LV14840B - Quinazolinones with triazole substituent in side chain - Google Patents

Quinazolinones with triazole substituent in side chain Download PDF

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LV14840B
LV14840B LVP-13-188A LV130188A LV14840B LV 14840 B LV14840 B LV 14840B LV 130188 A LV130188 A LV 130188A LV 14840 B LV14840 B LV 14840B
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arom
side chain
quinazolinones
mmol
triazole
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LVP-13-188A
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LV14840A (en
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Irisa RĀVIŅA
Daina ZICĀNE
Zenta Tetere
Māris TURKS
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Rīgas Tehniskā Universitāte
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Abstract

Novel quinazolinone derivatives with triazole substituent in side chain have been synthesised.

Description

IZGUDROJUMA APRAKSTSDESCRIPTION OF THE INVENTION

Izgudrojums attiecas uz bioorganiskās ķīmijas nozari, konkrēti, jaunu hinazolinonatriazola atvasinājumu sintēzi.The present invention relates to the field of bioorganic chemistry, in particular to the synthesis of novel quinazolinonatriazole derivatives.

Hinazolinoni ir slāpekli saturoši sešlocekļu heterocikliski savienojumi, kam ir svarīga loma medicīnisku preparātu izstrādē. Zināms liels skaits hinazolīna ciklu saturošu bioloģiski aktīvu savienojumu ar pretvēža [1], pretdrudža [2], pretiekaisuma [3] un antialerģisku [4] iedarbību.Quinazolinones are nitrogen-containing six-membered heterocyclic compounds that play an important role in the development of medicinal products. A large number of quinazoline cycle-containing biologically active compounds with anticancer [1], antipyretic [2], anti-inflammatory [3] and anti-allergic [4] effects are known.

Arvien palielinās ari triazola atvasinājumu loma farmācijas un citās ķīmijas nozarēs. Potenciāli farmaceitiski līdzekļi, kas balstīti uz 1,2,3-triazolu funkciju, ir, piemēram, klīniski pārbaudītais pretvēža līdzeklis ar pagaidu apzīmējumu CAI [5]. Organiskajā un medicīnas ķīmijā 1,2,3-triazolus izmanto kāpeptīdu saites izostērus [6].The role of triazole derivatives in the pharmaceutical and other chemical industries is also increasing. Potential pharmaceuticals based on 1,2,3-triazoles are, for example, the clinically tested anticancer agent temporarily labeled CAI [5]. In organic and medical chemistry, 1,2,3-triazoles are used as peptide bond isosters [6].

Pamatojoties uz augšminētajiem faktiem var sagaidīt, ka savstarpēji savienojot šos fragmentus - hinazolinonu un 1,2,3-triazolu, veidosies savienojumi ar pilnīgi jaunu vai modificētu bioloģisko aktivitāti. Literatūrā šāda tipa savienojumi nav aprakstīti, taču medicīnas ķīmijas jomā, kas apskata pretvēža, pretdrudža, pretiekaisuma un antialerģiskus preparātus uz hinazolīna bāzes, bioloģiskās aktivitātes modulēšanā nozīmīga loma var būt sānu ķēdes aizvietotājiem, tāpēc par izgudrojuma mērķi izvirzījām jaunu hinazolinona atvasinājumu ar triazola aizvietotāju sānu ķēdē sintēzi.Based on the above, it can be expected that the coupling of these moieties, quinazolinone and 1,2,3-triazole, will result in the formation of entirely new or modified biological activities. Compounds of this type have not been described in the literature, but in the field of medical chemistry, which deals with quinazoline based anticancer, antipyretic, anti-inflammatory and anti-allergic agents, side chain substitutions may play an important role in modulating biological activity. synthesis.

Izgudrojuma mērķis ir sintezēt jaunus hinazolinona atvasinājumus ar triazola aizvietotāju sānu ķēdē.The object of the invention is to synthesize new quinazolinone derivatives with a triazole substituent on the side chain.

