DE3220898A1 - Process for the preparation of pyrimidinones and their acid addition salts - Google Patents
Process for the preparation of pyrimidinones and their acid addition saltsInfo
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- DE3220898A1 DE3220898A1 DE19823220898 DE3220898A DE3220898A1 DE 3220898 A1 DE3220898 A1 DE 3220898A1 DE 19823220898 DE19823220898 DE 19823220898 DE 3220898 A DE3220898 A DE 3220898A DE 3220898 A1 DE3220898 A1 DE 3220898A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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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
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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Abstract
Description
Verfahren zur Herstellung von Pyrimidinonen Process for the preparation of pyrimidinones
und ihren Säureadditionssalzen In der europäischen Anmeldung 81 108 623.0 werden neue Pyrimidinone der allgemeinen Formel und deren Säureadditionssalze, insbesondere deren plhysiologisch verträgliche Säureadditionssalze mit anorganischen und organischen Säuren, sowie Verfahren zu ihrer Herstellung beschrieben.and their acid addition salts. In the European application 81 108 623.0, new pyrimidinones of the general formula and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic and organic acids, and processes for their preparation are described.
Diese Verbindungen weisen wertvolle pharmakologische Eigenschaften auf, insbesondere eine blutdrucksenkende, antiarrhythmische und ß-Rezeptoren-blockierende Wirkung.These compounds have valuable pharmacological properties on, especially an antihypertensive, anti-arrhythmic and ß-receptor-blocking one Effect.
In der obigen allgemeinen Formel I bedeutet A und B zusammen mit den beiden dazwischenliegenden Kohlenstoffatomen einen Pyridinring oder einen Phenylring, der durch die Reste R1 und/oder R2 substituiert sein kann, wobei R1 ein Halogenatom, eine Amino- oder Nitrogruppe, eine Alkyl-oder Alkoxygruppe mit jeweils 1 bis 3 Kohlenstoffatomen und R2 eine Alkoxygruppe mit 1 bis 3 Kohlenstoffatomen darstellen, D eine gegebenenfalls durch eine Hydroxygruppe substituierte Alkylengruppe mit 3 oder 4 Kohlenstoffatomen, R3 und R5, die gleich oder verschieden sein können, je ein Wasserstoffatom oder eine Alkylgruppe mit 1 bis 3 Kohlen-, stoffatomen, R4 ein Wasserstoffatom oder eine Alkoxygruppe mit 1 bis 3 Kohlenstoffatomen und R6 eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 6 Kohlenstoffatomen oder eine gegebenenfalls durch eine Hydroxygruppe substituierte geradkettige gesättigte Alkylen gruppe mit 2 bis 4 Kohlenstoffatomen, welche endständig durch eine Phenyl- oder Phenoxygruppe substituiert ist, wobei der Phenylkern jeweils durch Alkyl- und/oder Alkoxygruppen mit jeweils 1 bis 3 Kohlenstoffatomen mono- oder disubstituiert sein kann.In the above general formula I, A and B together with the two intervening carbon atoms a pyridine ring or a phenyl ring, which can be substituted by the radicals R1 and / or R2, where R1 a halogen atom, an amino or nitro group, an alkyl or alkoxy group with in each case 1 to 3 carbon atoms and R2 is an alkoxy group having 1 to 3 carbon atoms represent, D an alkylene group optionally substituted by a hydroxyl group with 3 or 4 carbon atoms, R3 and R5, which can be the same or different, each a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R4 represents a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms and R6 a straight or branched chain alkyl group having 1 to 6 carbon atoms or a straight-chain saturated one optionally substituted by a hydroxyl group Alkylene group with 2 to 4 carbon atoms, which is terminated by a phenyl or phenoxy group, the phenyl nucleus in each case by alkyl and / or Alkoxy groups each having 1 to 3 carbon atoms can be mono- or disubstituted can.
Für die bei der Definition der Reste A, B, D, R3, R4, R5 und R6 eingangs erwähnten Bedeutungen kommen beispielsweise für A und B zusammen mit den beiden dazwischenliegenden Kohlenstoffatomen die des Pyridin-, Phenyl-, Chlorphenyl-, Bromphenyl-, Fluorphenyl-, Aminophenyl-, Nitrophenyl-, Methoxyphenyl-, thoxyphenyl-, Propoxyphenyl-, Isopropoxyphenyl-, Dimethoxyphenyl-, Diäthoxyphenyl-, Methoxy-äthoxyphenyl-, Methoxypropoxyphenyl-, Äthoxy-isopropoxyphenyl-, Methoxy-chlorphenyl-, Athoxy-bromphenyl- oder Isopropoxy-fluorphenylringes, für D die der n-Propylen-' n-Butylen-, 2-Hydroxy-n-propylen-, 2-Hydroxy-n-butylen- oder 3-Hydroxy-n-butylengruppe, für R3 und R5 jeweils die eines Wasserstoffatoms, der Methyl-, Äthyl-, Propyl- oder Isopropylgruppe, für R4 die eines Wasserstoffatoms, der Methoxy-, Äthoxy-, Propoxy-oder Isopropoxygruppe, für R6 die der Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, tert.Butyl-, Pentyl-, Neopentyl-, tert.Pentyl-, Hexyl-, 2-Phenyläthyl-, 3-Phenylpropyl-, 4-Phenylbutyl-, 2-Hydroxy-3-phenylpropyl-, 2-Hydroxy-4-phenylbutyl-, 3-Hydroxy-4-phenyl-butyl-, 2-(Methoxyphenyl)-äthyl-, 3-(Methoxyphenyl)-propyl-, 4-(Methoxyphenyl)-butyl-, 2-Hydroxy-3-(methoxyphenyl) -propyl-, 2- (Äthoxyphenyl) -äthyl-, 3-(Isopropoxyphenyl)-propyl-, 2-(Dimethoxyphenyl)-äthyl-, 3-(Dimethoxyphenyl)-propyl-, 2-Hydroxy-3- (dimethoxyphenyl) -propyl-, 2- (Methylphenyl)-äthyl-, 2-(Isopropylphenyl)-äthyl-, 3-(Methylpheny)-propyl-, 2-Hydroxy-3-(methylphenyl)-propyl-, 4-(Methylphenyl)-butyl-, 2-(Dimethylphenyl)-äthyl-, 3-(Dimethylphenyl)-propyl-, 2-Hydroxy-3- (dimethylphenyl) -propyl-, 2-Phenoxyäthyl-, 3-Phenoxypropyl-, 4-Phenoxybutyl-, 2-Hydroxy-3-phenoxypropyl-, 2-Hydroxy-4-phenoxybutyl-, 3-Hydroxy-4-phenoxybutyl-, 2-(Methoxyphenoxy)-äthyl-, 3-(Methoxyphenoxy)-propyl-, 4-(Methoxyphenoxy)-butyl-, 2- (Äthoxyphenoxy) -äthyl-, 3-(Isopropoxyphenoxy)-propyl-, 2-(Dimethoxyphenoxy)-äthyl-, 3-(Dimethoxyphenoxy) -propyl-, 2-Hydroxy-3-(dimethoxyphenoxy)-propyl-, 2-Hydroxy-4-(dimethoxyphenoxy)-butyl-, 2-(Methylphenoxy)-äthyl-, 2-(Isopropylphenoxy)-äthyl-, 3-(Methylphenoxy)-propyl-, 2-Hydroxy-3-(methylphenoxy)-propyl-, 4-(Methylphenoxy)-butyl-, 2-(Dimethylphenoxy)-äthyl-, 3-(Dimethylphenoxy)-propyl-, 2-Hydroxy-3-(dimethylphenoxy)-propyl-, 2-(Methylmethoxyphenyl)-äthyl-, 3-(Methyl-methoxyphenyl)-propyl-, 2-Hydroxy-3-(methyl-methoxyphenyl)-propyl-, 4-(Methyl-methoxyphenyl)-butyl-, 2-(Methyl-äthoxyphenyl)-äthyl-, 3-(Äthyläthoxyphenyl)-propyl-, 2-Hydroxy-3-(methyl-propoxyphenyl)-propyl-, 2- 2-(Methyl-methoxyphenoxy)-äthyl-, 3-(Methyl-methoxyphenoxy)-propyl-, 2-Hydroxy-3-(methyl-methoxyphenoxy)-propyl -, 4-(Methyl-methoxyphenoxy)-butyl-, 2-(Isopropyl-methoxyphenoxy)-äthyl-, 2-Hydroxy-3- (methyl-isopropoxyphenoxy) -propyl- oder 2-Hydroxy-3- (isopropyl-isopropoxyphenoxy) -pro,-pylgruppe in Betracht.For the definition of the radicals A, B, D, R3, R4, R5 and R6 at the beginning mentioned meanings come for example for A and B together with the two intermediate carbon atoms those of pyridine, phenyl, chlorophenyl, bromophenyl, Fluorophenyl, aminophenyl, nitrophenyl, methoxyphenyl, thoxyphenyl, propoxyphenyl, Isopropoxyphenyl, dimethoxyphenyl, diethoxyphenyl, methoxy-ethoxyphenyl, methoxypropoxyphenyl, Ethoxy-isopropoxyphenyl, methoxy-chlorophenyl, ethoxy-bromophenyl or isopropoxy-fluorophenyl ring, for D the n-propylene- 'n-butylene-, 2-hydroxy-n-propylene-, 2-hydroxy-n-butylene- or 3-hydroxy-n-butylene group, for R3 and R5 each have one Hydrogen atom, the methyl, ethyl, propyl or isopropyl group, for R4 the a hydrogen atom, the methoxy, ethoxy, propoxy or isopropoxy group, for R6 that of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl, neopentyl, tert-pentyl, hexyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-hydroxy-3-phenylpropyl-, 2-hydroxy-4-phenylbutyl-, 3-hydroxy-4-phenyl-butyl-, 2- (methoxyphenyl) ethyl, 3- (methoxyphenyl) propyl, 4- (methoxyphenyl) butyl, 2-hydroxy-3- (methoxyphenyl) -propyl-, 2- (ethoxyphenyl) -ethyl-, 3- (isopropoxyphenyl) -propyl-, 2- (dimethoxyphenyl) -ethyl-, 3- (dimethoxyphenyl) propyl, 2-hydroxy-3- (dimethoxyphenyl) propyl, 2- (methylphenyl) ethyl, 2- (isopropylphenyl) ethyl, 3- (methylpheny) propyl, 2-hydroxy-3- (methylphenyl) propyl, 4- (methylphenyl) -butyl-, 2- (dimethylphenyl) -ethyl-, 3- (dimethylphenyl) -propyl-, 2-hydroxy-3- (dimethylphenyl) propyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 2-hydroxy-3-phenoxypropyl-, 2-hydroxy-4-phenoxybutyl-, 3-hydroxy-4-phenoxybutyl-, 2- (methoxyphenoxy) -ethyl-, 3- (methoxyphenoxy) -propyl-, 4- (methoxyphenoxy) -butyl-, 2- (ethoxyphenoxy) -ethyl-, 3- (isopropoxyphenoxy) -propyl-, 2- (dimethoxyphenoxy) -ethyl-, 3- (dimethoxyphenoxy) propyl, 2-hydroxy-3- (dimethoxyphenoxy) propyl, 2-hydroxy-4- (dimethoxyphenoxy) butyl, 2- (methylphenoxy) ethyl, 2- (isopropylphenoxy) ethyl, 3- (methylphenoxy) propyl, 2-hydroxy-3- (methylphenoxy) propyl, 4- (methylphenoxy) butyl, 2- (dimethylphenoxy) ethyl, 3- (dimethylphenoxy) propyl, 2-hydroxy-3- (dimethylphenoxy) propyl, 2- (methylmethoxyphenyl) ethyl, 3- (methyl-methoxyphenyl) -propyl-, 2-hydroxy-3- (methyl-methoxyphenyl) -propyl-, 4- (methyl-methoxyphenyl) -butyl-, 2- (Methyl-ethoxyphenyl) -äthyl-, 3- (Ethyläthoxyphenyl) -propyl-, 2-Hydroxy-3- (methyl-propoxyphenyl) -propyl-, 2- 2- (methyl-methoxyphenoxy) -ethyl-, 3- (methyl-methoxyphenoxy) -propyl-, 2-hydroxy-3- (methyl-methoxyphenoxy) -propyl -, 4- (methyl-methoxyphenoxy) -butyl-, 2- (isopropyl-methoxyphenoxy) -ethyl-, 2-hydroxy-3- (methyl-isopropoxyphenoxy) -propyl- or 2-hydroxy-3- (isopropyl-isopropoxyphenoxy) -pro, -pyl group into consideration.
