EA007655B1 - Aminoindane derivatives as serotonin reuptake and norepinephrine uptake inhibitors - Google Patents

Abstract

The present invention relates to aminoindane derivatives having the formula I wherein X, Y, U, R, Rand R are as defined in the claims, or acid addition salts thereof. The compounds of the invention posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition.

Description

The invention relates to new aminoindane derivatives that are useful in the treatment of affective disorders, such as depression and anxiety disorders.

BACKGROUND OF THE INVENTION

The combined effects of inhibition of serotonin reuptake and inhibition of norepinephrine uptake on depression have been studied in clinical studies of compounds such as duloxetine (Shopd Т. T: Vi1oheEpe (ΕΥ-248686): Serotonin and norepinephrine uptake inhibitor and antidepressant drug 1 §Eiagiopa1 Ogndz (1988) 7 10 1691-1699) and venlafaxine (Kyap-A; Eabe-BE; Kibo1py-K: venlafaxine for depression in ambulatory patients, Rzujeoryagshaeodu Vi11eEp (1991) 27, 141-144).

The present invention provides novel compounds that possess the combined effects of inhibiting serotonin reuptake and inhibiting norepinephrine uptake for the treatment of affective disorders such as depression, anxiety disorders, including generalized anxiety disorder, social anxiety disorder, post-traumatic stress, obsessive compulsive disorder, acute anxiety disorder with panic reaction, panic disorder, specific phobias, social phobia and fear of indoor space.

Summary of the invention

This invention relates to compounds having the formula I

where X is -Ο-, -8- or -SK ⁴ K ⁵ -;

Υ means -SK ⁶ K ⁷ -, -SK ⁶ K ⁷ -SK ⁸ K ⁹ - or -SK ⁶ = SK ⁷ -; or X and Υ together form a group —SK ⁴ = SK ⁵ or —SK ⁴ = SK ⁵ —SK ⁶ K ⁷ -; and and means -Ο-, -8- or -SK ¹⁰ K ¹¹ ; or

X is -Ο-, -8- or -SK ⁴ K ⁵ -; and

Υ and together form the group SK ⁶ = SK ⁷ -, -SK ⁶ = SK ⁷ -SK ¹⁰ K ¹¹ - or -SK ⁶ To ⁷ -SK ¹⁰ = SK ¹¹ -; or X, Υ and together form —SC ⁴ = SC ⁵ —SC ⁶ = SC ⁷ -;

K ¹ and K ^{2 are} independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, or K ¹ and K ² together with the nitrogen to which they are attached form a 3-7 membered ring, optionally containing one additional heteroatom;

K ¹³ , K ¹⁴ , K ¹⁵ and K ¹⁶ are each independently selected from hydrogen, halogen, cyano, nitro, C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-8 cycloalkyl;

K is hydrogen, halogen, C _1-6 alkyl or cyano;

K ⁴ , K ⁵ , K ⁶ , K ⁷ , K ⁸ , K ⁹ , K ¹⁰ and K ^{11 are} independently selected from hydrogen and C _1-4 alkyl; or to their acid addition salts.

The invention also provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.

The invention further provides the use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of affective disorders such as depression and anxiety disorders, including generalized anxiety disorders, social anxiety disorders, post-traumatic stress, obsessive compulsive disorder, panic disorder such as acute anxiety states with a panic reaction, specific phobias, social phobia and fear of open space state.

The invention also provides a method of treating an affective disorder, as described above, in higher animals, including humans, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

According to one specific embodiment of the invention, X and and are selected from —O— and —8— and Υ means —SK ⁶ K ⁷ - or —SK ⁶ K ⁷ —SK ⁸ K ⁹ -.

According to another specific embodiment of the invention, X, Υ and together form —SC ⁴ = SC ⁵ —SC ⁶ = SC ⁷ -.

