PL144111B2 - Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides - Google Patents

Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides Download PDF

Info

Publication number
PL144111B2
PL144111B2 PL25374685A PL25374685A PL144111B2 PL 144111 B2 PL144111 B2 PL 144111B2 PL 25374685 A PL25374685 A PL 25374685A PL 25374685 A PL25374685 A PL 25374685A PL 144111 B2 PL144111 B2 PL 144111B2
Authority
PL
Poland
Prior art keywords
hydroxy
methyl
hydroxyethylamino
conhr
general formula
Prior art date
Application number
PL25374685A
Other languages
Polish (pl)
Other versions
PL253746A2 (en
Inventor
Anna Dlugosz
Zdzislaw Machon
Original Assignee
Akad Medyczna
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akad Medyczna filed Critical Akad Medyczna
Priority to PL25374685A priority Critical patent/PL144111B2/en
Publication of PL253746A2 publication Critical patent/PL253746A2/en
Publication of PL144111B2 publication Critical patent/PL144111B2/en

Links

Landscapes

  • Pyridine Compounds (AREA)

Description

Przedmiotem wynalazku jest sposób wytwarzania nowych amidów kwasu 2-hydroksy-4-/$- hydroksyetyloamino-6-metylo-5-pirymidynokarboksylowego o wzorze ogólnym 1, w którym R oznacza reszte p-chlorofenylowa, p-etoksyfenylowa lub cykloheksylowa. Zwiazek wytworzony sposobem wedlug wynalazku jest pólproduktem do wytwarzania zwiazków wykazujacych dziala¬ nie biologiczne.Wedlug wynalazku sposób wytwarzania nowych amidów kwasu 2-hydroksy-4- /3-hydroksy- etyloamino-6-metylo-5-pirymidynokarboksylowego o wzorze ogólnym 1, w którym R oznacza reszte p-chlorofenylowa lub cykloheksylowa lub p-etoksyfenylowa, polega na tym, ze amidy kwasu 2-hydroksy-4-merkapto -6-metylo-5-pirymidynokarboksylowego o wzorze ogólnym 2, w którym R ma wyzej podane znaczenie, ogrzewa sie z etanoloamina w bezwodnej pirydynie.Zwiazek wytworzony sposobem wedlug wynalazku ogrzewany z chlorkiem tionylu w chloro¬ formie prowadzi do otrzymania amidów kwasu 2-hydroksy-4-/3-chloroetyloamino -6-metylo-5- pirymidyno-karboksylowego o wzorze ogólnym 3, w którym R oznacza reszte p-chlorofenylowa, p-etoksyfenylowa lub cykloheksylowa, które nastepnie ogrzewane w tetrahydrofuranie lub pirydy¬ nie daja nowe chlorowodorki kwasu l-H-7-metylo-5- okso-2,3-dihydroimidazo (1,2-c) pirymi- dyno-8-karboksylowego o wzorze ogólnym 4, w którym R ma wyzej podane znaczenie.Zwiazki finalne wykazuja dzialanie przeciwzapalne i przeciwbólowe. Zwiazek o wzorze 4, w którym R jest reszta cykloheksylowa badany byl w szeregu testach na osrodkowyuklad nerwowy i aktywnosc przeciwbólowa na myszach. Oznaczona toksycznosc dootrzewnowa i doustna wynosila odpowiednio 865 i 1294 mg/kg. W tescie na dzialanie przeciwserotoninowe wykazywal aktywnosc jak imipramina, w tescie na antagonizm z rezerpina wykazal 60% dzialania imipraminy, a w tescie na dzialanie przeciwagresyjne znosil agresje u 80% myszy. W tescie goracej plytki i w tescie czolgania wykazal statystycznie istotne dzialanie przeciwbólowe, porównywalne z petydyna, podawany w dawce 0,lLDso.Zwiazki o wzorze 4, w których R jest reszta p-chlorofenylowa i p-etoksyfenylowa badano na aktywnosc przeciwzapalna na modelu ostrego stanu zapalnego u szczura w tescie karageninowym.2 144 111 Preparaty podawano dozoladkowo w dawce 100 mg/kg w zawiesinach w 5% roztworze gumy arabskiej. Jako lek standardowy zastosowano aspiryne w dawce 75 mg/kg. Zwiazek o wzorze 4, gdzie R jest reszta