The subject matter of the invention

The invention relates to various new salts of rasagiline, anhydrous forms, hydrates and solvates thereof, a process for the preparation of said compounds, pharmaceutical compositions containing the same and the therapeutical use of said compounds.

More particularly the invention relates to new uniform crystal forms of salts of rasagiline formed with hydroxy acetic acid, (5)-mandelic acid, saccharine, 2-hydroxy-benzoic acid, naphthalene-l,5-disulfonic acid, ( 1 £)-(+)- 10-camphorsulfonic acid (referred to further on as (S)- camphor-sulfonic acid), (7i?)-10-camphor-sulfonic acid (referred to further on as (i^-carnphor-sulfonic acid), (Z ⁾ -malic acid and (J)-malic acid, a process for the preparation thereof, pharmaceutical compositions containing the same and the therapeutical use of said compounds.

State of the art

It is known that (7i?)-N-prop-2-in-l-yl-2,3-dihydro-lH-inden-l-amine of the Formula X having the INN rasagiline, acts on the central nervous system by MAO-B inhibitory mechanism and can be preferably used in the therapy of Parkinson's disease. The pharmaceutical composition contains the mes late salt of rasagiline of the Formula XI.

The racemic form of the active in redient of the Formula XII

and the preparation thereof was first described in BE 633 762 together with several other propargylamino benzocycloalkanes of similar type. Said Belgian patent discloses this family of molecules as MAO inhibitors having reserpine activity increasing effect; the compounds may be suitable for the treatment of exhaustion and depression. The racemic compound is discussed together with other analogues in NL 6408887: the effect of said molecules is tested in the antidepressant, psychostimulant and cardiovascular field.

Rasagiline of the Formula X is the ©-optical antipode of N- propargylaminoindane and was first described in EP 0436492. Said compound was prepared by reacting racemic amino-indane or (R)- aminoindane with propargyl chloride or propargyl bromide and purifying the product by chromatography (if racemic starting material was used, by chiral chromatography) or resolution. From the rasagiline salts only the hydrochloric acid salt is described in said EP which is characterized by 1H NMR spectrum, melting, point and specific optical rotation.

According to EP 0812190 Bl the racemic base of the Formula XII is subjected to resolution with L-tartaric acid and the corresponding hemi-L-tartarate diastereomeric salt is obtained by recrystallization from a 1 : 1 mixture of methanol and isopropyl alcohol. The product is heated to reflux with methanesulfonic acid to yield the rasagiline methanesulfonate salt of the Formula XI. The hemi-L-tartarate and mesylate salts are characterized by melting point and optical rotation. In the EP several further salts are mentioned, namely the maleate, sulfate, chloride, tosylate, fumarate, phosphate, esylate and acetate. These salts are characterized by physico-chemical data (pH, melting point, solubility). The comparative experiments of Example 31 of said patent show that rasagiline sulfate, esylate and mesylate possess significantly better stability and solubility properties than the other salts.

In international patent application WO 2008019871 salts of rasagiline formed with several dibasic aliphatic acids are claimed in which the two acidic functions may be - independently from each other - a carboxylic (-COOH) or sulfonic acid (S0 ₃ H) group. Said salts are characterized by a general Formula. Dependent claims of the international patent application protect specifically the oxalate and edisylate salts of rasagiline which are characterized by physico- chemical parameters as well. According the Example 7 of the WO the stability data of the hydrochloride, tartarate and phosphate salts are inferior to those of the sulfonate type salts, i.e. the mesylate and edisylate salts.

In WO 2008076315 the preparation of several rasagiline containing tannate salts is described and the products are characterized by Karl Fischer, TGA, IR, XRPD and DSC analysis. All the described salts are of an amorphous structure.

In WO 2008076348 a crystalline modification of the rasagiline base is described and characterized by IR spectrum and melting point.

WO 2009118657 relates to the Form I modification of rasagiline mesylate which is characterized by IR and X-ray powder diffractogram.

In US patent application 20100010098 Al new polymorphic forms of rasagiline hydrochloride are disclosed. According to the US patent application Form II is thermodinamically the most stable polymorph while the other two modifications - namely those of the Formulae I and III - show a lower stability. The polymorphs are characterized by X-ray powder diffractograms.

WO 2010013048 claims the crystalline modification of rasagiline mesylate and the preparation thereof. According to the X-ray powder diffractogram the morphology of the product is identical with the product described in WO 2009118657. US 7572834 protects compositions containing rasagiline mesylate active ingredient with a content of 0.7-30 ppm of the impurity of the Formula XIII.

