EP1434777A1

EP1434777A1 - Benzisothiazolyl-substituted aminomethyl chromanes for treating diseases of the central nervous system

Info

Publication number: EP1434777A1
Application number: EP02767489A
Authority: EP
Inventors: Dietrich Scherling; Wolfgang Karl; Dietrich Seidel; Corinna Weinz; Rudolf Schohe-Loop; Frank Mauler
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2001-10-01
Filing date: 2002-09-18
Publication date: 2004-07-07
Also published as: JP2005507901A; US6919360B2; WO2003029250A1; DE10148425A1; US20040259924A1; CA2462142A1

Abstract

The invention relates to chromanes of formula (I), to a method for the production thereof and to their use in medicaments, particularly as agents for fighting diseases of the central nervous system.

Description

BENZISOTHIAZOLYL-SUBSTITUTED AMINOMETHYLCHROMANE FOR THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM

The present invention relates to chromans, processes for their preparation and their use in medicaments, in particular as agents for combating diseases of the central nervous system.

From DE-A-195 43 476, EP-A-0 352 613, EP-A-0 749 970 and WO 99/26621, chromanes with affinity or agonistic activity on the serotonin receptor of the 5HTi subtype or 5HTi _A especially known for the treatment of diseases of the central nervous system.

BAY x3702, (-) - 2- (4 - {[(2R) -3,4-dihydro-2H-chromen-2-ylmethyl] amino} butyl) -l, 2-benzisothiazol-3 (2H) -one 1 , 1-Dioxide hydrochloride (generic name: Repinotan hydrochloride), is being developed clinically for the indications of traumatic brain injury and stroke (De Vry et al. Drugs Fut. 1997, 22, 341-349).

Surprisingly, it was found that metabolites of repinotan also bind to the 5HTj _.A receptor.

The invention therefore relates to new compounds of the general formula (I)

in which

the radicals R, ι, R and R have the following meaning:

The Nerbindungen according to the invention can exist in stereoisomeric forms that either behave like image and mirror image (enantiomers), or that do not behave like image and mirror image (diastereomers). The invention relates to both

Enantiomers or diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.

The inventive compounds can also be in the form of their salts, hydrates and / or solvates.

In the context of the invention, preferred salts are physiologically acceptable salts of the Nerbindungen according to the invention.

Physiologically acceptable salts of the Nerbindungen invention can be acid addition salts of the Nerbindungen with mineral acids, carboxylic acids or sulfonic acids. For example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, eansulfonic acid, toluenesulfonic acid, benzenesulfonic acid, Νaphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid are particularly preferred. Hydrates of the compounds according to the invention are stoichiometric compositions of the compounds or its salts with water.

Solvates of the compounds according to the invention are stoichiometric compositions of the compounds or its salts with solvent, optionally in an isomeric form, and their salts.

Preferred compounds of the general formula (I) are those which have the R configuration in the 2-position of the chroman radical.

The R configuration in the 2-position of the Chroman residue can be illustrated by the following formula:

The inventive compounds of the general formula (I) can be prepared as illustrated in the following formula schemes and as described in the exemplary embodiments:

Scheme 1

1. NaH, PhCH ₂ Br,. 2. separation of enantiomers

Scheme 2

Scheme 3

CH, N.

The compounds according to the invention can be used as active ingredients in pharmaceuticals. The substances according to the invention have a particularly high affinity for cerebral 5-hydroxy-tryptamine receptors of the 5-HTi _A type.

The compounds described in the present invention are thus

Active substances for combating diseases which are characterized by disorders of the serotoninergic system, in particular when receptors of the 5-HT ^ type are involved. They are therefore suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for

Regulation of pathological disorders in the intake of food, beverages and addictive substances. They are also suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease.

These active ingredients are also suitable for modulating the cardiovascular system. They also intervene in the regulation of cerebral blood flow and are therefore effective means of fighting migraines.

In addition, the compounds of the general formula (I) and the pharmaceutical compositions derived from these compounds, as for other 5HT]! _A ligands shown in WO 99/26621 are used for the post-acute therapeutic treatment of various neurological conditions in which various cell types of the nervous system have been degenerated and / or damaged as a result of neurodegenerative diseases or interventions or exposures. In particular, compounds of the general formula (T) can be used for the treatment of secondary conditions in which damage to cells of the nervous system due to surgical interventions, infections, exposure to toxic agents, tumors, nutritional deficits or metabolic diseases has occurred. In addition, compounds of the general Formula (I) are used to treat the consequences of neurodegenerative diseases, such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, substance abuse or drug addiction (alcohol, cocaine, heroin, amphetamine or the like), spinal cord diseases and / or - Injuries, dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathy and / or peripheral neuropathies induced by toxins. In addition, compounds of general formula (I) can be used in conjunction with surgical implantation of tissues and / or prostheses for the treatment of Alzheimer's disease or other neurological diseases and / or malfunctions in which an implantation is indicated.

