RU2054426C1 - 4,5-DIMETHYL-2-H-PROPYLTHIO-2-ω-H-PERFLUOROBUTYL-3H, 6H-THIAINE POSSESSING INOTROPIC ACTION AND METHOD FOR ITS PRODUCTION - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: 4,5-dimethyl-2-H-propylthio-2ω-H-perfluorobutyl-3H, 6H-thiaine is prepared by interaction of 1,1-dichlorω-H-perfluoropentyl propyl sulfide with zinc sulfide or with cadmium sulfide. Thus prepared propyl ester of ω-H-perfluorvaleric acid then interacts at 20-25 C with diene hydrocarbon. EFFECT: improves quality of desired product. 4 cl, 1 tbl

Description

 The invention relates to organic chemistry, in particular to a new compound 4,5-dimethyl-2-n-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiaine and a method for its preparation. This compound has an inotropic effect, which suggests its use as a cardiotonic agent in the treatment of heart failure.

It is known that cardiac glycosides and compounds of a non-glycosidic nature have a pronounced cardiotonic effect. Cardiac glycosides are substances of plant origin, which to date are the main treatment for circulatory failure of various etiologies [1, 2]
The cardiotonic effect of cardiac glycosides is that they increase the strength and speed of contraction of the heart muscle, exerting a positive inotropic effect, which allows, based on these properties, to relate them to analogues of the claimed compounds in action. The receptor for the cardiotonic effect of glycosides is magnesium-dependent potassium sodium adenosine triphosphatase (Na-K-ATF-aza).

 However, in addition to affecting contractile function, glycosides slow down the heart rhythm, having a negative chronotropic effect, which can contribute to the onset of their positive inotropic and negative chronotropic effects. In addition to reducing the heart rate, glycosides can also have a vagotropic effect, which makes it necessary to use vagolytic drugs to eliminate unwanted bradycardia.

 Among cardiotonic agents of a non-glycosidic nature, which are also analogues in the action of the claimed compound, Amrinon, 5-amino-3,4-bipyridin-6 (1H) -1-derivative of bipyridine with positive inotropic and vasodilator activity should be attributed. Amrinon is very different from glycosides in chemical structure and mechanism of action. It does not activate membrane adenylate cyclase of cardiac cells, however, it increases the concentration of c AMP, inhibiting phosphodiesterase. Due to the large number of side effects, the use of Amrinon in clinical practice is limited only by a short course, mainly for internal administration in severe cases of heart failure [1] Amrinon was used as a comparison drug in determining the inotropic activity of the claimed compound.

Указанное соединение характеризуется сложностью метода его получения, что относится как в стадии синтеза промежуточного фторсодержащего дитиокарбоксилата, так и к стадии образования конечного аддукта, а также отсутствием данных о способности 4,5-диметил-2-этилтио-2-трифторметил-3Н- 6Н-тиаина к проявлению инотропного действия. Другие структурные аналоги, проявляющие положительное инотропное действие, также в литературе не описаны.Also known is the thiain derivative 4,5-dimethyl-2-ethylthio-2-trifluoromethyl-3H-6H-thiain [3] which is the closest structural analogue of the claimed compound. This was prepared by reaction of ethyl mercaptan with triftortiouksusnoy acid fluoride followed by reaction of the resulting ftorditiokarboksilata as triftorditiouksusnoy acid ethyl ester, which is an active dienophile with dimetilbutadienom at ⁰ ° C to form an adduct of the following formula:

The specified compound is characterized by the complexity of the method for its preparation, which relates both to the stage of synthesis of the intermediate fluorine-containing dithiocarboxylate, and to the stage of formation of the final adduct, as well as the lack of data on the ability of 4,5-dimethyl-2-ethylthio-2-trifluoromethyl-3H-6H- thiain to the manifestation of inotropic action. Other structural analogues exhibiting a positive inotropic effect are also not described in the literature.

 The basis of the invention is the task of creating a new compound, which is an effective cardiotonic agent that does not affect the temporal parameters of the process of reducing relaxation of the heart muscle and has an inotropic effect and low toxicity. Another object of the invention is to provide a method for producing a compound having the above properties.