Preferred compounds of the invention are trans- (3-benzo [1, 3] dioxol-5-yl-indan-1-yl) dimethylamine, cis- (3-benzo [1,3] dioxol-5-yl-indan-1 -yl) dimethylamine,

- 1 007655 trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) diethylamine, cis- (3-benzo [1, 3] dioxol-5-yl-indan-1-yl ) diethylamine, trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylamine, cis- (3-benzo [1, 3] dioxol-5-yl-indan-1-yl ) ethylamine, trans- (3-benzo [1, 3] dioxol-5-yl-indan-1-yl) methylamine, cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl ) methylamine, (+) - trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, (-) - trans- (3-benzo [1,3] dioxol-5 -yl-indan-1-yl) dimethylamine, (+) - cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, (-) - cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, trans- (3-benzo [1,3] dioxol-5-yl- indan-1-yl) ethylmethylamine, cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylmethylamine, cis- [3 - (2, 3-dihydrobenzo [1, 4] dioxin -6-yl) indan-1-yl] dimethylamine, trans- [3- (2,3-dihydrobenzo [1,4] dioxin-6-yl) indan-1-yl] dimethylamine, cis-dimethyl- (3 - naphthalen-2-yl-indan-1-yl) amine, trans-dimethyl- (3-naphthalen-2-yl-indan-1-yl) amine, cis- [3 - (6-chlorobenzo [1,3] dioxol -5-yl) indan-1-yl] dimethylamine, trans- [3- (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] dimethylamine, cis- [3 - (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] methylamine, trans- [3- (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] methylamine, cis enantiomer -1- (3-benzo [1, 3] dioxol-5-yl-indan-1-yl) methylamine and cis-enantiomer-2- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) methylamine or their acid addition salts .

As used here, halogen means fluoro, chloro, bromo or iodo.

The term C _6-6 alkyl refers to a branched or unbranched alkyl group having from 1 to 6 carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2methyl-2- propyl and 2-methyl-1-propyl.

Similarly, C _2-6 alkenyl and C _2-6 alkynyl, respectively, mean such groups having from 2 to 6 carbon atoms and including one double bond and a triple bond, respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The term C _3-8 cycloalkyl means a monocyclic or bicyclic carbocycle having from 3 to 8 C atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

K ¹ and K ² together with the nitrogen atom to which they are attached form a 3–7 membered ring, optionally containing one additional heteroatom, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

Examples of additive salts of organic acids according to the invention are (salts) formed with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylene salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, malonic, malonic, gluconic cinnamic, citraconic, aspartic, stearic, palmitic, taconic, glycolic, para-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as with 8-halogenotheophylline, e.g. 8bromteofillinom measures. Examples of the inorganic acid addition salts of the invention are (salts) formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.

The compounds of this invention can exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Solvated forms for the purposes of this invention are considered equivalent to unsolvated forms.

Some compounds of this invention contain chiral centers and such compounds exist in the form of isomers (eg, enantiomers or diastereomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Racemic forms can be resolved into optical antipodes by known methods, for example, by separating their diastereomeric salts with optically active acids and releasing the optically active amine by treatment with a base. The racemic compounds of this invention can be cleaved into their optical antipodes, for example, by fractional crystallization of the D and 1 salts (for example, tartrates, mandelates or camphorsulfonates). Another method for cleaving racemates into optical antipodes is based on chromatography on an optically active matrix. The compounds of this invention can also be cleaved by the formation of diastereomeric derivatives or by enzymatic cleavage.

Additional methods for the resolution of optical isomers known to those skilled in the art can be used. Such methods include those described by Yadiek, A.Co11e1, and 8. \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ out Reg ones years Our Chemistry Of Your Competition - Yours, Kabe, App, Proof, Science, and Science (1981).

Optically active compounds can also be obtained from optically active starting materials.

