CH664960A5 - METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. - Google Patents
METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. Download PDFInfo
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- CH664960A5 CH664960A5 CH4395/86A CH439586A CH664960A5 CH 664960 A5 CH664960 A5 CH 664960A5 CH 4395/86 A CH4395/86 A CH 4395/86A CH 439586 A CH439586 A CH 439586A CH 664960 A5 CH664960 A5 CH 664960A5
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- 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
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- 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
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Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung einer Gruppe von substituierten 2,4-Diamino-5-benzylpyrimidinen. The present invention relates to a process for the preparation of a group of substituted 2,4-diamino-5-benzylpyrimidines.
Die deutsche Patentanmeldung Nr. 2 443 682 offenbart 45 unter anderem Verbindungen der Formel I German patent application No. 2 443 682 discloses 45 inter alia compounds of the formula I.
(IV) (IV)
mit 5-Dimethylaminomethyluracil umsetzt und danach die Aminogruppe entsprechend alkyliert, und die erhaltene Verbindung halogeniert und aminiert. reacted with 5-dimethylaminomethyluracil and then the amino group was alkylated accordingly, and the compound obtained was halogenated and aminated.
3. Verfahren zur Herstellung einer Verbindung der Formel I IIb) 3. Process for the preparation of a compound of formula I IIb)
„5 H-N "5 H-N
50. 50.
55 55
_4 4a R R N _4 4a R R N
worin wherein
O O
CHi CHi
(I) (I)
2 \ / ""2 N 2 \ / "" 2 N
O O
NH„ NH "
(Mb) (Mb)
R4 Wasserstoff oder Q 4-Alkyl, R4a Q 4-Alkyl und R5 und R'1 gleich oder verschieden sind und je Halogen, Q 4-Al- R4 is hydrogen or Q 4-alkyl, R4a Q 4-alkyl and R5 and R'1 are the same or different and each halogen, Q 4-Al-
und deren Salze, worin and their salts, in which
R1 und R2 gleich oder verschieden sind und je C, 3-Alkyl, C, j-Alkoxy, C2 3-Alkenyl oder C2 rAlkenyloxy und Z Amino oder alkylsubstituiertes 60 Amino bedeuten. R1 and R2 are the same or different and each is C, 3-alkyl, C, j-alkoxy, C2 3-alkenyl or C2 ralkenyloxy and Z is amino or alkyl-substituted 60 amino.
Diesen Verbindungen wird antibakterielle Aktivität zugeschrieben und für 2,4-Diamino-5(4-amino-3,5-dimethoxy-benzyl)pyrimidin wurde nachträglich gefunden, dass es gute 65diuretische Aktivität besitzt. Antibacterial activity is attributed to these compounds and it was subsequently found that 2,4-diamino-5 (4-amino-3,5-dimethoxy-benzyl) pyrimidine had good diuretic activity.
Die deutsche Patentanmeldung Nr. 2 634 358 offenbart unter anderem Verbindungen der Formel II The German patent application No. 2 634 358 discloses inter alia compounds of the formula II
3 3rd
664 960 664 960
Rr »2^ Rr »2 ^
r3/ r3 /
(II) (II)
und deren Salze, worin and their salts, in which
R/ ein Halogenatom und R / is a halogen atom and
Z Amino oder alkylsubstituiertes Amino bedeutet. Z means amino or alkyl-substituted amino.
Diesen Verbindungen wurde ebenfalls antibakterielle Aktivität zugeschrieben. Antibacterial activity has also been attributed to these compounds.
Eine neue Synthese der Verbindungen der Formeln I und II wurde nun gefunden. A new synthesis of the compounds of the formulas I and II has now been found.
