Pharmaceutical compositions for the treatment of neurological disorders comprising s-(-)-n-propargyl-1-amino indan

Description

The invention relates to a novel therapeutic use of S-(-)-N-propargyl-1-aminoindan and its pharmaceutically acceptable salts, in particular for the treatment of neurotrauma and for improving the memory of a patient. More particularly, the invention relates to the use of S-(-)-N-propargyl-1-aminoindan or its pharmaceutically acceptable salt for the preparation of a medicament for the treatment of a) neurotrauma or b) for improving the memory of patients who have undergone closed head injury (post-CHI). As used herein, the term "neurotrauma" refers to damage to the central and / or peripheral nervous system, which may occur as a result of ischemic injury, such as stroke, hypoxia or anoxia, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, neurotoxic injuries, head trauma, spinal cord injury, or any other form of nerve damage. R(-)-deprenyl [also known as Selegiline, L-deprenyl or L-(-)-N,a-dimethyl-N-2-propynylphenethylamine] is well known to inhibit the B-form of the monoamine oxidase enzyme (hereinafter referred to as MAO-B). The effect of R(-)-deprenyl on maintaining, preventing or restoring nerve growth function is also known (PCT publication WO 92 / 17169). The latter publication included a list of derivatives related to deprenyl, which were assumed to have similar effects, although no data were provided to support this claim. The list included AGN-1135, a racemic N-propargyl-1-aminoindane. In a later publication [Tatton WG et al. J. Neuroscience 13 (9), pp. 4042-4053 (1993)] it was reported that the neuroprotective effect of deprenyl is limited to the R(-)-enantiomer. The S(-)-enantiomer was 2000-fold less effective in enhancing the survival of axotomized immature rat facial mononeurons. It was further shown that neuroprotective activity was associated only with the R-enantiomers of propargyl derivatives that have MAO-B inhibitory activity. It was found that in various models of neuroprotective activity, the R-enantiomers of certain aliphatic N-methylpropargylamines (which are selective MAO-B inhibitors) protected damaged neurons more effectively than the corresponding S-enantiomers [Davis et al. J. Neurochem. Supplement 1,64 60 pages (1995) - summarizing the papers presented by the same authors at the 26th meeting of the American Neurochemical Society in 1995 in Santa Monica California, United States of America. The development of work on deprenyl has led to the assumption that the neuroprotective activity is not related to MAO-B inhibition, as R(-)-deprenyl prevents neuronal cell death at doses below those of MAO-B inhibitors [Tatton, Movement Disorders, 8 (1), pp. 20-30 (1993)]. It has been suggested that the effect of R(-)-deprenyl may be due to interaction with a subtype of MAO-B that is extremely sensitive to R(-)-deprenyl. Later, the activity of R(-)- and S(+)-deprenyl, as well as several aliphatic propargylamine derivatives, was described [Yu et al., J. Neurosci, 63, pp. 1820-1827 (1994)] in reversing the noradrenaline depletion induced in rodents by the administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). The % recovery of noradrenaline relative to untreated control was adopted as the endpoint and as an indication of “neuroprotective activity.” The results described showed that R(-)-deprenyl and several propargylamine derivatives containing a longer N-aliphatic substituent exhibited “neuroprotective activity.” According to the publication, S(+)-deprenyl was listed as the known noradrenaline uptake inhibitor desipramine, which has significantly lower "neuroprotective activity" than R(-)deprenyl.In short, S(+)-deprenyl has been shown to be a better noradrenaline uptake inhibitor than R(-)-deprenyl, but is significantly weaker in terms of “neuroprotective activity” in the manner described. In European Patent Specification No. 436,492, the R(+)-enantiomer of N-propargyl-1-aminoindane [hereinafter referred to as R(+)PAI] was described as a selective irreversible inhibitor of MAO-B. Due to this specific activity, the use of R(+)PAI was proposed for the treatment of Parkinson's disease, memory disorders, dementia (especially Alzheimer's type), depression and hyperactive syndrome in children. Patents (U.S. Patents 5,387,612, 5,453,446, and 5,457,133) are known which relate to R(+)PAI and to the treatment of patients with Parkinson's disease with R(+)PAI. In the said publications it was emphasized that R(+)PAI has a more potent MAO-B inhibitory effect compared to its antipode, the S(-)-enantiomer N-propargyl-1-aminoindane [hereinafter S(-)PAI]. In vitro tests of R(+)PAI showed that R(+)PAI is nearly 7000 times more active as an MAO-B inhibitor than S(-)PAI. It was also shown in these tests that while R(+)PAI inhibited MAO-B more than 29-fold more selectively than MAO-A (the monoamine oxidase enzyme), S(-)PAI did not discriminate between these substrates. This effect was observed both during acute and chronic in vivo administration. It has also been reported (PCT Publication No. WO 95 / 11016) that R(+)PAI is effective as a “neuroprotective agent”. According to the data reported, it was used to prevent NMDA-induced cell death in rat cerebellar cells and was also used to slow neuronal degeneration when administered after crushing the optic nerve of rats. The aforementioned publication did not mention the mechanism by which the “neuroprotective effect” exerted by R(+)PAI could occur. WO 96 / 37199 discloses (R)-N-propargyl-1-aminoindan and its