ES2383369T3 - Salts of succinate and malonate from TRANS-4 - ((1R, 3S) -6-CHLORO-3-FENILINDAN-1-IL) -1,2,2-TRIMETHYLIPIPERAZINE and use as a medicine - Google Patents

Abstract

A succinate salt or a malonate salt of the compound of formula (I) ** Formula ** [trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2- trimethylpiperazine].

Description

Salts of succinate and malonate of trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine and use as a medicine

The present invention relates to 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine, in particular the hydrogen succinate and hydrogen malonate salts thereof, to methods for the preparation of 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine and salts thereof, to pharmaceutical compositions containing these salts, and to Medical use thereof, including the treatment of schizophrenia or other diseases that involve psychotic symptoms.

BACKGROUND OF THE INVENTION

The compound that 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 described generically in EP 638 073.

EP 638 073 covers a group of trans isomers of 3-aryl-1- (1-piperazinyl) indanes substituted at position 2 and / or 3 of the piperazine ring. It is described that the compounds have a high affinity for the D1 and D2 receptors of dopamine and the 5-HT2 receptor, and it is suggested that they are useful for the treatment of various diseases of the central nervous system, including schizophrenia. EP 638 073 does not describe the specific enantiomeric form of the compound of formula (I) above, only trans isomers in the form of racemates are described.

The enantiomer of formula (I) above has been described by Bøgesø et al. in J. Med. Chem., 1995, 38, pp. 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 D1 / D2 antagonists that indicate some D1 selectivity in vitro while in vivo it is equipotent as a D1 and D2 antagonist. The compound is also described as a potent 5-HT2 antagonist and as having a high affinity for α1 adrenoceptors. It is also mentioned that the compound does not induce catalepsy in rats.

The corresponding racemate, as well as the fumarate salt of the compound of formula (I) above is also described by Klaus P. Bøgesø in "Drug Hunting, the Medicinal Chemistry of 1-piperazino-3-phenylindans and Related Compounds", 1998, ISBN 87 -88085-10-4 (see eg compound 69 in table 3, p. 47 and in table 9A, p. 101).

Thus, the compound of formula (I) is a mixed D1 / D2 antagonist, a 5-HT2 antagonist and also has affinity for a1 adrenoceptors. In the following, a diagram is made of the possible link between different diseases and the D1 and D2 dopamine receptors, the 5-HT2 receptors and the a1 adrenoceptors, respectively.

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, has provided a theoretical framework for Understanding the biological mechanisms that are found under this disorder. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion that is supported by the fact that all antipsychotic drugs on the market currently exert a certain antagonism of the dopamine D2 receptor (Seeman Science and Medicine 1995, 2, 28-37). However, although it is generally accepted that antagonism of dopamine D2 receptors in the limbic regions of the brain play a key role in the treatment of positive symptoms of schizophrenia, blocking D2 receptors in striatal regions of the brain causes extrapyramidal symptoms ( EPS). As described in EP 638 073, a mixed D1 / D2 receptor receptor inhibition profile has been observed with something called "atypical" antipsychotic compounds, in particular with clozapine, used in the treatment of schizophrenic patients.

It also has 1 contribute to improve the properties

suggested that central antipsychotic antagonistic actions (Millan et al, JPET, 2000, 292, 38-53).

In addition, selective D1 antagonists have been linked to the treatment of sleep disorders and alcohol addiction (D. N. Eder, Current Opinion in Investigational Drugs, 2002 3 (2): 284-288).

Dopamine can also play an important role in the etiology of affective disorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237-246; J. Med. Chem., 1985, 28, 1817-1828).

EP 638 073 describes how compounds have been suggested that have affinity for 5-HT2 receptors, in particular 5-HT2 receptor antagonists, for the treatment of different diseases, such as schizophrenia, including negative symptoms in patients. schizophrenics, depression, anxiety, sleep disturbances, migraine attacks and neuroleptic-induced parkinsonism. It has also been suggested that 5-HT2 receptor antagonism reduces the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Shows an X-ray powder diffractogram of the alpha crystalline form of the hydrogen succinate salt of Compound I (obtained using Ka1 copper radiation (A = 1.5406 Å)).

Figure 2: Shows an X-ray powder diffractogram of the beta crystalline form of the hydrogen succinate salt of Compound I (obtained using Ka1 copper radiation (A = 1.5406 Å)).

