KR20070107043A - Tartrate and malate salts of trans-1-((1r,3s)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine - Google Patents

Abstract

A tartrate and malate salt of trans-1-(6-chloro-3-phenylindan-1-yl)-3, 3-dimethylpiperazine, in particular for medical use, pharmaceutical formulations thereof, including for treatment of schizophrenia or other diseases involving psychotic symptoms.

Description

Tartrate and malate salts of trans-l-((lR, 3S) -6-chloro-3-phenylindan-l-yl) -3,3-dimethylpiperazine {TARTRATE AND MALATE SALTS OF TRANS-1- ( (1R, 3S) -6-CHLORO-3-PHENYLINDAN-1-YL) -3,3-DIMETHYLPIPERAZINE}

Tart of trans-1- (6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine for medical use including the treatment of schizophrenia or other diseases with psychotic symptoms Rate and maleate salts, and pharmaceutical formulations of such salts.

The compound (compound I, trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine), which is the subject of the present invention, is represented by the following general formula (I) Have

Compound I, and salts thereof, including fumarate and malate salts, are described in PCT / DK04 / 000546 (WO05 / 016901).

As described in PCT / DK04 / 000546, the inventors found that Compound I exhibits strong affinity for the dopamine (DA) D1 receptor, DA D2 receptor and alpha 1 adrenoceptor. In addition, Compound I was found to be an antagonist at the dopamine D1 and D2 receptors and the serotonin 5-HT2a receptor. As further described in PCT / DK04 / 000546, Compound I is a relatively weak inhibitor of CYP2D6 (ie, the likelihood of drug-drug interactions is reduced) and the impact on the QT interval in rabbit models is relatively Low (ie, the likelihood of introducing drug-induced QT interval prolongation and the appearance of lethal de pointes (TdP) in humans is reduced). In addition, the 5-HT ₂ antagonistic activity of Compound I suggests that Compound I may have a relatively low risk of extrapyramidal side effects.

The above specified properties such as binding assays (including alpha-1, DA D1 or D2 receptors), efficacy assays (including DA D1 or D2 receptors or serotonin 5-HT _2A receptors), CYP2D6 inhibition and QT intervals are described in PCT / DK04. It can be measured as described in / 000546 and can be compared in particular to the "Examples" portion of pages 19 to 24 of the application body filed in PCT / DK04 / 000546.

In addition, the inventors have shown that when tested in haloperidol sensitized pigs, compound I does not cause myotonia, indicating that compound I does not have an EPS (extravertebral symptom) response / trend in humans.

 PCT / DK04 / 000546 describes the following medicinal uses of compound I: psychosis, in particular schizophrenia (eg positive, negative and / or depressive symptoms), or for example schizophrenia, schizophrenia disorders, schizoaffective disorders, Central nervous system disorders, including delusional disorders, short-term psychotic disorders, other disorders with shared psychotic disorders, and other psychotic disorders or disorders exhibiting psychotic symptoms such as mania in bipolar disorder. Also described are the use of Compound I for the treatment of anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced Parkinson's disease, or cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders.

Compound I, as shown in PCT / DK04 / 000546, structurally related to the trans isomer of 3-aryl-1- (1-piperazinyl) indane substituted at the 2- and / or 3-position of the piperazine ring The group [EP 638 073; Bøgesø et al., J. Med. Chem., 1995, 38, 4380-4392 and Klaus P. Bøgesø, "Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Re1ated Compounds", 1998, ISBN 87-88085-10-4I] It is described in. For example, optically pure compounds which correspond to formula (I) but differ in that piperazine has N -methyl groups instead of N -hydrogen are described in Bøgesø et al., J. Med. Chem., 1995, 38, 4380-4392, Table 5, compound (-)-38.

None of the references, except PCT / DK04 / 000546, disclose any particular isomeric form of (compound I) or medical use thereof. The trans isomers in the form of racemic compounds of Compound I are described only in Bøgesø et al., J. Med. Chem., 1995, 38, 4380-4392, are indirectly disclosed as intermediates in the synthesis of compound 38, while the medical use of Compound I or its corresponding racemic compound is not described. Compound I as an intermediate is disclosed in PCT / DK04 / 000545 (WO05 / 016900).

1: X-ray powder diffractogram (obtained using copper K _α1 radioactivity (λ = 1.5406 kPa)) of the crystalline hydrogen maleate salt of compound I is shown.

2: X-ray powder diffractogram (obtained using copper K _α1 radioactivity (λ = 1.5406 Hz)) of the crystalline hydrogen tartrate salt of compound I.

Further details of the drawings are presented in the following examples.

The present invention relates to the maleate and tartrate salts of compound I. We find that it is generally difficult to obtain solid Compound I in the formation of salts suitable for pharmaceutical formulations, ie water or salts in the salts and / or crystals of Compound I having a well defined stoichiometry with respect to acid to base ratios. It has been found difficult to find and regenerate salts that are not solvates with organic solvents. The present invention overcomes the above problems with the maleate and tartrate salts described herein.

It has also been found that effective purification of compound I can be obtained during the preparation of compound I by precipitation of the salts of the present invention. Some cis diastereomers of Compound I (ie 1-((1S, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazin) form as impurities in the final product during synthesis Can be. We have found that the final content of cis isomers can be reduced by precipitation of the salts of Compound I described herein. In addition, purification of other impurities detected by HPLC was significantly improved by precipitation of the salts of the present invention (see Examples 10b and 11b).

