RU2514007C1 - Anti-protist activity of 2-(4,5-dichloroimidazolyl-1)-5 nitropyridine - Google Patents
Anti-protist activity of 2-(4,5-dichloroimidazolyl-1)-5 nitropyridine Download PDFInfo
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- RU2514007C1 RU2514007C1 RU2012142539/15A RU2012142539A RU2514007C1 RU 2514007 C1 RU2514007 C1 RU 2514007C1 RU 2012142539/15 A RU2012142539/15 A RU 2012142539/15A RU 2012142539 A RU2012142539 A RU 2012142539A RU 2514007 C1 RU2514007 C1 RU 2514007C1
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- activity
- nitropyridine
- protist
- dichloroimidazolyl
- protistocidal
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- 230000000694 effects Effects 0.000 title abstract description 11
- 239000003814 drug Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 4
- 241000892918 Colpoda steinii Species 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 231100001228 moderately toxic Toxicity 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229960003683 amprolium Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OCINXEZVIIVXFU-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]phenyl]-1,3,5-triazinane-2,4,6-trione Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(SC(F)(F)F)C=C1 OCINXEZVIIVXFU-UHFFFAOYSA-N 0.000 description 2
- LCTXBFGHZLGBNU-UHFFFAOYSA-M amprolium Chemical compound [Cl-].NC1=NC(CCC)=NC=C1C[N+]1=CC=CC=C1C LCTXBFGHZLGBNU-UHFFFAOYSA-M 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229960001625 furazolidone Drugs 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229960000973 sulfadimethoxine Drugs 0.000 description 2
- 229960000898 toltrazuril Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- QAJJXHRQPLATMK-UHFFFAOYSA-N 4,5-dichloro-1h-imidazole Chemical compound ClC=1N=CNC=1Cl QAJJXHRQPLATMK-UHFFFAOYSA-N 0.000 description 1
- 208000003495 Coccidiosis Diseases 0.000 description 1
- 241000248332 Colpoda Species 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001165 anti-coccidial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
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- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Изобретение относится к области медицины и сельского хозяйства, а именно к химиотерапевтическим средствам для лечения заболеваний, вызываемых простейшими.The invention relates to the field of medicine and agriculture, namely to chemotherapeutic agents for the treatment of diseases caused by protozoa.
Известны производные ряда бензола, обладающие протистоцидными свойствами, к примеру, препарат химкокцид и другие (Хованских А.Е.,Илюшечкин Ю.П., Дириллов Ю.П. Кокцидиоз сельскохозяйственной птицы. - Ленинград, "Агропромиздат". - 1990. - с.71-91).Derivatives of a series of benzene with protistocidal properties are known, for example, the drug chemcocid and others (Khovanskikh A.E., Ilyushechkin Yu.P., Dirillov Yu.P. Coccidiosis of agricultural poultry. - Leningrad, Agropromizdat. - 1990. - p. .71-91).
Известны производные пиримидина, обладающие антикокцидийной активностью, к примеру препарат Байкокс (толтразурил, эйметерм, интракокс орал) и другие. Байкокс выбран нами в качестве прототипа (Липин А.В. и др., 2002).Derivatives of pyrimidine with anticoccidial activity are known, for example, the Baykoks preparation (toltrazuril, eimeterm, intracoxum) and others. We selected Baykoks as a prototype (A. Lipin et al., 2002).
Однако к протистоцидным препаратам, в том числе к байкоксу, быстро появляются резистентные штаммы паразитов, что заставляет разрабатывать новые препараты.However, resistive strains of parasites quickly appear against protistocidal drugs, including bycox, which forces them to develop new drugs.
Целью изобретения является применение 2-(4,5-дихлоримидазолил-1)-5-нитропиридина в качестве протистоцидного средства. Поставленная цель достигается синтезом и установлением протистоцидной активности 2-(4,5-дихлоримидазолил-1)-5-нитропиридина, который оказался в опытах ин витро в 2-4 раза более активным на модели Colpoda steinii, чем известный препарат байкокс.The aim of the invention is the use of 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine as a protistocidal agent. This goal is achieved by the synthesis and establishment of the protistocidal activity of 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine, which turned out to be in vitro experiments 2-4 times more active on the Colpoda steinii model than the well-known bikeox preparation.
