EP0000334B1 - 2,4-diamino-5-benzyl-pyrimidines, process for their preparation and medicines containing them - Google Patents
2,4-diamino-5-benzyl-pyrimidines, process for their preparation and medicines containing them Download PDFInfo
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- 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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- trimethoxybenzyl
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- amino
- pyrimidine
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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
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- 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
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- 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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Description
Die Erfindung betrifft 2,4-Diamino-5-benzylpyrimidine der allgemeinen Formel I
Bevorzugt stehen die Substituenten R1, R2 und R3 in der 3-, 4- und 5-Stellung des Benzolrings.The substituents R 1 , R 2 and R 3 are preferably in the 3, 4 and 5 positions of the benzene ring.
Ganz besonders bevorzugt sind dabei diejenigen Verbindungen der allgemeinen Formel I, in der R', R2 und R3 Methoxygruppen bedeuten.Those compounds of the general formula I in which R ', R 2 and R 3 are methoxy groups are very particularly preferred.
Die Verbindungen der allgemeinen Formel l und deren Salze sind antimikrobiell wirksam bei durch Bakterien und Protozoen hervorgerufenen Krankheiten und potenzieren, kombiniert mit Sulfonamiden, deren antimikrobielle Wirkung. Sie können beispielsweise bei bakteriellen Erkrankungen der Atmungsorgane, Verdauungsorgane und Harnwege sowie bei Hals-, Nasen-, Ohreninfektionen und allgemein systemischen Infektionskrankheiten und bei Malaria verwendet werden.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.
Solche Sulfonamide sind beispielsweise:
- 2-Sulfanilamidopyrimidin, 2-Sulfanilamido-5-methoxypyrimidin, 4-Sulfanilamido-2,6-dimethoxy- pyrimidin, 3-Sulfanilamido-5-methylisoxazol, 2-Sulfanilamido-4,5-dimethyloxazol, 3-Sulfanilamido-6-methoxypyridazin, 4-Sulfanilamido-2,6-dimethylpyrimidin, 4-Sulfanilamido-5,6-dimethoxypyrimidin, 2-Sulfanilamido-3-methoxypyrazin.
- 2-sulfanilamidopyrimidine, 2-sulfanilamido-5-methoxypyrimidine, 4-sulfanilamido-2,6-dimethoxypyrimidine, 3-sulfanilamido-5-methylisoxazole, 2-sulfanilamido-4,5-dimethyloxazole, 3-sulfanilamido-6-methoxypyridazine, 4-sulfanilamido-2,6-dimethylpyrimidine, 4-sulfanilamido-5,6-dimethoxypyrimidine, 2-sulfanilamido-3-methoxypyrazine.
Als übliche Säuren zur Bildung pharmakologisch verträglicher Salze kommen in Frage:
- Salzsäure, Schwefelsäure, Phosphorsäure, Salpetersäure, Essigsäure, Milchsäure, Weinsäure und Zitronensäure.
- Hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, lactic acid, tartaric acid and citric acid.
Bevorzugt werden jedoch die genannten anorganischen Säuren, insbesondere Salzsäure und Schwefelsäure, die mit den erfindungsgemäßen Substanzen besonders gut kristallisierende Salze bilden.However, preference is given to the inorganic acids mentioned, in particular hydrochloric acid and sulfuric acid, which form particularly well crystallizing salts with the substances according to the invention.
Die Verbindungen der allgemeinen Formel l und deren Salze können mit den beispielhaft genannten Sulfonamiden in verschiedenen Mischungsverhältnissen kombiniert werden, wobei das Verhältnis Substanz nach allgemeiner Formel l: Sulfonamid in dem Bereich 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 500 mg eines Wirkstoffs der allgemeinen Formel I in Betracht.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.