The vz ^' / ro effect of the compounds according to the invention can be shown in the following assays:

1. Affinity for the 5-HTi _A receptor

(Dompert et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1985, 328, 467-470).

In this test, the binding of [H] -8-OH-DPAT to 5-HTi _A receptors in

Rat hippocampal membranes measured. It was found that the Nerbindungen compete with the radioligand for the binding and inhibit it.

Table B

In the binding assay IC indicating at what concentration of test substance 50% of the binding of the radioligand is displaced are determined ₅ o values. Taking into account the dissociation constant and the concentration of radioligands, the inhibition constants Ki are calculated from this.

The suitability of the inventive compounds for the treatment of, for example, stroke or traumatic brain injury can be shown in the following animal models:

Permanent focal cerebral ischemia

Animal model: permanent focal cerebral ischemia ("middle cerebral artery occlusion" = MCA-O). MCA occlusion in rodents is a widely accepted animal model of stroke. Literature: Bederson et al, Stroke, 1986, 17, 472-476.

To cause permanent focal cerebral ischemia, the left cerebral artery in rats is occluded by electrocoagulation. The resulting infarct volume in cortical (subcortical) regions that are supplied by the middle cerebral artery is used as a measure of the size of the stroke-induced neuronal damage.

Substance application: After occlusion as a continuous IV. Infusion (4 hours) of the test substance, starting immediately after the operation. The animals are sacrificed for evaluation 7 days after the operation.

The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more Nerbindungen of the general formula (I), or which consist of a or several active ingredients of the formula (I), and processes for the preparation of these preparations.

The active compounds of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.

In addition to the active ingredients of the formula (I), the pharmaceutical preparations can also contain other pharmaceutical active ingredients.

The pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.

In general, it has proven advantageous to use the active ingredient (s)

Formula (I) in total amounts from about 0.01 to about 100 mg / kg, preferably in total amounts from about 1 mg / kg to 50 mg / kg body weight per 24 hours, optionally in the form of several doses, to achieve the desired result ,

However, it may be advantageous to deviate from the amounts mentioned, depending on the type and body weight of the object being treated, on the individual behavior towards the medication, the type and severity of the disease, the type of preparation and application, and the Time or interval at which the administration takes place. Ausftthrungsbeispiele:

example 1

(R) - (-) - 2- (4- {[(7-Hydroxy-6-methoxy-3,4,4-dihydro-2H-chromen-2-yl) methyl] - amino} butyl) - 1,2 benzisothiazol-3 (2H) -one-1,1-dioxide hydrochloride

Stage a):

Ethyl 7- (benzyloxy) -6-methoxy-4-oxo-4H-chromene-2-carboxylate

A mixture of 0.37 mmol l- [2-hydroxy-5-methoxy-4- (phenyl-methoxy) phenyl] -ethanone [Beutler et al.] Is added to 1.1 ml of a sodium ethylate solution, prepared from 0.5 g sodium in 30 ml ethanol , J. Med. Chem. 41, 2333 (1998)] and 1.38 mmol of diethyl oxalate in 2 ml of ethanol were added within 5 minutes at room temperature. After heating to reflux for 3 hours, 0.55 ml of concentrated hydrochloric acid are added and the mixture is heated to reflux for a further 3 hours. After dilution with ethanol, the solid is separated off and discarded. The filtrate is concentrated in vacuo, taken up in ethyl acetate and with Water, then washed with saturated saline. After drying over magnesium sulfate, the mixture is concentrated and the residue is purified by flash chromatography (silica gel, mobile phase cyclohexane / ethyl acetate, gradient 10: 1 to 1: 1). In this way, ethyl 7- (benzyloxy) -6-methoxy-4-oxo-4H-chromen-2-carboxylate is obtained in 58% yield as a colorless solid. Mp 168 ° C.

Level b):

Ethyl 7-hydroxy-6-methoxy-2-chroman carboxylate

A solution of 7.5 mmol of ethyl 7- (benzyloxy) -6-methoxy-4-oxo-4H-chromene-2-carboxylate in 60 ml of ethyl acetate and 30 ml of glacial acetic acid is in the presence of 1.2 g of 10% palladium on activated carbon at 3 bar and 50 ° C hydrogenated. After 4 days, the hydrogenation is ended and diluted with ethyl acetate. It is filtered through kieselguhr and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate and the organic phase is washed with water and saturated sodium chloride solution. After drying over sodium sulfate and concentration, ethyl 7-hydroxy-6-methoxy-2-chroman carboxylate is obtained in 94% yield as a colorless oil, which is directly reacted further. Stage c):

