RU2417082C2 - N, n '-substituted 3, 7-diazabicyclo[3,3,1]nonane drug for memory regeneration in health and disease in patients of all age groups, based pharmaceutical composition and method of application thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine, and concerns the application of N,N-substituted 3,7-diazabicyclo[3.3.1]nonane derivatives, including bases and salts with pharmacologically acceptable acids of general formula

as a drug for memory regeneration in health and disease in patients of all age groups, to the based drug for memory regeneration and a method for memory regeneration.

EFFECT: invention provides higher clinical effectiveness.

4 cl, 2 tbl, 2 ex

Description

The invention relates to the use of chemical compounds in the field of medicine and can be used in the manufacture of pharmacological preparations for the restoration of memory lost as a result of pathology, adverse effects or time.

The formation of memory is a multi-stage process. Its first step is the learning process associated with the acquisition of new information. Activation of AMPA receptors plays a decisive role at this stage, and therefore, substances that potentiate the work of AMPA receptors, as a rule, improve the memorization process (JCQuirk, ES Nisenbaum. A novel positive allosteric modulator of AMPA receptors. CNS Drug reviews. 2002, 8, 3 : 255-282). However, after the learning process has ended, these substances lose their effectiveness. In this case, the memory itself undergoes further consolidation, in which it passes from short-term to long-term form. This process is supported by other intracellular mechanisms, including gene expression and the synthesis of new proteins and not involving AMPA receptor activity.

Training can be strong or weak depending on the intensity and strength of the training event. With poor learning, additional tools are needed to form a long-term memory. With poor learning, short-term memory is formed, which manifests itself during testing after 4-6, but not 24 hours after training. This memory can be enhanced by the administration of certain compounds, for example, nitric oxide agonists, steroid hormones, certain peptides (Rickard NS, Ng KT, Gibbs ME A nitric oxide agonist stimulates consolidation of long-term memory in the 1-day-old chick. Behav Neurosci 1994, 108: 640-4; Sandi C., Rose SP, Mileusnic R., Lancashire C. Corticosterone facilitates long-term memory formation via enhanced glycoprotein synthesis. Neuroscience 1995, 69: 1087-93; Mileusnic R., Lancashire CL , Rose SP The peptide sequence Arg-Glu-Arg, present in the amyloid precursor protein, protects against memory loss caused by A beta and acts as a cognitive enhancer. Eur J Neurosci. 2004, 19: 1933-8).

The formation of long-term memory begins with strong training and is provided by the synthesis of new proteins in the brain, which begins immediately after training (Davis H.P., Squire L. R. Protein synthesis and memory: a review. Psychol. Bull. 1984, 96: 518-559). The introduction of protein synthesis blockers into the brain prevents the formation of long-term memory, as a result of which, when tested 24 hours after training, the proportion of animals exhibiting learned behavior is reduced (Goelet P., Castelluci VF, Schacher S., Kandel ER The long and short of long- term memory - a molecular framework. Nature, 1986, 322: 419-423; Gibbs ME, Ng KT Psychobiology of memory: Towards a model of memory formation. Biobehav. Rev. 1977, 1: 113-136; Mark RF, Watts ME Drug inhibition of memory formation in chickens. II. Long-term memory. Proc. R. Soc. Lond. B. Biol. Sci. 1971,178: 439-454).

Memory retrieval. Forgetting is manifested in the impossibility or difficulty of extracting memory. The nature of forgetting remains poorly understood, and the scenarios of both the loss of traces of memory over time and the difficulties of extracting information that remains in memory are considered. One way to remove memory, including weak memory, is to remind. A reminder is a presentation to the subject of one of the components of a learning situation, leading to the reactivation of a previously formed memory trace.

Methods and substances that can restore lost memory are extremely few and inconvenient for use from a practical point of view. They include a combination of reminders with certain effects: electrical stimulation of the reticular formation of the brain or blue spot, administration of monosaccharides or strychnine (DeVietti TL, Hopfer TM Complete amnesia induced by ECS and complete recovery of memory following reinstatement treatment. Physiol. Behav. 1974, 12: 599-603; Rodriguez WA, Home CA, Padilla JL Effects of glucose and fructose on recently reactivated and recently acquired memories. Prog. Neuropsychopharmacol. Biol. Psychiatry 1999, 23: 1285-1317; Sara SJ, Deweer B., Hars B. , Reticular stimulation facilitates retrieval of a "forgotten" maze habit. 1980, Neurosci. Lett. 18: 211-217; Gordon WC Susceptibility of a reactivated memory to the effects of strychnine: a time-dependent phenomenon. Physiol. Behav. 1977, 18: 95-99).