In the patent attention is drawn to the disadvantage of the hydrochloric acid salt of rasagiline. Namely in the addition reaction between rasagiline base and hydrochloric acid vinyl chloride type compounds of the Formulae XIII and XIV

are formed which accumulate during storage.

WO 2009147430 Al, WO 2009147432 Al and WO 2010059913 also belong to the state of the art. Although in these international patent applications acids which can be used for the preparation of rasagiline salts are mentioned in form of an enumeration, the preparation of the salts according to the present invention is described neither in the body of the application nor in the _^ working examples. The physico- chemical properties of the invention salts are not disclosed either.

The object of the invention

Recently serious demands have emerged in pharmaceutical industry for the reproducible manufacture of pure and morphologically uniform products. This is a basic condition to fulfil the requirements of pharmaceutical formulation. It is namely well-known that various salts and polymorphs differ from each other in such essential properties as dissolution rate, bioavailability, chemical stability, filterability, dryability, solubility and tabletting properties.

From the point of view of the economy of the manufacturing process it is of utmost importance that morphologically uniform active ingredients free of impurities should be prepared by a process feasible on industrial scale in a reproducible manner.

From the rasagiline salts disclosed in prior art the sulfonic acid type salts possess the most favourable stability properties. From prior art there are no known non-sulfonic acid salts which would have such a high stability as the sulfonic acid salts.

The general disadvantage of mesylate salts is that, due to the alkyl mesylates which might get into the pharmaceutical compositions, the individual steps of the manufacturing process of the active ingredient must be carried out with greatest care. The use of alcohols - particularly ethanol - in the course of the manufacture of the active ingredient and the subsequent technological steps can cause the formation of extremely harmful alkyl mesylates (in case of ethanol ethyl mesylate). The latter compound is highly mutagenic and carcinogenic, said properties are known from prior art, e.g. from the following references: Thompson, L. H., Mutant Isolation. Meth. Enzymol. 1979, 58, 308-322; Alderson, T., Chemically Induced Delayed Germinal Mutation in Drosophila. Nature 1965, 207, 164- 167; Jenkins, J. B., The Induction of Mosaic and Complete Dumpy Mutants in Drosophila Melanogaster with Ethyl Methanesulfonate. Mutat. Res. 1967, 4, 90-92; Schalet, A. P., Interspecific Comparison of Ethyl Methanesulfonate-induced Mutation Rates in Relation to Genome Size. Mutat. Res. 1978, 49, 313-340.

Some medicines were already withdrawn from the market because of the presence of ethyl mesylate impurity which had entered into the active ingredient as a result of the unsuitable technological procedure. Consequently in January 2008 the European Medicines Agency sent an official warning to the pharmaceutical manufacturers and called their attention to the increased control relating to the mesylate, tosylate and besylate salts.

The object of the present invention is to provide new non-sulfonic acid rasagiline salts of high purity and uniform morphology which possess stability and physico-chemical properties meeting the requirements of pharmaceutical industry and can be readily manufactured on industrial scale too.

The above object is solved by the new rasagiline salts formed with hydroxyacetic acid (glycolic acid), (S -mandelic acid, saccharine, 2- hydroxy-benzoic acid (salicylic acid), (ZJ-malic acid, (Z) -malic acid, naphthalene- 1, 5 -disulfonic acid (2:1), (S -camphorsulfonic acid and ®-camphorsulfonic acid. Detailed description of the invention

The present invention is directed to

- the hydroxyacetic acid salt of rasagiline of the Formula I,

the (S -mandelic acid salt of rasagiline of the Formula II.

the saccharinate salt of rasagiline of the Formula III,

the 2-hydroxybenzoate salt of rasagiline of the Formula IV,

the (L) -malic acid salt of rasagiline of the Formula VIII,

the (Z¾)-malic acid salt of rasagiline of the Formula IX,

the naphthalene-l,5-disulfonate (2:1) salt of rasagiline Formula V,

rasagiline (SJ-cam horsulfonate salt of the Formula VI,

- the rasa iline ( -camphorsulfonate salt of the Formula VII.

The present invention also relates to a process for the preparation of the new rasagiline salts according to the present invention.