Mērķis tiek sasniegts sintezējot jaunus hinazolīn-4(3//)-onus ar triazola ciklu saturošu sānu ķēdi hinazolinona cikla C(3) pozīcijā. Sintēze veikta saskaņā ar 1. shēmu, pēc kuras literatūrā zināmajam hinazolīna benzsulfonilatvasinājumam (3) tozilgrupu aizvieto ar azidogrupu un iegūto 3-azido-4(3//)-hinazolinonu (4) apstrādā ar acetilēna atvasinājumu, pielietojot Huisgena sintēzes metodi, kas pamatojas uz vara(I) katalizētu alkīnu 1,3ciklopievienošanos azīdiem. Reakciju rezultātā iegūti deviņi jauni hinazolīn-4(3H)-oni ar triazola ciklu sānu ķēdē (5), kur R ir sānu ķēdē aizvietota vai neaizvietota alkil- vai cikloalkilgrupa.The object is achieved by the synthesis of new quinazolin-4 (3 H) -ones with a triazole ring-containing side chain at the C (3) position of the quinazolinone ring. The synthesis is carried out according to Scheme 1 whereby the tosyl group of the quinazoline benzenesulfonyl derivative (3) known in the literature is replaced by an azido group and the resulting 3-azido-4 (3 H) -quinazolinone (4) is treated with an acetylene derivative using Huisgen synthesis method. on copper (I) catalyzed 1,3-cycloaddition of alkynes to azides. The reactions yielded nine new quinazolin-4 (3H) -ones with a triazole ring in the side chain (5), where R is a substituted or unsubstituted alkyl or cycloalkyl group in the side chain.

1. shēmaScheme 1

Izgudrojuma realizācijas piemēri:Examples of realization of the invention:

1. piemērs.Example 1:

3-(2-azidoetil)hinazolīh-4(37/)-ons (4)3- (2-Azidoethyl) quinazolin-4 (3 H) -one (4)

2,8 g (8 mmol) 2-(4-oksohinazolīn-3(4^-il)etil-4-metilbenzosulfonāta šķīdumam (3) 30 ml dimetilformamīda pievieno 2,6 g (40 mmol) nātrija azīda un karsē 1 stundu 60°C temperatūrā (PHS (plānā slāņa hromatogrāfija) kontrole). Reakcijas maisījumam pievieno metil-trešbutilēteri (300 ml) un mazgā ar piesātinātu nātrija hlorīda šķīdumu (10 x 20 ml). Organisko fāzi žāvē ar bezūdens nātrija sulfātu un ietvaicē pazeminātā spiedienā. Iegūst 1,7 g (99%) savienojumu 4 baltas kristāliskas vielas veidā, kuru bez attīrīšanas izmanto tālākām reakcijām. K. p. 63-64°C ^-KMRQOOMHx, CDC13), δ, ppm: 3.77 (2H, t, 7=5.7, СН2); 4.13 (2Н, t, 7=5.7, СН2); 7.53 (1Н, t, 7=6.8, arom.); 7.69 (2Н, m, arom.); 8.05 (1Н, pl.s, =CH); 8.32 (1H, d, 7=7.9, arom.).To a solution of 2.8 g (8 mmol) of 2- (4-oxoquinazolin-3 (4'-yl) ethyl 4-methylbenzosulfonate (3) in 30 ml of dimethylformamide add 2.6 g (40 mmol) of sodium azide and heat for 1 hour 60. ° C (PHS (thin layer chromatography) control) Methyl tert-butyl ether (300 mL) is added to the reaction mixture and washed with saturated sodium chloride solution (10 x 20 mL) The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. 1.7 g (99%) compound 4 in the form of white crystalline substance, which without purification used for further reactions. K. p. 63-64 ° C @ -KMRQOOMHx, CDC1 3) δ ppm: 3.77 (2H, t, 7 = 5.7, С 2 ); 4.13 (2Н, t, 7 = 5.7, СН 2); 7.53 (1N, t, 7 = 6.8, arom.); 7.69 (2N, m, arom.); 8.05 (1N, pl.s, = CH); 8.32 (1H, d, J = 7.9, arom.).

