ME00154B - Succinate and malonate salt of trans-4-(ir,3s)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and the use as a medicament - Google Patents

Abstract

4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine hydrogen succinate or hydrogenmalonate, pharmaceutical compositions containing these salts, and their medical uses, including treatment for schizophrenia and others psychotic disorders. Methods for the preparation of 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine and their use in medicine are also described. 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine hydrogen succinate or hydrogenmalonate, pharmaceutical compositions containing these salts, and their medical uses, including treatment for schizophrenia and others psychotic disorders. Methods for the preparation of 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine and their use in medicine are also described.

Description

The present invention relates to 4-((7R3S)-6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine, especially its hydrogensuccinate and hydrogenmalonate salts, processes for the preparation of 4-((1R, 3S) -6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine and its salts, pharmaceutical compositions containing these salts and their use, including the treatment of schizophrenia and other diseases involving psychotic symptoms.

STATE OF THE ART

The compound, which is the subject of the present invention [4-((1R, 3S)-6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine] has the general formula (I):

and is generically described in EP 638 073.

EP 638 073 covers a group of trans isomers of 3-aryl-1-(1-piperazinyl)indanes substituted at the 2- and/or 3-position of piperazine prestenes. These compounds have been described as having high affinity for dopamine D1 and D2 receptors and the 5-HT2 receptor and have been suggested to be useful for the treatment of several central nervous system diseases, including schizophrenia. EP 638 073 does not disclose the specific enantiomeric form of the above compound of formula (I), only trans isomers in racemate form are described.

The enantiomer of the above formula (I) was described by Bogeso et al. in J. Med. Chem., 1995, 38, 4380-4392, in the form of the fumarate salt, see Table 5, compound (-)-38. This publication concludes that the (-)-enantiomers of compound 38 are potent DJD2 antagonists that display some D1 selectivity in vitro while being equipotent as a Dt and D2 antagonist in vivo. The compound is also described as a potent 5-HT2 antagonist, which has a high affinity for adrenoceptors. It was also mentioned that the compound does not cause catalepsy in rats.

The corresponding racemate as well as the fumarate salt of the above compound of formula (I) is also described by Klaus P. Bogeso in "Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindanes and Related Compounds", 1998, ISBN 87-88085-10- 4 (compare, e.g., compound 69 in Table 3, p47 and Table 9A, p101).

Thus, the compound of formula (I) is mixed D! /D2 antagonists, 5-HT2 antagonist and also has affinity for a- and adrenoceptors. In the following, the possible connection between various diseases and dopamine D1 and D2 receptors, 5-HT2 receptors and α1 adrenoceptors, each individually, is highlighted.

The etiology of schizophrenia is unknown, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173), formulated in the early 1960s, provides a theoretical framework for understanding the biological mechanisms underlying this disorder. In its simplest form, the dopamine hypothesis asserts that schizophrenia is associated with a hyperdopaminergic state, a proposition supported by the fact that all antipsychotic drugs on the market today exhibit some dopamine D2 receptor antagonism (Seeman Science and Medicine 1995, 2, 28-37). However, where it is generally accepted that antagonism of dopamine D2 receptors in limbic brain regions plays a key role in the treatment of positive symptoms of schizophrenia, blockade of D2 receptors in striatal brain regions induces extrapyramidal symptoms (EPS). As described in EP 638 073 mixed dopamine D 1 /D 2 receptor inhibition profiles have been observed with certain so-called "atypical" antipsychotic compounds, especially clozapine, used in the treatment of schizophrenic patients.

Central antagonist actions are also suggested to contribute to enhanced antipsychotic properties (Millan et al, JPET, 2000 292, 3853).

Furthermore, selective Di antagonists have been associated with the treatment of sleep disorders and alcohol abuse (D. N Eder, Current Opinion in Investigational Drugs, 2002 3(2): 284-288).

Dopamine may also play an important role in the etiology of affective disorders (P. Villner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237246; J. Med. Chem. 1985, 28, 1817-1828) .

EP 638 073 describes how compounds having an affinity for 5-HT2 receptors, in particular 5-HT2 receptor antagonists, are suggested for the treatment of various diseases, such as schizophrenia including negative symptoms in schizophrenic patients, depression, anxiety, panic disorder, migraine attacks and neuroleptics. - induced parkinsonism. 5-HT2 receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

BRIEF DESCRIPTION OF PICTURES

Figure 1: Shows the X-ray powder diffraction pattern of the alpha crystalline form

hydrogen succinate salt of Compound I (obtained using copper Kα1 radiation (λ=1.5406 Å))

Figure 2: Shows the powder X-ray diffraction pattern of the beta crystalline form

hydrogen succinate salt of Compound I (obtained using copper Kα1 radiation (λ=1.5406 Å))

Figure 3: Shows the powder X-ray diffraction pattern of hydrogen malonate salt

Compounds I (obtained using copper Kα1 radiation (λ=1.5406 Å))

DETAILED DESCRIPTION OF THE INVENTION

Salts of invention

It has been found that the aqueous solubility of the hydrogen succinate salt and the hydrogen malonate salt of the compound of formula (I) is significantly greater than the aqueous solubility of the corresponding fumarate salt.

How is the term "hydrogen succinate" used here?

of formula (I) refers to a 1:1 ratio of a salt of a compound of formula (I) and succinic acid.

How is the term "hydrogen malonate" used here?

of formula (I) refers to the ratio of 11 salts of compounds of formula (I) and malonic acid

The hydrogen succinate salt was found to be more stable than the fumarate salt and then than the hydrogen malonate salt and to be non-hygroscopic

The hydrogen malonate salt of Compound 1 was found to have stability similar to the fumarate salt when exposed to light and more stable when exposed to 60°C/80% relative humidity (RH), but less stable than the fumarate salt at 90°C. 90°C is still a very stressful condition, and does not necessarily apply to

stability under normal conditions. Malonate absorbs gradually up to 1%

of water when the relative humidity rises to 95%, but not with hysteresis. Therefore, it is considered non-hogroscopic, but with good wetting properties, which indicates good favorable solubility properties.

The invention also covers crystalline salts of the invention, n. pr, anhydrates, hydrates, and solvates of salts of the invention. The term "anhydrate" refers to the salts of the invention that do not contain crystals bound by water. Hydrates are the salts of the invention that contain crystals bound by water molecules. Hydrates are usually prepared by forming salts in the presence of some water. By solvates are meant salts of the invention that contain crystals bound by solvent molecules. Solvates are usually prepared

by forming a succinate salt in the presence of a solvent. Solvent molecules in one solvate can be from one or two different solvents. The solvate may consist of water as one of two or more organic solvents or may be a non-aqueous solvent only.

One embodiment of the invention relates to the 1: 1 salt of trans-4-((1R, 3S)-6-chloro-S-phenylindan-1-yl-I, Ž, Ž-trimethylpiperazine, i.e. the compound of formula (I), and amber acid in the form of crystalline anhydrate.

The inventors have discovered 2 crystalline forms of the hydrogen succinate salt of Compound I (named alpha and beta).

Thus, one embodiment relates to a crystalline form of the hydrogen succinate salt of Compound I, a form referred to as alpha and characterized by one or more of:

(i) X-ray powder diffractogram as shown in Figure 1;

(ii) the model X-ray powder diffractogram as illustrated in Table I obtained using copper Kα1 radiation (λ=1, 5406 Å) showing the main peaks at the given 2θ-angles;

(iii) have DSC (Differential Scanning Calorimetry) traces showing a rapid onset endotherm at 139-141 °C.

A further embodiment relates to a crystalline form of the hydrogen succinate salt of Compound I, a form called beta and characterized by one or more of:

(i) X-ray powder diffractogram as shown in Figure 2;

(ii) the model X-ray powder diffractogram as illustrated in Table I obtained using copper Kα1 radiation (λ=1, 5406 Å) showing the main peaks at the given 2θ-angles;

(iii) have DSC traces indicating a rapid onset endotherm at 135-138°C

A further embodiment relates to a crystalline hydrogen malonate salt of Compound I characterized by one or more of:

(i) X-ray powder diffractogram as shown in Figure 3;

(ii) the model X-ray powder diffractogram as illustrated in Table I obtained using copper Kα1 radiation (λ=1, 5406 Å) showing the main peaks at the given 2θ-angles.