According to the process of the present invention the new salts are prepared by dissolving rasagiline base in a suitable solvent (preferably in a C C alkanol, particularly methanol, ethanol or isopropyl alcohol, whereupon 0.4-3.0 moles, preferably 0.5-1.0 mole of an acid are added per se or in solution, at a temperature between 0 °C and the reflux temperature of the solution. If the salt precipitates at the temperature of addition or on cooling, it is filtered, if desired purified by trituration or recrystallization and finally filtered, washed and dried. Should the salt not precipitate spontaneously, the solvent is evaporated in vacuo and the residue is crystallized by adding a suitable solvent or solvent mixture, if desired purified by trituration or recrystallization and finally filtered, washed and dried.

It has been surprisingly found that the new salts of the present invention are more stable than the salts known from prior art when stored under various conditions. Said very advantageous property of the new rasagiline salts of the present invention is very important from the point of view of the formulation and storage of the pharmaceutical compositions and also in the minimalization of the harmful effects exerted on human organism.

The above recognition is therefore surprising while according to prior art salts formed with mineral acids and carboxylic acids were considered to be less stable than the sulfonic acid type salts.

A further common advantage of the new non-sulfonic acid type salts of the present invention over the rasagiline mesylate salt contained in the Azilect® medicine of the originator is that in course of the manufacturing procedure no highly mutagenic carcinogenic alkyl (ethyl) mesylates are formed. According to US 200701 12217 rasagiline mesylate salt is prepared from rasagiline base by reacting it with an excess of methanesulfonic acid in isopropyl alcohol under heating at reflux temperature. Thus the presence of the isopropyl mesylate contamination in the active ingredient can be rendered to be probable. This is supported by the teaching of US7781616B2: the subject matter of this patent is the preparation of rasagiline mesylate completely free from isopropyl mesylate. The inventors of said patent also verified experimentally the presence of the genotoxic contamination.

According to a further aspect of the present invention there are provided pharmaceutical compositions comprising a therapeutically active amount of a rasagiline salt of the present invention and optionally therapeutically acceptable carriers.

According to a further aspect of the present invention there is provided the use of the new rasagiline salts of the invention as therapeutical active ingredient.

According to the present invention there is provided the use of the new rasagiline salts for the preparation of pharmaceutical compositions.

The pharmaceutical compositions according to the present invention are preferably suitable for oral or parenteral administration. Oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions. For parenteral administration preferably intravenous or intramuscular injections or infusions may be applied. The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents. As carrier e.g. magnesium carbonate, talc, sugar, lactose, pectine, dextrine, starch, gelatine, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, lower melting wax, PEG, cocoa butter etc. may be used.

In case of capsules the carrier may be the material of the capsule per se and no additional carrier may be required. Pouch and losenge also belong to oral compositions. Tablets, powders, capsules, pills, pouches and losenges are particularly suitable for the preparation of solid dosage forms.

Suppositories contain lower melting waxes (e.g. mixtures of fatty acid glycerides, PEG or cocoa butter) as carrier. The wax is melt and the active ingredient is homogenously distributed in the melt. Thereafter the melt homogenous mixture is poured into a mould of suitable form and size and allowed to solidify under cooling.

Tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and the mixture is pressed into tablets of suitable size and form.

Powders are prepared by admixing the finely powdered active ingredient with finely powdered carriers. Liquid compositions may be e.g. solutions, suspensions or emulsions whereby if desired sustained release pharmaceutical compositions can be prepared as well. Aqueous and propylene glycol solutions are advantageous. Liquid pharmaceutical compositions for parenteral administration can be preferably prepared in the form of aqueous polyethylene glycol solutions.

Aqueous solutions for oral administration are prepared by dissolving the active ingredient in water, and adding suitable colourants, flavouring agents, stabilizers and thickeners. Oral aqueous suspensions may be prepared by suspending the active ingredient in the presence of a viscous substance (e.g. natural or artificial resins, gums, methyl cellulose, sodium-carboxymethyl-cellulose or other known suspending agents) in water.

A further type of solid pharmaceutical compositions are ready-for-use preparations which are converted into liquid compositions before use and administered orally in this form. The liquid compositions may be solutions, suspensions or emulsions which may contain in addition to the active ingredient colourants, flavouring agents, preservatives, buffers, artificial or natural sweeteners, dispersing agents, thickeners etc.