Die Herstellung der erfindungsgemäßen Substanzen nach der allgemeinen Formel I geschieht in der Weise, daß man
- a) eine Verbindung der allgemeinen Formel II
- b) eine Verbindung der allgemeinen Formel IV
- c) eine Verbindung der allgemeinen Formel VI
- a) a compound of general formula II
- b) a compound of the general formula IV
- c) a compound of the general formula VI
Gegenüber den zahlreichen literaturbekannten, über eine Ringschlußreaktion mit Verbindungen der allgemeinen Formel V verlaufenden Synthesemöglichkeiten sollen die Verfahren a) bis c) keine Einschränkungen darstellen.Processes a) to c) are not intended to be any restrictions in relation to the numerous synthesis possibilities known from the literature which proceed via a ring closure reaction with compounds of the general formula V.
Bei der Verfahrensweise a) wird im allgemeinen in einem aprotischen Verdünnungsmittel, wie beispielsweise Dioxan, Tetrahydrofuran, Benzol, Chlorbenzol, Chloroform oder Pyridin gearbeitet, wobei die Reaktionstemperaturen je nach Reaktivität der Verbindung der allgemeinen Formel III zwischen 0 und 200°C liegen.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.
Bei der Verfahrensweise b) wird in Alkoholen, vorzugsweise in Methanol oder Äthanol, oder in Dimethylformamid oder Dimethylsulfoxid als Lösungsmittel gearbeitet, wobei die Reaktionstemperaturen zwischen 50 und 150°C liegen. Temperaturen um 150°C sind dann erforderlich, wenn die Abgangsgruppe X eine schwer reagierend aliphatische Aminogruppe bedeutet. Die Abgangsgruppe in der allgemeinen Formel IV bedeutet eine Alkoxygruppe, vorzugsweise die Methoxy-und die Athoxygruppe, oder eine sekundäre aliphatische Aminogruppe, vorzugsweise eine Morpholino-oder Dimethylaminogruppe, oder eine primäre aromatische Aminogruppe, vorzugsweise die Anilinogruppe oder den Imidazolyl-1-rest.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.
Zum Wirkungsnachweis 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-dimethyl-oxazol + 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 3-fachen hervor.
Gegenstand der Erfindung sind demnach auch chemotherapeutische Mittel, die neben üblichen Träger- und Verdünnungsmitteln eine Verbindung der allgemeinen Formel I, insbesondere in Kombination mit einem Sulfonamid als Wirkstoffe enthalten, sowie die Verwendung der Verbindungen der allgemeinen Formel I als Sulfonamidpotentiatoren.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.
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.
5,8 g 2,4-Diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidin wurden in 60 ml of Pyridin bei 60°C gelöst und die Lösung bei dieser Temperatur tropfenweise mit 3,0 ml Chlordimethyläther versetzt. Anschließend wurde das Pyridin im Vakuum abdestilliert und der Rückstand aus 250 ml Äthanol umkristallisiert. Es wurden so 5,5 g (74% d.Th.) 2-Methoxymethylamino-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-HCI mit dem Fp.: 227°C erhalten.5.8 g of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine were dissolved in 60 ml of pyridine at 60 ° C., and 3.0 ml of chlorodimethyl ether were added dropwise to the solution at this temperature. The pyridine was then distilled off in vacuo and the residue was recrystallized from 250 ml of ethanol. 5.5 g (74% of theory) of 2-methoxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine-HCl were obtained with the mp: 227 ° C.
5,8 g 2,4-Diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidin wurden in 100 ml Dioxan bei 80°C gelöst und die Lösung mit 2,97 g Chlormethylcyclohexyläther tropfenweise versetzt. Nach Beendigung der Zugabe wurde noch 30 Minuten bei 90°C gerührt. Der nach dem Abkühlen erhaltene Niederschlag wurde aus Methylglykol unter Zusatz von Äther umkristallisiert. Es wurden 6,8 g (77% d.Th.) 2-Cyclohexyloxymethylamino-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-HCI mit dem Fp.: 208°C erhalten.5.8 g of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine were dissolved in 100 ml of dioxane at 80 ° C., and 2.97 g of chloromethylcyclohexyl ether were added dropwise to the solution. After the addition had ended, the mixture was stirred at 90 ° C. for a further 30 minutes. The precipitate obtained after cooling was recrystallized from methyl glycol with the addition of ether. 6.8 g (77% of theory) of 2-cyclohexyloxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine-HCl were obtained with the mp: 208 ° C.
