RU2715884C1 - 2-benzyl derivative of 4-(3h)quinazolinone, having analgesic, anti-parkinsonian, antihypoxant, tranquilising action - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to a dimethoxy derivative of quinazoline-4(3H)-one, specifically to 2-(3,4-dimethoxybenzyl)-3H-quinazolin-4-one of formula (1), and a method for production thereof, which is carried out by reacting amide homoveratric acid with 2-aminobenzamide by fusion of mixture.(1)EFFECT: technical result is obtaining a novel compound which can be used in medicine to create drugs analgesic, anti-Parkinsonian, antihypoxant, anxiolytic action.2 cl, 11 dwg

Description

The invention relates to the field of the pharmaceutical industry and medicine, more specifically to a newly synthesized dimethoxy derivative of quinazolin-4 (3H) -one, characterized by high biological activity in combination with low toxicity, which can be used to create drugs analgesic, antiparkinsonian, antihypoxic , anxiolytic action. The compound can be used to obtain drugs for the treatment of pain; with neurodegenerative conditions, parkinsonism; conditions accompanied by hypoxia to enhance antioxidant protection; neurosis, neurosis-like conditions, psychosomatic disorders, accompanied by emotional stress and anxiety-phobic disorders. The invention expands the number of drugs with analgesic, antiparkinsonian, antihypoxic, anxiolytic activity.

State of the art

The relevance of research results on the search for substances that affect the central nervous system among purposefully synthesized biologically active compounds is determined by the relevance of the problem of creating new domestic original medicines. The creation of new analgesic drugs - safe and highly effective - is an urgent task of pharmacology and pharmacy, which can be solved by the synthesis and study of new biologically active compounds [1-4]. Derivatives of 4- (3) quinazolinone are known that affect the central nervous system, but have significant toxicity [5].

In the process of searching for substances that affect the central nervous system, special emphasis is placed on the targeted synthesis of compounds exhibiting agonistic activity with respect to dopamine receptors. The increase in the number of people of older age groups in the structure of society is accompanied by an increase in the incidence of Parkinson's disease, which has become a social problem. In the pharmacotherapy of Parkinson's disease in the early stages, it is recommended to use dopaminomimetics, which can exhibit a neuroprotective effect, protect neurons from the negative effects, and restore damaged nerve cells. For a number of quinazolinone-4 derivatives, a neuroprotective effect is shown [6]. Of interest to researchers are hydroxy- and methoxyphenyl derivatives of quinazolinone-4, which may have dopaminergic activity.

Medicines with an antioxidant effect are indicated to enhance antioxidant protection in extreme conditions of natural and anthropogenic origin, when working in complicated situations (to the Ministry of Emergencies, rescue workers, military personnel, climbers, athletes, etc.). In diseases, especially neurodegenerative ones, the endogenous antioxidant defense system functions inefficiently. Antihypoxic drugs increase the resistance of organisms to hypoxia, are used to improve the supply of oxygen to the body, reduce the need for it, including ischemia, cardiac failure, impaired cerebral hemodynamics, with neurodegenerative conditions, weakening of memory and intelligence, etc. [7-8]. In this regard, the search for compounds with antihypoxic properties is promising for their subsequent development in order to create new drugs.

The creation of new drugs with anti-anxiety effects, including in combination with antihypoxic and nootropic effects, will improve the medical treatment of anxiety disorders, often accompanying and depressive states, and other mental disorders. Existing anxiolytics have a pronounced sedative effect, cause amnesia, adversely affect the blood picture, etc., are not recommended for patients whose work requires attention. In this regard, compounds with 2 or more types of positive action will be advantageous.

The closest in structure to the claimed compound are hydroxy- and methoxy derivatives of 4- (3) quinazolinone with dopaminergic activity [9].

This information indicates the prospect of a search for new highly effective and low-toxic painkillers, antiparkinsonian, antihypoxic substances with anxiolytic properties in the series of derivatives of 3H-quinazolin-4-one.

The present invention relates to a newly synthesized 4- (3H) quinazolinone derivative having analgesic, antiparkinsonian, antihypoxic ability in combination with tranquilizing properties and with almost complete absence of toxicity.