Compounds of the invention can be obtained by

1) alkylation of an amine of formula III with an alkylating reagent of formula II

where K, K? -K ² , K ^13-16 , X, Υ and both have the above meanings and k means a leaving group such as halogen, mesylate or tosylate;

2) reductive alkylation of indanketone of formula IV with an amine of formula III

(IV) (W) where K, K ¹ -K ² , K ^13-16 , X, Υ and and have the above meanings;

3) ring opening in an epoxide of formula V with an amine of formula III

where K, K ¹ -K ² , K ^13-16 , X, Υ and and have the above meanings.

Alkylation according to method 1) is usually carried out in an organic solvent, such as alcohol or a ketone with a suitable boiling point, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be carried out at a predetermined temperature, which differs from the boiling point, in one of the above solvents or in dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or Y-methylpyrrolidin-2-one (ΝΜΡ), preferably in the presence of a base such as above. Alkylating derivatives of formula II are described in the literature (e.g., Vesozo, Κ.Ρ. B. Meb. SN. 26, 1983, 935-947; Vesozo, Κ.Ρ. et al. Meb. SN. 28, 1985, 1817 -1828; Zotteg, M.V. et al. B. Ogd. SN. 55, 1990, 4822-2827 and the references cited therein), and amines of the formula III are commercially available.

The reductive alkylation according to method 2) is carried out according to standard methods described in the literature. The reaction can be carried out in one step under standard reductive amination conditions using, for example, sodium cyanoborohydride, or in two steps, for example, by condensation of amines of formula III with a reagent of formula IV, followed by reduction of the resulting imine with sodium cyanoborohydride or sodium borohydride. Ketones of formula IV can be obtained as described in the literature (for example, Bo§ego, K.R. B. Meb. SN. 26, 1983, 935-947; Vodezo, Κ.Ρ. and others. Meb. SN. 28, 1985, 1817-1828; Zotteg, M.V. et al. Ogd. SN. 55, 1990, 4822-2827 and in the references cited therein).

The ring opening in the epoxide according to method 3) is usually carried out in an organic solvent, such as alcohol or a ketone with a suitable boiling point, using an excess of the amine of formula III at reflux temperature.

Epoxides of formula IV can be obtained by methods described in the literature (for example, CHOSN, A.K. et al. ZupFe§1 § 5; 1997; 541-544; Ραΐηκτ, M. B. et al.; B. SNet. Zoe ΙΑτ1 <ίΗ Тгапз. 1, 2002, 416-427).

The pharmaceutical medicaments of the invention can be prepared by conventional methods known in the art. For example, tablets can be prepared by mixing the active ingredient with conventional adjuvants and / or diluents, followed by compressing the mixture on a conventional tablet machine. Examples of adjuvants or diluents are corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum, and the like. Any adjuvants or additives commonly used for purposes such as coloring, changing taste and smell, preservation, etc., can be used provided that they are compatible with the active ingredients.

Injectable solutions can be prepared by dissolving the active ingredient and possible additives in a portion of the injection solvent, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling in suitable ampoules or vials. Any additives commonly used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

The pharmaceutical compositions of this invention or obtained in accordance with this invention can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of injection solutions. Methods well known in the art can be used to produce these compositions, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives commonly used in the art can be used.

Typically, the compounds of the invention are administered in the form of dosage forms containing the compounds in an amount of from about 0.01 to 100 mg. The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.

experimental part

The compounds of the invention, which serve as an example hereinafter, were characterized using the following methods.

Melting points were determined on a Viesa B-540 apparatus and were not corrected. Mass spectra were obtained on the OiaIgo M8-M8 system from the state system Vyu1esy, Iyoi 1i51tity15. The analytical data of L-M8 was obtained on a PE 8 tool ш 150EX, equipped with an electrostatic deposition source and the 81 ί ί η η system; · ά ά ι ι С-8A / 8L-10A С C. The bC conditions (50x4.6 mm, UMS ΟΌ8-Α, particle size 5 μm) had a linear gradient of elution from the mixture (90: 10: 0.05) water / acetonitrile / trifluoroacetic acid to the mixture (10: 90: 0.03) water / acetonitrile / trifluoroacetic acid for 7 min at a flow rate of 2 ml / min. Purity was determined by UV spectroscopy (254 nm). The retention time Λ was expressed in minutes. Preparative L-M8 separation was performed on the same instruments. The bC conditions (50x20 mm, UMS ΟΌ8-Α, particle size 5 μm) had a linear gradient of elution from a mixture (80: 20: 0.05) water / acetonitrile / trifluoroacetic acid to a mixture (5: 95: 0.03) water / acetonitrile / trifluoroacetic acid for 7 minutes at a rate of 22.7 ml / min. The selection of fractions was carried out by determining the flow in the mass spectrometer.