Bevorzugte Verbindungen der obigen allgemeinen Formel I sind jedoch diejenigen, in denen A und B zusammen mit den beiden dazwischenliegenden Kohlenstoffatomen, einen Pyridinring oder einen Phenylring, der durch die Reste R1 und/oder R2 substituiert sein kann, wobei R1 ein Chloratom, eine Methyl-, Methoxy- oder Nitrogruppe und R2 eine Methoxygruppe darstellen, D eine n-Propylen-, n-Butylen-, 2-Hydroxy-n-prQpylen-, 2-Hydroxy-n-butylen- oder 3-Hydroxy-n-butylengruppe, R3 und R5, die gleich oder verschieden sein können, je eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen oder ein Wasserstoffatom, R4 ein Wasserstoffatom oder die Methoxygruppe und R6 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine in 2-Stellung durch eine Methoxyphenyl-, Dimethoxyphenyl-, Methylphenoxy- oder Methoxyphenoxygruppe substituierte Athylgruppe oder eine in 3-Stellung durch eine Methoxyphenoxy- oder Methylphenoxygruppe substituierte 2-Hydroxypropylgruppe bedeuten, und deren physiologisch verträgliche Säureadditionssalze.Preferred compounds of the above general formula I, however, are those in which A and B together with the two intervening carbon atoms, a pyridine ring or a phenyl ring which is substituted by the radicals R1 and / or R2 can be, where R1 is a chlorine atom, a methyl, methoxy or nitro group and R2 represent a methoxy group, D an n-propylene, n-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group, R3 and R5 which are the same or can be different, each an alkyl group with 1 to 3 carbon atoms or is a hydrogen atom, R4 is a hydrogen atom or the methoxy group and R6 is an alkyl group with 1 to 4 carbon atoms, one in the 2-position by a methoxyphenyl, dimethoxyphenyl, Methylphenoxy or methoxyphenoxy group substituted ethyl group or an in 3-position 2-hydroxypropyl group substituted by a methoxyphenoxy or methylphenoxy group mean, and their physiologically acceptable acid addition salts.
Besonders bevorzugte Verbindungen der obigen allgemeinen Formel I sind jedoch diejenigen, in denen A und B zusammen mit den beiden dazwischenliegenden Kohlenstoffatomen einen Phenyl-, Methoxyphenyl-, Dimethoxyphenyl- oder Pyridinring, D die n-Propylen- oder 2-Hydroxy-n-propylengruppe, R3 ein Wasserstoffatom oder die Methylgruppe, R4 ein Wasserstoffatom oder die Methoxygruppe, R5 ein Wasserstoffatom oder eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen und R6 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine in 2-Stellung durch eine Methoxyphenyl-, Dimethoxyphenyl-, Methylphenoxy- oder Methoxyphenoxygruppe substituierte Äthylgruppe oder eine in 3-Stellung durch eine Methoxyphenoxy- oder Methylphenoxygruppe substituierte 2-Hydroxypropylgruppe bedeuten, insbesondere die Verbindungen der allgemeinen Formel in der R1 in 6- oder 8-Stellung eine Methoxygruppe, R2 ein Wasserstoffatom oder in 7-Stellung eine Methoxygruppe und R5 und R6 zusammen mit dem dazwischenliegenden Stickstoffatom eine Isopropylamino-, tert.Butylamino-, N-Methyl-2-(3,4-dimethoxy-phenyl)-äthylamino-, 2- (2-Methoxyphenyl) -äthylamino-, 2- (2-Methylphenoxy) -äthylamino- oder 2-(4-Methoxyphenoxy)-äthylaminogruppe bedeuten, und deren physiologisch verträgliche Säureadditionssalze mit anorganischen oder organischen Säuren.Particularly preferred compounds of the above general formula I, however, are those in which A and B together with the two intervening carbon atoms form a phenyl, methoxyphenyl, dimethoxyphenyl or pyridine ring, D the n-propylene or 2-hydroxy-n-propylene group, R3 is a hydrogen atom or the methyl group, R4 is a hydrogen atom or the methoxy group, R5 is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms and R6 is an alkyl group with 1 to 4 carbon atoms, one in the 2-position by a methoxyphenyl, dimethoxyphenyl, methylphenoxy or methoxyphenoxy group-substituted ethyl group or a 2-hydroxypropyl group substituted in the 3-position by a methoxyphenoxy or methylphenoxy group, in particular the compounds of the general formula in R1 in the 6- or 8-position a methoxy group, R2 a hydrogen atom or in the 7-position a methoxy group and R5 and R6 together with the intermediate nitrogen atom an isopropylamino, tert-butylamino, N-methyl-2- (3, 4-dimethoxyphenyl) ethylamino, 2- (2-methoxyphenyl) ethylamino, 2- (2-methylphenoxy) ethylamino or 2- (4-methoxyphenoxy) ethylamino group, and their physiologically acceptable acid addition salts with inorganic ones or organic acids.