salts, and medicaments containing them. WO 97 / 12583 relates to the -S(-)- and R(+)-enantiomers of N-propargyl-1-aminoindan. WO 95 / 18617 discloses 1-aminoindan derivatives and medicaments containing them. N-propargyl-substituted derivatives have been described as being useful in the treatment of epilepsy and seizures2 HU 226 961 Β1 sak. European patent application EP 538134 relates to derivatives of N-propargyl-1-aminoindane monofluorinated on the phenyl group, and to their medicinal use and preparation. The use of MAO inhibitors as neuronal rescue agents in clinical situations where neuronal survival is compromised has the important disadvantage of potentially causing cardiovascular side effects, either alone or as a consequence of drug / drug interactions or drug / food interactions. These side effects are attributed to partial or complete inhibition of peripheral MAO-A, which is a consequence of the high concentrations of norepinephrine present in the cardiovascular system [see, for example, "Eldepryl" in Physician's Desk Reference, 48th edition (1994), Medical Economics Data, Montvale NJ.] Selective MAO-B inhibitors, such as R(-)-deprenyl, are less likely to compromise the cardiovascular system than less specific agents such as pargyline or chlorgyline. Therefore, the former are presumably safer agents.The selectivity of these agents against MAO subtypes determined in vitro, however, is significantly reduced in vivo. Thus, the ratio of IC50 values ​​determined in vitro for MAO-A / MAO-B using R(-)-deprenyl was 400, 247, 360, and 16, respectively, according to different authors, which indicates a safety factor of about 100 or more. [Compilation by Paul and Szelenyi, “Monoamine Oxidase-B inhibitors”, Birkhauser and Szelenyi Publishing, Basel, p. 353, 1993], The recommended daily dose of R(-)deprenyl for human patients is 10 mg, while the value at which cardiovascular function is still acceptable is 30-40 mg (Physician's Desk Reference, see above). Thus, in clinical practice, the safety factor is about 3 to 4, while in in vitro experimental systems it is about 100-400. There remains a need, therefore, for a neuroprotective agent that is effective and free from the side effects that have been associated with MAO-B inhibitor-type neuroprotective agents. The present invention aims to provide a method and pharmaceutical compositions suitable for the treatment of CNS or PNS disorders, particularly those associated with neurotrauma, and an agent which has a neuroprotective effect but does not exhibit the peripheral side effects that may be associated with known MAO-B inhibitors. The use of MAO inhibitors as neuronal rescue agents in clinical situations where neuronal survival is compromised has the important disadvantage of potentially causing cardiovascular side effects, either alone or as a consequence of drug-drug interactions or drug-food interactions. These side effects are attributed to partial or complete inhibition of peripheral MAO-A, which is a consequence of the high concentrations of norepinephrine present in the cardiovascular system [see, for example, "Eldepryl" in Physician's Desk Reference, 48th edition (1994), Medical Economics Data, Montvale NJ.] Selective MAO-B inhibitors, such as R(-)-deprenyl, are less likely to compromise the cardiovascular system than less specific agents, such as pargyline or chlorgyline. Therefore, the former are presumably safer agents.However, the selectivity of these agents against MAO subtypes determined in vitro is significantly reduced in vivo. Thus, the ratio of IC50 values ​​determined in vitro for MAO-A / MAO-B when using R(-)-deprenyl was 400, 247, 360, and 16, respectively, according to different authors, which indicates a safety factor of about 100 or more. [Compilation by Paul and Szelenyi, “Monoamine Oxidase-B inhibitors”, Birkhauser and Szelenyi Publishing, Basel, p. 353, 1993]. The recommended daily dose of R(-)deprenyl for human patients is 10 mg, while the value at which cardiovascular function is still acceptable is 30-40 mg (Physician's Desk Reference, see above). Thus, in clinical practice, the safety factor is about 3 to 4, while in in vitro experimental systems it is about 100-400. There remains a need, therefore, for a neuroprotective agent that is effective and free from the side effects that have been associated with MAO-B inhibitor-type neuroprotective agents. The present invention aims to provide a method and pharmaceutical compositions suitable for the treatment of CNS or PNS disorders, particularly those associated with neurotrauma, and an agent which has neuroprotective effects but does not exhibit the peripheral side effects that may be associated with known MAO-B inhibitors. The present invention relates to the use of S-(-)-N-propargyl-1-aminoindane or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a) neurotrauma or b) memory improvement in patients with closed head injury (post-CHI). The invention particularly relates to the above use for a medicament intended for the treatment of individuals suffering from neurodegenerative diseases who have been subjected to neurotoxic injury, cerebral ischemia, or cerebral hemorrhage. The invention also particularly relates to the above use for a medicament intended for the treatment of a patient suffering from neurotrauma to the central or peripheral nervous system, due to hypoxia or anoxia, or trauma caused by head injury, or trauma caused by spinal injury. The invention also particularly relates to the above use for a medicament intended to prevent nerve death in a patient. The