BG67301B1 - Adamantane derivative with antiviral and anti-parkinson activity - Google Patents

Abstract

The invention relates to an adamantane derivative of formula I: to a method for its preparation and to its application as an antiviral and anti-parkinson agent.

Description

Field of technology

The invention relates to an adamantane derivative with antiviral and antiparkinsonian activity, useful for the prevention and treatment of diseases associated with impaired biosynthesis and dopamine excretion.

BACKGROUND OF THE INVENTION

Dopamine is known to be a compound that the body naturally produces in the brain and functions as a neurotransmitter. This is a critical component used by the brain to control the movement of the body, which is why any change in its level in the brain leads to very poor results. Elevated levels of dopamine in the brain are associated with conditions such as drug addiction and psychiatric conditions such as schizophrenia, while its decrease leads to depression, Parkinson's disease (BP) and Parkinson's-like disorders.

Parkinson's disease is a progressive disorder of the central nervous system that affects thousands of people around the world and is associated with loss of dopamine production in a specific area of the brain. Although it usually affects the elderly, more and more people have recently been diagnosed with the disease before the age of 50. It is a chronic and progressive disease, the symptoms of which worsen and become irreversible over time. Typical symptoms include decreased spontaneous movements, difficulty walking, orthostatic instability, stiffness and tremor.

Like many neurological diseases, the true cause of Parkinson's disease is unknown. However, studies have shown that BP occurs when a group of neuronal cells in an area of the brain called the substantia nigra pars compacta (SNc) has reduced activity and eventually dies, leading to a decrease in dopamine levels in the brain. and which in turn leads to a violation of traffic control and coordination. BP is currently considered incurable. The drugs used are symptomatic and are aimed at increasing dopamine levels in the brain, but more often invasive surgical methods of treatment by neuronal ablation or deep brain stimulation are used. Unfortunately, these methods have drawbacks, some of which are very serious and compromising the quality of life of patients.

Therefore, the researchers' efforts are focused on finding new ways to understand and study dopaminergic diseases and conditions, as well as new ways to treat them without affecting the normal function of neurons and the quality of life of patients.

The results of Prof. James Surmeier's research, as well as his inventions, are based on the understanding that the death of dopaminergic neurons is directly dependent on calcium ion channels in mammalian cells, in particular Ca _v L3a as well as Kv3. 1, Kv3.2, Kv3.3 and Kv3.4 ion channels. The inventor proposes a method for the prevention and treatment of Parkinson's Disease comprising direct action on Ca _v 1.3a calcium ion channels with blockers, in particular a dihydropyridine calcium channel blocker (US 2018064697 A1; US 2013345230 A1), which protects damaged cells and protects them from further degradation and eventual death. In some embodiments, nifidipine, nimodipine, and / or izradipine are used as the dihydropyridine calcium channel blocker, and in others, in addition to a blocker, a therapeutic agent selected from the group consisting of levodopa, carbidopa, entacapone, apomorphine, hydrochloride is additionally administered. bromocriptine, pergolide, pramipexole, ropinerol, benzotropine mesylate, trihexyphenidyl HCl, selegiline, tolcapone, amantadine, riluzole and / or L-dopa ethyl ether.

In U.S. Pat. No. 7,629,323 (B2), the same author claims that manipulating the activity of ion channels in the group comprising K _v 3.1, K _v 3.2, Κ _ν 3.3 and Κ _ν 3.4 and associated with BP and other neurological diseases and conditions may is accomplished by transfecting damaged neuronal cells containing these ion channels by introducing siRNA that is capable of inhibiting the expression of these ion channels in the cells.

On the other hand, the property of adamantine to inhibit the replication of influenza virus type A by blocking the M2 protein in the ion channel is known. In addition, other important clinical applications of amantadine have recently been identified, such as Parkinson's disease, neuralgia, depression, etc., which, according to recent studies, are due to its ability to block the serotonin activating ion channel, the nicotine-acetylcholine receptor ion channel, and and the ion channel of N-methyl-O-aspartate receptors. As far as is known, it is the ability of adamantine to block neuromuscular transmission, which affects the biosynthesis and excretion of dopamine [1]. The biological activity of adamantine is also due to the symmetry and spatial arrangement of the molecule, as well as its significant lipophilicity, thanks to the stable hydrocarbon framework, which allows it to penetrate easily through biological membranes [2].