p-chlorofenylowa w czasie czterogodzinnej obserwacji hamowal obrzek w 52,2-56,7%, a zwiazek o wzorze 4, gdzie R jest reszta p-etoksyfenylowa hamowal obrzek w 38,5-43%. Wzorcowa aspiryna hamowala obrzek w 64,2-69,5%.Przedmiot wynalazku jest przedstawiony w trzech przykladach wykonania.Przyklad I. 2g p-chlorofenyloamidu kwasu 2-hydroksy-4- merkapto -6-metylo -5-piry- midynokarboksylowego i 2,1 g etanoloaminy ogrzewa sie w 15 ml suchej pirydyny przez 4 godziny w temperaturze wrzenia. Odsacza sie na goraco 1,2g p-chlorofenyloamidu kwasu 2-hydroksy-4-/3- hydroksyetyloamino-6 -metylo-5-pirymidynokarboksylowego. Zwiazek ma temperature topnienia 338 K i otrzymuje sie go z wydajnoscia równa 52% wydajnosci teoretycznej.Przykladll. 10g p-etoksyfenyloamidu kwasu 2-hydroksy-6- metylo -4-merkapto -5- pirymidynokarboksylowego i 10 g etanoloaminy ogrzewa sie w 100 ml pirydyny przez 6 godzin w temperaturze wrzenia. Odsacza sie na goraco 6g p-etoksyfenyloamidu kwasu 2-hydroksy-4-/J -hydroksyetyloamino-6-metylo-5-pirymidynokarboksylowego. Zwiazek ma temperature topnie¬ nia 338-340 K i jest otrzymywany z wydajnoscia równa 55% wydajnosci teoretycznej.Przyklad III. 2,6g cykloheksyloamidu kwasu 2-hydroksy-4-merkapto -6-metylo-5-piry- midynokarboksylowego ogrzewa sie z 3 g etanoloaminy w 26 ml suchej pirydyny przez 6 godzin.Mieszanine przesacza sie i pozostawia do krystalizacji. Odsacza sie 2,5 g cykloheksyloamidu kwasu 2-hydroksy-4-/3-hydroksyetyloamino-6-metylo -5-pirymidynokarboksylowego. Zwiazek ma tem¬ perature topnienia 504-506 K i jest otrzymywany z wydajnoscia 68% wydajnosci teoretycznej.Zastrzezenie patentowe Sposób wytwarzania nowych amidów kwasu 2-hydroksy-4-/J- hydroksyetyloamino-6-metylo- 5-pirymidynokarboksylowego o wzorze ogólnym 1, w którym R oznacza reszte p-chlorofenylowa, p-etoksyfenylowa lub cykloheksylowa, znamienny tym, ze amidy kwasu 2-hydroksy-4-merkapto -6-metylo-5-pirymidynokarboksylowego o wzorze ogólnym 2, w którym R ma wyzej podane znaczenie, ogrzewa sie z etanoloamina w bezwodnej pirydynie.144111 HN(CH2)20H N<*s!\^C0NHR HO ^ N^ CH3 WZOR1 SH I N-,' ^ CONHR Jk HO/ TT^CHj WZÓR 2144111 N hn(ch4ci ^s^CONHR kJ H0^N/XCH5 WZiDR 3 IJJH HCl CONHR WZÓR 4 Pracownia Poligraficzna UP PRL. Naklad 100 egz.Cena 220 zl PLThe present invention relates to a process for the preparation of new 2-hydroxy-4 - [beta] -hydroxyethylamino-6-methyl-5-pyrimidinecarboxylic acid amides of the general formula I, in which R is a p-chlorophenyl, p-ethoxyphenyl or cyclohexyl residue. The compound according to the invention is an intermediate for the preparation of compounds exhibiting biological activity. According to the invention, a method for the preparation of new 2-hydroxy-4- (3-hydroxy-ethylamino-6-methyl-5-pyrimidine carboxylic acid amides of general formula I) R is a p-chlorophenyl or cyclohexyl or p-ethoxyphenyl residue, it consists in the fact that 2-hydroxy-4-mercapto -6-methyl-5-pyrimidinecarboxylic acid amides of the general formula 2, in which R is as defined above, are heated with ethanolamine in anhydrous pyridine. The compound according to the invention, heated with thionyl chloride in chloroform, gives the 2-hydroxy-4- (3-chloroethylamino-6-methyl-5-pyrimidine-carboxylic acid amides of general formula 3) wherein R is a p-chlorophenyl, p-ethoxyphenyl or cyclohexyl residue which is then heated in tetrahydrofuran or pyridine to give new hydrochlorides