CS691A3 - R-enantiomers of n-propargyl-1-aminoindane compounds, method of their preparation and pharmaceutical preparations that they contain - Google Patents

Abstract

R-(+)-N-propargyl-1-aminoindane of formula (I) and its pharmaceutically acceptable acid addn. salts are new. (I) is prepd. by reacting R(-)-1-aminoindane with propargyl bromide or chloride in the presence of base (and opt. of solvent), then (I) is isolated by e.g. chromatography, distn. or selective extraction. The racemic starting material can be used instead and (I) then recovered by fractional crystallisation of salts formed with an optically active acid.

Description

The present invention relates to the field of selective irreversible inhibitors of the enzyme monoamine oxidase (hereinafter referred to as MAO) and relates to the R (+) enantiomer of N-propargyl-1-aminoindan (hereinafter PAI), which is a selective irreversible inhibitor of the B-enzyme enzyme monoamine oxidase (hereinafter MAO-B) ). The invention also relates to pharmaceutical compositions containing R (+) PAI, which is particularly useful in the treatment of Parkinson's disease, memory impairment and Alzheimer's type dementia (DAT), depression and hyperactive syndrome in children.

Parkinson's disease is generally considered to be the consequence of the degradation of presynaptic dopaminger neurons in the brain by subsequent reductions in the amount of dopamine released by the neurotransmitter dopamine. Insufficient dopamine release will result in the onset of spontaneous muscle control disorders symptomatic of Parkinson's disease. Various procedures 7 for the treatment of Parkinson's disease have been developed and widely used, e.g., by the administration of L-Dopa together with a decarboxylase inhibitor such as L-carbidopa or benzerazide. The decarboxylase inhibitor protects the L-Dopa molecule from peripheral decarboxylation and thus provides L-Dopa uptake by the remaining dopaminergic neuronymozic striatum. Here, L-Dopa is converted to dopamine, resulting in an increase in dopamine levels in these neurons. As a result of the physiological impulses of these neurons, the ability to release larger amounts of dopamine, which is normal to the desired values, results. This treatment therefore moderates the symptoms of the disease and contributes to the good condition of the patients.

However, the treatment of L-Dopa with my disadvantages is that the efficacy of the treatment is optimal only in the first few years after treatment. Following this initial periodic response, it disappears and is accompanied by undesirable side effects, including discinesis, day-out efficacy ("on-off effect") and psychiatric symptoms such as confusion, paranoia, and hallucinations. This effect of L-Dopa treatment is attributed to many factors including natural disease progression, dopamine receptor change due to increased dopamine production or increased levels of dopamine metabolites, and pharmacokinetic problems associated with L-Dopa uptake (summarized above). Youdinva et al., Progress in Medicinal Chemistry, Vol. 21, Chapter 4, pp. 138-167 (1984), edited by Ellis and West, Else-vier, Amsterdam.

In order to overcome the disadvantages of L-Dopa treatment, various treatments have been proposed in which L-Dopa is combined with MAO inhibitors to metabolically destroy the newly formed dopamine (see, eg, US Patent No. 4,826S75). MAO exists in two forms known as MAO-A and MAO-B, which are selective for various substrates and inhibitors. E.g. MAO-B metabolizes more efficiently substrates such as 2-phenylethylamine and is selectively and irreversibly inhibited by (-) - deprenyl (as described below). -3-

It should be noted, however, that the combination of L-Dopa with inhibitors of both MAQ-A and MAO-B leads to undesirable side effects related to the elevation of catecholamine levels by unneuraxone. Further, the complete inhibition of 3A0 is also undesirable because it potentiates the effect of symptomimetic amines such as jetyramine, resulting in a "cheeseffect." Summary See Youdim et al., Hondbook of Sxperimental Pharmacology, vol.90, Chapter 3 (1988), ed. Trendelenburg and '.'. 'einer, Springer-Verlag). Since MAC-3 has been shown to be a predominant form of MAO in the brain, selective inhibitors of this form are considered a possible way to achieve a reduction in dopamine disruption on the one hand, and, together with minimizing the systemic effects of total MAO inhibition, on the other.

One of these selective MAO-B inhibitors is - (-) - deprenyl, which has been extensively studied and has been used as a MAO-B inhibitor to supplement L-Dop treatment. This treatment with (-) - deprenyl is generally preferred because it does not cause a "cheese effect" at doses causing almost complete inhibition of MAO-B (Elsworth et al., Phychopharmaco-logs, 577, 33 (1978)). Furthermore, the addition of (-) - deprenyl to the combination of L-Dopa and the decarboxylase inhibitor to patients with Parkinson's disease results in improved akinesia and overall functional capacity as well as to eliminate on-off failures (see Birkmayer and Riederer in "Parkinson" with DiSease "pp. 138-149, Springer-Verlag (1983).

Thus, (-) - deprenyl increases and prolongs the effect of L-Dopa and allows for the reduction of L-Dopa doses, thereby reducing the undesirable side effects of L-Dopa treatment.

However, (-) - deprenyl is not without its own undesirable effects, including activation of pre-existing gastric ulcers and occasional hypertensive events. Further, (-) - deprenyl is a derivative of amphetamine and is metabolised by the formation of amphetamine and methamphetamines, which may lead to undesirable side effects associated with such substances such as increased heart rate (Simpson, Bio-chemical Pharmacology, 27, 1591 (1978)) Finberg et al., In "Monoamine Oxidase-inhibitors-Lhe State of the Art", pp.31-43, by Youdim and Paykel, (1981) Wiley).

Other compounds that are selective irreversible MAO-B inhibitors that are free of undesirable side effects associated with (-) - deprenyl have already been described. One such compound is N-prodrug-1-aminoindan.HG1 (racemic PAI.HCl) described in GB1003686 and GB1037014 and US 3513244. it is an effective selective irreversible MAO-B inhibitor that is not metabolised by amphetamines and does not result in an increase in undesirable symmetry. -Patomimetic effects.

In animal comparative tests, racemic PAI has been shown to have significant advantages over (-) - deprenyl, for example, racemic PAI does not induce any significant tachycardia, does not cause increased blood pressure (effects induced by 5 mg / kg (-) - deprenyl), does not induce contraction or increase heart rate at doses up to 5 mg / kg (effects caused by (-) - deprenyl at doses above 0.5 mg / kg), further racemic PAI.IICl does not potentiate cardiovascular the effect of pyramine (Finberg et al. in "Enzvmes and NeurotransmittersInnental Disease", pp. 205-119 (1980), edited by Usdin et al., John V / iley and sons, NY $ Finberg et al (1981)) in Moanamine Oxidase Inhibitors State of the Art, ibidjFinberg and Youdim, British Journal Pharmacol., 85 451 (1985).

