atoms in the alkyl radical, which in turn can be substituted by an alkoxy radical having 1 to 4 carbon atoms, an allyloxy radical, a cyclohexyloxy radical or a benzyloxy radical
  • R 4 means allyl or an alkyl radical having 1 to 3 carbon atoms, which is substituted by phenyl, chlorophenyl, hydroxy, alkoxy having 1 to 2 carbon atoms, dialkylamino having 1 to 2 carbon atoms in the alkyl or
  • the substituents R 1 , R 2 and R 3 are preferably in the 3, 4 and 5 positions of the benzene ring.
  • the compounds of the general formula I and their salts are antimicrobially active in diseases caused by bacteria and protozoa and potentiate, combined with sulfonamides, their antimicrobial action. They can be used, for example, for bacterial diseases of the respiratory, digestive and urinary tract, as well as for throat, nose and ear infections and general systemic infectious diseases and malaria.
  • the compounds of the general formula I and their salts can be combined with the sulfonamides mentioned by way of example in various mixing ratios, the ratio of substance according to the general formula I: sulfonamide being able to vary in the range from 1:10 to 5: 1. However, preferred mixing ratios are 1: 1 to 1: 5. As a rule, 20 to 500 mg of an active ingredient of the general formula I are suitable as doses.
  • Procedure a) is generally carried out in an aprotic diluent, such as, for example, dioxane, tetrahydrofuran, benzene, chlorobenzene, chloroform or pyridine, the reaction temperatures being between 0 and 200 ° C., depending on the reactivity of the compound of the general formula III.
  • an aprotic diluent such as, for example, dioxane, tetrahydrofuran, benzene, chlorobenzene, chloroform or pyridine
  • Procedure b) is carried out in alcohols, preferably in methanol or ethanol, or in dimethylformamide or dimethyl sulfoxide as the solvent, the reaction temperatures being between 50 and 150.degree. Temperatures around 150 ° C are required when the leaving group X is a difficult to react aliphatic amino group.
  • the leaving group in the general formula IV denotes an alkoxy group, preferably the methoxy and the ethoxy group, or a secondary aliphatic amino group, preferably a morpholino or dimethylamino group, or a primary aromatic amino group, preferably the anilino group or the imidazolyl-1 radical.
  • the invention accordingly also relates to chemotherapeutic agents which, in addition to conventional carriers and diluents, contain a compound of the general formula I, in particular in combination with a sulfonamide, as active ingredients, and the use of the compounds of the general 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, are 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 g with water.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (3)

1. 2,4-diamino-5-benzylpyrimidines de formule générale l
Figure imgb0020
dans laquelle R1, R2 et R3 peuvent être identiques ou différents les uns des autres et représentent hydrogène, méthyle, méthoxy ou chlore et R4 représente un reste méthyle qui est substitué par un reste alcoxy en C1 à C6, dont le reste alkyle est en outre éventuellement substitué par un atome de chlore ou un groupe alcoxy ayant 1 ou 2 atomes C dans le reste alkyle, qui à son tour peut être substitué par un reste alcoxy ayant 1 à 4 atomes de carbone, un reste allyloxy, un reste cyclohexyloxy ou un reste benzyloxy, ou bien R4 représente allyle ou un reste alkyle en C1 à C3 qui est substitué par phényle, chlor- phényle, hydroxy, alcoxy en C1 à C2, dialkylamino en C1 à C2 dans l'alkyle ou un reste pyrrolidino ou morpholino, ou bien R4 représente un reste 3-alkylisoxazolyl-5-méthyle ayant 1 à 4 atomes de C dans l'alkyle, ainsi que les sels d'addition d'acide compatibles du point de vue pharmacologique, avec des acides usuels pour cela.
2. Procédé pour la préparation de composés selon la revendication 1, caractérisé par le fait que:
a) on fait réagir un composé de formule générale II
Figure imgb0021
dans laquelle R1, R2, R3 ont la même signification que dans la formule l, avec un composé de formule générale III
Figure imgb0022
dans laquelle R4 a la même signification que dans la formule l est Hal est un atome d'halogène, ou bien
b) on fait réagir un composé de formule générale IV
Figure imgb0023
dans laquelle R1, R2 et R3 ont la même signification que dans la formule l et X est un groupe alcoxy, un groupe amino secondaire aliphatique, le groupe anilino ou un reste imidazolyl-1, avec un composé de formule générale V
Figure imgb0024
dans laquelle R4 a la même signification que dans la formule 1,
ou bien
c) on fait réagir un composé de formule générale VI
Figure imgb0025
dans laquelle R1, R2 et R3 ont la même signification que dans la formule l, R7 et RS représentent des restes alkyle inférieur, avec un composé de formule générale V et le composé obtenu, de formule générale l, est transformé, si on le désire, en un sel d'addition d'acide compatible du point de vue pharmacologique.
3. Médicament contenant un composé selon la revendication 1, éventuellement avec un sulfonamide et des supports non toxiques solides ou liquides et compatibles du point de 'vué thérapeutique et avec des adjuvants galéniques.
EP78100180A 1977-07-06 1978-06-16 2,4-Diamino-5-benzylpyrimidines, procédé pour leur préparation et médicaments les contenant Expired EP0000334B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19772730467 DE2730467A1 (de) 1977-07-06 1977-07-06 Benzylpyrimidine, verfahren zu ihrer herstellung und diese enthaltende arzneimittel
DE2730467 1977-07-06