EFFECT: 4- (3H) quinazolinone derivative, which has an analgesic effect, which in tests with formalin, “vinegar cramps” is superior to comparison drugs metamizole sodium and lidocaine. The compound exhibits antiparkinsonian properties, superior to the anticaleptogenic effect of bromocriptine in the haloperidol catalepsy test. The newly obtained compound also has an antihypoxic effect, superior to the prototypes piracetam, mexidol, trimetazidine in the normobaric hypoxia test with hypercapnia. The resulting compound also has a tranquilizing effect, which in tests "elevated cross-shaped labyrinth", "open field" is superior to the reference drug diazepam. Compound 1 was obtained by a new method.

The inventive object is 2 (3,4-dimethoxybenzyl) -3H-quinazolin-4-one of formula (1), which has analgesic, antihypoxic, antiparkinsonian, tranquilizing activity.

A new method for producing 2 (3,4-dimethoxybenzyl) -3H-quinazolin-4-one (1) is based on the interaction of homoveratric acid amide with 2-aminobenzamide by fusing the mixture. Unlike other known methods for the synthesis of 2 (3,4-dimethoxybenzyl) -3H-quinazolin-4-one [10], the patented method is simpler and more cost-effective.

RECEIPT DIAGRAM

A new way to obtain a derivative of 4- (3H) quinazolinone, which exhibits analgesic, antiparkinsonian, antihypoxic, tranquilizing effect.

SYNTHESIS EXAMPLE

The melt of a mixture of 195 g (0.1 mol) of homo-humic (3,4-dimethoxyphenylacetic) amide (3) amide and 15.2 g (0.11 mol) of 2-aminobenzamide (2) is heated in an open vessel at 110-180 ° С until termination emission of water vapor (~ 40-60 min). The melt is cooled to 90-70 ° C and diluted with 100 ml of acetic acid, heated to the same temperature. The crystalline precipitate of 2- (3,4-dimethoxybenzyl) -4 (3H) -quinazolinone (1) precipitated after cooling was filtered off, washed twice with cold isopropyl alcohol, and dried at room temperature. Yield 79-82%. T. pl. 225-226 ° C (colorless crystals).

Found (%): C 68.95, H 5.39, N 9.48. C ₁₇ H ₁₆ O ₃ N ₂ .

Calculated (%): C 68.91, H 5.44, N 9.45.

¹ H NMR spectrum (300 MHz), δ, ppm, DMSO-d ₆ : 3.70 (s, 3H, OCH ₃ ), 3.74 (s, 3H, OCH ₃ ), 3.00 (s, 2H, CH ₂ ) , 6.91 (d, 1H, Ar), 6.93 (d, 1H, Ar), 7.07 (s, 1H, Ar), 7.58 (t, 1H, Ar), 7.67 (d, 1H, Ar), 7.88 (t, 1H, Ar), 8.11 (d, 1H, Ar)

Assessment of pharmacological activity

The pharmacological psychotropic activity of the compound was evaluated in four directions. The analgesic, antiparkinsonian, antihypoxic, and anxiolytic effects of compound 1 were studied.

For research, we used white sexually mature male rats (5–11 per group) and females (10–12 per group) of the Wistar strain weighing 200–250 g, which were kept with free access to water and food under standard vivarium conditions. Care, feeding, work with animals was carried out in accordance with international recommendations on the protection of vertebrate animals used for experiments or for other scientific purposes [11-12].

The control animals in each series of experiments for each method in assessing the studied activity were groups of rats — females, males, which were injected intraperitoneally with 0.4 ml of solvent (1-2 drops of Tween-80 per 10 ml of water) or physiological saline (control group for animals who received prototypes in similar regimes - reference preparations (metamizole sodium, lidocaine, bromocriptine, piracetam, mexidol, trimetazidine, diazepam). The groups of animals included 5-12 individuals (experimental, control, comparison preparations). All solutions of substances in all with A series of experiments was injected intraperitoneally, taking into account the chronotropic properties of psychotropic drugs, studies were carried out in the daytime (from 12-00 to 17-00 h) and in the evening (from 18-00 to 20-00 h) [13].