One object of the present invention is to separate the racemic PAI compounds and to produce the MAO-B inhibitory enantiomer.

Since deprenyl has a structure similar to that of PAI and it is common knowledge that the (-) - enantiomer of deprenyl, i.e. (-) - deprenyl, significantly more pharmaceutically active than the (+) - enantiomer, those skilled in the art assumed that only the (-) - enantiomer of PAI could is an effective MAO-B inhibitor.

However, in contrast to these assumptions, after the digestion of the two enantiomers, it has been found, according to the present invention, that the (+) - PAl enantiomer is an effective inhibitor of ΜΑΟ-ΰ, while (-) - enantiomer has extremely low MAG-3 inhibitory activity. Furthermore, the (+) -PAI enantiomer also had a surprisingly higher degree of selectivity for MAO-B inhibition than the corresponding racemic form and may thus have fewer adverse side effects in the treatment of the indicated disease. These findings are based on both in vitro and in vivo experiments and are presented in more detail. Subsequently, (+) - PAI was found to be my absolute R configuration. This was also surprising due to the expected structural analogy with deprenyl and amphetamines.

The high degree of stereoselectivity of pharmacological activity between R (+), PAI and the S (-) enantiomer is also noteworthy. Compounds R (+) - PAI are almost four orders of magnitude more active than the S (-) enantiomer in inhibiting MAO-B. This ratio is significantly higher than that observed between two deprenyl enantiomers (Knoll and Magyar, Adv. Biochem. Phys. Pharmacol., 5, 393 (1972); Wagy & Ra., Acta, Physiol. Acad. 377 (1967). Furthermore, in some physiological tests, (+) - deprenyl indicates that it has the same or even higher potency than the (-) enantiomer (TSkes et al., Pol.J.Pharmol. Pharm.4Q, 653 (1988)). N-Methyl-N-propargyiaminoindane (MPAI) is a more potent MAO inhibitor, but with lower selectivity for MAO-B over MAO-A (Tipton et al., Biochem. Pharmacol., 31, 1250 (1982)). found that there were only minor differences in the relative efficacy of the two enantiomers, further highlighting the remarkable case of R (+) - PAI (see Table I).

It is a further object of the present invention to provide the first use of a pharmaceutically effective PAI-engntiomer alone (without L-Dopa) for the treatment of Park4 ' nson ' s disease, depression and depression (see Youdim et al. In Handbook of Experiential Pharmacology, Vol 90/1, (1988), Chapter 3, Trend-lenberg and Wiener).

Yet another object of the invention is to provide the use of a pharmaceutically effective PAI-engntiomer for pre-treatment with or without synergistic agents for Parkinson's disease so as to delay L-Dopa treatment and the associated side effects. This approach has been studied with respect to (-) - deprenyl, which has been shown to be effective alone in early stages of parkinsonism, and may also have a synergistic effect in these patients with co-administration with alpha-tocopherol (a derivative of vitamin A), (The? Arkinsonzs Study Group, New England J.Med., 321 (20), 1364-1371 (1989).

In addition to being useful in the treatment of Parkinson's disease, (-) - deprenyl has also proven to be very suitable for the treatment of patients suffering from dementia of the Alzheimer type (Dari) (Tariota et al., Psychopharmacology, 91, 489-495, 1987) and in the treatment of depression (Mandelewicz et al. Youdim, Brit. J.Psychiat.142,508-511, 1983). This resulted in the use of the R (+) - PAI compound, which has been shown to be effective in restoring memory, the possibility of treating memory disorders, and particularly suitable for the treatment of Alzheimer's disease and for the treatment of hyperactive hypersyndrome in children.

Thus, the present invention provides a novel compound R (+) - enantiomer of N-propargyi-1-aminoindan / R (+) PAI) / Formula I

H and pharmaceutically acceptable acid addition salts thereof. The present invention also relates to the preparation of R (+) PAI, pharmaceutical compositions comprising R (+) PAI together with suitable carriers and the use of R (+) FAI for the treatment of human patients suffering from Parkinson's disease, memory disorders, Alzheimer's dementia and overactive syndrome. R (+) PAI can be obtained by optical resolution of the racemic mixture of the R and S-enantiomers of PAI. Such cleavage may be accomplished by any conventional cleavage method well known to those skilled in the art, such as those described by " Enantiomers, Racemates and Resolutions " by J. Jacques, -9- A.Jollet, and S.'A'ilen, Pub. For example, a resolution may be performed by preparative chromium on a chiral column. Another example of a suitable method of optical resolution is the preparation of diastereomeric salts with optically active acids such as tartaric acid, malic acid, mandelic acid or N-acetyl derivatives of amino acids such as K-acetylleucine, followed by recrystallization to isolate the diastereomeric salt of the desired R-enantiomer.

The racemic mixture of R and S enantiomers can be prepared e.g. as described in GB Patent Nos. 1,003676 and C-B 1,03701 4. The chemical mixture of PAI can also be prepared by reacting 1-chloroindane or 1-bromoindane with propargylamine. Alternatively, the racemate may be prepared by reacting propargylamine with 1-indanol to form the corresponding imine followed by reduction of the carbon-nitrogen double bond in the imine with a suitable reagent such as sodium borohydride. In accordance with the present invention, the R 1 -antiomer PAI can also be prepared directly from the optically active R-enantiomer 1-aminoindan by reaction with propargyl bromide or propargyl chloride in the presence of an organic or inorganic base and optionally in the presence of a suitable solvent.

Suitable organic or inorganic bases for use in the above reaction include, for example, triethylamine, pyridine, alkali metal carbonates or bicarbonates, etc. If the reaction is carried out in the presence of a solvent, this may be selected from the group consisting of, for example, toluene , methylene chloride and acetonitrile. A preferred method for preparing the above compounds involves the reaction between R-1-aminoindane and propargyl chloride using potassium hydrogen carbonate as the base and acetonitrile as the solvent.