The 'H NMR spectrum was recorded at 250.13 MHz at Vgikeg AC 250 or at 500.13 MHz at Vgikeg ΌΚΧ 500. Deuterized chloroform (99.8% Ό) or dimethyl sulfoxide (99.9% Ό) were used as solvents. Tetramethylsilane (TM8) was used as an internal standard. Chemical shifts were expressed as ppm. The following abbreviations were used for the multiplicity of NMR signals: 5 = singlet, b = doublet, 1 = triplet, d = quartet, c | y = quintet, d = heptet, bb = double doublet, b! = Double triplet, bs | = double quartet , 11 = triple triplet, m = multiplet, b = width. NMR signals corresponding to acidic protons were neglected to some extent. The water content in crystalline compounds was determined by Karl Fischer titration. For column chromatography, silica gel of the type K1eye1de1 60, 40-60 mesh A8TM was used. The following materials were used for ion-exchange chromatography: 8CX columns (1 g) from Uapap Meda Voib E1i1®, Sotogrask ca1. Νο. 220776. Prior to use, the 8CX columns were preconditioned with a 10% solution of acetic acid in methanol (3 ml).

Examples

Obtaining intermediate products

A. Alkylating reagents

3-amino-1- (benzo [1,3] dioxol-5-yl) -1-cyano-1H-indene-2-carboxylic acid methyl ester

A mixture of 2-chlorobenzonitrile (12.3 g) and benzo [1,3] dioxol-5-yl-acetonitrile (10 g) in dimethylformamide (25 ml) was added with stirring and cooling in an ice bath to potassium tert-butoxide (20, 1 g) dissolved in dimethylformamide (50 ml) at such a rate that the temperature does not exceed 25 ° C. After stirring (for) 0.5 h, methyl chloroacetate (11.1 g) was added over 10 min. After stirring (for) 24 hours at room temperature, the mixture was poured into a mixture of 0.1 M HC1 (200 ml), heptane (30 ml) and toluene (15 ml). By stirring for 1 h, filtering and washing with water (2x50 ml), toluene (2x10 ml) and heptane (2x25 ml), 79% of 3amino-1-benzo [1,3] dioxol-5-yl-1-cyano methyl ester was obtained -1H-indene-2-carboxylic acid.

- 4 007655

3- (Benzo [1,3] dioxol-5-yl) -indan-1-one

A mixture of 3-amino-1-benzo [1,3] dioxol-5-yl-1-cyano-1H-indene-2-carboxylic acid methyl ester (10 g) and acetic acid (30 ml) was heated to 100 ° C; 60% aqueous sulfuric acid (20 ml) was added with stirring over 30 minutes. The mixture was heated to 110 ° C for 6 h, cooled to room temperature, extracted with toluene (50 + 10 ml), washed with water (3x100 ml), extracted with 0.1 M aqueous sodium hydroxide (100 + 20 ml), acidified with concentrated hydrochloric acid , extracted with toluene (25 + 10 ml) and filtered through activated carbon. Removal of toluene afforded 80% 1- (benzo [1,3] dioxol-5-yl) -3-oxo-indan-1-carboxylic acid.

The acid was then decarboxylated by heating to 100 ° C in Ν-methylpyrrolidone (15 ml) for 1 h. After cooling, the solution was poured into water (40 ml) with vigorous stirring.