Thus, in one aspect, the present invention relates to the maleate salt of Compound I (eg, L-maleate salt), which has a well defined stoichiometry with respect to acid to base ratios, eg For example, as with the 1: 1 salts of compound I and L-maleate, the ratio between compound I and malate is 1: 1.

A further embodiment of the invention relates to the crystalline L-maleate salt of Compound I, such as the crystalline maleate salt of Compound I, for example the crystalline 1: 1 L-maleate salt of Compound I. One embodiment of the invention relates to 1: 1 salts of Compound I and malic acid (eg L-malic acid) in crystalline form that are substantially anhydrous and solventless.

The present invention further relates to crystalline hydrogen L-maleate salts (1: 1 salts) of compound I characterized by one or more of the following.

(i) the X-ray powder diffractogram shown in FIG. 1;

(ii) an X-ray powder diffractogram pattern obtained using copper K _α1 radioactivity (λ = 1.5406 Hz) showing major peaks at the 2θ angles given in Table 1 below;

(iii) have a differential scanning calorimeter (DSC) trace showing endotherm at an onset temperature of 132-135 ° C;

(iv) substantially anhydrous and / or solventless.

The present invention also relates to the tartrate salt of Compound I (e.g., L-tartrate salt), which has a well defined stoichiometry with respect to the ratio of acid to base, for example Compound I Like the 1: 1 salt of and L-tartrate, the ratio between compound I and tartrate is 1: 1.

One embodiment of the present invention relates to the crystalline t-tartrate salt of Compound I, such as the crystalline 1: 1 L-tartrate salt of Compound I, for example. The present invention also relates to 1: 1 salts of compound I and tartaric acid (eg, L-tartaric acid) in substantially crystalline form of anhydrous and solventless.

A further embodiment of the invention relates to the crystalline hydrogen L-tartrate salt (1: 1 salt) of Compound I characterized by one or more of the following:

(i) the X-ray powder diffractogram shown in FIG. 2;

(ii) an X-ray powder diffractogram pattern obtained using copper K _α1 radioactivity (λ = 1.5406 Hz) showing main peak at the 2θ-angles given in Table 1 below;

(iii) have a differential scanning calorimeter (DSC) trace showing endotherm at an onset temperature of 195-199 ° C;

(iv) substantially anhydrous and / or solventless.

Characteristic reflection (2θ °) in X-ray powder diffractogram obtained using copper K _α1 radioactivity (λ = 1.5406 Hz) salt Characteristic reflection-main peak (expressed as the degree of diffraction angle 2θ) Hydrogen maleate 8.7, 9.9, 11.7, 13.1, 13.7, 15.1, 16.7, 18.9, 20.0 Hydrogen tartrate 8.2, 10.0, 10.6, 11.5, 12.2, 12.7, 15.0, 18.5, 19.1

The invention also relates to the salts of the invention having a purity of at least 90%, at least 95% or at least 98% as determined by HPLC (area).

As used herein, “the crystalline form of a particular salt of Compound I characterized by the X-ray powder diffractogram shown in FIG. (1)” yields an X-ray powder diffractogram that is substantially similar to FIG. (1). Eggplant, ie, a crystalline form of the salt of Compound I, which exhibits an X-ray powder diffraction pattern measured under conditions or in any corresponding manner substantially equivalent to that illustrated in FIG. 1 and described herein.

It can be judged by TGA analysis, for example, as described in the Examples herein, that the crystalline salts of the present invention are substantially anhydrous and solventless.

In general, all data herein are approximate and are understood to be subject to, for example, normal measurement errors depending on the machine used and other parameters affecting peak position and peak intensity.

 Furthermore, as set forth above, the present invention relates to crystalline salts of the present invention that are not solvates, ie, the crystalline salts of the present invention do not contain crystal binding solvent molecules. In particular, the present invention relates to 1: 1 crystalline salts of malic acid such as, for example, compound I and L-malic acid, which crystalline salts are not solvates. In a further embodiment the invention relates to 1: 1 crystalline salts of tartaric acid, such as compound I and L-tartaric acid, which is not a solvate.

In broad terms, the present invention relates to crystalline salts of Compound I, which are stoichiometrically defined salts, eg, the ratio between Compound I and each salt former is 1: 1. In one embodiment, this crystalline salt is substantially free of solvent, for example this crystalline salt is substantially anhydrous and free of solvent. In one embodiment, this crystalline salt is not a fumarate or malate salt of Compound I. In a further embodiment, the salt of Compound I is not selected from the group consisting of hydrogen chloride, fumarate salt and malate salt of Compound I.

Further embodiments of the present invention relate to salts of the invention that are at least 80% crystalline or at least 90% crystalline or at least 95% crystalline, and their use and formulations as described herein for Compound I.

Compounds of formula (I) in the form of racemic compounds are described, for example, in EP 638 073 and in Bøgesø et al., J. Med. Chem., 1995, 38, pages 4380-4392, i.e. compounds which are enantiomers of formula (I) by optical splitting of racemic compounds by crystallization of diastereomeric salts I can be obtained. Alternatively, compound I is described in international patent application PCT / DK04 / 000546 from pure V of enantiomers, ie compound Va ((1S, 3S) -6-chloro-3-phenylindan-1-ol, below). It may be obtained by the same method. Compound V has the following formula (V) in cis configuration:

.