Analog Beispiel 1 und 2 wurden außerdem hergestellt:
- 3. 2 - Äthoxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 206°C aus 2,4 - Diamino - 5 - (3,4,5, - trimethoxybenzyl) - pyrimidin und Chlormethyläthyl- äther.
- 4. 2 - n - Propyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 249°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyl - n - propyläther.
- 5. 2 - n - Butyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxy - benzyl) - pyrimidin - HCI mit dem Fp.: 235°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyln - butyläther.
- 6. 2 - n - Hexyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 228°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyl - n - hexyläther.
- 7. 2 - Allyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 220 bis 222°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethylallyläther.
- 8. 2 - (ß - Chloräthoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 218°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyl - ß - chloräthyläther.
- 9. 2 - (2 - Chlor - 1 - methyl - äthoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 230°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyl - (2 - chlor - 1 - methyläthyl) - äther.
- 10. 2 - Benzyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 227°C aus 2,4 - Diamino - 5 - (3,4,5, - trimethoxybenzyl) - pyrimidin und Chlormethylbenzyläther.
- 11. 2 - (ß - Methoxyäthoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 226°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyl ß - methoxyäthyläther.
- 12. 2 - (ß - Athoxyäthoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 216°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und Chlormethyl - ß -äthoxyäthyläther.
- 13. 2 - Cyclohexyloxymethylamino - 4 - amino - 5 - (4 - methoxybenzyl) - pyrimidin - HCI mit dem Fp.: 297°C aus 2,4 - Diamino - 5 - (4 - methoxy) - pyrimidin und Chlormethylcyclohexyläther.
- 14. 2 - Benzyloxymethylamino - 4 - amino - 5 - (3,4, - dimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 182°C aus 2,4 - Diamino - 5 - (3,4 - Dimethoxybenzyl) - pyrimidin und Chlormethylbenzyl- äther.
- 15. 2 - (ß - Chloräthoxymethylamino) - 4 - amino - 5 - (2 - chlorbenzyl) - pyrimidin - HCI mit dem Fp.: 222°C aus 2,4 - Diamino - 5 - (2 - chlorbenzyl) - pyrimidin und Chlormethyl - ß - chloräthyläther.
- 16. 2 - (ß - Äthoxyäthoxymethylamino) - 4 - amino - 5 - (4 - chlorbenzyl) - pyrimidin - HCI mit dem Fp.: 218°C aus 2,4 - Diamino - 5 - (4 - chlorbenzyl) - pyrimidin und Chlormethyl - β- äthoxyäthyläther.
- 17. 2 - Allyloxymethylamino - 4 - amino - 5 - (2,4 - dimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 200°C aus 2,4 - Diamino - 5 - (2,4 - dimethoxybenzyl) - pyrimidin und Chlormethylallyläther.
- 18. 2 - (3 - Methylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 290°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und 3 - Methyl - 5 - chlormethyl - isoxazol.
- 19. 2 - (3 - Äthylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 291 °C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und 3 - Äthyl - 5 - chlormethyl - isoxazol.
- 20. 2 - (3 - Isopropylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 290°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und 3 - Isopropyl - 5 - chlormethyl - isoxazol.
- 21. 2 - (3 - Tertiärbutylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - HCI mit dem Fp.: 280°C aus 2,4 - Diamino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin und 3 - Tertiärbutyl - 5 - chlormethyl - isoxazol.
- 3. 2 - ethoxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 206 ° C from 2,4 - diamino - 5 - (3,4,5, - trimethoxybenzyl) pyrimidine and chloromethyl ethyl ether.
- 4. 2 - n - propyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 249 ° C from 2,4 - diamino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine and chloromethyl - n - propyl ether.
