RU2063966C1 - Method of synthesis of 5-hydrazones of 7-substituted 2,3,5,6,7,8-hexahydrocinnoline-3,5-diones - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: products: 5-hydrazones of 7-substituted 2,3,5,6,7,8-hexahydrocinnoline-3,5-diones of the formula (I)

. Reagent 1: derivatives of cyclohexane-1,3-dione of the formula (II)

. Reagent 2: sodium alcoholate of the formula A: R₂ONa where R₂ - lower alkyl. Conditions: boiling in absolute alcohol medium followed by treatment of obtained reaction mass containing an intermediate compound of the formula (III)

Description

где R R₁ атом водорода (I а)
R R₁ метил (I б)
R атом водорода, R1 фенил (I в),
обладающих антигипертензивной и спазмолитической активностью.The present invention relates to a new method for the synthesis of 2,3,5,6,7,8-hexahydrocinnolin-3,5-dione derivatives of the general formula I, which are not described in the literature at the filing date of the application:

where RR _{1 is} a hydrogen atom (I a)
RR ₁ methyl (I b)
R is a hydrogen atom, R1 is phenyl (I in),
possessing antihypertensive and antispasmodic activity.

 It is known that among organic compounds containing a pyridazine ring as a fragment, a number of substances with high biological activity have been found. Compounds of this series include the antihypertensive drug apressin, antimicrobial sulfaliridazine, salazopyridazine [1] In this regard, the creation of new structures containing the pyridazine cycle seems to be very promising. In addition, it should be noted that the presence of highly reactive functional groups, such as a 3-oxo group and a hydrazine moiety in position 5, in the structure of the claimed compounds provides the possibility of transforming the compounds we first obtained into various derivatives of annelated pyridazines, which are potential biologically active compounds.

A known method for producing 3,5-dioxo derivatives of cinnolin, based on the interaction of 1- (1 ¹ , 2 ¹ dimethylhydrazino) -1-cyclohexen-Z-one with an ether of acetylenedicarboxylic acid. The yield of the target product is only 8-10 [2]
The aim of the invention is the synthesis of a new, previously undescribed group of compounds, a structural feature of which is the presence of 2,3,5,6,7,8-hexahydrocinnolinone-3-th cycle having a hydrazone group at position 5.

 The essence of the proposed method is that the new claimed compounds are obtained directly from derivatives of cyclohexane-1, 3-dione of the general formula II (available domestic raw materials), which are subjected to alkylation using sodium alcoholate, through the formation of intermediate compounds of the general formula III, the latter are not isolating, they undergo cyclization using hydrazine hydrate, and through the formation of intermediate compounds of the general formula IV, which are spontaneously dehydrogenated during the reaction (see process diagram).

 It should be noted that on the day of application for the synthesis of cinnolin derivatives, the use of cyclohexanedione as starting compounds using their C-alkylation was not described.

где R и R₁ имеют вышеуказанные значения, подвергают взаимодействию с этиловым эфиром бромуксусной кислоты в присутствии алкоголята натрия общей формулы А: R₂ ОNa (А)
где R₂ низший алкил,
в среде абсолютного низшего спирта при кипячении с последующей обработкой полученной реакционной массы, содержащей образовавшееся соответствующее производное 2-карбометиленциклогексан-1,3-диона общей формулы III:

где R, R₁ и R₂ имеют вышеуказанные значения, гидразин-гидратом при кипячении в среде низшего спирта согласно схеме.The inventive method for producing 5-hydrazone of 7-substituted 2,3,5,6, 7,8-hexahydrocinnoline-3,5-dione of general formula 1, is as follows: derivatives of cyclohexane-1,3-dione of general formula II:

where R and R ₁ have the above meanings, are reacted with ethyl bromoacetic acid in the presence of sodium alcoholate of the general formula A: R ₂ ONa (A)
where R ₂ lower alkyl,
in a medium of absolute lower alcohol during boiling, followed by treatment of the resulting reaction mass containing the resulting corresponding derivative of 2-carbomethylene cyclohexane-1,3-dione of the general formula III:

where R, R ₁ and R ₂ have the above meanings, hydrazine hydrate when boiled in a lower alcohol medium according to the scheme.

где R и R₁ имеют вышеуказанные значения.The scheme of the proposed method for producing compounds of General formula II

where R and R ₁ have the above meanings.

Get the target product I (a-b) with the release of:
1a 25.5 33.7%
1b 18.5 25.0% counting on II a-c.

 1v 24.0 30.0% The starting compounds of the general formula II and ethyl bromoacetic acid used in the proposed synthesis are available and are produced by the domestic industry.

Compounds III b and III to new, not previously described in the literature, III a - known [3]
Ethyl alcohol is preferable as lower alcohol, and sodium ethylate is used as sodium alcoholate (table 1). It is known that alkylation [3 7] including ethoxycarbomethylation [3] of cyclohexane-1,3-dione derivatives with the best results is carried out in the presence of potassium alcoholates with the formation of 2-alkyl cyclohexane-1,3-dione derivatives.

