RU2312660C2 - 4-acetyl-3-hydroxy-1-(2-hydroxyethylaminoethyl)-5-phenyl-3-pyrrolin-2-one eliciting anti-coagulant activity - Google Patents
4-acetyl-3-hydroxy-1-(2-hydroxyethylaminoethyl)-5-phenyl-3-pyrrolin-2-one eliciting anti-coagulant activity Download PDFInfo
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- RU2312660C2 RU2312660C2 RU2005123564/15A RU2005123564A RU2312660C2 RU 2312660 C2 RU2312660 C2 RU 2312660C2 RU 2005123564/15 A RU2005123564/15 A RU 2005123564/15A RU 2005123564 A RU2005123564 A RU 2005123564A RU 2312660 C2 RU2312660 C2 RU 2312660C2
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- pyrrolin
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- hydroxyethylaminoethyl
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- QEEVEESGESRIHZ-UHFFFAOYSA-N 3-acetyl-1-[2-(2-hydroxyethylazaniumyl)ethyl]-5-oxo-2-phenyl-2h-pyrrol-4-olate Chemical compound CC(=O)C1=C(O)C(=O)N(CCNCCO)C1C1=CC=CC=C1 QEEVEESGESRIHZ-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 230000014508 negative regulation of coagulation Effects 0.000 title claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract 4
- 239000008280 blood Substances 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 6
- 230000015271 coagulation Effects 0.000 abstract description 6
- 238000005345 coagulation Methods 0.000 abstract description 6
- 230000002429 anti-coagulating effect Effects 0.000 abstract description 5
- 230000023555 blood coagulation Effects 0.000 abstract description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FSJPDHBGNBBFDI-UHFFFAOYSA-N 4-(4-hydroxy-3-methylsulfonyl-5-oxo-2-phenyl-2h-pyrrol-1-yl)butanoic acid Chemical compound CS(=O)(=O)C1=C(O)C(=O)N(CCCC(O)=O)C1C1=CC=CC=C1 FSJPDHBGNBBFDI-UHFFFAOYSA-N 0.000 description 2
- JKSIQHDUIKCERS-UHFFFAOYSA-N 4-hydroxy-1,2-dihydropyrrol-5-one Chemical compound OC1=CCNC1=O JKSIQHDUIKCERS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- LHIJANUOQQMGNT-UHFFFAOYSA-N aminoethylethanolamine Chemical compound NCCNCCO LHIJANUOQQMGNT-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- UNRQTHVKJQUDDF-UHFFFAOYSA-N acetylpyruvic acid Chemical compound CC(=O)CC(=O)C(O)=O UNRQTHVKJQUDDF-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- OMHOEQINEXASKE-UHFFFAOYSA-N methyl 2,4-dioxopentanoate Chemical compound COC(=O)C(=O)CC(C)=O OMHOEQINEXASKE-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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Abstract
Description
Изобретение относится к новому биологически активному веществу ряда 3-гидрокси-3-пирролин-2-она, а именно к 4-ацетил-3-гидрокси-1-(2-гидроксиэтиламиноэтил)-5-фенил-3-пирролин-2-ону формулы:The invention relates to a new biologically active substance of the series 3-hydroxy-3-pyrrolin-2-one, namely to 4-acetyl-3-hydroxy-1- (2-hydroxyethylaminoethyl) -5-phenyl-3-pyrrolin-2-one formulas:
обладающему антикоагулянтной активностью, что позволяет предполагать возможность использования его в медицине в качестве препарата, эффективно снижающего свертываемость крови.possessing anticoagulant activity, which suggests the possibility of using it in medicine as a drug that effectively reduces blood coagulation.
