JPS62128B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to medicines, and more particularly to pharmaceutical preparations for use in neuropsychiatric diseases, which have pronounced vegetotropic and antiepileptic effects. Synthetic drugs to treat paroxysmal and persistent vegetovascular disorders and temporal lobe epilepsy syndromes began in the 1950s and
It began to be commonly used in the 1960s. Such preparations primarily include tranquilizers such as diazepam, chlorodiazepoxide, nitrazepam, tazepam and the like. The active principle in these preparations is one compound among the benzodiazepine derivatives. Diazepam and chlorodiazepoxide have shown the most pronounced phytotropic and antiepileptic effects, but even these preparations are not effective enough to treat the disease. For example, in the case of diencephalic syndromes with a pronounced vegetative onset, said tranquilizers featuring phytotropic activity only serve to suppress the manifestation of the disease without reducing the frequency of vegetative onset. As a result, the treatment is ineffective and the patient's condition remains unchanged. Similarly, in the case of temporal lobe epilepsy with psychoperceptual, psychomotor and vegetative onset, the use of benzodiazepine derivative tranquilizers only achieves temporary relief of paroxysmal activity without suppressing the development of psychotic abnormalities. It is. This has led to attempts at surgical treatment of temporal lobe epilepsy, which demonstrates the inherent limitations of drug therapy. Furthermore, diazepam and chlorodiazepoxide exhibit diminished efficacy and functional decline when taken over a long period of time. Magnesia, vitamins, calcium iontophoresis, diphenylhydramine hydrochloride,
Attempts to treat the disease with novocaine (procaine) and botanical sedatives (belladonna, Vlaeriana pharmacopoeia) generally produce only limited and temporary effects. On the other hand, there are a large number of cases of organic brain lesions that affect vegetative functions and are psychosomatic diseases, and drug therapy is an important issue in the treatment of such cases. The aim of the present invention is to provide a new pharmaceutical preparation for the treatment of neuropsychiatric diseases, which is characterized by a strong phytotropic and antiepileptic action and a high therapeutic activity. The purpose is to use the formula

It is characterized by containing the active principal ingredient which is the hydrazide of diphenylphosphinyl acetic acid with the formula: This is achieved by means of pharmaceutical preparations. In a narrow sense, the present invention provides a pharmaceutical preparation for temporal lobe epilepsy, characterized in that it contains the above-mentioned hydrazide of diphenylphosphinyl acetic acid as the active principle and a filler for this active principle. . The filler can be starch and calcium stearate. The drug is prepared in the form of a bill with an active principle content of 83.3% by weight. Attempts to use phosphorus-containing compounds, including the pharmaceutical preparations of the invention, which do not have anticholinesterase properties as neurotropic and psychotropic drugs have not yet been described in the literature. Although the preparation of the present invention is a relatively weak tranquilizer, it acts primarily on the vegetative regulatory centers of the proximal and diencephalic tissues of the brain, which are found as the focal point causing epileptic seizures in cases of temporal lobe epilepsy. . Diphenylphosphinyl acetic acid hydrazide is
It is an odorless white powder with a bitter taste. It is chemically stable in both powder and solution form and has a lifespan of more than 2 years. Animal experiments showed a pronounced sedative effect of this preparation. In the tolerance starting from 1/3DMT, “on−
intraperitoneal administration of 1/3 DMT dose 1 hour before the experiment does not affect the orientating response of the mice. When anesthetics and hypnotics interact, the hydrazide of diphenylphosphinyl acetate has a synergistic effect with hexenal, barbamyl, urethane and chloral hydrate and is a true Brodie Potentiator. Show characteristics.1/5
Doses of DMT are synergistic with Barbamil. Hexenal introduced within the action period of diphenylacetic hydrazide from 2 to 22 hours after administration induces sleep of equal duration, indicating that the preparation does not suppress monoamino oxidase activity. 30mg/Kg (1/7DMT) and 60mg/Kg (1/3