Filtration, washing with water (5x20 ml), dissolving in ethyl acetate (40 ml), filtering through activated carbon and removing ethyl acetate gave 80% 3- (benzo [1,3] dioxol-5-yl) indan-1-one.

Cis-3 - (benzo [1,3] dioxol-5-yl) indan-1-ol

Sodium borohydride (1.5 g) was added portionwise with stirring at 10-15 ° C to a solution of 3 (benzo [1,3] dioxol-5-yl) indan-1-one (10 g) in a mixture of ethanol (75 ml) and dimethoxyethane (75 ml). The mixture was stirred at room temperature for 1 h and then evaporated in vacuo. The resulting oil was treated with water and diethyl ether, and the organic phase was separated, washed with water and 0.1 N. HCl, dried (Mg§ ₄ ) and evaporated in vacuo to give cis-3- (benzo [1,3] dioxol-5-yl) indan-1-ol as a brown oil (10 g).

5- (3-Clorindan-1-yl) benzo [1,3] dioxol

Thionyl chloride (7 ml) was added with stirring and cooling to 15 ° C to a solution of cis-3 (benzo [1,3] dioxol-5-yl) indan-1-ol (10 g) in dichloromethane (300 ml). The mixture was stirred at room temperature for 40 minutes. The mixture was washed twice with water, dried (Mg§ ₄ ) and evaporated in vacuo to give 5- (3-chloroindan-1-yl) benzo [1,3] dioxol in quantitative yield as an oil, which was used in the next step without additional cleaning.

Obtaining compounds of the invention

Example 1. Trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (1) and cis- (3-benzo [1,3] dioxol-5-ylindan-1- silt) dimethylamine (2)

A mixture of 5- (3-chloroindan-1-yl) benzo [1,3] dioxol (11 g) and 70 ml of 33% dimethylamine in ethanol was kept at 100 ° C in a steel autoclave for 16 hours. The mixture was cooled and evaporated in vacuum. The residue was dissolved in diethyl ether and washed with water and 2 N. ΝαΟΗ. The organic phase was dried (magnesium sulfate), evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a gradient eluent: 1) ethyl acetate / heptane (80:20) and 2) ethyl acetate / ethanol / triethylamine (90: 10: 4) getting raw products in the form of clear oils.

Trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (1)

The slowly washed compound is the trans isomer (3 g).

'H NMR (SBS1 ₃ ): 1.95-2.05 (m, 1H); 2.30 (s, 6H); 2.60-2.70 (m, 1H); 4.40 (m, 2H); 5.90 (s, 2H); 6.55 (m, 1H), 6.65 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.25 (m, 1H), 7.45 (m , 1H). The compound may be converted to the ethyl acetate / ethanol fumarate salt as a white crystalline compound.

Cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (2)

The rapidly washed out compound is the cis isomer (1 g).

'H NMR (SBS1 ₃ ): 1.95-2.05 (m, 1H); 2.30 (s, 6H); 2.60-2.70 (m, 1H); 4.10 (m, 1H); 4.45 (m, 1H); 5.90 (s, 2H); 6.55 (m, 1H), 6.65 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.25 (m, 1H), 7.45 (m , 1H). The compound may be converted to the ethyl acetate / ethanol fumarate salt as a white crystalline compound.

The following compounds 3-14 were obtained similarly, the retention time of HPLC and purity are described in table. one:

trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) diethylamine (3), cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl ) diethylamine (4), trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylamine (5), cis- (3-benzo [1,3] dioxol-5-yl -indan-1-yl) ethylamine (6), ttrans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) methylamine (7), cis- (3-benzo [1,3 ] dioxol-5-yl-indan-1-yl) methylamine (8), trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylmethylamine (13), cis- (3 -benzo [1,3] dioxol-5-yl-indan-1-yl) ethylmethylamine (14), cis- [3 - (2,3-dihydrobenzo [1,4] dioxin-6-yl) indan-1 - yl] dimethylamine (15), trans- [3- (2,3-dihydrobenzo [1,4] dioxin-6-yl) indan-1-yl] dimethylamide in (16), cis-dimethyl- (3-naphthalen-2-yl-indan-1-yl) amine (17), trans-dimethyl- (3-naphthalen-2-yl-indan-1-yl) amine ( 18), cis- [3 - (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] dimethylamine (19), trans- [3- (6-chlorobenzo [1,3] dioxol- 5-yl) indan-1-yl] dimethylamine (20, cis- [3 - (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] methylamine (21), trans- [3- (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] methylamine (22),

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Table 1

Compound Time retention (min) Chistova% (UV) Purity% (EZB) one 1.88 85.18 99.12 2 1.9 93, 92 99.26 3 1.83 99.25 99.72 four 1.87 95.85 99.69 five 1,58 100 95.80 6 1.73 8691 99.74 7 1.79 94.36 99.59 eight 1.86 95.34 99, 70 13 1.83 78.3 98.1 14 1.89 81.8 93.3 15 1.73 78.1 99, 8 sixteen 1.68 84.7 92.7 17 2.10 92.5 99.8 18 2.10 92.8 99, 9 nineteen 2.08 75.1 97.7 20 1.89 96, 4 99.7 21 2.08 81.8 96.3 22 2.00 86.8 97.1 23 1.83 82,4 99.1 24 1.87 77.3 98.5

Example 2

(+) -trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (9) and (-) -trans- (3-benzo [1,3] dioxol-5 -yl-indan-1-yl) dimethylamine (10).

Compound 1, trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, was digested with chiral HPLC using a Supercritical Liquid Chromatography System Οΐίδοπ 5T3 equipped with C1ig1ce1O1 columns (4.6 mm x 25) cm for analysis and 10 mmx25 cm for preparative work). The particle size in the columns was 10 μm. A solution of compound 1, trans- (3-benzo [1,3] dioxol-5-yl-indan-1yl) dimethylamine (1 g) in methanol (1 ml) was injected in 40 μl portions into a preparative column. The column was eluted with carbon dioxide modifier (75:25). The modifier was 2-propanol with diethylamine (0.5%) and trifluoroacetic acid (0.5%). The flow rate was 18.9 ml / min at 20 MPa. Fractions were collected and determined in the UV region (210 nM). Fractions containing individual products were sedimented and evaporated in vacuo to give enantiomers 9 and 10.

(+) -trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (9): α = + 14.0 (conc. = 1% in methanol) (-) -trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (10): α = -14.7 (conc. = 1% in methanol)

Example 3

(+) - cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (11) and (-) - cis- (3-benzo [1,3] dioxol-5yl -indan-1-yl) dimethylamine (12)

Compound 2, cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, was digested with chiral HPLC using a Supercritical Liquid Chromatography System Οΐίδοπ 8Р3 equipped with С1иг1се1О1 columns (4.6 mm x 25 cm) for analysis and 10 mmx25 cm for preparative work). The particle size in the columns was 10 μm. A solution of compound 2, cis- (3-benzo [1,3] dioxol-5-yl-indan-1yl) dimethylamine (1 g) in methanol (1 ml) was injected in 40 μl portions into a preparative column. The column was eluted with carbon dioxide modifier (75:25). The modifier was 2-propanol with diethylamine (0.5%) and trifluoroacetic acid (0.5%). The flow rate was 18.9 ml / min at 20 MPa. Fractions were collected and determined in the UV region (210 nM). Fractions containing individual products were sedimented and evaporated in vacuo to give enantiomers 11 and 12.

(+) -cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (11): α = + 3.3 (conc. = 1% in methanol) (-) -cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine (12): α = -4.4 (conc. = 1% in methanol)

The following compounds were prepared analogously:

- 6 007655 (+) -Cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) methylamine (23) (-) -Cis- (3-benzo [1,3] dioxol -5-yl-indan-1-yl) methylamine (24)

Pharmacological tests

Compounds were tested using well-recognized and reliable tests. The tests were as follows:

Measurement of [ ³ H] noradrenaline uptake by rat cortical synaptosomes.

