RU2649141C2 - 3,4-dimethyl-6-(3-pyridyl)-n-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide with antifungal activity against the candida albicans strain - Google Patents

3,4-dimethyl-6-(3-pyridyl)-n-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide with antifungal activity against the candida albicans strain Download PDF

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RU2649141C2
RU2649141C2 RU2015114858A RU2015114858A RU2649141C2 RU 2649141 C2 RU2649141 C2 RU 2649141C2 RU 2015114858 A RU2015114858 A RU 2015114858A RU 2015114858 A RU2015114858 A RU 2015114858A RU 2649141 C2 RU2649141 C2 RU 2649141C2
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candida albicans
tetrahydropyrimidine
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Владимир Леонидович Гейн
Татьяна Федоровна Одегова
Татьяна Михайловна Замараева
Андрей Юрьевич Федотов
Борис Яковлевич Сыропятов
Михаил Валерьевич Томилов
Наталия Викторовна Аликина
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государственное бюджетное образовательное учреждение высшего профессионального образования "Пермская государственная фармацевтическая академия" Министерства здравоохранения Российской Федерации (ГБОУ ВПО ПГФА Минздрава России)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

FIELD: pharmaceuticals.
SUBSTANCE: invention relates to novel pyrimidine derivative, namely to 3,4-dimethyl-6-(3-pyridyl)-N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide of formula (1). Compound has antifungal effect against the strain of Candida albicans, which suggests its use in medical practice as antifungal agent.
Figure 00000007
. Compound 1 is prepared by reacting a three-component condensation of acetoacetanilide, 3-pyridinecarboxaldehyde, N-methylurea while maintaining the reagents at a temperature of 120–150 °C before the gas evolution ceases and the reaction mixture solidifies, after cooling, the residue is treated with ethanol. Claimed compound is a colorless crystal with Tpl 243–245 °C, soluble in dimethylformamide, acetic acid, when heated – in ethanol, stable during storage. Compound has antifungal activity with a minimum inhibitory concentration of 31.25 mcg/ml with respect to Candida albicans. LD50 when administered intraperitoneally to white mice was 5,640 mg/kg.
EFFECT: compound has antifungal effect.
1 cl, 1 tbl, 1 ex

Description

Изобретение относится к области органической химии, производным пиримидина, а именно новому биологически активному 3,4-диметил-6-(3-пиридил)-N-фенил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамиду (1) формулы:The invention relates to the field of organic chemistry, derivatives of pyrimidine, namely the new biologically active 3,4-dimethyl-6- (3-pyridyl) -N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide (1) formulas:

Figure 00000001
Figure 00000001

обладающему противогрибковым действием в отношении штамма Candida albicans, что позволяет предположить его использование в медицинской практике в качестве противогрибкового средства.possessing an antifungal effect against the strain of Candida albicans, which suggests its use in medical practice as an antifungal agent.

Ближайшим структурным аналогом к заявляемому соединению является соединение формулы 2, проявляющее антигипертензивное свойство [Wan, Jie-Ping. Synthesis of Dihydropyrimidinones and Thiones by Multicomponent Reactions: Strategies Beyond the Classical Biginelli Reaction / Jie-Ping Wan, Yunyun Liu // Synthesis. - 2012. - №23. - P. 3943-3953].The closest structural analogue to the claimed compound is a compound of formula 2, exhibiting antihypertensive property [Wan, Jie-Ping. Synthesis of Dihydropyrimidinones and Thiones by Multicomponent Reactions: Strategies Beyond the Classical Biginelli Reaction / Jie-Ping Wan, Yunyun Liu // Synthesis. - 2012. - No. 23. - P. 3943-3953].

Figure 00000002
Figure 00000002

Целью предлагаемого изобретения является поиск среди производных пиримидина соединений, обладающих противогрибковой активностью в отношении штамма Candida albicans.The aim of the invention is to search among derivatives of pyrimidine compounds having antifungal activity against a strain of Candida albicans.

Поставленная цель достигается получением 3,4-диметил-6-(3-пиридил)-N-фенил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамида (1), который синтезируют трехкомпонентной реакцией ацетоацетанилида, 3-пиридинкарбоксальдегида, N-метилмочевины [Синтез диарилзамещенных 3,4-диметил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамидов / В.Л. Гейн, А.Ю. Федотов, Т.М. Замараева [и др.] // Журн. общей химии. - 2013. - Т. 83, №4. - С. 701-702].This goal is achieved by obtaining 3,4-dimethyl-6- (3-pyridyl) -N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide (1), which is synthesized by a three-way reaction of acetoacetanilide, 3 -pyridinecarboxaldehyde, N-methylurea [Synthesis of diaryl-substituted 3,4-dimethyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides / V.L. Gain, A.Yu. Fedotov, T.M. Zamaraeva [et al.] // Zh. general chemistry. - 2013. - T. 83, No. 4. - S. 701-702].