Es wurde nun gefunden, daß di neuen Verbindungen erfindungsgemäß auch nach folgenden Verfahren hergestellt werden können: a) Durch Umsetzung eines Hydroxyphenylderivates der allgemeinen Formel in der R3, R4, A und B wie eingangs definiert sind, mit einer Verbindung der allgemeinen Formel in der R5, R6 und D wie eingangs definiert sind und X eine nukleophil austauschbare Gruppe wie ein Halogenatom oder X zusammen mit einem ß-ständigen Wasserstoffatom des Restes D ein Sauerstoffatom darstellt, wobei R5 einen Schutzrest für eine Aminogruppe darstellen und/oder D eine durch einen Schutzrest geschützte Hydroxygruppe enthalten-kann.It has now been found that the new compounds can also be prepared according to the invention by the following processes: a) By reacting a hydroxyphenyl derivative of the general formula in which R3, R4, A and B are as defined at the outset, with a compound of the general formula in which R5, R6 and D are as defined at the outset and X represents a nucleophilically exchangeable group such as a halogen atom or X together with a β-hydrogen atom of the radical D represents an oxygen atom, where R5 represents a protective radical for an amino group and / or D represents a through may contain a protective radical protected hydroxyl group.
Die Umsetzung erfolgt gegebenenfalls in einem Lösungsmittel, z.B. in äthanol, Isopropanol, Tetrahydrofuran, Toluol, Dimethylformamid oder Dimethylsulfoxid, vorzugsweise in Gegenwart eines säurebindenden Mittels, z.B. eines Alkoholats oder Alkalicarbonats wie Kalium-tert.butylat oder Kaliumkarbonat, und gegebenenfalls in einem Druckgefäß bei Temperaturen zwischen 50 und 2000C, vorzugsweise jedoch bei Temperaturen zwischen 70 und 1500C. Die Umsetzung kann jedoch auch ohne Lösungsmittel durchgeführt werden.The reaction is optionally carried out in a solvent, e.g. in ethanol, isopropanol, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide, preferably in the presence of an acid-binding agent such as an alcoholate or Alkali carbonate such as potassium tert-butoxide or potassium carbonate, and optionally in a pressure vessel at temperatures between 50 and 2000C, but preferably at temperatures between 70 and 1500C. However, the implementation can can also be carried out without a solvent.
Ein gegebenenfalls als Schutzrest verwendeter Acylrest wird anschließend hydrolytisch in Gegenwart einer Säure oder Base, vorzu.gsweise jedoch in Gegenwart einer Base wie Natronlauge, bei Temperaturen bis zur Siedetemperatur des verwendeten Lösungsmittels oder Lösungsmittelgemisches und ein gegebenenfalls als Schutzrest verwendeter Benzylrest wird anschließend hydrogenolytisch, vorzugsweise mit Wasserstoff in Gegenwart von Palladium/Kohle oder Platin, bei Temperaturen zwischen 0 und 500C abgespalten. An acyl radical, optionally used as a protective radical, is then used hydrolytically in the presence of an acid or base, but preferably in the presence a base such as sodium hydroxide solution, at temperatures up to the boiling point of the one used Solvent or solvent mixture and optionally as a protective radical the benzyl radical used is then hydrogenolytically, preferably with hydrogen in the presence of palladium / carbon or platinum, at temperatures between 0 and 500C cleaved.
b) Dehydrierung einer Verbindung der allgemeinen Formel in der R3 bis R6, A, B und D wie eingangs definiert sind.b) dehydrogenation of a compound of the general formula in which R3 to R6, A, B and D are as defined at the outset.
Die Dehydrierung wird mit einem Dehydrierungsmittel wie Schwefel, Selendioxid, Selen, Perbenzoesäure, Kupfer-Chromoxyd, Natriumborhydrid, mit einem Chinon wie o-Chloranil, 1,4-Benzochinon oder 2,3-Dichlor-5,6-dicyan-1,4-benzochinon, oder einem Hydrierungskatalysator wie Palladium, Raney-Nickel, Nickel-Kobalt oder Platin in der Schmelze oder in einem geeigneten Lösungsmittel oder Lösungsmittelgemisch wie Benzol, Toluol, Nitrobenzol, Dimethylsulfoxid oder Tetrachloräthan und je nach dem verwendeten Dehydrierungsmittei bei Temperaturen zwischen 0 und 2000C durchgeführt. So wird beispielsweise die Dehydrierung mit Schwefel vorzugsweise in der Schmelze bei Temperaturen zwischen 140-180°C und mit o-Chloranil bei Temperaturen zwischen 20 und 50°C durchgeführt.Dehydration is done with a dehydrating agent such as sulfur, Selenium dioxide, selenium, perbenzoic acid, copper chromium oxide, sodium borohydride, with one Quinone such as o-chloranil, 1,4-benzoquinone or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or a hydrogenation catalyst such as palladium, Raney nickel, nickel-cobalt or Platinum in the melt or in a suitable solvent or solvent mixture such as benzene, toluene, nitrobenzene, dimethyl sulfoxide or tetrachloroethane and depending on the dehydrating agent used at temperatures between 0 and 2000C carried out. For example, sulfur dehydration is preferred in the melt at temperatures between 140-180 ° C and with o-chloranil at temperatures carried out between 20 and 50 ° C.
Die erfindungsgemäß erhaltenen neuen Verbindungen lassen sich anschließend gewünschtenfalls in ihre Säureadditionssalze, insbesondere in ihre physiologisch verträglichen Salze mit anorganischen und organischen Säuren, überführen. Als Säuren kommen beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Milchsäure, Zitronensäure, Weinsäure, Oxalsäure oder Maleinsäure in Betracht.The new compounds obtained according to the invention can then be if desired in their acid addition salts, especially in their physiological compatible salts with inorganic and organic acids. As acids for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Lactic acid, citric acid, tartaric acid, oxalic acid or maleic acid can be considered.
Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formeln II bis IV erhält man nach literaturbekannten Verfahren bzw. sind literaturbekannt. So erhält man beispielsweise eine Verbindung der allgemeinen Formel II durch Umsetzung (siehe beispielsweise J. chem. Soc. 1972, 709; DE-OS 2 114 884 und Syn. Comm. 10, 241-243 (1980)) eines entsprechenden Oxazins der allgemeinen Formel mit einem entsprechenden Amin der allgemeinen Formel R3 - NH2 ,(VI) anschließender Abspaltung des Acetylrestes.The compounds of the general formulas II to IV used as starting materials are obtained by processes known from the literature or are known from the literature. For example, a compound of the general formula II is obtained by reaction (see, for example, J. chem. Soc. 1972, 709; DE-OS 2 114 884 and Syn. Comm. 10, 241-243 (1980)) of a corresponding oxazine of the general formula with a corresponding amine of the general formula R3 - NH2, (VI) subsequent cleavage of the acetyl radical.
Eine als Ausgangsstoff verwendete Verbindung der allgemeinen Formel IV erhält man beispielsweise durch Umsetzung eines entsprechenden Amids der allgemeinen Formel mit einem entsprechenden Aldehyd der allgemeinen Formel in Gegenwart einer Base (siehe US-PS 3.265.697).A compound of the general formula IV used as a starting material is obtained, for example, by reacting a corresponding amide of the general formula with a corresponding aldehyde of the general formula in the presence of a base (see U.S. Patent 3,265,697).
Wie bereits eingangs erwähnt, weisen die neuen Verbindungen der allgemeinen Formel I sowie deren physiologisch verträgliche Säureadditionssalze mit anorganischen und organischen Säuren wertvolle pharmakologische Eigenschaften auf, insbesondere eine blutdrucksenkende, antiarrhythmische und ß-rezeptorenblJckierende Wirkung.As already mentioned at the beginning, the new compounds have the general Formula I and their physiologically acceptable acid addition salts with inorganic and organic acids have valuable pharmacological properties, in particular a blood pressure lowering, antiarrhythmic and ß-receptor blocking effect.
Die nachfolgenden Beispiele sollen die Erfindung näher erläutern: Beispiel 1 2-[4-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on 0,52 g (1,8 mMol) 2-(4-Hydroxyphenyl)-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on werden in 50 ml Äthanol mit 2,2 ml 2n Natronlauge (2 indol + 10 %) mit 1,4 g (8 mMol) 2-Chlor-3-tert.butylamino-2-propanol (hergestellt analog M. Dubes et al.The following examples are intended to explain the invention in more detail: example 1 2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) -phenyl] -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one 0.52 g (1.8 mmol) of 2- (4-hydroxyphenyl) -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one are in 50 ml of ethanol with 2.2 ml of 2N sodium hydroxide solution (2 indole + 10%) with 1.4 g (8 mmol) 2-chloro-3-tert-butylamino-2-propanol (prepared analogously to M. Dubes et al.
J. Med. chem. 14, 328 (1971)) 10 Stunden am Rückfluß gekocht.J. Med. Chem. 14, 328 (1971)) refluxed for 10 hours.
Anschließend wird zur Trockene eingedampft, der erhaltene Rückstand in Wasser aufgenommen und mit Methylenchlorid ausgeschüttelt. Die vereinten organischen Extrakte werden mit 2n Natronlauge und mit Wasser gewaschen, anschließend über Natriumsulfat getrocknet und eingedampft.The residue obtained is then evaporated to dryness taken up in water and extracted with methylene chloride. The united organic Extracts are washed with 2N sodium hydroxide solution and with water, then over sodium sulfate dried and evaporated.
Ausbeute: 210 mg (27,6 % der Theorie), Schmelzpunkt: 154-1560C (Aceton) C23H29N304 Ber.: C 67,13 H 7,10 N 10,21 Gef.: 67,06 7,08 10,16 Beispiel 2 2-[4-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-3, 4-dihydro-chinazolin-4-on 2,06 g (5 mMol) 2-[4-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-1,2,3,4-tetrahydro-chinazolin-4-on werden mit 180 mg (5 mMol + 10 %) Schwefel bei 170°C zur Reation belassen. Nach 3 Stunden ist die Umsetzung beendet und das erhaltene Rohprodukt wird über eine Kieselgelsäule (Korngröße: 0,2-0,5 mm; Elutionsmittel: Methylenchlorid:Methanol = 19:1, 9:1) gereinigt. Das nach dem Eindampfen resultierende farblose öl wird aus Aceton kristallisiert.Yield: 210 mg (27.6% of theory), melting point: 154-1560C (acetone) C23H29N304 Calc .: C 67.13 H 7.10 N 10.21 Found: 67.06 7.08 10.16 Example 2 2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) -phenyl] - 3-methyl-6-methoxy-3, 4-dihydro-quinazolin-4-one 2.06 g (5 mmol) 2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) -phenyl] -3-methyl-6-methoxy-1,2,3 , 4-tetrahydro-quinazolin-4-one are left with 180 mg (5 mmol + 10%) sulfur at 170 ° C for reaction. To 3 hours, the reaction has ended and the crude product obtained is over a Silica gel column (particle size: 0.2-0.5 mm; eluent: methylene chloride: methanol = 19: 1, 9: 1) cleaned. The colorless oil resulting after evaporation turns out Acetone crystallizes.
