RU2303026C1 - N-(2-methylphenoxyethyl)-n-cyclohexylamine hydrochloride possessing hypotensive activity - Google Patents
N-(2-methylphenoxyethyl)-n-cyclohexylamine hydrochloride possessing hypotensive activity Download PDFInfo
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- RU2303026C1 RU2303026C1 RU2005130966/04A RU2005130966A RU2303026C1 RU 2303026 C1 RU2303026 C1 RU 2303026C1 RU 2005130966/04 A RU2005130966/04 A RU 2005130966/04A RU 2005130966 A RU2005130966 A RU 2005130966A RU 2303026 C1 RU2303026 C1 RU 2303026C1
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- methylphenoxyethyl
- cyclohexylamine hydrochloride
- hypotensive activity
- hydrochloride
- compound
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- 230000001077 hypotensive effect Effects 0.000 title claims abstract description 12
- GCEKJUGEBLRABA-UHFFFAOYSA-N N-[2-(2-methylphenoxy)ethyl]cyclohexanamine hydrochloride Chemical compound Cl.CC1=C(OCCNC2CCCCC2)C=CC=C1 GCEKJUGEBLRABA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 229960003207 papaverine hydrochloride Drugs 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 3
- ABXRTJHEVCZIAG-UHFFFAOYSA-N 1-(2-bromoethoxy)-2-methylbenzene Chemical compound CC1=CC=CC=C1OCCBr ABXRTJHEVCZIAG-UHFFFAOYSA-N 0.000 description 2
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical class CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-M 5,5-diethyl-4,6-dioxo-1h-pyrimidin-2-olate Chemical compound CCC1(CC)C(=O)NC([O-])=NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-M 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960004604 propranolol hydrochloride Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- RGHFKWPGWBFQLN-UHFFFAOYSA-M sodium;5,5-diethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CCC1(CC)C([O-])=NC(=O)NC1=O RGHFKWPGWBFQLN-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 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
Заявляемое соединение относится к области органической химии, классу арилоксиалкиламинов, а именно к новому биологически активному N-(2-метилфеноксиэтил)-N-циклогексиламина гидрохлориду (I) формулыThe inventive compound relates to the field of organic chemistry, the class of aryloxyalkylamines, namely to a new biologically active N- (2-methylphenoxyethyl) -N-cyclohexylamine hydrochloride (I) of the formula
который может найти применение в качестве лекарственного гипотензивного препарата.which may find application as a hypotensive drug.
В качестве эталонов сравнения гипотензивного действия нами взяты: известный гипотензивный препарат папаверина гидрохлорид и ближайший структурный аналог пропранолола гидрохлорид (анаприлин) [Машковский М.Д. Лекарственные средства: В 2 т. - 14-е изд., перераб., испр. и доп. - М.: ООО "Издательство Новая Волна", 2000].As standards for the comparison of the hypotensive effect we took: the well-known antihypertensive drug papaverine hydrochloride and the closest structural analogue of propranolol hydrochloride (anaprilin) [Mashkovsky M. D. Medicines: In 2 vols. - 14th ed., Revised., Rev. and add. - M.: Publishing House New Wave LLC, 2000].
Целью предлагаемого изобретения является получение нового не описанного ранее N-(2-метилфеноксиэтил)-N-циклогексиламина гидрохлорида (I), обладающего гипотензивным действием.The aim of the invention is to obtain a new not previously described N- (2-methylphenoxyethyl) -N-cyclohexylamine hydrochloride (I), which has a hypotensive effect.
Поставленная цель достигается получением N-(2-метилфеноксиэтил)-N-циклогексиламина гидрохлорида (I) взаимодействием 2-метилфеноксиэтилбромида с циклогексиламином (см схему):The goal is achieved by obtaining N- (2-methylphenoxyethyl) -N-cyclohexylamine hydrochloride (I) by the interaction of 2-methylphenoxyethyl bromide with cyclohexylamine (see scheme):
Методика получения N-(2-метилфеноксиэтил)-N-циклогексиламина гидрохлорида. The method of obtaining N- (2-methylphenoxyethyl) -N-cyclohexylamine hydrochloride.
Смесь 21,5 г (0,1 моль) 2-метилфеноксиэтилбромида, 9,9 г (0,1 моль) циклогексиламина, 15,2 г (0,15 моль) триэтиламина в 50 мл бензола кипятят на песчаной бане в течение 5 часов. Оставляют на ночь, осадок триэтиламина гидробромида отфильтровывают, промывают бензолом. Бензол отгоняют, остаток растворяют в диэтиловом эфире. Эфирную вытяжку сушат NaOH кристаллическим, насыщают HCl (газ), выпавший осадок отфильтровывают и досушивают на воздухе. Перекристаллизовывают из ацетона, т. пл. 161-163°, выход продукта 54% (14,55 г).A mixture of 21.5 g (0.1 mol) of 2-methylphenoxyethyl bromide, 9.9 g (0.1 mol) of cyclohexylamine, 15.2 g (0.15 mol) of triethylamine in 50 ml of benzene is boiled in a sand bath for 5 hours . Leave overnight, the precipitate of triethylamine hydrobromide is filtered off, washed with benzene. Benzene is distilled off, the residue is dissolved in diethyl ether. The ether extract was dried with crystalline NaOH, saturated with HCl (gas), the precipitate formed was filtered off and dried in air. Recrystallized from acetone, so pl. 161-163 °, yield 54% (14.55 g).