It is an object of the invention to provide a compound which exhibits both antiviral and anti-Parkinsonian activity and which is useful for the prevention and treatment of diseases associated with impaired biosynthesis and dopamine excretion [3].

Technical essence of the invention

In essence, the invention relates to an adamantane derivative of Formula I.

HE

BG 67301 Bl

(·)

The compound was prepared in the following sequence of syntheses: first tert-butyloxycarbonyl-O-tert-butyl-tyrosine-OH (Boc-Tyr (tBu) -OH) was dissolved in dichloromethane and triethylamine was added. With stirring, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethylamine tetrafluoroborate (TBTU) is added thereto [4]. Amantadine hydrochloride was dissolved in dichloromethane and added to the reaction mixture. After completion of the reaction, the reaction mixture was washed with 4% NaHCO ₃ solution, NaCl and water. The organic layer was dried over anhydrous Na ₂ SO ₄ , the solvent was evaporated to give an oil product. To the resulting tert-butyloxycarbonyl-O-tert-butyl-tyrosinyl-amantadine dissolved in dichloromethane at 0 ° C was added trifluoroacetic acid (TFA). After completion of the reaction, the solvent was evaporated and diethyl ether was added. The trifluoroacetate salt of tyrosinyl-amantadine is obtained. _{Concentrated NH 4} OH was added to the trifluoroacetic salt of tyrosinyl-amantadine and the pH of the solution was adjusted to 7.0. The resulting compound is the UPAC name: 2-amino-3- (4-hydroxyphenyl) propanoyl-1-adamantylamine.

1 H-NMR: (DMSO-d ₆ ) δ (ppm): 0.75 (d, J = 6.7 Hz, 3H, H-2 ', D2), 0.93 (d, J = 6.7 Hz, 3H, H-2', DI), 1.18 (3H, H2 ', DI), 1.26 (3H, H-2', DI), 1.45 (6H, H-2 ', D2), 1.49 (3H, H) -4b ', D1), 1.57 (3H, H-4a', DI), 1.57 (3H, H-4b ', D2), 1.65 (3H, H-4a', D2), 1.84 (br, 3H, H-3, DI), 1.93 (br, 3H, H-3, D2), 2.87 (m, 2H, CH ₂ , D1 + D2), 3.44 (D1 + D2), 3.93 (m, 1H, CH, D 2), 3.99 (m, 1H, CH, DI), 6.69 (m, 2H, Ar, DI), 6.70 (m, 2H, Ar, D 2), 7.04 (m, 2H, Ar, DI) , 7.01 (m, 2H, Ar, D2), 7.78 (d, 1H, J = 9.4 Hz, NH-amide, D2), 7.89 (d, 2H, J = 9.4 Hz, NH-amide, DI), 8.12 br, 1H, NH 2, D 2), 8.17 (br, 2H, NH 2, DI); C-NMR: (DMSO-d ₆ ) δ (ppm): 13.6 (CH ₃ , D 2), 13.9 (CH ₃ , DI), 36.3 (CH ₂ , D 1 + D 2), 37.5 (C-4, amantadine, DI ), 37.6 (C-4, amantadine, D2), 37.5 (C-2, amantadine, DI), 37.6 (C-2, amantadine, D2), 52.7 (CH, DI), 52.6 (CH, DI), 53.6 (CH, DI), 53.5 (CH, DI), CQau amantadine. 115 (CH-Ar, D1 + D2), 124.7 (Cquat, D1 + D2) 130.4 (CH-Ar, D2) 130.2 (CH-Ar, D2), 156.5 (Cquat, DI), 156.4 (Cquat, D2) ), 167.1 (CO, DI), 167.1 (CO, D2); ESI-MS: 509 [M + K] < + >, 493 [M + Na] < + >, 471 [M + H] < + >.

The steps of the synthesis of the compound of formula I according to the invention are summarized in Scheme I below.

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Scheme I

The chemical modification of the existing anti-influenza drug amantadine thus achieved leads to the production of a new adamantane derivative, which in the body is hydrolyzed and divided into the two components: amantadine and the dopamine precursor in the body, the amino acid tyrosine, due to which the newly synthesized compound both as a viral neuraminidase inhibitor and as a dopamine precursor [5].