Пример осуществления изобретения.An example embodiment of the invention.
Синтез 2-(4,5-дихлоримидазолил-1)-5-нитропиридина 1 осуществляется по схемеThe synthesis of 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine 1 is carried out according to the scheme
Методика синтеза: смесь 15.85 г (0,1 моль) 2-хлор-5-нитропирида 2, 13.7 г (0,1 моль) 4,5-дихлоримидазола 3, 27.6 г (0,2 моль) измельченного поташа и 80 мл диметилформамида интенсивно перемешивают 4 часа при 50-550°C. Реакционную смесь охлаждают до 20-25°C и выливают в 200 мл воды. Перемешивают 10 минут, отфильтровывают осадок, промывают водой 3×50 мл. Выход 22.0 (85%), т.пл. 116-118°C. Спектр ЯМР 1Н, б, м.д.: 8.042-8.071, дублет; 8.34, синглет; 8.83-8.87, квартет; 9.36-9.37, дублет. Найдено, %: C, 37.45; H, 1.33; N, 21.91. C8H4Cl2N4O2. Вычислено, %: C, 37.09; H, 1.55; N, 21.63.Synthesis procedure: a mixture of 15.85 g (0.1 mol) of 2-chloro-5-nitropyrid 2, 13.7 g (0.1 mol) of 4,5-dichlorimidazole 3, 27.6 g (0.2 mol) of ground potash and 80 ml of dimethylformamide stir vigorously for 4 hours at 50-550 ° C. The reaction mixture is cooled to 20-25 ° C and poured into 200 ml of water. It is stirred for 10 minutes, the precipitate is filtered off, washed with water 3 × 50 ml. Yield 22.0 (85%), mp. 116-118 ° C. NMR spectrum 1 H, b, ppm: 8.042-8.071, doublet; 8.34, singlet; 8.83-8.87, quartet; 9.36-9.37, doublet. Found,%: C, 37.45; H, 1.33; N, 21.91. C 8 H 4 Cl 2 N 4 O 2 . Calculated,%: C, 37.09; H, 1.55; N, 21.63.
Пример испытания протистоцидной активности.An example of a protistocidal activity test.
Протистоцидную активность определяли по методике, описанной в кн.: "Научное обеспечение инновационного развития отечественного животноводства". - Мат-лы Всероссийской научно-практической конференции. - Новочеркасск, 2011. - ГНУ СКЗНИВИ Россельхозакадемии. - С.162-165. В качестве тест-культуры использовали трехсуточную културу колпод вида Colpoda steinii. Помимо байкокса препаратами сравнения были ампролиум, метронидазол (трихопол), фуразолидон, сульфадиметоксин, ципрофлоксацин. Результаты испытаний приведены в таблице.Protistocidal activity was determined according to the method described in the book: "Scientific support for the innovative development of domestic livestock." - Materials of the All-Russian Scientific and Practical Conference. - Novocherkassk, 2011. - GNU SKZNIVI Russian Agricultural Academy. - S.162-165. As a test culture, a three-day culture of colpoda species Colpoda steinii was used. In addition to baykoks, comparison drugs were amprolium, metronidazole (trichopolum), furazolidone, sulfadimethoxin, ciprofloxacin. The test results are shown in the table.
Обозначения: (+) - все простейшие погиблиDesignations: (+) - all protozoa died
(-) - простейшие живы(-) - the simplest are alive
Данные таблицы показывают, что минимальная протистоцидная активность соединения 2-(4,5-дихлоримидазолил-1)-5-нитропиридин составляет 15,6 мкг/мл, что в 4 раза выше, чем у байкокса и ампролиума. Другие препараты в изученных концентрациях не проявили протистоцидной активности. Таким образом, в сравнительных испытаниях у вещества 2-(4,5-дихлоримидазолил-1)-5-нитропиридин обнаружена высокая протистоцидная активность.The data in the table show that the minimum protistocidal activity of the compound 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine is 15.6 μg / ml, which is 4 times higher than that of baykoks and amprolium. Other drugs in the studied concentrations did not show protistocidal activity. Thus, in comparative tests, the substance 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine was found to have high protistocidal activity.