invention also particularly relates to the above use for a medicament intended for the treatment of memory disorders. S(-)-Propargyl-1-aminoindan can be prepared in a known manner by the method described in U.S. Patent No. 5,457,133. HU 226 961 B1 and the compositions can also be prepared as described therein. In the practice of the invention, it is preferred to use or prepare S(-)propargyl-1-aminoindan in the form of its pharmaceutically acceptable organic or inorganic salts. Such pharmaceutically acceptable salts may include, for example, the mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p-toluenesulfonate, benzoate, acetate, phosphate, or sulfate salts. However, other salts may also be used. It is particularly preferred to use the hydrochloride, mesylate, esylate, or sulfate salt of S(-)propargyl-1-aminoindan. The mesylate salt is considered to be the most suitable pharmaceutically acceptable salt. To prepare a pharmaceutically acceptable acid addition salt of S(-)PAI, the free base can be reacted with the desired acid in the presence of a suitable solvent by conventional methods. Similarly, the acid addition salts can be converted to the free base by known methods. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of S(-)-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. A "therapeutically effective amount" of S(-)-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof can be determined by methods known to those skilled in the art. These compositions can be formulated into pharmaceutical compositions suitable for direct, oral, parenteral, rectal or transdermal administration. Preferred doses of the S(-)PAI active ingredient are within the following ranges: for oral or suppository administration, a daily dose of 0.1-100 mg can be administered, and a daily dose of 1-10 mg / dose is preferred. For injectable preparations, a daily dose of 0.1-100 mg / ml can be administered, and a daily dose of 1-10 mg / ml is preferred. These preparations can be used alone to treat the disorders listed above, or they can be used in conjunction with conventional treatments. Preferred forms for oral administration include tablets, compressed or coated pills, dragees, cachets, hard or soft gelatin capsules, sublingual tablets, syrups, suspensions, etc. In one preferred embodiment, the pharmaceutically acceptable carrier solid and the pharmaceutical composition are in the form of tablets. A therapeutically effective amount of the active ingredient is between 0.1 and 100 mg, preferably between 1 mg and about 10 mg. In an alternative embodiment, a liquid material is used as the pharmaceutically acceptable carrier and the pharmaceutical composition is presented as an injectable solution. A therapeutically effective amount of the active ingredient is between 0.1 mg / ml and 100 mg / ml, preferably between about 1 mg / ml and about 10 mg / ml. It is preferred that the medicament is administered by infusion. The pharmaceutical composition can also be prepared on a gel carrier material, in which case the pharmaceutical composition is presented in the form of a suppository, which is administered rectally. For parenteral administration, according to the invention, ampoules or powder ampoules containing the active ingredient in an aqueous or non-aqueous solution or emulsion are used. For rectal administration, suppositories are prepared on hydrophilic or hydrophobic carriers. For topical application, ointments or various suitable drug delivery systems developed for transdermal administration can be used, which are known per se. Further details of the invention are described in the following examples, without any intention of limitation. Examples 1. Chemical synthesis Example 1.1 Di[S-(-)-N-propargyl-1-aminoindan]-D-tartrate a) Racemic N-propargyl-1-aminoindane To a mixture of racemic 1-aminoindane, 141 g of 15% aqueous sodium hydroxide solution, 107 ml of water and 192 ml of toluene, 94.3 g of propargylbenzenesulfonate are added within 20 minutes at room temperature. The mixture is heated at 45 °C for 4 hours. During this time, it is checked that the pH is > 12 (if necessary, 45% aqueous sodium hydroxide solution is added) and the phases are separated. 64 ml of water are added to the organic phase and the pH is adjusted to 2 with 30% aqueous sulfuric acid. The aqueous phase that then forms is separated, diluted with water and mixed with toluene. The pH was adjusted to 6 with 25% aqueous sodium hydroxide solution and the phases were separated. The aqueous phase was extracted again with toluene to a pH of 6. The combined organic phases were evaporated in vacuo to give 51 g of crude racemic N-propargyl-1-aminoindane as a yellow oil. b) Di[S-(—)-N-propargyl-1-amino-indan]-D-tartrate To a solution of 46.5 g of crude racemic N-propargyl-1-amino-indan in 157 ml of isopropanol at reflux, 15.3 g of D-tartaric acid in 28 ml of water are added. After boiling for 1 hour, the mixture is slowly cooled to room temperature and the precipitate that appears is removed by suction filtration and then washed with isopropanol. The crude di[S-(—)-N-propargyl-1-amino-indan]-D-tartrate is recrystallized from 1 liter of isopropanol containing 15% water. The product is 26.5 g of di[S-(—)-N-propargyl-1-amino-indan]-D-tartrate. Op: 175-177 °C; [α]D=(-34.3)° (1.5, H2O); Analysis: calcd: C25H32O6N2C:68.26; H:6.56; N:5.69 found: 0:68.76; H:6.57; N:5.61 Example 2 S-(-)-N-Propargyl-1-aminoindane mesylate 15 g of di[S-(—)-N-propargyl-1-aminoindan]-D-tartrate prepared according to Example 1 are refluxed for 30 minutes with a solution of 