Figure 3: Shows an X-ray powder diffractogram of the hydrogen malonate salt of Compound I (obtained using Ka1 copper radiation (A = 1.5406 Å)).

DETAILED DESCRIPTION OF THE INVENTION

Salts of the invention

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

As used herein, the term "hydrogen succinate" salt of the compound of formula (I) refers to the 1: 1 salt of the compound of formula (I) and succinic acid.

As used herein, the term "hydrogen malonate" salt of the compound of formula (I) refers to salt 1: 1 of the compound of formula (I) and malonic acid.

It was found that the hydrogen succinate salt was more stable than the fumarate salt and that the hydrogen malonate salt and that it was non-hygroscopic.

It was found that the hydrogen malonate salt of Compound I has a stability similar to the fumarate salt when exposed to light and is more stable when exposed to 60 ° C and 80% relative humidity (RH), but less stable than fumarate salt at 90 ° C. However, the temperature of 90 ° C is a very severe condition, and is not necessarily related to stability under normal conditions. The malonate gradually absorbs up to 1% of water when the relative humidity increases up to 95%, but without hysteresis. Therefore it is considered as non-hygroscopic, but with good moisturizing properties, which indicates favorable dissolution properties.

The invention also covers crystalline salts of the invention, including e.g. ex. anhydrates, hydrates and solvates of the salts of the invention. The term "anhydrate" means the salts of the invention that do not contain water bound in the crystal. By hydrates are understood the salts of the invention that contain water molecules attached to the crystal. Hydrates are normally prepared by salt formation in the presence of some water. Solvates are the salts of the invention that contain solvent molecules bound in the crystal. Solvates are normally prepared by formation of the succinate salt in the presence of the solvent. The solvent molecules in an individual solvate can be one or two, or more, different solvents. A solvate may comprise water, as one of two or more organic solvents, or be only a non-aqueous solvent.

An embodiment of the invention relates to the 1: 1 salt of trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine, that is, the compound of formula (I), and succinic acid in the form of a crystalline anhydrate.

The authors of the present invention have discovered two crystalline forms of the hydrogen succinate salt of Compound I (called alpha and beta).

Thus, one embodiment refers to a crystalline form of the hydrogen succinate salt of Compound I, which form is called alpha and is characterized by one or more of the following aspects:

(i)

an X-ray powder diffractogram as shown in Figure 1;

(ii)

an X-ray powder diffractogram pattern as illustrated in Table I obtained using Ka1 copper radiation (A = 1.5406 Å) showing major peaks at the given angles 28;

(iii) that has a DSC (Differential Scanning Calorimetry) profile that shows an endothermic with appearance at 139-141 ° C.

Another embodiment relates to a crystalline form of the hydrogen succinate salt of Compound I, which form is called beta and is characterized by one or more of the following aspects:

(i)

an X-ray powder diffractogram as shown in Figure 2;

(ii)

an X-ray powder diffractogram pattern as illustrated in Table I obtained using Ka1 copper radiation (A = 1.5406 Å) showing major peaks at the given angles 28;

(iii) that has a DSC profile that shows an endothermic with an appearance at 135-138 ° C.

Another embodiment relates to a crystalline form of the hydrogen malonate salt of Compound I, characterized by one or more of the following aspects:

(i)

an X-ray powder diffractogram as shown in Figure 3;

(ii)

an X-ray powder diffractogram pattern as illustrated in Table I obtained using Ka1 copper radiation (A = 1.5406 A) showing major peaks at the given angles 28;

Table 1. Characteristic X-ray powder diffractograms obtained using Ka1 copper radiation (A = 1.5406 Å) of the alpha and beta crystalline forms of the hydrogen succinate salt of Compound I, and of the crystalline malonate hydrogen salt of Compound I Fig; see also Fig. 1, Fig. 2 and Fig. 3 which provide a representative XRPD pattern of the alpha and beta polymorphic form of the hydrogen succinate salt and the malonate salt of Compound I, respectively.