Токсические свойства 2-(4,5-дихлоримидазолил-1)-5-нитропиридина:Toxic properties of 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine:
При введении в желудок лабораторным крысам данного соединения дозы 0,2 г/кг, 0,3 г/кг и 0,35 г/кг не вызывают острого токсического действия. Предварительно вещество может быть отнесено к среднетоксичным лекарственным препаратам.When this compound is administered to laboratory rats in the stomach, doses of 0.2 g / kg, 0.3 g / kg and 0.35 g / kg do not cause acute toxic effects. Previously, the substance can be attributed to medium toxic drugs.
Список литературыBibliography
1. Зубенко А.А. Определение протистоцидной активности новых соединений в ряду азотсодержащих гетероциклов / А.А.Зубенко, Л.Н.Фетисов, А.Н.Бодряков и др. // «Научное обеспечение инновационного развития отечественного животноводства» Материалы Всероссийской научно практической конференции ГНУ СКЗНИВИ - Новочеркасск. 2011. - С.162-165.1. Zubenko A.A. Determination of the protistocidal activity of new compounds in a series of nitrogen-containing heterocycles / A.A. Zubenko, L.N. Fetisov, A.N. Bodryakov, etc. // "Scientific support for the innovative development of domestic animal husbandry" Materials of the All-Russian Scientific and Practical Conference GNU SKZNIVI - Novocherkassk. 2011 .-- S.162-165.
2. Хованских А.Е., Илюшечкин Ю.П., Кириллов Ю.П. Кокцидиоз сельскохозяйственной птицы. - Ленинград, "Агропромиздат". - 1990. - С.71-91.2. Khovanskikh A.E., Ilyushechkin Yu.P., Kirillov Yu.P. Coccidiosis of poultry. - Leningrad, "Agropromizdat". - 1990. - S. 71-91.
3. Липин А.В., Санин А.В., Зинченко Е.В. Ветеринарный справочник М., 2002. - С.354.3. Lipin A.V., Sanin A.V., Zinchenko E.V. Veterinary reference book M., 2002. - P.354.
Claims (1)
в качестве протистоцидного средства. The use of 2- (4,5-dichlorimidazolyl-1) -5-nitropyridine of the formula 1
as a protistocidal agent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1171127B1 (en) * | 1999-04-20 | 2005-09-14 | Targacept, Inc. | Pharmaceutical compositions containing pyridine or pyrimidine derivatives for inhibition of cytokine production and secretion |
| US20120232063A1 (en) * | 2009-10-30 | 2012-09-13 | Ralph Mazitschek | 2-Aminoindole Compounds And Methods For The Treatment Of Malaria |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1171127B1 (en) * | 1999-04-20 | 2005-09-14 | Targacept, Inc. | Pharmaceutical compositions containing pyridine or pyrimidine derivatives for inhibition of cytokine production and secretion |
| US20120232063A1 (en) * | 2009-10-30 | 2012-09-13 | Ralph Mazitschek | 2-Aminoindole Compounds And Methods For The Treatment Of Malaria |
Non-Patent Citations (3)
| Title |
|---|
| STN on the web, базa данных CAS RN 1219550-27-2 Entered STN: 19 Apr 2010 [on line] [найдено 08.11.2013] . * |
| И.Б.МИХАЙЛОВ Настольная книга врача по клинической фармакологии. С-Пб Фолиант 2001 с.126-137, §§3.6.1.-3.6.4. * |
| Реферат [он-лайн] [найдено 06.11.2013] (Найдено из базы данных PatSearch (DWPI) . TOLTRAZURIL { USAN:INN:BAN} RN: 69004-03-1 Реферат [он-лайн] [найдено 06.11.2013] (Найдено из Интернет: chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=Search&actionHandle=getAl…) * |
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