6 g of methanesulfonic acid in 150 ml of isopropanol. The reaction mixture is cooled to room temperature and the precipitate formed is separated by suction filtration. The product is 11.1 g of S-(—)-N-propargyl-1-aminoindan mesylate. Mp: 157 °C. HU 226 961 B1 Analysis: Calcd.: C13H17NSO3C: 58.43; H: 6.37; N: 5.24; S: 11.98 Found: C: 58.70; H: 6.39; N: 5.20; S: 11.82 Example 3 S-(-)-N-Propargyl-1-amino-indane mesylate Di-[S-(—)-N-propargyl-1-amino-indane]-D-tartrate prepared according to Example 1 and 80 ml of toluene were added to a solution of 4.8 g of sodium hydroxide in 80 ml of water. After stirring for 30 minutes, the reaction mixture was filtered through a celite filter, the organic phase was separated and washed with water. The organic phase was then concentrated in vacuo, diluted with isopropanol and concentrated again. The residue was dissolved in 125 ml of isopropanol and treated with 11.5 g of methanesulfonic acid. The resulting mixture was refluxed for 30 minutes, filtered (Celite) and cooled to room temperature. The precipitate formed was separated by filtration and washed with isopropanol. The product is S-(-)-N-propargyl-1-aminoindan mesylate, the physical and chemical properties of which are identical to those obtained in Example 2. Example 4 S-(-)-N-Propargyl-1-aminoindane mesylate The method of Example 1a is used, except that instead of racemic 1-aminoindan, S-(-)1-aminoindan prepared according to Examples 76-80 of U.S. Patent No. 0.8 / 372064 (filed: January 12, 1995, published: WO 96 / XXXX PCT publication) is used. 30 g of a yellow oil is obtained, which is dissolved in 180 ml of isopropanol, 17.7 g of methanesulfonic acid is added and the resulting mixture is boiled and then cooled. The precipitate is separated by filtration, recrystallized with isopropanol and carbon. The product obtained is S-(-)-N-propargyl-1-aminoindan mesylate, the physical and chemical properties of which are identical to the product prepared according to Example 2. Example 5 S-(-)-N-Propargyl-1-aminoindane hydrochloride 12.4 g of S-(-)-1-aminoindane and 12.9 g of potassium carbonate were added to 95 ml of acetonitrile. The resulting suspension was heated to 60 °C and 5.6 g of propargyl chloride were added dropwise. The mixture was stirred at 60 °C for 16 hours. Most of the relevant components were then removed by vacuum distillation. The residue was partitioned by adding 10% aqueous sodium hydroxide and methylene chloride. The phases were separated; the organic phase was dried and the solvent was evaporated in vacuo. The residue was flash chromatographed on silica gel using 40% ethyl acetate / 60% hexane as eluent. Fractions containing the desired product as the free base were combined and the solvent was exchanged for ether. The ethereal solution is treated with hydrochloric acid gas and the precipitate is separated by suction filtration and then crystallized from isopropanol. The product is 6.8 g of S-(-)-N-propargyl-1-aminoindan hydrochloride. Mp.: 183-185. °C; [α]D=(-30.3)° (2% ethanol). / / . Biological Examples II. Example 1 Lack of inhibition of MAO activity in vivo with S(-)PAI mesylate. Rats (male Sprague-Dawley) weighing 250±20 g were treated with one of the enantiomers or the racemic form of PAI by intraperitoneal injection (ip) or oral gavage (po) and were decapitated after 1 h and 2 h, respectively. Groups of 3 rats were used for each dose level of the drug and MAO activity was determined in the brain and liver using the general method described in Example 19 of U.S. Patent No. 5,387,612. The amount of protein in each incubation was determined by the Follin-Lowry method and the enzyme activity was calculated as nmol of substrate metabolized per mg of protein per hour of incubation. (?) MAO activity is expressed as % enzyme activity from tissues of animals treated with the enantiomers or racemic forms of PAI, compared to a group of control animals that received the vehicle (water for oral administration, 0.9% saline for ip injection). Results: No detectable behavioral changes were observed at any of the dose levels used. The doses that caused 50% inhibition of MAO-A and MAO-B (IC50) were calculated from the inhibition curve and are presented in Table 1. These data indicate that S(-)PAI mesylate has remarkably low activity for inhibiting MAO-A and MAO-B compared to the selectivity for inhibiting MAO-B of R(+)PAI mesylate. Table / IC50 values ​​(mg / kg) of MAO-A and MAO-B inhibition of S(-)PAI mesylate and R(+)PAI mesylate in rat brain and liver after intraperitoneal injection (ip.) or oral administration (po.) MAO-A MAO-B S(-)PAI mesylate S(+)PAI mesylate S(-)PAI mesylate S(+)PAI mesylate Brain >10 1.2 >10 0.07 Liver >10 5 >10 0.06 Brain >10 >5 >10 0.17 Liver >10 >5 >10 0.05 Example 11.2 Neuroprotective effect of S(-)PAI in a hypobaric hypoxia model The model used is analogous to the following published methods: M. Nakanishi et al. published in: Life Sci 13: 467-476 (1973); Y. Oshiro et al. J. Med. Chem 34:2014-2023 (1991). HU 226 961 B1 A group of 4ICR male mice weighing 20-25 g are placed in a 2.5 L glass chamber (A) at atmospheric pressure. Chamber (A) is connected to a 12 L chamber (B) by a valve that is initially closed. Air is evacuated from chamber (B) until a pressure of 100 mm Hg is reached. The valve between the two chambers is opened rapidly, causing the pressure in chamber (A) to drop to 200 mm Hg in 14 s. The survival time of mice in chamber (A) is determined after 15 min of maximal hypobaric treatment. The effect of drug pretreatment is expressed as a percentage of