of 1H-7-methyl-5-oxo-2,3-dihydroimidazo (1,2-c) pyrim iDine-8-carboxylic acid of general formula IV, wherein R is as defined above. The final compounds have anti-inflammatory and analgesic activity. The compound of formula IV, wherein R is a cyclohexyl residue, has been tested in a series of tests for the CNS and analgesic activity in mice. The determined intraperitoneal and oral toxicity were 865 and 1294 mg / kg, respectively. In the anti-serotonin test, it showed activity like imipramine, in the reserpine antagonism test it showed 60% of imipramine, and in the anti-aggression test it was aggressive in 80% of mice. In the hot plate test and in the traversing test, it showed a statistically significant analgesic effect, comparable to pethidine, administered at a dose of 0.1LD50. Compounds of formula 4 in which R is a p-chlorophenyl and p-ethoxyphenyl residue were tested for anti-inflammatory activity in an acute inflammatory model in rats in the carrageenan test.2 144 111 The preparations were administered per dose at a dose of 100 mg / kg in suspensions in a 5% gum arabic solution. The standard drug used was aspirin at a dose of 75 mg / kg. The compound of formula 4, where R is a p-chlorophenyl residue, inhibited edema in 52.2-56.7% during the four-hour observation, and the compound of formula 4, where R is a p-ethoxyphenyl residue, inhibited edema in 38.5-43% . Standard aspirin inhibited edema in 64.2-69.5%. The subject of the invention is presented in three working examples. Example I. 2 g of p-chlorophenylamide 2-hydroxy-4-mercapto -6-methyl -5-pyrimidinecarboxylic acid and 2 1 g of ethanolamine is heated in 15 ml of dry pyridine for 4 hours under reflux. 1.2 g of 2-hydroxy-4- (3-hydroxyethylamino-6-methyl-5-pyrimidinecarboxylic acid) p-chlorophenylamide is filtered hot. The compound has a melting point of 338 K and is obtained in 52% of the theoretical yield. 10 g of 2-hydroxy-6-methyl-4-mercapto -5-pyrimidinecarboxylic acid p-ethoxyphenylamide and 10 g of ethanolamine are heated in 100 ml of pyridine for 6 hours under reflux. 6 g of 2-hydroxy-4- (J-hydroxyethylamino-6-methyl-5-pyrimidinecarboxylic acid p-ethoxyphenylamide) are filtered hot. The compound has a melting point of 338-340 K and is obtained in 55% of theoretical yield. 2.6 g of 2-hydroxy-4-mercapto -6-methyl-5-pyrimidinecarboxylic acid cyclohexylamide are heated with 3 g of ethanolamine in 26 ml of dry pyridine for 6 hours. The mixture is filtered and left to crystallize. 2.5 g of 2-hydroxy-4- (3-hydroxyethylamino-6-methyl -5-pyrimidinecarboxylic acid cyclohexylamide) are filtered off. The compound has a melting point of 504-506 K and is obtained with a yield of 68% of theoretical yield. Patent claim Method for the preparation of the new 2-hydroxy-4- (J-hydroxyethylamino-6-methyl-5-pyrimidine carboxylic acid amides of the general formula 1) in which R is a p-chlorophenyl, p-ethoxyphenyl or cyclohexyl residue, characterized in that 2-hydroxy-4-mercapto -6-methyl-5-pyrimidinecarboxylic acid amides of the general formula 2, in which R is as defined above, is heated with ethanolamine in anhydrous pyridine. 144 111 HN (CH2) 20H N <* s! \ ^ C0NHR HO ^ N ^ CH3 FORMULA SH I N-, '^ CONHR Jk HO / TT ^ CHj FORM 2144 111 N hn (ch4ch ^ s ^ CONHR kJ H0 ^ N / XCH5 WZiDR 3 IJJH HCl CONHR MODEL 4 Printing workshop of the Polish People's Republic. Circulation 100 copies Price PLN 220 PL