Ближайшим структурным аналогом заявляемого соединения является 3-гидрокси-1-(3-карбоксипропил)-4-метилсульфонил-5-фенил-3-пирролин-2-он (Катаева А.В. Синтез, свойства и биологическая активность 1-замещенных 5-арил-3-гидрокси-4-метилсульфонил-3-пирролин-2-онов: дисс.... канд. фармацевт. наук / Перм. гос. фармацевт. акад. - Пермь, 2000. - С.60) формулы:The closest structural analogue of the claimed compound is 3-hydroxy-1- (3-carboxypropyl) -4-methylsulfonyl-5-phenyl-3-pyrrolin-2-one (Kataeva A.V. Synthesis, properties and biological activity of 1-substituted 5- aryl-3-hydroxy-4-methylsulfonyl-3-pyrrolin-2-ones: diss .... Candidate of Pharmaceutical Sciences / Perm State Pharmacist Acad. - Perm, 2000. - P.60) formulas:
который взят за прототип и не обладает антикоагулянтным действием. Эталоном сравнения является гепарин (Машковский М.Д. Лекарственные средства: практ. пособие. - 15 изд. - М.: "Новая волна", 2005. - С.475), который применяется в медицинской практике и является аналогом по действию.which is taken as a prototype and does not have anticoagulant effect. The comparison standard is heparin (Mashkovsky MD Medicines: practical aid. - 15th ed. - M .: "New Wave", 2005. - P.475), which is used in medical practice and is an analogue in action.
Сущность изобретения - поиск в ряду 3-гидрокси-3-пирролин-2-онов соединения с выраженной антикоагулянтной активностью, снижающего свертываемость крови. Это достигается синтезом 4-ацетил-3-гидрокси-1-(2-гидроксиэтиламиноэтил)-5-фенил-3-пирролин-2-она, обладающего антикоагулянтным действием.The essence of the invention is the search in a series of 3-hydroxy-3-pyrrolin-2-ones for compounds with pronounced anticoagulant activity that reduces blood coagulation. This is achieved by the synthesis of 4-acetyl-3-hydroxy-1- (2-hydroxyethylaminoethyl) -5-phenyl-3-pyrrolin-2-one, which has an anticoagulant effect.
Заявляемое соединение получают взаимодействием метилового эфира ацетилпировиноградной кислоты, бензальдегида и 2-гидроксиэтиламиноэтиламина по схеме:The inventive compound is obtained by the interaction of methyl ester of acetylpyruvic acid, benzaldehyde and 2-hydroxyethylaminoethylamine according to the scheme:
Пример получения заявляемого соединения.An example of obtaining the claimed compounds.
Пример 1Example 1
4-Ацетил-3-гидрокси-1-(2-гидроксиэтиламиноэтил)-5-фенил-3-пирролин-2-он 4-acetyl-3-hydroxy-1- (2-hydroxyethylaminoethyl) -5-phenyl-3-pyrrolin-2-one
К раствору 1.02 мл (0.01 М) бензальдегида и 1.01 мл (0.01 М) 2-гидроксиэтиламиноэтиламина в 5 мл 1,4-диоксана при комнатной температуре добавляют раствор 1.44 г (0.01 М) метилового эфира ацетилпировиноградной кислоты в 5 мл 1,4-диоксана и оставляют при той же температуре на 1 сутки. Образовавшийся осадок отфильтровывают, перекристаллизовывают из этанола и высушивают. Выход 1.76 г (58%). Т.пл.: 180-182°С. Найдено, %: С 63.08; Н 6.47; N 9.15. C16H20N2О4. Вычислено, %: С 63.14; Н 6.62; N 9.21.To a solution of 1.02 ml (0.01 M) of benzaldehyde and 1.01 ml (0.01 M) of 2-hydroxyethylaminoethylamine in 5 ml of 1,4-dioxane at room temperature, a solution of 1.44 g (0.01 M) of acetylpyruvic acid methyl ester in 5 ml of 1,4-dioxane is added and left at the same temperature for 1 day. The precipitate formed is filtered off, recrystallized from ethanol and dried. Yield 1.76 g (58%). Mp: 180-182 ° C. Found,%: C 63.08; H 6.47; N 9.15. C 16 H 20 N 2 O 4 . Calculated,%: C 63.14; H, 6.62; N, 9.21.