survival time by comparing the drug-treated group with the groups that received saline or vehicle injections. As controls, 12-16 mice are used, 4 animals per group, and these are checked twice, before and after each experiment. Each tested group always contains 4 mice, in order to ensure a constant residual volume of oxygen in each experiment. The survival time of control mice is in the range of 108-180 seconds.The effect of each dose of the tested drug is determined in duplicate, in a total of 8 mice, 4 mice per group. All drugs are administered ip. 1 hour before hypoxia. As positive reference agents, sodium pentobarbital is used at a dose of 40 mg / kg, diazepam at a dose of 10 mg / kg, administered 0.5 hour before hypoxia. The results are shown in Table II. Table II Effect of drug treatment on relative survival time of mice at 200 mmHg expressed as a percentage of the corresponding control Active ingredient IP dose mg / kg Percent protection ±SD relative to control Saline / vehicle 0.5 ml 100 Diazepam 10 430±59, p<0.001 5 249166, p<0.05 Pentobarbital 40 446±10.5, p<0.001 20 325±166, p<0.002 R(-)-deprenyl 100 102±75, (ns) 50 79±23 (ns) 10 97±70, (ns) (R)(-)PAI mesylate 100 358±179, p<0.001 50 410±151, p<0.001 10 116±47, (ns) (S)(-)PAI mesylate 100 390±197, p<0.002 50 406±247, p<0.01 10 84±47 (ns) Example 11.3 Locomotor activity and cerebral infarct size in middle cerebral artery occlusion (MCA-O) in the absence and presence of PAI enantiomers in male Wistar rats. The method of Tamura et al. is used for the procedure [Tamura A., Graham D., McCulloch J., Teasdale GH (1981) J. Cereb. Blood Flow and Metab. 1:53-60]. Male Wistar rats (Olac England-Jerusalem) weighing 300-400 g are anesthetized with a dose of Equitesine solution ip. 3 ml / kg. Equitesine contains 13.5 ml sodium pentothal solution (60 mg / ml), 3.5 g chloral hydrate, 1.75 g magnesium sulfate, 33 ml propylene glycol, 8.3 ml absolute alcohol with 83 ml distilled water. The operation is performed under a high-power operating microscope (SMZ-2B model 102 type, NIKON, Japan). The incision is made in the temporal muscle to expose the internal middle cerebral artery. The coronal process of the mandible is also excised and removed using a fine bone forceps. A craniectomy is performed between the medial wall and the roof of the inferotemporal fossa using a dental drill. The dura mater is carefully opened with a 27-gauge needle. The MCA is permanently occluded by microbipolar coagulation at a low energy setting, starting 2-3 mm distal to the olfactory tract from the cortical branch to the rhinal cortex and the striated artery of the lateral artery. After coagulation, the MCA is dissected and divided with microscissors to ensure complete closure. The temporal muscle is then sutured and placed over the cramiectomy portion of the skull. The skin is closed with a continuous 3-0 silk suture. A similar craniectomy is performed on a parallel group of rats, but without cauterization of the MCA. During the entire surgical procedure (20-25 minutes), the temperature in each group is maintained at 37-38 °C using a body temperature controller (Kyoristsu, Japan). The controller consists of a self-regulating heating pad and a rectal thermistor connected to it. Neurological sections are performed 24 and 48 hours after surgery to determine the severity of the damage in the drug-treated rats compared to the untreated control. After 48 hours, the animals are anesthetized with Equitesine and the damage is visualized with 2,3,5-triphenyltetrazolium chloride (TTC) staining. The extent of brain tissue damage following ischemia is determined. The drugs are administered by ip injection in 0.3-0.4 ml of distilled water according to the following schedule: mg / kg 30 minutes before surgery; 2 mg / kg 60 minutes after occlusion; 3 mg / kg within 20-24 hours after surgery. After 48 hours of ischemia induced by sustained occlusion, infarct volume was determined morphometrically by TTC staining. Immediately before use, a 1% TTC solution was prepared in saline and protected from light with aluminum foil. MCA-0 rats were deeply anesthetized, and a 23-gauge butterfly needle with an extended tube and a 20 ml syringe were inserted into the ventricle by thoracic incision. The right atrium was opened to allow saline to drain. 50 iu of heparin was added to the saline until the perfusate was bloodless. The saline syringe was then reinserted into the ventricle. HU 226 961 Β1 is replaced with a 30 ml TTC-containing syringe and TTC is injected into the left ventricle at a rate of 3 ml / min. Both perfusate solutions are administered at 37.5 °C. The brains are removed and immersed in 20 ml of 1% TTC in a tightly closed glass tube. The vessels are then kept in a 37 °C water bath for 2 hours. The TTC solution is poured off, the brains are removed, wiped dry and placed in 10% buffered formalin for 3 days. 6 coronal slices are prepared 3, 5, 7, 9, 11 and 13 mm distal to the frontal pole using brain matrix (Apparatus, South Natick, MA), each 2 mm thick. Infarct areas are measured from both sides of the coronal slices using a video imager and analyzer and expressed in mm2. The volume of the infarct region is calculated in mm3 by taking into account the sum of the ischemic areas of all 6 slices. The infarct volume is presented in Table IV below. Scoring of neurological outcomes The neurological score is the sum of the scores for a specific locomotor activity of a given rat. The scale ranges from 0 (completely normal rat) to 13 (completely paralyzed rat). Most parameters are either 0 (normal) or 