- 5. 2-n-butyloxymethylamino-4-amino-5- (3,4,5-trimethoxy-benzyl) -pyrimidine-HCl with mp: 235 ° C. from 2,4-diamino-5 - (3,4 , 5 - trimethoxybenzyl) pyrimidine and chloromethyln - butyl ether.
- 6. 2 - n - hexyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 228 ° C from 2,4 - diamino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine and chloromethyl - n - hexyl ether.
- 7. 2-Allyloxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine-HCl with mp: 220 to 222 ° C from 2,4-diamino-5 - (3,4,5 - trimethoxybenzyl) - pyrimidine and chloromethylallyl ether.
- 8. 2 - (ß - chloroethoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 218 ° C from 2,4 - diamino - 5 - (3,4 , 5 - trimethoxybenzyl) pyrimidine and chloromethyl - ß - chloroethyl ether.
- 9. 2 - (2 - chloro - 1 - methyl - ethoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 230 ° C from 2,4 - diamino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine and chloromethyl - (2 - chloro - 1 - methylethyl) ether.
- 10. 2 - benzyloxymethylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 227 ° C from 2,4 - diamino - 5 - (3,4,5, - trimethoxybenzyl) pyrimidine and chloromethylbenzyl ether.
- 11. 2 - (ß - methoxyethoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 226 ° C from 2,4 - diamino - 5 - (3,4 , 5 - trimethoxybenzyl) pyrimidine and chloromethyl ß - methoxyethyl ether.
- 12. 2 - (ß - Athoxyäthoxymethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 216 ° C from 2,4 - diamino - 5 - (3,4 , 5-trimethoxybenzyl) pyrimidine and chloromethyl-ß-ethoxyethyl ether.
- 13. 2 - Cyclohexyloxymethylamino - 4 - amino - 5 - (4 - methoxybenzyl) pyrimidine - HCl with mp: 297 ° C from 2,4 - diamino - 5 - (4 - methoxy) pyrimidine and chloromethylcyclohexyl ether.
- 14. 2 - Benzyloxymethylamino - 4 - amino - 5 - (3,4, - dimethoxybenzyl) pyrimidine - HCl with mp: 182 ° C from 2,4 - diamino - 5 - (3,4 - dimethoxybenzyl) pyrimidine and chloromethylbenzyl ether.
- 15. 2 - (ß - Chloräthoxymethylamino) - 4 - amino - 5 - (2 - chlorobenzyl) - pyrimidine - HCl with mp: 222 ° C from 2,4 - diamino - 5 - (2 - chlorobenzyl) - pyrimidine and Chloromethyl - ß - chloroethyl ether.
- 16. 2 - (ß - ethoxyethoxymethylamino) - 4 - amino - 5 - (4 - chlorobenzyl) - pyrimidine - HCl with mp: 218 ° C from 2,4 - diamino - 5 - (4 - chlorobenzyl) - pyrimidine and Chloromethyl - β-ethoxyethyl ether.
- 17. 2 - Allyloxymethylamino - 4 - amino - 5 - (2,4 - dimethoxybenzyl) pyrimidine - HCl with the mp .: 200 ° C from 2,4 - diamino - 5 - (2,4 - dimethoxybenzyl) pyrimidine and Chloromethyl allyl ether.
- 18. 2 - (3 - Methylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 290 ° C from 2,4 - diamino - 5 - (3,4,5-trimethoxybenzyl) pyrimidine and 3-methyl-5-chloromethyl-isoxazole.
- 19. 2 - (3 - ethylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 291 ° C from 2,4 - diamino - 5 - (3,4,5-trimethoxybenzyl) pyrimidine and 3-ethyl-5-chloromethyl-isoxazole.
- 20. 2 - (3 - isopropylisoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 290 ° C from 2,4 - diamino - 5 - (3,4,5-trimethoxybenzyl) pyrimidine and 3-isopropyl-5-chloromethyl-isoxazole.
- 21. 2 - (3 - tertiary butyl isoxazolyl - 5) - methylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - HCl with mp: 280 ° C from 2,4 - diamino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine and 3 - tertiary butyl - 5 - chloromethyl - isoxazole.