2. piemērs.Example 2:

[(l,2,3-triazol-l-il)etil]hinazolm-4(37/)-°ni (5a-h)[(1,2,3-Triazol-1-yl) ethyl] quinazol-4 (37H) -N (5a-h)

A metode:Method A:

0,32 g (1,5 mmol)3-(2-azidoetil)hmazolm-4(377)-ona (4) šķīdumam 5 ml acetona pievieno 1,8 mmol alkīna, 60 mg (0,30 mmol) nātrija askorbāta šķīdumu 0,1 ml ūdens un 37,5 mg (0.15 mmol) vara sulfāta (CuSO4-5 H2O) šķīdumu 0,1 ml ūdens. Iegūto maisījumu maisa un vāra 17 stundas (PSH kontrole). Acetonu ietvaicē pazeminātā spiedienā. Atlikumu šķīdina dihlormetānā (20 ml) un mazgā ar piesātinātu nātrija hlorīda ūdens šķīdumu (3 x 10 ml). Organisko fāzi žāvē ar bezūdens nātrija sulfātu, filtrē un ietvaicē pazeminātā spiedienā. Atlikumu pārkristalizē.To a solution of 0.32 g (1.5 mmol) of 3- (2-azidoethyl) -mazol-4 (377) -one (4) in 5 ml of acetone add 1.8 mmol of alkyne, 60 mg (0.30 mmol) of sodium ascorbate solution 0.1 ml of water and 37.5 mg (0:15 mmol) of copper sulfate (CuSO4-5 H 2 O) solution of 0.1 ml of water. Stir the resulting mixture for 17 hours (PSH control). The acetone is evaporated under reduced pressure. The residue is dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium chloride solution (3 x 10 ml). The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is recrystallized.

В metode:Method В:

0,32 g (1,5 mmol) 3-azidoetil)hinazolm-4(377)-ona (4) šķīdumam 5 ml tetrahidrofurāna pievieno 34 mg (0,18 mmol) varajodīda, 63 μΐ (0,36 mmol) diizopropiletilamīna un 1,8 mmol alkīnu. Iegūto maisījumu maisa un vāra 1-3 stundas (PSH kontrole). Šķīdinātāju ietvaicē pazeminātā spiedienā. Atlikumu šķīdina dihlormetānā (20 ml), mazgā ar trilona В buferšķīdumu (5 x 2 ml) un piesātinātu nātrija hlorīda šķīdumu (2x2 ml). Organisko fāzi žāvē ar bezūdens nātrija sulfātu, filtrē un ietvaicē pazeminātā spiedienā. Atlikumu pārkristalizē.To a solution of 3-azidoethyl) quinazol-4 (377) -one (4) (0.32 g, 1.5 mmol) in 5 mL of tetrahydrofuran was added 34 mg (0.18 mmol) of varaiodide, 63 μΐ (0.36 mmol) of diisopropylethylamine and 1.8 mmol of alkyne. Stir the resulting mixture for 1-3 hours (PSH control). The solvent is evaporated off under reduced pressure. The residue is dissolved in dichloromethane (20 ml), washed with trilone В buffer (5 x 2 ml) and saturated sodium chloride solution (2x2 ml). The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is recrystallized.

Savienojumu 5a-h analītiskie rādītāji atspoguļoti 1. tabulā; ’H-KMR spektru dati - 2. tabulā.The analytical data for compounds 5a-h are shown in Table 1; 'H-NMR spectra data in Table 2.

' . . . . . 1. tabula [(l,2,3-Triazol-l-il)etil]hinazolīn-4(377)-onu(5a-h) analītiskie rādītāji'. . . . . Table 1 [(1,2,3-Triazol-1-yl) ethyl] quinazolin-4 (377) -one (5a-h) analytical data

Savienojums Connection Metode The method Vanšanas ilgums, h Cutting time, h Iznākums, % Yield% Summāra formula Summative formula Atrasts, % Aprēķināts, % % Found,% calculated Kuš.t., °C Drying point, ° C C C H H N N 5a 5a В В 2 2 64 64 C16H19N5O C16H19N5O 64.24 64.63 64.24 64.63 6.29 6.44 6.29 6.44 23.39 23.55 23.39 23.55 126-129 126-129 5b 5b А А 1 1 42 42 C17H21N5O C17H21N5O 65.19 65.58 65.19 65.58 6.78 6.80 6.78 6.80 22.31 22.49 22.31 22.49 108-109 108-109 5c 5c А А 7 7th 58 58 C18H23N5O C18H23N5O 66.16 66.44 66.16 66.44 7.14 7.12 7.14 7.12 21.48 21.52 21.48 21.52 116-117 116-117 5d 5d А А 4 4 63 63 C13H13N5O2 C13H13N5O2 57.21 57.55 57.21 57.55 4.70 4.83 4.70 4.83 25.80 25.82 25.80 25.82 196-197 196-197