Hydrazide of diphenylphosphinyl acetate at a dose of 200 mg/Kg (DMT) has no effect on the body temperature of mice; at a dose of 200 mg/Kg (DMT), a dose of 1.5
and after 3 hours produce a hypothermic effect resulting in a decrease in body temperature of 4.3 and 3.4°C, respectively. The hydrazide of diphenylphosphinyl acetate also potentiates the hypothermic effects of central anti-adrenergic drugs, namely aminezine (chlorpromazine). This is another evidence that the hydrazide of diphenylphosphinyl acetate has sedative properties. The action of diphenylphosphinyl acetic acid hydrazide is related to its central anti-adrenergic action. The preparation of the invention prevents death in 60% of mice receiving lethal doses of cocaine. It also eliminates the congenital toxicity of phenamine (amphetamine) and
In this case, death of 30-60% of mice is prevented. At a wide range of doses (10-400 mg/Kg), it caused a statistically reliable reduction in the duration of phenamine stereotypy in rats, and when administered in higher doses it inhibited the appearance of phenamine stereotypy. To prevent. Experiments on isolated intestines and examination of the effect of the hydrazide of diphenylphosphinyl acetic acid on blood pressure and respiration in rabbits show that this preparation does not have peripheral anti-adrenergic effects. Studies of the function of the isolated intestines of rabbits, rats and guinea pigs subjected to the action of the hydrazide of diphenylphosphinyl acetic acid in combination with acetylcholine, barium chloride, histamine and serotonin have been carried out in rats in which the preparations of the invention were isolated. It has been shown to interfere with the action of serotonin in the intestines. The preparation was also found to reduce serotonin content in brain tissue of mice. The antiserotonin action of the hydrazide of diphenylphosphinyl acetate is also responsible for its synergistic effect with the action of nibufine, another organophosphorus compound with antiserotonin properties. Similar to reservin, diphenylphosphinyl acetic acid hydrazide increases the sensitivity of mice to the convulsive effects of corazole (pentylenetetrazole) and caffein. however,
Compared to hydrazide antidepressants that inhibit monoamine oxidase, diphenylphosphinyl acetate hydrazide has no cumulative effect, does not increase apomorphine toxicity in mice, and does not affect the duration of apomorphine stereotypy. I won't give it. Thus, with regard to its action on phenamine (amphetamine) stereotypy in mice, the hydrazide of diphenylphosphinyl acetate exhibits central anti-adrenergic properties, and with respect to its action on apomorphine stereotypy, it exhibits anticholinergic properties. The latter is further confirmed by the ability of the preparation to reduce nicotine-induced convulsions in mice, which increases the survival rate to 50%. Hydrazine diphenylphosphinyl acetate has no anti-M-cholinergic effect, which does not reduce arecoline tremor in mice and does not affect its duration. Animal studies have therefore shown that diphenylphosphinyl acetic acid hydrazide acts as a depressant, and this is due to its anti-adrenergic and possibly anti-N-cholinergic action. Regarding the effect of this preparation on the convulsions induced in animals during the experimental process, the mechanism of action appears to be more and more complex. This preparation does not inhibit convulsions produced by corazole, strychnine, and electroconvulsive therapy. However, 20-100mg/
When administered in doses of Kg, microscopic injection of penicillin into the hippocampal eminence of the brain prevents or reduces the frequency of epileptic seizures in rabbits. In mouse experiments, this preparation
showed analgesic effects starting from a dose of . 1/2DMT
hydrazide of diphenylphosphinyl acetate exhibited analgesic effects for 3 hours after administration. DMT showed no pain sensation for more than 5 hours. Diphenylphosphinyl acetic acid hydrazide enhanced the analgesic effect of analginium at a dose of 1/2 DMT, and enhanced the analgesic effect of morphine at a dose of 1/4 DMT. A clinical study of 32 cases of phytovascular myotonia showed that a series of treatments normalized the function of the sympathoadrenal and hypothalamohypophysioadrenal systems. A marked normalization of urinary excretion of adrenaline and 17-oxycorticosteroids was observed, along with a trend towards normalized extraction of norepinephrine. Determining the region of brain tissue most sensitive to diphenylphosphinyl acetic acid hydrazide.