Entsprechend betrifft die vorliegende Erfindung ein Verfahren zur Herstellung einer Verbindung der Formel III Accordingly, the present invention relates to a process for the preparation of a compound of formula III
(III) (III)
worin wherein
R4 und R4a gleich oder verschieden sind und je ein Wasserstoffatom oder eine C, 4-Alkylgruppe, R4 and R4a are the same or different and each represents a hydrogen atom or a C, 4-alkyl group,
R- Halogen, Q 4-Alkyl oder C| 4-Alkoxy und R° Halogen, C| 4-Alkyl oder C, 4-Alkoxy bedeuten. Dieses Verfahren umschliesst die Reaktion einer Verbindung der Formel IV R-halogen, Q 4-alkyl or C | 4-alkoxy and R ° halogen, C | 4-alkyl or C, 4-alkoxy mean. This process involves the reaction of a compound of formula IV
(IV) (IV)
worin wherein
R4. R- und R(l wie oben definiert sind mit 5-Dimethyl-aminomethyl-uracil, gefolgt von aufeinanderfolgender Al-kylierung der Aminogruppe (wenn erwünscht), Halogenie-rung und Aminierung des resultierenden Uracilderivates der Formel VIII R4. R- and R (l are as defined above with 5-dimethylaminomethyl-uracil, followed by sequential alkylation of the amino group (if desired), halogenation and amination of the resulting uracil derivative of the formula VIII
CH. CH.
(VIII) (VIII)
und anschliessend gegebenenfalls die Alkylierung einer Verbindung der Formel III, worin R42 Wasserstoff bedeutet, zu einer Verbindung der Formel III, worin R4a Cj 4-Alkyl bedeutet. and then optionally the alkylation of a compound of the formula III in which R42 is hydrogen to a compound of the formula III in which R4a is Cj 4-alkyl.
Dieses Verfahren ist besonders geeignet zur Herstellung jener Verbindungen, worin R4 Wasserstoff bedeutet. This method is particularly suitable for the preparation of those compounds in which R4 is hydrogen.
Geeignete Reste R5 und R6 sind gleich und bedeuten je Methoxy, Chlor oder Q 4-AlkyI. Suitable radicals R5 and R6 are the same and each represent methoxy, chlorine or Q 4-alkyl.
Die Reaktion einer Verbindung der Formel IV mit 5-Dimethylaminomethyluracil wird normalerweise in einem inerten, hochsiedenden polaren Lösungsmittel, z.B. einem hochsiedenden C2 6-AlkanolT wie Äthylenglykol, zwischen 100 °C und 200 C, z.B. zwischen 130 C und 160 °C, durchgeführt. Die Reaktion wird normalerweise unter sauren Bedingungen, z.B. in Anwesenheit von Chlorwasserstoff oder Salzsäure, durchgeführt. Die Halogenierung der Verbindung der Formel VIII und die folgende Aminierung kann zweckmässig mit Verfahren durchgeführt werden, die dem Fachmann 5 gut bekannt sind, z.B. unter Anwendung der Reaktionsbedingungen, die im britischen Patent Nr. 875 662 oder 1 132 082 oder in der DE-OS 2 258 238 beschrieben werden. The reaction of a compound of formula IV with 5-dimethylaminomethyluracil is normally carried out in an inert, high-boiling polar solvent, e.g. a high boiling C2 6 alkanol T such as ethylene glycol, between 100 ° C and 200 C, e.g. between 130 ° C and 160 ° C. The reaction is usually carried out under acidic conditions, e.g. in the presence of hydrogen chloride or hydrochloric acid. The halogenation of the compound of formula VIII and the following amination can conveniently be carried out using methods well known to those skilled in the art, e.g. using the reaction conditions described in British Patent No. 875 662 or 1 132 082 or in DE-OS 2 258 238.
Die Alkylierung der Aminogruppe wird unter bekannten Bedingungen durchgeführt, die den Uracilteil des Moleküls 10 nicht beeinflussen, z.B. durch Reaktion des Amins mit Ameisensäure und dem geeigneten Aldehyd. Die Reaktion ist vorzugsweise eine Methylierung und in diesem Fall ist der Aldehyd Formaldehyd. Die allfällige Alkylierung der Aminogruppe NR4H wird unter Bedingungen durchgeführt, die 15 die Aminogruppen, die am Pyrimidinring gebunden sind, nicht beeinflussen. Geeignete Bedingungen sind dem Fachmann wiederum bekannt, z.B. die Reaktion mit Ameisensäure und dem geeigneten Aldehyd. The alkylation of the amino group is carried out under known conditions which do not affect the uracil part of the molecule 10, e.g. by reacting the amine with formic acid and the appropriate aldehyde. The reaction is preferably methylation and in this case the aldehyde is formaldehyde. Any alkylation of the amino group NR4H is carried out under conditions which do not affect the amino groups bonded to the pyrimidine ring. Suitable conditions are again known to the person skilled in the art, e.g. the reaction with formic acid and the appropriate aldehyde.
