SU798099A1 - 1-benzyl-2,6-dimethyl-4-0- or -m-nitrophenyl-3,5-diethoxycarbonyl-1,4-dihydropyridines possessing coronarodilating activity - Google Patents

1-benzyl-2,6-dimethyl-4-0- or -m-nitrophenyl-3,5-diethoxycarbonyl-1,4-dihydropyridines possessing coronarodilating activity Download PDF

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SU798099A1
SU798099A1 SU782587345A SU2587345A SU798099A1 SU 798099 A1 SU798099 A1 SU 798099A1 SU 782587345 A SU782587345 A SU 782587345A SU 2587345 A SU2587345 A SU 2587345A SU 798099 A1 SU798099 A1 SU 798099A1
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coronary
compound
papaverine
activity
effect
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SU782587345A
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Russian (ru)
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Гунар Янович Дубур
Бригита Северяновна Чекавичус
Алвил Эрнестович Саусинь
Расма Оскаровна Витолинь
Агрис Адольфович Кименис
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Ордена Трудового Красного Знамениинститут Органического Синтезаан Латвийской Ccp
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Priority to SU782587345A priority Critical patent/SU798099A1/en
Priority to FR7905509A priority patent/FR2419283A1/en
Priority to GB7907727A priority patent/GB2015516A/en
Priority to DE19792908738 priority patent/DE2908738A1/en
Priority to JP2517579A priority patent/JPS54138569A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Urology & Nephrology (AREA)
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  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The dihydropyridine derivatives have the formula: <IMAGE> in which R is a nitro group in the ortho- or meta- position. These compounds have a pronounced coronarodilating activity.

Description

сол нокислого бензиламина benzylamine hydrochloride

при нагрева- НИИ цо 1ОО С в подход щем растворителе в присутствии основани .by heating in a suitable solvent in the presence of a base.

Пример 1. 1-Бензил-2,6-диме тил-4-о-нитрофенил-3,5-диэтoкcикapбo- нил-l,4-aиrиapoпиpиaин (l).Example 1. 1-Benzyl-2,6-dime-4-o-nitrophenyl-3,5-diethoxycarbonyl-1, 4-ai-iropiridin (l).

3,8 г (0,025 моль) о- Штробензальаегиаа;6 ,5г (0,О5 моль) ацетоуксусного эфира и 4,25 i (0,ОЗ моль) сол нокислого бензиламин  в 20 мл пиридина нагревают при 1ОО С 4 ч. Отгон ют пиридин, масл нистый осадок затвердевает при обработке 1ОО мл метанола. Кристаллизуют из метанола желтые кристаллы с Т. пл. 121-125°С. Выкод 4,2 ( 36%).3.8 g (0.025 mol) o-Strobenzallagiaa; 6, 5 g (0, O5 mol) of acetoacetic ester and 4.25 i (0, OZ mol) of benzylamine hydrochloride in 20 ml of pyridine are heated at 1OO C 4 hours. pyridine, an oily precipitate solidifies by treating 1OO ml of methanol. Yellow crystals with T. pl. Are crystallized from methanol. 121-125 ° C. Code code 4.2 (36%).

Элементный анализ: Elemental analysis:

И 6,0; М 6,0. Вычислено,%: (. 37,3;And 6.0; M 6.0. Calculated,%: (. 37.3;

С2бН2 2 бS2BN2 2 b

И 6,3; N 6,3,And 6.3; N 6.3

Найдено,: С 67,1;Found: C 67.1;

УФ-спектр (в ),Яп,аХ () : 206(4,54); 246(4,35) и 3193 8 (3,72).UV spectrum (c), Yap, aX (): 206 (4.54); 246 (4.35) and 3193 8 (3.72).

ИК-спектр (в нуйоле), см (% поглощени ) :.1693( 87); 1631(72) и 1571 (75)..-г.IR (nuyol), cm (% absorption): .1693 (87); 1631 (72) and 1571 (75) ..- g.