.

Compound Va also has the following formula (Va) which is a cis configuration:

.

.

During synthesis as set out above, some cis diastereomers of Compound I (ie, 1-((1S, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazin) Is formed as an impurity in the final product. The cis forms of compound I are suitable salts of compounds of formula I, for example organic acid salts such as HCl or organoacids, for example L-(+)-maleate, L- (of compounds of formula I). It may alternatively or additionally be removed by precipitating the +)-tartarate, fumarate or malate salt and then optionally re-crystallizing once more. The cis form of Compound I can also be removed by precipitation of the maleate or tartrate salts of the present invention.

In general, the crystalline salts of the present invention may be prepared by mixing a solution of either reactant in a solvent, i.e., a suitable single solvent or a suitable solvent mixture, preferably at room temperature or at an elevated temperature, or It can be prepared by adding to the solid form of the other reactants and then precipitating the salt of crystalline Compound I. The term "solvent" as used herein includes both a single solvent or a mixture of different solvents. It is understood that the solvent may comprise water, for example when about 0% to 20% of water is present. Compound I can be prepared using methods known in the art, such as those described herein. The solvent is preferably an organic solvent, for example selected ketones or alcohols such as acetone, 2-propanol or ethanol.

The present invention also provides a process for the preparation of compound I, comprising the step of preparing and preferably isolating a salt of the invention, in particular a maleate or tartrate salt described herein.

A further aspect of the invention is to liberate and precipitate the base of compound I to obtain the free base of compound I, optionally in one or more recrystallized crystalline forms, and then convert to the maleate or tartrate salt of invention I It relates to a method for producing Compound I, characterized by the above-mentioned. In one embodiment, the base of Compound I is liberated from the crude salt or crude mixture of Compound I. The term crude mixture in this context means a mixture comprising one or more impurities to be removed, for example the cis diastereomer of Compound I set forth above. The crude mixture may be separated directly from the reaction mixture or the crude reaction mixture may undergo some initial purification. The present invention therefore also relates to malate or tartrate salts of, for example, Compound I obtained, which are obtainable by a process comprising the steps of: (i) base crystallization of Compound I, and (ii ), Then forming a maleate or tartrate salt of the present invention. Crystalline bases of Compound I can be prepared by crystallizing (optionally one or more times recrystallizing) the base of Compound I from a solvent such as ethyl acetate or heptane or a mixture thereof, as described in the Examples herein. .

The present invention also provides compounds of the formula [II] [trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin; Compound II], or a process for preparing a salt thereof, comprising the step of obtaining a free base of Compound II by methylation in a secondary amine of Compound I, alternatively, precipitating the compound as a salt, Compound I is prepared according to the process of the invention as described herein, ie, comprises in particular precipitating Compound I as a salt of the invention:

.

.

The process for the synthesis of compound II from compound I is described in WO05 / 016900. The salt of compound II can be, for example, a succinate or malonate salt and can be, for example, a hydrogen succinate salt or hydrogen malonate salt described in WO05 / 016900. In further embodiments, Compound II or a salt thereof may then be formulated into a pharmaceutical composition.

The nature of compound I suggests that it will be particularly useful as a medicament. Accordingly, the present invention further relates to pharmaceutical compositions of the salts of the present invention. The invention also relates to psychosis, in particular schizophrenia or schizophrenia, schizophrenic disorders, schizoaffective disorders, delusional disorders, short-term psychotic disorders, other disorders with psychotic symptoms such as shared psychotic disorders, and mania in bipolar disorder It relates to the medical use of the salts and compositions for the treatment of central nervous system diseases, including other psychotic disorders or diseases exhibiting psychotic symptoms such as.

The invention also provides an anxiety disorder, affective disorders including depression, sleep disorders, migraines, neuroleptic-induced Parkinson's disease, cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders It relates to the use of the salts of the invention.

The invention also relates to a method of treating mania in a schizophrenic disorder, schizoaffective disorder, delusional disorder, short term psychotic disorder, shared psychotic disorder or bipolar disorder comprising administering a therapeutically effective amount of a salt of the invention. .

A further embodiment of the invention relates to a method of treating positive symptoms of schizophrenia comprising administration of a therapeutically effective amount of a salt of the invention. Another embodiment of the invention relates to a method of treating negative symptoms of schizophrenia comprising administration of a therapeutically effective amount of a salt of the invention. A further embodiment of the present invention relates to a method of treating depressive symptoms of schizophrenia comprising administration of a therapeutically effective amount of a salt of the present invention.

A further aspect of the invention relates to a method of treating manic and / or sustained bipolar disorder comprising administering a therapeutically effective amount of a salt of the invention.

The present invention further relates to a method for the treatment of drug abuse, eg nicotine, alcohol or cocaine abuse, comprising administration of a therapeutically effective amount of a salt of the invention.

Particularly for pharmaceutical use in this context, when the form of the isomer is specified as formula (I) of compound I, the compound is relatively stereochemically pure, preferably at least 70% and more preferably enantiomeric excess Is understood to be at least 80% (80% enantiomeric means that the ratio of I to its isomer is 90:10 in the mixture), at least 90%, at least 96%, or preferably at least 98%. . In a preferred embodiment, the diastereomeric surplus of Compound I is at least 90% (90% diastereomeric surplus is Compound I vs. cis-1-((1S, 3S) -6-chloro-3-phenylindan-1-yl ), The ratio of 3,3-dimethylpiperazine is 95: 5), at least 95%, at least 97%, or at least 98%.