20 Beispiel 1 20 Example 1
Herstellung von 5-Dimethylaminomethyluracil-hydrochlorid Uracil (56,05 g, 0,50 Mol) wurde mit Dimethylaminhy-drochlorid (81,55 g, 1,0 Mol) und 37%-igem wässrigem Formaldehyd (61 ml, 1,0 Mol) in Wasser (100 ml) während 2 25 Tagen unter Rückfluss erhitzt. Das Lösungsmittel wurde abgedampft und das Produkt mit Methanol zerrieben. Nach dem Filtrieren und Trocknen wurde die Titelverbindung isoliert (80,6 g, 78,3%). Preparation of 5-dimethylaminomethyluracil hydrochloride uracil (56.05 g, 0.50 mol) was treated with dimethylamine hydrochloride (81.55 g, 1.0 mol) and 37% aqueous formaldehyde (61 ml, 1.0 mol ) in water (100 ml) heated under reflux for 2 to 25 days. The solvent was evaporated and the product was triturated with methanol. After filtering and drying, the title compound was isolated (80.6 g, 78.3%).
■H NMR (DMSO-d6 + D20): 2,90 (s, 6, NMe2), 4,10 (s, 30 2, NCH2), 7,95 (s, 1, Uracil 6-H). ■ H NMR (DMSO-d6 + D20): 2.90 (s, 6, NMe2), 4.10 (s, 30 2, NCH2), 7.95 (s, 1, uracil 6-H).
Herstellung von 5- (4-amino-3,5-diisopropylbenzyl)uracil Preparation of 5- (4-amino-3,5-diisopropylbenzyl) uracil
Eine Mischung von 5-Dimethylaminomethyluracil-hy-drochlorid (10,28 g, 50,0 mMol) und 2,6-Diisopropylanilin 35 (10,64 g, 60,0 mMol) in Äthylenglykol (75 ml) wurde während 4!/2 Stunden bei 134° bis 137 °C erhitzt. Nach dem Abkühlen wurde die Titelverbindung filtriert, mit Äthanol gewaschen und getrocknet (5,55 g, 37%). Eine zweite Menge wurde nach Stehenlassen aus der Mutterlauge erhalten 40 (3,24 g, 21,5%). Die beiden Mengen wurden vereinigt und aus Methanol umkristallisiert, wobei die gereinigte Titelverbindung erhalten wurde (5,84 g, 38,8%). A mixture of 5-dimethylaminomethyluracil-hydrochloride (10.28 g, 50.0 mmol) and 2,6-diisopropylaniline 35 (10.64 g, 60.0 mmol) in ethylene glycol (75 ml) was added during 4! / Heated at 134 ° to 137 ° C for 2 hours. After cooling, the title compound was filtered, washed with ethanol and dried (5.55 g, 37%). A second amount was obtained from the mother liquor 40 (3.24 g, 21.5%). The two amounts were combined and recrystallized from methanol to give the purified title compound (5.84 g, 38.8%).
Ci7H23N302: Ci7H23N302:
berechnet: C 67,75; H 7,69; N 13,94 « gefunden: C 67,59; H 7,75; N 13,88. calculated: C 67.75; H 7.69; N, 13.94. Found: C, 67.59; H 7.75; N 13.88.
Die Titelverbindung kann zu VII (R4=H, R5 = R6=CHMe2, R9=H) durch aufeinanderfolgende Halogenierung und Aminierung überführt werden, wie z.B. beschrieben im britischen Patent Nr. 875 562 oder 1 132 082 so oder nach DE-OS 2 258 238. The title compound can be converted to VII (R4 = H, R5 = R6 = CHMe2, R9 = H) by successive halogenation and amination, e.g. described in British Patent No. 875 562 or 1 132 082 as described or in DE-OS 2 258 238.