Спектр ПМР в t(CH.3)jSO-d6 0 , м. д. : 1.08(6Н , м ); 2,27(бН,с, 2,6 ); 3,95 (4Н. кв, 4,99(2Н, с, М гСН);PMR spectrum at t (CH.3) jSO-d6 0, ppm: 1.08 (6H, m); 2.27 (bN, s, 2.6); 3.95 (4H. Q., 4.99 (2H, s, M gSN);

CHjCfcH, 4-СбН4).CHjCfcH, 4-CbH4).

Пример 2. 1-Е ензил-2,6-диметил -П )-нитрофенил-3,5-ди9Токсикарбонил-1 ,4-дигидропирицин (2).Example 2. 1-E enzyl-2,6-dimethyl -P) -nitrophenyl-3,5-di-9 Toxycarbonyl-1, 4-dihydropyricin (2).

11,3 г (0,075 моль) м-нитробензаль цегида; 19,5 г (0,15 моль) ацетоуксусного эфира и 12,8 г (0,09 моль) сол нокислого бензиламина в 40 мл пиридина нагревают при 100 С 4 ч. Отгон ют пиридин, масл нистый остаток затвердевает при обработке 150 мл этанола. Кристаллизуют из этанола желтые кристаллы с Т. пл. 102-1ОЗ С. Выход 13 г (38%).11.3 g (0.075 mol) m-nitrobenzal cegid; 19.5 g (0.15 mol) of acetoacetic ester and 12.8 g (0.09 mol) of benzylamine hydrochloride in 40 ml of pyridine are heated at 100 ° C for 4 hours. Pyridine is distilled off and the oily residue solidifies upon treatment with 150 ml of ethanol . Yellow crystals with m.p. are crystallized from ethanol. 102-1POZ C. Yield 13 g (38%).

Элементный анализ:Elemental analysis:

Вычислено, %: С 67,3; Н 6,0; N 6,0.Calculated,%: C 67.3; H 6.0; N 6.0.

Сгб ОбНайдено ,%: С 67,3; Н 6,3; N 6,1.Sgb Found,%: C 67.3; H 6.3; N 6.1.

УФ-спектр (в ), гпдх (Btfe) : 202(4,53); 242(4,47); . 262(4,30) и 347(3,86).UV spectrum (c), hpdh (Btfe): 202 (4.53); 242 (4.47); . 262 (4.30) and 347 (3.86).

ИК-спектр (в нуйоле), см (% поглощени ) : 1682( 82); 1641(62) и 1574(62).IR (nuyol), cm (% absorption): 1682 (82); 1641 (62) and 1574 (62).

В таблице приведены результаты фармкологического изучени  предлагаемых соединений: 1-бензил-2,6-диметил-4--о- ит- рофенил-3,5-диэтоксикарбонил-1,4-ди( идропиридина (1) и 1-бензил-2,6-аиметил- 4-м-нитрофенил-3,5-диэтоксикарбонил- -1,4-аигидропиридина (2).The table shows the results of the pharmacological study of the proposed compounds: 1-benzyl-2,6-dimethyl-4 - o-itrophenyl-3,5-diethoxycarbonyl-1,4-di (idropyridine (1) and 1-benzyl-2 , 6-aimethyl-4-m-nitrophenyl-3,5-diethoxycarbonyl--1,4-ahydropyridine (2).

Claims (1)

