PL136563B2 - Method of obtaining new 2-methyl-3-beta-hydroxy-gamma-morpholinopropylo-3,4-dihydropyrido-/2,3-d/-pyrimidin-4-none - Google Patents
Method of obtaining new 2-methyl-3-beta-hydroxy-gamma-morpholinopropylo-3,4-dihydropyrido-/2,3-d/-pyrimidin-4-none Download PDFInfo
- Publication number
- PL136563B2 PL136563B2 PL24580684A PL24580684A PL136563B2 PL 136563 B2 PL136563 B2 PL 136563B2 PL 24580684 A PL24580684 A PL 24580684A PL 24580684 A PL24580684 A PL 24580684A PL 136563 B2 PL136563 B2 PL 136563B2
- Authority
- PL
- Poland
- Prior art keywords
- hydroxy
- methyl
- pyrimidin
- morpholinopropylo
- dihydropyrido
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 4
- HTPCDVLWYUXWQR-UHFFFAOYSA-N 2-aminopyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1N HTPCDVLWYUXWQR-UHFFFAOYSA-N 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- IWZJQGIFUBWZAE-UHFFFAOYSA-N 1-chloro-3-morpholin-4-ylpropan-2-ol Chemical compound ClCC(O)CN1CCOCC1 IWZJQGIFUBWZAE-UHFFFAOYSA-N 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Przedmiotem wynalazku jest sposób wytwarzania nowego 2-metylo-3-/?-hydroksy-y- morfolinopropylo-3,4-dihydropirydo- [2,3-d]-pirymidyn-4-onu o wzorze 1, charakteryzujacego sie dzialaniem hipotensyjnym.Ze stanu techniki nie sa znane sposoby wytwarzania /?-hydroksy-y-morfolinopropylowej pochodnej pirydo-[2,3-d]-pirymidyny.Wedlug wynalazku sposób wytwarzania nowego 2-metylo-3-/?-hydroksy-y- morfolinopropy- lo-3,4-dihydropirydo-[2,3-d]-pirymidyn-4-onu o wzorze 1 polega na tym, ze na 2-aminonikotyno- amid dziala sie nadmiarem acetamidu w temperaturze 403-413 K i otrzymuje 2-metylo-3,4-dihy- dropirydo-[2,3-d]-pirymidyn-4-on o wzorze 2, na który nastepnie dziala sie nadmiarem chlorku j8-hydroksy-y-morfolinopropylowego w temperaturze 363 K.Na podstawie stanu techniki nie mozna bylo z góry przewidziec, ze uzyska sie reakcje przebiegajaca pomiedzy reagentami uzytymi w sposobie wedlug wynalazku i ze otrzyma sie produkt o dzialaniu farmakologicznym. Zwiazek wytworzony sposobem wedlug wynalazku wyka¬ zuje w badaniach farmakologicznych dzialanie hipotensyjne. Zwiazek ten podawany szczurom w dawce 30 mg/kg powoduje spadek cisnienia, który narasta z uplywem minut, osiagajac po 60 minutach od podania 50 mm Hg. W zakresie wplywu zwiazku na czynnosc oddechowa u szczurów, powoduje niewielkie zwolnienie czestosci oddechu. Zwiazek ten w sposób statystycznie znamienny w dawce 50 mg/kg znosi wzrost obwodowego oporu naczyniowego, wywolanego podaniem 50 mcg noradrenaliny oraz zapobiega temu wzrostowi. Toksycznosc przyblizona zwiazku oznaczona w tescie po podaniu dootrzewnowym u myszy wynosi 400 mg/kg.Przedmiot wynalazku jest przedstawiony w przykladzie wykonania.Przyklad. Mieszanine 10 g (0,072 mola) 2-aminonikotynoamidu ogrzewa sie z 5 g(0,08 mola) acetamidu w temperaturze 403-413-K w czasie 4 godzin, a nastepnie ochladza, odfiltrowuje osad i przemywa acetonem, po czym przekrystalizowuje z metanolu. Otrzymuje sie 10,57 g 2-metylo-3,4- -dihydropirydo-[2,3-d]-pirymidyn-4-onu. Do 20 cm3 suchego ksylenu i 0,3g (0,007 mola)amidku sodowego wprowadza sie zawiesine 1 g (0,0062 mola) 2-metylo-3,4-dihydropirydo-[2,3-d]-pirymi-2 136 563 dyn-4-onu w 10cm3 suchego ksylenu. Mieszanine reagentów ogrzewa sie w lekkim wrzeniu 2 godziny, sól sodowa odsacza sie, rozpuszcza sie ja w 20cm3 metanolu, a nastepnie ogrzewa 4 godziny z 1,3 g (0,007 mola) chlorku /^hydroksy-7-morfolinopropylowego. Odsacza sie od nie- przereagowanej soli sodowej, rozpuszczalnik oddestylowuje sie, z pozostalosci wyodrebnia sie krystaliczny produkt, który przekrystalizowuje sie z metanolu. Otrzymuje sie l,56g, co stanowi 83% wydajnosci teoretycznej, 2-metylo-3-j8-hydroksy-7-morlblinopropylo-3,4-dihydropirydo- [2,3-d]-pirymidyn-4-onu. Zwiazek ten jest bezbarwna, krystaliczna substancja o temperaturze topnienia 492-493 K, rozpuszczalna w metanolu, acetonie, dimetylosulfotlenku, tetrahydrofura- nie,'zas nierozpuszczalna w benzenie, wodzie, eterze etylowym i naftowym, która nie podlega zmianom pod wplywem powietrza i swiatla.Zastrzezenie patentowe Sposób wytwarzania nowego 2-metylo-3-j8-hydroksy-7-morfolinopropylo-3,4-dihydropiry- do-[2,3-d]-pirymidyn-4-onu o wzorze 1, znamienny tym, ze na 2-aminonikotynoamid dziala sie nad¬ miarem acetamidu w temperaturze 403-413 K i otrzymuje 2-metylo-3,4-dihydropirydo-[2,3-d]- -pirymidyn-4-on o wzorze 2, na który nastepnie dziala sie nadmiarem chlorku /J-hydroksy-7-mor- folinopropylowego w temperaturze 363 K.Nj-CH,- CH-CHi-l/ ^ CHs OH WZbR 1 WZÓR 2 Pracownia Poligraficzna UP PRL, Naklad 100 egz.Cena 100 zl PLThe subject of the