Said reaction of 1-aminoindan generally results in a mixture of unreacted primary amine, desired secondary amine and tertiary amine Ν, β-bispropargylamine product, the desired secondary amine, ie, N-propargyl-1-aminoindane, can be separated from the mixture by any by a conventional separation method such as chromatography, distillation, selective extraction, etc. The starting R-1-aminoindan can be prepared by methods known in the literature, eg as reported by Lawson and Rao, Sioche-masters (1980) 1 9 2133 and references cited therein and European Patent No. 235590. R-1-Aminoindane can also be prepared by optical expansion of a racemic mixture of R and S enantiomers, e.g., by formation of diastereomeric salts with optically active acids, or by other known methods such as is a method set forth in "Enantiomers, acemates and esolutions" by J.Uccques et al., J.B. John Wiley and Sons, NY, 1981. It can be prepared by reacting 1-indanone with an optically active amine followed by reduction of the carbon-nitrogen double bond in the resulting imine by hydrogenation over a suitable catalyst such as palladium on carbon, palladium oxide, Haney nickel and the like. Preferred optically active amines are, for example, one of the phenethylamine antipodes or an amino acid ester such as valine or phenylalanine. The benzylic N-C bond may subsequently be cleaved by hydrogenation under mild conditions.

Other methods for the preparation of R-1-aminoindan are the hydrogenation as described above, of indan-1-onoximathers, the alkyl portion of the ether containing an optically pure chiral center. Alternatively, non-cellular indan-1-one derivatives containing a carbon-nitrogen double bond, such as an imine or oxime, may be reduced with a chiral reducing agent, e.g. a complex of lithium aluminum hydride and ephedrine.

To prepare pharmaceutically acceptable addition salts of R (+) PAI, the free base is reacted with the desired acids in the presence of a suitable solvent by conventional methods. Similarly, acid addition salts may be converted into the free base by known methods. In accordance with the present invention, the compound B (+) PAI may be prepared as a pharmaceutical composition particularly useful for the treatment of Parkinson's disease, dementia of Alzheimer's type (DAT) or depression. Such formulations may contain the compound R (+) PAI or pharmaceutically acceptable acid addition salts thereof, together with pharmaceutically acceptable carriers and / or additives. For example, these preparations may be formulated as drugs that can be administered orally, parenterally, rectally or transdermally. suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions; for parenteral administration, the invention provides ampoules or vials containing an aqueous or non-aqueous solution or emulsion; suppositories with hydrophilic or hydrophobic vehicles are intended for rectal administration; and for topical application, the ointment and transdermal delivery are accomplished by appropriate transport transfer known in the art. The aforementioned formulations can be used alone to treat Parkinson's disease, Alzheimer's disease, or to undergo depression, or alternatively, in the case of Parkinson's disease, they can be used as an addition to conventional L-Dopa therapy. Preferred doses of the active ingredient, i.e., R-PAI compounds, in the above formulations are within the following ranges: for oral or suppository formulations 2 to 20 mg per dosage unit per day, and preferably 5 to 10 mg per dosage unit day; for injectable preparations, 1 to 10 mg / ml of dosage unit per day, and more preferably 2 to 5 mg / ml per dosage unit of naden.

Description of the picture:

FIG. is a graphical representation of the results of Example 19. -13-

FIG. 2 is an example 19. FIG. 3 is a graphical representation of the results according to FIG. 4 is a graphical representation. Example 20 Results »

Fig. 5 is a schematic diagram of the results of Fig. 5. 6 is a graphical representation of the results of Example 20, O'or. 7 is a graphical representation of the results of Example 20.

Fig.8. is a graphical representation of the results of Example 20.

Figure 9 is a graphical representation of the results of Example 20.

Figure 10 is a graphical representation of the results of Example 20.

Figure 11 is a graphical representation of the results of Example 20.

Figure 12 is a graphical representation of the results of Example 21.

Figure 13 is a graphical representation of the results of Example 21.

Figure 14 is a graphical representation of the results of Example 21. -14-

Figure 15 is a graphical representation of the results of Example 21.

Figure 16 is a graphical representation of the results of Example 22.

The invention is described in more detail in the following examples, tables and figures, which do not limit it in any way. Example 1

Eacemic N-propargyl-1-aminoindan hydrochloride

Racemic 1-aminoindane (10.0 g) and 10.4 g of potassium carbonate are added to 75 ml of acetonitrile. The resulting mixture was heated to 60 ° C and 4.5 g of propargyl chloride was added dropwise.

The mixture was stirred at 60 ° C for 16 hours, then the volatile substances were removed by vacuum distillation. The residue was partitioned between 10% aqueous sodium hydroxide and methylene chloride.

The organic phase is dried and the solvent is removed by distillation. The residue was flash chromatographed on silica gel eluting with 40% ethyl acetate / 60% hexane. The free base fractions containing the title compound were combined and the eluent was replaced with ether. The ether solution was treated with gaseous hydrogen chloride, the precipitate formed was collected by suction and recrystallized from isopropanol to give 7.3 g of the title -15-compound, m.p. 182-184 ° C.

Chromatographic and spectroscopic values are in accordance with literature (US 3513244) and an authentic sample. NMR (CDCl 3): 2.45 (2H, m), 2.60 (1H, t), 2.90 (1H, m), 3.45 (1H, m), 3.70 (2H, m); d), 4.95 (1H, t), 7.5 (4H, m) ppm. Example 2

The S - (-) - N-propargyl-1-aminoindan-1-yl salt of the free base is isolated by optical resolution of the racemic mixture of the free base of Example 1 with a preparative HPLG Chiracel OJ (cellulose tris / p-methylbenzoate) eluting with 10% isopropanol Hexane and collecting the first eluted main peak. The resulting oil is converted to the title compound (hydrochloride) by treatment with 10% diethyl ether ether oil solution with HCl gas and aspiration of the resulting precipitate. [Α] 29.2 ° (1%, ethanol), m.p. 182-184 ° C. Further chromatographic and spectroscopic data are identical to the hydrochloride salt of Example 1 o Example 3 R - (+) - N-propargyl-1-aminoindan hydrochloride

The title compound was prepared in the same manner as in Example 2 above, except that the second eluted peak from the preparative HPLG was separated: mp 29.1 ° (0.8%, ethan-16-ol), m.p. Mp 179-181 ° C. Further chromatographic and spectroscopic data are identical to the hydrochloride salt of Example 1. Example 4 R - (+) - N-Propargyl-1-aminoindan R - (-) - 1-Aminoindane (12.4 g) and 12 9 g of potassium carbonate are added to 95 ml of acetonitrile. The resulting suspension is heated to 60 ° C and 5.6 g of propargyl chloride are added dropwise. The mixture was stirred at 60 ° C for 16 hours, removing the most volatile substances in vacuo. The residue was partitioned between 10% aqueous sodium hydroxide and methylene chloride.