Заявляемое соединение представляет собой белое кристаллическое вещество, растворимое в горячей воде, этаноле, хлороформе, ДМСО, ДМФА, 2-бутаноле, 1-пропаноле, труднорастворимое в ацетоне. В спектре ЯМР 1Н (BS-567A, (100 МГц) в CDCl3, внутренний стандарт - ГМДС) соединения I имеются: мультиплет десяти протонов циклогексильного кольца в области 1,05-1,89 м.д., синглет трех протонов метильной группы ароматического кольца при 2,15 м.д., мультиплет протона СН-группы циклогексильного кольца при 3,00 м.д., квадруплет двух протонов группы CH2N при 3,33 м.д., триплет двух протонов группы ОСН2 при 4,27 м.д., синглет протона аминогруппы при 4,70 м.д., мультиплет четырех протонов ароматического кольца в области 6,72-7,00 м.д., уширенный синглет протона хлористоводородной кислоты при 9,30 м.д.The inventive compound is a white crystalline substance, soluble in hot water, ethanol, chloroform, DMSO, DMF, 2-butanol, 1-propanol, sparingly soluble in acetone. The 1 H NMR spectrum (BS-567A, (100 MHz) in CDCl 3 , internal standard - HMDS) of compound I contains the multiplet of ten protons of the cyclohexyl ring in the region of 1.05-1.89 ppm, the singlet of three methyl protons aromatic ring groups at 2.15 ppm; proton multiplet of the CH group of the cyclohexyl ring at 3.00 ppm; quadruplet of two protons of the CH 2 N group at 3.33 ppm; triplet of two protons of the OCH 2 group at 4.27 ppm, amino proton singlet at 4.70 ppm, multiplet of four protons of the aromatic ring in the region of 6.72-7.00 ppm, broadened proton singlet, hydrochloric acid at 9.30 ppm
Острую токсичность при внутривенном введении определяли на белых нелинейных мышах массой 20-25 г. Исследуемое вещество и препараты сравнения вводили в хвостовую вену 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 (ЛД50) при Р=0,05 [Прозоровский В.В., Прозоровская М.П., Демченко В.М. Фармакол. токсикол., T41., №4, С.497-502 (1978)].Acute toxicity after intravenous administration was determined on nonlinear white mice weighing 20-25 g. The test substance and comparison preparations were injected into the tail vein 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 (LD 50 ) at P = 0.05 [Prozorovsky VV, Prozorovskaya MP, Demchenko VM Farmakol. Toxicol., T41., No. 4, C.497-502 (1978)].
Соединение I исследовали на наличие гипотензивной активности. Опыты проводили на здоровых кошках обоего пола, наркотизированных барбиталом натрия (мединал) в дозе 400 мг/кг, внутрибрюшинно. Заявляемое вещество и препараты сравнения вводили животным в дозе 0,1 ЛД50, внутривенно. Артериальное давление измеряли в сонной артерии прямым методом. В каждой серии опытов было использовано 5-6 животных. Степень гипотензивной активности исследуемого соединения выражали в мм рт. ст. относительно исходного уровня в определенные промежутки времени и статистически обрабатывали разностным методом с использованием коэффициента Стьюдента [Сернов Л.Н., Гацура В.В. Элементы экспериментальной фармакологии, М., С.312-313, (2000)]. Выраженность и продолжительность гипотензивного эффекта сравнивали у заявляемого соединения и эталонных препаратов в эквитоксических дозах.Compound I was tested for the presence of antihypertensive activity. The experiments were performed on healthy cats of both sexes, anesthetized with sodium barbital (medinal) at a dose of 400 mg / kg, intraperitoneally. The inventive substance and comparison preparations were administered to animals at a dose of 0.1 LD 50 , intravenously. Blood pressure was measured in the carotid artery by a direct method. In each series of experiments, 5-6 animals were used. The degree of hypotensive activity of the test compound was expressed in mm RT. Art. relative to the initial level at certain time intervals and statistically processed by the difference method using the student coefficient [Sernov LN, Gatsura VV Elements of experimental pharmacology, M., S.312-313, (2000)]. The severity and duration of the hypotensive effect was compared in the claimed compounds and reference drugs in equitoxic doses.
Результаты испытаний представлены в таблице. Динамика гипотензивного эффекта заявляемого соединения в сравнении с действием папаверина гидрохлоридом и анаприлином показана на чертеже.The test results are presented in the table. The dynamics of the hypotensive effect of the claimed compounds in comparison with the action of papaverine hydrochloride and anaprilin is shown in the drawing.
Острая токсичность, выраженность и продолжительность гипотензивного эффекта заявляемого соединения (I) и эталонов сравненияTable
Acute toxicity, severity and duration of the hypotensive effect of the claimed compound (I) and reference standards
Как видно из таблицы и чертежа, исследуемое соединение проявляет высокую гипотензивную активность, значительно превосходя препараты сравнения по продолжительности действия. Токсичность соединения I ниже, чем у папаверина гидрохлорида.As can be seen from the table and drawing, the test compound exhibits high hypotensive activity, significantly superior to the comparison drugs in terms of duration of action. The toxicity of compound I is lower than that of papaverine hydrochloride.
Таким образом, N-(2-метилфеноксиэтил)-N-циклогексиламина гидрохлорид (I) проявляет достоверно более продолжительное гипотензивное действие. Следовательно, заявляемое соединение (I) может найти применение в медицине в качестве гипотензивного лекарственного средства с длительным эффектом.Thus, N- (2-methylphenoxyethyl) -N-cyclohexylamine hydrochloride (I) exhibits a significantly longer hypotensive effect. Therefore, the claimed compound (I) may find application in medicine as a hypotensive drug with a long-lasting effect.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB849342A (en) * | 1956-06-05 | 1960-09-28 | Julius Mackerle | Hydro-pneumatic suspension device |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB849342A (en) * | 1956-06-05 | 1960-09-28 | Julius Mackerle | Hydro-pneumatic suspension device |
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