Ethyl 7- (benzyloxy) -6-methoxy-2-chroman carboxylate

1.86 g of ethyl 7-hydroxy-6-methoxy-2-chroman carboxylate in 23 ml of dimethylformamide are mixed in portions with 8.9 mmol of 60% sodium hydride suspension in paraffin oil under argon. After stirring for 60 minutes at room temperature, 8.1 mmol of benzyl bromide are added. The reaction mixture is stirred for 5 hours at room temperature. For aqueous work-up (wash three times with

Water, once with saturated saline) is diluted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. Recrystallization twice from cyclohexane gives pure ethyl 7- (benzyloxy) -6-methoxy-2-chroman carboxylate; further product fractions are obtained from the mother liquors from the primary crystallizations by preparative HPLC purification (column:

Chromosil, eluent: acetonitrile / water). Overall yield: 72% of theory Mp 100 ° C.

Stage d):

(+) - and (-) - ethyl 7- (benzyloxy) -6-methoxy-2-chroman carboxylate

Preparative HPLC separation of the racemic ethyl 7- (benzyloxy) -6-methoxy-2-chroman carboxylate on a chiral phase (Chiracel OD 500 x 20 mm; isohexane / isopropanol 6: 4) gives the (S) - (-) - Enantiomer [mp. 95 ° C, CCD ²⁰ - -12.2 ° (c = 0.6, dichloromethane)] and the (R) - (+) - enantiomer [mp. 94 ° C, α _D ²⁰ = + 11.5 ° (c = 0.5, dichloromethane)] as colorless solids.

Stage e):

(R) - (-) - [7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methanol

2.6 mmol (R) - (+) - ethyl 7- (benzyloxy) -6-methoxy-2-chroman carboxylate are dissolved in 9 ml of toluene and a solution of 6.5 mmol of sodium bis (2-methoxyethoxy) aluminum dihydride in 18 ml Toluene added dropwise under argon at room temperature. After 2 hours at room temperature, the mixture is diluted with ethyl acetate. After washing twice with water, the undissolved matter is filtered off and the filtrate is washed again with water and then with saturated sodium chloride solution. Drying over sodium sulfate and evaporation in vacuo gives a solidifying oil which is purified by flash chromatography (silica gel, solvent cyclohexane / ethyl acetate 2: 1). This gives (R) - (-) - [7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methanol in 89% yield. Mp 109-112 ° C α _D ²⁰ = -71 ° (c = 0.5, dichloromethane) optical purity> 99.5% (HPLC on chiral column Chiral OD-H).

Level f):

(R) - [7- (Benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methyl methane sulfonate

245 mg are added to the solution of 1.8 mmol (R) - (-) - [7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methanol in 0.35 ml pyridine and 5 ml dichloromethane Methanesulfonic acid chloride added dropwise. After stirring overnight, the mixture is diluted with dichloromethane. Aqueous workup (washing with water and brine), drying and concentration give a crude product which is purified by flash chromatography (silica gel, eluent toluene / ethyl acetate, gradient 10: 1 to 1: 1). The product fraction obtained after evaporation is recrystallized from dichloromethane / cyclohexane. This gives 93% yield (R) - [7- (Benzyloxy) -6-me oxy-3,4-dihydro-2H-chromen-2-yl] methyl methane sulfonate.

Mp 147 ° C.

Level g):

(R) - (-) - pST-benzyl-N - {[7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methyl} amine

A mixture of 1.4 mmol (R) - [7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methyl methanesulfonate, 15 mg sodium iodide and 1.6 ml benzylamine is at room temperature for 14 days ditched. Then heated to 100 ° C for 5 hours. After cooling, the reaction mixture is diluted with toluene and the solid which precipitates is filtered off. The filtrate is freed of volatile components, most recently at 100 ° C. and a vacuum of approx. 1 mbar. The solution of the residue in ethyl acetate is worked up with water (washing with water and brine) and dried. The residue obtained after concentration is purified by flash chromatography (silica gel, eluent toluene / ethyl acetate, gradient 2: 1 to 1: 1). Treatment of the evaporated product fractions with cyclohexane gives a solid which is recrystallized from cyclohexane. After washing with pentane, (R) - (-) - [N-benzyl-N - {[7- (benzyl-oxy) -6-methoxy-3,4-dihydro-2H-chromen-2 -yl] methyl} amine as colorless crystals. Mp 94 ° C α _D ²⁰ = -76.5 ° (c = 0.5, methanol). Level h):

(R) - (-) - [2- [4- (Benzyl {[7- (benzyloxy) -6-methoxy-3,4,4-dihydro-2H-chromen-2-yl] methyl} amino) -2- butynyl] - 1, 2-benzisothiazol-3 (2H) -on-1, 1 -dioxide