Statistical analysis of the results of the study was carried out using software packages "Excel", "BIOSTAT", "Statistica 10". The normality of the distribution of the obtained data was determined using the Shapiro-Wilk test. Student's t-test was used in the normal distribution of the obtained data. In the distribution of research data other than normal, the Kruskal-Wallis criteria and the Wilcoxon-Mann-Whitney U-test were applied. A comparative analysis was carried out, during which the results of the experimental groups were compared with the data of the control animals (taken equal to 100%). A comparative analysis of differences in the action of substances in female animals was also carried out in the stages of the estrous cycle diestrus 1/2 and proestrus / estrus. The differences were statistically significant at p <0-5 for all types of analysis [14-16].

The analgesic activity of compound 1 was studied in tests with formalin and "vinegar cramps"; antihypoxic activity - on a normobaric hypoxia model with hypercapnia; antiparkinsonian effect - on the model of haloperidol catalepsy; tranquilizing activity - in tests of an elevated cruciform labyrinth, “open field” [17].

Analgesic activity

The influence of the claimed object on analgesic activity was carried out on models of nociceptive reactions caused by chemical stimuli (formalin test and "vinegar cramps"). Using tests, the peripheral level of pain sensitivity was evaluated [18].

The formalin test allows you to evaluate algogeninduced somatic pain, simulates reactions in surgical incisions of the skin. The first (acute) stage develops immediately, manifested by the action on the primary afferents of pain; the second (inflammatory) stage is delayed in time and caused by an inflammatory response. Pain sensitivity was modeled by subplanetary injection of 50 μl of an aqueous solution of 2% formalin into the dorsum of the hind right paw. Subsequently, within 60 minutes of observation, the so-called “flinches” were recorded - nociceptive responses (raising the paw, licking, biting the injection site): 1) the first 10 minutes from the moment of formalin administration (acute phase); 2) from the 10th to the 60th minute of a pain reaction (inflammatory phase). The analgesic effect of the test compound was determined in total and separately for phases I and II of the pain response by reducing the frequency of reactions with respect to the parameters of the group of control rats (taken as 100%).

Using the “Acetic Cramps” technique, peritovisceral pain was determined. Using this generally accepted model of visceral nociception, the peripheral antinociceptive effect of new substances with the use of chemical algogen to irritate the peritoneal pain receptors was studied and specific motor reactions - cramps - were evaluated. “Cramps” are painful characteristic behavioral responses that arise under the influence of chemical algogens that irritate the serous membranes, and are manifested by contraction and relaxation of the abdominal muscles, back deflection, extension of the hind legs, similar to pain with peritonitis. Cramps were caused by a single injection of a 1% solution of acetic acid (0.5 ml / 100 g of animal body weight; intraperitoneally). The analgesic effect was evaluated by reducing the number of “writhing” for 15 minutes of observation after the introduction of acetic acid solution (in% of the data of the group of control animals, which are taken as 100%).

Substance 1 at a dose of 0.2 of the molecular weight in mg / kg (59.2 mg / kg), reference drugs in therapeutically effective doses: metamizole sodium - 55 mg / kg (Metamizolum natrium; analgin, solution for intravenous and intramuscular injection 500 mg / ml 2 ml ampoules; Moskhimpharmpreparat named after N. A. Semashko, Russia), 1 mg / kg (Lidocainum; ampoules 2% 2 ml; Dalchimpharm, Russia) was administered intraperitoneally once 40 minutes before the start of administration chemical irritants. The dose of the investigated compound 1 and reference preparations were selected by the dose titration method and taking into account the literature data [19–20]. Tween-80 solubilizate and distilled water (0.4 ml intraperitoneally) were respectively injected into the males and females of the control groups under similar conditions. Given the differences in the activity of drugs depending on gender, phases of the estrous cycle, studies were conducted in males and female rats, including females in various phases of the estrous cycle (EC). Prior to testing, the phases of the estrous cycle (proestrus / estrus (PE) and diestrus ½ (D)) were determined by vaginal smears of female animals [21]. The experiments were conducted in the daytime.

When studying the analgesic activity in tests with formalin and “vinegar cramps”, a high activity of compound 1 was noted (table 1, 2). Compared with the data from the control male group, when using compound 1 in the formalin test, pain sensation was suppressed, more effective than analogues: more than 1.64 times metamizole sodium and 3 times lidocaine.