The pharmaceutical compositions of the present invention can be prepared in the form of dosage units which contain the desired amount of the active ingredient. Said dosage units can be put on the market in packaged form which contains discrete amounts of the composition (e.g. packaged tablets, capsules, powders in vials or in ampoules). The term„dosage unit" relates to the capsules, tablets, pouches, losenges and the packages which contain the desired number of the dosage units. According to a further aspect of the invention there is provided a process for the preparation of pharmaceuticeutical compositions which comprises admixing a rasagiline salt of the Formulae I-IX or a mixture thereof with solid or liquid diluents and(or auxiliary agents and bringing the mixture to a galenic form.

The pharmaceutical compositions according to the present invention can be prepared by known methods of pharmaceutical industry.

The pharmaceutical compositions according to the present invention may also contain further pharmaceutical active ingredients which are compatible with the compounds of the general Formulae I-IX or mixtures thereof.

According to a further aspect of the present invention there is provided the use of the compounds of the general Formule I-IX as pharmaceutical active ingredients.

The present invention also relates to the use of any rasagiline salt of the Formulae I-IX for the preparation of pharmaceutical compositions useful in the treatment or prophylaxis of Parkinson disease, amnesia, mental disorders, depression, hyperactive syndrome, affective disease, neurodegenerative disease, neurotoxic injury, cerebral ischemie, traumatic head injury, traumatic vertebral injury, schizophrenia, attention defective disorder, sclerosis multiplex, withdrawal symptoms or the damage of the optic nerve. According to a further feature of the present invention there is provided the use of the new rasagiline salts of the Formulae I-IX for the treatment or prophylaxis of Parkinson disease, amnesia, mental disorders, depression, hyperactive syndrome, affective disease, neurodegenerative disease, neurotoxic injury, cerebral ischemie, traumatic head injury, traaumatic vertebral injury, scizophrenia, attention defective disorder, sclerosis multiplex, withdrawal symptoms or the damage of the optic nerve.

The advantage of the present invention is that the compounds of the Formulae I-IX are substances of uniform morphology. For this reason the new rasagiline salts of the present invention possess reproducible dissolution velocity, biological availability, chemical stability and processing (filtrability, drying, tabletting behaviour etc.) properties.

The compounds of the Formulae I-IX can be prepared by a process which is reproducible and readily feasible on industrial scale.

Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples which only serve as illustration of the invention.

Example 1

Preparation of the hydroxyacetic acid salt of rasagiline (rasagiline glycolate, compound of the Formula I)

500 mg (2.920 mmol) of rasagiline base are dissolved in 1.5 ml of methanol, whereupon 220 mg (2.920 mmol) of hydroxyacetic acid are added. The solution is stirred at room temperature for an hour. The solvent is removed in vacuo and the residue is crystallized from a mixture of isopropyl alcohol and diisopropyl ether. The crystals are filtered, washed with cold diisopropyl ether and air-dried at room temperature.

Yield: 452 mg (62 %), off-white crystals

Melting point: 78.0-79.5 °C

Elementary analysis for the Formula C ₁₄ Hj ₇ N0 ₃ (247.30):

Calculated [%] C: 68.00 H: 6.93 N: 5.66 O: 19.41 Found [%] C: 67.82 H: 6.86 N: 5.55

IR (KBr): 3333, 3276, 2916, 1630, 1550, 1460, 1400, 1314,

1082 cm ^"1 . '

1H-NMR (DMSO- , 400 MHz): δ 7.35 (m, 1H), 7.22 (m, 1H), 7.18 (m, 1H), 7.16 (m, 1H), 4.30 (m, 1H), 3.87 (m, 2H), 3.43 (s, 2H), 3.11 (m, 1H), 2.93 (m, 1H), 2.74 (m, 1H), 2.22 (m, 1H), 1.79 (m, 1H) ppm. HPLC purity: >99.8 %

[a] ²² D = +20,0 (c=l; EtOH)

The X-ray powder diffraction of the hydroxyacetic acid salt is shown on Figure 1 and the characteristic X-ray powder diffractogram data are summarized in Table 1. Table 1

Position of diffraction lines and relative intensities

The X-ray powder diffraction data were obtained for each salt according to the following measuring conditions:

Apparatus: Rigaku Corporation, Miniflex II.