где R и R₁ имеют вышеуказанные значения, R₃ -этоксикарбометилен и др. которые не пригодны для синтеза соединений общей формулы 1 [3, 4]
Учитывая вышесказанное, применение в заявляемом способе в качестве алкоголята щелочного металла алкоголята натрия общей формулы А неожиданно позволило провести процесс с образованием 2-алкил производных циклогексан-1,3-диона (III), а не 0-алкилпроизводных циклогексан-1,3-диона (V) (см. схему).The use of alcoholates of other alkali metals in the above process shifts the reaction towards the formation of 0-alkyl derivatives of cyclohexane-1,3-dione V:

where R and R ₁ have the above meanings, R ₃ -ethoxycarbomethylene and others which are not suitable for the synthesis of compounds of General formula 1 [3, 4]
Given the above, the use in the present method as an alkali metal alcoholate of sodium alcoholate of the general formula A unexpectedly allowed to carry out the process with the formation of 2-alkyl derivatives of cyclohexane-1,3-dione (III), and not 0-alkyl derivatives of cyclohexane-1,3-dione (V) (see diagram).

Нижеследующие примеры иллюстрируют заявляемый способ.

The following examples illustrate the claimed method.

 Example 1

 Obtaining 5-hydrazone 2,3,5,6,7,8-hexahydrocinnolin-3,5-dione (Ia).

To a boiling solution of sodium ethylate (obtained from 4.0 g (0.2 mol) of sodium and 100 ml of absolute ethanol), 22.4 g (0.2 mol) of cyclohexane-1,3-dione are added. The reaction mass is boiled for 15 minutes, then 35 g (0.21 mol) of ethyl bromoacetic acid are added dropwise and boiled for 1 hour. The mixture is cooled, acidified with dilute (1 1) hydrochloric acid until neutral. The precipitated sodium bromide precipitate is filtered off, washed with ethyl alcohol. The combined filtrates were evaporated. To the residue containing the resulting 2-ethoxycarbonylmethylenecyclohexane-1, 3-dione, add 25 ml of ethyl alcohol and 70 ml of hydrazine hydrate and boil for 1 hour. The reaction mass is cooled to 0 ^o C, precipitated in the form of a precipitate of the target product 1A is filtered off, washed with alcohol and dried.

12 g of 5-hydrazone of 2,3,5,6,7,8-hexahydrocinnolin-3,5-dione (1a) are obtained, 33.7 counting on starting material II a; so pl. 265 267 ^o With M ⁺ 178 / Lit.pl. 266 267 ^o C /.

IR spectrum, ν _max , cm ^-1 : 3442, 3322 (NH ₂ ), 3222 (NH) 1640 (C 0).

UV spectrum, λ _max , NM (logε) 234 (4.12), 334 (4.00).

 Example 2

 Obtaining 5-hydrazone 7,7-dimethyl-2,3,5,6,7,8-hexahydrocinnolin-3,5-dione (IB).

 To a boiling solution of sodium ethylate (obtained 4.6 g (0.2 mol) of sodium and 100 ml of absolute ethanol), 28 g (0.2 mol) of 5.5-dimethylcyclohexane-1,3-dione are added. The reaction mixture is boiled for 15 minutes and then 35 g (0.21 mol) of ethyl bromoacetic acid are added. Processing and isolation of the target product I b is carried out under the conditions of example 1.

Obtain 10.3 g (25 counting on II b) of 5-hydrazone 7,7-dimethyl-2,3,5,6,7,8-hexahydrocinnolin-3,5-dione (IB), so pl. 273 - 274 ^o C, M +. 206 / lit. so pl. 272 274 ^o C /.

IR spectrum, n _max , cm ^-1 3390, 3330 (NH ₂ ), 3180 (NH), 1635 (C 0).

UV spectrum. λ _max , N.M. (log ε) 234 (4.08), 330 (3.90).

 Example 3

 Preparation of 5-hydrazone 7-phenyl-2,3,5,6,7,8-hexahydrocinnolin-3,5-dione (I c).

 To a boiling solution of sodium ethylate (obtained from 4.0 g (0.2 mol) of sodium and 100 ml of absolute ethanol), 37.6 g (0.2 mol) of 5-phenylcyclohexane-1,3-dione are added. The reaction mass is boiled for 15 minutes, and then 35 g (0.21 mol) of ethyl bromoacetic acid are pinned. Processing and isolation of I in is carried out under the conditions of example 1.

15.24 g are obtained (30 counting on (II c) 5-hydrazone 7-phenyl-2,3, 5,6,7,8-hexahydrocinnolin-3,5-dione (I c), mp 268,269 ^o C, M ⁺ 254 / lt. mp 267 268 ^o C /.