Ausbeute: 462 mg (23 % der Theorie), Schmelzpunkt: 158-1 600C C23 H 29N304 Ber.: C 67,13 H 7,10 N 10,21 Gef.: 67,10 7,08 10,09 Analog werden folgende Verbindungen erhalten: 2-[4-(3-Diäthylamino-propoxy)-phenyl]-3-methyl-3,4-dihydrochinazolin-4-on-hydrojodid Schmelzpunkt: 218-2220C 2-[4-(3-tert.Butylamino-propoxy)-phenyl]-8-methoxy-3,4-dihydrochinazolin-4-on Schmelzpunkt des Dihydrochlorids: 133-1350C 2-[4-(3-tert.Butylamino-propoxy)-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Hydrochlorids: 283-286°C 2-[4-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl]-3-methyl-6-nitro-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 267-270°C (Aceton/Äther) 2-[4-[4-(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-butoxy]-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Hydrochlorids: 105-107°C 2-[4-(2-Hydroxy-3-(2-3,4-dimethoxyphenyl)-N-methyl-äthylamino)-propoxy]-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Dihydrochlorids: 152-1550C 2-[4-[3-(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-propoxy]-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 134-136°C 2-[4-(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl]-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 189-191°C 2-[4-(2-Hydroxy-3-(2-(2-methoxyphenyl)-äthylamino)-propoxy]-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Dihydrochlorids: 156-158°C 2-[4-(2-Hydroxy-3-diäthylamino-propoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 123-125°C (Aceton/Äther) 2-[4-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl]-6-methoxy-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 130-132°C 2-[4-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl]-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 198-201°C 2-[4-[2-Hydroxy-3-(2-(2-methoxyphenyl)-äthylamino)-propoxy]-phenyl]-3-methyl-8-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Dihydrochlorids: 120-123°C 2-[4-(2-Hydroxy-3-diäthylamino-propoxy)-phenyl]-3-methyl-8-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Dihydrochlorids: 127-130°C 2-[4-(2-Hydroxy-3-(2-(2-methylphenoxy)-äthylamino)-propoxy]-phenyl]-3-methyl-8-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Hydrochlorids: 122-125°C 2-[4-[3-(2-Hydroxy-3-(3-methylphenoxy)-propylamino)-propoxy]-phenyl]-3-methyl-8-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 138-140°C 2-[4-[2-Hydroxy-3-(2-(2-methoxyphenyl)-äthylamino)-propoxy]-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Trihydrochlorids: 188-192°C 2-[4-[2-Hydroxy-3-(2-(2-methylphenoxy)-äthylamino)-propoxy]-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 195-198°C 2-[4-[3-(2-Hydroxy-3-(3-methylphenoxy)-propylamino)-propoxy]-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Hydrochlorids: 222°C 2-[3-Methoxy-4-(2-hydroxy-3-tert.butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 102-105°C (Aceton/Äther) 2-[4-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl]-3,6-dimethyl-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 146-150°C (Aceton/Äther) 2-[4-(2-Hydroxy-3-isopropylaminopropoxy)-phenyl]-3,6-dimethyl-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 150-153°C (Aceton/Äther) 2-[4-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl]-3-methyl-6-chlor-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 166-168°C (Aceton/Äther) 2-[4-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl]-3-methyl-3,4-dihydro-pyrido[2,3-e]pyrimidin-4-on Schmelzpunkt des Dihydrochlorids: 142-145°C 2-R-(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl/-3-methyl-3,4-dihydro-pyrido[2,3-e]pyrimidin-4-on Schmelzpunkt des Dihydrochlorids: 168-171°C 2-[4-[2-Hydroxy-3-(2-(4-methoxy-phenoxy)-äthylamino)-propoxy]-phenyl]-3-methyl-3,4-dihydro-pyrido[2,3-e]pyrimidin-4-on Schmelzpunkt: 132-135°C 2-[4-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl]-3-methyl-3,4-dihydro-pyrido/3,4-e/pyrimidin-4-on 0 Schmelzpunkt des Dihydrochlorids: 122-125 C 2-[4-(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl]-3-methyl-3,4-dihydro-pyrido[2,3-e]pyrimidin-4-on Schmelzpunkt des Dihydrochlorids: 171-173°C 2-[4-[3-(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino-propoxy]-phenyl]-8-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt des Dihydrochlorids: 190-193°C 2-[4-(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl]-3-isopropyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzpunkt: 145-147°C 2-[4-(2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)-N-propyl-äthylamino)-propoxy]-phenyl]-3-methyl-6-methoxy-3,4-dihydro-chinazolin-4-on Schmelzbereich: 112-1170C.Yield: 462 mg (23% of theory), melting point: 158-160 ° C. C23 H 29N304 Calc .: C 67.13 H 7.10 N 10.21 Found: 67.10 7.08 10.09 The following are analogous Compounds obtained: 