Figure 00000003
Figure 00000003

Методика получения 3,4-диметил-6-(3-пиридил)-N-фенил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамидаThe method of obtaining 3,4-dimethyl-6- (3-pyridyl) -N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide

Смесь 1.77 г (0.01 моль) ацетоацетанилида, 0.94 мл (0.01 моль) 3-пиридинкарбоксальдегида и 0.74 (0.01 моль) N-метилмочевины выдерживали при температуре 120-150°C до прекращения газовыделения и затвердения реакционной смеси, после охлаждения остаток обрабатывали этанолом, отфильтровывали и перекристаллизовывали из этилового спирта. Выход составляет 2.77 г (86%).A mixture of 1.77 g (0.01 mol) of acetoacetanilide, 0.94 ml (0.01 mol) of 3-pyridinecarboxaldehyde and 0.74 (0.01 mol) of N-methylurea was kept at a temperature of 120-150 ° C until gas evolution ceased and the reaction mixture solidified, after cooling, the residue was treated with ethanol and filtered and recrystallized from ethyl alcohol. The yield is 2.77 g (86%).

Заявляемое соединение представляет собой бесцветное кристаллическое вещество, растворимое в ДМФА, уксусной кислоте, при нагревании - в этиловом спирте, устойчивое при хранении. Tпл 243-245°C. Вычислено, % С 67.07; Н 5.63; N 17.38. C18H18N4O2. Найдено, % С 67.19, 66.96; Н 5.71, 5.54; N 17.48, 17.27.The inventive compound is a colorless crystalline substance soluble in DMF, acetic acid, when heated in ethanol, stable during storage. T mp 243-245 ° C. Calculated,% C 67.07; H 5.63; N, 17.38. C 18 H 18 N 4 O 2 . Found,% C 67.19, 66.96; H 5.71, 5.54; N 17.48, 17.27.

Спектр ЯМР 1Н соединения 1 снят при рабочей частоте 300 Мгц, внутренний эталон ТМС. Спектр ЯМР 1Н, δ, м.д. J, Гц: 2.17 с (3Н, 4-СН3), 3.06 с (3Н, 3-СН3), 5.26 д (1Н, 6-СН, J=1.8 Гц), 6.91-7.56 м (9Н, С6Н5, C5H4N), 7.66 д (1Н, 1-NH, J=1.8 Гц), 9.68 с (1Н, NH).The 1 H NMR spectrum of compound 1 was recorded at an operating frequency of 300 MHz, and the internal TMS standard. 1 H NMR spectrum, δ, ppm J, Hz: 2.17 s (3H, 4-CH 3 ), 3.06 s (3H, 3-CH 3 ), 5.26 d (1H, 6-CH, J = 1.8 Hz), 6.91-7.56 m (9H, C 6 H 5 , C 5 H 4 N), 7.66 d (1H, 1-NH, J = 1.8 Hz), 9.68 s (1H, NH).

ИК-спектр снят для соединения 1 в вазелиновом масле. В ИК-спектре соединения 1 наблюдаются полосы, обусловленные валентными колебаниями амидной группы (1696 см-1), связи NH (3136 см-1), а также полоса С=С в области 1608 см-1.The IR spectrum was taken for compound 1 in liquid paraffin. In the IR spectrum of compound 1, bands are observed due to stretching vibrations of the amide group (1696 cm -1 ), NH bonds (3136 cm -1 ), and the C = C band in the region of 1608 cm -1 .

Соединение 1 исследовали на наличие противогрибковой активности. Противогрибковую активность определяли методом серийных разведений в жидкой питательной среде Сабуро. Для испытуемого соединения была определена минимальная подавляющая концентрация (МПК, мкг/мл) в отношении фармакопейного штамма Candida albicans.Compound 1 was tested for antifungal activity. Antifungal activity was determined by the method of serial dilutions in a liquid nutrient medium Saburo. For the test compound, the minimum inhibitory concentration (MIC, μg / ml) was determined for the pharmacopeia strain of Candida albicans.

В качестве эталона сравнения использовали флуконазол. Результаты исследования приведены в таблице 1.Fluconazole was used as a reference standard. The results of the study are shown in table 1.