It is obvious that in real life it is impossible to restore people's memory using stimulation of the reticular formation or the blue spot of the brain using electrodes implanted in the brain. The use of "rat poison" strychnine is also practically inapplicable. Eating pieces of sugar is good for the brain, but it can hardly be considered as a significant help for extracting memory, especially in case of pathological disorders of this process. Thus, in the pharmacopeia there are practically no drugs that can restore lost memory.

The task to which the invention is directed is to expand the arsenal of tools that can be used as new drugs to restore lost memory in normal and pathological conditions in patients of all age groups who have a directed action and do not affect other body functions.

The problem is solved by the use of derivatives of N, N'-substituted 3,7-diazabicyclo [3.3.1] nonanes, by the general formula (1):

as a means to restore lost memory in normal and pathological conditions in patients of all age groups.

In the case of the use of compounds of formula (1), HY hereinafter represents a pharmacologically acceptable acid; E represents a carbonyl group, CHR;

R represents H, lower alkyl, hydroxyl, halogen, alkoxy;

R ₁ represents H, lower alkyl, hydroxyl, phenyl;

R ₂ , R ₂ ', R ₃ , R ₃ ', R ₅ and R ₅ 'may be the same or different, and each independently represents H, lower alkyl, hydroxyl, alkoxy;

R ₄ represents H, lower alkyl, cycloalkyl, heteroaryl, hydroxyl, nitro, halogen, alkoxy, acyl;

X represents a group of the general formula:

- (CH ₂ ) _m -Z-,

in which m = 0-4, and Z is selected from the group consisting of:

acyl;

isoalkyl;

acetoxy;

or X represents a valence bond.

The most preferred as a means to restore lost memory in normal and pathological conditions in patients of all age groups are the following compounds of formula 1 (in the form of pharmacologically acceptable salts and / or free bases):

1,5-dimethyl-3,7-bis [(2,2,7-trimethyl-1,3-benzodioxol-5-yl) carbonyl] -3,7-diazabicyclo [3.3.1] nonan-9-one

3,7-bis [(4-chloro-2,2,7-trimethyl-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonane 9-he

3,7-bis [(2-acetyl-4-chloro-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one

3,7-bis (1,3-benzodioxol-5-ylcarbonyl) -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one

3,7-bis [(7-bromo-2-methoxy-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one

1,5-diethyl-3,7-bis [(6-iodo-2-methoxy-1,3-benzodioxol-5-yl) carbonyl] -3,7-diazabicyclo [3.3.1] nonan-9-one

3,7-bis [(6-iodo-2,2-dimethyl-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonane

3,7-bis [(2-acetyl-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one

It was previously shown that compounds, which include compounds of formula 1, potentiate AMPA receptor currents and, thus, can be useful for improving learning and cognitive functions (RF No. 2333211, C07D 471/08, published September 10, 2008).

Unexpectedly, we found that the compounds of formula 1, in addition, also have the ability to influence other memory units: namely, to improve the processes of memory extraction, which makes them unique and especially valuable among all known drugs that affect memory.

Thus, the compounds of formula 1, due to their discovery of new unexpected properties that do not follow from the chemical structure of these compounds, can be used as a means to restore lost memory in normal and pathological conditions in patients of all age groups.

As is commonly accepted in medicine, the compounds of formula 1 according to the present invention are recommended to be used in the form of a pharmacological agent, constituting respectively the next aspect of the invention.

According to the invention, a pharmacological agent for restoring lost memory in normal and pathological conditions in patients of all age groups, containing an active principle and a pharmaceutically acceptable carrier, contains as an active principle an effective amount of a compound of formula 1.

The term "pharmacological agent" means the use of any dosage form containing a compound of formula 1, which could find prophylactic or therapeutic use in medicine as a means to restore memory lost as a result of pathology, adverse effects or time.

The term "effective amount" as used in this application means the use of that amount of a compound of formula 1 which, in combination with its activity and toxicity indices, as well as on the basis of specialist knowledge, should be effective in this dosage form.