Fresh cerebral cortex of male rats ^ 1§1: ag (125-225 g) was homogenized in 0.32 M sucrose, softened with 1 mM nialamide, in a glass / Teflon homogenizer. The homogenate was centrifuged at 600 d for 10 min at 4 ° C. The granules were unloaded and the supernatant was centrifuged at 20,000 x d for 55 minutes. The final granules were homogenized (20 s) in the indicated test buffer mixture (6 mg of the original tissue / ml = 4 mg / well). The test compounds (or buffer mixtures) and 10 nM [ ³ H] -noradrenaline were added to the recesses of the 96-well plate and shaken briefly. The composition of the buffer mixture: 123 mM IaC1, 4.82 mM KC1, 0.973 mM CaC1 ₂ , 1.12 mM Md8O ₄ , 12.66 mM Ia ₂ NRA ₄ , 2.97 mM IaN ₂ PO ₄ , 0.162 mM ΕΌΤΆ, 10 mM glucose and 1 mm ascorbic acid. The buffer mixture was oxidized with 95% O ₂ /5% C0 ₂ for 10 min at 37 ° C and the pH was adjusted to 7.4. Incubation was started by adding tissue to the final sample volume of 1 ml. After 15 minutes of incubation with a radioligand at 37 ° С, the samples were filtered directly onto Ishiyeg SG / S glass fiber filters (impregnated for 1 h in 0.1% polyethyleneimine) in vacuum and washed immediately with 3x1 ml of buffer mixture. Non-specific uptake was determined using talsupram (final concentration of 10 μM). All experiments included duloxetine as a reference substance for the dose-response curve.

Measurement of capture of [ ³ H] -5-HT by rat cortical synatoprops.

The whole brain of male rats 1 1ь1агag (125-225 g), excluding the cerebellum, was homogenized in 0.32 M sucrose, softened with 1 mM nialamide, in a glass / Teflon homogenizer. The homogenate was centrifuged at 600 xd for 10 min at 4 ° C. The granules were discharged and the supernatant was centrifuged at 20,000 xd for 55 minutes. The final granules were homogenized (20 s) in the indicated buffer mixture (0.5 mg of the original tissue / well). Test compounds (or buffer mixtures) and 10 nM [ ³ H] -5-HT were added to a 96-well plate and shaken briefly. The composition of the buffer mixture: 123 mM IaC1, 4.82 mM KC1, 0.973 mM CaC1 ₂ , 1.12 mM Md8O ₄ , 12.66 mM Ia ₂ NRA ₄ , 2.97 mM IaN ₂ PO ₄ , 0.162 mM ΕΌΤΆ, 10 mM glucose and 1 mm ascorbic acid. The buffer mixture was oxidized with 95% O ₂ /5% CO ₂ for 10 min at 37 ° C and the pH was adjusted to 7.4. Cultivation was started by adding tissue to the final sample volume of 0.2 ml. After 15 min of cultivation with a radioligand at 37 ° С, the samples were filtered directly onto Ishiyeg SG / S glass fiber filters (impregnated for 1 h in 0.1% polyethyleneimine) in vacuum and immediately washed with 3x0.2 ml of test buffer mixture. Non-specific uptake was determined using citalopram (final concentration of 10 μM). All experiments included citalopram as a reference substance for the dose-response curve.

The experimental results showed that all compounds of the invention inhibit the uptake of norepinephrine and serotonin with 1C ₅₀ below 200 nM.