A solution of 1.1 mmol (R) - (-) - [N-benzyl-N - {[7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methyl} amine in 3 ml of dioxane is successively at room temperature under argon with 42 mg of paraformaldehyde, 14 mg of copper (II) acetate and 308 mg of 2- (2-propynyl) -l, 2-benzisothiazol-3 (2H) -on-l, l-dioxide (obtained from the sodium salt of saccharin and propargyl bromide) and then heated to 80 ° C. for 90 minutes. After dilution with ethyl acetate, the mixture is worked up with water (washing with water and saturated sodium chloride solution). The organic phase is dried over sodium sulfate and concentrated. Flash chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 1: 1) provides a crude product which is chromatographed again (silica gel, mobile phase dichloromethane, then cyclohexane / ethyl acetate 1: 2). In this way, (R) ~ (-) - [2- [4- (benzyl {[7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl ] - methyl} amino) -2-butynyl] - 1, 2-benzisothiazol-3 (2H) -on-1, 1 -dioxide as an oil. α _D ²⁰ = -35.2 ° (c = 0.5, methanol).

Stage i):

(R) - (-) - 2- (4 - {[(7-Hydroxy-6-methoxy-3,4-dihydro-2H-chromen-2-yl) methyl] - amino} butyl) - 1,2 benzisothiazol-3 (2H) -one-1,1-dioxide hydrochloride

A mixture of 0.88 mmol (R) - (-) - 2- [4- (benzyl {[7- (benzyloxy) -6-methoxy-3,4-dihydro-2H-chromen-2-yl] methyl} amino) -2-butynyl] - 1, 2-benzisothiazol-3 (2H) -on-1,1-dioxide and 0.1 g 10% palladium on activated carbon in 7 ml methanol and 2 ml concentrated hydrochloric acid is hydrogenated at normal pressure without external cooling. After 2 hours, the same amount of catalyst is again added and hydrogenated for a further 4 hours. The reaction mixture is diluted with dichloromethane and filtered through diatomaceous earth. The filtrate is washed with saturated saline and dried over sodium sulfate. The oil obtained after concentration is low

Dichloromethane taken up in the heat and mixed with cyclohexane. Distillation of the dichloromethane under reduced pressure leads to crystal formation. The resulting precipitate is filtered off, washed with cyclohexane and dried in vacuo. This gives (R) - (-) - [2- (4 - {[(7-hydroxy-6-methoxy-3,4-dihydro-2H-chromen-2-yl) methyl] amino} in 64% yield butyl) -l, 2-benz-isothiazole-

3 (2H) -on- 1, 1-dioxide hydrochloride. Mp 195-198 ° C (with decomposition) α _D ²⁰ = -65.7 ° (c = 0.5, methanol) MS (ESI pos): mz = 447 [M + H] ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.5-2.2 (m, 6H), 2.6-3.2 (m, 6H), 3.65 (s, 3H),

3.75 (m, 2H), 4.2 (m, 1H), 6.25 (s, 1H), 6.6 (s, 1H), 7.9-8.15 (m, 3H), 8.3 (m, 1H), 8.6-9.0 (broad, 2H). Example 2

2- [4 - ({[(2R) -6-Hydroxy-3,4-dihydro-2H-chromen-2-yl] methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) -on- 1, 1-dioxide hydrochloride

Stage a):

Benzyl (2R) -3,4-dihydro-2H-chromen-2-ylmethyl [4- (1,1-dioxido-3-oxo-1,2-benzisothiazol-2 (3H) -yl) butyl] carbamate

A suspension of 1.2 g (5 mmol) of (-) - (R) -2- [4 - [[(3,4-dihydro-2H-l-chromen-2-yl) methyl] amino] butyl] -l, 2-benzisothiazol-3 (2H) -on-l, l-dioxide hydrochloride (EP

352 613 B1) in 40 ml of diethyl ether, 40 ml of water and 2.5 g (30 mmol) of sodium hydrogen carbonate are added. The mixture is cooled to 0 ° C. A solution of 1.0 g (6 mmol) of benzyloxy-carbonyl chloride in 5 ml of diethyl ether is added dropwise at an internal temperature of not more than 5 ° C. After stirring for 2 hours at room temperature, the organic phase is separated off and the aqueous phase is extracted with diethyl ether. The combined organic phases are dried over magnesium sulfate and concentrated. After chromatography (silica gel, eluent toluene / Ethyl acetate, gradient 1: 0 to 5: 1) gives 2.6 g (90% of theory) of benzyl (2R) -3,4-dihydro-2H-chromen-2-ylmethyl [4- (l, l-dioxido -3-oxo-l, 2-benzisothiazol- 2 (3H) -yl) butyl] carbamate as an oil, which is reacted directly without further purification. R _f (silica gel, toluene / ethyl acetate 3: 1) = 0.70

Level b):

Benzyl [(2R) -6-acetyl-3,4-dihydro-2H-chromen-2-yl] methyl [4- (1,1-dioxido-3-oxo-1,2-benzisothiazole-2 (3 H) -yl) butyl] carbamate