To obtain a pharmacological agent, the compound of formula 1 is mixed as an active ingredient with a pharmaceutically acceptable carrier known in medicine according to pharmaceutical methods. Depending on the dosage form of the preparation, the carrier may take various forms. The pharmacological agent according to the invention is prepared using methods generally accepted in the art and includes a pharmacologically effective amount of an active agent representing a compound of formula 1 or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active compound"), typically from 1 to 20% by weight, in in combination with one or more pharmaceutically acceptable adjuvants, such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents you. In accordance with known methods, the pharmacological agent may be in various liquid or solid forms.

Examples of solid dosage forms include, for example, tablets, pills, gelatine capsules, etc.

Examples of liquid dosage forms for injection and parenteral administration include solutions, emulsions, suspensions, etc.

Another aspect of the invention is a method of restoring lost memory in normal and pathological conditions in patients of all age groups, comprising administering to a patient a pharmacological agent containing an effective amount of a compound of formula 1 at a dose of 0.005-1 mg / kg body weight at least once a day the course of the period necessary to achieve a therapeutic effect.

The compound of formula 1 can be administered to patients in the form of conventional oral compositions, such as tablets, coated tablets, hard and soft gelatine capsules, emulsions or suspensions.

The dose of the active component (compound of formula 1) prescribed for administration varies depending on many factors, such as the age, gender, weight of the patient, symptoms and severity of the disease, the compound specifically prescribed, the method of administration, the form of the preparation in which the active compound is prescribed.

Typically, the total prescribed dose is from 0.5 to 80 mg per day. The total dose can be divided into several doses, for example, for taking from 1 to 4 times a day. For oral administration, the interval of total doses of the active substance is from 1 to 80 mg per day. For parenteral administration, the prescribed dosage range is from 0.5 to 40 mg per day, preferably, and for intravenous injections, from 0.1 to 5 mg per day is preferred. The exact dose can be chosen by the attending physician.

The technical result that can be obtained by carrying out the invention is the restoration of lost memory in normal and pathological conditions in patients of all age groups.

Table 1 shows the data characterizing the effect of systemic administration of 0.005 mg / kg of compound 1, a typical representative of which is 3,7-bis (1,3-benzodioxol-5-ylcarbonyl) -1,5-dimethyl-3,7-diazabicyclo [ 3.3.1] nonan-9-one, of the following structural formula:

The compound is administered 30 minutes before training for memory impaired by the administration of anisomycin 5 minutes after training, where i.p. - intraperitoneal (intraperitoneal) administration of saline, i.c. - intracerebral injection of the substance, * - significant difference from the control (p <0.05) - (saline solution + Anisomycin).

Table 2 shows the data characterizing the effect of systemic administration of 0.005 mg / kg of compound 1 5 minutes before the reminder to reproduce the skill 24 hours after training.

The possibility of carrying out the invention with the implementation of the claimed purpose is confirmed, but not limited to the following information.

Data on the effect of new compounds on the restoration of lost memory.

The authors used a model for training experimental animals in a “passive avoidance” model to evaluate the properties of new compounds. Compounds were tested in two main ways: (1) the possibility of restoration with their help of memory impaired by pharmacological intervention was investigated; (2) investigated the possibility of pharmacological enhancement of weak memory at the time of reminder.

Method for assessing the effect of new compounds on memory.

To study the effect of the compounds on the memory of animals, a one-time training method for passive avoidance of chickens (Gallus gallus domesticus) at the age of 1-3 days was used. This experimental model serves as one of the basic techniques used to study patterns and mechanisms of memory formation (Gibbs ME, NG CT Psychobiology of memory: Towards a model of memory formation. Biobehav. Rev. 1977, 1: 113-136; Rose SPR Biochemical mechanisms involved in memory formation in the chick. Behavioral and Neural Plasticity: the Use of the Domestic Chick as a Model. // Ed. Andrew. RJ Oxford: Oxford Univ. Press, 1991, 277-304; Rose SPR, Stewart MG, 1999 Cellular correlates of memory formation in the chick following passive avoidance training. Behav. Brain Res., 98: 237-243; Patterson TA, Alvarado MC, Warren IT, Bennett EL, Rosenzweig MR Memory stages and brain asymmetry in chick learning. Behav Neurosci. 1986, 100: 856-865; Stewart, 1991, Rose, 1991, 1995). The advantage of the model is very fast (seconds) training, which allows you to accurately capture the moment of acquisition of new information in the nervous system. The sequence of intracellular and synaptic processes unfolding after this, which ensure the formation of long-term memory in the passive avoidance model, has now been studied in detail. An additional advantage of this model is that the non-ossified skull of newborn chickens allows you to enter pharmacological preparations with a microsyringe directly into predetermined brain structures, without surgery and anesthesia; systemic administration of drugs is also used, the penetration of which into the brain is facilitated by the immature blood-brain barrier.

