PL211998B1 - New derivative of pyrimidopyrimidine and production method of new derivative of pyrimidopyrimidine - Google Patents
New derivative of pyrimidopyrimidine and production method of new derivative of pyrimidopyrimidineInfo
- Publication number
- PL211998B1 PL211998B1 PL381649A PL38164907A PL211998B1 PL 211998 B1 PL211998 B1 PL 211998B1 PL 381649 A PL381649 A PL 381649A PL 38164907 A PL38164907 A PL 38164907A PL 211998 B1 PL211998 B1 PL 211998B1
- Authority
- PL
- Poland
- Prior art keywords
- pyrimidopyrimidine
- chlorophenyl
- new
- new derivative
- derivative
- Prior art date
Links
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 title description 8
- 238000004519 manufacturing process Methods 0.000 title 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- -1 1,3-di- (4'-chlorophenyl) -2- (2'-chlorophenyl) -7-phenyl-5-methyl-1,2,3 , 4-tetrahydropyrimido [4,5-d] pyrimidine Chemical compound 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 229960005091 chloramphenicol Drugs 0.000 description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 3
- 229960003276 erythromycin Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KIVZOUOOHOSWCF-UHFFFAOYSA-N NC(N)=CC1=C(C(C=C2)=CC=C2Cl)C(C(C=C2)=CC=C2Cl)=NC(C2=CC=CC=C2)=N1 Chemical compound NC(N)=CC1=C(C(C=C2)=CC=C2Cl)C(C(C=C2)=CC=C2Cl)=NC(C2=CC=CC=C2)=N1 KIVZOUOOHOSWCF-UHFFFAOYSA-N 0.000 description 2
- 241000588767 Proteus vulgaris Species 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940007042 proteus vulgaris Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012009 microbiological test Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Przedmiotem wynalazku jest nowa pochodna pirymidopirymidyny i sposób wytwarzania nowej pochodnej pirymidopirymidyny o nazwie chemicznej 1,3-di-(4'-chlorofenylo)-2-(2'-chlorofenylo)-7-fenylo-5-metylo-1,2,3,4-tetrahydropirymido[4,5-d]pirymidyna i wzorze 1. Nowa pochodna wykazuje bardzo silne działanie przeciwbakteryjne, porównywalne z działaniem chloramfenikolu lub erytromycyny.The subject of the invention is a new pyrimidopyrimidine derivative and a method for the preparation of a new pyrimidopyrimidine derivative with the chemical name 1,3-di- (4'-chlorophenyl) -2- (2'-chlorophenyl) -7-phenyl-5-methyl-1,2,3 , 4-tetrahydropyrimido [4,5-d] pyrimidine and formula 1. The new derivative has a very strong antibacterial activity comparable to that of chloramphenicol or erythromycin.
Wynalazek dotyczy nowej pochodnej pirymidopirymidyny o nazwie chemicznej 1,3-di-(4'-chlorofenylo)-2-(2'-chlorofenylo)-7-fenylo-5-metylo-1,2,3,4-tetrahydropirymido[4,5-d]pirymidyna i wzorze 1.The invention relates to a new pyrimidopyrimidine derivative with the chemical name 1,3-di- (4'-chlorophenyl) -2- (2'-chlorophenyl) -7-phenyl-5-methyl-1,2,3,4-tetrahydropyrimido [4, 5-d] pyrimidine and formula 1.
Wynalazek dotyczy także sposobu wytwarzania nowej pochodnej pirymidopirymidyny o nazwie 1,3-di-(4'-chlorofenylo)-2-(2'-chlo-rofenylo)-7-fenylo-5-metylo-1,2,3,4-tetrahydropirymido[4,5-d]pirydyna i wzorze 1.The invention also relates to a process for the preparation of a new pyrimidopyrimidine derivative named 1,3-di- (4'-chlorophenyl) -2- (2'-chlorophenyl) -7-phenyl-5-methyl-1,2,3,4- tetrahydropyrimido [4,5-d] pyridine and formula 1.
