UA106251C2 - 3-(3-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinyl)-propanoic acid exhibiting diuretic activity - Google Patents

Abstract

The invention relates to chemico-pharmaceutical industry, in particular to bioactive substances such as amidated derivates of 1-quinolinyl propanoic acids exhibiting diuretic activity. Disclosed are 3-(3-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinyl)-propanoic acids of general formula:,wherein R = -CHCH=CH, or -i-CH,exhibiting diuretic activity.

Description

he (c) in the city

N

М (c) where В - -SNESNESN", or -I-C5Ni, which show diuretic activity. he (o) in dere I

N

M (in) x

The invention belongs to the chemical and pharmaceutical industry and concerns biologically active substances, in particular amidated derivatives of 1-quinolinylpropanoic acids, namely 3-(3-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinylpropanoic acids, which show diuretic activity.

Diuretics are widely used in medical practice for the treatment of many diseases that are accompanied by fluid retention in the human body: peripheral edema, chronic circulatory failure, hypertension, glaucoma, etc. (Mashkovsky M.D. Medicines. - M.: RIA "Novaya volna": Izdatel Umerenkov, 2009. - P. 498-514). They are means of first aid for acute poisoning, heart failure, swelling of the lungs and brain. For this reason, diuretics belong to vital medicines.

Unfortunately, new drugs with this type of biological activity did not appear for a long time (Ukrainets I.V., Bereznyakova N.L. Heterocyclic diuretics // Chemistry of heterocyclic compounds, 2012, Mo 1, pp. 161-174), although the need for them is completely obvious and does not require any special justification.

An analogue of the claimed compounds in terms of action is the drug hypothiazide (hydrochlorothiazide), widely known in medicine, which, due to its pronounced diuretic properties, belongs to the particularly valuable and time-tested diuretics (Mashkovsky M. D. Lekarstvennye srednat. -

M.: RIA Novaya volna: Umerenkov publisher, 2009. - p. 499). Unfortunately, this drug is not without significant drawbacks, which significantly limit its practical use. The main ones are rather high toxicity and the need to take significant doses of the drug to achieve the effect, which are the cause of various negative conditions and, as a result, a number of limitations in use.

The basis of the invention is the task of obtaining new individual chemical compounds with a higher diuretic effect and low toxicity.

The task of the invention is solved by obtaining 3-(3-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinylpropanoic acids of the general formula (1):

He (in) vk --k M

N ro (1) but (c) where EK - -SNSNASN", (Ta), or -i-С5Ны:, (16),

Which show diuretic activity.

In accordance with the invention, 2 individual chemical compounds are claimed, presented in Table 1.

The claimed compounds are synthesized by alkaline hydrolysis of the corresponding 4-hydroxy-2-oxo-1-(2-cyanoethyl)-1,2-dihydroquinoline-3-carboxamides with a boiling aqueous solution of potassium hydroxide, acidification of the reaction mixture and subsequent separation of the formed precipitate.

Table 1

Variants of the claimed compounds

Option | In | Claimed compound 3-(3-allylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinyl/upropanoic acid) -oxo-1 2-dihydro-1-

AI quinolinylpropanoic acid

The invention is illustrated by the following examples.

Example 1. Preparation of 3-(33-allylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinyl)upropanoic acid (Ta).

A mixture of 2.97 g (0.01 mol) of M-allyl-4-hydroxy-2-oxo-1-(2-cyanoethyl)-1,2-dihydroquinoline-3-carboxamide and 20 ml of 20 95% aqueous KOH solution refluxed until the release of ammonia stopped (4 hours). The reaction mixture is cooled and filtered.

The filtrate is acidified with diluted HCl to pH 3. The precipitate of quinolinylpropanoic acid is filtered off, washed with cold water, and dried. Yield - 2.75 g (87 90). Crystallize from ethyl alcohol. Tpl. 215-217 "S. NMR spectrum "H, b, m. h., (U, Hz): 17.29 (1H, c, 4-OH); 12.48 (IN, ush. s, SOON); 10.40 (1H, t, 9-5.7, МН); 8.08 (1H, d, 9-81, H-5); 7.79 (1H, t, 9-81, H-7); 7.67 (IN, d, U-8.6, H-8); 7.36 (1H, t, 9U-7.4, H-6); 5.94 (1H, m, CH); 5.22 (1H, d. k, U-17.1, U-1.5, trans-

MNONSNASN); 5.15 (1H, d. k, U-10.2, 9U-1.5, cis-MNSNHNASN); 4.45 (2H, t, 9U-7.8, MON"); 4.01 (2Н, т, У-5.3, МНОН»); 2.56 (2H, t, U-7.8, MSNeCH").: Found, 90: C - 60.89; H - 5.20; M - 8.94.

StivNieM2O5. Calculated, 9: C - 60.76; H - 5.10; M - 8.86.

Example 2. Preparation of 3-(3-isoamylcarbamoyl-4-hydroxy-2-oxo-1 2-dihydro-1-quinolinyl)upropanoic acid (16).