IR spectrum, n _max , cm ^-1 : 3360, 3310 (NH ₂ ); 3180 (NH), 1635 (C 0)
UV spectrum: λ _max , nm (lgε); shoulder 230 (4.01), 334 (3.90).

 Below are examples of the synthesis of compounds Ia and Ic in the presence of other lower sodium alcohols and alcoholates under the same reagent ratios and reaction conditions as described above (see table. 1).

 Based on the proposed method, it is possible to create domestic production of potential antihypertensive and antispasmodic drugs of a number of cinnoline.

 Compounds of the general formula I were examined for the presence of biological activity according to the following indicators: acute toxicity, antihypertensive activity, antispasmodic activity.

 1. The acute toxicity of the compounds was studied in male mice weighing 18 to 20 g when administered orally.

 2. The antihypertensive activity of the compounds was studied on spontaneously hypertensive male rats weighing 280,300 g using an indirect method for recording blood pressure (BP) in the caudal artery of animals. The inventive compounds were administered orally in the form of an aqueous suspension on Tween-80 at a dose of 10 mg / kg Registration of blood pressure was carried out before administration of the compounds (initial level of blood pressure) and after 1.3.5 and 24 hours after administration. In these experiments, apressin in the same dose was used as a comparison drug.

The antispasmodic activity of the compounds was studied in vitro by the effect on the spasmogenic effect of norepinephrine (HA) on an isolated rat thoracic aorta preparation. HA was administered at a fixed concentration of 1 • 10 ^-7 g / ml. In the experiments, IC ₅₀ compounds were determined, i.e. concentration inhibiting 50 spasmogenic effect of HA. Apressin was used as a comparison drug.

 The data of experiments on the study of acute toxicity and antihypertensive activity of the compounds are presented in table 2.

 As follows from the presented table 2, compounds I are of low toxicity. The comparison drug apressin is moderately toxic, i.e. is significantly more toxic than the investigated derivatives of cinnolin.

By its effect on blood pressure in spontaneously hypertensive rats, the most active among compounds I was compound I in (5-hydrazone-7-phenyl-2,3,5,6,7,8-hexahydrocinnolindione-3,5), the antihypertensive effect of which is almost 2 times superior to the effect of apressin taken in the same dose (10 mg / kg, by mouth). Compound Ia (5-hydrazone-7,7-dimethyl-2, 3,5,6,7,8-hexahydrocinnolindione-3,5) is comparable with apressin in antihypertensive activity. However, when comparing the ratio of the LD ₅₀ value to the effective antihypertensive dose (10 mg / kg), it can be concluded that the therapeutic effect of the cinnoline derivatives of general formula I is much wider than that of the standard (apressin).

 The results of a study of the antispasmodic activity of cinnolin derivatives of general formula 1 are presented below.

Compound Antispasmodic activity of norepinephrine IR ₅₀ g / ml
Ia 1 • 10 ^-7
I 6 1 • 10 3
I in 1 • 10 7 Apressin 1 • 10 5
From the data presented it follows that the antispasmodic activity of compounds Ia and Ib is superior to the comparison drug apressin by 2 orders of magnitude (IC ₅₀ 1 • 10 ^-7 g / ml).

 Thus, among the derivatives of cinnoline of general formula I, the following compounds were found: Ia 5-hydrazone-7,7-dimethyl-2,3,5,6,7,8-hexahydrocinnolindione-3, 5 and Ic 5-hydrazone-7-phenyl- 2,3,5,6,7,8-hexahydrocinnolindinedione-3, 5, possessing antihypertensive and antispasmodic activity. Derivatives of cinnolin I are superior in the indicated types of activity to the widely used drug apressin in medical practice. A significant difference between the compounds of formula I and the reference preparation is their low toxicity and the wide breadth of the therapeutic effect.

 Therefore, in this way it was possible to obtain substances with high antihypertensive and antispasmodic activity. TTT1 TTT2

Claims (1)

The method of obtaining 5-hydrazone 7-substituted 2, 3, 5, 6, 7, 8-hexahydrocinnoline-3,5-diones of General formula 1

where RR _{1 is} a hydrogen atom (1a), RR _{1 is} methyl (1b), R is a hydrogen atom and R _{1 is} phenyl (Ic),
characterized in that the derivatives of cyclohexane-1,3-dione of General formula II

where R and R ₁ have the above meanings, are directly reacted with ethyl bromoacetic acid in the presence of sodium alcoholate of the general formula A R ₂ ONa, where R _{2 is} lower alkyl,
in a medium of absolute lower alcohol during boiling followed by treatment of the resulting reaction mass containing the corresponding cyclohexane-1, 3-dione derivative of the general formula III

,
where R and R ₁ have the above meanings,
hydrazine hydrate in a lower alcohol environment while boiling.

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