12.7 g (95 mmol) of anhydrous aluminum chloride are suspended in 10 ml of 1,2-dichloroethane. At 0 ° C., 5.9 ml (82 mmol) of acetyl chloride are first added. A solution of 34 g (63 mmol) of benzyl (2R) -3,4-dihydro-2H-chromen-2-ynethyl [4- (1, 1 -dioxido-3-oxo- 1, 2 -benzisothiazol-2 (3H) -yl) butyl] - carbamate slowly added dropwise in 100 ml of 1,2-dichloroethane. The reaction is stirred at room temperature overnight. After pouring onto ice water, the organic phase is separated off and the aqueous phase is extracted several times with dichloromethane. The combined organic extracts are dried over magnesium sulfate and concentrated. The crude product thus obtained is purified by chromatography (silica gel,

Eluent toluene / ethyl acetate 3: 1) cleaned. 9.6 g (26.5% of theory) of benzyl [(2R) -6-acetyl-3,4-dihydro-2H-chromen-2-yl] methyl [4- (l, l-dioxido-3-oxo -l, 2-benzisothiazol-2 (3H) -yl) butyl] carbamate. R _f (silica gel, toluene / ethyl acetate 3: 1) = 0.32 Stage c):

(2R) -2 - ({[(Benzyloxy) carbonyl] [4- (1,1-dioxido-3-oxo-1,2-benzisothiazol-2 (3H) -yl butyl] amino} methyl) -3,4 dihydro-2H-chromen-6-yl acetate

2.9 g (5 mmol) benzyl [(2R) -6-acetyl-3,4-dihydro-2H-chromen-2-yl] methyl [4- (l, l-dioxido-3-oxo-l, 2-benzisothiazole -2 (3H) -yl) butyl] carbamate in 30 ml dichloromethane are mixed at 0 ° C. with the exclusion of light with 2.2 g (13 mmol) m-chloroperoxybenzoic acid. 570 mg (5 mmol) of trifluoroacetic acid are then slowly added dropwise at this temperature. After stirring overnight at room temperature, the mixture is diluted with dichloromethane and mixed with saturated sodium bicarbonate solution. The organic phase is separated off, dried over magnesium sulfate and concentrated. Chromatography (silica gel, mobile phase toluene / ethyl acetate, gradient 1: 0 to 3: 1) gives 2.8 g (94% of theory) (2R) -2 - ({[(benzyloxy) carbonyl] [ 4- (l, l-dioxido-3-oxo-l, 2-benzisothiazol-2 (3H) -yl) butyl] - amino} methyl) -3,4-dihydro-2H-chromen-6-yl acetate as Oil. R _f (silica gel, toluene / ethyl acetate 3: 1) = 0.44

Stage d):

2- [4 - ({[(2R) -6-Hydroxy-3, 4-dihydro-2H-chromen-2-yl] methyl} amino) butyl] -l, 2-benzisothiazol-3 (2H) -one- 1, 1-dioxide hydrochloride

11.2 g (19 mmol) of (2R) -2 - ({[(benzyloxy) carbonyl] [4- (l, l-dioxido-3-oxo-l, 2-benzisothiazol-2 (3H) -yl) butyl ] amino} methyl) -3,4-dihydro-2H-chromen-6-yl acetate in 200 ml glacial acetic acid and 67 ml concentrated hydrochloric acid are mixed with 2 g 10% palladium on activated carbon and hydrogenated for 4 hours at 3 bar and room temperature. After filtering off the catalyst, 5 ml of 25% ammonia water are added and concentrated. The residue is purified by chromatography (silica gel, mobile phase dichloromethane / ethanol, gradient 1: 0 to 5: 1). The product fractions thus obtained are freed from the solvent by concentration, taken up in ethanol and carefully mixed with 10 ml of a 4 N solution of HCl gas in ethanol. After cooling in ice, the solid obtained is suction filtered, dissolved in 550 ml of hot heat and treated with activated carbon. After filtration, the mixture is concentrated to about 100 ml. The crystals which precipitate are filtered off with suction and dried in vacuo. 3.15 g (37% of theory) of 2- [4 - ({[(2R) -6-Hydroxy-3,4-dihydro-2H-chromen-2-ylmethyl} amino) butyl] -1 are obtained. 2-benzisothiazol-3 (2H) -one-1, 1-dioxide hydrochloride as colorless crystals. Mp 220-222 ° C MS (FAB): m / z = 417 [M + H] ⁺

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.5-2.1 (m, 6H), 2.6-3.2 (, 6H), 3.75 (m, 2H), 4.2 (m, 1H), 6.45-6.65 ( m, 3H), 7.9-8.15 (m, 3H), 8.3 (m, 1H), 8.6-9.0 (broad, 2H) Elemental analysis: C ₂₁ H ₅ ClN ₂ O ₅ S

