EP1353670A2

EP1353670A2 - Use of chromanes

Info

Publication number: EP1353670A2
Application number: EP02729419A
Authority: EP
Inventors: Thomas Fahrig; Irene Gerlach; Ervin Horvath; Reinhard Jork; Frank Mauler
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2001-01-16
Filing date: 2002-01-03
Publication date: 2003-10-22
Also published as: UY27123A1; WO2002055078A3; US20020177616A1; CA2436811A1; BR0206475A; WO2002055078A2; CN1529596A; SV2003000843A; PL362869A1; DE10101917A1; MXPA03006333A; PE20020841A1; KR20040025885A; GT200200002A; AR032070A1; IL156839A0; JP2004520342A

Abstract

The invention relates to the use of 2-[4-({[(2R)-8-isopropoxy-chromane-2-yl]methyl}amino)butyl]-1,2-benzisothiazole-3(2H)-on 1.1 dioxide, the physiological compatible salts, hydrates and/or solvates thereof, particularly the hydrochloride thereof, for the production of a medicament for prophylaxis and/or for treating Parkinson's disease.

Description

Use of chromanes

The invention relates to the use of 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) -one 1,1 -dioxide, its physiologically acceptable salts, hydrates and / or solvates, in particular its hydrochloride, for the manufacture of a medicament for the prophylaxis and / or treatment of Parkinson's disease.

Parkinson's disease is a chronic, progressive disease of the central nervous system. It is caused by the degeneration of dopaminergic neurons in the substantia nigra, which produce and release the neurotransmitter dopamine. The resulting reduction in dopaminergic neurotransmission leads to massive dysfunctions of the extrapyramidal system of motion control. These disorders affect not only the basal ganglia but also other closely linked brain areas.

The aetiology of idiopathic Parkinsonism is still largely unknown. However, increasing evidence indicates that the cell death of dopaminergic neurons in the substantia nigra due to apoptosis is more mitochondrial

Malfunction occurs. In addition to possible genetic disorders, increased glutamate levels and / or a deficient supply of neurotrophic factors are discussed as the cause of the mitochondrial malfunction.

Proceeding from this, a progressive neuronal cell death should be prevented by a neuroprotective pharmacological influence on the neurodegenerative processes, whereby the progression of the disease could be stopped without necessarily interacting with the causal pathophysiological mechanisms. It has been shown that stimulation of neuronal 5-HTi _A receptors in various in vitro and in vivo systems has both neuroprotective and anti-apoptotic and neurotrophic effects. A stimulation of 5-HTIA receptors could therefore also prevent the further degeneration of dopaminergic neurons in Parkinson's disease and thus ultimately the progression of the

Delay disease.

Most of the clinically used therapeutics for Parkinson's disease follow a purely symptomatic approach. The aim of these therapies is either to directly replace the missing dopamine with a dopamine precursor molecule (L-DOPA), which is metabolized to dopamine in the body, or to stimulate deficient dopaminergic neurotransmission processes using agonists on dopamine receptors or by reducing dopamine breakdown (MAO inhibitors, COMT inhibitors). However, all current therapies are characterized by strong side effects (e.g. dyskinesias, psychoses, sleep disorders) or long-term

Loss of effectiveness marked.

Chroman derivatives and especially 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} - amino) butyl] -l, 2-benzisothiazol-3 (2H) -one 1.1 -dioxide hydrochloride and its agonistic effect on the 5-HTIA receptor are used as a treatment for

Central nervous system disorders known from EP-A-0 352 613 and EP-A-0 749 970.

WO 99/26621 describes chroman derivatives, in particular 2- [4 - ({[(2R) - chroman-2-yl] methyl} amino) butyl] -1, 2-benzisothiazol-3 (2H) -one 1, 1-dioxide hydrochloride (genetic name: repinotan hydrochloride), as a means of promoting neuroregeneration in neurological diseases such as Parkinson's disease.

Surprisingly, with 2- [4 - ({[(2R) -8-isoproρoxy-chroman-2-yi] - methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) -one 1,1- dioxide a 5-HT _1A - receptor Agonist found, who not only has a neuroprotective effect, but also has a symptomatic effect and thus has a positive effect on the course of Parkinson's disease in two ways.

The invention therefore relates to the use of 2- [4 - ({[(2R) -8-isopropoxychroman-2-yl] methyl} amino) butyl] -1, 2-benzisothiazol-3 (2H) -one 1 , 1-dioxide, its physiologically acceptable salts, hydrates and / or solvates, in particular 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -l, 2-benzisothiazole - 3 (2H) -one 1,1-dioxide hydrochloride, for the manufacture of a medicament for the prophylaxis and / or control of Parkinson's disease.