The organic phase is dried and the solvent is removed in vacuo, the residue is chromatographed on silica gel with 40% ethyl acetate / 60% hexane. The fractions containing the free base of the title compound are combined and the solvent is replaced with ether. The ether solution was treated with hydrogen chloride gas and the resulting precipitate was collected by suction and recrystallized from isopropanol. Gets. 6.8 g of the title compound, m.p. 183-185 ° C // & + 30.90 ° (2%, ethanol). The spectral properties are the same as those given for Example 1 · -17- Example 5 S - (-) - N-propargyl-1-aminoindan 1 hydrochloride The title compound was prepared by the method of Example 4 except that the starting material using S - (+) - 1-aminoindane. The product showed /X / β -30.3 ° (2%, ethanol), m.p. 183 to 185 ° Ge The spectral properties are identical to those given for the compound of Example 1, Example 6

Di (E - (+) - N-propargyl-1-aminoindan) L-tartrate To a solution of L-tartaric acid (4.4 g) in 48 ml of boiling methanol is added a solution of R - (+) - N-propargyl-1 aminoindanoate free base (5.0 g) in methanol (48 mL). The solution was warmed to room temperature and 284 ml of tert-butyl methyl ether was added over 20 minutes. The mixture was heated for an additional 30 minutes, cooled and the resulting precipitate was filtered off with suction, yielding 6.7 g of the title compound, m.p. 175-177 ° C. / <á / d (1.5, H2O) = +34.3; Elemental analysis for G28H32O6N2 Calculated: 68.26% G, 6.56% H, 5.69% N, found 68.76% C, 6.57% H, 5.61% N. Example 7

R - (+) - N-Methyl-N-propargyl-1-aminoindan hydrochloride

The free base of R - (+) - N-propargyl-1-aminoindan from Example 4 (1.2 g), potassium carbonate (0.97 g) and methyl iodide -18- (1 g) was added to 15 mL of acetone and the resulting the suspension was heated to reflux under a nitrogen atmosphere for 8 hours. Then the volatiles were removed under reduced pressure and the residue was partitioned between 10% aqueous sodium hydroxide (30 mL) and methylene chloride (30 mL). The organic phase was dried and the solvent removed in vacuo. The residue was flash chromatographed on silica gel eluting with 40% ethyl acetate / 60% hexane to give the title compound as the free base and the solvent was replaced with diethyl ether. The ether solution was treated with hydrochloric acid gas. the volatiles were removed in vacuo and the residue was recrystallized from isopropanol to give 400 mg of the title compound as a white crystalline solid, m.p. 134-136 ° C, [α] D +31.40 (ethanol). NMR (CDCl 3): 2.55 (2H, m), 2.7 (1K, br.s.), 2.8 (3H, s), 3.0 (1H, m), 3.4 (1H, m), m), 3.9 (2H, br.s), 5.05 (1H, m), 7.7 (4H, m) ppm. Example 8

S - (-) - N-Methyl-N-propargyl-1-aminoindan hydrochloride

The title compound was prepared as in Example 7 above except that S - (-) - N-propargyl-1-aminoindan (free base) from Example 5 was used as the starting material. All physical and spectral properties of the title compound were identical with these properties of Example 7 except for (c / d-34.9 ® (ethanol)). Example 9 Composing Tablets

R (+) - N-propargyl-1-aminoindan hydrochloride 5.0 mg pregelatinized starch 47.0 mg lactose undried 66.0 mg microcrystalline cellulose 20.0 mg sodium starch glycolate 3.0 mg talc 1.5 mg magnesium stearate 0 , 7 mg

The required amount of pre-treated water is added to the granulation. Example 10

Tablet composition

R (+) - N-propargyl-1-aminoindan hydrochloride 1.0 mg lactose undried 50.0 mg pregelatinized starch 36.0 mg microcrystalline cellulose 14.0 mg sodium starch glycolate 2.2 mg talc 1.0 mg magnesium stearate 0 , 5 mg

The required amount of pre-treated water is added to the granulation. Example 1I

Composition of capsules

R (+) - N-propargyl-1-aminoindan hydrochloride 5.0 mg pregelatinized starch 10.0 mg -2 0- starch 44.0 mg λ microcrystalline cellulose 25.0 mg ethyl cellulose 1.0 mg talc 1.5 mg

The required amount of pre-treated water is added to the granulation. Example 12

Composition of injections

R (+) - N-propargyl-1-aminoindan hydrochloride 5.0 mg anhydrous dextro 44.0 mg HG1 to pH 5 Purified water is added at a rate of 1 ml. Example 13

Injection Composition R (+) - N-propargyl-1-aminoindan hydrochloride 1.0 mg sodium chloride 8.9 mg HCl to pH 5 Purified water to 1 ml is added. Example 14

Composition of injections

R (+) - N-propargyl-1-aminoindan hydrochloride 2.0 mg sodium chloride 8.9 mg HCl to pH 5 Purified water is added to 1 ml as needed. Example 15System Composition

R (+) - N-propargyl-1-aminoindan hydrochloride 5.0 mg sucrose 2250.0 mg saccharin sodium 5.0 mg methylparaben 6.0 mg propylparaben 1.0 mg flavoring 20.0 mg glycerin USP 500 mg alcohol 95% USP 200 mg Purified water is added in amounts up to 5.0 ml. Example 16 Suhlingual tablets Nydrochloride R (+) - N-propargyl-1-aminoindan 2.5 mg microcrystalline cellulose 20.0 mg undried lactose 5.0 mg pregelatinized starch 3.0 mg povidone 0.3 mg coloring agent Q · 5 · flavoring qs sweeteners q.s. talc 0.3 mg -22-

The mixture of additives and active substance is granulated with the Povidone ethanol solution. After drying and weighing, it is blended and compressed. Example 17 PAI sublingual tablets Hydrochloride R (+) - N-propar gyl-1-aminoindan 5.0 mg microcrystalline cellulose 15.0 mg pregelatinized starch 12.0 mg ethyl cellulose • 0.3 mg talc 0.3 mg add purified water. Example 18 Composition of tablets Hydrochloride R (+) -N-propar, gyl-1-aminoindan 5.0 mg levodopa 100.0 mg Carbidopa 25.0 mg pregelatinized starch 24.0 mg starch 40.0 mg microcrystalline cellulose 49.5 mg color D ^ G Yellow No.1 0 0.5 mg color D ^ C Yellow No. 0.02 mg