В исследовани х использованы общеприн тые методы, позвол ющие получить характеристику действи  веществ на сердечно-сосудистую и вегетативную, нервную системы. Действие соелннриий срав-ниваетс  с фенигидином - жтивным коронароцилатирующим срецсгвом ТОРО жб р да, а также с папаверином - иавестньп препаратом, примен емым при коронарной недостаточности. В опытах на наркотизированных кошках установлено, что предлагаемые соединени  про вл ют отчетливую коронаро- дилатирующую активность, увеличива  объемную скорость коронарного кровотока как при внутривенном, так и при пероральном введени х. Наиболее активным  вл етс  соединение (2), которое при внутривенном введении в дозе 1 мг/кг увеличивает венечный кровоток на 6D- 9О% от исходного уровн . Этот эффект про вл етс  быстро (через 3-5 мин) и  вл етс  продолжительным - до 60 70 мин. Внутривенное введение соединени  существенно не измен ет общее арте риальное давление. При внутрибрюшинном или внутрижелудочном введении (Юмг/к вещество (2) ослабл ет вызываемый п;; питуитрином спазм коронарн{э1х сосудов. Соединение (2) действует более активно и продолжительно, чем папаверин, но менее активно, чем фенигидин. Однако в св зи с тем, что соединение (2) очень мало токсично, индекс широты его фарма кологического действи  в 100 раз больше , чем у папаверина и в 1,5 раза больше , чем у фенигидина. По сравнению с фенигидином и папаверином данное вещес во практически не оказывает вли ни  на общее артериальное давление, что может иметь положительное значение при его использовании в качестве коронарного дилататора. Несколько слабее и менее продолжительно действует соединение (1). Соединени  (1) и (2) в дозах, увеличивающих коронарный кровоток, про вл ет антогонизм- в отношении гемединамического эффекта биогенных аминов - адреналина , изадрина и ацетилхолина. Данные исследовани  острой токсичности соединений в опытах на белых мышах при внутрибрюшинном введении представлены в таблице. Оказалось, что соединение (2) в 50 раз менее токсично, чем папаверин, и в 25 раз менее токсично , чем фенигидин. Так как у предлагаемых соединений выраженна  коронародилатирующа  активность и низка  токсичность/ г. е. больша  широта терапевтического действи , они могут быть применены в медицинской практике в качестве средств дл  лечени  ишемической болезни сердца. . Формула изобретени  1-Бензил-2,6-димeтил-4-o-или-м-нитpoфeнил-3 ,5-диэтoкcикapбoнил-l,4-дигидpoпиpидины общей формулы Н/,00, , где . R о WOg, W N0.3,, про вл ющие коронародипатирующую активность . Источники информации, прин тые во внимание при экспертизе i.Q.A.Berson, Е. Broivn . Q. А men. hem.Soc Н955 , 77,р.447.The studies used conventional methods to obtain a characteristic of the effects of substances on the cardiovascular and autonomic, nervous systems. The effect of soelennria is compared with fenigidine, a healthy coronary soothing sorense, and also with papaverine, the most common drug used in coronary insufficiency. In experiments on anesthetized cats, it was found that the proposed compounds exhibit a distinct coronary dilating activity, increasing the volumetric rate of coronary blood flow in both intravenous and oral administration. The most active is compound (2), which, when administered intravenously at a dose of 1 mg / kg, increases coronary blood flow by 6 D-9O% from the initial level. This effect appears quickly (after 3-5 minutes) and is long lasting up to 60–70 minutes. Intravenous administration of the compound does not significantly alter the total arterial pressure. When administered intraperitoneally or intragastrically (Yumg / K, substance (2) weakens the n-induced coronary spasm of the vessels. Compound (2) is more active and prolonged than papaverine, but less active than fenigidin. However, because due to the fact that compound (2) is very little toxic, its pharmacological index is 100 times greater than papaverine and 1.5 times more than fenigidin. Compared to fenigidine and papaverine, this substance has almost no effect on total blood pressure have a positive meaning when used as a coronary dilator. Compound (1) acts somewhat weaker and less permanently. Compounds (1) and (2) in doses that increase coronary blood flow show an antagonism in relation to the hemodynamic effect of biogenic amines - adrenaline , izadrina and acetylcholine.The data of the study of the acute toxicity of the compounds in experiments on white mice with intraperitoneal administration are presented in the table. It turned out that compound (2) is 50 times less toxic than papaverine, and 25 times less toxic than fenigidin. Since the proposed compounds have pronounced coronary dilating activity and low toxicity / g. E. A greater breadth of therapeutic effect, they can be applied in medical practice as a means for treating ischemic heart disease. . Claim 1-Benzyl-2,6-dimethyl-4-o-or-m-nitrophenyl-3, 5-diethoxycarbonyl-1, 4-dihydropyridines of the general formula H /, 00, where. R o WOg, W N0.3, exhibiting coronary endipating activity. Sources of information taken into account in the examination of i.Q.A.Berson, E. Broivn. Q. And men. hem.Soc H955, 77, p.447.
SU782587345A 1978-03-06 1978-03-06 1-benzyl-2,6-dimethyl-4-0- or -m-nitrophenyl-3,5-diethoxycarbonyl-1,4-dihydropyridines possessing coronarodilating activity SU798099A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
SU782587345A SU798099A1 (en) 1978-03-06 1978-03-06 1-benzyl-2,6-dimethyl-4-0- or -m-nitrophenyl-3,5-diethoxycarbonyl-1,4-dihydropyridines possessing coronarodilating activity
FR7905509A FR2419283A1 (en) 1978-03-06 1979-03-02 1-BENZYL-2,6-DIMETHYL-4-O- (OR M-) NITROPHENYL-3,5-DIETHOXYCARBONYL-1,4-DIHYDROPYRIDINE
GB7907727A GB2015516A (en) 1978-03-06 1979-03-05 Pharmacologically active dihydropyridine derivatives
DE19792908738 DE2908738A1 (en) 1978-03-06 1979-03-06 1-BENZYL-2,6-DIMETHYL-4-O- (OR M-) NITROPHENYL-3,5-DIAETHOXYCARBONYL-1,4-DIHYDROPYRIDINE
JP2517579A JPS54138569A (en) 1978-03-06 1979-03-06 11benzyll2*66dimethyll44orthoo*or meta* nitrophenyll3* 55diethoxycarbonyll1*44dihydropyridine