Salt

Characteristic reflections - main peaks (expressed in degrees of diffraction angle 28)

Succinate, alpha

9.36; 10.23; 11.81; 13.45; 16.21; 16.57; 17.49; 18.89; 19.20; 19.63; 20.01; 20.30; 21.15; 21.53; 21.93; 22.34; 24.37; 25.34; 27.27; 29.65

Succinate, beta

8.1; 10.5; 11.4; 14.0; 14.6; 15.6; 15.7; 16.2; 17.2; 17.5; 17.9; 18.4; 18.9; 19.2; 20.3; 21.0; 21.9; 22.5; 23.3; 26.3

Malonate

8.3; 10.6; 11.5; 12.8; 14.2; 14.5; 14.7; 15.8; 16.5; 17.4; 17.6; 18.0; 18.6; 19.2; 21.2; 22.0; 22.9; 23.7; 24.7; 28.8

As used herein, "crystalline form of a specific salt of Compound I characterized by the X-ray powder diffractogram shown in Figure (1)" means the crystalline form of the salt of Compound I in question, having an X-ray powder diffractogram substantially similar to that of Figure (1), that is, showing a powder X-ray diffraction pattern that is substantially as exemplified in that Figure, and measured under conditions comparable to those described herein or by any comparable method.

Generally, it is understood that all data in this text are approximate and subject to normal measurement error depending, e.g. eg, of the apparatus used and other parameters that influence the positions of the peaks and their intensities.

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

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

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

Preparation of the salts of the invention.

The succinate salt according to the invention can be obtained by treating the free base of a 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 dry or wet milling, or other convenient procedure, or preparation of particles from a solvent emulsification process.

Precipitation of the succinate salt of the invention is preferably carried out by dissolving the free base of the compound of formula (I) in a suitable solvent, such as acetone or toluene, and then mixing this solution with a suspension or a 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, e.g. ex. a mixture consisting essentially of acetone and about 2% to 10%, preferably about 5%, of water, based on the weight of the mixture. The resulting suspension may be heated or solvent may be added until all succinic acid has dissolved. The succinate salt of the compound of the invention precipitates, preferably upon cooling the solution. The succinate salt of the invention can optionally be recrystallized one or more times, and isolated by filtration, washing, e.g. ex. with acetone, and dried.

The invention also relates to a method for the preparation of the beta crystalline form of the hydrogen succinate salt of Compound I, which method comprises leaving an aqueous solution of hydrogen succinate salt of Compound I for slow evaporation of the solvent in ambient conditions.

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

Precipitation of the malonate salt of the invention is preferably carried out by dissolving the free base of the compound of formula (I) in a suitable solvent, e.g. ex. 2-propanol, and then mixing this solution with a suspension or solution of malonic acid in a suitable solvent, e.g. ex. 2-propanol. The suspension can be heated until all the malonic acid has dissolved. The malonate salt of the compound of the invention precipitates, preferably upon cooling of the solution. The malonate salt of the invention can optionally be recrystallized one or more times, and isolated by filtration, washing, e.g. ex. in 2-propanol, and dried.

Preparation of the compound of formula (I).

The compound of formula (I) in racemic form can be prepared as described in EP 638 073, and in Bøgesø et al. J. Med. Chem., 1995, 38, p. 4380-4392, it is described how the optical resolution of the racemic compound can be achieved by crystallization of the diastereomeric salts, thereby obtaining the enantiomer of formula (I).

The authors of the present invention have now developed an improved synthesis route, in which the enantiomer of formula (I) is obtained by a synthesis sequence from the pure enantiomeric form V, that is, compound Va '((1S , 3S) -6-chloro-3-phenylindan-1-ol, see below). Thus, in this procedure, the intermediate product of formula V is resolved, e.g. ex. by chiral chromatography or enzymatically, to obtain the enantiomer of formula Va. This new synthesis route to obtain the compound of formula (I) is much more efficient than the crystallization of diastereomeric salts of the aforementioned final product I. In particular, the resolution yield is substantially higher in this new method (45% relative to the amount of racemic starting material, that is, the maximum theoretical yield is 50%) compared to the yield (relative 22% at the amount of racemic starting material, that is, the maximum theoretical yield is 50%) for the resolution of the final product I by crystallization of the diastereomeric salts. Another advantage of this invention is that the enantiomeric purity of (I) is higher (greater than 99% ee) when synthesized according to the invention compared to the synthesis using the crystallization of diastereomeric salts (95.4% from ee). In addition, the resolution of an intermediate product instead of that of the final product gives a much more efficient synthesis, since only the correct enantiomer is used in subsequent stages, giving p. ex. higher volume yields and lower reagent consumption.