Figure 00000004
Figure 00000004

Острую токсичность определяли при внутрибрюшинном введении нелинейным белым мышам массой 20-25 г. Результаты обрабатывали по Прозоровскому с вычислением средней смертельной дозы (ЛД50) [Прозоровский В.В., Прозоровская М.П., Демченко В.М. // Фармакология и токсикология. - 1978. - Т. 41. - №4. - С. 497-502]. Острая токсичность (ЛД50) заявляемого соединения составила 5640 (>5100) мг/кг.Acute toxicity was determined by intraperitoneal administration to nonlinear white mice weighing 20-25 g. The results were processed according to Prozorovsky with the calculation of the average lethal dose (LD 50 ) [Prozorovsky VV, Prozorovskaya MP, Demchenko VM // Pharmacology and toxicology. - 1978. - T. 41. - No. 4. - S. 497-502]. Acute toxicity (LD 50 ) of the claimed compounds was 5640 (> 5100) mg / kg

Таким образом, заявляемое соединение 1 -3,4-диметил-6-(3-пиридил)-N-фенил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамид проявляет противогрибковое действие в отношении штамма Candida albicans, равное активности флуконазола, но менее токсичное в 3 раза.Thus, the claimed compound 1 -3,4-dimethyl-6- (3-pyridyl) -N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide exhibits antifungal activity against a strain of Candida albicans equal to the activity of fluconazole, but less toxic 3 times.

ЛитератураLiterature

1. Wan, Jie-Ping. Synthesis of Dihydropyrimidinones and Thiones by Multicomponent Reactions: Strategies Beyond the Classical Biginelli Reaction / Jie-Ping Wan, Yunyun Liu // Synthesis. - 2012. - №23. - P. 3943-3953.1. Wan, Jie-Ping. Synthesis of Dihydropyrimidinones and Thiones by Multicomponent Reactions: Strategies Beyond the Classical Biginelli Reaction / Jie-Ping Wan, Yunyun Liu // Synthesis. - 2012. - No. 23. - P. 3943-3953.

2. Синтез диарилзамещенных 3,4-диметил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамидов / В.Л. Гейн, А.Ю. Федотов, Т.М. Замараева [и др.] // Журн. общей химии. - 2013. - Т. 83, №4. - С. 701-702.2. Synthesis of diaryl substituted 3,4-dimethyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides / V.L. Gain, A.Yu. Fedotov, T.M. Zamaraeva [et al.] // Zh. general chemistry. - 2013. - T. 83, No. 4. - S. 701-702.

3. Прозоровский В.В., Прозоровская М.П., Демченко В.М. // Фармакология и токсикология. - 1978. - Т. 41. - №4. - С. 497-502.3. Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. // Pharmacology and toxicology. - 1978. - T. 41. - No. 4. - S. 497-502.

Claims (3)

3,4-Диметил-6-(3-пиридил)-N-фенил-2-оксо-1,2,3,6-тетрагидропиримидин-5-карбоксамид формулы3,4-Dimethyl-6- (3-pyridyl) -N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide of the formula
Figure 00000005
,
Figure 00000005
, проявляющий противогрибковое действие в отношении штамма Candida albicans.exhibiting antifungal activity against a strain of Candida albicans.
RU2015114858A 2015-04-20 2015-04-20 3,4-dimethyl-6-(3-pyridyl)-n-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide with antifungal activity against the candida albicans strain RU2649141C2 (en)

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Cited By (1)

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RU2785688C1 (en) * 2022-07-06 2022-12-12 Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермская государственная фармацевтическая академия" Министерства здравоохранения Российской Федерации Use of 3,4-dimethyl-6-(3-nitrophenyl)-2-oxo-n-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxamide as agent with analgesic activity

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RU2004135554A (en) * 2002-05-09 2006-01-20 Цитокинетикс, Инк. (Us) Pyrimidinones, compositions based on them and methods for their use
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Title
RU 2473549 C2 ( ДЖЕНЕНТЕК, ИНК.), 27.01.2013. RU 2004135554 А (ЦИТОКИНЕТИКС, ИНК.), 20.01.2006. WO 2013093484 A1 (ONO PHARMACEUTICAL CO., LTD), 27.06.2013. *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2785688C1 (en) * 2022-07-06 2022-12-12 Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермская государственная фармацевтическая академия" Министерства здравоохранения Российской Федерации Use of 3,4-dimethyl-6-(3-nitrophenyl)-2-oxo-n-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxamide as agent with analgesic activity

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