5e 5e A A 2,5 2.5 76 76 C14H15N5O2 C14H15N5O2 58.94 58.94 58.94 58.94 24.46 24.55 24.46 24.55 5.23 5.30 5.23 5.30 153-154 153-154 5f 5f A A 5 5 65 65 C15H17N5O2 C15H17N5O2 59.89 60.19 59.89 60.19 5.65 5.72 5.65 5.72 23.01 23.40 23.01 23.40 171-173 171-173 5g 5g В В 3 3 65 65 C18H21N5O2 C18H21N5O2 63.49 63.70 63.49 63.70 6.17 6.24 6.17 6.24 20.44 20.63 20.44 20.63 158-160 158-160 5h 5h В В 1 1 74 74 C15H15N5O C15H15N5O 63.86 64.04 63.86 64.04 5.11 5.37 5.11 5.37 24.59 24.89 24.59 24.89 171-173 171-173 5i 5i В В 1 1 47 47 C28H28N10O2 C28H28N10O2 62.27 62.67 62.27 62.67 5.22 5.27 5.22 5.27 25.81 26.10 25.81 26.10 215-217 215-217

2. tabula [(1,2,3-Triazol-l-il)etil]hmazolīn-4(377)-onu (5a-h) ’H-KMR spektriTable 2 [1 H-NMR Spectrum of [(1,2,3-Triazol-1-yl) ethyl] hexolin-4 (377) -one (5a-h)