Istota wynalazku polega na tym, że 4-(4'-chlorofenylo)amino-5-(4'-chlorofenylo)aminometyleno2-fenylo-6-metylopirymidyna o wzorze 2 poddaje się reakcji Mannicha przy pomocy aldehydu 2-chlorobenzoesowego w tetrahydrofuranie (THF).The essence of the invention is that 4- (4'-chlorophenyl) amino-5- (4'-chlorophenyl) aminomethylene-2-phenyl-6-methylpyrimidine of formula 2 is subjected to a Mannich reaction with 2-chlorobenzaldehyde in tetrahydrofuran (THF) .
Otrzymaną nową pochodną poddaje się kondensacji w niepolarnym rozpuszczalniku w temperaturze wrzenia, korzystnie w tetrahydrofuranie lub dioksanie.The resulting novel derivative is condensed in a non-polar solvent at reflux temperature, preferably in tetrahydrofuran or dioxane.
Nieoczekiwanie okazało się, że otrzymana nowa, wyżej wymieniona pochodna, wykazuje działanie przeciwbakteryjne, czego nie można było z góry przewidzieć. Badania wykazały, że działanie to jest związane ze strukturą pirymidopirymidyny, wykazującej pewną analogię do chinolonowych pochodnych, działających przeciwbakteryjnie przez hamowanie enzymu gyrazy. Jak się okazało na działanie przeciwbakteryjne mają także wpływ rodniki elektrofilowe np. (chlor) w pierścieniach aromatycznym przyłączony do układu pirymidopirymidynowego. Działanie przeciwbakteryjne zostało potwierdzone badaniami mikrobiologicznymi na wybranych szczepach bakteryjnych. Do oznaczeń wybrano metodę cylinderkową, określając strefy zahamowań wzrostu bakterii hodowlanych przez 24 h. Po tym czasie dokonywano odczytu. Badania przeprowadzono na następujących szczepach: Escherichia coli, Enterococcus faecalis, Staphylococcus aweus, Pseudomonas aeruginosa, Bacillus sibtilis, Serratia marcesceus, Proteus vulgaris, Staphylococcus epidermidis, Klebsiella Pneumoniae, Candida albicans. Otrzymane wyniki w porównaniu do wzorcowego Chloramfenikolu, oraz Erytromycyny są szczególnie interesujące wobec takich szczepów bakteryjnych jak Bacillus subtilis oraz Klebsiella pneumaniae.Surprisingly, it turned out that the obtained new, above-mentioned derivative has an antimicrobial effect, which could not be predicted in advance. Studies have shown that this effect is related to the structure of the pyrimidopyrimidine, which is somewhat analogous to the quinolone derivatives, which have an antibacterial effect by inhibiting the gyrase enzyme. As it turned out, the antimicrobial activity is also influenced by electrophilic radicals, e.g. (chlorine) in aromatic rings attached to the pyrimidopyrimidine system. The antibacterial activity has been confirmed by microbiological tests on selected bacterial strains. The cylinder method was chosen for determinations, determining the zones of inhibition of growth of cultured bacteria for 24 hours. After this time, the readings were made. The research was carried out on the following strains: Escherichia coli, Enterococcus faecalis, Staphylococcus aweus, Pseudomonas aeruginosa, Bacillus sibtilis, Serratia marcesceus, Proteus vulgaris, Staphylococcus epidermidis, Klebsiella Pneumoniae, Candida albicans. The obtained results in comparison to the standard Chloramphenicol and Erythromycin are of particular interest for such bacterial strains as Bacillus subtilis and Klebsiella pneumaniae.
Przedmiot wynalazku jest przedstawiony w przykładzie wykonania.The subject of the invention is presented in an exemplary embodiment.