2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) -one 1,1-dioxide has the following structure:

Physiologically acceptable salts of the compounds used according to the invention can be salts of the compounds with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,

Toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, oxalic acid, citric acid, fumaric acid, maleic acid or benzoic acid.

For the purposes of the invention, hydrates are stoichiometric compositions of 2- [4-

({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) - one 1,1-dioxide or its salts with water. Solvates for the purposes of the invention are stoichiometric compositions of 2- [4- ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -1, 2-benzisothiazol-3 (2H) - one 1,1-dioxide or its salts with solvents.

The compounds used according to the invention can be prepared by the processes specified in EP-A-0 749 970. For example, 2- [4- ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -1,2-benzisothiazol-3 (2H) -one corresponds to 1,1-dioxide hydrochloride ( called Example 11 below) in EP-A-0 749 970, Example 7.

The salts of 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) -one 1,1-dioxide can are obtained by reacting the free base in a suitable solvent with stoichiometric or superstoichiometric amounts of the acid on which the salt is based in a temperature range from 0 ° C. to the boiling point of the solvent. Suitable solvents are, for example, water, aliphatic alcohols such as methanol, ethanol or 2-propanol, aliphatic open-chain or cyclic ethers such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran or aliphatic ketones such as 2-propanone, 2-butanone, and mixtures thereof , The salts are obtained directly from this mixture, if appropriate after partial or complete removal of the solvent by distillation, as a solid; they can be purified by recrystallization or reprecipitation in, for example, the solvents listed above or their mixtures.

The active substance can act systemically and / or locally. For this purpose it can be applied in a suitable way, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant. The application is preferably oral.

The active ingredient can be administered in suitable administration forms for these administration routes. Known application forms which release the active ingredient quickly and / or modified, such as tablets (non-coated and coated tablets, for example enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions are suitable for oral administration.

Parenteral administration can be done by bypassing an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). Application forms suitable for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, e.g. Inhaled drug forms (e.g. powder inhalers, nebulizers), nasal dropper solutions, sprays; tablets or capsules, suppositories, ear and lingual tablets to be administered lingually, sublingually or buccally

Eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g.

Antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) or taste and / or smell corrections.

In general, it has proven to be advantageous in the case of parenteral administration to use amounts of approximately 0.001 to 30 mg / kg, preferably approximately 0.01 to 10 mg / kg

Body weight to achieve effective results. With oral Application, the amount is about 0.01 to 100 mg / kg, preferably about 0.1 to 30 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out.

Determination of the agonistic effect on human recombinant 5-HTIA receptors

Signal transduction studies were carried out on human recombinant 5-HT- _A receptors using the guanosine 5'-O- (3- [S-35] thio) triphosphate (GTP gamma [S-35]) binding technique (modified according to Elliott and Reynolds Europ J. Pharmacol 1999, 386, 313-315 and Sim et al. J Neurosci 1996, 16, 8057-8066).

Repinotan hydrochloride and Example 11 achieved EC ₅₀ values of 0.51 nM and 0.19 nM in this test, that is, both substances are 5-HT _1A agonists, with Example 11 acting about twice as potent as Repinotan hydrochloride.

MPTP monkey model

The in vivo action of Repinotan hydrochloride and of Example 11 was tested in a monkey model for Parkinson's disease, the so-called chronic MPTP model (Bezard et al. Brain Res. 1997, 766, 107-112.). MPTP (= 1-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine) is a neurotoxin that causes the degeneration of dopaminergic neurons in the substantia nigra typical of Parkinson's disease in humans and animals. In addition, MPTP produces the motor symptoms typical of Parkinson's disease in humans and monkeys. These symptoms are rated on a Parkinsonian scale for monkeys. For the experiments, rhesus monkeys (Macaca fascicularis) were treated daily with MPTP (0.2 mg / kg iv) until they reached a score of 8 on the Parkinson scale. The first Parkinson's symptoms appear after 5-10 days of MPTP treatment. Due to the long-term effects of the neurotoxin, the clinical symptoms of the animals develop to full Parkinsonism (score> 15). Five groups of animals were examined: the first received only MPTP, the second received MPTP plus repinotan hydrochloride (2mg / kg po bid), the third received Example 11 (lmg / kg po bid). Treatment with Repinotan Hydrochloride and Example 11 each started from the day the animals first showed clinical symptoms. Both repinotan hydrochloride and Example 11 were neuroprotective after oral administration, that is, both substances slowed the development of parkinsonism symptoms in this monkey model. However, it was completely surprising to find that Example 11 also reduced the severity of the symptoms, i.e. had a symptomatic effect (22% reduction compared to control). However, such a symptomatic effect was not observed with repinotan hydrochloride (see Table 1).