A further aspect of the invention relates to the treatment methods described herein wherein the patient treated with the salts of the invention is also treated with one or more other agents. In this regard, a particularly related embodiment is the treatment with other agents that are metabolized by CYP2D6. In suitable embodiments, the other agent is an antipsychotic. Thus, one embodiment relates to the use of a salt of the present invention for treating a patient suffering from schizophrenia or other psychotic patients who are also treated with other agents (eg, the other agent is an antipsychotic). In another embodiment, the present invention relates to the use of a salt of the present invention for treating a patient suffering from schizophrenia or other psychotic patients who are drug abusers of, for example, alcohol or drugs.

The compounds, salts or compositions of the invention may be administered by any suitable method such as, for example, oral, oral, sublingual or parenteral, and the compounds or salts may be in a form suitable for such administration, for example tablets, It may be presented as a capsule, powder, syrup, or an injectable solution or dispersion. In one embodiment, the compound or salt of the present invention is administered in the form of a solid pharmaceutical substance, suitably as a tablet or capsule.

Methods of preparing solid pharmaceutical formulations are well known in the art. Thus, tablets can be prepared by mixing the active ingredient with conventional adjuvants, fillers and diluents and then compacting the mixture in a conventional tablet press. Examples of adjuvants, fillers and diluents include cornstarch, lactose, talc, magnesium stearate, gelatin, gums and the like. Other auxiliaries or additives such as colorants, fragrances, preservatives and the like may also be used if compatible with the active ingredient.

Injectable solutions are prepared by dissolving the salts and possible additives of the present invention in a portion of the injection solvent, preferably in sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling into a suitable ampoule or vial. Can be. Any suitable additive commonly used in the art may be added, such as tonicity, preservatives, antioxidants, solubilizers and the like.

The daily dose of the compound of formula (I) calculated as the free base is suitably from 1.0 to 160 mg / day, more suitably from 1 to 100 mg, for example preferably from 2 to 55 mg.

As set forth above, the present invention relates in particular to:

Salts of the invention;

The pharmaceutical composition described herein comprising a salt of the invention;

The medical use of said salt of the invention as described herein for Compound I;

Wherein Compound I is at least 60% (60% enantiomeric means that the ratio of Compound I to its enantiomer is 80:20 in the mixture), at least 70%, at least 80%, at least 85%, 90 At least 96%, preferably at least 98% enantiomeric excess).

One embodiment relates to salts of the invention or pharmaceutical compositions and uses of the invention as described herein, wherein Compound I is at least 10% (10% diastereomeric surplus is Compound I vs. cis- (1S, 3S) means that the proportion of diastereomers is 55:45 in the mixture), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% , Preferably having at least 98% diastereomeric surplus).

As used herein, the term "treatment" associated with a disease also optionally includes prophylaxis. As used herein, “disease” also optionally includes a disorder.

The invention will be illustrated in the following non-limiting examples.

Analytical Method

Example 1 Compound of the mirror (Ⅴa) in the body is excess was determined by chiral HPLC using a 0.46cm ID X 25 cm L, 10μm in CHIRALCEL® OD column at 40 ℃. n-hexane / ethanol 95: 5 (volume / volume) was used as the mobile phase at a flow rate of 1.0 ml / min and detected using a UV detector at 220 nm.

Enantiomeric excess of Compound I was determined by fused silica capillary electrophoresis (CE) using the following conditions: capillary: 50 μm ID × 48.5 cm L, running buffer: 1.25 mM β cyclodextrin in 25 mM sodium dihydrogen phosphate, pH 1.5, voltage: 16 kV, temperature: 22 ° C., injection: 40 mbar for 4 seconds, detection: column diode assay detection 195 nm, sample concentration: 500 μg / ml. In this device, Compound I had a residence time of about 10 minutes and the other enantiomer had a residence time of about 11 minutes.

¹ H NMR spectra were recorded at 500.13 MHz with a Bruker Avance DRX500 instrument or at 250.13 MHz with a Bruker AC 250 instrument. Chloroform (99.8% D) or dimethyl sulfoxide (99.8% D) was used as solvent and tetramethylxylene (TMS) was used as internal standard.

The purity of compound I was determined by HPLC (eg also cis / trans ratio) using a Luna C18 (2) 150 * 4.6 mm (3 μm) column at 40 ° C. The mobile phase had a gradient of pH 7.4 phosphate buffer / acetonitrile 40/60, run time 60 minutes, after 32 minutes acetonitrile / water 90/10. Detection was made using a UV detector at 220 nm.

Cis / trans ratios and important intermediates of Compound I are described in Bøgesø et al., J. Med. Chem. 1995, 38, 4380-4392 (page 4388, right column), were determined using ¹ H NMR. In general, unwanted isomers in a content of about 1% can be detected by NMR.

Melting points were measured using differential scanning calorimetry (DSC). The apparatus is TA-Instruments DSC-Q10O, calibrated at 5 ° C. per minute to provide a melting point as starting value. About 2 mg of sample was heated to 5 ° C. per minute in a loosely closed pan under nitrogen leakage.