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In this way, a new tool has been created which, on the one hand, is effective in overcoming the development of resistance to viral mutations, and on the other hand, is effective in the treatment of Parkinson's disease. The obtained compound has high stability: at pH = 1 it is 52 h, and at pH - 7.4 it is 73 h.

The adamantane derivative according to the invention exhibits significant neurobiological and biochemical effects on mice and rats at significantly lower doses (about 2.5-fold) than the reference amantadine, moderate intraperitoneal toxicity and absence of skin lesions after treatment; administered at much lower doses in an experimental method to rats with 6-hydroxy dopamine, the protective effect against BP showed a comparable effect, and in some cases superior to that of the reference.

The invention is illustrated by the following exemplary embodiments without limiting its scope.

Example 1. Preparation of a compound of formula I according to the invention

To give a compound of formula (I), at room temperature 7.7 mmol (2.8 g) of tert-butyloxycarbonyl-O-tert-butyl-tyrosine-OH was dissolved in dichloromethane and 7.7 mmol (1 ml) of triethylamine and 10.8 mmol were added with constant stirring. (3.5 g) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethylamine tetrafluoroborate (TBTU). After 30 minutes, 8.5 mmol (1.6 g) of amantadine hydrochloride dissolved in dichloromethane was added to the solution. After completion of the reaction, the reaction mixture was washed with 4% NaHCO ₃ solution, NaHSCU and water. The organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration, the solvent was evaporated to give a product as an oil.

To the resulting tert-butyloxycarbonyl-O-tert-butyl-tyrosinyl-amantadine dissolved in dichloromethane at 0 ° C was added 8.5 mmol (1.2 ml) trifluoroacetic acid (TFA). After completion of the reaction, the solvent was evaporated and diethyl ether was added. The trifluoroacetate salt of tyrosinyl-amantadine is obtained. _{Concentrated NH 4} OH was added to the trifluoroacetic salt of tyrosinyl-amantadine and the pH of the solution was adjusted to 7.0. Yield -1.4 g (59%).

The resulting compound is named UPAC: 2-amino-3- (4-hydroxyphenyl) propanoyl-1-adamantylamine.

1 H-NMR: (DMSO-d ₆ ) δ (ppm): 0.75 (d, J = 6.7 Hz, 3H, H-2 ', D2), 0.93 (d, J = 6.7 Hz, 3H, H-2) , DI), 1.18 (3H, H2 ', DI), 1.26 (3H, H-2', DI), 1.45 (6H, H-2 ', D2), 1.49 (3H, H-4b ', DI), 1.57 (3H, H-4a', DI), 1.57 (3H, H-4b ', D2), 1.65 (3H, H-4a', D2), 1.84 (br, 3H, H-3, DI), 1.93 (br, 3H, H-3, D2), 2.87 (m, 2H, CH ₂ , D1 + D2), 3.44 (D1 + D2) 3.93 (m, 1H, CH, D 2), 3.99 (m, 1H, CH, DI), 6.69 (m, 2H, Ar, DI), 6.70 (m, 2H, Ar, D 2), 7.04 (m, 2H, Ar, DI) , 7.01 (m, 2H, Ar, D2), 7.78 (d, 1H, J = 9.4 Hz, NH-amide, D2), 7.89 (d, 2H, J = 9.4 Hz, NH-amide, DI), 8.12 br, 1H, NH 2, D 2), 8.17 (br, 2H, NH 2, DI); ¹ C-NMR: (DMSO-d ₆ ) δ (ppm): 13.6 (CH ₃ , D 2), 13.9 (CH ₃ , DI), 36.3 (CH ₂ , D 1 + D 2), 37.5 (C-4, amantadine, DI), 37.6 (C-4, amantadine, D2), 37.5 (C-2, amantadine, DI), 37.6 (C-2, amantadine, D2), 52.7 (CH, DI), 52.6 (CH, DI), 53.6 (CH, DI), 53.5 (CH, DI), CQau amantadine, 115 (CH-Ar, D1 + D2), 124.7 (Cquat, D1 + D2), 130.4 (CH-Ar, D2), 130.2 CH-Ar, D2), 156.5 (Cquat, DI), 156.4 (Cquat, D2), 167.1 (CO, DI), 167.1 (CO, D2); ESI-MS: 509 [M + K] < + >, 493 [M + Na] < + >, 471 [M + H] < + >.