The USP alcohol is added according to the granulation needs. The following examples and the attached tables and figures refer to biological experiments carried out in accordance with the present invention. Example 19 Inhibition of MAO activity in vitro

Experimental Protocol:

The source of the MAO enzyme was a rat brain homogenate at 0.3 Msaccharose, which was blasted at 600 g for 15 minutes. The supernatant was diluted in about 0.05 M phosphate buffer and preincubated with sero-dilutions of general formula I compounds: R (+) - PAI, S (-) - PAI and racemic-PAI (where A indicates hydrogen) for 20 minutes at 37 ° C . Subsequently, C-labeled substrates (2-phenylethylamine, PEA, 5-hydroxytrypine, 5-HT) are added and incubation is continued for a further 20 min (PEA) or 30-45 min (5-HT) . Substrate concentrations used were 50 µM (PEA) and 1 mM (5-HT). In the case of PEA, the concentration of the enzyme was chosen such that no more than 10% of the substrate was volatilized during the reaction, then the reaction was terminated by the addition of tranylcypromine (to a final concentration of 1 mM) and incubate. The solution was filtered through a small column of Amberlite CG-50 buffered to pH 6.3. The column is washed with 1.5 ml of water, the eluates are pooled and the radioactivity content determined by liquid scintillation spectrometry. Since the amine substrate is completely captured on the column, the radioactivity in the eluate demonstrates the production of -24- neutrile and acidic metabolites produced by the MAO activity. the sample was expressed as a percentage of the control activity in the absence of inhibitors, reading the respective blank values. The activity determined using PEA as a substrate is designated as MAO-B and using 5-HT as MAO-A. Results:

Inhibitory activities of R (+) - PAI, S (- (- PAI and racemic PAI compounds of formula I were separately tested in vitro and the results of typical experiments are shown in Figures 1 and 2). % inhibition of substrate metabolism (IC-50) was calculated from the inhibition curves as shown in Table 1. From these data it is clear that: (a) R (+) - PAI is twice as active as the racemet for MAO-B inhibition, b ) R (+) - PAI is 29-fold more active for MAO-B inhibition than MAO-A, c) S (-) - PAI * ith only 1/6800 MAO-B inhibitory activity of R (+) - PAI and shows little or no MAO-B and IvIAO-A selectivity. -25-

Table 1 IC-50 (nM) values for MAO-A and MAO-B inhibition of racemic PAI and its R (+) and S (-) enantiomers in in vitro rat bovine homogenate IC-50 (nM)

MAO-A MAO-B

SlouSe-

nina: S (-) PAI R (+) PAI Rac S (-) PAI R (+) PAI Rac 26000 73 140 17000 2.5 5 Results of the same experiment using R (+) and S (-) - MPAI (N -methyl-N-propargyl-1-aminoindan) are shown in Table 1A. Each of the MPAI enantiomers is a less selective inter-inhibition of MAO-B and MAO-A than R (+) PAI. Further, R (+) is only five times more active than S (-) MPAI in MAOBB inhibition, as opposed to R (+) PAI, which is about 7000 times more active than S (-) PAI in this experiment.

Table IA IC-50 (nM) values for inhibition of MAO-A and MAO-B R (+) and S (-) enantiomers of MPAI in in vitro rat brain homogenate IC-50 (nM) MAO-A _____ MAO-B_

Compound: S (-) MPAI R (+) MPAI 70 S (-) MPAI R (+) MPAI50 10-6 experiments were also performed with human cerebral tissue obtained 6 hours after death and treated as described above. The results of these experiments are shown in Figure 3 (where R (+) PAI, S (-) PAI and racemic PAI compounds are equivalent to Formula I). Example 20

Inhibition of MAO activity in vivo: acute treatment

Experimental Protocol:

The 250 + 20 g male Sprague-Dawley rats were treated with one of the enantiomers or with the racemic form of PAI by intraperitoneal injection (Ig) or oral gavage (gS) and either 1 or 2 hours after administration. Groups of three rats were used for each inhibitor dose evaluation and MAO activity was determined in the brain and jitter using the general technique described previously, the protein deity in each incubation was determined using the Folin-Lowry method and the enzyme activity was calculated as nmol substrate metabolyzed per hour of incubation per mg of protein. MAO activity in animal tissues of animals treated with inhibitors was expressed as a percentage of the enzyme activity of a group of vehicle control animals (water for oral administration, 0.9% saline for ip) and killed as described above . Results: None of the doses used with inhibitor drugs showed obvious changes in behavior. The results are shown in Figures 4 to 11. ip administration of compound R (+) - PAI yields 90% inhibition of brain MAO-B activity at 0.5 mg / kg. The same dose achieves only 20% inhibition of MAO-Aactivity. On oral administration, the same dose of R (+) - PAI achieves MAO-B inhibition of 80% with undetectable MAO-A inhibition. Substantially the same results were obtained for inhibition of BO as for MAO. Doses achieving 50% inhibition of MAO-A and MAO-B (10-50) were calculated from inhibition curves and are shown in Table 2. It is clear from these data that: a) MAO inhibitory activity of R (+) - PAI compounds is in vivo in rats,

b) selectivity of MAO-B inhibition relative to MAO-A for R (+) - PAI in vivo, c) much greater (+) - activity is maintained in vivo with respect to (-) enantiomer, d) compounds they are more effectively absorbed after oral administration and e) the compounds pass more effectively through the blood-brain barrier and more effectively inhibit brain MAO. The fact that R (+) - PAI is about twice more active than the racemic MAO-B inhibiting compound reflects the extremely low S (-) - PAI activity for MAO-B inhibition. -28- f ·

Table 2 IC-50 values (mg / kg) for inhibition of MAO-A and MOA-B by R (+) - PAI, S (-) - PAI or racemic PAI, in rats following intraperitoneal (IP) injection or oral (PO) administration of IC-50 (mg / kg)

___ MAO-A ___________ MAO-B

Compound: S (-) PAI R (+) PAI Rac S (-) PAI> 10> 1 0 R (+) PAI 0,07 0,06 Rac 0,22 0,11 IP IP brain liver> 10> 10 1.2 5 2.5 5 PO brain> 10> 5> 5 7Ί 0 0.17 0.29 PO liver> 1 0> 5 r5> 1 0 0.05 0.09 Example 21 xn inhibition of MAO activity in vivo: chronic treatment

