EP0000335B1 - Esters de l'acide N-pyrimidinyl-carboximidique, procédé pour leur préparation et médicaments les contenant. - Google Patents

Esters de l'acide N-pyrimidinyl-carboximidique, procédé pour leur préparation et médicaments les contenant. Download PDF

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Publication number
EP0000335B1
EP0000335B1 EP78100183A EP78100183A EP0000335B1 EP 0000335 B1 EP0000335 B1 EP 0000335B1 EP 78100183 A EP78100183 A EP 78100183A EP 78100183 A EP78100183 A EP 78100183A EP 0000335 B1 EP0000335 B1 EP 0000335B1
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EP
European Patent Office
Prior art keywords
pyrimidin
amino
sulfanilamido
acid
ester
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
EP78100183A
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German (de)
English (en)
Other versions
EP0000335A1 (fr
Inventor
Peter Dr. Scharwaechter
Klaus Dr. Gutsche
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
Original Assignee
BASF SE
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Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP0000335A1 publication Critical patent/EP0000335A1/fr
Application granted granted Critical
Publication of EP0000335B1 publication Critical patent/EP0000335B1/fr
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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
    • 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
    • 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 imidates of the general formula I. 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 hydrogen or alkyl having 1-4 C atoms, R 5 is alkyl having 1-6 C -Atoms or benzyl, R 6 is alkyl with 1-4 carbon atoms or benzyl, and n can be 0 or 1.
  • 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 according to the invention are prepared by the methods customary for the preparation of imidates, as described, inter alia, in Houben-Weyl, "Methods of Organic Chemistry", volume 6/3, by using a compound of the general formula II wherein R 1 , R 2 , R 3 , R 4 and n have the meaning given above, with an orthocarboxylic acid ester of the general formula III in which R 5 and R 6 have the meaning given above.
  • the compounds of the general formula I can be prepared with or without a solvent, the latter being carried out with an excess of the orthocarboxylic acid ester used.
  • suitable solvents are dimethylformamide or dioxane.
  • the reaction temperatures are between 0 and 150 ° C, preferably between 50 and 100 ° C or at temperatures up to the boiling point of the solvent or orthocarboxylic acid ester used.
  • the reaction can optionally be carried out in the presence of catalytic amounts of an acid, such as hydrochloric acid.
  • the compounds of the general formula according to the invention are antimicrobially active in diseases caused by bacteria and protozoa and, combined with sulfonamides, potentiate their antimicrobial activity. They can therefore 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 can be combined with the sulfonamides mentioned by way of example in various mixing ratios, the ratio of compound of the general formula I to sulfonamide varying from 1:10 to 5: 1.
  • Preferred mixing ratios are 1: 1 to 1: 5.
  • 20 to 500 mg of an active ingredient of the general formula are suitable as doses.
  • the present 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 1 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 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 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 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.

Landscapes

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

Claims (8)

1. Ester de N-pyrimidinyl-imido-acide de formule générale
Figure imgb0016
dans laquelle R1, R2 et R3, qui peuvent être identiques ou différents les uns des autres, représentent hydrogène, méthyle, méthoxy, ou chlore, R4 hydrogène ou alkyle en C1 à C4, R5 alkyle en C1 à C6 ou benzyle, R6 alkyle en C1 à C4 ou benzyle et n est 0 ou 1.
2. Ester méthylique de N-[4-amino--5-(3,4,5-triméthoxybenzyl)-pyrimidin-2-yl]-acétimido-acide.
3. Ester éthylique de N-[4-amino-5-(3,4-diméthoxybenzyl)-pyrimidin-2-yl]-acétimido-acide.
4. Ester éthylique de N-[4-amino-6-éthyl-5-(4-chlorophényl)-pyrimidin-2-yl]-acétimido-acide.
5. Ester méthylique de N-[4-amino-6-éthyl-5-(4-chlorophényl)-pyrimidin-2-yl]-acétimido-acide.
6. Ester éthylique de N-[4-amino-6-éthyl-5-(4-chlorophényl)-pyrimidin-2-yl]-propionimido-acide.
7. Procédé de préparation de composés selon l'une des revendications 1 à 6, caractérisé par le fait qu'on fait réagir un composé de formule générale Il
Figure imgb0017
dans laquelle R1, R2, R3, R4 et n ont les mêmes significations que dans la formule I de la revendication 1, avec un ester d'acide orthocarboxylique de formule III
Figure imgb0018
dans laquelle R5 et R6 ont la même signification que dans la formule I de la revendication 1, éventuellement en présence d'un solvant et de quantités catalytiques d'un acide.
8. Médicament contenant un composé selon l'une des revendications 1 à 6, éventuellement, en même temps qu'un sulfonamide, des supports solides ou liquides, non toxiques et compatibles thérapeutiquement et des adjuvants galéniques.
EP78100183A 1977-07-06 1978-06-19 Esters de l'acide N-pyrimidinyl-carboximidique, procédé pour leur préparation et médicaments les contenant. Expired EP0000335B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2730468 1977-07-06
DE19772730468 DE2730468A1 (de) 1977-07-06 1977-07-06 Neue n-pyrimidinyl-imidsaeureester, verfahren zu ihrer herstellung und diese enthaltende arzneimittel