5-(4-Amino-3,5-dimethoxybenzyl)-2,4-( 1H, 3H)-pyrimidin-dion 5- (4-amino-3,5-dimethoxybenzyl) -2,4- (1H, 3H) pyrimidine dione
Eine Mischung von 10,04 g (49 mMol) 5-(Dimethylami-55 no)-methyluracil-hydrochlorid (B. Roth, J.Z. Strelitz, und B.S. Hauckman, J. Med. Chem. 23, 379 (1980) ) und 7,48 g (49 mMol) 2,6-Dimethoxyanilin [Schmelzpunkt 73 °C bis 74,5°; hergestellt aus 2,6-Dimethoxybenzoesäure nach dem Verfahren in Org. Reactions 3, 330 (1946)] in 50 ml Äthylen-60 glykol wurde unter Stickstoff während 5 Stunden auf 145 °C erhitzt. Die Mischung wurde gekühlt und der ausgefällte Festkörper wurde gesammelt, in 300 ml siedendem Äthanol suspendiert und gesammelt, wobei 3,91 g der Titelverbindung (29%) erhalten wurde. Schmelzpunkt: 243 °C bis 65 245 °C (Zersetzung). A mixture of 10.04 g (49 mmol) of 5- (dimethylami-55 no) -methyluracil hydrochloride (B. Roth, JZ Strelitz, and BS Hauckman, J. Med. Chem. 23, 379 (1980)) and 7 , 48 g (49 mmol) of 2,6-dimethoxyaniline [melting point 73 ° C to 74.5 °; prepared from 2,6-dimethoxybenzoic acid by the method in Org. Reactions 3, 330 (1946)] in 50 ml of ethylene-60 glycol was heated to 145 ° C. under nitrogen for 5 hours. The mixture was cooled and the precipitated solid was collected, suspended in 300 ml of boiling ethanol and collected to give 3.91 g of the title compound (29%). Melting point: 243 ° C to 65 245 ° C (decomposition).
Analyse analysis
C13H15N304- 1/4 HA berechnet: C 55,41; H 5,54; N 14,91 C13H15N304- 1/4 HA calculated: C 55.41; H 5.54; N 14.91
664 960 664 960
4 4th
gefunden: C 55,46; H 5,54; N 14,94. found: C 55.46; H 5.54; N 14.94.
Eine zweite Menge von 2,0 g (15%) wurde durch Einengen des Äthanol Extraktes erhalten. A second amount of 2.0 g (15%) was obtained by concentrating the ethanol extract.
5-(3,5-Dimethoxy-4-dimethylaminobenzyl)-2,4-( 1H, 3H)-py- 5- (3,5-dimethoxy-4-dimethylaminobenzyl) -2,4- (1H, 3H) -py-
rimidindion rimidindione
Zu einer Lösung von 5-(4-Amino-3,5-dimethoxybenzyl)-2,4-(lH, 3H)-pyrimidindion (5,4 g, 19,5 mMol) in 88%-iger Ameisensäure (70 ml) wurde 37%-iger Formaldehyd (1,75 g) hinzugegeben. Nach dem Erhitzen unter Rückfluss während 18 Stunden wurde die Reaktionslösung gekühlt mit 2 ml konzentrierter Salzsäure versetzt. Die Lösung wurde eingedampft und der Rückstand wurde in 200 ml Wasser gelöst. Die Neutralisation dieser Lösung mit 5N Natronlauge ergab 5,25 g (89%) der Titelverbindung. To a solution of 5- (4-amino-3,5-dimethoxybenzyl) -2,4- (1H, 3H) -pyrimidinedione (5.4 g, 19.5 mmol) in 88% formic acid (70 ml) 37% formaldehyde (1.75 g) was added. After refluxing for 18 hours, the reaction solution was cooled with 2 ml of concentrated hydrochloric acid. The solution was evaporated and the residue was dissolved in 200 ml of water. Neutralization of this solution with 5N sodium hydroxide solution gave 5.25 g (89%) of the title compound.
Schmelzpunkt: 228 °C bis 230 °C (Zersetzung). Melting point: 228 ° C to 230 ° C (decomposition).
Analyse analysis
C15H,9N304 • 0,1 H2: C15H, 9N304 • 0.1 H2:
berechnet: C 58,66; H 6,30; N 13,68 calculated: C 58.66; H 6.30; N 13.68
gefunden: C 58,55; H 6,30; N 13,69. found: C 58.55; H 6.30; N 13.69.