When using Compound 1 in females, the number of painful responses was statistically significantly reduced in general and throughout all stages of testing with formalin (Table 3). Moreover, the decrease in the frequency of raises of the paws, licking, biting the injection site under the influence of compound 1 was more pronounced in comparison with the effects of the comparison drugs. When testing "vinegar cramps" when using compound 1, the frequency of painful responses was statistically significantly limited (table 4). In this case, the effect of compound 1 was more distinct compared with the effect of lidocaine.

Therefore, compound 1 decreased the frequency of pain responses in tests with formalin and “vinegar cramps” in female animals, showing analgesic activity.

When analyzing the analgesic activity of the studied substance 1 in female animals, taking into account the phase of the estrous cycle, a statistically significant decrease in the total number of pain reactions during the entire period of testing with formalin was noted with the administration of compound 1 significantly in individuals in the proestrus / estrus stage (physiological stress phase). The decrease in the frequency of pain responses was more distinct than with the introduction of comparison drugs (table 5).

Evaluation of the analgesic effect of compound 1, taking into account the test phases, established a significant limitation of the number of pain reactions in females in proestrus / oestrus in both acute and inflammatory phases. The decrease in the frequency of pain reactions with the introduction of compound 1 was more pronounced compared with the effect of comparison drugs.

In the test “vinegar cramps” with the introduction of compound 1, the number of “cramps” was significantly limited in female rats that were in both 1/2 diestrus and proestrus / estrus, while a significant decrease was noted in 1/2 diestrus when lidocaine was introduced (table 6) . Moreover, the decrease in the number of “vinegar cramps” was more pronounced compared with the effect of lidocaine in female animals in both phases of the estrous cycle.

Conclusion: Compound 1 has analgesic activity exceeding the effect of drugs for comparing metamizole sodium and lidocaine.

Antihypoxic activity

The definition of antihypoxic activity of the claimed object was carried out under conditions of normobaric hypoxia with hypercapnia.

Compound 1 at a dose of 59.2 mg / kg (0.2 of the molecular weight in mg / kg), solubilized with tween-80, reference preparations: piracetam (Piracetamum, 400 mg capsules, Severnaya Zvezda, Russia) and Mexidol B a dose of 100 mg / kg (Mexidol, 5% solution for intravenous and intramuscular administration, 2 ml ampoules; Pharmasoft, Russia), 6.7 mg / kg trimetazidine (Trimethazidinum, 20 mg capsules, VERTEX JSC , Russia) were injected 40 minutes before the start of testing once intraperitoneally. The groups of control females under similar conditions were injected with a solvent (Tween-80 solution, 1-2 drops per 10 ml of distilled water) and physiological saline (0.4 ml intraperitoneally). Doses of the test compound and reference drugs were selected taking into account the literature data [22-23]. At the beginning of the experiment, the phases of the estrous cycle in females were determined by vaginal smears. The experiments were carried out in the evening.

When studying antihypoxic activity in a normobaric hypoxia model with hypercapnia, a high activity of compound 1 was noted (table 7).

Compared with the data from the control female group, when using compound 1, the duration of hypoxia tolerance, the time of the first agonal inhalation, and seizures increased by more than a third (+ 36.3%; p <0.001). An analysis of differences in the activity of the compound at different stages of the estrous cycle revealed a longer duration of hypoxia tolerance in proestrus / estrus, however, the severity of the antihypoxic effect (shift in relation to the data of control females in the corresponding stage of the estrous cycle) compared to compound 1 was greater in female animals in the diestrus phase ½ than in proestrus / estrus. The manifested activity of the compound exceeded the antihypoxic effect of piracetam, mexidol, trimetazidine in the studied doses, including in different phases of the estrous cycle.

Conclusion: Compound 1 has antihypoxic activity, statically significantly exceeding the effect of drugs comparing piracetam, mexidol, trimetazidine.