Experimental Protocol:

Rats (Specification as in Example 20: 4 animals per dose value) are treated with R (+) - PAI in non-racemic form at three dose levels (0.05, 0.1 and 0.5 mg / kg) by oral administration, one dose per day for 21 days and then decapitate 2 hours after the last dose. The MAO-29- type A and B activity was determined in the brain and liver by the procedure described in Example 20. Results: A dose of 0.1 mg / kg daily of R (+) - PAI gave a good degree of selective inhibition with more than 80% inhibition site MAO-B and 20% or less inhibition of brain MAO-A. At a higher dose of 0.5 mg / kg daily, the MAO-A is still less than 50% inhibited (Figures 12 and 13). Liver MAO shows the same degree of selective inhibition (Figs. 14 and 15). Compound R (+) - PAI is always more potent than the racemic form of the inhibitor, with a factor of about two. In the case of brain MAO, R (+) tPAI has a better degree of selectivity for inhibition of MAO-Not racemic form.

These results indicate that the MAO-B selectivity inhibition can be maintained by the following chronic treatment with the compounds. As with other irreversible inhibitors, the degree of enzyme inhibition is higher in chronic treatment than in a single dose of drug. Compound R (+) - PAI shows a better degree of brain MAO inhibition selectivity than the racemic compound. Example 22

Irreversible character of MAO inhibition

Experimental Protocol:

A single dose of compound R (+) - PAI (1 mg / kg) was -30- given ip injections to groups of 4 rats and animals were sacrificed 2, 6, 18, 24, 48 and 72 hours later. MAO-B activity was determined throughout the brain as described above. Results' Results are shown in Figure 16. The axial MAO-B inhibition was achieved 6 hours after injection. The lvIAO activity was returned to 30% of the control activity after 72 hours after injection. This experiment demonstrates the irreversible nature of the MAO inhibition of R (+) - PAI. Example 23

Increasing the effect of tyramine on pressure in conscious rats

Experimental Protocol:

Rats were anesthetized with a mixture of pentobarbital (30mg / kg) and chloral hydrate (120mg / kg) by intraperitoneal injection. The left carotid and jugular vein were cannulated with a fine polythene tube (artery) or a fine silicone rubber tube attached to a polyethylene tube (vein), the distal end of which was introduced through the neck and neck. The tubes were filled with heparinized saline and sealed with a fine steel stopper. The animals were treated with 20 mg of chloramphenicol by intramuscular injection and left overnight after surgery. The next day, the rats were placed in a high-wall container allowing for free movement, the iální -term catheter was connected to a pressure-31-sensor 100 cm long, saline-filled polyethylene tube of fine clarity, and the venous catheter was attached to a 1 ml syringe with a tube of stiff length. which, together with the syringe, contains a solution of the thyme hydrochloride in saline (1 mg / ml). Following an equilibrium period of 30 to 40 minutes, a tyramine injection (50 or 100 µg) is administered and blood pressure is recorded. An interval of at least 15 minutes is maintained between the injections after the blood pressure has returned to the control value, the control pressure responses are determined and then the single drug is injected intraperitoneally and the tyramine responses are repeated for a further 4 hours. The flat-pressure curve response was evaluated and the ratio of this area after treatment to the pre-treatment area was determined using an average of 3 to 4 values obtained in the control period, 1 to 3 hours after compound injection. Results: The results are shown in Table 3. Compound R (+) - PAI at a dose of 1 mg / kg (which causes 40 to 50% inhibition of MAO-A in the brain and liver and complete inhibition of MAO-S in these tissues) does not induce significant tyramine pressure response enhancement . At a higher dose of R (+) - PAI 5 mg / kg (which exerts a more extensive inhibition of MAO-A in the brain and periphery), it greatly increases the pressure response to tyramine, which to some extent was consistent with the response elicited by the same dose of deprenyl and less than -32-response. induced by Clorgylin (at a dose that inhibits hepatic MAO-A activity above 85%). ^ 3

Increase of Tyramine Influence on Live Rat by MAO Inhibitors xnhibitor Dose Rat Number (mg / kg) (n) Area Relative Response Pressure Ratio; after / before

SEM saline 12 1,25 0,28 Clorgyline 2 6 10,39 2,13 (-) deprenyl 1 2 1,15 (-) deprenyl 5 3 2,36 0,16 R (+) PAI 1 3 1, 38 0.7 R (+) PAI 5 3.49 0.98 From this experiment, it appears that R (+) - PAI does not induce a tyramine effect on the dose pressure that is effective for MAO-B inhibition. Example 24 of

MPTP-induced dopaminergic toxicity R (+) - PAI 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin because it damages nigrostjiatal dopaminergic-33 neurons in some mammalian species including mice and parkinsonian syndrome in humans and primates. The pivotal step in its neurotoxicity mechanism is the conversion of MPTP to its toxic metabolite, 1-methyl-4-phenylpyridinium ion (MPP +). This reaction is catalyzed by the MAO-B enzyme and is likely to occur outside the dopaminergic neurons, especially in the glia. MPTP is known to be a substrate and an irreversible inhibitor of MAO-B. Prior treatment of experimental animals with MAO-B inhibitors such as deprenyl or propargylin protects against MPTP-induced risk of nigrostrial neurons because the oxidative conversion of MPTP to MPP + is blocked. One of the main general hypotheses suggests that progressive nigrostriatal degeneration in parkinism can be induced by exposure to environmental-derived MPTP-like neurotoxins. In such a case, another strong indication for initiating MAO-B inhibitor treatment is already in the very early stages of Parkinson's disease, where it is hoped that it will neutralize the harmful effects of these previously suspected MPTP-like toxins, thereby preventing or slowing disease progression. . Successful use of the MAO-B inhibitor as a drug is believed to be due to its ability to block MPTP-induced damage to nigrostriatal dopaminergic neurons in vivo

Therefore, PAI (-) and (+) enantiomers were tested for their efficacy in preventing or reducing MPTP-induced 34-striatal dopamine depletion in mice.