Powder diffractometer

Radiation: CuKod (1=1.54059 A), CuKa2

(1=1.54439 A)

Accelerating voltage: 30 kV

Anode current: 15 mA

Initial speed: 1.5 °/minute

Step distance: 0.02 °

Measuring domain: 3.0-40.0 °2θ (continuous Θ-Θ, reflexion)

Sample holder: zero background, Si single

crystal

Rotation speed of sampl 1 rotation/sec

Type of detector: MiniFlex2

Soller: 2.5 ⁰

Orifices: 1.25° (divergence, scattered);

0.3 mm (receiving) Pre-treatment of sample: without powdering, at room

temperature

Reference std. : RSRP-43275 Si powder

Example 2

Preparation of the (iSVmandelic acid salt of rasagiline (rasagiline-(S)- mandelate of the Formula II)

500 mg (2.920 mmoles) of rasagiline base are dissolved in 3.3 ml of isopropanol whereupon a hot solution of 444 mg (2.918 mmoles) of (S)-mandelic acid and 3.4 ml of isopropanol is added. The warm solution is cooled to room temperature under stirring, whereby intensive crystal formation begins. The suspension is cooled with icecold water, the precipitated crystals are filtered.

Yield 800 mg (85 %), white crystals

Melting point: 111.5-112.5 °C

Elementary analysis for the Formula: C ₂ oH ₂₁ N0 ₃ (323.40):

Calculated [%] C: 74.28 H: 6.55 N: 4.33 0: 14.84 Found [%] C: 74.09 H: 6.44 N: 4.27

IR (KBr): 3406, 3233, 2129, 1639, 1560, 1454, 1344, 1189, 1088, 1063 cm ^"1 .

1H-NMR (DMSO-i¾, 400 MHz) δ 7.41 (d, 2H), 7.35 (d, 1H), 7.33 (t, 2H), 7.26 (t, 1H), 7.23 (d, 1H), 7.19 (t, 1H), 7.16 (t, 1H), 4.95 (s, 1H), 4.31 (t, 1H, J = 6.4 Hz), 3.44 (d, 2H, J = 2.4 Hz), 3.13 (t, 1H, J = 2.4 Hz), 2.95 (m, 1H), 2.75 (m, 1H), 2.29 (m, 1H), 1.81 (m, 1H) ppm. HPLC purity: >99.8%

[a] ²² _D = +66.8 (c-l; EtOH) The X-ray powder diffractogram of the (S)-mandelic acid salt is shown on Figure 2 and the characteristic X-ray powder diffractogram data are summarized in Table 2.

Table 2

Position of diffraction lines and relative intensities

Example 3

Preparation of the saccharine salt of rasagiline (rasagiline saccharinate, compound of the Formula IIP

500 mg (2.920 mmoles) of rasagiline base are dissolved in 6.0 ml of isopropyl alcohol whereupon 534 mg (2.915 mmoles) of saccharine are added. The solution is allowed to stand overnight at room temperature. The solvent is evaporated in vacuo, the residue is treated with a mixture of diisopropyl acetate and diisopropyl ether and the precipitated solid substance is filtered. Thus 826 mg of the title compound are obtained which is dissolved in 4.0 ml of hot isopropanol, to the solution 5.0 ml of diisopropyl ether are added and the product is crystallized by slow cooling of the solution. The suspension is cooled with icecold water, the precipitated crystals are filtered off and finally washed with cold diisopropyl ether. Yield 653 mg (63 %), off-white crystals.

Melting point: 107.0-108..5 °C

Elementary analysis for the Formula: C19H18N2O3S (354.43) :

Calculated [%] C: 64.39 H: 5.12 N: 7.90 S: 9.05 O: 13.54 Found [%] C: 64.34 H: 5.08 N: 7.98 S: 9.13

IR (KBr): 3289, 2953, 2830, 2731, 1622, 1583, 1455, 1271, 1152, 1118 cm ^"1 .

1H-NMR (DMSO-t , 400 MHz) δ 7.66 (m, 1H), 7.60 (m, 4H), 7.38 (m, 1H), 7.37 (m, 1H), 7.31 (t, 1H), 4.81 (dd, 1H, J = 7.3, 4.2 Hz), 4.00 (m, 2H), 3.75 (m, 1H), 3.10 (m, 1H), 2.89 (m, 1H), 2.43 (m, 1H), 2.19 (m, lH) ppm.

HPLC purity: >99.8%

[a] ²² _D =+13.5 (c=l; EtOH)

The X-ray powder diffractogram of the saccharine salt is shown on Figure 3 and the X-ray powder diffractogram data are summarized in Table 3.