Anticaleptic activity

The antiparkinsonian (anti-cataleptic) effect of compound 1 was studied on sexually mature white rats: females and males (Wistar strain, weighing 200-250 g, 9-10 in groups) in the haloperidol catalepsy test (haloperidol at a dose of 1 mg / kg intraperitoneally) [21] . Compound 1 at a dose of 59.2 mg / kg (in suspension with tween-80), the reference drug bromocriptine (at a dose of 0.125 mg / kg) (Bromocriptinum, 2.5 mg tablets, "Gedeon Richter", Hungary) was administered intraperitoneally at the same time haloperidol (Haloperidolum, 1.5 mg tablets, Biocom, Russia). The groups of control males and females of animals in a similar mode introduced one antipsychotic drug. The experiments were conducted in the daytime.

The dynamics of motor disturbances in animals was determined against the background of the studied substances. Changes in the intensity of haloperidol catalepsy — the time (in seconds) of verticalization (in the “pose of the lecturer”) - the duration of the rat's upright position on the support, were estimated. Latent periods of time were established after which the rat removed one / second paw: 1st / 2nd results. The results were recorded after the introduction of the solubilizate of compound 1, a solution of the comparison drug bromocriptine after 30, 60, 120, 180 minutes [17]. The phases of the estrous cycle in female rats (proestrus / estrus, diestrus Ѕ) were determined by vaginal smears.

When using a combination of compound 1 with a neuroleptic at 120 and 180 minutes of the test, motor disturbances were weakened, statistically significant at 120 minutes of the experiment (table 8). The effect was more distinct than with the introduction of the comparison drug.

Conclusion: Compound 1 has anticaleptogenic activity exceeding the effect of the drug bromocriptine in the studied dose.

Anxiolytic activity

Evaluation of the tranquilizing activity of compound 1 according to the elevated cruciform labyrinth (PCL) test was carried out in an experimental setup consisting of 4 arms 50 × 10 cm in size, fastened at right angles to each other. The two opposite arms of the PKL are closed (dark on both sides) and the other two open (light). The labyrinth is raised above the floor to a height of 0.5 m. The height of the walls in the closed sleeves is 10 cm. The sleeves are open at the top. At the intersection (at right angles) of the arms there is a site measuring 10 × 10 cm. During testing, animals were placed on the central platform of the maze and then behavior parameters were visually recorded for 5 min: the total number of entries into the maze arms (open or closed) and time presence in them (s). The anxiolytic activity of the test compound was determined by the increase in the animal’s entry into the light (open) arms and the increase in the residence time in them, the decrease in the number of peeps and the residence time in the dark (closed) arms [24].

The study was performed on male white rats. Compound 1 at a dose of 29.6 mg / kg (0.1 of the molecular weight in mg / kg), the reference drug is the prototype diazepam at a dose of 0.1 mg / kg (Diazepamum, solution for intravenous and intramuscular injection of 10 mg / 2 ml ; 2 ml ampoules; Relanium, Polfa, Poland) were injected once intraperitoneally 40 minutes before the start of testing. Control males in similar modes were injected intraperitoneally with physiological saline.

With the introduction of compound 1, the number of visits of male rats and the residence time in open arms increased while limiting the time spent in the dark arms of the labyrinth compared with the behavior parameters of control animals of group K1. Under the action of compound 1, the time spent in the dark arms was limited more than under the influence of diazepam in the studied dose (table 9). Slow grooming was also more frequent with Compound 1 (1450%, P = 0.05).

Conclusion. Compound 1 showed a tranquilizing antiphobic effect in male rats in PKL. Moreover, the antiphobic effect of compound 1 was more pronounced than that of the diazepam comparison drug in the studied dose.

When studying the anti-anxiety activity of compound 1 using the “open field” method [25], the following were recorded: 1) the latent period of exit from the center of the field; 2) horizontal motor activity - the number of sectors crossed; 3) vertical activity - the number of vertical racks; 4) research activity - the number of holes examined - “mink” (sniffing); 5) quick grooming - the number of acts of quick washing; 6) the number of boluses. The experiment time was 2 minutes. Based on the combination of increasing the latent period of exit from the center of the field, decreasing vertical and horizontal activity, a “sedative” effect of the substance was judged, with an increase in research activity, limiting the frequency of rapid grooming and the number of fecal boluses (vegetative presentation of stress) - “anti-anxiety” action [26].