Rabbits with permanently implanted electrodes at different locations in the cerebral cortex and subcortical structures were studied. 100
At doses of ~200 mg/Kg, the preparation was found to reduce electrical activity in the hippocampal eminence and amygdala-like nucleus of the brain. Diphenylphosphinyl acetic acid hydrazide is
It has no local irritating effects and limited toxicity (LD ₅₀ is 293 mg/Kg for intravenous injection). Intramuscular administration of this preparation to rabbits is 50mg/
Even at doses of Kg there was no effect on the animal's behavior. Long-term treatment with hydrazide of diphenylphosphinyl acetic acid (35mg/Kg-1/9
Intraperitoneal administration to mice at a dose of LD ₅₀ , 50mg/Kg
(intramuscular administration to rabbits) did not cause any changes in the blood and internal organs of the animals, which was confirmed by anatomical and histological examination. The action of this preparation can be demonstrated in neuroses (neurasthenia, hysterical neurosis, obsessive-compulsive neurosis), reactive depression, degenerative depression, alcoholism with acute alcohol withdrawal, temporal lobe epilepsy, and vegetative vasculopathy. A total of 157 patients suffering from various neurological and psychiatric diseases, including diencephalic (hypothalamic) syndromes, were studied in clinical conditions. The preparation was administered in the form of a pill containing 0.25-0.5 g of active principle. Average daily dose is 1.0-3.0g
(doses of 0.5-1 g were given two or three times a day, regardless of mealtime). Treatment continued for 1-6 weeks and even for 8 weeks. 3-3 for temporal lobe epilepsy
It took five months. According to clinical studies, this preparation exhibits a sedative effect, although it is less marked than that of diazepam and chlorodiazepoxide. The preparation acts as a mild stimulant for night sleep in neuroses, promoting the onset of sleep and reducing the number of times the patient is awake during the night. Clinical studies have also shown that the preparation is well tolerated, without significant laxative effects typical of benzodiazepine derivatives, and without side effects or complications caused by the preparation. The fundamental advantage of the preparations according to the invention lies in their pronounced action against vegetative dysregulation and their antiepileptic action. Of the 20 cases of hypothalamic syndrome with sympatho-adrenal onset, significant improvement was observed in 5 cases, in which the vegetative episodes ceased and the patient's work capacity was restored. In 12 cases, the number and intensity of attacks decreased and six improvements were observed. Early on, all patients received drug treatment, including the use of benzodiazepine derivative tranquilizers,
He was repeatedly admitted to a neurological hospital receiving various forms of treatment. The effects of such treatment were modest and erratic, showing only a reduction in the number of attacks and a slight improvement in the patient's general condition. The preparation also proved to be therapeutically effective in cases of mental weakness with pronounced vegetative angiomyotonic symptoms. Eight of the 11 patients showed significant improvement immediately at the end of the first week of treatment, as well as a number of vegetative episodes with palpitations, dyspnea, increased arterial blood pressure, phobias, and anxiety. showed a reduction or even complete elimination. Of 30 alcoholic patients in acute alcohol withdrawal with significant vegetative vasculopathy and phobia, 20 showed significant improvement during the first 2 days of treatment, compared with 30 control patients given a placebo. Of these, 10
Only the name showed some improvement. Overall, the preparation reduced the withdrawal period by 2-3 times. Good results were also obtained in the treatment of 18 cases of temporal lobe epilepsy with prominent psychoperceptual, psychomotor, vegetative and affective seizures. For many years all patients were given benzodiazepine derivatives, anticonvulsants and tranquilizers. Conventional treatments were ineffective in most of these cases. This preparation caused dramatic changes. In 14 cases, seizures were either completely stopped or their frequency was reduced by more than half. The patient's condition improves, the discomfort becomes more bearable,
The patient's behavior became more controlled. Electroencephalography showed decreased seizure activity and normalization of recordings. Long-term use of this preparation (more than 8-12 weeks)
did not produce any changes in the morphological or biochemical composition of the blood, and no changes were found by electrocardiogram. The said clinical data show that the present preparation is very effective in the treatment of neurological and psychiatric diseases accompanied by vegetative vasculopathy and non-convulsive epileptic seizures, and is superior to conventional drugs in this regard. ing. The preparations of the invention have no side effects or complications, have low toxicity, and are non-habit-forming, so
Administration can be carried out over a long period of time. The preparation can be used for the treatment of both young and old patients as well as patients with concomitant diseases of internal organs. The only contraindication sign is gastric ulcer, which has a tendency to rapidly worsen. The use of this preparation does not impede motorists. The hydrazide of diphenylphosphinyl acetic acid of the following formula is a generally known compound that can be produced by the interaction of ethyl ester of diphenylphosphinyl acetic acid and hydrazine hydrate. A manufacturing example of this preparation is shown below. Ethyl ether of diphenylphosphinyl acetic acid
Place 296 g into a 0.5 volume flask equipped with a thermometer and condenser set for distillation.