Experimental protocol: male G57 black mice (20-25 g weight were injected with MPTP-HCl (30 mg / kg, dissolved in distilled water, sc) or vehicle alone or one hour before treatment with (-) or (+) isomers of PAI (2.5 mg (kg), (ip) or deprenyl (5 mg / kg, ip) and decapitated five days later, the brains removed and the striatum was gutted on an ice-cooled glass plate and frozen with a dry leek. 1M acid chloroacid and deproteinized dihydroxybenzylamine-containing portions as internal standard were analyzed for dopamine by its major metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC) using HPLC with electrochemical detection.

Table 4 shows the results of this experiment. Treatment with sMPTP alone provides significant dopamine (DA) and DOPAC depletion. Treatment with (-) and (+) enantiomers of PAI or with (-) deprenyl does not affect striatal DA concentrations. Previous treatment with (-) isomer of PAI does not affect MPTP-induced DA and COPAC levels in the striatum. PAI (+) - Isomer administered prior to MPTP completely prevented toxin-induced reduction of striatal DA and DOPAC levels. At (2.5 mg / kg), both (-) - deprehyl (5 mg / kg) was as effective as the protective effect. -35- ^ 4

Effect of prior treatment of (-) and (+) enantiomers of MAO-Binhibitor PAI on depletion of striatal DA and DOPAC induced MPTP in mice in vivo

DA DOPAC (ng / mg protein) control 162.8 + 7.2 θ, 4 ± 0.5 (-) - PAI 174.0 + 4.8 7.5 + 0.2 (-) - PAI + MPTP 53 , 4 + 6.9 7.0 + 0.6 (+) - PAI 185.0 + 6.9 3.3 + 0.3 (+) - PAI + MPTP 177.8 + 14.4 6.0+ 0.3 (-) deprenyl 170.6 + 7.1 5.6 + 0.3 (-) deprenyl1 + MPTP 197.0 + 8.0 6.4 + 0.5 MPTP 53.1 + 6.2 3 , 2 + 0.3 The above DA and DOPAC values are expressed as mean + SEM, and n = 7-11 in each group. These results indicate that R (+) - PAI is an excellent MAO-B inhibitor in vivo and is particularly effective in the treatment of Parkinson's disease. Although the invention has been described by the above examples and related tables and figures, it is not limited thereto. Various modifications and applications of the invention are possible, for example, compounds of the formula may be combined synergistically with the tocopherol (a vitamin E derivative) for the treatment of Parkinson's disease. Example 25

The effect of PAI enantiomers on amphetamine-induced behavior of percent rats amphetamine is known to induce stereotyped behavior (Sulser F. and Sanders-Bush, E. Ann. Rev. Pharmacol. 11: 209-230 (1971)) mobilizing endogenous dopamine. Amphetamine is metabolized by MAO-B. The inhibition of MAO-B by an effective inhibitor and administration of amphetamine induces the release of dopamine which does not undergo MAO-B inhibited degradation. Thus, an increase in synaptic dopamine after administration of amphetamine and an effective MAO-B inhibitor is expected to lead to an increase in the stereo-typical behavior of potentiation of the amphetamine effect. The extent of this behavior is evaluated by the number of lateral head movements within 1 minute.

Experimental Protocol:

The test compound was administered at a dose of 0.5 mg / kg / day in drinking water, 24 hours before induction of hypoxia (92% nitrogen + 8% oxygen in 6 hours). Furthermore, amphetamine scv was injected at 0.5 mg / kg 45 min later , lateral head movements are counted. Results: The results of these experiments are shown in Table 5 · -37-

Table 5

Effect of PAI isomers on amphetamine-induced stereotyping of senescent rats (controlled and induced by hypoxia)

Treatment group stereotyped rat behavior control (6) - 87 + 1 0 control (5) (+) PAI 126 + 16- control (4) (-) PAI 94 + 18 induced hypoxia (5) - 93 + 12 induced hypoxia (o) (+) PAI 143i 6- Numbers in parentheses indicate the number of animals testedF <0.001 relative to the untreated hypoxia group or untreated control group Results in Table 5 show that (+) induces a marked increase in amphetamine-induced stereotyped behavior in hypoxia-induced rats and control animals, (-) PAI was completely ineffective in this respect. xyto results in vivo confirm previous biochemical findings that (+) PAI is a potent inhibitor of KAO-B in the brain, while (-) is ineffective in this respect. Example 26

Effect of R (+) PAI on improving or restoring memory

The newly born rat pups were subjected to the described anoxia puff and then allowed to continue to develop in the normal manner, with long-term memory disorders developing (Speiser et al., Behav.Brain.Res 30: 89-94.1988). memory is expressed as a deterioration of the progressive obstruction test.

The effect of R (+) PAI and S (-) PAI on memory improvement or recovery was assessed by a passive obstruction test. If the drug is effective, it increases the latent response to entry into the dark space or space where the test cages can, as before, get an electric shock. The maximum response latency is 300 seconds.

Experimental Protocol:

Young rats were subjected to post-natal anoxia as described in Example 27. R (+) PAI or S (-) PAI were administered according to one of the following protocols:

Protocol A - Breastfeeding mothers were given either a single or a second isomer of 1.5 to 1.5 mg / kg / day in drinking water until weaning after 21 days. Cancer was weaned post-dosed with the same dose for 20 days. The treatment was terminated 40 days and the test was performed 60 days, ie 20 days after the last dose of drug. -39-

Protocol B - The dose administered to nursing mothers was reduced by 0.5 mg / kg / day until weaning day 21 and then directly administered to rat rats up to day 60 when the Passive Obstruction Test was performed.

The apparatus contains a light chamber with a dark chamber attached and a sliding door separating these training chambers, the rats being placed in the illuminated chamber for 30 seconds, and then opened the door. The rats then moved to a dark chamber with a delay that was recorded. After the rats entered the dark space, the door was closed and the rats received a paw shock for 3 sec 0.3 m.

Retention (memory) at 48 hours was determined by retesting the assay and recording the transition delay from light to dark chamber to a maximum response of 300 s. Results: The results of these experiments are shown in Table 6. -40

Table 6

Effect of PAI isomers on passive response to overcoming obstacles in dim rats (60 days old)

Protocol A

Electroshock treatment group After electroshock control - 49 + 13 201 + 111 control (+) PAI 49 + 19 220 + 100 (+ 9%) X control (-) PAI 48 + 13 192 + 116 induced anoxia - 45 + 11 183+ 109 induced anoxia (+) PAI 49 + 1 0 239 + 99 (+ 19%) x induced anoxia (-) PAI 55 + 27 179 + 123 Protocol B Treatment group before electroshock electroshock control - 53 + 20 104 + 101 control ( +) PAI 48 + 11 128 + 119 (+ 23%) induced anoxia - 45 + 8 1 19 + 105 induced anoxia (+) PAI 52 + 12 137 + 126 (+ 15%) induced anoxia (-) PAI 48 + 1 Figures represent delays in seconds before entering a dark chamber where test rats have already experienced first electroshock. x The indicated percentages of increase are based on the rat anoxia group or control group.