NMR spectra of the obtained compounds were taken on a high resolution spectrometer Bruker DRX 500 (Germany) and were performed in IOHCF - BAS. NMR chemical shifts of the synthesized adamantane derivative were measured in a standard solution of deuterated chloroform and deuterated dimethyl sulfoxide (DMSO).

The mass spectra were taken using a Bruker Esquire 3000 Plus Ion Trap Mass Spectrometer (Germany) using electrospray ionization mass spectrometry and performed at Charles University, Prague. Methanol solvent was used prior to analysis for sample preparation.

Example 2. Study of the antiviral activity of the compound according to the invention

A study of the antiviral activity of the compound of the present invention against influenza A / H3N2 virus, Hong Kong strain / 68 was performed at Friedrich Schiller University, Jena, Germany. Cytotoxicity and antiviral results were compared with amantadine and oseltamivir and are presented in Table 1 below.

Table 1

Compound CCm (pM) MDCK cells HNTC (μΜ) MDCK cells Xia (pM) to A / Hong Copd / 68 average average average L-Tyr-Am > 100 > 100 3.93 Amantadine n / a n / a 0.39 Oseltamivir n / a n / a 0.002

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Where:

virus - influenza virus A / H3N2, strain A / Hong Kong / 68 cells: MDCK (Madin-Darby canine kidney cell cultures)

- L-Tyr-Am is the compound according to the invention

- CC ₅ o denotes cytotoxic concentration

- HNTC indicates the highest non-toxic concentration

- IC ₅₀ denotes an inhibitory concentration

- η / а = not applicable

From the obtained data on antiviral activity of the newly synthesized adamantane derivative against influenza A / Hong Kong / 68 it is clear that the compound has low cytotoxicity and exhibits antiviral activity. Its antiviral activity in vitro is lower than that of amantadine, but shows high stability at pH = 1 (52 h), corresponding to the gastrointestinal tract, and at pH = 7.4 is 73 h.

Example 3 Investigation of the Antioxidant (AO) Activity of the Compound of the Invention The compound of the invention was tested in systems generating reactive oxygen species: Hydroxyl radical generating system - The method of Halliwell et al. (1988) [6], in which the measured amount of thiobarbituric acid-reactive substances (TBARS) resulting from the degradation of deoxyribose serves as a measure of the production of hydroxyl (HO *) radicals. The absorption of the formed TBARS was reported at 532 [mu] m. The reduction in TBARS production in the presence of the test substance is a measure of its antioxidant capacity.

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System generating superoxide anionic radicals - The method of Beauchamp and Fndovich was used [7]. Superoxide anionic radicals (Of) are generated photochemically from the riboflavin contained in the reaction medium using a mercury lamp. The radicals formed reduced nitro-blutetrazolium (NBT) to a blue formazan product, the absorption of which was measured at 560 nm. Reducing the color intensity of the reaction medium is a measure of the antioxidant capacity of the test substance.

The results of the study show that the antioxidant activity of the compound according to the invention at concentrations up to 50 μΜ against DPPH radicals is negligible (from 3% to 10%); with respect to superoxide anionic radicals, the compound at concentrations of 50 μΜ causes a 12% inhibition of the reduction of ΝΒΤ; both deoxyribose assays (in the presence and absence of a chelator) were used to assess the capture or chelating potential of the compound - the results show that they are negligible - below 4%.

In conclusion, the adamantane derivative according to the invention did not show high antioxidant potential, but had low cytotoxicity and showed antiviral activity against influenza virus Α / Η3Ν2, strain A / Hong Kong / 68.

Example 4. Determination of the toxicity of the compound in vivo

White male sexually mature ICR mice with an initial body weight of 18-24 g were used, kept in the vivarium of the Institute of Neurobiology, BAS, at room temperature, free access to food and water and automatically controlled 12-hour light-dark cycle.

