PL194098B1 - 3-substituted 2-methyl pyrimido[5,4-c]cinnoline-4(3h)one and its derivatives and method of manufacture of 3-substituted 2-methyl pyrimido[5,4-c]cinnoline-4(3h)one and its derivatives - Google Patents

3-substituted 2-methyl pyrimido[5,4-c]cinnoline-4(3h)one and its derivatives and method of manufacture of 3-substituted 2-methyl pyrimido[5,4-c]cinnoline-4(3h)one and its derivatives

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PL194098B1
PL194098B1 PL358571A PL35857103A PL194098B1 PL 194098 B1 PL194098 B1 PL 194098B1 PL 358571 A PL358571 A PL 358571A PL 35857103 A PL35857103 A PL 35857103A PL 194098 B1 PL194098 B1 PL 194098B1
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substituted
cinnoline
derivatives
methyl
cinnolin
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Andrzej Stańczak
Zbigniew Ochocki
Wiesława Lewgowd
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Univ Medyczny
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Abstract

1. 3-podstawiony 2-metylopirymido[5,4-c]cynnolin-4(3H)-on o wzorze I w którym R1, R2 i R3 są takie same lub różne i oznaczają atom wodoru albo atom fluorowca, albo grupę metylową, a R4 oznacza amino(C1-C4)alkil albo aminofenol.1. 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)-one of formula I wherein R1, R2 and R3 are the same or different and represent a hydrogen atom or a halogen atom or a methyl group, and R4 represents amino(C1-C4)alkyl or aminophenol.

Description

RZECZPOSPOLITAREPUBLIC

POLSKAPOLAND

Urząd Patentowy Rzeczypospolitej Polskiej (12) OPIS PATENTOWY (19) PL (11) (13) B1 (21) Numer zgłoszenia: 358571 (51) Int.Cl.Patent Office of the Republic of Poland (12) PATENT DESCRIPTION (19) PL (11) (13) B1 ( 21 ) Application number: 35 8571 ( 51 ) Int.Cl.

C07D 487/04 (2006.01) A61K 31/519 (2006.01) A61P 25/00 (2006.01) (22) Data zgłoszenia: 03.02.2003C07D 487/04 (2006.01) A61K 31/519 (2006.01) A61P 25/00 (2006.01) (22) Date of filing: 03.02.2003

3-podstawiony 2-metylopirymido[5,4-c]cynnolin-4(3H)on oraz sposób otrzymywania 3-podstawionego 2-metylopirymido[5,4-c]cynnolin-4(3H)onu3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)one and method for obtaining 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)one

(73) Uprawniony z patentu:(73) Patent holder: (43) Zgłoszenie ogłoszono:(43) The application was announced: Uniwersytet Medyczny,Łódź,PLMedical University of Lodz, Poland 09.08.2004 BUP 16/04 09/08/2004 BUP 16/04 (72) Twórca(y) wynalazku:(72) Inventor(s): (45) O udzieleniu patentu ogłoszono: 30.04.2007 WUP 04/07(45) The patent was granted on: April 30, 2007, WUP 04/07 Andrzej Stańczak,Łódź,PL Zbigniew Ochocki,Łódź,PL Wiesława Lewgowd,Łódź,PLAndrzej Stańczak, Lodz, PL Zbigniew Ochocki, Lodz, PL Wiesława Lewgowd, Lodz, PL

(57) 1. 3-podstawiony 2-metylopirymido[5,4-c]cynnolin-4(3H)-on o wzorze I w którym R^ R2 i R3 są takie same lub różne i oznaczają atom wodoru albo atom fluorowca, albo grupę metylową, a R4 oznacza amino(C1-C4)alkil albo aminofenol.(57) 1. 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)-one of formula I wherein R^ R2 and R3 are the same or different and represent a hydrogen atom or a halogen atom or a methyl group, and R4 represents amino(C1-C4)alkyl or aminophenol.

PL 194 098 B1PL 194 098 B1

Opis wynalazkuDescription of the invention

Przedmiotem wynalazku jest 3-podstawiony 2-metylopirymido[5,4-c]-cynnolin-4(3H)-on oraz sposób otrzymywania 3-podstawionego 2-metylopirymido[5,4-c]cynnolin-4(3H)-onu.The subject of the invention is 3-substituted 2-methylpyrimido[5,4-c]-cinnolin-4(3H)-one and a method for obtaining 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)-one.

Związki według wynalazku są nowe, nie zostały opisane w literaturze chemicznej.The compounds of the invention are new and have not been described in the chemical literature.