Thermogravimetric analysis ( TGA ), which is used to determine the solvent / water content of dry materials, was performed using a TA-instruments TGA-Q500. 1-10 mg samples were heated to 10 ° C. per minute in an open pan under nitrogen leakage.

X-ray powder diffractogram was measured with a PANalytical X'Pert PRO X-ray diffractometer using CuK _α1 radioactivity. This sample was measured in reflection mode in the 2θ-range 5-40 ° using an X'celerator detector.

The fluorescence was measured on a Perkin Elmer model 241 polarimeter.

Synthetic Method

Example  (1S, 3S) -6- using 1 chiral chromatography Chloro -3- Phenylindan -1-ol ( Va Synthesis of

Racemic cis-6-chloro-3-phenylindan-1-ol (V) (prepared as described in PCT / DK04 / 000546, ie using ethanol as a solvent and carrying out the reaction at about 0 ° C. [Bøgesø et al. , J. Med. Chem. 1995, 38, 4380-4392) (492 g) were prepared by preparative chromatography using a CHIRALPAK® AD column at 10 cm ID X 50 cm L, 10 μm at 40 ° C. Analyzed. Methanol was used as the mobile phase at a flow rate of 190 ml per minute and detected using a UV detector at 287 nm. Racemic chain alcohol (V) was injected as an aqueous 50,000 ppm solution in methanol; 90 ml were injected at 28 minute intervals. All fractions containing the title compound with greater than 98% enantiomeric excess were combined, evaporated to dryness using a rotary evaporator, and then dried in vacuo at 40 ° C. Yield as a solid 220 g. Basic analysis and NMR were consistent with the structure, and enantiomeric excess was higher than 98% according to chiral HPLC. [α] _D ^{2 0} + 44.5 ° (c = 1.0, methanol)

Example  2 (1S, 3S) -3,5- Dichloro -One- Phenylindan  synthesis

Cis- (1S, 3S) -6-chloro-3-phenylindan-1-ol (Va) (204 g) obtained as described in Example 1 was dissolved in THF (1500 ml) and cooled to minus 5 ° C. I was. Thionyl chloride (119 g) was added dropwise over 1 hour as a solution in THF (500 ml). The mixture was stirred at rt overnight. Ice (100 g) was added to the reaction mixture. The aqueous phase (A) and the organic phase (B) were separated when the ice dissolved and the organic phase (B) was washed twice with aqueous saturated sodium bicarbonate (200 ml). The aqueous sodium bicarbonate phase was combined with the aqueous phase (A) and adjusted to pH 9 with sodium hydroxide (28%), which was used to wash the organic phase (B) once again. The resulting aqueous phase (C) and organic phase (B) were separated and the aqueous phase (C) was extracted with ethyl acetate. The ethyl acetate phase was combined with organic phase B, dried over magnesium sulfate and evaporated to dryness using a rotary evaporator to afford the title compound as an oil. The yield is 240 g, which was used directly in Example 5a. The ratio of cis / trans to NMR was 77:23.

Example  3 Synthesis of 3,3-dimethylpiperazin-2-one

Potassium carbonate (390 g) and ethylenediamine (1001 g) were stirred with toluene (1.50 L). A solution of ethyl 2-bromoisobutyrate (500 g) in toluene (750 ml) was added. The suspension was heated to reflux overnight and filtered. The filter residue was washed with toluene (500 L). The combined filtrates (vol. 4.0 L) were heated in a water bath and distilled at 0.3 atmospheres using a C1aisen apparatus; The first 1200 ml distillate was collected at 35 ° C. (mixture temperature was 75 ° C.). More toluene was added (600 ml) and another 1200 ml distillate was collected at 76 ° C. (mixture temperature is 80 ° C.). Toluene (750 ml) was added again and 1100 ml of distillate was collected at 66 ° C. (mixture temperature was 71 ° C.). The mixture was stirred in an ice bath and injected to precipitate the product. The product was isolated by filtration, washed with toluene and dried overnight at 50 ° C. in a vacuum oven. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one. NMR was consistent with the structure.

Example  4 Synthesis of 2,2-dimethylpiperazine

A mixture of 3,3-dimethylpiperazin-2-one (8.28 kg, 64.6 mo1, a large formulation similar to the formulation described in Example 3) and tetrahydrofuran (THF) (60 kg) were heated to 50-60 ° C., A slightly cloudy solution was obtained. THF (50 kg) was stirred under nitrogen and LiAlH ₄ (250 g, in soluble plastic bag) was added, which caused slow evolution of the gas. After the end of gas evolution, additional LiAlH ₄ was added (3.0 kg total, 79.1 mol was used) and the temperature rose from 22 ° C. to 50 ° C. due to exotherm. A solution of 3,3-dimethylpiperazin-2-one was added slowly at 41-59 ° C. over 2 hours. The suspension was stirred at 59 ° C. for another hour (jacket temperature 60 ° C.). The mixture was cooled and water (3 L) was added over two hours keeping the temperature below 25 ° C. (cooling with a jacket temperature of 0 ° C. was required). Thereafter, aqueous sodium hydroxide (15%, 3.50 kg) was added at 23 ° C. over 20 minutes and cooling was needed. Additional water (9 L) was added over half an hour (need cooling) and the mixture was stirred under nitrogen overnight. Filter Celite (4 kg) was added and the mixture was filtered. The filter residue was washed with THF (40 kg). The combined filtrates were concentrated in the reactor until the temperature of the reactor reached 70 ° C. at 800 mbar (distillation temperature 66 ° C.). The remainder (12.8 kg) was further concentrated to about 10 liters on a rotary evaporator. Finally, the mixture was fractionally distilled at atmospheric pressure and the product was collected at 163-164 ° C. Yield 5.3 kg (72%). NMR was consistent with this structure.