The following main toxicological parameters were studied: a) Threshold of acute action (Lim _ac ) - this is the minimum dose causing a biological effect registered by the changes in the behavioral parameters of the animals after a single administration of the substances; B) Determination of the level of missing effect - this is the dose of the substance, applied once, at which there is no noticeable effect (No Observed Effect Level - NOEL). For this purpose, the substance was administered to 5-6 mice with initial doses above 1/20 LD ₅ o and 1/50 LD ₅ o, the change in the behavior of the animals was monitored after the introduction of single, ascending doses of tirsinyl-amantadine - 1- i, 2nd, 4th, 6th and 8th hour from the introduction, and for comparison a control group of animals was carefully observed in parallel; c) Determination of acute toxicity - average lethal (lethal) dose (LD ₅₀ ), causing lethal outcome in 50% of the animals, as in the 1st group of animals - the initial dissolution of the compound of the invention is done with deuterated dimethyl sulfoxide (DMSO), and subsequent dilutions are with water; in group II animals the stock solution and subsequent dilutions were made with DMSO only; Doses are calculated in milligrams of active substance per kilogram of body weight, administration is intraperitoneal within the allowable volumes for mice (0.10 ml / 10 g body weight). The working doses of the substance are: 10, 16, 32, 100, 150, 300,320, 350, 500 and 1000 mg / kg. Mortality in the groups was monitored on the 1st, 24th and 48th hour of the administration of the substances. The control group received the same volume of solvent. The effective dose of ED _{50 is also determined} ; d) Study of prolonged toxicity of the compound - the following indicators were monitored: general condition, appetite, total weight, appearance, rough skin, salivation, exophthalmos (bulging of the eyes), mucosal discoloration (cyanosis, redness). reported on the 5th and 7th day after a single application of the substance, f) Macroscopic examination - at the end of the study periods (24th and 48th hour and 5th and 7th day)

EN 67301 Bl dissection of the animals, their internal organs (liver, lungs and stomach) being examined macroscopically for possible damage by the substances administered; f) Reversibility of toxic lesions - the reversibility of toxic lesions on the 15th day after a single treatment is also monitored.

The results of the acute toxicity study of the compound of the present invention show that:

- The LD50 is 320 mg / kg (intraperitoneally) in mice

- The LD50 is 150 mg / kg (intraperitoneally) in rats

- Therapeutic index - 20

- NOEL - 5 mg / kg (intraperitoneal)

- Liniac - 8 mg / kg (intraperitoneal)

- ED ₅ o 16 mg / kg m.p. (intraperitoneally)

The results of the prolonged toxicity study of the compound according to the invention show some prolonged toxicity combined with low aqueous solubility, which also implies a slowed hepatic metabolism.

The results of the macroscopic examination after administration of the compound according to the invention show slight changes in the appearance of the liver, no changes in the lungs and reversibility of the observed changes.

Example 5 Assay for neuropharmacological activity of a compound of the invention in healthy rodents

Each group contains 6 pcs. male ICR sexually mature mice (18-24 g) and 6 pcs. male sexually mature Wistar rats (180-230 g) treated once with 16 mg / kg of the compound compared to a group of control animals. The animals were bred in the standard conditions of the Vivarium of the Institute of Neurobiology of BAS. After one week of adaptation to the vivarium, the animals were subjected to the following behavioral tests:

a) Monitoring for changes in neuromuscular coordination in rodents (Rotarod test) by the method of Dunham and Miya [8]. An apparatus with a rotating lever diameter of 3.5 cm and a rotation speed of 7 rpm was used. The test period is 3 minutes, and depending on the needs of the experiment, either the length of stay on the device or the number of falls during the observed period is taken into account.

B) Monitoring for changes in rodent orientation behavior (Hole board test) by the method of Boissier and Simon [9]. For this purpose, a black plastic plate with dimensions of 50-50 cm was used, on which there are 16 symmetrically arranged round holes with a diameter of 3 cm. The plastic panel serves as the floor of a box with walls 25 cm high, and the panel itself is 10 cm high. The study behavior of the mice was monitored for 3 minutes by two independent observers. The number of peeks of the animal placed in the apparatus is reported.

c) Tracking for changes in memory and training in rodents (step through test; passive avoidance with negative reinforcement) by the method of Jarvik and Corr [10]. The device was constructed at the Institute of Neurobiology, BAS and consists of a light and a dark chamber connected to each other by a movable barrier. The floor in the dark part of the device is a metal grid, through which a current irritation with a force of 1 mA and a duration of 1 s can be applied. We distinguish between training and test phase of the method. During the training phase, the animal is placed on a platform in the light part of the apparatus, after which the movable barrier is opened and it passes into its dark part, where it receives current irritation of the paws. In this phase, the time (in seconds) for which the animal has passed from the light to the dark part of the apparatus is taken into account. Animals that have been in the light of the apparatus for more than one minute are excluded from the experiment. The test phase follows. The degree of memorization of the task to stay in the light part of the device is tested in different periods of time after the training. The time (in seconds) for which the animal remains on the platform in the illuminated part is taken into account. The test is performed for a period of 180 s.