Table 1: Effect of repinotan hydrochloride and compound 1 in the MPTP monkey model

!) 0 = no slowdown in the development of Parkinsonism + = statistically significant delay in reaching Score 8 Preparation Examples

example 1

2-Hydroxy-3-methoxy-benzonitrile

A suspension of 6375 g (41.94 mol) of o-vanillin, 3823 g (55 mol) of hydroxylamine hydrochloride and 6375 g (93.75 mol) of sodium formate in 14 l of formic acid was heated to about 90 to 95 ° C. with stirring , In this temperature range increased gas development and exothermic reaction started (heating was switched off). The exothermic reaction lasted for about 10 to 15 minutes (temperature rise to about 115 ° C.). The mixture was then stirred under reflux for 45 minutes. After the reaction had ended, the mixture was cooled to about + 6 ° C. and converted into a mixture

6 kg of ice and 25 1 of water are stirred in. After 1 h, the product was filtered off with suction and washed with about 12 l of water. The mixture was then dried for 24 hours at room temperature in a fresh air drying cabinet and for 120 hours over P ₂ O ₅ in a vacuum drying cabinet (room temperature).

Yield: 4816 g (77%) crystals, mp 54 ° C, R _f : 0.34 (toluene-ethyl acetate 3: 1) Example 2

2-hydroxy-3-methoxy-acetophenone

750 g (30.8 mol) of magnesium shavings and 3 g of iodine were placed in a dry reaction vessel flushed with nitrogen. 10 l of methoxybenzene were added and the mixture was heated to 40 ° C. with slow stirring. The stirring was stopped and 25 ml of methyl iodide and a starting mixture ¹ ) were added directly to the

Magnesium turnings. After the reaction had started, the stirrer was switched on again and a solution of 1916 ml (30.8 mol) of methyl iodide in 2.5 l of methoxybenzene was added with moderate cooling in such a way that a temperature of 40 to 43 ° C. could be maintained (1.5 h). The mixture was then stirred for 5 h at 40 ° C and 15 h at room temperature. The mixture was cooled to + 5 ° C., a solution of 1840 g (12.3 mol) of 2-hydroxy-3-methoxy-benzonitrile in 6.5 l of methoxybenzene was run in over the course of 1.5 h and the mixture was stirred at 40 for 1.5 h ° C after. After the reaction had ended (TLC control / toluene / ethyl acetate 3: 1), the reaction mixture was cooled to + 10 ° C. and stirred into a mixture of 24 kg of ice and 8 l of water. The mixture was then acidified by adding 12 l of 6N hydrochloric acid, the temperature not exceeding 0 to 5 ° C. The organic phase was separated and washed with 2.5 1 6N hydrochloric acid. The combined aqueous phases were extracted 3 times with 41 toluene each. Then the aqueous phase was stirred for 1.5 h at an internal temperature of 98 ° C. The heating was switched off and 6 kg of sodium chloride were added and the mixture was stirred at room temperature overnight. After cooling to + 5 ° C for a long time, a precipitate of ocher-colored crystals was obtained. This was suctioned off, washed with 4 l ice water (2x) and dried for 5 days (120 h) in a vacuum drying cabinet over P2O5 and NaOH cookies.

Yield: 1587 g (78%), mp. 53 ° C, R _f : 0.33 (Toluok ethyl acetate 9: 1)

the same reaction on a 1 mol scale served as the “starting point”

Example 3

8-methoxy-chromone-2-carboxylic acid ethyl ester

A largely dissolved mixture of 1140 g (6.86 mol) of 2-hydroxy-3-methoxy-acetophenone, 2 1 (at 50 ° C. was added to a cooled solution of 1024 g (15.04 mol) of sodium ethylate in 20 1 of ethanol. 14.86 mol) of diethyl oxalate and 7 l of ethanol rapidly. The mixture was heated to reflux for 3 h. It was cooled to 50 ° C, gave 2 1 conc.

Hydrochloric acid and heated to reflux for 30 min. The mixture was then cooled to 50 ° C., suction filtered, the filter residue washed with ethanol and the filtrate concentrated in a rotary evaporator.