Example  5a trans-1-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpi Ferrazinium (Compound I) Hydrogen Malate  Synthesis of Salts

 Cis- (1S, 3S) -3,5-dichloro-1-phenylindan (240 g) was dissolved in butan-2-one (1800 ml). Potassium carbonate (272 g) and 2,2-dimethylpiperazine (prepared as described in Example 4) (113 g) were added and the mixture was heated at reflux for 40 hours. Diethyl ether (2 L) and hydrochloric acid (1M, 6 L) were added to the reaction mixture. The phases were separated and the pH in the aqueous phase was lowered from 8 to 1 with concentrated hydrochloric acid. To ensure that all products are in the aqueous phase, the organic phase was washed once more with the aqueous phase. Sodium hydroxide (28%) was added to the aqueous phase until pH was 10, and the aqueous phase was extracted twice with diethyl ether (2 L). The diethyl ether extracts were combined, dried over sodium sulfate and evaporated to dryness using a rotary evaporator. Obtained as a free base (251 g) oil of compound I. According to NMR, the cis / trans ratio was 18:82. The crude oil (approximately 20 g) was further purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 90: 5: 5) and then evaporated to dryness using a rotary evaporator. The free base (12 g) of compound I was obtained as an oil. (Acs / trans ratio according to NMR is 10:90).

The oil was dissolved in ethanol (100 ml) and a solution of malic acid in ethanol was added until pH 3. The resulting mixture was stirred at rt for 16 h, and the formed precipitate was collected by filtration. The volume of ethanol was reduced and another batch of sediment was collected. 3.5 g of solid, ie Compound I hydrogen malate salt of the title compound, were obtained (cis isomer was not detected according to NMR).

According to the CE, the enantiomeric surplus was above 99%. Melting point 175-178 ° C. NMR was consistent with the structure.

Example  5b trans-1-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpiperazinium  (Compound I) Hydrogen  Synthesis of Chloride Salts

Cis- (1S, 3S) -3,5-dichloro-1-phenylindane (large scale formulation similar to the formulation as described in Example 2) (50.9 kg) was dissolved in MIBK (248 kg). Potassium carbonate (56.8 kg) and 2,2-dimethyl piperazine (29.6 kg) were added and the mixture was heated to 100 ° C. for 8 hours. After cooling the reaction mixture to room temperature, the insoluble inorganic material was removed by filtration. The filtrate is then washed with water (520 L), the phases are separated and the pH of the organic phase is adjusted to a value between 3 and 6 by gentle addition of hydrogen chloride (15.4 kg, 37% aqueous solution), and the product is separated during the addition. It was. The product was filtered through a suction filter (nutsche) and the filter residue was washed with MIBK (100 kg) and cyclohexane (80 kg). The product was dried at 50 ° C. and 0.05 bar for 12 hours.

Yield: 40 kg. Compound I (cis isomer was not detected according to NMR analysis. The enantiomeric excess was greater than 99% according to CE. The NMR spectrum was consistent with the structure.

Example  6a Hydrogen Malate  Synthesis of Free Base of Compound I from Salt

Trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium hydrogen maleate (9.9 g), concentrated aqueous ammonia (100 ml), A mixture of brine (150 ml) and ethyl acetate (250 ml) was stirred for 30 minutes at room temperature. The phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. 7.5 g of compound I were obtained as an oil, which could solidify if left alone. NMR was consistent with the structure.

Example  6b Hydrogen  Synthesis of Free Base of Compound I from Chloride Salt

The free base of compound I is trans- as a substituent for trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium hydrogen maleate. Prepared as described in Example 6a using 1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium hydrogen chloride.

Yield of compound I was 9.0 g, starting from trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium hydrochloride 10.2.

Example  Preparation of Crystalline Base of Compound I from 7a 6a

Compound I (9.0 g obtained as described in Example 6a) was dissolved in ethyl acetate (30 ml), and then heptane (75 ml) was added to this solution. This solution was left under stirring for 4-16 hours. In some cases crystallization was observed and crystalline material was collected by filtration. In other cases, no crystallization was observed and some of the solvent was removed by distillation. The distillation stopped when the distillation temperature changed from the boiling point of ethyl acetate to the boiling point of heptane. The remaining solution was left at ambient temperature to cool to room temperature and placed in a water / ice bath prior to filtration. Crystallization can be started by scraping or seeding with a free spatula. Crystalline Compound I was isolated by filtration. Yield 6.8 g (74%). NMR was consistent with the structure. Melting point: 92.4 ° C. (DSC onset temperature), enantiomeric excess according to CE was greater than 99%.

Example  Preparation of Crystalline Base of Compound I from 7b 6b

Prepared as described in Example 7a starting with 9.0 g of crude base. Yield 6.8 g. The melting point was 92.3 ° C. (DSC onset temperature) and the enantiomeric excess determined by CE was greater than 99%.