Applications Claiming Priority (1)

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SU782587345A SU798099A1 (en) 1978-03-06 1978-03-06 1-benzyl-2,6-dimethyl-4-0- or -m-nitrophenyl-3,5-diethoxycarbonyl-1,4-dihydropyridines possessing coronarodilating activity

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SU798099A1 true SU798099A1 (en) 1981-01-23

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SU782587345A SU798099A1 (en) 1978-03-06 1978-03-06 1-benzyl-2,6-dimethyl-4-0- or -m-nitrophenyl-3,5-diethoxycarbonyl-1,4-dihydropyridines possessing coronarodilating activity

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JP (1) JPS54138569A (en)
DE (1) DE2908738A1 (en)
FR (1) FR2419283A1 (en)
GB (1) GB2015516A (en)
SU (1) SU798099A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5216172A (en) * 1988-02-24 1993-06-01 Ajinomoto Co., Inc. 1,4-dihydropyridine-4-aryl-2,6-dimethyl-3,5-dicarboxylates useful as agents against drug resistant tumor cells
EP0330470A3 (en) * 1988-02-24 1992-01-02 Ajinomoto Co., Inc. 1,4-dihydropyridine derivatives useful against tumour cells
DE4011695A1 (en) * 1990-04-11 1991-10-17 Bayer Ag USE OF N-ALKYLATED 1,4-DIHYDROPYRIDE INDICARBOXIC ACID ESTERS AS DRUGS, NEW COMPOUNDS AND METHOD FOR THEIR PREPARATION
JPH076059U (en) * 1993-06-24 1995-01-27 貞夫 庄司 Bicycle saddle cover and storage

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1813436C3 (en) * 1968-12-07 1979-01-11 Bayer Ag, 5090 Leverkusen N-substituted 2,6-dimethyl-1,4-dihydropyridines
DE1923990C3 (en) * 1969-05-10 1978-11-23 Bayer Ag Process for the preparation of N-substituted M-dihydropyridine-S.S-dicarboxylic acid esters
DE2210672C3 (en) * 1972-03-06 1980-03-20 Bayer Ag, 5090 Leverkusen N-substituted asymmetrical 1 ^ -dihydropyridine-S ^ -dicarboxylic acid esters, process for their preparation and their use as medicaments

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GB2015516A (en) 1979-09-12
FR2419283A1 (en) 1979-10-05
JPS54138569A (en) 1979-10-27
DE2908738A1 (en) 1979-09-13

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