The yellow crystalline residue was dissolved in 15 1 dichloromethane and 14 1

10% NaHCO 3 solution stirred well for 30 minutes. The organic phase was separated, washed with 2 1 10% NaHC03 solution and dried over a mixture of 2 kg Na ₂ S04 and 1 kg Tonsil. It was then suctioned off through diatomaceous earth, washed with dichloromethane and the filtrate was concentrated in a rotary evaporator. The residue was mixed in a rotary evaporator with 2.5 l of petroleum ether and 15 min. stirred at room temperature, cooled to + 5 ° C and suction filtered. The pale yellow crystals were dried for 2 hours in a fresh air drying cabinet and for 24 hours in a vacuum drying cabinet over P2O5.

Yield: 1304 g (76%) crystals, mp. 129-130 ° C, ref .: 0.53 (toluene-ethyl acetate = 85:15) Example 4

8-methoxy-chroman-2-carboxylic acid ethyl ester

A mixture of 5.30 kg (22.45 mol) of 8-methoxy-chromon-2-carboxylic acid ethyl ester in 100 1 of ethyl acetate and 50 1 of glacial acetic acid were in the presence of 500 g of 10% Pd / C for 24 h at 50 ° C under a Hydrogen pressure of 3 bar hydrogen. For working up, the reaction solution was suctioned off through kieselguhr and the filtrate was concentrated in a rotary evaporator. In order to remove azeotropic residues from glacial acetic acid, the contents of the flask were mixed twice with 6 l of toluene and concentrated. After drying the residue in a steam jet vacuum (8 h / 8 mm), the product was obtained as a dark oil.

Yield: 5.002 kg (94%) oil, b.p. 110-114 ° C / 0.04 mm, R _f : 0.42 (toluene: ethyl acetate 3: 1)

Example 5

(R) -2-Hydroxymethyl-8-methoxy-chroman

To 540 g of 65% RedAl in toluene, 235 g of (R) -8-methoxy-chroman-2-carboxylic acid ethyl ester (obtained according to the process given in DE-A 4430089 from (R, S) -8-methoxy-chroman- 2-carboxylic acid ethyl ester) slowly added dropwise in toluene; a total of 1.5 l of toluene was used. After stirring at room temperature for 18 h, the mixture was first heated to 50 ° C. for 1 h and then to 80 ° C. for a further hour. After cooling to room temperature, 100 g of ice was added with external cooling, followed by 600 ml of 15% potassium sodium tartrate solution. The mixture was diluted with 500 ml of toluene and 500 ml of ethyl acetate. The organic phase was separated off, dried over magnesium sulfate and clarified by adding Tonsil. After concentrating to a volume of approximately 500 ml, 1 liter of cyclohexane was added and the mixture was stirred at room temperature for 30 min. The precipitated solid was filtered off, washed and dried. This gave 135.5 g of the target compound.

Mp 77-78 ° C

Example 6

(R) -8-hydroxy-2-hydroxymethylchroman

135.5 g (0.7 mol) of (-) - 2-hydroxymethyl-8-methoxychroman are heated in 0.7 1 48% aqueous HBr solution for 20 hours. After cooling and diluting with 1.2 l of ice water, the mixture is stirred for 30 minutes and the precipitate which has separated out is filtered off with suction. Washing with ice water and drying over Phosphoφentoxid provide 109.5 g (87%) of the title compound, mp. 131-132 ° C. α ²⁰ ₂₈₉ = -133.8 (c = 0.7 methanol)

Example 7

(R) -2-Hydroxymethyl-8-isopropoxy-chroman

4.5 g (25 mmol) of (R) -8-hydroxy-2-hydroxymethyl-chroman, 4.6 g (27 mmol) of 2-iodopropane and 5.2 g (37.5 mmol) of powdered potassium carbonate in 50 ml of dimethylformamide are heated to 60 ° C for 40 hours. After adding a further 0.9 g of iodopropane, the mixture is heated to 80 ° C. for 24 hours and then to 95 ° C. for a further 24 hours. After cool is partitioned between toluene / water and filtered through Celite ^® . The organic phase is dried (magnesium sulfate) and concentrated. After flash chromatography (silica gel; elution with toluene / ethyl acetate gradient 3: 1 - 2: 1), 7 g of crude product are obtained, which is purified by chromatography on silica gel (gradient toluene / ethyl acetate 1: 0 - 8: 1). Yield: 2.9 g (52%) oil. R _F (silica gel, toluene / ethyl acetate 1: 1): 0.4

W ²⁰ 289 = - ⁸⁵ t ^c = °>⁵; CHC1 ₃ ]