Example  8 Crystalline Base of Compound I Characterization

The crystalline base of Compound I obtained in the same manner as described in Examples 7a and 7b had an X-ray powder diffractogram (XRPD) shown in FIG. 1 and 2θ angles: 6.1, 11.1, 12.1, 16.2, 16.8, 18.3, Characterized by the following reflection (peak) in X-ray powder diffractogram measured using CuK _α1 radioactivity at 18.6, 20.0. The crystalline base additionally had a DSC thermogram corresponding to that of FIG. 2 and a DSC trace starting at about 91-93 ° C. and showing endotherm. The crystalline base obtained was anhydrous and solventless as determined from TGA analysis.

Example  9 trans-1-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethyl pipe Ragenium (Compound I) Fumarate  Synthesis of Salts

 A solution of trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (obtained as described in Example 6a) (1 g) It was dissolved in acetone (100 ml). To this solution a fumaric acid solution in ethanol was added until the pH of the resulting solution became 4. The resulting mixture was cooled in an ice bath for 1.5 hours, whereby a precipitate formed. Solid compound was collected by filtration. The compound was dried in vacuo to yield a white solid compound (1.0 g). Enantiomeric excess was greater than 99%. Melting point 193-196 캜. NMR was consistent with the structure.

Example  10a trans-1-(( 1R , 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpi Ferrazinium (Compound I) L- Tartrate  Synthesis of Salts

Trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (obtained as described in Example 6b) (2 g) was added to ethanol ( 20 ml). 1-tartaric acid (0.88 g) was added at 60 ° C. When precipitation was detected, the reaction mixture was cooled to below room temperature and kept at this temperature for 1 hour. The precipitate of trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium L-tartrate was filtered off, and the residue was filtered off with ethanol (5 ml). The filter residue was aspirated without most of the solvent and the product was dried “in vacuum” at 50 ° C. overnight. TGA analysis showed a weight loss of only 0.5% or less, so the product was considered substantially free of residual solvent or water.

Yield 2.50 g (87%), enantiomeric excess was greater than 99%.

Example  10b trans-1-(( 1R , 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpi Ferrazinium (Compound I) L- Tartrate  Synthesis of Salts

Compound I (2.4 g of crude oil obtained as described in Example 5a, purity determined by HPLC: 73 area%, cis / trans ratio of 17/73) was dissolved in ethanol (20 ml). L-tartaric acid (1.06 g) was added at 60 ° C. The reaction mixture was cooled to below room temperature when a precipitate was detected and kept at this temperature for one hour. The precipitate of trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium L-tartrate was filtered off and the ethanol (10 ml). The filter residue was aspirated without most of the solvent and the product was dried “in vacuum” at 50 ° C. overnight. Yield 2.01 g. Further purification was by recrystallization from ethanol. Yield: 1.1 g. NMR was consistent with the structure. Since TGA analysis showed no weight loss before decomposition occurred, the product was considered to be practically free of residual solvent or water. HPLC purity (area%): 96%, content of cis-trans: 4%, enantiomeric excess according to CE was greater than 99%.

Example  11a Trans-1-(( 1R , 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpi Ferrazinium (Compound I) L- Malate  Synthesis of Salts

Trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (obtained as described in Example 6b) (2 g) It was dissolved in propanol (20 ml). L-malic acid (0.79 g) was added at 60 ° C. When a precipitate was detected the reaction mixture was cooled to below room temperature and kept at this temperature for 1 hour. The precipitate of trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium L-maleate is filtered off and the residue is filtered through 2-propanol ( 5 ml). The filter residue was aspirated free of most solvent before the product was dried “in vacuum” at 50 ° C. overnight. The product was considered to be substantially free of residual solvent or water as the TGA analysis showed only 0.5% or less weight loss.

Yield 2.38 g (85%). Enantiomeric excess was greater than 99%.

Example  11b Trans-1-(( 1R , 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpi Ferrazinium (Compound I) L- Malate  Synthesis of Salts

Compound I (2.25 g of crude oil obtained as described in Example 5a, purity determined by HPLC: 73% area, cis / trans ratio of 17/73) was dissolved in 2-propanol (22.5 ml). L-malic acid (0.89 g) was added at 60 ° C. When a precipitate was detected the reaction mixture was cooled to below room temperature and kept at this temperature for 1 hour. The precipitate of trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium L-maleate was filtered off and the residue was filtered through 2-propanol ( 10 ml). Before the product was dried “in vacuum” at 50 ° C. overnight, the filter residue was aspirated free of most solvent. Since TGA analysis showed no weight loss before decomposition occurred, the product was considered substantially free of residual solvent or water.

Yield 1.55 g. NMR was consistent with the structure. HPLC purity (area%): 96%, cis isomer content: 2%. Enantiomeric surplus according to CE was greater than 99%.

Example  12 L- Malate  And L- Tartrate salt  Specialization

L-maleate and L-tartrate salts obtained by the methods described in Examples 10 and 11 above were crystalline and stoichiometric as 1: 1 salts, meaning that they are hydrogen L-maleate and hydrogen L-tartrate, respectively. Well defined.

1 shows the X-ray powder diffractogram of the crystalline hydrogen L-maleate salt of compound I. 2 shows an X-ray powder diffractogram of the crystalline hydrogen L-tartrate salt of Compound I.