Evaluation of the effect of compound 1 on the behavior of male rats in the test "open field" revealed a limitation in the number of vertical struts and crossed lines compared with the data of the control group of animals treated with solvent (table 10). Also, in animals, research activity was statistically significantly increased and the frequency of rapid grooming was reduced, which indicated a decrease in the emotionality of animals. Compared with the effect of diazepam on the background of the use of compound 1, the number of studied “minks” was statistically significantly larger, the frequency of rapid grooming was significantly reduced.

Conclusion. When testing male rats in an open field, compound 1 exhibited an anti-anxiety effect upon single administration. The anti-anxiety effect was more pronounced compared with the effect of diazepam in the studied doses.

Chronic toxicity

The effect of the chronic use of compound 1 on the peripheral blood leukocyte formula was evaluated. Original animal blood smears, prior to administration of compounds (K1) and groups of rats receiving a tween-80 (K2) solution for 7 days, compound 1 at a dose of 59.2 mg / kg, piroxicam (0.5 mg / kg), was stained with Romanovsky-Giemsa method [27]. Leukocyte counting included the determination of the relative number of individual leukocytes [28].

When analyzing the leukocyte blood count of male rats treated chronically with Compound 1, a slight increase in the number of monocytes was found while limiting the number of segmented cells. Also, compared with K2, an increase in the content of basophils and eosinophils was noted. However, the observed changes in the level of peripheral blood eosinophils fraction occurred within the physiological norm (table 11).

Chronic use of piroxicam led to an increase in the number of basophils and eosinophils compared to K1 and K2, the number of monocytes in relation to the control group K1, the number of lymphocytes in relation to K1 also decreased.

Compound 1 compared with the effect of piroxicam had statistically significantly less basophils. When using compound 1, compared with the action of diazepam, young forms were absent [29].

Conclusion. Compound 1 in chronic use on the leukocyte blood count had a less pronounced effect in contrast to piroxicam, diazepam.

Acute toxicity

When assessing the acute toxicity of compound (1) in rats of males and females, male mice with the introduction of 2000 mg / kg intraperitoneally, the death of animals was not recorded, LD _{50 is} assumed to be 2000 mg / kg The determination of acute toxicity and the calculation of LD ₅₀ in female mice was carried out according to the Behrens method and found that for compound (I) LD ₅₀ = 1625 mg / kg of animal body weight with intraperitoneal administration. LD ₅₀ metamizole sodium for mice - 250 mg / kg (intraperitoneally) [30]. LD _{50 of} lidocaine: for rats is 317 mg / kg, for mice was 220 mg / kg (oral) [31]. LD _{50 of} bromocriptine: for rats - 72 mg / kg (intravenously) [32]; bromocriptine mesylate: for rats - 10.5 mg / kg (intravenously), mice - 189 mg / kg (intravenously) [33].

Piracetam LD ₅₀ for rats is 10.6 g / kg (intravenously) [34]. Mexidol LD ₅₀ for mice - 430 mg / kg, for rats - 820 (625-1025) mg / kg (intraperitoneal) [35-36]. LD _{50 of} trimetazidine dihydrochloride: for rats - 345 mg / kg (intraperitoneally), for mice - 125 mg / kg (intravenous) [37].

Diazepam LD ₅₀ for mice - 700 mg / kg, rats - 1200 mg / kg (oral) [38].

Thus, the test compound (1) is practically non-toxic, belongs to the V class of toxicity according to Sidorov K.K. (1973). [39].

Conclusion. The results of the studies show that the studied compound 1 has analgesic, antihypoxic, anti-cataleptic and tranquilizing activity.

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The study was supported by the Foundation for the Promotion of the Development of Small Forms of Enterprises in the Scientific and Technical Field (the Foundation for the Promotion of Innovations; agreement No. 12575GU / 2017 dated 04/18/2018).

Claims (3)

1. The method of obtaining 2- (3,4-dimethoxybenzyl) -3H-quinazolin-4-one

(1), corresponding to formula (1), in which Me is a methyl radical based on the interaction of a homoveratric acid amide with 2-aminobenzamide by fusion of the mixture. 2. 2- (3,4-Dimethoxybenzyl) -3H-quinazolin-4-one, corresponding to formula (1), having analgesic, antiparkinsonian, antihypoxic, tranquilizing activity.

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