WO2012066366A1 - New salts suitable for the preparation of pharmaceutical compositions - Google Patents

New salts suitable for the preparation of pharmaceutical compositions Download PDF

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Publication number
WO2012066366A1
WO2012066366A1 PCT/HU2011/000108 HU2011000108W WO2012066366A1 WO 2012066366 A1 WO2012066366 A1 WO 2012066366A1 HU 2011000108 W HU2011000108 W HU 2011000108W WO 2012066366 A1 WO2012066366 A1 WO 2012066366A1
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Prior art keywords
rasagiline
salt
formula
salts
preparation
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PCT/HU2011/000108
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French (fr)
Inventor
Tamás Nagy
Imre KÖHEGYI
Gábor NÉMETH
Balázs VOLK
Lászlo SZÁZDI
György RUZSICS
Gyula LUKÁCS
József Barkóczy
Gabriella PÁKAINÉ VARGA
Zoltán VARGA
Zsuzsanna SZENT-KIRÁLLYI
Mónika MEZÖVÁRI
Original Assignee
Egis Győgyszergyár Nyilvánosan Működö Részvénytár-Saság
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Publication of WO2012066366A1 publication Critical patent/WO2012066366A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/19—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/06—Glycolic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C07C59/50—Mandelic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • 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.
  • 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.
  • the pharmaceutical composition contains the mes late salt of rasagiline of the Formula XI.
  • 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.
  • 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.
  • several further salts are mentioned, namely the maleate, sulfate, chloride, tosylate, fumarate, phosphate, esylate and acetate.
  • 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.
  • 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.
  • 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.
  • WO 2009147430 Al, WO 2009147432 Al and WO 2010059913 also belong to the state of the art.
  • 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.
  • mesylate salts 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.
  • 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 present invention is directed to
  • the present invention also relates to a process for the preparation of the new rasagiline salts according to 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.
  • a suitable solvent or solvent mixture if desired purified by trituration or recrystallization and finally filtered, washed and dried.
  • 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.
  • 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.
  • 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.
  • compositions comprising a therapeutically active amount of a rasagiline salt of the present invention and optionally therapeutically acceptable carriers.
  • 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.
  • 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.
  • 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.
  • 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 viscous substance e.g. natural or artificial resins, gums, methyl cellulose, sodium-carboxymethyl-cellulose or other known suspending agents
  • 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.
  • 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 corpdosage unit" relates to the capsules, tablets, pouches, losenges and the packages which contain the desired number of the dosage units.
  • a process for the preparation of pharmaceutical 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.
  • compositions according to the present invention can be prepared by known methods of pharmaceutical industry.
  • 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.
  • 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.
  • 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.
  • the X-ray powder diffraction data were obtained for each salt according to the following measuring conditions:
  • Orifices 1.25° (divergence, scattered);

Abstract

The invention relates to non-sulfonic acid type new rasagiline salts, a process for the preparation thereof, pharmaceutical compositions containing said salts and the use thereof for the treatment or prophylaxis of various diseases, namely Parkinson's disease, amnesia, mental disorders, depression, hyperactive syndrome, affective disease, neurodegenerative disease, neurotoxic injury, cerebral ischemy, traumatic head injury, traumatic vertebral injury, schizophrenia, attention defective disorder, multiple sclerosis, withdrawal symptoms or the damage of the optic nerve.

Description

New salts suitable for the preparation of pharmaceutical compositions
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
Figure imgf000002_0001
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.
Figure imgf000003_0001
The racemic form of the active in redient of the Formula XII
Figure imgf000003_0002
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 (S03H) 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.
Figure imgf000006_0001
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
Figure imgf000006_0002
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,
Figure imgf000009_0001
the (S -mandelic acid salt of rasagiline of the Formula II.
Figure imgf000009_0002
the saccharinate salt of rasagiline of the Formula III,
Figure imgf000009_0003
the 2-hydroxybenzoate salt of rasagiline of the Formula IV,
Figure imgf000009_0004
the (L) -malic acid salt of rasagiline of the Formula VIII,
Figure imgf000009_0005
the (Z¾)-malic acid salt of rasagiline of the Formula IX,
Figure imgf000010_0001
the naphthalene-l,5-disulfonate (2:1) salt of rasagiline Formula V,
Figure imgf000010_0002
rasagiline (SJ-cam horsulfonate salt of the Formula VI,
Figure imgf000010_0003
- the rasa iline ( -camphorsulfonate salt of the Formula VII.
Figure imgf000010_0004
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 C14Hj7N03 (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] 22D = +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
Figure imgf000018_0001
Figure imgf000019_0001
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: C2oH21N03 (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
Figure imgf000021_0001
Figure imgf000022_0001
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
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
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-d6, 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] 22D = +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
Figure imgf000026_0001
Figure imgf000027_0001
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: C34H34N206S2 (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
Figure imgf000028_0001
Figure imgf000029_0001
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: C22H29N04S (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
Figure imgf000031_0001
Figure imgf000032_0001
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: C22H29N04S (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] 22D = +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
Figure imgf000033_0001
Figure imgf000034_0001
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: C16H19N05 (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
Figure imgf000036_0001
Figure imgf000037_0001
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: Ci6Hi9N0 (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] 22D = +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
Figure imgf000038_0001
Figure imgf000039_0001