Istotą wynalazku jest 3-podstawiony 2-metylopirymido[5,4-c]cynnolin-4(3H)-on o wzorze I, w którym R1, R2 i R3 są takie same lub różne i oznaczają atom, wodoru albo atom fluorowca albo grupę metylową, a R4 oznacza aminoalkil albo aminofenol.The invention is based on a 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)-one of formula I, wherein R1 , R2 and R3 are the same or different and represent a hydrogen atom or a halogen atom or a methyl group, and R4 represents an aminoalkyl or aminophenol.

Istotą wynalazku jest również sposób otrzymywania 3-podstawionego 2-metylopirymido[5,4-c]cynnolin-4(3H)-onu.The essence of the invention is also a method for obtaining 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)-one.

Sposób otrzymywania według wynalazku 3-podstawionego 2-metylopirymido[5,4-c]cynnolin-4(3H)-onu polega na ogrzewaniu w temperaturze wrzenia mieszaniny reakcyjnej 1,3-oksazyno[5,4-c]-cynnolino-4-onu z pochodną hydrazyną korzystnie z fenylohydrazyną. Reakcje prowadzi się w rozpuszczalniku polarnym, korzystnie w acetonitrylu.The method for obtaining 3-substituted 2-methylpyrimido[5,4-c]cinnolin-4(3H)-one according to the invention consists in heating the reaction mixture of 1,3-oxazino[5,4-c]-cinnolin-4-one with a hydrazine derivative, preferably phenylhydrazine, to the boiling point. The reactions are carried out in a polar solvent, preferably in acetonitrile.

Sposób otrzymywania 3-podstawionych 2-metylo-pirymido[5,4-c]cynnolin-4(3H)-onu polega również na kondensacji w temperaturze wrzenia odpowiedniego metylohydrazydu kwasu 4-amino-3-cynnolinokarboksylowego z ortooctanem trietylu w środowisku rozpuszczalnika polarnego, korzystnie w bezwodnym kwasie octowym. Po całkowitym rozpuszczeniu substratów mieszaninę schładza się, a wytracony osad odsącza się i krystalizuje.The method for obtaining 3-substituted 2-methyl-pyrimido[5,4-c]cinnolin-4(3H)-ones also involves condensation of the corresponding 4-amino-3-cinnolinecarboxylic acid methylhydrazide with triethyl orthoacetate at the boiling point in a polar solvent, preferably anhydrous acetic acid. After complete dissolution of the starting materials, the mixture is cooled, and the precipitate is filtered off and crystallized.

Układ pirymido[5,4-c]cynnolin-4(3H)-onu został otrzymany po raz pierwszy przez K. Gewalda i współpracowników na drodze kondensacji 4-aminocynnolino-3-karboksamidu z formamidem albo ortomrówczanem trietylu w środowisku kwasu octowego [Gewald K., Calderon O., Schafer H., Hain U.,: Liebigs Ann. Chem. 5,1390 (1984)].The pyrimido[5,4-c]cinnolin-4(3H)-one system was obtained for the first time by K. Gewald and co-workers by condensation of 4-aminocinnoline-3-carboxamide with formamide or triethyl orthoformate in acetic acid [Gewald K., Calderon O., Schafer H., Hain U., Liebigs Ann. Chem. 5, 1390 (1984)].

Znane metody nie pozwalają wprowadzać dowolnych podstawników w pozycje 3.Known methods do not allow the introduction of arbitrary substituents into the 3-position.

Stosując sposoby według wynalazku można obok grupy metylowej, znajdującej się w pozycji 2, wprowadzić w pozycję 3 różne podstawniki, którymi mogą być aminofenol albo amino(C1-C4)alkile.Using the methods of the invention, in addition to the methyl group located in position 2, various substituents can be introduced in position 3, which may be aminophenol or amino(C1-C4)alkyl.

Związki otrzymane sposobami według wynalazku wykazują działanie depresyjne na ośrodkowy układ nerwowy (OUN).The compounds obtained by the methods of the invention have a depressant effect on the central nervous system (CNS).