Table 1. Characteristic powder X-ray diffractograms obtained using Kα1 radiation (λ=1, 5406 Å) of the crystal forms of the alpha and beza hydrogensuccinate salts of Compound I, and the crystalline hydrogenmalonate salts of Compound I. Figure: compare also Figure 1, Figure 2 and Figure 3 which provide a representative XRPD pattern of the alpha and beta hydrogen succinate and malonate salts of Compound I, respectively.

As used herein, the expression "a crystalline form of a specific salt of Compound I characterized by the X-ray powder diffraction pattern shown in Figure (1)" means a crystalline form of the salt of Compound I in question having an X-ray powder diffraction pattern substantially as given for example in that Figure measured under comparable conditions as described here or by means of a comparative procedure.

In general, all data given here should be understood as approximate and subject to normal measurement error depending on, n. eg, the equipment used and other parameters that affect the highest positions and the highest intensities.

The invention also relates to the solid hydrogensuccinate salt of Compound I, the solid salt containing mainly the alpha form compared to the total amount of salt. In one embodiment, the term "substantially" means that the solid hydrogensuccinate salt of Compound I consists of at least 75%, such as at least 80%, at least 90%, or at least 95% of the crystalline alpha form compared to the total hydrogensuccinate salt of Compound I present.

The invention also relates to a solid form of the hydrogensuccinate salt of Compound I, the solid state of which consists mainly of the beta form compared to the total amount of salt. In one embodiment, the term "predominantly" means that the solid hydrogensuccinate salt of Compound I consists of at least 75%, such as that is at least 80%, at least 90%, or at least 95% of the crystalline beta form compared to the total hydrogen succinate salt of Compound I present.

The invention also relates to any mixture of crystalline forms of the hydrogen succinate salt of the invention, n. e.g., a mixture of alpha and beta crystalline form of the hydrogen succinate salt of Compound I

Preparation of the salt of the invention

The succinate salt according to the invention can be obtained by treating the free base of the compound of formula (I) with succinic acid in an inert solvent followed by precipitation, isolation and optionally recrystallization. If desired, the crystalline salt can then be subjected to micronization by wet or dry milling or other suitable process, or by preparing particles from a solvent-emulsification process.

Precipitation of the succinate salt of the invention is presumably performed by dissolving the free base of compound (I) in a suitable solvent. such as acetone or toluene, and then stirring this solution to a suspension of the H1 solution of succinic acid in a suitable solvent, such as acetone, aqueous acetone or toluene. In one embodiment, the solvent is a mixture of acetone and water, n. eg, a mixture consisting essentially of acetone and about 2% to 10%, assumed to be 5% water, based on the weight of the mixture. The resulting suspension may be heated or solvent may be added until the succinic acid dissolves. The succinate salt of the compound of the invention precipitates, presumably after cooling the solution. The succinate salt of the invention can optionally be recrystallized one or more times and isolated by filtration, washed, n. eg, with acetone, and dried.

The invention also relates to a process for preparing the crystalline beta form of the hydrogen succinate salt of Compound I, a process consisting of

The malonate salt can be obtained using analogous procedures. Accordingly, the malonate salt of the invention can be obtained by treating the free base of the compound of formula (I) with malonic acid in an inert solvent followed by precipitation, isolation and optional recrystallization. If desired, the crystalline salt may then be subjected to micronization by wet or dry milling or other suitable process, or by preparation of particles from a solvent-emulsification process.

Precipitation of the malonate salt of the invention is presumably performed by dissolving the free base of compound (I) in a suitable solvent, n. pr2-propanol, and then mixing this solution to a suspension or solution of malonic acid in a suitable solvent, n. eg, 2-propanol. The suspension can be heated until all the malonic acid is dissolved. The malonate salt of the compound of the invention precipitates, presumably after cooling the solution. The malonate salt of the invention can optionally be recrystallized one or more times and isolated by filtration, washing, n. e.g., in 2-propanol, and dry.

Preparation of compounds of formula (I)

The compound of formula (I) in racemic form can be prepared as described in EP 638 073, and Bogeso et al. J. Med. Chem., 1995, 38, page 4380-4392, where it is described how the optical separation of the racemic compound can be achieved by crystallizing diastereomeric salts and thus obtaining enantiomers of formula (I).

The present inventors have developed a synthetic route in which the enantiomer of formula (I) is obtained by a synthetic sequence starting from the enantiomerically pure V, that is, the compound Va ((1S, 3S)-6-chloro-3-phenylindan-1-ol, see below) . Thus, in this process, the intermediate product of formula V is resolved, either by chiral chromatography or enzymatically, to obtain the enantiomer of formula Va. This new synthesis route to obtain the compound of formula (I) is more efficient than the above-mentioned crystallization of the diastereomeric salts of the final product I. More precisely, the separation yield is significantly higher in this new procedure (45% compared to the amount of starting racemic material, i.e., the maximum theoretical yield is 50%) compared with the yield (22% relative to the amount of starting racemic material, therefore, the maximum theoretical yield is 50%) by separation of the final product and crystallization of diastereomeric salts. A further advantage of the present invention is that the enantiomeric purity of (I) is higher (greater than 99% e v) when synthesized according to the invention compared to the synthesis using the crystallization of diastereomeric salts (95.4% e. v). Moreover, the separation of the intermediate product instead of the final product gives a much more efficient synthesis, since only the desired enantiomer is used in the latter steps, giving, n. eg, higher volume yields and lower reagent consumption.

Accordingly, the enantiomer of formula (I) may be obtained by a process comprising the following steps:

Benzyl cyanide reacts with 2 5-dichlorobenzonitrile in the presence of a base, suitable potassium tert-butoxide (t-BuOK) in a suitable solvent such as dimethyl ether (DME), and further reaction with methyl chloroacetate (MCA) leads to spontaneous ring closure and one in the shape of a vessel forming a compound of formula (II).

The compound of formula (II) is then subjected to acid hydrolysis to form the compound of formula (III), conveniently by heating in a mixture of acetic acid, sulfuric acid and water, and then decarboxylated by heating the compound of formula (III) in a suitable solvent, such as toluene with triethyl amine or N-methyl pyrrolidin-2-one: to form a compound of formula (IV).

The compound of formula (IV) is then reduced, conveniently with NaBH 4 in a solvent such as alcohol, n. e.g., ethanol or iso-propanol, and assumed at a temperature ranging from -30°C to +30°C, n. eg below 30°C, below 20°C, below 10°C, or presumably below 5°C, to form a compound of formula (V) with the cis configuration:

Separation (V) to (Va) can, n. e.g., be performed using chiral chromatography, presumably liquid chromatography 7 conveniently on a chiral column of silica gel coated with a chiral polymer, n. eg, modified amylose, presumably amylose tris-(3,5-dimethylphenylcarbamate) coated on silica gel. Suitable solvents are used for chiral liquid chromatography, such as, n. e.g., an alcohol, nitrile, ether, or alkane, or mixtures thereof, suitably ethanol, methanol, iso-propanol, acetonitrile, or methyl tert-butyl ether or mixtures thereof, preferably methanol or acetonitrile. Chiral liquid chromatography can be scaled up using suitable technologies, n. eg, simulated moving bed (SMB) technology.

Alternatively, a compound of formula (V) is cleaved to afford Compound Va by enzymatic cleavage. It has been found that enantiomerically pure Compound Va, or its acylated derivatives, can be prepared by enzymatic enantio-selective acylation of the hydroxyl group in racemic Compound V to give Compound Va or its acylated derivative with high optical purity. Alternatively, an enantiomerically pure Compound

Va can also be obtained by a process consisting of converting racemic Compound V to the corresponding ester at the hydroxyl position followed by enantioselective deacylation by enzyme. The use of enzymatic enantio-selective deacylation has already been reported for other compounds.

Accordingly, the resolution of Compound V to Compound Va can be accomplished by selective enzymatic acylation. Selective enzymatic acylation means that the enzymatic acylation is assumed effective to convert one of the cis-enantiomers of a compound of formula V leaving the other cis-enantiomer of Compound V, n. eg, compound Va, as unconverted in the reaction mixture.