The salt was a crystalline solid. The solubility of the maleate salt was 0.8 mg / ml and the solubility of the tartrate salt was 0.5 mg / ml.

Claims (42)

As the maleate salt of compound I, wherein compound I (trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine) is represented by the formula Salts with

. The salt according to claim 1, which is the L-maleate salt of Compound I. The salt according to claim 1 or 2, which is a salt of 1: 1. The salt according to any one of claims 1 to 3, which is crystalline. 2. The salt of claim 1 which is a crystalline 1: 1 L-maleate salt of Compound I. The salt according to claim 5, characterized by an X-ray powder diffractogram corresponding to that of FIG. 1. 7. X according to claim 5 or 6, obtained using CuK _α1 radioactivity (λ = 1.5406 Hz) showing peaks at the following 2θ angles: 8.7, 9.9, 11.7, 13.1, 13.7, 15.1, 16.7, 18.9, 20.0 Salt characterized by a ray powder diffractogram. 8. Salt according to any one of claims 1 to 7, characterized in that it has a DSC trace showing an endotherm with an onset temperature of about 132-135 ° C. As the tartrate salt of compound I, wherein compound I (trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine) is represented by the formula Salts with

. The L-tartrate salt of compound I according to claim 9. The salt according to claim 9 or 10, which is a salt of 1: 1. The salt according to any one of claims 9 to 11, which is crystalline. The crystalline 1: 1 L-tartrate salt of Compound I according to claim 9. The salt according to claim 13, characterized by an X-ray powder diffractogram corresponding to that of FIG. 2. 15. The X according to claim 13 or 14, obtained using CuK _α1 radioactivity (λ = 1.5406 Hz) exhibiting peaks at the following 2θ angles: 8.2, 10.0, 10.6, 11.5, 12.2, 12.7, 15.0, 18.5, 19.1 Salt characterized by a ray powder diffractogram. 16. The salt according to any one of claims 9 to 15, having a DSC trace showing an endotherm with an onset temperature of about 195 to 199 ° C. The salt according to any one of claims 1 to 16, wherein at least 80% is crystalline. 18. The salt according to any one of claims 1 to 17, which is a substantially anhydrous crystalline salt of Compound I. 19. The salt of claim 18, wherein the salt is free of solvent. 20. The salt according to any one of claims 1 to 19, wherein compound I has a purity of at least 95% or at least 98% as measured by HPLC (area). A pharmaceutical composition comprising the salt of claim 1. The pharmaceutical composition of claim 21 wherein the enantiomeric excess of Compound I is at least 70%, at least 80%, at least 90%, at least 96% or at least 98%. The pharmaceutical composition of claim 21 wherein the diastereomeric surplus of Compound I is at least 80%, at least 90%, at least 96% or at least 98%. The salt according to any one of claims 1 to 20 for medical use. A disease selected from the group consisting of disorders with psychotic symptoms, anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced Parkinson's disease or abuse disorders such as cocaine abuse, nicotine abuse or alcohol abuse Use of a salt according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of. Use of a salt according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of schizophrenia or other psychotic disorder. 1 to 1 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of schizophrenia, schizophrenia disorder, schizophrenia disorder, delusional disorder, short term psychotic disorder, shared psychotic disorder, and bipolar disorder Use of a salt according to claim 20. Use of a salt according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of one or more of the positive, negative and depressive symptoms of schizophrenia. Diseases involving psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, comprising administering a therapeutically effective amount of a salt according to any one of claims 1 to 20 , Neuroleptic-induced Parkinson's disease or a disorder selected from the group consisting of abuse disorders such as cocaine abuse, nicotine abuse or alcohol abuse. The method of claim 29, wherein the schizophrenia or other psychotic disorder is treated. 31. The method of claim 30, wherein at least one of the positive, negative and depressive symptoms of schizophrenia. 20. Schizophrenia, schizophrenia disorders, schizophrenia disorders, delusional disorders, short-term psychotic disorders, shared psychotic disorders, comprising administering a therapeutically effective amount of a salt according to any one of claims 1 to 20, And mania in bipolar disorder. Use according to any one of claims 25 to 28, or a method according to any one of claims 29 to 32, wherein the patient is also treated with one or more other agents besides compound I. . A process for preparing Compound I or a salt thereof, comprising the step of preparing and isolating a salt according to any one of claims 1 to 20. A process for the preparation of compound I, wherein the base of compound I is liberated, precipitated in crystalline form, optionally re-crystallized one or more times, and then with a salt of compound I according to any one of claims 1 to 20. How to switch. 36. The process of claim 35, wherein the base of Compound I is liberated from the crude salt of Compound I or the crude mixture. 37. The method of any one of claims 34 to 36, further comprising preparing a pharmaceutical composition comprising said compound I. 38. The compound according to any one of claims 34 to 37, which comprises crystallizing the base of compound I by precipitation from a solvent such as heptane and separating the solvent from the crystalline base of compound I obtained. Process for obtaining crystalline base of I. 39. The process according to any one of claims 34 to 38, comprising the step of obtaining a free base of the compound of formula II by methylation in the secondary amine of compound I.

. 40. The process of claim 39, wherein the compound of formula II is precipitated as a salt. 41. The process of claim 40, wherein the salt formed is a succinate or malonate salt of Compound II. 42. The method of claim 39, further comprising preparing a pharmaceutical composition comprising Compound II or a salt thereof.

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