Publications (2)

Publication Number Publication Date
EP0000334A1 EP0000334A1 (fr) 1979-01-24
EP0000334B1 true EP0000334B1 (fr) 1981-08-12

Family

ID=6013252

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100180A Expired EP0000334B1 (fr) 1977-07-06 1978-06-16 2,4-Diamino-5-benzylpyrimidines, procédé pour leur préparation et médicaments les contenant

Country Status (17)

Country Link
US (1) US4279899A (fr)
EP (1) EP0000334B1 (fr)
JP (1) JPS5416482A (fr)
AR (1) AR223465A1 (fr)
AT (1) AT361931B (fr)
AU (1) AU515661B2 (fr)
CA (1) CA1102324A (fr)
DE (2) DE2730467A1 (fr)
DK (1) DK142578C (fr)
FI (1) FI782173A (fr)
HU (1) HU179407B (fr)
IE (1) IE781308L (fr)
IL (1) IL55018A (fr)
IN (1) IN149577B (fr)
IT (1) IT7825220A0 (fr)
NO (1) NO782340L (fr)
ZA (1) ZA783873B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4438267A (en) * 1980-11-11 1984-03-20 Daluge Susan M Monoheteroring compounds and their use
DE3045720A1 (de) * 1980-12-04 1982-07-08 Basf Ag, 6700 Ludwigshafen N-pyrimidinyl-carbaminsaeureester, verfahren zu ihrer herstellung und diese enthaltende arzneimittel
HU186413B (en) * 1981-06-26 1985-07-29 Egyt Gyogyszervegyeszeti Gyar Process for producing 2,4-diamino-5-bracket-3-comma above,4-comma above,5-comma above-trimethoxy-benzyl-bracket closed-pyrimidine
HU187370B (en) * 1981-06-26 1985-12-28 Egyt Gyogyszervegyeszeti Gyar Improved process for producing 2,4-diamino-5-bracket-3-comma above, 4-comma above,5-comma above-trimethoxy-benzyl-bracket closed-pyrimidine
CA2463989C (fr) * 2001-10-17 2012-01-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives pyrimidine, compositions pharmaceutiques contenant ces composes, utilisation et procede de fabrication de ces composes
AR081626A1 (es) 2010-04-23 2012-10-10 Cytokinetics Inc Compuestos amino-piridazinicos, composiciones farmaceuticas que los contienen y uso de los mismos para tratar trastornos musculares cardiacos y esqueleticos
AR081331A1 (es) 2010-04-23 2012-08-08 Cytokinetics Inc Amino- pirimidinas composiciones de las mismas y metodos para el uso de los mismos
WO2011133920A1 (fr) 2010-04-23 2011-10-27 Cytokinetics, Inc. Aminopyridines et aminotriazines, leurs compositions et leurs procédés d'utilisation

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3049544A (en) * 1962-08-14 Method for the preparation of
US2723975A (en) * 1952-04-03 1955-11-15 Nepera Chemical Co Inc 2, 4-di-piperidino-5-benzylpyrimidine
US2649449A (en) * 1952-04-04 1953-08-18 Nepera Chemical Co Inc 2-cyclohexylamino-4-amino-5-benzylpyrimidine
CH376115A (de) * 1957-12-06 1964-03-31 Ciba Geigy Verfahren zur Herstellung neuer substituierter Pyrimidine
US3515783A (en) 1967-10-20 1970-06-02 Hoffmann La Roche Antibacterial composition containing 5-methyl - 3 - sulfanilamidoisoxazole and trimethoxybenzyl pyrimidine
US4115650A (en) * 1976-11-17 1978-09-19 Hoffmann-La Roche Inc. Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines

Also Published As

Publication number Publication date
NO782340L (no) 1979-01-09
IL55018A0 (en) 1978-08-31
CA1102324A (fr) 1981-06-02
DK142578C (da) 1981-07-20
IE781308L (en) 1979-01-06
AR223465A1 (es) 1981-08-31
DE2860928D1 (en) 1981-11-12
IN149577B (fr) 1982-01-30
FI782173A (fi) 1979-01-07
AU515661B2 (en) 1981-04-16
DK303178A (da) 1979-01-07
IT7825220A0 (it) 1978-06-30
AT361931B (de) 1981-04-10
ZA783873B (en) 1979-08-29
ATA487478A (de) 1980-09-15
JPS5416482A (en) 1979-02-07
DE2730467A1 (de) 1979-01-18
AU3764478A (en) 1980-01-03
US4279899A (en) 1981-07-21
EP0000334A1 (fr) 1979-01-24
IL55018A (en) 1983-03-31
HU179407B (en) 1982-10-28
DK142578B (da) 1980-11-24

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