C: calc. 55.7, found 56.0; H: calc. 5.6, found 5.7

N: calc. 6.2, found. 6.2; S: calc. 7.1, found. 7.1 Example 3

Stage a):

4-hydroxychroman-2-carboxylic acid

1 g (5.2 mmol) chromon-2-carboxylic acid is dissolved in 25 ml 1,4-dioxane and 5 ml dry ethanol. After adding 1 g (26.3 mmol) of sodium borohydride, the mixture is heated under reflux for 1 hour. It is cooled to room temperature and acidified with 1 ml of 1 M hydrochloric acid and then with 4.5 ml of 6 M hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted twice with 20 ml of diethyl ether each time. The organic phases are combined and evaporated to dryness. The residue is dissolved in a solvent mixture of 1.5% acetic acid and 5% methanol (v / v) in dichloromethane and the product is isolated chromatographically under the following conditions: column Lobar ^® LiChroprep ^® Si 60 size B, column temperature room temperature, solvent 1.5% acetic acid and 5% methanol (v / v) in dichloromethane, flow 15 ml min., UN detection at 230 nm. The product-containing fractions are combined and evaporated to dryness. Yield: 420 mg (37% of theory)

GC / MS (after methylation): m / z = 208 [M] ⁺ (methyl ester) GC / MS (after silylation): m / z = 338 [M] ⁺ (bistrimethylsilyl derivative) 1H-NMR (400 MHz, CD ₃ OD, with CD ₂ HOD adjusted to δ = 3.30): δ = 2.16 (H-3a, IH, ddd); 2.48 (H-3e, IH, ddd); 4.79 (H-2a, IH, dd); 4.88 (H-4a, IH, dd); 6.86 (H-8, IH, d); 6.92 (H-6, IH, dt); 7.16 (H-7, IH, German); 7.37 (H-5, IH, d).

Level b):

4-hydroxychroman-2-carbonsäuremethylester

250 mg of 4-hydroxychroman-2-carboxylic acid are suspended in 4.5 ml of diethyl ether, a solution of about 4.5 mmol of diazomethane in 4.5 ml of diethyl ether is added and the mixture is stirred at room temperature for 30 minutes. After concentration to dryness, the product is obtained as an oily residue. Yield: 268 mg (quant.) 1H-NMR (400 MHz, CD ₃ OD, adjusted to δ = 3.30 with CD ₂ HOD): δ = 2.26 (H-3a,

IH, ddd); 2.66 (H-3e, IH, ddd); 3.67 (CH ₃ O, 3H, s); 4.79 (H-2a, IH, dd); 4.92 (H-4a, IH, dd); 6.9 (H-8 / H-6, 2H, m); 7.2 (H-7 / H-5, 2H, m).

Step c): 4- (tert-butyldimethylsilanyloxy) -chroman-2-carboxylic acid benzylamide

Method 1

55 mg (0.24 mmol) of 4-hydroxychroman-2-carboxylic acid methyl ester are dissolved in 0.25 ml of ethylene glycol dimethyl ether. After adding 0.15 ml (1.37 mmol) of benzylamine and 5 mg (0.04 mmol) of lithium iodide, the mixture is stirred at 60 ° C. for 3 hours. The product is precipitated with 1 ml of 0.1 M hydrochloric acid, the solid is filtered off, washed with water and dried in a desiccator over blue gel.

80 mg (0.28 mmol) of the 4-hydroxychroman-2-carboxylic acid benzylamide obtained in this way are dissolved in 2 ml of dichloromethane, and 150 μl (1.29 mmol) of 2,6-lutidine are added. Then 150 μl (0.65 mmol) of trifluoromethane-sulfonic acid tert-butyldimethylsilyl ester are added and the solution is stirred for 8 hours at room temperature. After the reaction had been terminated by adding 0.53 ml of 10% ammonium chloride solution, 0.5 ml of dichloromethane were added. The product-containing organic phase is washed 7 times with 0.73 ml of 0.1 M hydrochloric acid and then with 0.29 ml of a saturated sodium bicarbonate solution and then to

Dry evaporated. The crude product is purified by HPLC (see below).

Method 2

268 mg (1.2 mmol) of 4-hydroxychroman-2-carboxylic acid methyl ester are dissolved in 2.5 ml of dichloromethane. After adding 0.6 ml (5.15 mmol) of 2,6-lutidine and 0.6 ml

(2.61 mmol) trifluoromethanesulfonic acid tert-butyldimethylsilyl ester, the solution is stirred for 6 hours at room temperature. After stopping the reaction by adding 2 ml of a 10% ammonium chloride solution, the product-containing organic phase is washed 7 times with 3 ml of 0.1 M hydrochloric acid and then with 1 ml of a saturated sodium bicarbonate solution and then concentrated to dryness.