Animals. The chickens (males) of the Ptichnoe cross were used in the experiments.The animals were delivered from the poultry farm on the day of hatching and kept in pairs in canisters measuring 20 × 25 × 20, with constant access to water and feed, at a temperature of 28 ° C and a light cycle of 12: 12 hours The minimum time to adapt to the situation before the experiment was two hours.

Injection For systemic administration of solutions, intraperitoneal injections in a volume of 0.1 ml were used. Intracranial injections were performed bilaterally with micro-syringes (Hamilton) with a volume of 25 μl using a plastic head holder and sent to the region of the lateral ventricles of the brain. The injection volume was 10 μl per hemisphere. After the experiment and decapitation of the animals, the surface of the skull and brain was monitored to control the localization of injections. Stock solution of compounds 1 (belongs to the group of compounds of formula 1.2) (3,7-bis (1,3-benzodioxol-5-ylcarbonyl) -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9- he) was prepared in 95% ethanol (4 mg / ml) and then adjusted with a 0.9% NaCl solution to a working concentration (0.002-0.04 mg / ml). The solutions were administered intraperitoneally in a volume of 0.1 ml.

Models of “strong” and “weak” passive avoidance training

Training in the “strong” model of passive avoidance was carried out according to the standard method (Rose SPR Biochemical mechanisms involved in memory formation in the chick. Behavioral and Neural Plasticity: the Use of the Domestic Chick as a Model. // Ed. Andrew. RJ Oxford: Oxford Univ. Press, 1991, 277-304). 20 minutes before the training, pre-training was carried out, consisting of a double presentation of a “neutral” (dry) bead attached to the rod. Most chickens ate a bead at least once during the first 10 seconds; chickens that refused to bite during two of the three presentations (less than 15%) were excluded from the experiment. For training, the chickens were presented with a new ("aversive") bead moistened with a burning substance (methylanthranilate, Sigma). Chickens pecking a bead showed a typical species-specific aversive reaction. “Weak” passive avoidance training was carried out according to a similar protocol, but a 10% solution of methylanthranilate in ethanol (Gibbs ME, Summers RJ Effects of glucose and 2-deoxyglucose on memory formation in chicks: interaction with beta ( 3) -adrenoceptor agonist. Neurosci. 2002, 114: 69-79). Testing was carried out 24 hours after training and consisted of a 10-second presentation of the same “aversive” bead as in training, but dry, and then a neutral bead. The selective reaction of avoiding the "aversive" bead was assessed as the presence of long-term memory. To assess the level of memory, the percentage of animals exhibiting an avoidance response was compared in different experimental groups; the statistical significance of the differences was evaluated using the nonparametric criterion χ ² .

Example 1. The ability to restore pharmacologically impaired memory.

The introduction to chickens of compound 1 before learning passive avoidance associated with impaired protein synthesis leads to memory preservation. Animals were trained in the standard model of passive avoidance, leading to the formation of a stable memory. 5 min after training, anisomycin protein synthesis blocker (80 μg, 10 μl per hemisphere) was injected into the lateral ventricles of the brain. When tested after 24 hours, the memory in animals treated with anisomycin was impaired compared to the control. At the same time, administration of 0.005 mg / kg of Compound 1 30 minutes before training increased the level of avoidance when tested after 24 hours in animals treated with anisomycin (see table 1).

From the presented results it is seen that the introduction of compound 1 before training prevents the development of amnesia caused by a blockade of protein synthesis in the brain. This property of compound 1 opens up the possibility of restoring memory impaired as a result of intoxication by pharmacological memory impairment, which leads to a disturbance or decrease in the intensity of metabolic processes in the brain, for example, during weakening or aging of the body.

Example 2. The possibility of pharmacological enhancement of weak memory at the time of reminder.

The authors used an experimental model of weak learning combined with a reminder procedure to test the ability of Compound 1 to enhance the memory retrieval process. Reactivation of the memory with a reminder was performed 2 hours after poor learning; 5 minutes before the reminder, animals were injected intraperitoneally with 0.005 mg / kg of compound 1 and the memory was tested 24 hours after training. The results are presented in table 2.