Alternatively, the resolution of Compound V to Compound Va can be accomplished by selective enzymatic deacylation. Selective enzymatic deacylation means that the enzymatic deacylation is assumed to be effective to convert one of the esters of the compound of formula V, leaving the other cis-enantiomer of the ester of the compound of formula V unconverted in the reaction mixture.

Suitable esters (Vb) of compounds of formula (V) are esters such as acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-

pri cemu je R, n. pr., acetat, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-metilbutyrate, 3-metilbutyrate, pivalate, 2-metilvalerat, 3-metilvalerat, ili 4-metilvalerat

Thus, one embodiment relates to the procedure for preparing the (S, S)- or (R, R)-enantiomer of the compound of formula V (that is, with the cis configuration), which consists of:

a) subjecting racemic Compound V to enantio-selectivity

enzymatic acylation using an acylating agent, or

b) subjecting the racemic Compound Vb to enantio-selectivity

enzymatic deacylation to form a mixture of deacylated Compound Va.

Enantio-selective enzymatic acylation means that the enzymatic acylation is assumed to be effective for the conversion of one of the enantiomers of the compound of formula (V) assumed leaving the other enantiomer of the compound of formula (V) unconverted in the reaction mixture. Enantio-selective enzymatic deacylation means that the enzymatic deacylation is assumed to be effective for the conversion of one of the enantiomers of the compound of formula (Vb), presumably leaving the other enantiomer of the compound of formula (Vb) unconverted in the reaction mixture.

The mixtures obtained by enzymatic separation may not be completely pure, n pn, they may contain a smaller amount of the other enantiomer in addition to a larger amount of the desired enantiomer (Va). The resulting composition of the mixture after acylation or deacylation according to the invention depends, n. e.g., from the specific hydrolase used and the conditions under which the reaction is carried out. A characteristic of enzymatic acylation/deacylation according to the invention is that a significantly larger part of one enantimer is converted compared to the other. Enantio-selective acylation according to the invention thus results in a mixture containing the presumed compound of formula (Vb) in (R, R)-form and the compound of formula (Va) in (S, S)-form, or may result in a mixture containing the presumed compound of formula (Vb) in (S, S)-form and compound of formula (Va) in (R, R)-form. In the same way, enantio-selective enzymatic deacylation can result in a mixture containing the putative compound of formula (Vb) in the (S, S)-form and the compound of formula (V) in the (R, R)-form, or it can result in a mixture which presumably contains the compound of formula (Va) in the (R, R)-form and the compound of formula (Va) in the (S, S)-form. The optical purity Va obtained by the optical separation process of the present invention is typically at least 90% e. v., assumed at least 95% e v., preferably at least 97% e. v., and preferably at least 98% e. c. However, lower optical purity values are also acceptable.

According to the invention, enantio-selective enzymatic acylation is carried out under conditions that substantially prevent hydrolysis. Hydrolysis, which is the reverse of the acylation reaction, takes place if water is present in the reaction system. Thus enantio-selective enzymatic acylation is assumed to be carried out in a water-free organic solvent or a nearly anhydrous organic solvent (enzymes normally require

the presence of some water to be active). Suitable solvents include hydrocarbons such as hexane, heptane, benzene and toluene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether and dimethoxyethane; ketones such as acetone, diethyl ketone, butanone, and methyl ethyl ketone; esters such as methylacetate, ethylacetate, ethylbutyrate, vimylbutyrate and ethylbenzoate; halogenated hydrocarbons such as methylene chloride. chloroform and 1, 1, 1-trichloroethane; secondary and tertiary alcohols such as tert-butanol; nitrogen-containing solvents such as dimethylformamide. acetoamide, formamide, acetonitrile and propionitrile; and aprotic polar solvents such as dimethylsulfoxide, N-methylpyrrolidone, and hexamethylphosphorus triamide. Presumably organic solvents for enzymatic acylation are organic solvents such as toluene, hexane. heptaneb. dioxane and tetrahydrofuran (THF),

Suitable irreversible acylating agents are, n. pre-solidifiers such as vinyl esters,

2-propenyl-estri ili 2, 2, 2-trihalid-etil-estri.

Enantio-selective enzymatic deacylation is presumably carried out in water or a mixture of water and an organic solvent, preferably in the presence of a buffer. Suitable organic solvents, n. e.g., are water-miscible solvents such as alcohols, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1, 4-dioxane. DME and diglim.

It has been found that the enzymatic acylation according to the invention can be carried out using Novozym 435 (Candida Antractica lipase B, from Novozymes A/S, Fluka Cat. -No. 73940). In general, the enzymatic acylation or deacylation according to the invention is presumably carried out using a lipase. esterases, acylases or proteases. Enzymes useful according to the invention are those enzymes which

are capable of performing R-selective acylation or S-selective acylation of the hydroxy group in the racemic compound of formula (V) or such enzymes which are capable of performing R-selective deacylation or S-selective deacylation of the acyl group in the racemic compound of formula (Vb). In particular, immobilized forms of enzymes, including Cross-Linked Enzyme Crystals (CLECs), are useful according to the invention. A putative embodiment relates to the use of a lipase to perform the enzymatic separation of Compound V. The most preferred lipase is Candida Antarctica lipase (Fluka Cat. -No. 62299); Pseudomonas cepacia lipase (Fluka Cat. -No 62309); Novozym CALB L (Candida Antarctica lipase B)(Novozymes A/S); Novozym 435 (Candida Antarctica lipase B) (Novozymes A/S); or Lipozyme TL IM (Thermomyces lanuginosus lipase) (Novozymes A/S), presumably in immobilized form.

The alcohol group of the cis-alcohol of formula (Va) is converted to a corresponding leaving group, such as, n. eg, halogen, n. ex. Cl or Br, assumed Cl, or sulfonate, n. eg, mesylate or tosylate, conveniently by reaction with an agent, such as thionyl chloride, mesyl chloride or tosyl chloride, in an inert solvent, n. e.g., ether, suitable for tetrahydrofuran. The resulting compound has formula (VI), where LG is the leaving group

In the assumed embodiment, LG is Cl, i.e., the cis-chloride of the formula (Via):

Compound VI, n. pr, with LG as chloro, then react with 2, 2-dimethylpiperazine in a suitable solvent, n. eg, a ketone such as, n. eg, methyl isobutyl ketone or methyl ethyl ketone, presumably methyl isobutyl ketone in the presence of a base, such as, n. eg, potassium carbonate. The resulting compound of formula (VII)

is methylated at the secondary amine functionality (appropriately by reductive amination using suitable agents, such as, e.g., formaldehyde, paraformaldehyde, trioxane, or diethoxy methane (DEM)) to give the free base of the compound of formula (I).

Alternatively, the methyl group can be introduced directly by using 1,2,2-trimethyl piperazine (Formula VIII below) instead of 2,2-dimethyl piperazine when reacting with Compound VI, n. pr, where LG Cl will be, thereby shortening the synthesis by one step.

Further, the piperazine portion of the molecule may be introduced by reacting Compound VI with Compound (IX) below, wherein PG is a protecting group such as, but not limited to, n. e.g., phenylmethoxycarbonyl (often referred to as Cbz or Z), tert-butyloxycarbonyl (often referred to as BOC), ethoxycarbonyl, or benzyl, giving the compound of formula (X) below

After deprotection of the product to (VII), methylation as discussed above affords the final product Compound I Alternatively, a protecting group such as, n. eg, ethoxycarbonyl can be directly converted to a methyl group by using a suitable reducing agent, n. eg, lithium aluminum hydride

During the synthesis some cis diastereomer of Compound I (e.g., 4-((?S,3S)-6-chloro-

3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazm) is formed as an impurity in the final product. This impurity is mainly due to the formation of one of the trans species (VI) (e.g., (1Sr3R)-3, 5-dichloro-1-phenylindane when LG is Cl) in the step where Compound VI is formed. Therefore, the impurity can be minimized. by crystallization of the desired cis form of Compound VI, from a mixture of trans and cis (VI); in the case where LG is Cl in Compound VI this can be done by mixing the mixture with a suitable solvent, n. e.g., alkane. such as heptane, whereby the desired cis form of VI precipitates and the undesired trans form of Compound VI goes into solution. The desired cis form of Compound VI (eg, when LG is Cl) is isolated by filtration, washed with the solvent in question and dried.