2- [4- (3-Diethylamino-propoxy) -phenyl] -3-methyl-3,4-dihydroquinazolin-4-one-hydroiodide Melting point: 218-2220C 2- [4- (3-tert-butylamino-propoxy) -phenyl] -8-methoxy-3,4-dihydroquinazolin-4-one Melting point of the dihydrochloride: 133-1350C 2- [4- (3-tert-butylamino-propoxy) -phenyl] -3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one Melting point of the hydrochloride: 283-286 ° C 2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) -phenyl] -3-methyl-6-nitro-3,4-dihydro-quinazolin-4-one Melting point: 267-270 ° C (acetone / ether) 2- [4- [4- (2-Hydroxy-3- (4-methoxyphenoxy) -propylamino) -butoxy] -phenyl] -3-methyl-6-methoxy- 3,4-dihydro-quinazolin-4-one Melting point of the hydrochloride: 105-107 ° C 2- [4- (2-Hydroxy-3- (2-3,4-dimethoxyphenyl) -N-methyl-ethylamino) -propoxy] -phenyl] -3-methyl-6- methoxy-3,4-dihydro-quinazolin-4-one Melting point of the dihydrochloride: 152-1550C 2- [4- [3- (2-Hydroxy-3- (4-methoxyphenoxy) propylamino) propoxy] phenyl] -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 134-136 ° C 2- [4- (2-Hydroxy-3-tert-butylamino-propoxy) -phenyl] -6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 189-191 ° C 2- [4- (2-Hydroxy-3- (2- (2-methoxyphenyl) -ethylamino) -propoxy] -phenyl] -3-methyl-6-methoxy-3,4-dihydro -quinazolin-4-one Melting point of the dihydrochloride: 156-158 ° C. 2- [4- (2-Hydroxy-3-diethylamino-propoxy) -phenyl] -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 123-125 ° C (acetone / ether) 2- [4- (2-Hydroxy-3-isopropylamino-propoxy) -phenyl] -6-methoxy-6-methoxy-3,4-dihydro-quinazoline-4- on Melting point: 130-132 ° C 2- [4- (2-Hydroxy-3-isopropylamino-propoxy) -phenyl] -6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 198-201 ° C 2- [4- [2-Hydroxy-3- (2- (2-methoxyphenyl) -ethylamino) -propoxy] -phenyl] -3-methyl-8-methoxy-3,4-dihydro -quinazolin-4-one Melting point of the dihydrochloride: 120-123 ° C 2- [4- (2-Hydroxy-3-diethylamino-propoxy) -phenyl] -3-methyl-8-methoxy-3,4-dihydro-quinazolin-4-one Melting point of the dihydrochloride: 127-130 ° C 2- [4- (2-Hydroxy-3- (2- (2-methylphenoxy) ethylamino) propoxy] phenyl] -3-methyl-8-methoxy-3,4-dihydro-quinazolin-4-one Melting point of the hydrochloride: 122-125 ° C 2- [4- [3- (2-Hydroxy-3- (3-methylphenoxy) propylamino) propoxy] phenyl] -3-methyl-8-methoxy-3,4 -dihydro-quinazolin-4-one Melting point: 138-140 ° C 2- [4- [2-Hydroxy-3- (2- (2-methoxyphenyl) -ethylamino) -propoxy] -phenyl] -3-methyl-6,7-dimethoxy-3,4 -dihydro-quinazolin-4-one Melting point of the trihydrochloride: 188-192 ° C 2- [4- [2-hydroxy-3- (2- (2-methylphenoxy) ethylamino) propoxy] phenyl] -3-methyl-6,7-dimethoxy-3 , 4-dihydro-quinazolin-4-one Melting point: 195-198 ° C 2- [4- [3- (2-Hydroxy-3- (3-methylphenoxy) propylamino) propoxy] phenyl] -3-methyl-6,7-dimethoxy-3,4 -dihydro-quinazolin-4-one Melting point of the hydrochloride: 222 ° C 2- [3-methoxy-4- (2-hydroxy-3-tert-butylaminopropoxy) -phenyl] -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 102-105 ° C (acetone / ether) 2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) -phenyl] -3,6-dimethyl-3,4-dihydro-quinazolin-4-one Melting point: 146-150 ° C (acetone / ether) 2- [4- (2-Hydroxy-3-isopropylaminopropoxy) phenyl] -3,6-dimethyl-3,4-dihydro-quinazolin-4-one Melting point: 150-153 ° C (acetone / ether) 2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) -phenyl] -3-methyl-6-chloro-3,4-dihydro-quinazoline-4- on Melting point: 166-168 ° C (acetone / ether) 2- [4- (2-Hydroxy-3-isopropylamino-propoxy) -phenyl] -3-methyl-3,4-dihydro-pyrido [2,3-e] pyrimidin-4-one Melting point of the dihydrochloride: 142-145 ° C 2-R- (2-Hydroxy-3-tert-butylamino-propoxy) -phenyl / -3-methyl-3,4-dihydro-pyrido [2,3-e] pyrimidine- 4-on Melting point of the dihydrochloride: 168-171 ° C 2- [4- [2-Hydroxy-3- (2- (4-methoxy-phenoxy) -ethylamino) -propoxy] -phenyl] -3-methyl-3,4-dihydro -pyrido [2,3-e] pyrimidin-4-one Melting point: 132-135 ° C 2- [4- (2-Hydroxy-3-isopropylamino-propoxy) -phenyl] -3-methyl-3,4-dihydro-pyrido / 3,4-e / pyrimidin-4-one 0 Melting point of the dihydrochloride: 122-125 C 2- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -3-methyl-3,4-dihydro-pyrido [2,3-e] pyrimidine -4-on Melting point of the dihydrochloride: 171-173 ° C 2- [4- [3- (2-Hydroxy-3- (4-methoxyphenoxy) -propylamino-propoxy] -phenyl] -8-methoxy-3,4-dihydro-quinazoline- 4-on Melting point of the dihydrochloride: 190-193 ° C 2- [4- (2-Hydroxy-3-tert-butylamino-propoxy) -phenyl] -3-isopropyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 145-147 ° C 2- [4- (2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) -N-propyl-ethylamino) -propoxy] -phenyl] -3-methyl-6-methoxy -3,4-dihydro-quinazolin-4-one Melting range: 112-1170C.