Savienoi urns Connect the urn ’H-KMR-spektri (J, Hz) 1 H NMR Spectrum (J, Hz) 5a 5a 0.86 (3H, t, >7.5, CH3); 1.26 (2H, sekst, >7.5, CH2); 1.54 (2H, kv, J=7.5, CH2); 2.64 (2H, t, J=7.5, CH2); 4.52 (2H, t, >5.8, CH2); 4.76 (2H, t, >5.8, CH2); 7.10 (1H, pl.s, =CH); 7.53 (1H, t, >7.7, arom.); 7.57 (1H, pl.s, =CH); 7.68 (1H, d, >8.1, arom.); 7.78 (1H, t, >7.7, arom.); 8.31 (1H, d,>8.1, arom.)0.86 (3H, t,> 7.5, CH 3 ); 1.26 (2H, sext,> 7.5, CH 2 ); 1.54 (2H, kv, J = 7.5, CH 2 ); 2.64 (2H, t, J = 7.5, CH 2 ); 4.52 (2H, t,> 5.8, CH 2 ); 4.76 (2H, t,> 5.8, CH 2 ); 7.10 (1H, pl.s, = CH); 7.53 (1H, t, > 7.7, arom.); 7.57 (1H, m.p. = CH); 7.68 (1H, d, > 8.1, arom.); 7.78 (1H, t, > 7.7, arom.); 8.31 (1H, d, > 8.1, arom.) 5b 5b 0.85 (3H, t,>6.6, СНз); 1.19-1.35 (4H, m, 2CH2); 1.51-1.63 (2H, m, CH2); 2.562.71 (2H, m, CH2); 4.56 (2H, t, >6.1, CH2); 4.79 (2H, t, >6.1, CH2); 7.19 (1H, pl.s, =CH); 7.52 (1H, t, >7.7, arom.); 7.71 (1H, pl.s, =CH); 7.74-7.81 (2H, m, arom.); 8.32 (1H, d, >7.5, arom.)0.85 (3H, t,> 6.6, Si); 1.19-1.35 (4H, m, 2CH 2 ); 1.51-1.63 (2 H, m, CH 2 ); 2.562.71 (2H, m, CH 2 ); 4.56 (2H, t,> 6.1, CH 2 ); 4.79 (2H, t,> 6.1, CH 2 ); 7.19 (1H, m.p. = CH); 7.52 (1H, t, > 7.7, arom.); 7.71 (1H, m.p. = CH); 7.74-7.81 (2H, m, arom.); 8.32 (1H, d, > 7.5, arom.) 5c 5c 0.85 (3H, t, >6.4, СНз); 1.19-1.29 (6H, m, 3CH2); 1.48-1.66 (2H, m, CH2); 2.63 (2H, t, >7.5, CH2); 4.53 (1H, t, >5.8, CH2); 4.76 (1H, t, >5.8, CH2); 7.09 (1H, pl.s, =CH); 7.54 (1H, t, >7.3, arom.); 7.57 (1H, pl.s, =CH); 7.68 (1H, d, >8.1, arom.); 7.78 (1H, t, >8.1, arom.); 8.32 (1H, d, >7.3, arom.)0.85 (3H, t,> 6.4, Si); 1:19 to 1:29 (6H, m, 3CH 2); 1.48-1.66 (2 H, m, CH 2 ); 2.63 (2H, t,> 7.5, CH 2 ); 4.53 (1H, t,> 5.8, CH 2 ); 4.76 (1H, t,> 5.8, CH 2 ); 7.09 (1H, pl.s, = CH); 7.54 (1H, t,> 7.3, arom.); 7.57 (1H, m.p. = CH); 7.68 (1H, d, > 8.1, arom.); 7.78 (1H, t,> 8.1, arom.); 8.32 (1H, d, > 7.3, arom.) 5d 5d 4.46 (2H, d, >8.2, CH2); 4.49 (1H, t, >8.2, ОН); 4.77 (2H, t, >5.3, CH2); 5.23 (2H, t, >5.3, CH2); 7.55 (1H, t, >7.2, arom.); 7.62 (1H, d, >8.1, arom.); 7.82 (1H, t, >7.2, arom.); 7.89 (1H, pl.s, =CH); 8.03 (1H, pl.s, =CH); 8.15 (1H, d, >8.1, arom.)4.46 (2H, d,> 8.2, CH 2 ); 4.49 (1H, t, > 8.2, ON); 4.77 (2H, t,> 5.3, CH 2 ); 5.23 (2H, t,> 5.3, CH 2 ); 7.55 (1H, t,> 7.2, arom.); 7.62 (1H, d, > 8.1, arom.); 7.82 (1H, t,> 7.2, arom.); 7.89 (1H, m.p. = CH); 8.03 (1H, m.p. = CH); 8.15 (1H, d,> 8.1, arom.) 5e 5e 2.73 (2H, t, >6.8, CH2); 3.57 (2H, kv., >6.8, CH2); 4.42 (2H, t, >5.4, CH2); 4.68 (1H, t, >5.4, ОН); 4.73 (2H, t, >5.4, CH2); 7.57 (1H, t, >7.3, arom.); 7.65 (1H, d, >7.9, arom.); 7.84 (1H, t, >7.9, arom.); 7.88 (1H, pl.s, =CH); 7.90 (1H, pl.s, =CH); 8.17 (1H, d, >7.3, arom.) . 