5 g α-Anilino-ß-(3,4,5-trimethoxybenzyl)-acrylnitril, 5,9 g Benzylguanidiniumsulfat und 1,6 g Natriummethylat wurden in 50 ml Äthanol 4 Stunden unter Rückfluß zum Sieden erhitzt. Danach wurde das Gemisch mit 10 ml Wasser versetzt und nach dem Abkühlen die Kristalle abgesaugt und mit Wasser gewaschen.5 g of α-anilino-β- (3,4,5-trimethoxybenzyl) acrylonitrile, 5.9 g of benzylguanidinium sulfate and 1.6 g of sodium methylate were refluxed in 50 ml of ethanol for 4 hours. The mixture was then mixed with 10 ml of water and, after cooling, the crystals were filtered off with suction and washed with water.
Nach Umkristallisieren des Produktes aus Isopropanol wurden 4,1 g (72% d.Th.) 2-Benzylamino-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin mit dem Fp.: 135°C erhalten.After recrystallization of the product from isopropanol, 4.1 g (72% of theory) of 2-benzylamino-4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine with mp: 135 ° C. were obtained.
- 23. 2 - Allylamino - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 132°C unter Verwendung von Allylguanidinsulfat.23. 2-Allylamino-4-amino-5 - (3,4,5-trimethoxybenzyl) pyrimidine with mp: 132 ° C using allyl guanidine sulfate.
- 24. 2 - (Phenäthyl - ß - amino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 124°C unter Verwendung von Phenäthylguanidinsulfat.24. 2 - (Phenethyl - ß - amino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp: 124 ° C using phenethylguanidine sulfate.
- 25. 2 - (4 - Chlorbenzylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 143°C unter Verwendung von 4-Chlorbenzylguanidinsulfat.25. 2 - (4 - Chlorobenzylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp: 143 ° C using 4-chlorobenzylguanidine sulfate.
- 26. 2 - (ß - Dimethylaminoäthylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 139°C unter Verwendung von β Dimethylaminoäthylguanidinsulfat.26. 2 - (ß - Dimethylaminoethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp: 139 ° C using β dimethylaminoethyl guanidine sulfate.
- 27. 2 - (ß - Morpholinoäthylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 140°C unter Verwendung von β - Morpholinäthylguanidinsulfat.27. 2 - (ß - Morpholinoethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp: 140 ° C using β - Morpholinäthylguanidinsulfat.
- 28. 2 - (ß - Pyrrolidinoäthylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 130°C unter Verwendung von β - Pyrrolidinoäthylguanidinsulfat.28. 2 - (ß - Pyrrolidinoethylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp: 130 ° C using β - pyrrolidinoethylguanidine sulfate.
- 29. 2 - (3 - Dimethylamino - n - propyl - 1 - amino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 139°C unter Verwendung von 3 - Dimethylamino - n - propyl - 1 - guanidinsulfat.29. 2 - (3-Dimethylamino - n - propyl - 1 - amino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp: 139 ° C using 3 - dimethylamino - n-propyl-1-guanidine sulfate.
- 30. 6,4 g α- Cyano - β - (3,4,5 - trimethoxyphenyl) - propionaldehyddimethylacetal, 3 g ß - Hydroxy- äthylguanidinsulfat und 1,1 g Natriummethylat wurden in 100 ml Äthanol 5 Stunden unter Rückfluß zum Sieden erhitzt. Danach wurde das Äthanol abdestilliert und der Rückstand in 100 ml Wasser gelöst. Durch Extraktion der Lösung mit Chloroform wurden 3,4 g (50% d.Th.) 2 - (ß - Hydroxyäthylamino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 146°C nach Umkristallisation aus Isopropanol erhalten.30. 6.4 g of α-cyano-β - (3,4,5-trimethoxyphenyl) propionaldehyde dimethyl acetal, 3 g of β-hydroxyethyl guanidine sulfate and 1.1 g of sodium methylate were heated to boiling under reflux in 100 ml of ethanol for 5 hours. The ethanol was then distilled off and the residue was dissolved in 100 ml of water. Extraction of the solution with chloroform gave 3.4 g (50% of theory) of 2 - (β-hydroxyethylamino) - 4-amino-5 - (3,4,5-trimethoxybenzyl) pyrimidine with mp: 146 ° C obtained after recrystallization from isopropanol.