Table 3

Position of diffraction lines and relative intensities

Example 4

Process for the preparation of the 2-hydroxybenzoate salt of rasagiline Crasagiline salicylate, compound of the Formula IV)

500 mg (2.920 mmoles) of rasagiline base are dissolved in 3.8 ml of isopropyl alcohol at room temperature, whereupon a hot solution of 403 mg (2.918 mmoles) of 2-hydroxy-benzoic acid and 1.4 ml of isopropyl alcohol is added. The solution is mixed, cooled, whereupon the precipitated crystals are filtered, washed with cold alcohol and dried on the air.

Yield: 596 mg (66 %), off-white crystals.

Melting point: 120.5-121.5 °C

Elementary analysis for the Formula: C^H^NC^ (309.37):

Calculated [%] C: 73.77 H: 6.19 N: 4.53 0: 15.51 Found [%] C: 73.47 H: 6.24 N: 4.45

IR (KBr): 3274, 3001, 2828, 2592, 2368, 1629, 1589, 1485, 1465, 1390, 1332 cm ^"1

Ή-NMR (DMSO-d ₆ , 400 MHz) δ 7.72 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (d, 1H, J = 7.4 Hz), 7.32 (m, 2H), 7.26 (m, 2H), 6.74 (d, 1H, J = 7.4 Hz), 6.71 (t, 1H, J = 8.8 Hz), 4.71 (dd, 1H, J = 7.4, 4.8 Hz), 3.85 (m, 2H), 3.54 (t, 1H, J = 2.4 Hz), 3.06 (m, 1H), 2.86 (m, 1H), 2.40 (m, lH), 2.15 (m, lH) ppm. HPLC purity: >99.8%

[a] ²² D = +16.4 (c=l ; EtOH)

The X-ray powder diffractogram of the hydroxybenzoate salt is shown on Figure 4 and the characteristic X-ray powder diffractogram data are summarized in Table 4.

Table 4

Position of diffraction lines and relative intensities

Example 5

Preparation of the naphthalene 1,5-disulfonic acid (2: 1) salt of rasagiline (rasagiline napadisylate, compound of the Formula V)

500 mg (2.920 mmoles) of rasagiline base are dissolved in 3.0 ml of isopropyl alcohol at room temperature whereupon a solution of 1053 mg (2.922 mmoles) of naphthalene-l,5-disulfonic acid-tetrahydrate in 4.0 ml of isopropyl alcohol is added. The solution is mixed and cooled in an icecold water-bath. The precipitated crystals are filtered, washed with cold isopropyl alcohol and air-dried.

Yield: 790 mg (86 %), white crystals Melting point: 204-220 °C

Elementary analysis for the Formula: C ₃₄ H ₃₄ N ₂ 0 ₆ S ₂ (630.79):

Calculated [%] C: 64.74 H: 5.43 N: 4.44 S: 10.17 0: 15.22 Found [%] C: 64.30 H: 5.62 N: 4.37 S: 10.36

IR (KBr): 3245, 2985, 2816, 1596, 1454, 1219, 1150, 1027 cm ^"1 . 1H-NMR (DMSO-i/ ₆ , 400 MHz) δ 8.87 (d, 2H, J = 8.7 Hz), 7.93 (dd, 2H, J = 7.1, 1.0 Hz), 7.59 (d, 2H, J = 7.6 Hz), 7.40 (dd, 2H, J = 8.5, 7.2 Hz), 7.38 (m, 2H), 7.37 (m, 2H), 7.31 (t, 2H), 4.81 (m, 2H), 4.00 (m, 4H), 3.77 (t, 2H, J = 2.5 Hz), 3.09 (m, 2H), 2.88 (m, 2H), 2.43 (m, 2H), 2.18 (m, 2H) ppm.

HPLC purity: >99.8%

[ ] ²² _D = +15.0 (c=l ; EtOH)

The X-ray powder diffractogram of the naphthalene- 1, 5 -disulfonate salt is shown on Figure 5 and the characteristic X-ray powder diffractogram data are summarized in Table 5.

Table 5

Position of diffraction lines and relative intensities

Example 6

Preparation of the (£)-(+)- 10-camphorsulfonic acid salt of rasagiline

(rasagiline (S)-camsylate, compound of the Formula VI) 500 mg (2.920 mmoles) of rasagiline base and 677 mg (2.915 mmoles) of (1 £)-(+)- 10-camphorsulfonic acid are dissolved in 1.0 ml of methanol at room temperature. The solution is stirred for an hour, then evaporated in vacuo and the residue is treated with diisopropyl ether. The solid product is filtered and washed with diisopropyl ether. Thus 1.094 g of a light yellow beige crude salt is obtained which is crystallized from 4.5 ml of hot isopropyl alcohol. The suspension thus obtained is cooled in an icecold water-bath. The precipitated crystals are filtered and finally washed with cold diisopropyl ether.