157.1 g of hydrazine hydrate are added and the reaction mixture is heated to a temperature of 120°C. Heating involves distilling the alcohol for 1.5-2 hours. After the distillation is finished, the temperature is raised to 150°C and the hydrazine hydrate is removed. Once the contents in the distillation flask begin to crystallize, the reaction mixture is cooled to 100°C and the remaining hydrazine hydrate is removed under reduced pressure with a residual pressure of 10-15 mmHg. The contents of the flask are cooled and recrystallized using 390 ml of ethyl alcohol. This produces a white crystalline product 236 with a melting point of 159-161 °C.
g is obtained. Yield is 85% of theory. The percentages of the basic constituents of the product obtained are as follows: P: 11.28, 11.35, N: 10.14, 10.17,
C ₁₄ H ₁₅ O ₂ N ₂ P ₀ so P: 11.31 and N: 10.22
%. Diphenylphosphinyl acetic acid hydrazide is
It is an odorless white crystalline powder with a bitter taste. It is soluble in water (1:100), alcohol and chloroform, but insoluble in benzene and ether. The compound is mixed with starch and calcium stearate and embossed into pills having a weight of 0.30 g and an active principle content of approximately 83% (0.25 g). Clinical data of the hydrazide of diphenylphosphinyl acetate in cases of psychoneurosis with marked vegetative dysregulation. This section presents the treatment with the hydrazide of diphenylphosphinyl acetate in 174 patients from the clinical institutions listed below. Results are shown. The location where the test was conducted was S. Viii.
Krasiyov Kazan State Medical
Institute (SVKurashov kazan
State Medical Institute) and many other medical facilities in Kazan, Moscow and other cities of the USSR. According to the disease diagnosis, the patients were classified into the following conditions: Neuroses: 47 Includes: debilitating 26 climacteric 17 hysterical 2 obsessive-compulsive 2 diencephalic syndrome, vegetative vascular type with neurotic-like disorders 58 epilepsy (temporal lobe) 41 reactive depression 8 Degenerative depression 8 Flaccid schizophrenia (neurosis-like syndrome) 7 Schizophrenia (movement depression) 5 Diphenylphosphinyl acetic acid hydrazide is used as a powder and pill containing 0.3-0.5 g. Ta. The average daily amount was 1.5-2.0 g (0.5-0.6 g three times a day) regardless of meal time. If no sufficient therapeutic effect is observed, the dose of diphenylphosphinyl acetic acid hydrazide may be increased up to 3 g per day (1 g per day up to 3 g per day).
times) was gradually increased. Treatment duration was 7 to 30 days; only for patients with temporal lobe epilepsy.