Заявляемое соединение представляет собой бесцветное кристаллическое вещество, растворимое в воде, этаноле, диметилформамиде, диметилсульфоксиде.The inventive compound is a colorless crystalline substance, soluble in water, ethanol, dimethylformamide, dimethyl sulfoxide.
ИК-спектр (SPECORD, вазелиновое масло, ν, см-1): 1648 (СО), 1706 (CON), 3150 (С(3)OH), 3360 (NH), 3420 (AlkOH).IR spectrum (SPECORD, liquid paraffin, ν, cm -1 ): 1648 (СО), 1706 (CON), 3150 (С (3) OH), 3360 (NH), 3420 (AlkOH).
ПМР-спектр (Bruker DRX500, 500.13 МГц, DMSO-D6, TMS, δ, м.д.): 2.11 (3Н, s, СН3СО), 2.74 (1Н, m,
Заявляемое соединение и аналог по структуре исследовали на наличие антикоагулянтной активности. Опыты проведены с помощью коагулометра "Минилаб 701". Для исследования использовали цитратную (3,8%) кровь (9:1) собаки. Влияние соединений на свертываемость крови испытывали в концентрации 1 мг/мл крови. В качестве эталона антикоагулянтной активности использовали раствор гепарина, который испытывали в концентрации 1 ЕД/мл крови. В каждой серии опытов было использовано восемь животных. Степень антикоагулянтной активности соединений определяли по изменению времени свертывания нитратной крови в сравнении с контролем и эталоном. Результаты обрабатывали с использованием коэффициента Стъюдента (Сернов Л.Н., Гацура В.В. Элементы экспериментальной фармакологии. М., 2000, с.312-313). Результаты испытаний представлены в таблице.The inventive compound and analogue in structure were examined for the presence of anticoagulant activity. The experiments were carried out using a Minilab 701 coagulometer. For the study, citrate (3.8%) blood (9: 1) of the dog was used. The effect of the compounds on blood coagulation was tested at a concentration of 1 mg / ml of blood. A heparin solution was used as a reference for anticoagulant activity, which was tested at a concentration of 1 U / ml of blood. In each series of experiments, eight animals were used. The degree of anticoagulant activity of the compounds was determined by the change in the coagulation time of nitrate blood in comparison with the control and the standard. The results were processed using Student's coefficient (Sernov L.N., Gatsura V.V. Elements of experimental pharmacology. M., 2000, pp. 313-313). The test results are presented in the table.
Как видно из таблицы, заявляемое соединение проявляет прямое антикоагулянтное действие, так как достоверно увеличивает время свертывания цитратной крови на 30,4%. Его структурный аналог достоверным антикоагулянтным эффектом не обладает. Эталон сравнения гепарин замедляет свертывание на 22,4%.As can be seen from the table, the claimed compound exhibits a direct anticoagulant effect, since it significantly increases the coagulation time of citrate blood by 30.4%. Its structural analogue does not have a reliable anticoagulant effect. Benchmark heparin slows down coagulation by 22.4%.
Острую токсичность заявляемого соединения определяли на беспородных белых мышах обоего пола массой 16-18 г. Соединение вводили внутрибрюшинно и внутривенно в виде водного раствора из расчета 0,1 мл на 10 г массы животного в возрастающих дозах. Результаты обрабатывали по Прозоровскому с вычислением средней смертельной дозы DL50 при Р=0,05 (Прозоровский В.Б. Экспресс-метод определения средней эффективной дозы и ее ошибки. / В.Б.Прозоровский, М.П. Прозоровская, В.М.Демченко. // Фармакол. и токсикол. - 1978. - Т.41, №4. - С.497-502).The acute toxicity of the claimed compound was determined on outbred white mice of both sexes weighing 16-18 g. The compound was administered intraperitoneally and intravenously in the form of an aqueous solution at the rate of 0.1 ml per 10 g of animal weight in increasing doses. The results were processed according to Prozorovsky with the calculation of the average lethal dose DL 50 at P = 0.05 (Prozorovsky V.B. Express method for determining the average effective dose and its errors. / VB Prozorovsky, MP Prozorovskaya, V.M. .Phemchenko. // Pharmacol. And Toxicol. - 1978. - T.41, No. 4. - S.497-502).