Claims (7)

Υ means -SK ⁶ K ⁷ -, -SK ⁶ K ⁷ -SK ⁸ K ⁹ - or -SK ⁶ = SK ⁷ -; or X and Υ together form a group —SK ⁴ = SK ⁵ or —SK ⁴ = SK ⁵ —SK ⁶ K ⁷ -; and and means -O-, -8- or -SK ¹⁰ K ¹¹ or X is —O—, —8— or —SK ⁴ K ⁵ -; and Υ and together form the group -SK ⁶ = SK ⁷ -, -SK ⁶ = SK ⁷ -SK ¹⁰ K ¹¹ - or -SK ⁶ To ⁷ -SK ¹⁰ = SK ¹¹ -; or X, and Υ, and together form —SC ⁴ = SC ⁵ —SC ⁶ = SC ⁷ -; K ¹ and K ^{2 are} independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, or K ¹ and K ² together with the nitrogen to which they are attached form a 3-7 membered ring, optionally containing one additional heteroatom; K ¹³ , K ¹⁴ , K ¹⁵ and K ¹⁶ , each independently selected from hydrogen, halogen, cyano, nitro, - 7 007655 S1_b -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl and C _3-8 -cycloalkyl; K is hydrogen, C _1-6 alkyl or cyano; K ⁴ , K ⁵ , K ⁶ , K ⁷ , K ⁸ , K ⁹ , K ¹⁰ and K ^{11 are} independently selected from hydrogen and C _1-4 alkyl; or an acid addition salt thereof. 2. The compound according to claim 1, where X and are selected from —O— and —8— and Υ means —SC ⁶ K ⁷ - or —SC ⁶ K ⁷ —SC ⁸ K ⁹ -. 3. The compound according to claim 1, where X, and Υ, and together form -SC ⁴ = SC ⁵ -SC ⁶ = SC ⁷ -. 4. The compound according to claim 1, which is trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, cis- (3-benzo [1,3] dioxol-5- yl-indan-1-yl) dimethylamine, trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) diethylamine, cis- (3-benzo [1,3] dioxol-5- yl-indan-1-yl) diethylamine, trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylamine, cis- (3-benzo [1,3] dioxol-5- yl-indan-1-yl) ethylamine, trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) methylamine, cis- (3-benzo [1,3] dioxol-5- yl-indan-1-yl) methylamine, (+) - trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, (-) - trans- (3-benzo [ 1,3] dioxol-5-yl-indan- 1-yl) dimethylamine, (+) - cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, (-) - cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) dimethylamine, trans- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylmethylamine, cis- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) ethylmethylamine, cis- [3 - (2,3-dihydrobenzo [1,4] dioxin-6-yl) indan-1-yl] dimethylamine, trans- [3- ( 2,3-dihydrobenzo [1,4] dioxin-6-yl) indan-1-yl] dimethylamine, cis-dimethyl- (3-naphthalen-2-yl-indan-1-yl) amine, trans-dimethyl- ( 3-naphthalen-2-yl-indan-1-yl) amine, cis- [3 - (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] dimethylamine, trans- [3- ( 6-chlorobenzo [1,3] dio xol-5-yl) indan-1-yl] dimethylamine, cis- [3 - (6-chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] methylamine, trans- [3- (6- chlorobenzo [1,3] dioxol-5-yl) indan-1-yl] methylamine, cis-enantiomer-1- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) methylamine and cis enantiomer-2- (3-benzo [1,3] dioxol-5-yl-indan-1-yl) methylamine or their acid addition salt. 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. 6. The use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for the treatment of affective disorders such as depression, anxiety disorders, including generalized anxiety disorders, social anxiety disorders, post-traumatic stress, compulsive compulsive disorder, acute anxiety disorders with a panic reaction, panic disorder, specific phobias, social phobia and fear of open space. 7. A method for treating affective disorders, including depression and anxiety disorders, including generalized anxiety disorder, social anxiety disorders, post-traumatic stress disorder, compulsive compulsive disorder, acute panic disorder disorders, panic disorders, specific phobias, social phobia and fear of open space, in higher animals, including humans, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 4 or its pharmaceutical and an acceptable acid addition salt.