1 (impaired); the others are intermediate grades. In this study, the following tests are performed: General observation: hypoactivity, sedation, hair standing up. Righting reflex: Rats are lifted by their tails approximately 15 cm above the ground. Normal rats assume a posture in which both forelegs are extended toward the ground while the hind legs are raised to the side in a trapezoidal shape. Severe cases of MCAO cause persistent flexion of the contralateral limbs. Mobility: The rat hangs from a rod by its armpit for 5-15 seconds, during the test we observe its ability to grasp the 1 cm diameter rod with its opposite limb. Movement coordination: Normal rats are able to walk up and down a 5 cm wide beam placed at a slight angle. If they deviate from the beam in any direction, this indicates a movement coordination problem, lack of balance, or limb weakness. Gait: When intentionally misplaced on a narrow beam, a normal rat is able to regain its normal position, both with respect to the hindlimb and the forelimb. Balance: The ability to grasp and balance on a narrow beam 2 cm wide. Locomotor activity: The sum of movements performed within 15 minutes in an automated activity cage. The results of the classifications for the above parameters are presented in Table III. / / / . Table neurological scoring for positioning and locomotor parameters Parameter Classification a) Activity in own cage normal=0 hypoactive=1 b) No sedation=0 pronounced c) No piloerection=0 pronounced d) When raising the tail, the first limb is extended towards the ground good=O bent limb=1 e) When raising the tail, the contralateral hind limb is extended (trapezoidal posture) good=O bent limb=1 f) When hung in the armpit, after 5-15 seconds, the contralateral limb grasps the bar good=O weak=1 g) Walking on a 5 cm wide beam good=0 weak=1 h) After deliberate misplacement, the contralateral hind and / or forelimb is returned to the original position good=0 weak=1 (one limb) 2 (two limbs) i) Holding and balancing on a 2 cm wide beam good=O weak=1 j) Locomotor activity compared to control for 15 minutes in an activity cage control 0-25%=3 controls 26-50%=2 controls 51-75%=1 controls 76-100%=0 k) Tendency to lean to the opposite side 1 I) Contralateral circling when tail-pulling 1 m) Spontaneous contralateral circling 1。 Results Table IV shows that both the neurological severity score (MMS) and infarct volume are lower in S(-)PAI-treated rats than in saline-treated rats. Table IV Neurological severity score±SEM and cerebral infarct size±SEM following permanent central cerebral artery occlusion in rats Parameter S(—)PAI-treated Saline-treated p-value Number of rats 24 24 Mean NSS±SEM after 24 hours 6.5±0.48 7.2±0.36 0.0543 HU 226 961 B1 Table IV (continued) Parameter S(—)PAI-treated Saline-treated p-value Mean NSS±SEM after 48 hours 5.0±0.41 6.6±0.44 0.0114 Mean infarct size±SME (mm3) 200±13 240±1.2 0.0259 % NSS improvement after 48 hours of treatment compared to saline 24 Under similar operating conditions, R(+)PAI treatment showed a 20% improvement in the severity of neurological grading, suggesting that specifically in this model of neuronal injury, both the R- and S-enantiomers of N-propargyl-1-aminoindane provided approximately equal neuroprotection. Example 11.4 Lack of activity of S(-)PAI on reserpine-induced ligament relaxation in the rat Reserpine-induced ptosis and the reverse test Reserpine induces depletion of catecholamine stores, especially norepinephrine. This effect is manifested, among other things, in the living animal by ptosis. Drugs that prevent or inhibit reserpine-induced ptosis either act directly on noradrenergic agonists or indirectly reduce or prevent the metabolic elimination of endogenous norepinephrine. MAO inhibitors belong to this latter group. Rats were pretreated with saline, R(-)-deprenyl, or S(-)PAI i.p. and then 2 hours later with 5 mg / kg i.p. reserpine injection. The degree of ptosis was assessed using a scale of 0 to 4. In this case, 4 represents a fully open eye and 0 represents a fully closed eye. The data reported in Table V are consistent with the observation that S(-)-PAI does not cause an increase in endogenous norepinephrine concentration. Table V Mean scores of ptosis induced by reserpine (5 mg / kg ip) with or without pretreatment with MAO inhibitors. Grading is done one hour after reserpine administration Active ingredient Dose mg / kg Number of animals (n) Average score Saline 12 0.86 R(- )-deprenyl 5 3 1.3 10 6 3.16 S(-)-RAI 5 6 1.8 10 6 2.5 20 6 1.5 Example 11.5 Lack of effect of intravenously administered S(-)PAI in anesthetized cats to increase blood pressure. Cats were anesthetized with an iv dose of non-buta (25 mg / kg). Anesthesia was maintained with additional 5 mg / kg injections of non-buta as needed. The afemoral artery was cannulated and connected to a Statham pressure transmitter connected to a Grass multichannel polygraph and capable of recording blood pressure. The femoral vein was cannulated for injection of the drugs. The results are shown in Table VI. It can be seen that neither mean arterial blood pressure (MABR) nor heart rate (HR) were affected by increasing doses of S(-)PAI intravenously until a cumulative dose of 1 mg / kg was reached, 46-60 minutes after injection. Table VI Changes in mean arterial blood pressure and heart rate in non-butal anesthetized cats 45-60 minutes after intravenous injection of S(-)PAI Dose MABP change (mmHg) HR change (beats / min) 0.01 4 -8 0.03 7 -12 0.01 -5 -10 0.03 5 8 0.1 -12 0 1.0 2 -5 Example 11.6 Lack of effect of