Установлено, что острая токсичность (DL50) заявляемого соединения при внутрибрюшинном введении составляет 1460,0 (610,4-2734,4) мг/кг, а при внутривенном - 467,2 (195,3-875,0) мг/кг.It was found that acute toxicity (DL 50 ) of the claimed compound with intraperitoneal administration is 1460.0 (610.4-2734.4) mg / kg, and with intravenous administration - 467.2 (195.3-875.0) mg / kg .
Работа выполнена при финансовой поддержке РФФИ (проект №04-03-96042).This work was supported by the Russian Foundation for Basic Research (project No. 04-03-96042).
ЛИТЕРАТУРАLITERATURE
1. Катаева А.В. Синтез, свойства и биологическая активность 1-замещенных 5-арил-3-гидрокси-4-метилсульфонил-3-пирролин-2-онов: дисс.... канд. фармацевт. наук. / Перм. гос. фармацевт. акад. - Пермь, 2000. - С.60.1. Kataeva A.V. Synthesis, properties and biological activity of 1-substituted 5-aryl-3-hydroxy-4-methylsulfonyl-3-pyrrolin-2-ones: diss .... cand. pharmacist. sciences. / Perm. state pharmacist. Acad. - Perm, 2000 .-- S.60.
2. Машковский М.Д. Лекарственные средства: практ. пособие. - 15 изд. - М.: "Новая волна", 2005. - С.475.2. Mashkovsky M.D. Medicines: pract. allowance. - 15th ed. - M.: "New Wave", 2005. - S. 475.
3. Сернов Л.Н., Гацура В.В. Элементы экспериментальной фармакологии. М., 2000, с.312-313.3. Sernov L.N., Gatsura V.V. Elements of experimental pharmacology. M., 2000, p. 312-313.
4. Прозоровский В.Б. Экспресс-метод определения средней эффективной дозы и ее ошибки. / В.Б.Прозоровский, М.П.Прозоровская, В.М.Демченко. // Фармакол. и токсикол. - 1978. - Т.41, №4. - С.497-502.4. Prozorovsky VB Express method for determining the average effective dose and its errors. / V.B. Prozorovsky, M.P. Prozorovskaya, V.M.Demchenko. // Farmakol. and toxicol. - 1978. - T.41, No. 4. - S.497-502.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5489693A (en) * | 1992-04-28 | 1996-02-06 | Linz; Guenter | Cyclic imino derivatives, pharmaceutical compositions containing these compounds and processes preparing them |
| GB2372986A (en) * | 2001-01-17 | 2002-09-11 | Xenova Ltd | 2-oxo, 4-hydroxy pyrroles and quinolines |
| RU2203887C2 (en) * | 1998-02-27 | 2003-05-10 | Санкио Компани, Лимитед | Cyclic amino-derivatives, pharmaceutical composition and method of disease prophylaxis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5489693A (en) * | 1992-04-28 | 1996-02-06 | Linz; Guenter | Cyclic imino derivatives, pharmaceutical compositions containing these compounds and processes preparing them |
| RU2203887C2 (en) * | 1998-02-27 | 2003-05-10 | Санкио Компани, Лимитед | Cyclic amino-derivatives, pharmaceutical composition and method of disease prophylaxis |
| GB2372986A (en) * | 2001-01-17 | 2002-09-11 | Xenova Ltd | 2-oxo, 4-hydroxy pyrroles and quinolines |
Non-Patent Citations (2)
| Title |
|---|
| CHEMCATS. AN2004:20694 RN681855-37-8 publication date 14.06.2004 [on line] [26.12.2005] Найдено из базы данных STN International Database. * |
| МАШКОВСКИЙ М.Д. Лекарственные средства. - М.: Медицина, 1993, ч.2, с.79-85. * |
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