Diphenylphosphinyl acetic acid hydrazide
The drug was administered for 1.5 to 6 months, with an average of 3.5 months. The main objectives of clinical research on the hydrazide of diphenylphosphinyl acetic acid were to clarify its psychoactive properties and to obtain applicable data for use in therapeutic practice. To ensure a more objective evaluation of the treatment outcome with diphenylphosphinyl acetic acid hydrazide, a placebo was used. All patients, except those with temporal lobe epilepsy, were given a placebo for the first 5-6 days;
Diphenylphosphinyl acetic acid hydrazide was then prescribed; the patient was not informed of the change. The therapeutic efficacy of diphenylphosphinyl acetic acid hydrazide in patients was determined by the
It was primarily evaluated by objective data from clinical observations and electropoliographie tests performed after weekly administration and after one week of administration of diphenylphosphinyl acetic acid hydrazide. A thorough physical and diametrical examination was performed, along with a psychopathological examination. Repeated blood and urine analyzes were performed during treatment. The most detailed kinetic tests were submitted to patients with hypothalamic syndromes requiring specific examination of the vegetative nervous system and biochemical evaluation. Clinical trials of diphenylphosphinyl acetic acid hydrazide have shown tranquilizer properties;
It has been shown that it is possible to suppress patients' emotional excitability and alleviate their anxiety and mental tension. The psychoactive effects of diphenylphosphinyl acetic acid hydrazide vary depending on the type of psychopathological syndrome and its nosological specific characteristics. However, despite the clinical characteristics of each disease in which diphenylphosphinyl acetic acid hydrazide was tested, some common characteristics were observed in its psychoactive effects. The therapeutic effect of diphenylphosphinyl acetic acid hydrazide was observed under study from the date of initiation of patient treatment. The first signs were changes in the patient's emotional vegetative state and improvement in nighttime sleep. For 3 to 5 days after prescription of the preparation, the patient himself,
I noticed a reduction in my feelings of fear, anxiety, and irritability. Their mood became more calm, and their tearfulness and emotional hyperactivity disappeared. By the end of 2-3 weeks, more significant and stable changes had occurred in the direction of improvement in the patient's condition. They became more mentally stable and their painful emotions and meditative feelings were less emotional. The tranquilizing effects of diphenylphosphinyl acetic acid hydrazide were most pronounced in neurotic patients and least pronounced in the presence of psychotic affective disorders. The sedative effect of diphenylphosphinyl acetic acid hydrazide was not accompanied by relaxation, sluggishness, drowsiness, or fatigue. The preparation is considered to have no significant relaxing effect. On the contrary, we could observe some increase in the patient's activity during the course of treatment;
This indicates that the preparation has a slight stimulant effect. During the course of treatment, several patients felt relief from irritation and felt physically refreshed. The previous stimulating and impatient treatment by those around him was replaced by only a milder form of response; the patient was able to remain calm in situations that previously caused irritation. The patient's expression, previously worried and anxious, became calmer. It was observed that active attention function was significantly improved, leading to improved memory; the patient clearly remembered the gist of reading books, current events, television broadcasts, etc. The normalization of active attention and the reduction of its decline were also observed on the basis of experimental psychological tests in cases of positive treatment results. The positive results of treatment with diphenylphosphinyl acetic acid hydrazide were also manifested in the improvement of the patient's mood. Although no antidepressant effect was observed with the use of diphenylphosphinyl acetic acid hydrazide, improvement in the patient's general symptoms, reduction of anxiety, mental tension, and fear led to an elevation of mood. The sedative effect of the diphenylphosphinyl acetic acid hydrazide also improved nighttime sleep, but it did not exhibit a hypnotic effect. Changes in sleep structure induced by diphenylphosphinyl acetic acid hydrazide by electropolyography examination: increased total nocturnal sleep time, decreased nocturnal wake time, active sleep with a slight decrease in this sleep phase in % It is now possible to fairly evaluate the increase in the incubation period. Additionally, an inconclusive increase was observed in percentage terms during the third phase of slow sleep. Experimental studies in animals have shown the blocking effect of diphenylphosphinyl acetic acid hydrazide on the bioelectrical activity of the rabbit limbic system. A comparison with the "placebo effect" showed a substantial difference. While the prescribed 5-7 day placebo regimen did not result in any significant change in the patient's condition or behavior, treatment with diphenylphosphinyl acetic acid hydrazide for the same period gave positive results. Significant therapeutic changes occurred in the patient's symptoms. The therapeutic effects of diphenylphosphinyl acetic acid hydrazide on patients with various mental disorders are listed in Table 1. To evaluate the therapeutic effect, all patients were divided into three groups based on the therapeutic effect. The group of patients who showed significant improvement in symptoms were