Publications (2)

Publication Number Publication Date
EP0000335A1 EP0000335A1 (fr) 1979-01-24
EP0000335B1 true EP0000335B1 (fr) 1981-10-07

Family

ID=6013253

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100183A Expired EP0000335B1 (fr) 1977-07-06 1978-06-19 Esters de l'acide N-pyrimidinyl-carboximidique, procédé pour leur préparation et médicaments les contenant.

Country Status (15)

Country Link
US (1) US4315931A (fr)
EP (1) EP0000335B1 (fr)
JP (1) JPS5416483A (fr)
AR (1) AR220139A1 (fr)
AT (1) AT360998B (fr)
AU (1) AU515679B2 (fr)
CA (1) CA1107733A (fr)
DE (2) DE2730468A1 (fr)
DK (1) DK142577C (fr)
FI (1) FI782174A (fr)
HU (1) HU178177B (fr)
IE (1) IE47013B1 (fr)
IL (1) IL55020A (fr)
NO (1) NO782341L (fr)
ZA (1) ZA783874B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3045720A1 (de) * 1980-12-04 1982-07-08 Basf Ag, 6700 Ludwigshafen N-pyrimidinyl-carbaminsaeureester, verfahren zu ihrer herstellung und diese enthaltende arzneimittel
US4767443A (en) * 1984-09-20 1988-08-30 Ciba-Geigy Corporation Antifungal and antibacterial diazine derivatives compositions, intermediates, and method of use therefor
CH668969A5 (de) * 1986-09-05 1989-02-15 Ciba Geigy Ag Verfahren zur bekaempfung unerwuenschten pflanzenwuchses sowie zur regulierung des pflanzenwachstums.

Family Cites Families (2)

* 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
DE2732029A1 (de) * 1977-07-15 1979-02-01 Basf Ag Neue amidino-benzylpyrimidine, verfahren zu ihrer herstellung und diese enthaltende arzneimittel

Also Published As

Publication number Publication date
DE2730468A1 (de) 1979-01-18
ZA783874B (en) 1979-08-29
FI782174A (fi) 1979-01-07
DK142577B (da) 1980-11-24
NO782341L (no) 1979-01-09
US4315931A (en) 1982-02-16
CA1107733A (fr) 1981-08-25
DE2861128D1 (en) 1981-12-17
IE781292L (en) 1979-01-06
DK142577C (da) 1981-07-20
AT360998B (de) 1981-02-10
EP0000335A1 (fr) 1979-01-24
DK303278A (da) 1979-01-07
HU178177B (en) 1982-03-28
JPS5416483A (en) 1979-02-07
ATA487678A (de) 1980-07-15
AU515679B2 (en) 1981-04-16
IL55020A0 (en) 1978-08-31
IL55020A (en) 1981-11-30
AR220139A1 (es) 1980-10-15
AU3764378A (en) 1980-01-03
IE47013B1 (en) 1983-11-30

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