Experimental results show that (+) PAI not (-) PAI is effective for improving the memory of rats with anoxia and control rats. Drugs in this active assay can be considered effective for the treatment of various memory disorders, dementia and especially senile dementia of the Alzheimer's type. Example 27

Effect of R (+) PAI on Anoxia-Induced Hyperactive Syndrome of Rat

The rats were exposed to postnatal anoxia and then left to develop under normal conditions, which showed increased motor activity in the open space at 10 to 42 days (Hertshkowitz et al., Dev.Brain Res. 7: 145-155 (1983)).

The effect of R (+) PAI and R (-) PAI on this overactive syndrome was observed.

Experimental Protocol:

Yesxia was induced in rat pups on the first postnatal day. They were placed in a glass chamber and treated with 100% nitrogen for 25 minutes. Then the rats were resuscitated by occasional massage gently applied to the chest and then returned to the respective mothers. Control rats were treated in the same manner using air instead of nitrogen.

Breastfeeding mothers were given R (+) PAI or S (-) PAI (0.5mg / kg / day) in drinking water to transfer to milked pups.

Locomotion was measured in six fully computerized cages (28 x 28 cm) by recording the number of transitions for a given period. The interruption of the infrared grid in 4cmintervales initiates electrical impulses transmitted to the counter. Motor activity records were made at 15 and 20 days for 15 minutes. Results:

Experimental results are shown in Table 7. -43-

Table 7

The effect of individual isomers on anoxia induced by hyperactive syndrome

Rat treatment group 1 5 days old rats old 2 0 days control - 414+ 92 (11) 808 + 212 (12) control (+) PAI 254 + 149 (1 1) c 719 + 110 (13) induced anoxia - 482 +119 (7) 858+ 96 (9) anoxia induced (+) PAI 276 + 186 (15) and 737 + 150 (16), induced by anoxia (-) PAI 334 + 196 (5) 778 + 232 (6) Numbers the numbers represent the number of infrared rays interrupted in the key to measure activity over a period of 15 minutes, and P < 0.001 compared to an untreated anoxia group P < 0.05 compared to an untreated anoxic group P < 0.05 compared to the control group.

These results indicate that chronic oral treatment with R (+) PAI at a dose of 0.5 mg / kg administered to nursing mothers and lactating and breastfed chicks significantly improves hyperactive syndrome. This implies that R (+) PAI is a potent drug for the treatment of overactive syndrome in children.

Claims (19)

-44- PATENT REQUIREMENTS S.- 1. R (+) - N-Phropargyl-1-aminoindan of Formula I (I) or a pharmaceutically acceptable acid addition salt thereof. 2. - Use R (+) - N-propargyl-1-aminoindan for the treatment of people suffering from Farkinson's disease, memory disorders, dementia-type dementia (DAT) depression and hyperactive syndrome. 3. using R (+) - N-propargyl-1-aminoindan for the manufacture of pharmaceuticals for the treatment of people suffering from Farkinon's disease, memory disorders, Alzheimer's disease (DAT), depression and overactive syndrome. -45- 4. A pharmaceutical composition for the treatment of people suffering from Parkinson's disease, memory disorders, Alzheimer's type dementia (DAT), depression and overactive syndrome in children, comprising R (+) - N-propargyl-1-aminoindan as active ingredient referred to in point 1. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in a form suitable for oral administration. 6. A pharmaceutical composition according to claim 4, which is in the form of an injectable solution or emulsion. 7. The pharmaceutical preparation of claim 4, wherein the pharmaceutical composition is in the form of a suppository for rectal administration. 8. The pharmaceutical preparation of claim 4, wherein the pharmaceutical composition is in a form suitable for transdermal administration. 9. A pharmaceutical preparation according to claim 5 or 7, wherein the dosage unit comprises 2 to 20 mg active ingredients. 10. A pharmaceutical composition according to claim 9 comprising 5 to 10 mg of active ingredient per dosage unit. -46- 11. The pharmaceutical preparation of claim 6, wherein the dosage unit form contains from 1 to 10 mg / ml of active ingredient. 12. The pharmaceutical preparation of claim 11, comprising 2-5 mg / ml of active ingredient per dosage unit. 13. A pharmaceutical composition for oral administration in the form of tablets or capsules comprising R (+) - N-propargyl-1-aminoindan, Levadop and a descarboxylase inhibitor. 14. A composition according to claim 13, comprising P (+) - N-propargyl-1-aminoindan, 50 to 250 mg of Leetopa and 10 to 25 mg of L-Carbidopa. 15. A formulation as claimed in claim 13, comprising 2 to 10 mg of R (+) - N-propargyl-1-aminoindan, 50 to 200 mg of Levadopa and 12.5 to 50 mg of henserazide. · A process for the preparation of R (+) - N-propargyl-1-aminoindan and its acid addition salts, characterized in that 1-aminoindan is reacted with propargyl bromide or propar-47-yl chloride in the presence of an organic or inorganic base in the presence of and isolating the R (+) - enantiomer of N-propargyl-1-aminoindan by chromatography, distillation, selective extraction and, if desired, converting the free base thus prepared into its acid addition salts. A process for the preparation of R (+ N-propargyl-1-aminoindan and its acid addition salts, characterized in that f r racemic 1-aminoindan is reacted with propargyl bromide or propargyl chloride in the presence of an organic or organic base optionally in the presence of a suitable and the R (+) - enantiomer of N-propargyl-1-amino-indan is isolated by chromatography, distillation, selective extraction and, if desired, the resulting free base of the acid addition salt is converted. 18. A process according to claim 17, comprising reacting the free base with an optically active acid to form two diastereomeric salts, separating the desired salt of R (+) - N-propargyl-1-aminoindan by known methods, and desired, the free base is regenerated. -48- 19. The process of claim 18 wherein the separation of the R (+) - N-propargyl-1-aminoindan salt is accomplished by fractional crystallization. Represents: MP — 1620-90-Ce *