If the cis form of Compound VI is present in batch (VI) used in the synthesis of Compound VII, this will give an increase in the formation of the trans form of Compound VII (ie, 4-((1 S,3S)-6-chloro-3-phenylindan-1 - yl)-3, 3-dimethylpiperazine) as impurities in (VII); this provides another option to avoid the cis form of Compound I in the final product; It has been found that the cis form of Compound VII can be removed by precipitation of the appropriate salt compound of the formula Compound VII, n. e.g., salts of an organic acid, such as an organic dibasic acid, preferably a hydrogen fumarate salt or a hydrogen maleate salt of a compound of formula (VII), optionally followed by one or more re-crystallizations.

Furthermore, it was found that impurities in the form of cis diastereomers in (I) (resp

4-((1S,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine) can be effectively removed by precipitation of the corresponding salt of the compound of formula (I), n. eg, a salt of an organic acid, such as an organic dibasic acid, correspondingly a fumarate salt, n. eg, a hydrogen fumarate salt of a compound of formula (I) optionally followed by one or more re-crystallizations.

In further aspects, the invention also relates to intermediate products as described here for the synthesis of compounds of formula (I), i.e. especially intermediate products Va, VI, n. ex. Via, and VII, or salts of Compound VII. In this context, it is understood that when the stereoisomeric form is specified, then the stereoisomer is the major constituent of the compound. In particular, when the enantiomeric form is specified, then the compound has an enantiomeric excess of the enantiomer in question.

Accordingly, one embodiment of the invention relates to a compound of formula (Va), assumed to have an enantiomeric excess of at least 60% (60% enantiomeric excess means that the ratio of Va to its enantiomer is 80:20 in the mixture in question), at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, assumed at least 98%. Furthermore, the diastereomeric excess of the compound was assumed to be 70% (70% diastereomeric excess means that the ratio of Compound Va to (1R,3S)-6-chloro-3-phenylindan-1-ol is 85:15 in the mixture in question) , at least 80%, at least 85%, at least 90%, or at least 95%. One embodiment relates to substantially pure Compound Va.

where LG is a potential leaving group, presumably selected from a halogen-containing group, n. eg, chloride, or sulfonate. One embodiment relates to the diastereomeric purity of Compound VI; that is, a compound that has a diastereomeric excess of assumedly at least 10% (10% diastereomeric excess means that the ratio of Compound VI to the trans diastereoisomer (e.g., (1S, 3R)-3 5-dichloro-1-phenylindane when LG=CI) 55 : 45 in the mixture in question), at least 25% or at least 50%. One embodiment relates to substantially pure Compound VI.

Accordingly, the invention also relates to a compound having the following formula (Via),

which is assumed to have an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, assumed at least 98%. One embodiment refers to the diastereomeric purity of the compound, that is, the compound having a diastereomeric excess of an assumed 10% (10% diastereomeric excess means that the ratio of Compound VI to the cis diastereoisomer, (1S. 3R)-3, 5-dichloro-1-phenylindane, 55: 45 in the mixture in question), at least 25% or at least 50%, One embodiment relates to essentially pure Compound VI where LG Cl.

The invention also relates to compound (VII) having the structure:

which is assumed to have an enantiomeric excess of at least 60% (60% enantiomeric excess means that the ratio of VII to its enantiomer is 80:20 in the mixture in question), at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, presumably at least 98%, or its salt, such as, n. pr, fumarate salt, n. eg, hydrogen fumarate, or maleate salt, n. eg, hydrogen maleate. One embodiment refers to the diastereomeric purity of Compound VII, i.e., a compound having a diastereomeric excess of assumedly at least 10% (10% diastereomeric excess means that the ratio of Compound VII to the cis-(1S, 3S) diastereoisomer is 55:45 in a mixture that is in question), baht 25%, at least 50%, at least 70%, at least 80%, at least

A further aspect relates to Compound I or a salt thereof, n. e.g., a fumarate, malonate, or succinate salt, which can be obtained, which is precisely obtained, by the process of the invention as described herein.

A further aspect relates to Compound VII or a salt thereof, n. e.g., the fumarate salt, which can be obtained, which is precisely obtained, by the process of the invention as described herein.

Pharmaceutical use

The physical properties of the salts of Compound I of the invention indicate that they will be particularly useful as a pharmaceutical agent.

Accordingly, the present invention relates to a pharmaceutical composition of a succinate salt, particularly a hydrogensuccinate salt as described herein (e.g., the alpha or beta form as described herein), or a malonate salt, particularly a hydrogenmalonate salt, of a compound of formula (I) . The invention also relates to the medical use of such salts and compositions, such as for the treatment of diseases in the central nervous system, including psychosis, especially schizophrenia or other diseases involving psychotic symptoms, n. eg, schizophrenia, schizophrenic disorder, schizoaffective disorder, apparition disorder, brief psychotic disorder, shared psychotic disorder as other psychotic disorders and diseases that are present with psychotic symptoms, n. eg, mania in bipolar disorder.

Additionally, the 5-HT2 antagonistic activity of the compounds of the invention suggests that the drug alone or a salt thereof may have a relatively low risk of extrapyramidal side effects.

The present invention also relates to the use of a succinate or malonate salt of the invention, presumably hydrogen succinate (n. pn, crystalline form alpha) or hydrogen malonate sily, of a compound of formula (I) for the treatment of diseases selected from the group consisting of anxiety disorders, affective disorders including depression, sleep, migraine, neuroleptic-induced parkinsonism, cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders.

In a broad aspect, the present invention relates to a method of treating schizophrenic disorders, schizoaffective disorder, delusional disorder, brief psychotic disorder, split psychotic disorder

disorder or mania in bipolar disorder, comprising administering a therapeutically effective amount of the compound trans-(4-(6-chloro-3-phenylindan-1-yl)-

1, 2, 2-trimethylpiperazine or its salts.

As the term "trans-4-(6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine" is used herein, that is, without any specific indication of the enantiomeric form (e.g., using ( +) and (-), or by using the R/S-convention, which is intended to refer to any enantiomeric form of this compound, that is, any of the two enantiomers, 4-((1/? 3S)~ 6- chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine (I) or 4-((1S, 3R)-6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine or mixtures of the two, e.g., racemic mixtures However, in this context it was assumed that the enantiomer content which

In the present context for pharmaceutical uses it is understood that when specifying the enantiomeric form of the compound frans-4-(6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine (e.g., as done in formula (I)), then the compound is relatively stereochemically pure, the assumed enantiomeric excess is at least 80% (80% enantiomeric excess means that the ratio of I to its enantiomer is 90:10 in the mixture in question) at least 90%, at least 96 %, or assumed at least 98%. In an assumed embodiment, the diastereomeric excess of Compound I is at least 90% (90% diastereomeric purity means that the ratio of Compound I to c/s-4-((1S,3S))-6-chloro-3-phenylindan-1-yl) -1, 2, 2-trimethylpiperazine 95: 5), at least 95%, at least 97%, or at least 93%.

In an assumed embodiment, the present invention relates to a method of treating a schizophrenic disorder, schizoaffective disorder, apparition disorder, brief psychotic disorder, shared psychotic disorder or mania in bipolar disorder, which comprises administering a therapeutically effective amount of a compound of formula (I) [ie, 4-(6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine| or its salts.

One embodiment of the invention relates to a method of treating positive symptoms of schizophrenia, negative symptoms and depressive symptoms of schizophrenia, which consists of administering a therapeutically effective amount of the compound frafls-4-(6-chloro-3-phenylindan-1-yl)-1,2,2 -trimethylpiperazine or its salts, presumably of the compound of formula (I) or its sophy, or in a presumed embodiment the succinate or rnalonate salt of the compound of formula (I),

assumed hydrogen succinate or hydrogen chmalonate salt of the compound forming (!)•

A further embodiment of the invention relates to a method of treating positive symptoms of schizophrenia, which consists of administering a therapeutically effective amount of the compound frans-4-(6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine or its salt, presumably a compound of formula (I) or a salt thereof, or in a putative embodiment a succinate or malonate salt of a compound of formula (I), a putative hydrogensuccinate or hydrogenmalonate salt of a compound of formula

(I).