2,4-Dichlor-5-( 3,5-dimethoxy-4-dimethylaminobenzyl ) pyrimi-din 2,4-dichloro-5- (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimi-din
Eine Mischung von 5,02 g (16,4 mMol) 5-(3,5-Dimeth-oxy-4-dimethylaminobenzyl)-2,4-(lH, 3H)-pyrimidindion in 100 ml Phosphorylchlorid wurde während 90 Minuten unter Rückfluss erhitzt. Der Überschuss POCl3 wurde unter Vakuum entfernt und der Rückstand wurde in Dichlormethan gelöst und mit wässriger Natriumbicarbonatlösung neutral gewaschen und dann mit Wasser gewaschen. Die Lösung wurde über Magnesiumsulfat getrocknet und dann mit Dichlormethan zu Methanol 19:1 als Elutionsmittel an einer Si-5 licagelsäule chromatographiert. Die Fraktionen, die das Produkt enthielten, wurden vereinigt und zu einem Ol konzentriert; 3,75 g, (67%). Die Struktur wurde durch NMR bestätigt. A mixture of 5.02 g (16.4 mmol) of 5- (3,5-dimeth-oxy-4-dimethylaminobenzyl) -2,4- (1H, 3H) -pyrimidinedione in 100 ml of phosphoryl chloride was refluxed for 90 minutes heated. The excess POCl3 was removed under vacuum and the residue was dissolved in dichloromethane and washed neutral with aqueous sodium bicarbonate solution and then washed with water. The solution was dried over magnesium sulfate and then chromatographed on an Si-5 licagel column with dichloromethane to give methanol 19: 1 as eluent. The fractions containing the product were pooled and concentrated to an oil; 3.75 g, (67%). The structure was confirmed by NMR.
10 2,4-Diamino-5- (3,5-dimethoxy-4-dimethylaminobenzyl)pyri-midin 10 2,4-diamino-5- (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine
Eine Lösung von 3,47 g (10,1 mMol) 2,4-Dichlor-5-(3,5-dimethoxy-4-dimethylaminobenzyl)pyrimidin in 200 ml mit Ammoniak gesättigtem Äthanol wurde in einem Autoklaven 15 während 8 Stunden auf 150 °C erhitzt. Das Lösungsmittel wurde unter Vakuum entfernt und der Rückstand wurde mit Wasser trituriet und gesammelt. Das Produkt wurde in einer Mischung von Dichlormethan zu Methanol 4:1 gelöst, auf Silicagel absorbiert und oben auf eine Silicagelsäule gegeben. 20 Die Elution mit demselben Lösungsmittel ergab 2,27 g (74%) der Titelverbindung. Ein Teil wurde in das Dihydro-chlorid durch Umkristallisation aus 95%-igem Äthanol mit konzentrierter Salzsäure überführt. A solution of 3.47 g (10.1 mmol) of 2,4-dichloro-5- (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine in 200 ml of ethanol saturated with ammonia was made up to 150 in an autoclave 15 for 8 hours ° C heated. The solvent was removed under vacuum and the residue was triturated with water and collected. The product was dissolved in a mixture of dichloromethane to methanol 4: 1, absorbed on silica gel and placed on top of a silica gel column. 20 Elution with the same solvent gave 2.27 g (74%) of the title compound. A portion was converted into the dihydrochloride by recrystallization from 95% ethanol with concentrated hydrochloric acid.
Schmelzpunkt: 228° bis 200° (Zersetzung). Melting point: 228 ° to 200 ° (decomposition).
25 Analyse 25 Analysis
C15H„N502 • 2 HCl • H2: C15H „N502 • 2 HCl • H2:
berechnet: C 75,69; H 6,39; N 17,76; Cl 17,98 calculated: C 75.69; H 6.39; N 17.76; Cl 17.98
gefunden: C 45,70; H 6,40; N 17,77; Cl 17,86. found: C 45.70; H 6.40; N 17.77; Cl 17.86.
C C.
