4-hydroxy-n-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1h-2λ6,1-benzothiazine-3-carboxamide, demonstrating diuretic activity

FIELD: chemistry.

SUBSTANCE: invention relates to 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6 ,1-benzothiazine-3-carboxamide, which possesses diuretic activity.

EFFECT: obtained is novel compound, possessing useful biological activity.

1 tbl, 3 ex

 

The invention relates to medicinal chemistry and relates to biologically active substances, in particular 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide, showing diuretic activity, and can therefore be used in pharmaceutical industry and medicine.

Diuretics are among the essential medicines, as already has been successfully applied for the salvation of people in severe pathological conditions: different kinds of poisoning, pulmonary edema or brain, chronic heart failure, arterial hypertension and others [1]. In recent years there has been a steady trend towards the expansion of the list of indications for the use of pharmacological drugs in this group. So, diuretics has been very successful in combating bronchial asthma, diabetes insipidus, glaucoma and even cancer and neuropsychiatric diseases that is clearly beyond their traditional applications [2]. Therefore, the search for new, more active and safe substances that can effectively strengthen the urinary kidney function does not lose its relevance.

The closest analogue of the claimed compounds and the structure is widely used in medical practice diuretic Hypatius is d (hydrochlorothiazide). This drug has a pronounced diuretic properties and belongs to the category of valuable and time-tested medicines. However, it has significant shortcomings, which causes some limitations to its use. The main of them is the relatively high toxicity and the necessity of taking fairly large doses of the drug to achieve a therapeutic effect [1].

The present invention is the task of obtaining a new chemical compounds with low toxicity and diuretic effect in low doses.

This object is achieved by obtaining 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide of the formula (1):

showing diuretic activity.

In accordance with the present claimed invention 1 individual chemical compound. It is synthesized by the interaction of the methyl ester of 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxylic acid with 2-carboxyaniline at a temperature of 150°C in xylene and in an argon atmosphere followed by the separation of the resulting precipitate.

The invention is illustrated in the following examples.

Example 1. Getting 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide. A mixture of 2.69 g (0.01 mol methyl ester 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ 6,1-benzothiazin-3-carboxylic acid, 1.37 g (0.01 mol) 2-carboxyaniline and 5 ml of xylene kept in a metal bath at 150°C in argon atmosphere for 1 hour. The reaction mixture is cool, add 5 ml of ethanol and leave for several hours at room temperature. The formed precipitate is filtered off, washed with cold ethyl alcohol and dried. Yield 3.48 g (93%). So pl. 226-228°C (DMF-ethanol, 1:3). An NMR spectrum1N, δ, M. D. (J, Hz): 15,76 (1H, s, 4-OH); 13,52 (1H, s, COOH); 11,83 (1H, s, NH); 8.35 (1H, d, J=8,4, H-3'); 8.07 (1H, d, J=8,1, H-6'); 8,03 (1H, d, J=7.8, H-5); 7,74 (1H, t, J=7.7, H-5'); 7.58 (1H, t, J=7.8, H-7); 7,44 (1H, d, J=8,4, H-8); 7.36 (1H, t, J=7.6, H-6); from 7.24 (1H, t, J=7.4, H-4'); 348 (3H, s, NCH3). Found, %: C 54.63; N, 3.85; N, 7.37; S 8.49. C17H14N2O6S. Calculated, %: C 54.54; H 3.77; N, 7.48; S 8.56.

An NMR spectrum1N stated the connection is recorded on the instrument Varian Mercury-400 (400 MHz) in a solution of DMSO-d6, internal standard TMS. Elemental analysis performed using a EuroVector EA-3000. The melting temperature determined in a capillary tube on the digital analyzer SMP10 melting point Stuart.

Example 2. Acute toxicity of 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide was studied in intact white mice weighing 18-23 g for 6 animals in series with each dose. The analyte was injected in the form of a thin water suspension, stabilized by tween-80), oral (p and high doses 2-3 times with an interval of 10 minutes). The number of surviving animals was recorded every 24 hours for 14 days. Srednetemperaturnyi dose (LD50) was calculated according to the method of Cerberus [3]. Are given in table.1 evidence suggests that the claimed substance, at least more than 2 times less toxic hypothiazid, sredneseriynoe dose (LD50for mice orally according to the literature [4] is only 1175 mg/kg

Example 3. Diuretic activity of the claimed 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide was studied on white outbred rats weighing 180-200 g by the standard method [3]. in parallel to and in comparison with hypothiazide. All experimental animals were given via a stomach tube water pressure at the rate of 25 ml/kg Control group of animals received only the same amount of water with tween-80. The claimed compound is administered orally at a dose of 10 mg/kg, and gipotiazid in its effective dose (40 mg/kg) in the form of a thin water suspension, stabilized by tween-80. After that, the test animals were placed in metabolic cages". The intensity of the urinary tract was the amount of urine, the selected animals for 4 hours. Presented in table experimental data allow to conclude that the claimed connection diuretic effects significant is but exceeds the reference product gipotiazid, and 4 times lower dose and lower toxicity.

Table
ConnectionLD50mg/kgThe diuresis for 4 h, mlDiuretic activity, %
The claimed connection>30009,71±0,42228
Gipotiazid1175 [4]to 6.43±0,38151
Control-4.26 deaths±0,33100

Thus, the claimed 4-hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide as a diuretic by their pharmacological characteristics significantly better than the known drug comparison gipotiazid. This compound is synthesized from available reagents and simple technique that can be reproduced in the chemical-pharmaceutical companies or laboratories using standard equipment.

4-Hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-carboxamide can be used as the substance when creating a diuretic funds in different dosage forms.

Sources of information

1. Mashkovsky M. D. Medicines. - M.: RIA "New wave": the Publisher Merenkov, 2009. - S. 498-514.

2. Ukrainian I. C., Bereznakova N. L. Heterocyclic diuretics // Chemistry of heterocycle. connect., 2012, No. 1, S. 161-174.

3. Sarnow L. N., Hazura centuries the Elements of experimental pharmacology. - M.: the "Printing "Science". - 2000. - S. 117-318.

4. Kleemann, A., Engel J. / Pharmaceutical substances. Synthesis, patents, applications. - Multimedia Viewer Version 2.00. - Stuttgart: Georg Thime Verlag, 2001.

4-Hydroxy-N-(2-carboxyphenyl)-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamide formula:

showing diuretic activity.



 

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