- 31. 5,6 g a - (3,4,5 - Trimethoxybenzyl) - ß - dimethylaminoacrylnitril, 3,8 g β - Äthoxyäthylguanidinsulfat und 2 g Natriummethylat wurden in 100 ml Dimethylsulfoxid 3 Stunden bei 150°C gerührt. Danach wurde das Dimethylsulfoxid im Vakuum abdestilliert und der Rückstand mit 100 ml Wasser versetzt. Das ölige Produkt wurde mit Chloroform extrahiert und der Rückstand nach dem Einengen der Extrakte mehrfach aus Essigester Isopropyläther umkristallisiert. Man erhielt so 1,4 g (20% d.Th.) 2-(ß-Äthoxyäthylamino)-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin mit dem Fp.: 147°C.31. 5.6 g of a - (3,4,5-trimethoxybenzyl) - ß-dimethylaminoacrylonitrile, 3.8 g of β-ethoxyethyl guanidine sulfate and 2 g of sodium methylate were stirred in 100 ml of dimethyl sulfoxide at 150 ° C. for 3 hours. The dimethyl sulfoxide was then distilled off in vacuo and 100 ml of water were added to the residue. The oily product was extracted with chloroform and, after concentrating the extracts, the residue was recrystallized several times from isopropyl ether. This gave 1.4 g (20% of theory) of 2- (β-ethoxyethylamino) -4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine with the mp: 147 ° C.
- 32. 12 g ß-Imidazolyl - 1 - propionitril, 6 g Natriummethylat und 19,6 g 3,4,5 - Trimethoxybenzaldehyd wurden 12 Stunden in 200 ml Methanol unter Rückfluß zum Sieden erhitzt. Danach wurden 37 g (3 - Äthoxy - n - propyl - 1) - guanidinsulfat und weitere 6 g Natriummethylat zugegeben, das Methanol langsam abdestilliert und der Rückstand 2 Stunden bei 110°C gerührt. Das Reaktionsgemisch wurde mit 200 ml Wasser verrührt und das halbfeste Produkt mit Chloroform extrahiert. Der Rückstand vom Chloroformextrakt wurde aus Essigester/lsopropyl- äther umkristallisiert. Man erhielt so 12 g (32% d.Th.) 2 - (3 - Äthoxy - n - propyl - 1 - amino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin mit dem Fp.: 118°C.32. 12 g of β-imidazolyl-1-propionitrile, 6 g of sodium methylate and 19.6 g of 3,4,5-trimethoxybenzaldehyde were refluxed in 200 ml of methanol for 12 hours. Then 37 g (3-ethoxy-n-propyl-1) guanidine sulfate and a further 6 g of sodium methylate were added, the methanol was slowly distilled off and the residue was stirred at 110 ° C. for 2 hours. The reaction mixture was stirred with 200 ml of water and the semi-solid product extracted with chloroform. The residue from the chloroform extract was recrystallized from ethyl acetate / isopropyl ether. This gave 12 g (32% of theory) of 2 - (3 - ethoxy - n - propyl - 1 - amino) - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) pyrimidine with mp. : 118 ° C.
-
33. Analog Beispiel 1 wurde erhalten:
- 2 - [ß(ß - Methoxyäthoxy) - äthoxymethylamino] - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidin - hydrochlorid mit dem Fp. 206 bis 209°C aus Trimethoprim und (ß - Methoxyäthoxy) - äthylchlormethyläther
- (R4=―CH2― 0―C2H4―0―C2H4― OCH3).