The next embodiment of the invention relates to a procedure for treating negative symptoms of schizophrenia, which consists of administering a therapeutically effective amount of the compound frans-4-(6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine or its salt, or putatively a compound of formula (I) or a salt thereof, or in a putative embodiment a succinate or malonate salt of a compound of formula (I), a putative hydrogensuccinate or hydrogenmalonate salt of a compound of formula

(D-

A further embodiment of the invention relates to a method of treating depressive symptoms of schizophrenia, which consists of administering a therapeutically effective amount of the compound frans-4-(6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine or its salt, assumed the compound of formula (I) or its salt, or in the assumed embodiment the hydrogen succinate or hydrogen malonate salt of the compound of formula (I).

A further aspect of the invention relates to a method of treating mania and/or maintaining bipolar disorder, which consists of administering a therapeutic

effective amounts of the compound trans-4-chloro-S-phenylindan-l-yl)-1,2,2-trimethylpiperazine and its salts, presumably of the compound of formula (I) or its salt, or in a presumed embodiment the succinate or malonate salt of the compound of formula ( I), presumed hydrogen succinate or hydrogen malonate salts of compounds of formula (I)

A further aspect of the invention relates to a method of treating neuroleptic-induced parkinsonism which consists of administering a therapeutically effective amount of the compound trans-4-(6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine or its salt, assumed compound of formula (I) or its salt, or in the assumed embodiment succinate or malonate salt of compound of formula (I), assumed hydrogen succinate or hydrogen malonate salt of compound of formula (I)-

The invention further relates to a method of treating substance abuse, e.g., nicotine, alcohol or cocaine abuse, comprising administering a therapeutically effective amount of the compound trans-4-(6-chloro-3-phenylindan-1-yl)-

1,2,2-trimethylpiperazine or its salts, presumably the compound of formula (I) or its salt, and in an assumed embodiment the succinate or malonate salt of the compound of formula (I), presumably the hydrogen succinate or hydrogen malonate salt of the compound of formula (I).

A salt or composition of the invention may be administered by any convenient route, e.g., orally, orally, sublingually, or parenterally, and the compound or salt may be presented in any form suitable for such administration, e.g., in tablet form, capsules, powders, syrups or injectable solutions or dispersions. In one embodiment, a compound or salt of the invention is provided in the form of a solid pharmaceutical entity, suitably as a tablet or capsule.

Processes for the preparation of solid pharmaceutical preparations are well known in the art. Tablets can thus be prepared by mixing the active ingredient with common adjuvants, fillers or diluents and then compressing the mixture in a conventional tableting machine. Examples of adjuvants, fillers, and diluents include corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive for providing color, aroma, protection, etc., may also be used provided it is compatible with the active ingredients.

Solutions for injections can be prepared by dissolving the salts of the invention and possible additives in a portion of the solvent for injection, presumably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling into appropriate ampoules or containers. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, solubilizing agents, etc.

The daily dose of the above compound of formula (I), calculated as free base, is suitably between 1.0 and 160 mg/day, more suitably between 1 and 100 mg, e.g., preferably between 2 and 55 mg.

The term "treatment" as used herein in connection with a disease or disorder also includes prevention as the case may be.

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

EXAMPLES

COMPOUND PREPARATION Analysis

The enantiomeric excess of ledininie (Va) in Example 1a is determined by chiral HPLC using a CHIRALCEL®OD column, 0.46 cm ID X 25 cm L, 10 pM at 40 °C. It is used as a mobile phase n-Hexane/ethanol 95 5 (vol./vol.) at a flow rate of 1.0 mL/min, detection is performed using a UV detector at 220 nm.

HPLC analysis for conversion rate used for Example 1b:

Column: Lichrospher RP-8 column, 250 x 4 mm (5 pm particle size) Eluent: Buffered MeOH/water prepared as follows: 1.1 mL Et3N added to 150 mL water, 10% H3PO4(water) added to pH=7 and water is added up to a total of 200 mL. Add the mixture to 1.8 L of MeOH

The enantiomeric excess of iedmiene (Va) in Example 1b is determined by chiral HPLC using a CHIRALPAK®AD column, 0.46 cm ID X 25 cm L, 1Q pm at 21 °C.

Heptane/ethanol/diethylamine 89.9:10:0.1 (stop/stop/stop) is used as the mobile phase at a flow rate of 1.0 mL/min, detection is performed using a UV detector at 220 nm.

Enantiomeric excess of compounds (I) is determined by fused silica capillary electrophoresis (CE) using the following conditions: Capillary: 50 pm ID X 48.5 cm L, running buffer: 1.25 mM p cyclodextrin in 25 mM

sodium hydrogen phosphate. pH 1.5, voltage 16 kV. temperature: 22°C, injection 50 mbar for 5 seconds, detection: diode array detection 195 nm, sample concentration 500 gg/mL In this system, Compound I has a retention time of approximately 33 minutes, and the other enantiomer has a retention time of approximately 35 minutes

1-1 NMR spectra are recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Chloroform (99.8% D) or dimethy are used as solvents! sulfoxide (99.8%D), and tetramethylsilane (TMS) is used as an internal reference standard.

The cis/trans ratio of compounds I and VII was determined using H NMR as described in Bogeso et al., J. Med. Chem. 1995, 38, 4380-4392 (page 4388, right column). The cis/trans ratio of compound VI is determined by NMR in chloroform, using the integral of the signal at 5.3 ppm for the cis isomer and the signal at 5.5 ppm for the trans isomer. Generally, a content of approximately 1% of the undesired isomer can be detected by NMR

Powder X-ray diffractograms are recorded on a PANalytical XrPert PRO X-ray diffractometer using CuK,^ radiation. The reflection mode is measured in 20 in the range 5-40°

Melting points are measured using differential scanning calorimetry (DSC). The equipment was TA-lnstruments DSC-2920 calibrated at 57min to give the melting point as an initial value. About 2 mg of the sample is heated for 57 minutes in a loosely closed vessel with a flow of nitrogen

Compound V is synthesized from IV by reduction with sodium borohydride (NaBH4) by adapting the procedure described by Bogeso J. Med. Chem. 1983, 26, 935, using ethanol as solvent, and performing the reaction at approximately 0 °C. Both compounds are described by Bogeso et al. J. Med. Chem. 1995, 38, 4380-4392. Compound IV is synthesized from II using the general procedures described in Sommer et al., J. Org. Chem. 1990, 55, 4822, where II and its synthesis are also described.

PrimeMa Sinteza (1S,3S)-6-hloro-3-fenilindan-1-ola (Va) using hiralne hromatografije

Racemic c/s-6-chloro-3-phenylindan-1-ol (V) (492 grams) was separated by preparative chromatography using a CHIRALPAK® AD column, 10 cm ID X 50 cm L, 10 pm at 40°C. Methanol is used as the mobile phase at a flow rate of 190 mL/min, detection is performed using a UV detector at 287 nm Racemic alcohol (V) is injected as a 50,000 ppm solution in methanol; 90 mL is injected at 28 minute intervals. All fractions, containing the title compound with greater than 98% enantiomeric excess, were combined and evaporated to dryness using a rotary evaporator, followed by drying in vacuo at 40°C. The yield is 220 grams in solid form. Elemental analysis and NMR were consistent with the structure, enantiomeric excess greater than 98% by chiral HPLC, [α]D20+44.5° (c=1.0, methanol).

Primerlb Sinteza (1S,3S)-6-chloro-3-phenylindan-1-ola (Va| upotrebom enzimskog razdvajanja

Compound V (5 g, 20.4 mmol) was dissolved in 150 mL of anhydrous toluene. 0.5 g of Novozym 435 (Candida Antarctica lipase B) (Novozymes A/S, Fluka Cat.-No. 73940) was added followed by vinyl butyrate (13 mL, 102.2 mmol). The mixture is stirred using a mechanical stirrer at 21 °C. After one day, an additional 0.5 g of Novozym 435 is added. After 4 days at 54% conversion, the mixture is filtered and concentrated in vacuo to give an oil containing a mixture of (1R,3R)-cis-6-chloro-3- phenylindan-1-ol-butyrate ester and the desired compound Va with an enantiomeric excess of 99.2% (99.6% compound Va and 0.4% (1 R,3R)-cis-6-chloro-3-phenylindan-1 -ol).