(1) где R₁ представляет собой группу H(CF₂)₄ и R₂ представляет собой пропильную группу.The tasks are solved by the synthesis of a new compound 4,5-dimethyl-2-H-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiaine, which is represented by formula I

(1) where R ₁ represents a group H (CF ₂ ) ₄ and R ₂ represents a propyl group.

The claimed compound is a pale yellow liquid, soluble at ²⁰ ° C in dimethyl sulfoxide, ethanol, chloroform, benzene, acetone, ether and insoluble in water. The compound is chemically stable. Useful properties of the claimed compounds are determined by the structure of 4,5-dimethyl-2-H-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiain, confirmed by NMR data. The biological activity of the claimed compounds was studied in animal experiments. The inotropic effect, allergic properties, as well as its acute toxicity were studied. For comparison, the well-known cardiotonic preparation Amrinon 5-amino-3,4-bipyridin-6- (1H) -1, which has a positive inotropic effect, was used. The study of compounds was carried out in experiments on guinea pigs and outbred white mice.

 1. Determination of the inotropic effect of 4,5-dimethyl-2-H-propylthio-2-ω-H-perfluoro-butyl-3H, 6H-thiain.

The inotropic effect was studied in vitro in experiments on isolated left atria of a guinea pig, contracting in a mode close to isometric, under the influence of electrical stimulation by rectangular stimuli with a current strength of 20% higher than the threshold. Perfusion of isolated atria placed in the chamber was performed with saline containing 1/3-normal concentration of calcium at a constant temperature of 32 ° ^C. The compound was studied at a concentration of 3-10 ug / ml. The effect of the studied compounds was evaluated by their ability to increase the strength of atrial contractions. The results are shown in the table.

 From the presented data it follows that the claimed compound has in vitro experiments on isolated guinea pig atria with positive inotropic activity 10 times higher than that of the standard action cardiotonic (caronotonic) Amrinon.

 2. Determination of acute toxicity of 4,5-dimethyl-2-H-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiain.

Toxicity was determined in acute experiments on outbred white mice of both sexes weighing 20-25 g with a single intraperitoneal and intragastric administration. Statistical processing of toxicological studies was carried out according to the method of Litchfield and Wilcoxon [4]
Observation of animals was carried out for 21 days. Studies have shown that the LD _{50 of the} claimed compound with intraperitoneal administration is 1500 mg / kg of animal body weight (1420-1580), and with intragastric administration more than 2000 mg / kg. The LD ₅₀ value for the Amrinon comparison drug is less than 300 mg / kg.

 According to GOST 12.1.007-76, the substance belongs to class 3 (moderately hazardous). An acute toxicity test report is attached.

 3. Determination of the allergenic properties of 4,5-dimethyl-2-H-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiain.

 When identifying the allergenic properties of the claimed compounds, experiments were conducted on guinea pigs with an initial weight of 200-370 g. Animals were sensitized with five subcutaneous injections of the claimed compounds. As a solvent, water for injection was used together with the detergent TWIN-80. Sensitization was carried out according to the following scheme: the second and third parts were introduced at intervals of three days, and the fourth at seven days. The incubation period was 14 days. The intervals between injections were selected so that the total time together with the incubation period in days was 33. The experiments were carried out on three groups of guinea pigs of both sexes, 10 animals each.

 The first control group was injected subcutaneously with water for injection with the addition of TWIN-80 detergent in a volume of 1 ml, the second group of the claimed compound at a dose of 10 mg per 1 kg in a volume of 1 ml. The third group at a dose of 100 mg per 1 kg in a volume of 1 ml. After sensitization of the animals for 14 days, a permitted dose of the claimed compound was administered intraperitoneally, which was 150 mg per 1 kg for all three groups.

 In order to eliminate the toxic effect of the compound and the possibility of the occurrence of pain shock, the administration of a permitted dose to guinea pigs was started from the control group. At the same time, they monitored the condition of the animals in groups for 6 hours. It was found that after intraperitoneal administration of the permitted dose of the claimed compound, signs of intoxication and shock were not found in animals of all three groups during 6 hours of observation.