The presented results show that when testing the memory 24 hours after poor learning, a reminder (memory reactivation) does not lead to an increase in the skill's reproduction level. At the same time, memory reactivation against the background of systemic administration of compound 1 leads to a memory enhancement of more than 200% compared with animals that received only a reminder or only the introduction of compound 1 2 hours after poor training.

Consequently, compound 1 can be used to enhance a weakened memory of previously acquired experience (about events that occurred in the past), which opens up completely new possibilities for its use in the clinic.

Thus, the claimed group of compounds of general formula 1 can be used with great effect as a means to restore lost memory in normal and pathological conditions in patients of all age groups.

Table 1 MEANS FOR RESTORING LOST MEMORY IN NORM AND PATHOLOGY IN PATIENTS OF ALL AGE GROUPS BASED ON N, N'-SUBSTITUTED 3,7-DIAZABICYCLO [3.3.1] NONAN, A PHARMACEUTICAL COMPOSITION BECAUSE OF IT. Injectable drugs % avoidance i. p. Phys. solution + i.c. Physical solution 95% * p <0.001 i.p. Saline + i.c. Anisomycin 17% i.p. Compound 1 + i.c. Anisomycin 68% * p = 0.003

table 2 Memory Ways % avoidance Poor learning 35% p = 0.063 Weak Learning + Reminder 31% p = 0.069 Weak learning + Reminder + connection 1 78% p <0.001 Weak learning + connection 1 37% p = 0.057

Claims (4)

1. The use of derivatives of N, N'-substituted 3,7-diazabicyclo [3.3.1] nonanes, including bases and their salts with pharmacologically acceptable acids, general formula (1) as a means to restore lost memory in normal and pathological conditions in patients of all age groups.

as a means to restore lost memory in normal and pathological conditions in patients of all age groups,
in the case of using compounds of the formula (1)
HY hereinafter represents a pharmacologically acceptable acid;
E represents a carbonyl group, CHR;
R represents And, lower alkyl, hydroxyl, halogen, alkoxy;
R ₁ represents H, lower alkyl, hydroxyl, phenyl;
R ₂ , R ₂ ', R ₃ , R ₃ ', R ₅ and R ₅ 'may be the same or different, and each independently represents H, lower alkyl, hydroxyl, alkoxy;
R ₄ represents H, lower alkyl, cycloalkyl, heteroaryl, hydroxyl, nitro, halogen, alkoxy, acyl;
X represents a group of the general formula:
- (CH ₂ ) _m -Z-,
in which m = 0-4, and Z is selected from the group consisting of
acyl;
isoalkyl;
acetoxy;
or X represents a valence bond; 2. The use according to claim 1, where these compounds are one of the compounds of formula 1 (in the form of pharmacologically acceptable salts and / or free bases):
1,5-dimethyl-3,7-bis [(2,2,7-trimethyl-1,3-benzodioxol-5-yl) carbonyl] -3,7-diazabicyclo [3.3.1] nonan-9-one
3,7-bis [(4-chloro-2,2,7-trimethyl-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonane 9-he
3,7-bis [(2-acetyl-4-chloro-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one
3,7-bis (1,3-benzodioxol-5-ylcarbonyl) -1,5-dimethyl-3,7-diazabicyclo13.3.1] nonan-9-one
3,7-bis [(7-bromo-2-methoxy-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one
1,5-diethyl-3,7-bis [(6-iodo-2-methoxy-1,3-benzodioxol-5-yl) carbonyl] -3,7-diazabicyclo [3.3.1] nonan-9-one
3,7-bis [(6-iodo-2,2-dimethyl-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonane
3,7-bis [(2-acetyl-1,3-benzodioxol-5-yl) carbonyl] -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one. 3. A pharmacological agent for restoring lost memory in normal and pathological conditions in patients of all age groups, containing an active principle and a pharmaceutically acceptable carrier, characterized in that it contains an effective amount of a compound of formula 1 as an active principle. 4. A method of restoring lost memory in normal and pathological conditions in patients of all age groups, which consists in administering to a patient a pharmacological agent containing an effective amount of a compound of formula (1) at a dose of 0.005-1 mg / kg body weight at least once a day for the period necessary to achieve a therapeutic effect.