Claims (1)

1. Zastrzezenie patentowe Sposób wytwarzania nowych amidów kwasu 2-hydroksy-4-/J- hydroksyetyloamino-6-metylo- 5-pirymidynokarboksylowego o wzorze ogólnym 1, w którym R oznacza reszte p-chlorofenylowa, p-etoksyfenylowa lub cykloheksylowa, znamienny tym, ze amidy kwasu 2-hydroksy-4-merkapto -6-metylo-5-pirymidynokarboksylowego o wzorze ogólnym 2, w którym R ma wyzej podane znaczenie, ogrzewa sie z etanoloamina w bezwodnej pirydynie.144111 HN(CH2)20H N<*s!\^C0NHR HO ^ N^ CH3 WZOR1 SH I N-,' ^ CONHR Jk HO/ TT^CHj WZÓR 2144111 N hn(ch4ci ^s^CONHR kJ H0^N/XCH5 WZiDR 3 IJJH HCl CONHR WZÓR 4 Pracownia Poligraficzna UP PRL. Naklad 100 egz. Cena 220 zl PLClaim 1. Process for the preparation of new 2-hydroxy-4- (J-hydroxyethylamino-6-methyl-5-pyrimidinecarboxylic acid amides of the general formula I, in which R is a p-chlorophenyl, p-ethoxyphenyl or cyclohexyl residue, characterized by that 2-hydroxy-4-mercapto -6-methyl-5-pyrimidinecarboxylic acid amides of the general formula 2, in which R is as defined above, are heated with ethanolamine in anhydrous pyridine. 144 111 HN (CH2) 20H N <* s! \ ^ C0NHR HO ^ N ^ CH3 PATTERN1 SH I N-, '^ CONHR Jk HO / TT ^ CHj PATTERN 2144111 N hn (ch4ci ^ s ^ CONHR kJ H0 ^ N / XCH5 WZiDR 3 IJJH HCl CONHR PATTERN 4 Printing workshop UP PRL Mintage 100 copies Price PLN 220 PL
PL25374685A 1985-05-30 1985-05-30 Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides PL144111B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL25374685A PL144111B2 (en) 1985-05-30 1985-05-30 Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PL25374685A PL144111B2 (en) 1985-05-30 1985-05-30 Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides

Publications (2)

Publication Number Publication Date
PL253746A2 PL253746A2 (en) 1987-02-23
PL144111B2 true PL144111B2 (en) 1988-04-30

Family

ID=20026907

Family Applications (1)

Application Number Title Priority Date Filing Date
PL25374685A PL144111B2 (en) 1985-05-30 1985-05-30 Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides

Country Status (1)

Country Link
PL (1) PL144111B2 (en)

Also Published As

Publication number Publication date
PL253746A2 (en) 1987-02-23

Similar Documents

Publication Publication Date Title
EP0004279B1 (en) Process for the preparation of 4-pyridone-3-carboxylic acids, 1-cyclopropyl-4-pyridone-3-carboxylic acid derivatives and medicines containing them
DE3854764T2 (en) Process for the preparation of (R) 5-pentylamino-5-oxopentanoic acid derivatives with anticholecystokine activity.
EP0049355B1 (en) 7-Amino-1-cyclopropyl-4-oxo-1,4-dihydro-(naphthyridine or quinoline)-3-carboxylic acids, process for their preparation and pharmaceutical compositions containing them
US2910488A (en) Aniline derivatives
DE1595915A1 (en) Process for the preparation of heterocyclic benzamides
DE2818676A1 (en) SUBSTITUTED 5,6-DIMETHYLPYRROLO 2,3-D PYRIMIDINE, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT
DE3145287A1 (en) Pyrrolo[2,3-d]pyrimidines, process for their preparation and their use as medicaments
GB1454777A (en) Dioxamates and the preparation thereof
DE3030982A1 (en) 2-PHENYLIMIDAZO (2,1-B) BENZOTHIAZOLE DERIVATIVES
CH618980A5 (en)
DE2505297A1 (en) NEW 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES AND A PROCESS FOR THEIR PRODUCTION
DE69821815T2 (en) Thiocolchicin derivatives with anti-inflammatory and muscle relaxant effects
DE68917211T2 (en) N- (5,6,7,8-tetrahydropyrido (2,3-d) pyrimidin-6-ylalkanoyl) glutamic acid derivatives.
CH396923A (en) Process for the preparation of 4-mercapto-pyrazolo (3,4-d) pyrimidines
DE69400024T2 (en) 2-cyano-2-hydroxypropenamide derivatives, processes for their preparation, their use as medicaments and pharmaceutical compositions containing them.
PL144111B2 (en) Method of obtaining novel 2-hydroxy-4-beta-hydroxyethylamino-6-methyl-5-pyrimidylocarkoxylamides
EP0014390B1 (en) 2-amino-8-cyclopropyl-5-oxo-5,8-dihydro-pyrido (2,3-d) pyrimidine-6-carboxylic acids, pharmaceutical compositions containing them and processes for their preparation
CH664564A5 (en) IMINOTHIAZOLIDINE DERIVATIVES.
DE69230110T2 (en) TETRAHYDROPYRIDINE DERIVATIVES SUBSTITUTED ON THREE RINGS
DE69009765T2 (en) KYNURIC ACID DERIVATIVES, THEIR PRODUCTION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
DE3245950A1 (en) Process for the preparation of substituted pyridines
CH651820A5 (en) AMINO ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN PHARMACEUTICALS.
US3303095A (en) Compositions and methods for producing tranquilizing activity
CH615681A5 (en)
US3324173A (en) (2-methylenealkanoyl)benzoic acids