A mixture of 3.27 g (0.01 mol) of M-isoamyl-4-hydroxy-2-oxo-1-(2-cyanoethyl)-1,2-dihydroquinoline-3-carboxamide and 20 ml of 20 95 aqueous KOH solution boil under reflux until the release of ammonia stops (4 hours). The reaction mixture is cooled and filtered.

The filtrate is acidified with diluted HCl to pH 3.

The precipitate of quinolinylpropanoic acid 16 is filtered off, washed with cold water, and dried. Yield 3.18 g (92 95). Crystallize from ethyl alcohol. Tpl. 133-135 "S. NMR spectrum "H, b, m. h., (U, Hz): 17.49 (1H, c, 4-OH); 12.52 (1Н, уш. с, СООН); 10.26 (1Н, т, У-5.2, МН); 8.06 (1H, d, 9U-8.1, H-5); 7.76 (1H, t, U-7.9, H-7); 7.64 (1H, d, 9-86, H-8); 7.34 (1TN, t, U-7.6, H-6); 4.42 (2H, t, 9-7.9, MON"); 3.37 (2H, k, 9U-6.6, MNON"); 2.55 (2H, t, 9U-7.9, MSNoCH"); 1.62 (1H, m, CH); 1.44 (2H, k, y-7.1, MNONECH»g); 0.90 (6H, d, 9U-6.6, 2CH3). Found, 95: C - 62.49; H - 6.48; M - 8.16.

SivNggM2O5. Calculated, 9: C - 62.42; H - 6.40; M - 8.09.

H NMR spectra of the claimed compounds were registered on the Magiap Megsygu-Uh-200 device (200

MHz) in DMSO-α solution, internal standard TMS.

Example 4

The acute toxicity of 3-(3-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinylpropanoic acids 1a-b) was determined on intact white mice weighing 18-22 g, 6 animals each in a series with each dose. substances were administered in the form of a thin aqueous suspension stabilized by Tween-80, orally (at high doses in 2-3 doses with an interval of 10 minutes). The number of surviving animals was recorded every 24 hours for 14 days. The average lethal doses (I ХОБо) were calculated according to Kerber's method (L.N. Sernov, V.V. Gatsura, Zlementyi! zxperimentalnoi pharmacology. - M. PPP "Typography "Nauka". - 2000. - P. 318). The data given in Table 2 indicate that all declared substances according to the classification of K.K. Sydorov (K.K. Sydorov OO classification of the toxicity of poisons by parenteral methods of administration // In the book Toxicology of new industrial chemicals. - M.: Medicine, 1973. - Issue 13. - C . 50) are at least mildly toxic. Hypothiazid is significantly inferior to them in this respect, since according to the data literature (Kieetapp A., Epdei! U. / Rpagptaseshisa! zireiapse5. Zupipebviv5, raiepiv, arriisayop5. - Miyiteadia Miemzheg, Megwiop 2.00. - Bishyda: beogd Tpite Meghpiad, 2001) its average lethal dose for mice orally is only 1175 mg/kg.

Example 5

The diuretic activity of the claimed 3-(33-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinylpropanoic acids 1Ta-b was studied on white purebred rats weighing 180-200 g according to the standard method (L.N. Sernov , Gatsura V.V. Zlementiy of experimental pharmacology. - M.: PPP "Typography "Nauka". - 2000. - P. 117) in parallel and in comparison with hypothiazide. All experimental animals received a water load at the rate of 25 ml/ kg. The control group of animals received only a similar amount of water with Tween-80. The studied compounds Ta-b were administered orally at a dose of 10 mg/kg, and hypothiazide - at its effective dose (40 mg/kg) in the form of a thin aqueous suspension stabilized by Tween -80. After that, the experimental animals were placed in "exchange cages". The amount of urine excreted by the animals in 4 hours served as an indicator of the intensity of urination (Table 2).

Table 2

Toxicity and diuretic activity of the claimed compounds in comparison with hypothiazide

Compound Diuresis in 4 hours, ml Diuretic activity, 95 »4000 8.59:0.45 »4000 9.05:0.36

Hypothiazide 1175 6,350.40

Control | - | 4.2150.33

Presented in the table. 2 experimental data allow us to conclude that all claimed compounds significantly exceed the hypothiazide comparison drug in terms of diuretic effect, and in 4 times smaller doses and with significantly lower toxicity.

Thus, 3-(3-alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinyl)propanoic acids are claimed, which in 4 times smaller doses exceed the diuretic activity of hypothiazides and at the same time are detected more than three times lower toxicity. All compounds are synthesized from available reagents and by simple methods that can be carried out in the conditions of chemical and pharmaceutical enterprises or laboratories using standard equipment. 3-(3-Alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinylpropanoic acids can be used as medicinal substances in the creation of diuretics in various dosage forms.

Claims (1)

FORMULA OF THE INVENTION 3-(3-Alkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydro-1-quinolinylpropanoic acid of the general formula: he (c) vk Ak M N M (c) vo de В - -СНаЕСНАСН», or -и-С5Нч, which exhibits diuretic activity.