Yield: 932 mg (79 %), off-white crystals

Melting point: 168.5-170.0 °C

Elementary analysis for the Formula: C ₂₂ H29N04S (403..54):

Calculated [%] C: 65.48 H: 7.24 N: 3.47 S: 7.95 0: 15.86 Found [%] C: 65.33 H: 7.06 N: 3.36 S: 8.17

IR (KBr): 3455, 3302, 2959, 2656, 1736, 1479, 1220, 1169,

1038 cm ^"1 .

1H-NMR (DMS0-< 400 MHz) δ 9.46 (s, 2H), 7.61 (d, 1H, J = 7.5 Hz), 7.38 (m, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 4.82 (dd, 1H, J - 7.7, 4.3 Hz), 4.02 (dd, 1H, J = 17.0, 2.5 Hz), 3.98 (dd, 1H, J - 17.0, 2.5 Hz), 3.76 (t, 1H, J = 2.5 Hz), 3.1 1 (m, 1H), 2.90 (m, 1H), 2.89 (d, 1H, J = 14.8 Hz), 2.68 (m, 1H), 2.44 (m, 1H), 2.39 (d, 1H, J = 14.8 Hz), 2.23 (m, 1H), 2.21 (m, 1H), 1.94 (t, 1H, J = 4.5 Hz), 1.86 (m, 1H), 1.79 (d, 1H, J = 18.5 Hz), 1.29 (m, 1H), 1.27 (m, 1H), 1.05 (s, 3H), 0.74 (s, 3H) ppm.

HPLC purity: >99.8%

[a] ²² _D =+36.7 (c=l; EtOH) The X-ray powder diffractogram of the camphorsulfonate salt is shown on Figure 6 and the characteristic X-ray powder difractogram data are summarized in Table 6.

Table 6

Position of diffraction lines and relative intensities

Example 7

Preparation of the (7i?V(-)-10-camphorsulfonic acid salt of rasagiline (rasagiline ( ?>camsylate of the Formula VII)

500 mg (2.920 mmoles) of rasagiline base and 677 mg (2.915 mmoles) of (li?)-10-camphorsulfonic acid are dissolved in 1.0 ml of methanol. The solution is stirred for an hour, evaporated to dryness in vacuo and the residue is treated with diisopropyl ether. The solid product is filtered off and washed with diisopropyl ether. Thus 1.051 g of a beige coloured crude salt is obtained which is crystallized from a mixture of hot isopropyl-alkohol and diisopropyl ether. The suspension thus formed is cooled with an ice-water bath, the precipitated crystals are filtered and finally washed with cold diisopropyl ether.

Yield 219 mg (19 %), off-white crystals.

Mp,: 140-142°C.

Elementary analysis for the Formula: C ₂₂ H ₂ 9N0 ₄ S (403.54):

Calculated [%] C: 65.48 H: 7.24 N: 3.47 S: 7.95 O: 15.86 Found [%] C: 65.23 H: 7.00 N: 3.34 S: 8.14

IR (KBr): 3442, 3228, 2958, 2806, 1745, 1482, 1230, 1 167,

1041 cm ^"1 .

1H-NMR (DMSO-i¾, 400 MHz) δ 9.47 (s, 2H), 7.61 (d, 1H, J = 7.6

Hz), 7.38 (m, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 4.82 (dd, 1H, J = 7.7, 4.3 Hz), 4.02 (dd, 1H, J = 17.6, 2.6 Hz), 3.98 (dd, 1H, J = 17.6, 2.5 Hz), 3.76 (t, 1H, J = 2.5 Hz), 3.12 (m, 1H), 2.90 (m, 1H), 2.89 (d, 1H, J= 14.8 Hz), 2.67 (m, 1H), 2.44 (m, 1H), 2.39 (d, 1H, J = 14.8 Hz), 2.23 (m, 1H), 2.21 (m, 1H), 1.94 (t, 1H, J = 4.6 Hz), 1.85 (m, 1H), 1.79 (d, 1H, J = 18.1 Hz), 1.29 (m, 1H), 1.27 (m, 1H), 1.05 (s, 3H), 0.74 (s, 3H) ppm.