430 mg (1.33 mmol) of the 4- (tert-butyldimethylsilanyloxy) -chroman-2-carboxylic acid methyl ester obtained in this way are dissolved in 1.25 ml of ethylene glycol dimethyl ether and mixed with 0.765 ml (7 mmol) of benzylamine. After adding 25.5 mg (0.19 mmol) of lithium iodide, the reaction mixture is 3 hours at 70 ° C. touched. The product is precipitated by adding 5 ml of 0.1 M hydrochloric acid. The supernatant is decanted off and the residue is washed with 2 ml of water. The residue is then dissolved in 1 ml of dichloromethane and the product-containing organic phase is evaporated to dryness.

The crude products obtained by Method 1 and Method 2 are combined and purified by preparative HPLC chromatography under the following conditions: Nucleosil ^® 100 C-18 column, 125 x 16 mm (particle size 7 μm), column temperature room temperature, mobile phase 75% acetonitrile / 25% Water (v / v), flow 6 ml / min., UN detection at 230 nm. The product-containing fractions are combined and evaporated to dryness. Yield: 265 mg (46% of theory)

1H-ΝMR (400 MHz, CD ₃ OD, with CD ₂ HOD set to δ = 3.30): δ = 0.20 / 0.23 (dimethylsilyl, 3H, s / 3H, s); 0.96 (t-butyl, 9H, s); 1.97 (H-3a, IH, m); 2.54 (H-3e, IH, ddd); 4.41 / 4.50 (CH ₂ phenyl, 2H, AB); 4.72 (H-2a, IH, dd); 5.09 (H-4a, IH, dd); 6.91 (H-8, IH, d); 6.94 (H-6, IH, t); 7.15 (H-7, IH, t); 7.20-7.35 (H-5 and phenyl, 6H, m).

Step d): Benzyl- [4- (tert -butyldimethylsilanyloxy) -chroman-2-ylmethyl] amine

A solution of 265 mg (0.66 mmol) of 4- (tert-butyldimethylsilanyloxy) -chroman-2-carboxylic acid benzylamide in 2 ml of toluene is cooled in an ice bath and with 2 ml

Sodium bis (2-methoxyethoxy) aluminum dihydride (70% solution in toluene) was added. The reaction mixture is stirred at 60 ° C. for 2 hours and at room temperature overnight. 10 ml of 1 M sodium hydroxide solution are then added in portions added and the mixture extracted with 20 ml dichloromethane and again with 10 ml dichloromethane. The combined organic phases are washed with 10 ml of water and evaporated to dryness. The product is obtained as an oily residue.

Yield: 226 mg (89% of theory)

1H-NMR (400 MHz, CD ₃ OD, with CD ₂ HOD adjusted to δ = 3.30): δ = 0.17 / 0.21 (dimethylsilyl, 3H, s / 3H, s); 0.96 (t-butyl, 9H, s); 1.75 (H-3a, IH, m); 2.18 (H-3e, IH, ddd); 2.77 (H-9, IH, dd); 2.90 (H-9 ', IH, dd); 3.84 (CH ₂ phenyl, 2H, s); 4.30 (H-2a, IH, m); 5.01 (H-4a, IH, dd); 6.76 (H-8, IH, d); 6.86 (H-6, IH, t); 7.10 (H-7, IH, t); 7.20-7.45 (H-5 and phenyl, 6H, m).

Stage e):

2- (4- {benzyl- [4- (tert-butyldimethylsilanyloxy) -chroman-2-ylme yl] amino} butyl) - 1, 1 -dioxo- 1, 2-dihydro-1 λ ⁶ -benzo [d] isothiazol-3-one

A solution of 224 mg (0.58 mmol)) benzyl- [4- (tert-butyldimethylsilanyloxy) - chroman-2-ylmethyl] amine in 1.25 ml dry N-methylpyrrolidinone is mixed with 380 mg (1.19 mmol) 2- (4 -Brombutyl) -l, l-dioxo-l, 2-dihydro-lλ ⁶ -benzo [<-] isothiazol-3-one and 263 μl (1.51 mmol) N-ethyldiisopropylamine were added. The reaction mixture is stirred at 120 ° C. for 3 hours. After cooling to room temperature, 2 ml of water are added, a dark-colored, viscous product precipitating. The supernatant is decanted off and the residue is washed twice with 1.5 ml of water each time. Then the product is dissolved in 3 ml dichloromethane, the water residues through

Drying removed and the solution evaporated to dryness. The raw product is purified by HPLC chromatography under the following conditions: Nucleosil ^® 100 C-18 column, 125 x 16 mm (particle size 7 μm), column temperature room temperature, eluent 85% acetonitrile / 15% water (v / v), Flow 6 ml / min., UV detection at 230 nm. The product-containing fractions are combined and evaporated to dryness. The residue is dissolved in 2.5 ml of ethanol and 6 ml of acetone and again evaporated to dryness. The product is dried in a desiccator over blue gel.