invention is a process for the preparation of the new 2-methyl-3 - / β-hydroxy-y-morpholinopropyl-3,4-dihydropyrid- [2,3-d] -pyrimidin-4-one of the formula 1, which is characterized by a hypotensive effect. There are no known processes for the preparation of the i-β-hydroxy-γ-morpholinopropyl derivative of pyrido [2,3-d] -pyrimidine according to the invention. The 3,4-dihydropyrid- [2,3-d] -pyrimidin-4-one of the formula 1 is based on the treatment of the 2-aminonicotinamide with an excess of acetamide at 403-413 K and gives 2-methyl-3 , 4-dihydropyrid- [2,3-d] -pyrimidin-4-one of the formula 2, which is then treated with an excess of β-hydroxy-γ-morpholinopropyl chloride at a temperature of 363 K. Based on the prior art, it was not possible to predict in advance that a reaction will be obtained between the reactants used in the process according to the invention and that a pharmacological product will be obtained. The compound according to the invention shows a hypotensive effect in pharmacological tests. This compound, administered to rats at a dose of 30 mg / kg, causes a drop in blood pressure that increases with the passage of minutes, reaching 50 mm Hg 60 minutes after administration. In terms of the effect of compound on respiratory function in rats, it causes a slight decrease in the respiratory rate. This compound is statistically significant at the dose of 50 mg / kg and prevents the increase in peripheral vascular resistance caused by the administration of 50 mcg of noradrenaline. The approximate toxicity of the compound determined in the test after intraperitoneal administration in mice is 400 mg / kg. The subject of the invention is illustrated in the embodiment. Example. A mixture of 10 g (0.072 mol) of 2-aminonicotinamide is heated with 5 g (0.08 mol) of acetamide at 403-413-K for 4 hours, then cooled, filtered and washed with acetone, then recrystallized from methanol. 10.57 g of 2-methyl-3,4-dihydropyrid- [2,3-d] -pyrimidin-4-one are obtained. A suspension of 1 g (0.0062 mol) of 2-methyl-3,4-dihydropyrid- [2,3-d] -pyrim-2 136 563 dynes is introduced into 20 cm 3 of dry xylene and 0.3 g (0.007 mol) of sodium amide. -4-one in 10cm3 dry xylene. The mixture of reagents is heated under slight boiling for 2 hours, the sodium salt is filtered off, dissolved in 20 ml of methanol and then heated for 4 hours with 1.3 g (0.007 mol) of N-hydroxy-7-morpholinopropyl chloride. It is filtered off from the unreacted sodium salt, the solvent is distilled off, and a crystalline product is isolated from the residue, which is recrystallized from methanol. 1.56 g (83% of theory) of 2-methyl-3-8-hydroxy-7-morlbinopropyl-3,4-dihydropyrid- [2,3-d] pyrimidin-4-one are obtained. This compound is a colorless, crystalline substance with a melting point of 492-493 K, soluble in methanol, acetone, dimethylsulfoxide, tetrahydrofuran, and insoluble in benzene, water, ethyl and petroleum ether, which is not affected by air and light. Claimed A method for the preparation of a new 2-methyl-3-8-hydroxy-7-morpholinopropyl-3,4-dihydropyrino- [2,3-d] -pyrimidin-4-one of formula 1, characterized by The -aminonicotinamide is treated with an excess of acetamide at 403-413 K to give 2-methyl-3,4-dihydropyrid- [2,3-d] -pyrimidin-4-one of the formula II, which is then treated with excess chloride / J-hydroxy-7-morpholinopropyl at the temperature of 363 K.Nj-CH, - CH-CHi-l / ^ CHs OH WZbR 1 MODEL 2 Printing workshop of the Polish People's Republic, Circulation 100 copies Price PLN 100 PL
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL24580684A PL136563B2 (en) | 1984-01-19 | 1984-01-19 | Method of obtaining new 2-methyl-3-beta-hydroxy-gamma-morpholinopropylo-3,4-dihydropyrido-/2,3-d/-pyrimidin-4-none |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL24580684A PL136563B2 (en) | 1984-01-19 | 1984-01-19 | Method of obtaining new 2-methyl-3-beta-hydroxy-gamma-morpholinopropylo-3,4-dihydropyrido-/2,3-d/-pyrimidin-4-none |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL245806A2 PL245806A2 (en) | 1984-12-03 |
| PL136563B2 true PL136563B2 (en) | 1986-02-28 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL24580684A PL136563B2 (en) | 1984-01-19 | 1984-01-19 | Method of obtaining new 2-methyl-3-beta-hydroxy-gamma-morpholinopropylo-3,4-dihydropyrido-/2,3-d/-pyrimidin-4-none |
Country Status (1)
| Country | Link |
|---|---|
| PL (1) | PL136563B2 (en) |
-
1984
- 1984-01-19 PL PL24580684A patent/PL136563B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL245806A2 (en) | 1984-12-03 |
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