HPLC purity: >99.8 %

[a] ²² D = +l l,l (c=l; EtOH)

The X-ray powder diffractogram of the (J?)-camphorsulfonate salt is shown on Figure 7 and the characteristic X-ray powder diffractogram data are summarized in Table 7.

Table 7

Position of diffraction lines and relative intensities

Example 8

Preparation of the (X)-malic acid salt of rasagiline (rasagiline-(X)- malate, compound of the Formula VIII)

500 mg (2.920 mmoles) of rasagiline base and 391 mg (2.915 mmoles) of ( )-malic acid are dissolved in 1.0 ml of methanol. The solution is stirred for an hour, evaporated to dryness in vacuo and the residue is treated with a mixture of isopropyl-alcohol and diisopropyl ether. The solid substance is filtered off, washed with the above solvent mixture and dried on the air.

Yield: 706 mg (79 %), off-white crystals.

Melting point: 83-89 °C

Elementary analysis for the Formula: C ₁₆ H ₁₉ N0 ₅ (305,33):

Calculated [%] C: 62.94 H: 6.27 N: 4.59 0: 26.20 Found [%] C: 62.68 H: 6.23 N: 4.47

IR (KBr): 3357, 3232, 2953, 2819, 1695, 1563, 1462, 1282, 1167, 1085 cm ^"1 .

1H-NMR (DMSO-<¾, 400 MHz) δ 7.41 (d, 1H), 7.26 (m, 1H), 7.23

(m, 1H), 7.20 (m, 1H), 4.43 (m, 1H), 4.13 (t, 1H, J = 6.3 Hz), 3.58 (m, 2H), 3.28 (m, 1H), 2.98 (m, 1H), 2.78 (m, 1H), 2.57 (dd, 1H, J = 15.6, 6.5 Hz), 2.40 (dd, 1H, 15.6, 6.2 Hz), 2.32 (m, 1H), 1.91 (m, 1H) ppm.

HPLC purity: >99,8%

[a] ²² _D = +20,8 (c=l ; EtOH) The X-ray powder diffractogram of the (I)-malic acid salt is shown on Figure 8 and the X-ray powder diffractogram data are summarized in Table 8.

Table 8

Position of diffraction lines and relative intensities

Example 9

Preparation of the (D)-malic acid salt of rasagiline (rasagiline (£>)- malate, compound of the Formula IX)

500 mg (2.920 mmoles) of rasagiline base and 391.5 (2.920 mmoles) of (Z ⁾ )-malic acid are dissolved in 5.0 ml of hot isopropyl-alcohol. The warm solution is slowly cooled and thereafter placed in an icecold water bath. The precipitated crystals are filtered and washed with cold isopropyl-alcohol; The off-white crude salt thus obtained (830 mg) is recrystallized from 1 1 ml of hot isopropyl-alcohol, filtered in the cold, washed with cooled isopropyl-alcohol and finally dried on the air. Yield : 745 mg (84 %), white crystals.

Melting point: 126-129 °C

Elementary analysis for the Formula: Ci ₆ Hi ₉ N0 (305,33): CAlculated [%] C: 62.94 H: 6.27 N: 4.59 O: 26.20 Found [%] C: 62.62 H: 6.40 N: 4.47

IR (ICBr): 3222, 2965, 2588, 2454, 1708, 1631, 1561 , 1412, 1311, 1276, 1216, 1183, 1091 cm ^"1 .

1H-NMR (DMSO- ₆ , 400 MHz) δ 8.41 (bs, 4H), 7.41 (d, 1H, J = 7.1 Hz), 7.26 (t, 1H, J = 7.0 Hz), 7.23 (d, 1H, J = 7.2 Hz), 7.20 (t, 1H, J = 7.0 Hz), 4.44 (dd, 1H, J = 6.8, 5.8 Hz), 4.13 (t, 1H, J = 6.6 Hz), 3.58 (d, 2H, J = 2.5 Hz), 3.28 (t, 1H, J = 2.5 Hz), 2.98 (m, 1H), 2.80 (m, 1H), 2.57 (dd, lH, J = 15.6, 6.6 Hz), 2.39 (dd, 1H, J = 15.6, 6.5 Hz), 2.33 (m, 1H), 1.90 (m, 1H) ppm.

HPLC purity: >99.8%

[a] ²² D = +14,l (c=l; EtOH)

The X-ray powder diffractogram of the salt is shown on Figure 9 and the characteristic X-ray powder diffractogram data are summarized in Table 9.

Table 9

Position of diffraction lines and relative intensities