Claims (4)
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19823220898 DE3220898A1 (en) | 1982-06-03 | 1982-06-03 | Process for the preparation of pyrimidinones and their acid addition salts |
FI831914A FI831914L (en) | 1982-06-03 | 1983-05-30 | FRAMEWORK FOR THE FRAMEWORK OF PYRIMIDINONERS AND THEIR SYRAADDITIONSSALT |
KR1019830002442A KR840005107A (en) | 1982-06-03 | 1983-06-01 | Method for preparing pyrimidion and acid addition salts thereof |
DD83251638A DD210904A5 (en) | 1982-06-03 | 1983-06-01 | PROCESS FOR PREPARING PYRIMIDINONES |
ES522898A ES8403115A1 (en) | 1982-06-03 | 1983-06-01 | Process for the preparation of pyrimidinones and their acid addition salts |
PT76806A PT76806B (en) | 1982-06-03 | 1983-06-01 | PROCESS FOR THE PREPARATION OF PYRIMIDINONES AND THEIR SAEUREADDITIONAL SALTS |
CA000429507A CA1217768A (en) | 1982-06-03 | 1983-06-02 | Process for the preparation of pyrimidinones and their acid addition salts |
HU831976A HU190846B (en) | 1982-06-03 | 1983-06-02 | Process for the production derivatives of pyrimidinones and of their acid addition salts |
NO831994A NO831994L (en) | 1982-06-03 | 1983-06-02 | PROCEDURE FOR PREPARATION OF PYRIMIDINON DERIVATIVES |
DK250883A DK250883A (en) | 1982-06-03 | 1983-06-02 | PROCEDURE FOR THE PREPARATION OF PYRIMIDINONES OR THEIR ACID ADDITION SALTS |
ES527906A ES8406450A1 (en) | 1982-06-03 | 1983-12-09 | Process for the preparation of pyrimidinones and their acid addition salts |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19823220898 DE3220898A1 (en) | 1982-06-03 | 1982-06-03 | Process for the preparation of pyrimidinones and their acid addition salts |
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Publication Number | Publication Date |
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DE3220898A1 true DE3220898A1 (en) | 1983-12-08 |
Family
ID=6165198
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DE19823220898 Withdrawn DE3220898A1 (en) | 1982-06-03 | 1982-06-03 | Process for the preparation of pyrimidinones and their acid addition salts |
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KR (1) | KR840005107A (en) |
CA (1) | CA1217768A (en) |
DD (1) | DD210904A5 (en) |
DE (1) | DE3220898A1 (en) |
DK (1) | DK250883A (en) |
ES (2) | ES8403115A1 (en) |
FI (1) | FI831914L (en) |
HU (1) | HU190846B (en) |
NO (1) | NO831994L (en) |
PT (1) | PT76806B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995024379A1 (en) * | 1994-03-09 | 1995-09-14 | Newcastle University Ventures Limited | Benzamide analogs, useful as parp (adp-ribosyltransferase, adprt) dna repair enzyme inhibitors |
EP1558260A2 (en) * | 2002-11-04 | 2005-08-03 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
WO2005115993A1 (en) | 2004-05-31 | 2005-12-08 | Banyu Pharmaceutical Co., Ltd. | Quinazoline derivative |
US7893071B2 (en) * | 2001-04-23 | 2011-02-22 | University Of Virginia Patent Foundation | Synthesis and evaluation of novel phthalimide mimics as anti-angiogenic |
CN101531638B (en) * | 2008-03-13 | 2011-12-28 | 中国科学院广州生物医药与健康研究院 | Compound used as a regulator of estrogen-related receptor and applications thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101628913B (en) | 2008-07-18 | 2013-01-23 | 中国科学院广州生物医药与健康研究院 | Compound as estrogen-related receptor modulator and application thereof |
-
1982
- 1982-06-03 DE DE19823220898 patent/DE3220898A1/en not_active Withdrawn
-
1983
- 1983-05-30 FI FI831914A patent/FI831914L/en not_active Application Discontinuation
- 1983-06-01 DD DD83251638A patent/DD210904A5/en unknown
- 1983-06-01 ES ES522898A patent/ES8403115A1/en not_active Expired
- 1983-06-01 KR KR1019830002442A patent/KR840005107A/en not_active Application Discontinuation
- 1983-06-01 PT PT76806A patent/PT76806B/en unknown
- 1983-06-02 NO NO831994A patent/NO831994L/en unknown
- 1983-06-02 DK DK250883A patent/DK250883A/en not_active Application Discontinuation
- 1983-06-02 CA CA000429507A patent/CA1217768A/en not_active Expired
- 1983-06-02 HU HU831976A patent/HU190846B/en unknown
- 1983-12-09 ES ES527906A patent/ES8406450A1/en not_active Expired
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995024379A1 (en) * | 1994-03-09 | 1995-09-14 | Newcastle University Ventures Limited | Benzamide analogs, useful as parp (adp-ribosyltransferase, adprt) dna repair enzyme inhibitors |
US5756510A (en) * | 1994-03-09 | 1998-05-26 | Newcastle University Ventures Limited | Benzamide analogs useful as PARP (ADP-ribosyltransferase, ADPRT) DNA repair enzyme inhibitors |
US6015827A (en) * | 1994-03-09 | 2000-01-18 | Newcastle University Ventures Limited | Benzoxazole-4-carboxamides and their use in inhibiting poly (adp-ribose) polymerase activity and improving cytotoxic effectiveness of cytotoxic drugs or radiotherapy |
US7893071B2 (en) * | 2001-04-23 | 2011-02-22 | University Of Virginia Patent Foundation | Synthesis and evaluation of novel phthalimide mimics as anti-angiogenic |
EP1558260A2 (en) * | 2002-11-04 | 2005-08-03 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
JP2006512315A (en) * | 2002-11-04 | 2006-04-13 | エヌピーエス ファーマスーティカルズ インコーポレイテッド | Quinazolinone compounds as calcilytics |
EP1558260A4 (en) * | 2002-11-04 | 2006-10-25 | Nps Pharma Inc | Quinazolinone compounds as calcilytics |
WO2005115993A1 (en) | 2004-05-31 | 2005-12-08 | Banyu Pharmaceutical Co., Ltd. | Quinazoline derivative |
US7960394B2 (en) | 2004-05-31 | 2011-06-14 | Banyu Pharmaceutical Co., Ltd. | Quinazoline derivative |
CN101531638B (en) * | 2008-03-13 | 2011-12-28 | 中国科学院广州生物医药与健康研究院 | Compound used as a regulator of estrogen-related receptor and applications thereof |
Also Published As
Publication number | Publication date |
---|---|
DK250883A (en) | 1983-12-04 |
DD210904A5 (en) | 1984-06-27 |
KR840005107A (en) | 1984-11-03 |
DK250883D0 (en) | 1983-06-02 |
FI831914L (en) | 1983-12-04 |
CA1217768A (en) | 1987-02-10 |
ES527906A0 (en) | 1984-08-01 |
ES522898A0 (en) | 1984-03-01 |
FI831914A0 (en) | 1983-05-30 |
NO831994L (en) | 1983-12-05 |
ES8403115A1 (en) | 1984-03-01 |
PT76806A (en) | 1983-07-01 |
HU190846B (en) | 1986-11-28 |
PT76806B (en) | 1986-04-09 |
ES8406450A1 (en) | 1984-08-01 |
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