- 2 - [ß (ß - methoxyethoxy) - ethoxymethylamino] - 4 - amino - 5 - (3,4,5 - trimethoxybenzyl) - pyrimidine - hydrochloride with mp. 206 to 209 ° C from trimethoprim and (ß - methoxyethoxy) - ethyl chloromethyl ether
- (R4 = - CH 2― 0 - C 2 H 4― 0 - C 2 H 4― OCH 3 ).
-
34. Analog Beispiel 1 wurde erhalten:
- 2 - [ß(ß - n - Butoxyäthoxy) - äthoxymethylaminol - 4 - amino - 5 - (3,4,5 - trimethoxy) - benzylpyrimidin - hydrochlorid mit dem Fp. 213°C aus Trimethoprim und β - (ß - n - Butoxyäthoxy) - äthylchlormethyläther
- (R4 = ―CH2―O―C2H4―O―C2H4―O―C2H9(n)).
- 2 - [ß (ß - n - butoxyethoxy) - ethoxymethylaminol - 4 - amino - 5 - (3,4,5 - trimethoxy) - benzylpyrimidine - hydrochloride with mp. 213 ° C from trimethoprim and β - (ß - n - Butoxyethoxy) - ethylchloromethyl ether
- (R 4 = ―CH 2 ―O ― C 2 H 4 ―O ― C 2 H 4 ―O ― C 2 H 9 (n)).
-
1. 400 mg 2-Sulfanilamido-4,5-dimethyloxazol
- 80 mg 2-Benzyloxymethylamino-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin
- 20 mg Maisstärke
- 10 mg Gelatine
- 8 mg Talkum
- 2 mg Magnesiumstearat
- 20 mg Primojel
- 80 mg of 2-benzyloxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine
- 20 mg corn starch
- 10 mg gelatin
- 8 mg talc
- 2 mg magnesium stearate
- 20 mg Primojel
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.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.
-
2. 160 mg 2-Sulfanilamido-5-methoxy-pyrimidin
- 80 mg 2-n-Hexyloxymethylamino-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin
- 5 mg Gelatine
- 30 mg Maisstärke
- 4 mg Talkum
- 1 mg Magnesiumstearat
- 80 mg of 2-n-hexyloxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine
- 5 mg gelatin
- 30 mg corn starch
- 4 mg talc
- 1 mg magnesium stearate
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.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.
-
3. 4,00 g 2-Sulfanilamido-5-methoxy-pyrimidin
- 2,00 g 2-n-Hexyloxymethylamino-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin
- 1,9 g Tylose® C 30
- 30,0 g Zucker
- 10,0 g Glycerin
- 2,5 g Bentonit
- 0,06 g Aroma
- 0,04 g Nipagin ®M
- 0,06 g Nipasol @Natrium
- ad 100,00 g demineralisiertes Wasser
- 2.00 g of 2-n-hexyloxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine
- 1.9 g Tylose® C 30
- 30.0 g sugar
- 10.0 g glycerin
- 2.5 g bentonite
- 0.06 g aroma
- 0.04 g Nipagin ®M
- 0.06 g Nipasol @ sodium
- ad 100.00 g demineralized water
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 g aufgefüllt.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.