Synthesis (I) and removal of impurity in the form of cis diastereoisomers by precipitation of hydrogen fumarate salt (I)

Primer 2 Synthesis (1S,3S)-3,5-dichloro-1-phenylindane (VI, LG=CI)

C/s-(1S,3S)-6-chloro-3-phenylindan-1-ol (Va) (204 grams) obtained as described in Example 1a was dissolved in THF (1500 mL) and cooled to -5 °C. Thionyl

chloride (119 grams) was added dropwise as a solution in THF (1500 mL) over a period of 1 h. Roe meat is left at room temperature overnight. Ice (100 g) was added to the reaction mixture. When the ice melts the aqueous phase (A) and the organic phase (B) are separated, and the organic phase B is washed twice with saturated sodium bicarbonate (200 mL). The sodium bicarbonate phases are combined with aqueous phase A, adjusted to pH 9 with sodium hydroxide (28%), and used to wash organic phase B once more. The resulting aqueous phase (C) and organic phase B are separated, and the aqueous phase C is 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 give the title compound as an oil. Yield 240 grams, used directly in Example 5. Cis/trans ratio 77:23 by NMR

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

Potassium carbonate (390 grams) and ethylene diamine (1001 grams) were mixed with toluene (1.50 L). A solution of et:L2-bromoisobutyrate (500 grams) in toluene (750 mL) was added. The suspension is heated to reflux overnight, and filtered. The filter cake was washed with toluene (500 mL). The combined filtrates (volume 4.0 L) are heated in a water bath and distilled at 0.3 atm., using a Claisen apparatus; the first 1200 mL of distillate is collected at 35 °C (temperature in the mixture is 75 °C). More toluene (600 mL) is added, and the next 1200 mL of distillate is collected at 76 °C (temperature in the mixture is 80 °C). Toluene (750 mL) was added again, and 1100 distillates were collected at 66 CC (mixture temperature 71 °C). The meat is tenderized in an ice bath and coil, where the product settles. The product is isolated by filtration, washed with

Primer 4 Sinteza 2,2-dimethylpiperazine

A mixture of 3,3-dimethylpiperazin-2-one (8.28 kg, 64.6 mol) and tetrahydrofuran (THF) (60 kg) was heated to 50-60 °C, giving a slightly cloudy solution. THF (50 kg) is stirred under nitrogen, and LiAIH4 (250 g, in a dissolvable plastic bag, from Chemetall) is added, giving slow gas evolution. After gas evolution is complete, more UAIH4 is added (a total of 3, used 0 kg, 79.1 mol), and the temperature rises from 22°C to 50°C due to the exotherm. A solution of 3,3-dimethylpiperazin-2-one is added slowly over 2 hours at 41-59°C. The suspension is stirred for the next hour at 59°C (jacket temperature 60°C). The mixture is cooled, and water (3 L) is added over two hours, keeping the temperature below 25°C (it is necessary to cool with a jacket temperature of 0°C). Then sodium hydroxide (15%, 3 50 kg) is added during 20 minutes at 23°C, necessary cooling. More water (9 L) was added over half an hour (cooling necessary), and the mixture was stirred overnight under nitrogen. Celite filter agent (4 kg) is added, and the mixture is filtered. The filter cake is washed with TFIF (40 kg). The combined filtrates are concentrated in the reactor until the temperature in the reactor is 70 °C (distillation temperature 66 °C) at 800 mbar. The residue (128 kg) is further concentrated on a rotary evaporator to approximately 10 L. Finally, the mixture is fractionally distilled at atmospheric pressure, and the product is collected at 163-4°C. Yield 5 3 kg (72%). NMR is consistent with the structure.

Primer 5 Sinteza fra/7S-1-(1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-

dimethylpiperazine (VII)

C/s-(1S,3S)-3,5-dichloro-1-phenylindane (VI, LG=CI) (240 g) was dissolved in butan-2-one (1800 mL). Potassium carbonate (272 g) and 2,2-dimethyl piperazine (prepared in Example 4) (113 g) were added and the mixture was heated at reflux for 40 h. Diethyl ether (2 L) and hydrochloric acid (1M, 6 L) were added to the reaction mixture. The phases were separated, and the pH of the aqueous phase was lowered from 8 to 1 with concentrated hydrochloric acid. The aqueous phase is used to wash the organic phase one more time to ensure that the entire product is in the aqueous phase. Sodium hydroxide (28%) was added to the aqueous phase until the pH was 10, the aqueous phase was extracted twice with diethyl ether (2 L). The diethyl ether extracts are combined, dried with sodium sulfate, and evaporated to dryness using a rotary evaporator. The yield is 251 g of the title compound as an oil, which is used directly in the following example Cis/trans ratio, 82:18 by NMR.

Example 6 Synthesis of frans-4-((fR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazinium (I) hydrogen fumarate

Crude fra/7S-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine (VII) (250 grams) was mixed with formaldehyde (37% in water, 300 mL) and formic acid (366 grams), and the mixture is slowly heated to reflux. The mixture was stirred at reflux for 3.5 hours, and after cooling to room temperature, water (1200 mL) was added. The mixture was extracted twice with ether (1200 mL), and then the aqueous phase was made alkaline by addition of sodium hydroxide (28%, approximately 500 mL). The aqueous phase was extracted three times with ether (900 mL). The organic phases are combined and washed with brine (650 mL), and two

road with water (500 m!_). The organic phase is dried with sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. Yield: 212 grams of fra/7S-4-((1R3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine free base (I) as an oil, with 19% cis diastereoisomers by NMR . The compound was dissolved in 1-propanol (3.18 L) and the mixture was heated to 50 °C, which gave a clear solution. Fumaric acid (69.3 grams) was added, giving a clear solution. The mixture is allowed to cool, whereupon the title compound precipitates. The product is isolated by filtration, washed with 1-propanol, and dried in vacuo at 60°C. Yield: 182 grams, contains <1% cis diastereoisomer by NMR Elemental analysis and NMR confirm the structure. The enantiomeric excess is greater than 99% according to chiral capillary electrophoresis (CE). [α]D20=-22.8° (c=1.0, methanol).

Primer 7 Sinteza 4-<(1 /?,3S)-6-hloro-3-fenilindan-1 -yl)-1,2,2-trimetilpiperazine free base (f)

7-rans-4-((1R3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazinium (I) hydrogen fumarate (25.0 grams) was suspended in toluene (125 ml_). A 25% aqueous solution of ammonia (75 mL) is added. The three phases are mixed until the solid forms disappear. The organic phase is separated, and the aqueous phase is washed with toluene (25 mL). The aqueous phase is discarded and the organic phase is dried over sodium sulfate. (35 grams), the precipitate was filtered and the filtrate evaporated to dryness on a rotary evaporator to give the title compound as an oil. The crude free base (15 grams) is used without further purification.

Crude frans-4-((7ft,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine (I) (850 grams of oil) obtained as described in Example 7 is dissolved in acetone (30 ml_). A suspension of succinic acid (3.25 grams) in acetone (32 mL) was prepared and trans-4-((7ft,3S)-6-chloro-3-phenylindan-1-yl)-

1,2,2-trimethylpiperazine (I) solution, the succinic acid dissolves and soon after precipitates tra/7s-4-(('/R,3S)-6-chloro-3-phenylindan-1-yl)- 1,2,2-trimethylpiperazinium (I) hydrogen succinate. The suspension was cooled to 0 °C over 90 minutes before the pellet was isolated by centrifugation. The supernatant was discarded and the precipitate was washed with acetone (20 mL). The precipitate is centrifuged and the surface layer is discarded and the precipitate is dried "in vacuo" at 50 °C. Yield 8.56 grams

When this procedure is first performed the isolated product is in the beta form, subsequent repetitions result in the more stable alpha hydrogen succinate form of Compound I.

Acetone in the experiment described above can be substituted with an aqueous solution of acetone (95%) which also results in the alpha-form of the hydrogen succinate of Compound I.

Differential scanning calorimetry (DSC) shows an endotherm with an initial temperature of 140 °C and a peak value at 141 °C corresponding to the alpha form. The XRPD diffractogram is consistent with the alpha form.