P r z y k ł a d 1. Otrzymywanie 2,8-dimetylo-3-(fenyloamino)pirymido-[5,4-c]cynnolino-4(3H)-onu części wagowe 2,8-dimetylo-1,3-oksazyno[5,4-c]cynnolino-4-onu zawieszano w 17 częściach objętościowych acetonitrylu, a następnie dodawano 1 część wagową fenylohydrazyny. Całość ogrzewano do całkowitego rozpuszczenia osadu i pozostawiano do następnego dnia w lodówce. Wytrącony osad 2,8-dimetylo-3-(fenyloamino)pirymido[5,4-c]cynnolino-4(3H)onu odsączano i krystalizowano z dioksanu.Example 1. Preparation of 2,8-dimethyl-3-(phenylamino)pyrimido-[5,4-c]cinnolin-4(3H)-one Parts by weight of 2,8-dimethyl-1,3-oxazino[5,4-c]cinnolin-4-one were suspended in 17 parts by volume of acetonitrile, and then 1 part by weight of phenylhydrazine was added. The whole was heated until the precipitate dissolved completely and left in a refrigerator until the next day. The precipitated precipitate of 2,8-dimethyl-3-(phenylamino)pyrimido[5,4-c]cinnolin-4(3H)-one was filtered off and crystallized from dioxane.

Otrzymano chromatograficznie czysty produkt o temperaturze topnienia 288-290°C. Wydajność procesu wynosiła 87.12%.A chromatographically pure product was obtained with a melting point of 288-290°C. The process yield was 87.12%.

Analiza elementarna: C18H15N5ClO (317,35)Elemental analysis: C18H1 5 N 5 ClO (317.35)

Obliczono: %C 68.13 %H 4.76 %N 22.07Calculated: %C 68.13 %H 4.76 %N 22.07

Oznaczono: 68.21 4.60 22.21 1H NMR (300 MH^ DMSO-d6): d (ppm) = 2.7 (s, 3H, CH3), 3.3 (s, 3H, CH3), 6.7-6.9 (t, 3H, arom.), 7.1-7.2 (m, 2H, arom.), 8.4 (d, 1H, arom.), 8.7 (s, 1H, arom.), 8.8 (d, 2H, arom.), 9.4 (s, 1H, NH).Determined: 68.21 4.60 22.21 1 H NMR ( 300 MH^ DMSO - d6 ): d (pp m) = 2.7 (s, 3H, CH3), 3.3 (s, 3H, CH 3 ), 6.7 - 6.9 (t, 3H, arom. ), 7.1-7.2 (m, 2H, arom.), 8.4 (d, 1H, aroma), 8.7 (s, 1H, aroma), 8.8 (d, 2H, aroma), 9.4 (s, 1H, NH).

IR (KBr): vmax cm-1 = 3360 (NH\ 1700 (C=O^ 1590, 820 (arom.)IR ( KBr ): vmax cm -1 = 3360 ( NH\ 1700 ( C=O^ 1590 , 820 (aroma)

P r z y k ł a d 2. Otrzymywanie 8-chloro-2-metylo-3-(metyloamino)-pirymido[5,4-c]cynnolino4(3H)-onuExample 2. Preparation of 8-chloro-2-methyl-3-(methylamino)-pyrimido[5,4-c]cinnolin4(3H)-one

Mieszaninę 1 części wagowej metylohydrazydu kwasu 4-amino-7-chloro-3-cynnolinokarboksylowego, 5 części objętościowych ortooctanu trietylu i 5 części objętościowych bezwodnego kwasu octowego utrzymywano w temperaturze wrzenia przez 2 godziny. Po ochłodzeniu wydzielony osad 8-chloro-2-metylo-3-(metyloamino)pirymido [5,4-c] cynnolino-4(3H)-onu odsączano i krystalizowano z etanolu.A mixture of 1 part by weight of 4-amino-7-chloro-3-cinnolinecarboxylic acid methylhydrazide, 5 parts by volume of triethyl orthoacetate and 5 parts by volume of anhydrous acetic acid was heated at reflux for 2 hours. After cooling, the separated precipitate of 8-chloro-2-methyl-3-(methylamino)pyrimido[5,4-c]cinnoline-4(3H)-one was filtered off and crystallized from ethanol.

Otrzymano chromatograficznie czysty produkt o temperaturze topnienia >360°C. Wydajność procesu wynosiła 52,01%.A chromatographically pure product was obtained with a melting point >360°C. The process yield was 52.01%.

Analiza elementarna: C12H10N5ClO (275.70)Elemental analysis: C12H1 0 N 5 ClO (275.70)

Obliczono: %C 52.28 %H 3.66 %N 25.40Calculated: %C 52.28 %H 3.66 %N 25.40

Oznaczono: 52.03 3.75 25.32 1H NMR (300 MH^ DMSO-d6): d (ppm) = 3.5 (s, 6H, CH3), 7.2-8.5 (m, 4H, arom.).Marked: 52.03 3.75 25.32 1 H NMR ( 300 MH^ DMSO - d6 ): d (pp m) = 3.5 (s, 6H, CH3), 7.2 - 8.5 (m, 4H, arom.).