7 '2.73 (2H, t,> 6.8, CH 2 ); 3.57 (2H, sq.,> 6.8, CH 2 ); 4.42 (2H, t,> 5.4, CH 2 ); 4.68 (1H, t, > 5.4, ON); 4.73 (2H, t,> 5.4, CH 2 ); 7.57 (1H, t,> 7.3, arom.); 7.65 (1H, d, > 7.9, arom.); 7.84 (1H, t, > 7.9, arom.); 7.88 (1H, m.p. = CH); 7.90 (1H, m.p. = CH); 8.17 (1H, d, > 7.3, arom.). 7 ' 5f5f 1.41 (6H, s, 2CH3); 4.46 (2H, t, >5.6, CH2); 4.74 (2H, t, >5,6, CH2); 5.11 (1H, s, ОН); 7.55 (1H, t, >7.3, arom.); 7.64 (1H, d, >8.1, arom.); 7.82 (1H, t, >7.3, arom.); 7.89 (1H, pl.s, =CH); 7.91 (1H, pl.s, =ČH); 8.17 (1H, d, >=8.1, arom.)1.41 (6H, s, 2CH 3 ); 4.46 (2H, t,> 5.6, CH 2 ); 4.74 (2H, t,> 5.6, CH 2 ); 5.11 (1H, s, ON); 7.55 (1H, t,> 7.3, arom.); 7.64 (1H, d, > 8.1, arom.); 7.82 (1H, t,> 7.3, arom.); 7.89 (1H, m.p. = CH); 7.91 (1H, pl.s, = C H); 8.17 (1H, d, > = 8.1, arom.) 5g 5g 1.17-1.97 (10H, iri, 5CH2); 2.77 (1H, s, ОН); 4.50 (2H, t, >5.8, CH2); 4.76 (2H, t, >5.8, CH2); 7.31 (1H, pl.s, =CH); 7.50 (1H, t, >7.4, arom.); 7.56 (1H, pl.s, =CH); 7.62 (1H, d, >7.9, arom.); 7.75 (1H, t, >7.4, arom.); 8.27 (1H, d, >7.9, arom.)1.17-1.97 (10H, iri, 5CH 2 ); 2.77 (1H, s, ON); 4.50 (2H, t,> 5.8, CH 2 ); 4.76 (2H, t,> 5.8, CH 2 ); 7.31 (1H, m.p. = CH); 7.50 (1H, t,> 7.4, arom.); 7.56 (1H, m.p. = CH); 7.62 (1H, d, > 7.9, arom.); 7.75 (1H, t,> 7.4, arom.); 8.27 (1H, d, > 7.9, arom.) 5h 5h CDCI3. 0.66-0.73 (2H, m, CH2); 0.86 (2H,t, >7.2, CH2); 1.84 (1H, m, CH); 4.48 (2H, t, >5.7, CH2); 4.70 (2H, t, >5.7, CH2); 7.08 (1H, pl.s, =CH.); 7.48 (1H, t, >7.2, arom.); 7.60 (1H, pl.s, =CH); 7.65 (1H, d, >8.1, arom.); 7.73 (1H, t, J=1.2, arom.); 8.24 (1H, d, >8.1, arom.)CDCl3. 0.66-0.73 (2 H, m, CH 2 ); 0.86 (2H, t,> 7.2, CH 2 ); 1.84 (1H, m, CH); 4.48 (2H, t,> 5.7, CH 2 ); 4.70 (2H, t,> 5.7, CH 2 ); 7.08 (1H, m.p. = CH); 7.48 (1H, t,> 7.2, arom.); 7.60 (1H, m.p. = CH); 7.65 (1H, d, > 8.1, arom.); 7.73 (1H, t, J = 1.2, arom.); 8.24 (1H, d, > 8.1, arom.) 5i 5i CDCI3. 1.51-1.61 (4H, m, 2CH2); 2.55-2.67 (4H, m, 2CH2); 4.51 (4H, t, >6.2, 2CH2); 4.74 (4H, t, >6.2,2CH2); 7.16 (2H, pl.s, 2=CH); 7.51 (2H, t, >7.7, arom.); 7.57 (2H, pl.s, 2=CH); 7.62 (2H, d, >8.2, arom.); 7.75 (2H, t,>7.7, arom.); 8.27 (2H, d, >8.2, arom.)CDCl3. 1.51-1.61 (4H, m, 2CH 2); 2.55-2.67 (4H, m, 2CH 2); 4.51 (4H, t,> 6.2, 2CH 2 ); 4.74 (4H, t,> 6.2,2CH 2); 7.16 (2H, m.p., 2 = CH); 7.51 (2H, t, > 7.7, arom.); 7.57 (2H, m.p., 2 = CH); 7.62 (2H, d, > 8.2, arom.); 7.75 (2H, t, > 7.7, arom.); 8.27 (2H, d, > 8.2, arom.)

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Claims (1)

Hinazolinoni ar triazola aizvietotāju sanu ķēdē ar vispārēju formulu I, kur R ir sānu ķēdē aizvietota vai neaizvietota alkil- vai cikloalkil- grupa.Quinazolinones with a triazole substituent on the side chain of general formula I, wherein R is a side chain substituted or unsubstituted alkyl or cycloalkyl group.
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