Claims

What we claim is,
1. Salts of rasagiline of uniform morphology formed with non- sulfonic acid type organic acids.
2. Rasagiline glycolate salt of the Formula I.
Figure imgf000040_0001
3. Rasagiline (<S)-mandelate salt of the Formula II.
Figure imgf000040_0002
Rasagiline saccharinate salt of the ormula III.
Figure imgf000040_0003
5. Rasagiline salic late salt of the Formula IV.
6. Rasagili
Figure imgf000040_0004
7. Rasagiline >)-malate salt of the Formula IX,
Figure imgf000041_0001
8. Rasagiline naphthalene- 1,5 -disulfonate (2:1) salt of the Formula V.
Figure imgf000041_0002
9. Rasagili -camphorsulfonate salt of the Formula VI.
Figure imgf000041_0003
10. Rasagiline i?)-camphorsulfonate salt of the Formula VII.
Figure imgf000041_0004
11. Process for the preparation of rasagiline salts according to any of Claims 1-10 which comprises dissolving rasagiline base in a suitable solvent - preferably a Ci-C6 alkanol, particularly methanol, ethanol or isopropyl alcohol -, thereafter adding a 0.4-3,0 molar, preferably 0.5-1.0 molar amount of the corresponding acid per se or in form of a solution at a temperature between 0 °C and the reflux temperature of the solution and
filtering the precipitated salt and if desired purifying the same, or
if necessary evaporating the solvent in vacuo and crystallizing the residue by adding a suitable solvent or solvent mixture, and if desired purifying the product.
12. Pharmaceutical composition comprising a therapeutically effective amount of a rasagiline salt according to any of Claims 1-10 if desired in admixture with pharmaceutically acceptable carriers.
13. Use of rasagiline salts according to any of Claims 1-10 as pharmaceutical active ingredient.
14. Use of rasagiline salts according to any of Claims 1-10 for the preparation of pharmaceutical compositions.
15. Use of a rasagiline salt according to any of Claims 1-10 for the preparation of pharmaceutical compositions useful in the treatment or prophylaxis of Parkinson's disease, amnesia, mental disorders, depression, hyperactive syndrome, affective disease, neurodegenerative disease, neurotoxic injury, cerebral ischemy, traumatic head injury, traumatic vertebral injury, schizophrenia, attention defective disorder, multiple sclerosis, withdrawal symptoms or the damage of the optic nerve.
16. Use of a rasagiline salt according to any of Claims 1-10 for the treatment or prophylaxis of Parkinson's disease, amnesia, mental disorders, depression, hyperactive syndrome, affective disease, neurodegenerative disease, neurotoxic injury, cerebral ischemy, traumatic head injury, traumatic vertebral injury, schizophrenia, attention defective disorder, multiple sclerosis, withdrawal symptoms or the damage of the optic nerve.
17. Method of treatment of the diseases and symptoms according to Claim 16 which comprises administering to the patient in need of such treatment a therapeutically active rasagiline salt according to any of Claims 1-10.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010085354A1 (en) * 2009-01-23 2010-07-29 Teva Pharmaceutical Industries Ltd. Delayed release rasagiline formulation
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WO2011064216A1 (en) * 2009-11-24 2011-06-03 Lek Pharmaceuticals D.D. Novel salts of rasagiline
WO2011080589A2 (en) * 2009-12-30 2011-07-07 Actavis Group Ptc Ehf Solid state forms of rasagiline salts
WO2011095985A2 (en) * 2010-02-02 2011-08-11 Glenmark Generics Limited Rasagiline salts and processes for the preparation thereof
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WO2010085354A1 (en) * 2009-01-23 2010-07-29 Teva Pharmaceutical Industries Ltd. Delayed release rasagiline formulation
WO2011003938A1 (en) * 2009-07-09 2011-01-13 Ratiopharm Gmbh Salts of rasagiline and pharmaceutical preparations thereof
WO2011064216A1 (en) * 2009-11-24 2011-06-03 Lek Pharmaceuticals D.D. Novel salts of rasagiline
WO2011080589A2 (en) * 2009-12-30 2011-07-07 Actavis Group Ptc Ehf Solid state forms of rasagiline salts
WO2011095985A2 (en) * 2010-02-02 2011-08-11 Glenmark Generics Limited Rasagiline salts and processes for the preparation thereof
WO2011121607A2 (en) * 2010-03-29 2011-10-06 Cadila Healthcare Limited Rasagiline and its pharmaceutically acceptable salts

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