Crude frans-4-(("/R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine (I) (1.0 g., 2.81 mmol, obtained dissolved in 2-propanol (5 mL) as described in Example 7. A solution of malonic acid (0.291 grams 2.46 mm.) in 2-propanol (5 mL) was prepared and trans-4-((1 R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine solution, during which trans-4-((7R,3S)-6-chloro-3-phenylindan- 1-yl)-1,2,2-trimethylpiperazinium hydrogenmalonate. The suspension was cooled to room temperature before the precipitate was isolated by centrifugation. The supernatant was discarded and the precipitate was washed with 2-propanol (5 ml_). The precipitate was centrifuged and the supernatant the layer was discarded and the residue was dried in vacuo at 50 °C. Yield: 0.98 grams (84%). Elemental analysis was consistent with the structure. The X-ray diffraction pattern was consistent with that of hydrogen malonate as shown in Fig. picture

3.

Synthesis of (I), salt formation (Vl) to remove the cis diastereoisomer (VII), and form the hydrogensuccinate salt from crude (I)

Example 10 Synthesis of frans-1-((f/?,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazinium (VII) hydrogen maleate

Examples 2 and 5 were repeated, giving crude trans -((fR,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine (VII) (ca. 20 grams) as an oil, which further purified by flash chromatography on silica gel (eluent: ethylacetate/ethanol/triethylamine 90:5:5) followed by evaporation to dryness on a rotary evaporator. The yield is 12 grams of the title compound as

oil (cis/trans ratio, 90:10 by NMR). The oil was dissolved in ethanol (100 mL), and to this solution was added a solution of maleic acid in ethanol to pH 3. The resulting mixture was stirred at room temperature for 16 hours, and the precipitate formed was collected by filtration. The volume of ethanol is reduced and the next batch of precipitate is collected. Yield 35 grams in solid form of the title compound (cis isomer not detected by NMR).

Melting point 175-178 °C

Primer 11 frans-1-((f/?,3S)-6-chloro-3-phenylindan-1-yl)-3,3-

dimethylpiperaz n (VII)

A mixture of frans-1-((fft,3S)-6-chloro-3-phenylindan-1-yl)-3,3-umethylpiperazinium hydrogen maleate (VII) (9.9 grams), concentrated aqueous ammonia solution (100 mL), of brine (150 mL) and ethyl acetate (250 mL) was stirred at room temperature for 30 minutes. The phases are separated, and the aqueous phase is extracted with ethyl acetate once more. The combined organic phases are washed with saline solution, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. Yield 7.5 grams of oil.

Example 12 Preparation of trans-4-((f/?,3S)-6-chloro-3-phenylindan-1 I)-

1,2,2-trimethylpiperazine free base (I)

7ra/?s-1-((fR,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine (8 9 grams) (VII) was dissolved in formic acid (10.5 mL ) and formaldehyde (10.5 mL) is added to the solution. It is heated to 60 °C and maintained at this temperature for 2 1/2 hours. Adjust pH with NaOH (27%, 33 mL) to pH>12. The hexane phase is washed with aq. NaCl (20 mL) and water (20 mL). The hexane was azeotroped with acetone (90 mL) and the mixture was concentrated crude

the free base in acetone (10 mL) was used without further purification.

Example 13 fra/7s-4-((fR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazinium (I) hydrogensuccinate

Crude trans-4-((7 H ,3 S )-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine (I) in acetone solution (10 mL). A suspension of succinic acid (3.4 grams) in acetone (20 mL) was prepared and frans-4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-

1,2,2-trimethylpiperazine (I) solution is added to the mixture and heated to reflux (55 °C). The succinic acid dissolves and during cooling the solution of trans-4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazinium (I)

of hydrogen succinate begins to precipitate. The suspension is left overnight to settle. 7rans-4-((fR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-

trimethylpiperazinium hydrogen succinate is isolated by filtration and washing with acetone (20 mL). The product is dried "in vacuo" at 60 °C.

Yield: 7.9 grams

Differential scanning calorimetry shows an endotherm with an initial temperature of 140 °C and a peak value at 141 °C corresponding to the alpha form. The XRPD diffractogram is consistent with the alpha form. [α]D20=-22.04° (c=1.0, methanol).

Synthesis I using 1,2,2-trimethylpiperazine

Primer 14 Sinteza 3,3,4-trimethylpiperazin-2-one

3,3-Dimethylpiperazin-2-one (50 grams) was suspended in 1,2-dimethoxyethane (DME) (150 mL) and potassium carbonate (70 grams) was added. Methyl iodide (66.4 grams) was added over half an hour while the mixture cooled slightly, allowing the temperature to reach 50°C. The mixture is stirred for 9 hours in an oil bath at 40-45°C, and the sample is withdrawn for NMR, which indicates that 8% of the starting material still remains (signal at 2.8 ppm). More methyl iodide (46 grams) was added, and the mixture was stirred for a further 2 hours at 40°C, and a new NMR pattern showed complete conversion. The mixture is filtered, and the filter cake is washed with DME. The filtrate was evaporated to dryness to give 41 grams of the title compound. NMR is consistent with the structure.

Primer15 Synthesis of 1,2,2-trimethylpiperazine

A solution of lithium aluminum hydride in tetrahydrofuran (THF) (1.0 M, Aldrich cat. No. 21,277-6, 90 ml_) is heated to 50°C in an oil batch Crude 3,3,4-trimethylpiperazin-2-one (10 d) is suspended in TFIF and slowly added, giving gas evolution. The resulting mixture was stirred at 45-56°C for 4 hours, giving full conversion of the title compound by NMR (no signal at 1.2 ppm of starting material). The mixture was cooled and water (3.3 mL) was added, giving evolution of gas. Then a solution of sodium hydroxide in water (15%, 3.3 mL) was added, giving more gas, and finally water (10 mL) was added. The mixture was filtered, and the filter cake was washed with THF (100 mL). The filtrates are concentrated on a rotary evaporator (0.3 atm., and 60°C in the water batch). The residue was dissolved in THF (200 mL) and dried with sodium sulfate, then the mixture was filtered, and the filtrate was concentrated on a rotary evaporator (0.2 atm and 60 °C in an aqueous batch) to give 6.4 grams of the title compound. NMR is consistent with the structure, the substance contains some THF.

C/s-(1S,3S)-3,5-dichloro-1-phenylindane (VI with LG=CI) (17.8 grams) was coupled with distilled 1,2,2-trimethylpipeiazine (VIII) (8.7 grams), using the procedure described in Example 5. The crude free amine product (15.6 grams), containing 6% of the cis isomer, was used to form the hydrogen fumarate salt, using the procedure of Example 6. Yield 157 grams of the title compound; NMR is consistent with the structure, no cis isomer observed.

Synthesis of the crystalline beta form of the hydrogen succinate salt of Compound I

Example 17 Synthesis of frans-4-((f/?,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazinium (I) hydrogensuccinate, beta form

The hydrogen succinate of Compound I (50 mg) was suspended in water (1 mL) and allowed to equilibrate for 3 days. Any redissolved material is removed by filtration. The beta hydrogen succinate form of Compound I is formed during natural solvent evaporation. The beta form is analyzed after complete evaporation of the solvent by XRPD and DSC.

Analytical results Differential scanning calorimetry (DSC) shows an endotherm with an initial temperature of 135.6°C and a peak value of 137.5°C, which corresponds to the beta form. XRPD is consistent with beta-form.

Example 18 Solubility of salts of compounds of formula (I)

The solubility of salt in water is determined by adding an excess (50 mg) of salt to 2 mL of water. The suspensions are left on the rotamix for at least 24 hours, and then the pH is measured and the concentration is determined with HPLC. The solid precipitate is isolated and allowed to dry in the laboratory. The results are summarized in Table 1.

Example 19 Stability of salts of compounds of formula (I)

Salt stability is investigated under the following circumstances:

Heat, 60°C/80%RH: Samples are stored at 60°C with 80%RH for one week. They are then dissolved and analyzed with HPLC Heat, 90°C: Samples (~10 mg) are stored at 90°C in closed containers containing 1 drop of water. Then they are dissolved and analyzed with HPLC.

Light: The samples are placed in a light cabinet with 250 w/m2 for 24 hours. Then they are dissolved and analyzed with HPLC.

The area of the highest values of the chromatogram next to the highest values of the corresponding substance or acid are given in summary. The succinate salt of the invention does not show any degradation at all.