Consists of patients whose symptoms have almost completely subsided with improvement of their symptoms and recovery of their working capacity. In the improved group, the symptoms of mental disorders completely disappeared, but the treatment effect with diphenylphosphinyl acetic acid hydrazide reduced anxiety and fear, and improved their medical conditions, night sleep, and appetite. Patients with observed improvement will be included. The same group includes patients who exhibit a unique symptomatology of "delamination" in which anxiety is resolved or alleviated but dysthymia and depression remain. Group 3 consists of patients who do not respond to treatment. As evident from Table 1, the majority of patients showed significant improvement in symptoms. They include patients suffering from debilitating or climacteric neurosis, vegetative vascular diencephalic syndrome, and reactive depression. Good results were also observed in cases of temporal lobe epilepsy. In cases of degenerative depression, the use of diphenylphosphinyl acetic acid hydrazide can lead to pathological manifestations,
In other words, it alleviated fear, mental tension, and agitation. The therapeutic effect was even more obvious in cases of diseases in which the above-mentioned symptoms were clinically dominant. However, diphenylphosphinyl acetic acid hydrazide did not relieve symptoms of depression and pain. Therefore, when dysthymia is markedly noticeable, treatment with diphenylphosphinyl acetic acid hydrazide alleviated the onset of anxiety and agitation, but antidepressants or EST (electroshock therapy) may continue to be prescribed. Ta. Among patients with reactive depression, the best treatment results with diphenylphosphinyl acetic acid hydrazide were obtained in patients with predominant anxiety-depressive symptoms: two cases with these symptoms. Patients were discharged from the hospital in satisfactory condition just 10 days after starting treatment. The least effective treatment was seen when obsessive-depressive, hysterical, and malaise hypochondriacal symptoms were observed along with dysthymia: two such patients received diphenylphosphinyl acetate. After four weeks of treatment with hydrazide, the patient was discharged from the hospital in significantly improved condition. Minimal treatment effects were observed in patients with endogenous neurotic-like disorders of schizophrenia and agitated depression. The preparation was well tolerated by the patients without complications or side effects. Even when administered for a long period of time (several months), the preparation does not cause changes in blood cell counts and urine analysis, and no adverse signs are observed in the liver, kidneys or other internal organs. It wasn't done. No complications were observed regarding worsening of neuropsychiatric or primarily psychotic symptoms upon administration of diphenylphosphinyl acetic acid hydrazide. The preparation was non-addictive.

[Table] Prior to administration of diphenylphosphinyl acetic acid hydrazide, the majority of patients had been receiving tranquilizers (diazepam, chlorodiazepoxide, meprobamate, tazepam) for a long period of time; Treatment results were not achieved. A specific comparative study on the effects of diphenylphosphinyl acetic acid hydrazide and chlorodiazepoxide was carried out in a group of 50 patients selected in a double-blind manner. The therapeutic efficacy of diphenylphosphinyl acetic acid hydrazide and chlorodiazepoxide is 5.
Their clinical activity was evaluated on the basis of the percentage distribution of treatment results: significant improvement, no improvement, in a graded system (0 points - no effect, 5 points - complete disappearance of psychopathological symptoms). Comparative results are listed in Tables 2 and 3.

[Table] Hydrazide of diphenylphosphinyl acetic acid 37 53 10

Claims (1)

[Claims] 1. As the active principal ingredient, the formula A pharmaceutical preparation for temporal lobe epilepsy, characterized in that it contains hydrazide of diphenylphosphinyl acetate and a filler for this active principle. 2. Pharmaceutical preparation according to claim 1, wherein the fillers are starch and calcium stearate. 3. Pharmaceutical preparation according to claim 1 or 2, having an active principle content of about 83%.