Example 8

(R) -8-isopropoxy-2-mesyloxymethyl-chroman

68 g (0.6 mol) of methanesulfonic acid chloride are added dropwise to 114 g (0.51 mol) of the compound from Example 7 in 95 g of pyridine at room temperature. After stirring at room temperature for 18 hours, the mixture is diluted with 700 ml of water and extracted with dichloromethane. Filtration through silica gel and concentration give 150 g of crude product, which is purified by crystallization from 1.5 1 cyclohexane / toluene mixture 3: 1. After concentration, the mother liquor is recrystallized from cyclohexane. This gives a total of 112 g of the title compound as a colorless solid, mp. 77-78 ° C. α ₂₈₉ ²⁰ = -56.2 [c = 0.9, CH ₃ OH] Example 9

(R) -2-benzylaminomethyl-8-isopropoxy-chroman

112 g (0.37 mol) of the compound from Example 8, 200 g (1.87 mol) of benzylamine and 3.0 g (0.02 mol) of sodium iodide are heated to 100 ° C. for 5 hours. After cooling, the solid is separated off and the organic phase is washed twice with 2.5 l of water each time. The remaining oil is taken up in 1 liter of ethyl acetate. Washing the Essigesteφhase with water and saturated saline, followed by drying and concentration give 114.5 g (quant.) Of the title compound (HPLC purity: 93%) as an oil, which is used in the next step. α ₂₈₉ ²⁰ = -104 [c = 0.5, CH ₃ OH]

Example 10

(R) -2- (N-benzyl-N- (4- (1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -2-butynyl) aminomethyl) -8- isopropoxy-chroman hydrochloride

114 g (0.37 mol) of the compound from Example 9 and 13.5 g (0.45 mol) of paraformaldehyde in 1 l of dioxane are mixed with 4 g of copper (II) acetate and heated to 50.degree. At this temperature 81 g (0.37 mol) of propargyl saccharin are added. After stirring at 80 ° C. for 2 hours, the mixture is concentrated and the residue is partitioned between toluene / water with the addition of tonsil. After filtration of the mixture through Celite ^®, the organic phase is separated and purified by flash chromatography on silica gel (toluene / Essigester 10: 1). Precipitation of the hydrochloride from ether with ethereal hydrochloric acid gives 226 g of crude product. After release of the free base with sodium hydrogen carbonate, this product is purified by chromatography on silica gel (elution with toluene / ethyl acetate 20: 1). The product fractions are treated with ethereal hydrochloric acid. This gives 139 g (65%) of the title compound as a solid, mp. 106-109 ° C. α ₂₈₉ ²⁰ = - 64.1 [c = 0.8, CH ₃ OH]

Example 11

2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -l, 2-benzisothiazole

3 (2H) -on 1,1-dioxide has the following structure:

120 g (0.21 mmol) of the compound from Example 10 in 1.4 1 of methanol are concentrated with 400 ml. Hydrochloric acid and 20 g of 10% palladium on activated carbon. After 4 hours of hydrogenation at normal pressure and 20 ° C., the catalyst is filtered off and concentrated. The residue is concentrated twice with toluene and dissolved in 400 ml of ethyl acetate. Addition of 800 ml of diethyl ether and stirring for 18 hours at room temperature yield 90.5 g of solid after suction and drying in vacuo. Recrystallization from 1 l of acetonitrile and washing the crystals with dieethyl ether give 70.8 g (69%) of the title compound as colorless crystals, mp. 153-154 ° C.

Elemental analysis: C ₂₄ H ₃₀ N ₂ O ₅ S x HCl calc .: C: 58.2 H: 6.3 N: 5.7 O: 16.2 CI: 7.2 S: 6.5 found: C: 58.0 H: 6.3 N: 5.7 O: 16.2 CI : 7.1 S: 6.3

Claims

claims

1. Use of 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) - butyl] -l, 2-benzisothiazol-3 (2H) -one 1,1- dioxide, its physiologically sensitive salts, hydrates and / or solvates for the manufacture of a medicament for the prophylaxis and / or treatment of Parkinson's disease.

2. Use according to claim 1, wherein the active ingredient 2- [4 - ({[(2R) -8- isopropoxy-chroman-2-yl] methyl} amino) butyl] -1, 2-benzisothiazol-3 (2H) - on 1,1 -dioxide is hydrochloride.

3. 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -1, 2-benzisothiazol-3 (2H) -one 1,1-dioxide , its physiologically acceptable salts, hydrates and / or solvates for the prophylaxis and / or treatment of Parkinson's disease.

4. 2- [4 - ({[(2R) -8-isopropoxy-chroman-2-yl] methyl} amino) butyl] -1, 2-benzisothiazol-3 (2H) -one 1,1-dioxide Hydrochloride for the prophylaxis and / or treatment of Parkinson's disease.