Claims (3)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2730467 | 1977-07-06 | ||
DE19772730467 DE2730467A1 (en) | 1977-07-06 | 1977-07-06 | BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THE SAME |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000334A1 EP0000334A1 (en) | 1979-01-24 |
EP0000334B1 true EP0000334B1 (en) | 1981-08-12 |
Family
ID=6013252
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100180A Expired EP0000334B1 (en) | 1977-07-06 | 1978-06-16 | 2,4-diamino-5-benzyl-pyrimidines, process for their preparation and medicines containing them |
Country Status (17)
Country | Link |
---|---|
US (1) | US4279899A (en) |
EP (1) | EP0000334B1 (en) |
JP (1) | JPS5416482A (en) |
AR (1) | AR223465A1 (en) |
AT (1) | AT361931B (en) |
AU (1) | AU515661B2 (en) |
CA (1) | CA1102324A (en) |
DE (2) | DE2730467A1 (en) |
DK (1) | DK142578C (en) |
FI (1) | FI782173A (en) |
HU (1) | HU179407B (en) |
IE (1) | IE781308L (en) |
IL (1) | IL55018A (en) |
IN (1) | IN149577B (en) |
IT (1) | IT7825220A0 (en) |
NO (1) | NO782340L (en) |
ZA (1) | ZA783873B (en) |
Families Citing this family (8)
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 (en) * | 1980-12-04 | 1982-07-08 | Basf Ag, 6700 Ludwigshafen | N-PYRIMIDINYL-CARBAMINE ACID ESTER, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
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 |
UY27487A1 (en) * | 2001-10-17 | 2003-05-30 | Boehringer Ingelheim Pharma | PIRIMIDINE DERIVATIVES, MEDICATIONS CONTAINING THESE COMPOUNDS, THEIR EMPLOYMENT AND PROCEDURE FOR PREPARATION |
AR081331A1 (en) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME |
AR081626A1 (en) | 2010-04-23 | 2012-10-10 | Cytokinetics Inc | AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS |
WO2011133920A1 (en) | 2010-04-23 | 2011-10-27 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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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 (en) * | 1957-12-06 | 1964-03-31 | Ciba Geigy | Process for the preparation of new substituted pyrimidines |
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 |
-
1977
- 1977-07-06 DE DE19772730467 patent/DE2730467A1/en not_active Withdrawn
-
1978
- 1978-06-16 DE DE7878100180T patent/DE2860928D1/en not_active Expired
- 1978-06-16 EP EP78100180A patent/EP0000334B1/en not_active Expired
- 1978-06-27 US US05/919,505 patent/US4279899A/en not_active Expired - Lifetime
- 1978-06-27 IL IL55018A patent/IL55018A/en unknown
- 1978-06-29 IE IE781308A patent/IE781308L/en unknown
- 1978-06-30 IT IT7825220A patent/IT7825220A0/en unknown
- 1978-06-30 AU AU37644/78A patent/AU515661B2/en not_active Expired
- 1978-07-04 AR AR272831A patent/AR223465A1/en active
- 1978-07-04 CA CA306,732A patent/CA1102324A/en not_active Expired
- 1978-07-04 HU HU78BA3672A patent/HU179407B/en unknown
- 1978-07-05 ZA ZA00783873A patent/ZA783873B/en unknown
- 1978-07-05 DK DK303178A patent/DK142578C/en active
- 1978-07-05 FI FI782173A patent/FI782173A/en not_active Application Discontinuation
- 1978-07-05 NO NO782340A patent/NO782340L/en unknown
- 1978-07-05 AT AT487478A patent/AT361931B/en not_active IP Right Cessation
- 1978-07-06 JP JP8153078A patent/JPS5416482A/en active Pending
- 1978-07-06 IN IN747/CAL/78A patent/IN149577B/en unknown
Also Published As
Publication number | Publication date |
---|---|
DE2730467A1 (en) | 1979-01-18 |
CA1102324A (en) | 1981-06-02 |
AU3764478A (en) | 1980-01-03 |
AU515661B2 (en) | 1981-04-16 |
IE781308L (en) | 1979-01-06 |
ZA783873B (en) | 1979-08-29 |
HU179407B (en) | 1982-10-28 |
IL55018A0 (en) | 1978-08-31 |
NO782340L (en) | 1979-01-09 |
IN149577B (en) | 1982-01-30 |
IL55018A (en) | 1983-03-31 |
EP0000334A1 (en) | 1979-01-24 |
DK142578B (en) | 1980-11-24 |
FI782173A (en) | 1979-01-07 |
AT361931B (en) | 1981-04-10 |
JPS5416482A (en) | 1979-02-07 |
US4279899A (en) | 1981-07-21 |
IT7825220A0 (en) | 1978-06-30 |
DK303178A (en) | 1979-01-07 |
DK142578C (en) | 1981-07-20 |
DE2860928D1 (en) | 1981-11-12 |
ATA487478A (en) | 1980-09-15 |
AR223465A1 (en) | 1981-08-31 |
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