P r z y k ł a d. 4 g (0.0092 mola) 4-(4'chlorofenylo)amino-5-(4'-chlorofenylo)aminometyleno-2-fenylo-6-metylopirymidynę o wzorze (2) rozpuszcza się w 50 ml tetrahydrofuranu (THF) i dodaje 10 ml aldehydu ortochlorobenzoesowego. Całość podgrzewa się pod chłodnicą zwrotną przez 7 godz. Następnie mieszaninę poreakcyjną oziębia się i wylewa do 100 ml wody. Roztwór wodny ekstrahuje się trzykrotnie chloroformem. Wyciągi chloroformowe łączy się i osusza nad siarczanem magnezu. Oleistą mieszaninę oczyszcza się w kolumnie chromatograficznej, zbierając frakcję Rf = 9/10. Uzyskuje się 3,7 g nowego związku o temperaturze topnienia 222- 224°C z wydajnością równą 78.3% wydajności teoretycznej.Example 4 g (0.0092 mol) of 4- (4'-chlorophenyl) amino-5- (4'-chlorophenyl) aminomethylene-2-phenyl-6-methylpyrimidine of formula (2) was dissolved in 50 ml of tetrahydrofuran ( THF) and 10 ml of orthochlorobenzaldehyde is added. The whole is heated under reflux for 7 hours. The reaction mixture was then cooled and poured into 100 ml of water. The aqueous solution is extracted three times with chloroform. The chloroform extracts are combined and dried over magnesium sulfate. The oily mixture is purified by column chromatography, collecting the Rf = 9/10 fraction. The obtained yield is 3.7 g of the new compound with a melting point of 222-224 ° C in a yield equal to 78.3% of theory.
Strukturę nowego związku 1 potwierdzono analizą krystalograficzną, a także badaniami fizykochemicznymi, a mianowicie analizą elementarną, protonowym rezonansem magnetycznym oraz spektroskopią w podczerwieni.The structure of the new compound 1 was confirmed by crystallographic analysis as well as physicochemical tests, namely elemental analysis, proton magnetic resonance and infrared spectroscopy.
HH.
4.14 4.404.14 4.40
CC.
66.9066.90
66.5266.52
NN
10.0710.07
10.3510.35
ClCl
18.8818.88
18.5418.54
Analiza elementarna:Elemental analysis:
Obliczono:Calculated:
Otrzymano:Received:
IR(KBr) v = cm-1 3370 (NH), 1H NMR δ = PPM 2.30 (s, 3H CH3), 2.70 (s - 2H, CH2), 3.80 (s- 1H, CH), 6.13-7.80 (m - 17 H aromat.).IR (KBr) v = 3370 cm -1 (NH), 1 H NMR δ = 2.30 PPM (s, 3H CH 3), 2.70 (s - 2H, CH2), 3.80 (s- 1H, CH), 6.13-7.80 ( m - 17 H aromat.).
Szczegółowe wyniki badań przedstawia poniższa tabela:Detailed research results are presented in the table below:
Minimalne stężenie hamowania szczepów bakteryjnych - Test M-7, A-5aThe minimum concentration of inhibition of bacterial strains - Test M-7, A-5a
PL 211 998 B1 ciąg dalszy tabeliThe table continues
Zastrzeżenia patentowePatent claims
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL381649A PL211998B1 (en) | 2007-01-31 | 2007-01-31 | New derivative of pyrimidopyrimidine and production method of new derivative of pyrimidopyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL381649A PL211998B1 (en) | 2007-01-31 | 2007-01-31 | New derivative of pyrimidopyrimidine and production method of new derivative of pyrimidopyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL381649A1 PL381649A1 (en) | 2008-08-04 |
| PL211998B1 true PL211998B1 (en) | 2012-07-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL381649A PL211998B1 (en) | 2007-01-31 | 2007-01-31 | New derivative of pyrimidopyrimidine and production method of new derivative of pyrimidopyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| PL (1) | PL211998B1 (en) |
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2007
- 2007-01-31 PL PL381649A patent/PL211998B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PL381649A1 (en) | 2008-08-04 |
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| LAPS | Decisions on the lapse of the protection rights |
Effective date: 20130131 |