S(-)PAI on catecholamine-induced blood pressure elevation in anesthetized cats. MAO inhibitors generally potentiate the blood pressure-increasing effect of catecholamines because they block their metabolic elimination by the MAO enzyme. This is particularly true for subtype A enzymes. Cats treated with S(-)PAI according to Example 5 were further treated with the following blood pressure-increasing agents: phenylephrine, tyramine and norepinephrine. In none of the cases did a significant blood pressure-increasing potentiation effect occur after pretreatment with S(-)PAI 1 mg / kg iv. The results are shown in Table VII. Table VII Intravenous catecholamine-induced blood pressure elevation before and after pretreatment with S(-)PAI 1 mg / kg iv injection Agent and dose (pg / kg) Mean arterial pressure (mmHg) before S(-)PAI Mean arterial pressure after S(-)PAI (mmHg) Norepinephrine 0.02 8 12 0.05 23 32 HU 226 961 B1 Table VII (continued) Agent and dose (F9 / kg) Δ mean arterial pressure (mmHg) before S(-)PAI Δ mean arterial pressure after S(—)PAI (mmHg) 0.10 31 23 0.20 46 46 Phenylephrine 0.20 9 2 0.50 17 17 1.0 21 17 2.0 40 42 Tyramine 2.0 11 3 5.0 19 9 10.0 26 58 20.0 42 39 Example II. 7 Lack of cardiovascular effects following acute oral administration of S(-)PAI in conscious rats Under light anesthesia induced with Averteen, a chronically inserted catheter is implanted in the cardiac artery. After the animals have recovered, the tests are performed 24 hours after implantation. The catheter is connected to a Statham pressure transmitter and blood pressure is monitored on a Grass multichannel polygraph. During this time, the rat is kept in a home cage to minimize blood pressure changes associated with handling and unnecessary manipulations. Two strains of rats are used: WKY and corresponding SHL (spontaneously hypertensive rats). WKY rats are from our own strain, weigh approximately 250 g. They have a maximum fluctuation of mean arterial pressure (MAP) and heart rate (HR) of 8 mmHg and 49 beats / min, respectively, at rest. SHR rats were obtained from Charles River Breeders in England. After the animals had acclimatized and recovered from the trip, they were used at 3 months of age to match the WKY control. SHR hypertension develops gradually, from 1 to 3 months of age. At this age, blood pressure is already above normal pressure values. S(-)PAI is administered at a dose of 100 mg / kg. Blood pressure and heart rate are then recorded for 45-60 minutes. The results are presented in Table VIII, which shows that acute oral administration of S(-)PAI has no effect on any of the parameters in any of the rat strains. Table Vili. Cardiovascular effects of S(-)PAI in awake rats 45-60 minutes after oral administration Rat strain Dose MBAP change mmHg HR change (beats / min) WKY 1 -9 70 -24 -130 Rat strain Dose MBAP change mmHg HR change (beats / min) 2 -6 -20 9 70 5 0 0 0 0 10 0 0 20 0 0 -12 0 SHR 1 -16 -30 2 -12 0 5 13 0 -6 -40 10 4 0 Example 11.8 Lack of effect of S(-)PAI on systolic blood pressure in SHR rats after chronic oral administration of 2 mg / kg / day. Spontaneously hypertensive rats aged 3 months were used for the experiment. Each rat was given 2 mg / kg S(-)PAI daily in 10 ml / kg tap water. The same volume of tap water was given as a control. The treatment lasted for 14 days. During this period, systolic blood pressure was monitored on days 0, 4, 7, and 11 by the tail ring method. On day 14, systolic blood pressure was determined by the internal catheter method described in Example 7. The results are presented in Tables 9 and 10. Chronic oral treatment with S(-)PAI at a dose of 2 mg / kg / day had no effect on the intraindividual and interindividual systolic blood pressure profile and heart rate. Table IX Lack of effect of S(-)PAI on systolic blood pressure in SHR rats after chronic oral administration of 2 mg / kg / day for 2 weeks Day of treatment Mean systolic blood pressure change (mmHg) Heart rate change (pulse / min) Tap water 0 169.55±7.73 374.09±37.17 4 177.82±9.08 403±23.3 7 177.67±10.21 392.67±24.66 11 178±8.65 371.25±27.22 S(-)PAI 0 166.88±6.11 404.13±32.86 4 168.5±12.8 394.5±37.43 7 172.13±14.62 394.38±24.47 11 167.43±14.23 408±40.04 HU 226 961 B1 Table X. Cardiovascular effects of 7-week chronic oral S(-)PAI treatment in SHR rats by direct measurement via implanted catheter Mean arterial blood pressure Systolic blood pressure Pulse rate Tap water 107.65±9.59 138.37±13.41 404.55±49.82 S(-)PAI 107.88±5.35 140.79±6.55 366.11 ±34.99 Example 11.9 Lack of effect of S(-)PAI on body weight of SHR rats following chronic oral administration of 1000 mg / kg / day. The rats used in Example 8 were continuously monitored for body weight gain / loss to assess the rate of food consumption. MAO inhibitors generally increase central catecholamine levels, which can lead to decreased appetite. Chronic treatment with 2 mg / kg / day of S(-)PAI did not cause any changes in body weight within 14 days. The results are shown in Table XI. Table XI Effect of S(-)PAI on body weight of SHR rats after chronic oral administration of 2 mg / kg / day Day Weight (g) Tap water 0 317±32.64 7 302.22±35.17 14 312.89 S(-)PAI 0 294.13±32.06 7 292.25±28.47 14 307.33±24.13 Summary Examples 4-9 illustrate that S(-)PAI has no effect on several MAO-mediated effects. Example 11.10 Effect of S(-)PAI on closed head injury (CHI mice) The closed head injury test is performed using the method described by Shoami et al. for rats [J. Neuortrauma (1993) 10. (2) 109-119.]