Example 20 Hygroscopicity of salts of compounds of formula (I)

The hygroscopicity of fumarate salts, succinate salts (alpha form) and malonate salts is investigated with dynamic vapor sorption (DVS). The fumarate and succinate salts are found to be non-hygroscopic. Malonate gradually absorbs up to 1% of water with a relative humidity that rises to 95%, but beige hysteresis.

Claims (46)

1. Succinate salt or malonate salt of the compound of formula I [trans-4-((1/R, 3S)-6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine]. 2. The succinate salt according to claim 1, characterized in that it is a hydrogen succinate salt of the compound of formula (I). 3. A crystalline hydrogen succinate salt of Compound I as defined in claim 1. 4. A salt according to claim 3, characterized in that it is the alpha crystalline form. 5. A salt according to claim 3 or 4, characterized in that its crystalline form is characterized by an X-ray powder diffraction pattern corresponding to that in Figure 1. 6. The salt of any one of claims 3-5, characterized in that its crystalline form is characterized by an X-ray powder diffractogram obtained using CuKα1 radiation (λ=1.5406 Å) showing the highest values at the following 2θ-angles: 9.36 ; 10, 23; 11, 81; 13, 45; 16, 21; 16, 57; 17, 49; 18, 89; 19, m20; 19, 63; 20, 01; 20, 30; 21, 15; 21, 53; 21, 93; 22, 34; 24, 37; 25, 34; 27, 27; 29, 65. 7. The salt of any one of claims 3-6, characterized in that its crystalline form has a DSC trace showing an endotherm with onset at about 139-141 °C. 8. The malonate salt according to claim 1, characterized in that it is a hydrogen malonate salt of the compound of formula (I). 9. The crystalline hydrogen malonate salt of Compound I, characterized in that it is defined in claim 1. 10. The crystalline salt according to claim 1, characterized in that the crystalline form is characterized by the X-ray powder diffractogram shown in Figure 3. 11. A crystalline salt according to claim 9 or 10, characterized in that its crystalline form is characterized by an X-ray powder diffractogram obtained using CuKα1 radiation (λ=1, 5406 Å) which shows the highest values at the following 2θ-angles: 8, 3; 10, 6; 11, 5; 12, 8; 14, 2; 14, 5; 14, 7; 15, 8; 16, 5; 17, 4; 17, 6; 18, 9; 18, 6; 19, 2; 21, 2; 22, 0; 22, 9; 23, 7; 24, 7; 28, 8. 12. A pharmaceutical composition, characterized in that it consists of a salt according to any one of claims 1-11 together with at least one pharmaceutically acceptable carrier, filler or diluent. 13. Salt according to any one of claims 1-11, characterized in that it is for use in medicine. 14. The use of a salt according to any one of claims 1-11 in the preparation of a medicament for the treatment of a disease selected from the group consisting of diseases including psychotic symptoms, anxiety disorders, affective disorders including depression, sleep disorders, migraines, neuroleptic-induced parkinsonism, or abuse disorders, n. eg, cocaine abuse, nicotine abuse, or alcohol abuse. 15. Use of the salt according to any one of claims 1-11 in the preparation of a medicament for the treatment of schizophrenia or other psychotic disorders. 16. Use of a salt according to any one of claims 1-11 in the preparation of a medicament for the treatment of a disease selected from the group consisting of schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and mania in bipolar disorder. 17. The use of a salt according to any one of claims 1-11 in the preparation of a medicament for the treatment of one or more of positive symptoms, negative symptoms and depressive symptoms of schizophrenia. 18. Process for the preparation of 4-((1R, 3S)-6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimethylpiperazine (formula I) or its salt, characterized in that the process consists of conversion of a compound of formula Va in the cis-configuration into a compound of formula I, wherein formulas I and Va are as follows: 19. The process according to claim 18, characterized in that it consists in the conversion of the alcohol group of the cis-alcohol of the formula Va into the corresponding leaving group LG resulting in the compound of the formula V! 20. The method according to claim 19, characterized in that LG is halogen, n. pn, Cl or Br, presumably Cl or sulfonate.. 21. A process according to claim 19 or 20, characterized in that Compound VI is precipitated from a suitable solvent. 22. The process of claim 21, wherein LG is a halogen, preferably Cl, and the solvent is an alkane, e.g., heptane. 23. A process according to any one of claims 19-22, wherein the Compound is reacted with 2, 2-dimethylpiperazine to give a compound of Formula VII. 24. A process according to claim 23, which comprises methylation on a secondary amine to give the free base of a compound of formula I. 25. A process according to any one of claims 23 or 24, characterized in that Compound VII is precipitated as the corresponding salt, n. eg, a salt of an organic acid, such as an organic dibasic acid. 26. The process according to claim 25, characterized in that the hydrogen fumarate salt or hydrogen maleate salt of Compound VII is formed. 27. The process according to any one of claims 19-22, characterized in that Compound VI is reacted with 1, 2, 2-trimethylpiperazine (formula VIII) to obtain the free base of the compound of formula (I). 28. A process according to any one of claims 20-24, characterized in that it consists of -   reacting Compound VI with 1-protected 2, 2-dimethylpiperazine (IX), wherein PG is the protecting group, thereby obtaining a compound of formula (X) ; and - deprotecting Compound X to give Compound VII or converting Compound X directly to Compound I, wherein Compound IX and X are as follows: 29. The method according to claim 28, characterized in that the protecting group PG is selected from the group of phenylmethoxycarbonyl, tert-butyloxycarbonyl, ethoxycarbonyl, and benzyl. 30. A process for the preparation of Compound I or a salt thereof, comprising reacting a compound of formula V! a (ie Compound VI for which LG=CI) with 2, 2-dimethylpiperazine to give the compound of formula VII, which follows methylation at the secondary amine. 31. A process for the preparation of a compound of formula I or a salt thereof, characterized in that it comprises reacting a compound of formula Via (ie Compound VI for which LG=CI) with 2,2-dimethylpiperazine in the presence of a base, followed by reductive amination with with appropriate reagents, such as formaldehyde, paraformaldehyde, trioxane or diethoxymethane followed by isolation of the compound of formula I as the free base or its salt. 32. A process for the production of 4-((1R, 3S)-6-chloro-3-phenylindan-1-yl)-1, 2, 2-trimteylpiperazine (formula I) or its salt, characterized in that the process consists of converting a compound of formula VII to a compound of formula I, wherein formula VII is as defined in claim 23. 33. The process according to any one of claims 18-32, characterized in that the compound of formula (I) is precipitated as the corresponding salt, n. eg, a salt of an organic acid, such as an organic dibasic acid, to remove the undesired cis diastereoisomer. 34. The process according to claim 34, characterized in that the hydrogen fumarate salt of Compound I is formed. 35. The process according to any one of claims 18-34, characterized in that it consists in preparing the succinate salt defined in any one of claims 1-7. 36. The process according to claim 35, characterized in that the hydrogen succinate of Compound I is prepared in a ketone solvent, preferably acetone, n. ex. aqueous acetone. 37. The process according to any one of claims 18-34, characterized in that it consists in preparing the malonate salt defined in any one of claims 8-11. 38. The process according to claim 37, characterized in that the hydrogen malonate of Compound I is prepared in an alcohol solvent, n. eg, 2-propanol. 39. A process according to any one of claims 18-38, characterized in that it consists in converting the free base of a compound of formula (I) into a salt as defined in any one of claims 1-14. 40. A process according to claim 39, characterized in that the resulting base of formula (I) is first isolated as its fumarate salt, which is optionally recrystallized one or more times and then treated with a base to liberate the free base of the compound of formula ( I) which is then converted into its succinate or malonate salt. 41. The process according to any one of claims 18-39, characterized in that it is followed by the isolation of the compound of formula I if the free base or its salt, n. eg, as a succinate salt as defined in any of claims 1-7 or as a malonate salt as defined in any of claims 8-11. 42. Compound (Va), characterized by having the structure: 43. Compound (VI), characterized in that it has the structure: Where LG is a potential leaving group, n. eg, selected from the group consisting of halogen, n. pr, Br or Cl, presumably Cl, or sulfonate. 44. Compound (VII), indicated by having the formula: or its salt. 45. A compound as defined in any of claims 42-44, wherein the compound is substantially pure. 46. A process according to any one of claims 18-31 or any one of claims 33-41, characterized in that Compound Va is obtained by enzymatic separation of Compound V.