Yield: 121 mg (33% of theory) MS (EI): m / z = 621 [M + H] ⁺ 1H-ΝMR (400 MHz, CD ₃ OD, with CD ₂ HOD set to δ = 3.30): δ = 0.11 / 0.16

(Dimethylsilyl, 3H, s / 3H, s); 0.92 (t-butyl, 9H, s); 1.51 (H-3a, IH, m); 1.63 (Hl, 2H, m); 1.88 (H-12, 2H, m); 2.26 (H-3e, IH, ddd); 2.6 (H-9 and H-10 / H-10 ', 3H, m); 2.76 (H-9 _'5 IH, dd); 3.58 / 3.73 (CH ₂ phenyl, 2H, AB); 3.74 (H-13, 2H, t); 4.17 (H-2a, IH, m); 4.91 (H-4a, IH, dd); 6.67 (H-8, IH, d); 6.82 (H-6, IH, t); 7.04 (H-7, IH, t); 7.15-7.40 (H-5 and phenyl, 6H, m); 7.90 (H-16, IH, German); 7.95 (H-15, IH, German);

8.03 (H-14 / H-17, 2H, d).

Level f):

2- (4- {[4-tert-Butyldimethylsilanyloxy) -chroman-2-ylmethyl] amino} butyl) - 1,1-dioxo-1,2-dihydro-1 λ ⁶ -benzo [d] isothiazol-3 - on

120 mg (0.19 mmol) of 2- (4- {benzyl- [4- (tert-butyldimethylsilanyloxy) -chroman-2-ylmethyl] amino} butyl) - 1, 1 -dioxo- 1, 2-dihydro-1 λ ⁶ -benzo [<] isothiazol-3 -one are dissolved in 2 ml of methanol and 1 ml of acetic acid and with 100 mg of Pearlman catalyst (20% Pd (OH) ₂ on activated carbon). Hydrogen is introduced at room temperature for 4 hours. After filtration, the mother liquor is geengt to dryness _r. The raw product is implemented directly without further purification. Yield: 107 mg MS (EI): m / z - 531 [M + H] ⁺

Level g):

2- {4- [(4-Hydroxy-chroman-2-ylmethyl) amino] butyl} - 1, 1-dioxo-1, 2-dihydro-1 λ ⁶ - benzo [d] isothiazol-3 -one

81 mg of 2- (4- {[4-tert-butyldimethylsilanyloxy) -chroman-2-ylmethyl] amino} butyl) - l, l-dioxo-l, 2-dihydro-lλ ⁶ -benzo [(flisothiazol-3- are dissolved in 4 ml of 1 M hydrochloric acid and 4 ml of methanol, and the solution is stirred overnight at room temperature.

A pH of 8 is set with sodium bicarbonate and the mixture is then extracted three times with 3 ml of dichloromethane each time. The combined organic phases are combined with a solution of 16 mg of product from a preliminary experiment, dried over sodium sulfate and evaporated to dryness. Yield: 74 mg

1H-NMR (500 MHz, CD ₃ OD, with CD ₂ HOD adjusted to δ = 3.30): δ = 1.68 (H-II, 2H, m); 1.74 (H-3a, IH, ddd); 1.89 (H-12, 2H, m); 2.24 (H-3e, IH, ddd); 2.85 (H-9, IH, dd); 2.75 (H-10 / H-10 ', 3H, t); 2.93 (H-9 ', IH, dd); 3.81 (H-13, 2H, t); 4.29 (H-2a, IH, m); 4.87 * (H-4a, IH, dd); 6.77 (H-8, IH, d); 6.88 (H-6, IH, t); 7.10 (H-7, IH, t); 7.41 (H-5, IH, dd); 7.93 (H-16, IH, German); 7.98 (H-15, IH, German); 8.05 (H-14, IH, m); 8.07 (H-17, IH, m). ^ This value was measured at 50 ° C.

Claims

Patentansprtiche

Compounds of the general formula (I),

in which

the radicals R, ι, R and R have the following meaning:

and their salts, hydrates and / or solvates.

2. Compounds according to claim 1, wherein the compounds in the 2-position of the chroman ring have the R configuration.

Compounds according to one of claims 1 or 2 for therapeutic use.

4. Medicament containing at least one compound according to one of claims 1 or 2 and conventional auxiliaries and additives.

5. Medicament according to claim 4 for the treatment of stroke or traumatic brain injury.

6. The process for producing medicaments according to one of claims 4 or 5, characterized in that the active ingredients are converted into a suitable form of administration using customary auxiliaries and additives.

7. Use of compounds according to one of claims 1 or 2 for the manufacture of medicaments.

Use of compounds according to one of claims 1 or 2 for the manufacture of medicaments for the treatment of stroke or skull-brain trauma.