Thus, when using the inventive compound in a therapeutic dose and 1/10 LD ₅₀ allergenic properties were not observed. Based on the data obtained, several advantages of the claimed compound can be distinguished:
high inotropic activity (10 times higher than that of Amrinon);
low toxicity (LD ₅₀ 1500-2000 mg / kg against LD ₅₀ less than 300 mg / kg for Amrinon);
lack of allergic reactions.

 Thus, the degree of inotropic activity and toxicity of the claimed compound exceeds the closest analogue in action of Amrinon and can be used in medical practice for the treatment of cardiovascular diseases and, in particular, heart failure.

SR₂ II где R₁ представляет собой группу H(CF₂)₄,
R₂ представляет собой пропильную группу, а затем проводят взаимодействие полученного соединения (II) в виде пропилового эфира ω -Н-перфтордитиовалериановой кислоты с диеновым углеводородом, в частности с 2,3-диметилбутадиеном. Ранее было указано о сложности метода получения фторсодержащего дитиокарбоксилата, являющегося промежуточным продуктом синтеза тиаинов и участвующего в реакции Дильса-Альдера с диеновым углеводородом [3]
Авторами предложен удобный метод синтеза, эфиров перфторалкандитиокарбоксилатов, в частности пропилового эфира перфтордитиовалериановой кислоты (II), путем взаимодействия соответствующего 1,1-дихлорперфторалкилпропилсульфида (II) с сульфидом цинка или кадмия. Полученный эфир представляет собой жидкость красного цвета с неприятным запахом. Наличие сильной электронно-отталкивающей перфторгруппы существенно облегчает взаимодействие дитиокарбоксилатов с диенами и позволяет проводить реакцию между соединением (II) и 2,3-диметилбутадиеном (IV) с получением тиаина формулы (I) при комнатной температуре.The inventive compound represented by formula I relates to fluorine-containing thiains and is formed as a result of a two-step process, according to which an intermediate perfluorodithiocarboxylate of formula II is first obtained
R

SR ₂ II where R ₁ represents a group H (CF ₂ ) ₄ ,
R ₂ represents a propyl group, and then the resulting compound (II) is reacted as ω-H-perfluorodithiovalerianic acid propyl ester with a diene hydrocarbon, in particular 2,3-dimethylbutadiene. Earlier, the complexity of the method for producing fluorine-containing dithiocarboxylate, an intermediate product of the synthesis of thiains and participating in the Diels-Alder reaction with a diene hydrocarbon, was noted [3]
The authors have proposed a convenient method for the synthesis of perfluoroalkanedithiocarboxylate esters, in particular perfluorodithiovalerianic acid (II) propyl ester, by reacting the corresponding 1,1-dichloroperfluoroalkylpropyl sulfide (II) with zinc or cadmium sulfide. The resulting ether is a red liquid with an unpleasant odor. The presence of a strong electron-repulsive perfluoro group substantially facilitates the interaction of dithiocarboxylates with dienes and allows the reaction between compound (II) and 2,3-dimethylbutadiene (IV) to produce a thiaine of formula (I) at room temperature.

+MS

H(CF

SC₃H₇

C₃H₇+ CH₂=

CH₂

П р и м е р 1. Получение пропилового эфира ω-Н-перфтордитиовалериановой кислоты (промежуточное соединение II).The process is illustrated by the following diagram:

+ MS

H (CF

SC ₃ H ₇

C ₃ H ₇ + CH ₂ =

CH ₂

PRI me R 1. Obtaining propyl ether ω-H-perfluorodithiovaleric acid (intermediate compound II).

A mixture of 9.51 g (26.5 mmol) of 1,1-dichloro-β-H-perfluoropentylpropyl sulfide and 7.74 g (79.5 mmol) of zinc or cadmium sulfide in 100 ml of acetonitrile is boiled under stirring for 6 hours. The mixture is cooled to 20 ° ^C, filtered, the acetonitrile was distilled off under atmospheric pressure, and the residue is fractionated in vacuo. Yield: 6.36 g (75%), boiling point 49-51 ^{° C} (0.05 mm Hg. V.).