Claims (5)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31964381A | 1981-11-09 | 1981-11-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
CH664960A5 true CH664960A5 (en) | 1988-04-15 |
Family
ID=23243118
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH6481/82A CH658246A5 (en) | 1981-11-09 | 1982-11-08 | METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
CH4396/86A CH664961A5 (en) | 1981-11-09 | 1982-11-08 | INTERMEDIATE PRODUCTS FOR THE SYNTHESIS OF SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
CH4394/86A CH664959A5 (en) | 1981-11-09 | 1982-11-08 | METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
CH4395/86A CH664960A5 (en) | 1981-11-09 | 1982-11-08 | METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH6481/82A CH658246A5 (en) | 1981-11-09 | 1982-11-08 | METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
CH4396/86A CH664961A5 (en) | 1981-11-09 | 1982-11-08 | INTERMEDIATE PRODUCTS FOR THE SYNTHESIS OF SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
CH4394/86A CH664959A5 (en) | 1981-11-09 | 1982-11-08 | METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. |
Country Status (5)
Country | Link |
---|---|
JP (4) | JPS5888368A (en) |
CH (4) | CH658246A5 (en) |
DE (1) | DE3241134C2 (en) |
FR (1) | FR2516081B1 (en) |
GB (3) | GB2109375B (en) |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE323746C (en) | 1919-10-30 | 1920-08-04 | Huebner Johannes | Fire protection apparatus for cinematographic projection apparatus |
GB1401612A (en) * | 1971-04-16 | 1975-07-16 | Wellcome Found | 2,4-diamino-5-benzylpyrimidines and preparations thereof |
CS194663B2 (en) * | 1971-04-16 | 1979-12-31 | Barbara Roth | Process for preparing 2,4-diamino-5-benzyl-pyrimidines |
CH592066A5 (en) * | 1973-02-26 | 1977-10-14 | Hoffmann La Roche | |
US3923807A (en) * | 1973-09-10 | 1975-12-02 | Takeda Chemical Industries Ltd | 6-Aminouracil derivatives |
CH591456A5 (en) * | 1973-09-12 | 1977-09-15 | Hoffmann La Roche | |
US4008236A (en) * | 1975-07-31 | 1977-02-15 | Abbott Laboratories | 2,4-Diamino-5-benzylpyrimidines |
JPS5353385A (en) * | 1976-10-26 | 1978-05-15 | Seiko Epson Corp | Clocking device |
GR71725B (en) * | 1977-11-10 | 1983-06-22 | Hoffmann La Roche | |
CH639273A5 (en) * | 1978-09-12 | 1983-11-15 | Hoffmann La Roche | DIURETIC MEANS. |
-
1982
- 1982-11-08 CH CH6481/82A patent/CH658246A5/en not_active IP Right Cessation
- 1982-11-08 CH CH4396/86A patent/CH664961A5/en not_active IP Right Cessation
- 1982-11-08 JP JP57195848A patent/JPS5888368A/en active Granted
- 1982-11-08 CH CH4394/86A patent/CH664959A5/en not_active IP Right Cessation
- 1982-11-08 CH CH4395/86A patent/CH664960A5/en not_active IP Right Cessation
- 1982-11-08 FR FR8218670A patent/FR2516081B1/en not_active Expired
- 1982-11-08 DE DE3241134A patent/DE3241134C2/en not_active Expired - Fee Related
- 1982-11-09 GB GB08231983A patent/GB2109375B/en not_active Expired
-
1985
- 1985-06-24 GB GB08515932A patent/GB2161158B/en not_active Expired
- 1985-06-24 GB GB08515931A patent/GB2161805B/en not_active Expired
-
1993
- 1993-01-28 JP JP5012770A patent/JPH07606B2/en not_active Expired - Lifetime
-
1994
- 1994-06-15 JP JP6133295A patent/JP2657150B2/en not_active Expired - Lifetime
-
1997
- 1997-02-20 JP JP9036735A patent/JPH09227530A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
GB2161805A (en) | 1986-01-22 |
GB2161158A (en) | 1986-01-08 |
JP2657150B2 (en) | 1997-09-24 |
JPH07606B2 (en) | 1995-01-11 |
FR2516081A1 (en) | 1983-05-13 |
JPH0549665B2 (en) | 1993-07-26 |
FR2516081B1 (en) | 1987-05-29 |
DE3241134C2 (en) | 1996-04-11 |
CH664961A5 (en) | 1988-04-15 |
CH664959A5 (en) | 1988-04-15 |
JPS5888368A (en) | 1983-05-26 |
GB2109375B (en) | 1986-08-06 |
JPH09227530A (en) | 1997-09-02 |
GB8515931D0 (en) | 1985-07-24 |
GB2109375A (en) | 1983-06-02 |
JPH08188574A (en) | 1996-07-23 |
GB2161158B (en) | 1986-07-30 |
JPH069576A (en) | 1994-01-18 |
GB8515932D0 (en) | 1985-07-24 |
GB2161805B (en) | 1986-07-30 |
DE3241134A1 (en) | 1983-05-19 |
CH658246A5 (en) | 1986-10-31 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUE | Assignment |
Owner name: MALLINCKRODT VETERINARY, INC. |
|
PL | Patent ceased |