. Animals: Male Sabra mice (Hebrew University strain) weighing 34-40 g were used. Animals were housed in groups of 10 per cage. 12 h:12 h light:dark cycle. Food and water were provided ad libitum. Trauma is induced under anesthesia. A longitudinal incision is made in the skin covering the skull and the skin is pulled back to expose the skull. The head is manually secured to the lower plate of the impact device. A 333 g mass is delivered by an electric device from a distance of 3 cm to the left hemisphere, 1-2 mm lateral to the mid-coronal plane. 15 minutes after CHI, a single subcutaneous injection of S(-)PAI (1 mg / kg) is given. Assessment of Motor Function Motor function and reflexes are assessed in injured mice at various times after closed head injury (CHI). The results are assessed using the Neurological Severity Score (NSS*) as shown in Table XII. The scoring is modified from that described for rats. One point is given if the reflex tested is absent or the animal is unable to perform the tasks given in the table. The highest score achievable within 1 hour after (CHI) is 25 points and at later times 21 points. The NSS value after 1 hour and at any other time point reflects spontaneous recovery and is denoted as Δ NSS. A score of 15-19 after 1 hour indicates severe injury, 11-14 moderate injury and less than 10 mild injury. *=The NSS in this example is not the same as in example 3, each depends on the observed parameter and the scoring system. Table XII Neurological severity scores following closed head injury (CHI) in mice Parameter Score given 1 hour after CHI Score given at any other time Unable to leave the center of a circle (30 cm diameter) for 30 minutes 1 60 minutes 1 >60 minutes 1 1 Loss of right sided reflex for 10 seconds 1 20 seconds 1 >30 seconds 1 1 Hemiplegia - mouse becomes unable to resist forced changes in position 1 1 Flexion of hind limb after lifting by the tail 1 1 Unable to walk straight when placed on the ground 1 1 Reflexes: Ear reflex 1 1 Corneal reflex 1 1 Startle reflex 1 1 HU 226 961 B1 Table XII (continued) Parameter Score given 1 hour after CHI Score given at any other time point Clinical grade Loss of searching ability 1 1 Falling 1 1 Absence of reflexes Left forelimb 1 1 Right forelimb 1 1 Left hindlimb 1 1 Right hindlimb 1 1 Functional test Loss of balance exercise on beam (0.5 cm wide) for 20 seconds 1 1 Up to 40 seconds 1 1 >60 seconds 1 1 Loss of balance exercise on cylindrical beam (0.5 cm diameter) for 10 seconds 1 1 Unable to walk across beam 3 cm wide 1 1 2 cm wide 1 1 1 cm wide 1 1 Maximum score 25 21 Testing reference memory We perform the Morris water maze test: The water maze is a circular aluminum pool, 1 m in diameter, 60 cm deep, and filled with water to a depth of 17.5 cm. The hidden target platform is a glass container (15 cm diameter x 16.5 cm height) that is inverted and placed in a fixed position in the pool, 1 cm below the water surface. The water temperature is maintained at 24 °C and the pool is always placed in the same position in the room to produce extramaze cues in the same location. Before the CHI, mice are trained on 3 trials per day for 5 consecutive days to establish a baseline level of proficiency, which is determined by the time to reach the platform from the same starting line. 24 hours after the CHI, mice are tested again daily for 3 trials per day for 2 weeks. The results are presented in Table XIII. Table XIII Changes in neurological severity scores in mice after CHI Active ingredient / dose ND NSS, 24 hours after CHI DNSS, 7 days after CHI D NSS, 14 days after CHI Saline 1 ml / kg 51 4.75±0.17 5.83±0.36 5.96±0.4 S(-)PAI 1 ml / kg 15 5.06±0.25 7.19±0.28 7.88±0.36 Examining the reference memory Figure 1 shows the decrease in latency following CHI in mice treated with S(-)PAI and saline as a control. The figure shows latency (sec) as a function of days. Legend -|- Control (1 ml); - ·- S-PAI 1 mg It can be seen that immediately after CHI, mice forget the location of the target. After treatment with S(-)PAI, the memory of mice improves compared to saline-treated controls.

Claims

PATENT CLAIMS 1. Use of S-(-)-N-propargyl-1-aminoindane or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a) treating neurotrauma or b) improving memory in patients with closed head injury (post-CHI).

2. Use of S-(-)-N-propargyl-1-aminoindane according to claim 1, wherein the medicament is in a form suitable for oral, rectal, intravenous, transdermal or parenteral administration.

3. Use of S-(-)-N-propargyl-1-aminoindane according to claim 1, wherein the medicament is in a form suitable for administration in a dose of 1-100 mg.

4. The use according to claim 3, wherein the dose is 10-100 mg.

5. The use according to claim 1, wherein the S-(-)-N-propargyl-1-aminoindane is in the form of the hydrochloride, mesylate, esylate or sulfate salt.

6. The use according to claim 1 for the preparation of a medicament for the treatment of neurotraumatic damage, wherein the damage to the central or peripheral nervous system is caused by ischemic damage, stroke, hypoxia or anoxia, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, neurotoxic injury, traumatic injury due to head injury, trauma due to spinal injury or any other form of nerve damage.

7. Use according to claim 1, wherein the medicaments comprise S-(-)-N-propargyl-1-aminoindane or a salt thereof in a dose of 1-1000 mg.

8. The use according to claim 1, wherein the medicament is suitable for preventing nerve necrosis.

9. The use according to claim 1, wherein the medicament is suitable for treating a patient suffering from memory impairment.