 Found, C, 29.98; 29.89; H 2.70; 2.71; S 19.89; 19.91.

 Calculated, C 30.00; H 2.70; S 20.02.

To prove the structure of compound (II), ¹ H NMR spectroscopy and 19 F · ¹ H NMR spectra were recorded on a 200 MHz Gemini spectrometer in a deuterochloroform solvent with external ethanol tetramethylsilane on a ppm scale. (parts per million).

The following data were obtained: 1.06 (m, 3H, J 7.4 Hz, CH ₃ ); 1.76 (sextet, 2H, J 7.4 Hz, CH ₂ ); 3.28 (m, 2H, J 7.4 Hz, CH ₂ ); 6.09 (mm, 1H, J 52.0, 5.0 Hz, CHF ₂ ). 19F NMR spectra were recorded on a Bruker-WP-200 spectrometer, 188.28 MHz, in a deuterochloroform solvent, with external ethanol trichlorofluoromethane on a ppm scale

The following data were obtained: -138.00 (d, 2F, J 52.0 Hz, CF ₂ H); -130.03 (m, 2F, CF ₂ ); -124.44 (m, 2F, CF ₂ ); -103.38 (m, 2F, CF ₂ ).

 PRI me R 2. Obtaining 4,4-dimethyl-2-H-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiaine (compound of formula I).

A mixture of 5.50 g (17.2 mmol) of propyl N-ω-perftorditiovalerianovoy acid and 2.90 g (35.4 mmol) dimethylbutadiene kept for 24 hours at 20 ° ^C and distilled in vacuo. Yield 5.46 g (79%), boiling point 90-92 ^{° C} (0.06 mm Hg. V.).

Found, C, 41.76; 41.77; H 4.30; 4.32; F 38.12; 38.24; S 15.96; 16.00
Calculated, C 41.75; H 4.50; F 37.75; S 15.93.

To prove the structure of the claimed compound (I), ¹ H NMR spectroscopy was used. The following data were obtained: ¹ H NMR, δ, ppm. 1.00 (m, 3H, J 7.4 Hz, CH ₃ ); 1.60 (sextet, 2H, J 7.4 Hz, CH ₂ ); 1.71 (s, 3H, CH ₃ ); 1.78 (s, 3H, CH ₃ ); 2.29, 2.87 (AB, 2H, J 16.0 Hz, CH ₂ ); 2.87, 3.39 (AB, 2H, J 16.0 Hz, CH ₂ ); 2.75 (m, 2H, J 7.4 Hz, CH ₂ ); 6.06 (mm, ¹ H, J 52.2, 5.6 Hz, CHF ₂ ). NMR ¹⁹ F, δ ppm -138.00 (d, 2F, J 52.2, CF ₂ H); -131.07 (m, 2F, CF ₂ ); -119.53 (AB, J 208.7 Hz, 1F); -116.52 (AB, J 208.7 Hz, 1F); 107.95 (AB, J 282.0 Hz, 1F); 106.35 (AB, J 282.0 Hz, 1F).

Claims (3)

1. 4, 5-dimethyl-2-H-propylthio-2-w-H-perfluorobutyl-3H, 6H-thiaine of the formula

possessing inotropic action. 2. The method of obtaining 4, 5-dimethyl-2-H-propylthio-2-ω-H-perfluorobutyl-3H, 6H-thiaine, characterized in that the process is carried out in two stages, with the reaction of 1, 1-dichlor - w-H-perfluoropentylpropyl sulfide with zinc or cadmium sulfide to produce propyl ester of w-H-perfluorovaleric acid, and then the resulting ester is reacted with a diene hydrocarbon at 20 - 25 ^o C.  3. The method according to claim 2, characterized in that 2, 3-dimethylbutadiene is used as a diene hydrocarbon.

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