The effect of the effects of single doses of 8, 16 and 32 mg / kg of the compound on neuromuscular coordination in mice at 3 h (1 A) and 24 h of administration (1B) is shown in Figs. 1 below.

• ·. «V» юитрогап

FIG. 1

The effect of single doses of the compound of 8, 16 and 32 mg / kg on memory and training of mice is shown in Figs. 2 below, where the dose efficacy of 16 mg / kg is markedly high.

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A. Time

• OM η intromt ·

B. 24 hours

• 0.M VI joitrolvta

FIG. 2

Where:

NL is the initial latency

STL is step tru latent time

The effect of a single dose of 16 mg / kg of the compound on the orientation behavior of mice is illustrated in FIG. 3, which shows that this effect is long-lasting and lasts until the 24th hour from the beginning of the experiment.

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FIG. 3

Studies on neuropharmacological activity in a 5-day treatment of healthy rodents at a dose of 16 mg / kg of the compound of the invention further showed that, like amantadine, the newly synthesized compound had no amnestic effect on animals.

Example 6. Study of the preventive effects of the compound according to the invention on rodents with a model of Parkinson's disease

The neuropharmacological activity of the compound according to the invention, as well as the possibility that it has a protective effect in the disease, was studied in rats with a BP model. Its effect was compared with that of an established drug from the same chemical group - Amantadine, which is used preventively as a neuroprotector at the beginning of treatment.

The neurotoxin 6-hydroxy dopamine (6-OHDA), which does not cross the blood-brain barrier and selectively impairs catecholaminergic neurotransmission at the central and peripheral nervous system, was used to create the experimental model of Parkinson's disease. For the purposes of the experiment, male, sexually mature Wistar rats weighing 250-300 g were used, which were anesthetized with chloral hydrate (400 mg / kg, ip) and fixed on a stereotactic apparatus. The neurotoxin 6-OHDA (10 pg / 2 μΐ) was injected unilaterally into the right striatum at coordinates AP = 0 mm, LR = 3.5 mm, Η = 5 mm, relative to the thigh and cranial surface [11]. In control animals, an opening was made with striatum-corresponding coordinates by injecting 2 μΐ 0.9% NaCl. In all groups, five-day intraperitoneal injections precede surgery and stereotactic administration of 6-OHDA toxin. Experimental animals were divided into experimental groups shown in Table 2 below.

Table 2

Groups Stereotactic injection (striatum) Intraperitoneal treatment (5 days) SO (falsely operated) 0.9% NaCl (2 μΙ) 0.9% NaCl 6-OHDA 6-OHDA (10 pg / 2 μΙ) 0.9% NaCl 6-OHDA * amantadine 6-OHDA (10 pg / 2 pl) amantadine (40 mg / kg) 6-OHDA + Compound of the invention 6-OHDA (10 pg / 2 μΙ) Compound of the invention (16 mg / kg)

The applied behavioral and biochemical methods of examination of the treated animals show that the compound according to the present invention significantly reduces the number of contralateral rotations (in the apomophin test) compared to the 6-OHDA group, which convincingly demonstrates the protective effect of the substance; also significantly improves the memory processes disturbed by BP in the group with 6-OHDA / step tru test /; reduces oxidative stress by reducing lipid peroxidation in the brain of rats with a PB model and does not affect brain acetylcholinesterase activity. In addition, the newly synthesized substance did not cause skin lesions, unlike animals treated with the reference Amantadine.

The observed significant neurobiological and biochemical effects on mice and rats are comparable to those of the reference Amantadine, but in significantly lower doses (about 2.5 times), which is an advantage of the newly synthesized substance; on an experimental model of rats with 6-OHDA, the protective effects of the compound according to the invention against BP are also very good - they are comparable, and in some cases superior to those of the reference Amantadine, but administered at significantly lower doses.

Claims (1)

Adamantan derivative of formula I