IR (KBr): uw cm-1 = 2700-3100 (NH^ 1650720 (C=O^ 1520, 790 (arom.)IR ( KBr ): uw cm -1 = 2700 - 3100 ( NH^ 1650720 ( C=O^ 1520 , 790 (aroma)

PL 194 098 B1PL 194 098 B1

Claims (4)

Zastrzeżenia patentowePatent claims 1. 2-^i^(^t^l<^[^ir^r^i(^(^[i5,^-^<3]<3^r^nolir^^-^((^H)-^on o wzorze I w którym R, R2 i R3 są takie same iub różne < oznaczają atom wodoru aibo atom fluorowca aibo grupę metylową, a R4 oznacza am<no(Ci-C4-aik<i albo aminofenol.1. 2- ^ i ^ (^ t ^ l <^ [^ ir ^ r ^ i (^ (^ [i5, ^ - ^ <3] <3 ^ r ^ nolir ^^ - ^ ((^ H) - ^ one of the formula I wherein R, R 2 and R 3 are the same different IUB <AIBO hydrogen atom, a halogen AIBO a methyl group, and R 4 is am <no (Ci-C4 -alk <i or aminophenol. 2. Sposób otrzymywania3-podstawionego 2-metylopirymido[5,4-c]cynnolin-4(3H)-onu o wzorze I, w którym R,, R-i R3 są takie same iub różne i oznaczają atom wodoru aibo atom fluorowca, aibo grupę metylową, a R4 oznacza amino(Ci-C4-alkil albo aminofenol, znamienny tym, że 1,3-oksazy-no[5,4-c]cynnolino-4-on poddaje się kondensacji z pochodną hydrazyny w środowisku rozpuszczalnika polarnego, korzystnie acetonitrylu, po czym mieszaninę schładza się, produkt odsącza się i krystalizuje.2. A method for the preparation of a 3-substituted 2-methylpyrimido [5,4-c] cinnolin-4 (3H) -one of formula I, wherein R 1, R 1 and R 3 are the same or different and represent a hydrogen atom or a halogen atom, a or a group methyl, and R4 is amino (C1-C4-alkyl or aminophenol, characterized in that 1,3-oxazino [5,4-c] cinnoline-4-one is condensed with a hydrazine derivative in a polar solvent, preferably acetonitrile, the mixture is cooled, the product is filtered off and crystallized. 3. Sposób według zastrz. 2, znamienny tym, że pochodną hydrazyny stanowi fenylohydrazyna.3. The method according to p. The process of claim 2, wherein the hydrazine derivative is phenylhydrazine. 4. Sposób orrzym\yvania 3^|^c^c^^t^\^i<^n^^^o 2-rm^tr^lc^|^irr^ι^i^or[^,,^^(3]]^c^ι^nc^lir^--4((3l^)-or^u o wzorze I, w którym R,, R2 i R3 są takie same lub różne i oznaczają atom wodoru albo atom fluorowca, albo grupę metylową, a R4 oznacza amino(Ci-C4-alkil albo aminofenol, znamienny tym, że metylohydrazyd kwasu 4-amino-3-cynnolinokarboksylowego poddaje się kondensacji z ortooctanem trójetylu w środowisku rozpuszczalnika polarnego, korzystnie w bezwodnym kwasie octowym, po czym mieszaninę schładza się, a odsączony osad krystalizuje się.4. Orrzym \ yvania 3 ^ | ^ c ^ c ^^ t ^ \ ^ i <^ n ^^^ o 2-rm ^ tr ^ lc ^ | ^ irr ^ ι ^ i ^ or [^ ,, ^^ (3]] &lt; 3 &gt; C &lt; &quot; &gt; &lt; &gt; lir &lt; 4 &gt; a methyl group, and R4 is amino (C1-C4-alkyl or aminophenol, characterized in that 4-amino-3-cinnolinecarboxylic acid methylhydrazide is condensed with triethyl orthoacetate in a polar solvent medium, preferably in anhydrous acetic acid, and then the mixture is cooled down) and the filtered precipitate crystallizes.
PL358571A 2003-02-03 2003-02-03 3-substituted 2-methyl pyrimido[5,4-c]cinnoline-4(3h)one and its derivatives and method of manufacture of 3-substituted 2-methyl pyrimido[5,4-c]cinnoline-4(3h)one and its derivatives PL194098B1 (en)

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