Accordingly, the enantiomer of formula (I) can be obtained by a procedure that involves the following steps:

The benzyl cyanide is reacted with 2,5-dichlorobenzonitrile in the presence of a base, suitably potassium tert-butoxide (t-BuOK), in a suitable solvent such as dimethyl ether (DME), the subsequent reaction with methyl chloroacetate (MCA) leads to spontaneous ring closure and one-step formation of the compound of

5 formula (II).

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

The compound of formula (IV) is then reduced, suitably with NaBH4, in a solvent such as an alcohol,

p. ex. ethanol or iso-propanol, and preferably at a temperature in the range of -30 ° to + 30 ° C, p. ex. below 30 ° C, below 20 ° C, below 10 ° C, or preferably below 5 ° C, to form a compound of formula (V) with cis configuration:

The compound of formula (V) is resolved to achieve the desired enantiomer (formula Va), that is, also with cis ((1S, 3S) -6-chloro-3-phenylindan-1-ol) configuration:

The resolution of (V) to (Va) can be carried out, e.g. eg, using chiral chromatography, preferably liquid chromatography, suitably on a chiral silica gel column coated with a chiral polymer,

p. ex. a modified amylose, preferably tris- (3,5-dimethylphenylcarbamate) amylose applied on silica gel. A suitable solvent is used for chiral liquid chromatography, such as, e.g. eg, an alcohol, a nitrile, an ether or an 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 using appropriate techniques, e.g. ex. Simulated mobile bed technology (SMB).

Alternatively, the compound of formula (V) is resolved to achieve Compound Va by enzymatic resolution. It has been found that the enantiomerically pure Compound Va, or acylated derivatives thereof, can be prepared by enantioselective enzymatic acylation of the hydroxyl group in racemic Compound V to obtain Compound Va or an acylated derivative thereof with high optical purity. Alternatively, Enantiomerically pure Compound Va can also be obtained by a process comprising converting racemic Compound V into the corresponding ester at the hydroxyl position, followed by an enantioselective enzymatic deacylation. The use of enantioselective enzyme deactivation has been published for others.

10 compounds

Accordingly, the resolution of Compound V to give Compound Va can be performed by selective enzymatic acylation. Selective enzymatic acylation means that enzymatic acylation is preferentially effective for the conversion of one of the cis enantiomers of the compound of formula V, leaving the other cis enantiomer of Compound V without converting into the reaction mixture.

Alternatively, the resolution of Compound V to give Compound Va can be carried out by selective enzymatic deacylation. Selective enzyme deactivation means that enzyme deactivation is preferentially effective for the conversion of one of the esters of compound of formula (V), leaving the other cis enantiomer of the esters of a compound of formula (V) without converting into the reaction mixture .

Suitable esters (Vb) of the compound of formula (V) are esters such as acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate, 3-methylvalerate and 4-methylvalerate

where R, p. eg, it is acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 225 methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate, 3-methylvalerate, 4-methylvalerate.

Thus, one embodiment refers to a process for the preparation of the enantiomer (S, S) or (R, R) of the compound of formula V (ie, with cis configuration) comprising:

a) subjecting a racemic Compound V to enantioselective enzymatic acylation using an acylation agent, or

b) subjecting a racemic Compound Vb to entantioselective enzymatic deacylation to form a mixture of deacylated Compound Va.

Enantioselective enzymatic acylation means that enzymatic acylation is preferably effective for the conversion of one of the enantiomers of a compound of formula (V) preferentially leaving the other enantiomer of the compound of formula (V) without converting into the reaction mixture. Enantioselective enzymatic deacylation means that enzymatic deacylation is preferably effective for the conversion of one of the enantiomers of a compound of formula (Vb), preferably leaving the other enantiomer of the compound of formula (Vb) without converting into the reaction mixture.

Mixtures obtained by enzymatic resolution may not be completely pure, e.g. ex. they may contain a smaller amount of the other enantiomer in addition to a larger amount of the desired enantiomer (Va). The mixture of composition obtained after acylation or deacylation according to the invention depends, among other things, on the specific hydrolase used and the conditions under which the reaction is carried out. A characteristic of enzymatic acylation / deacilation according to the invention is that a considerably larger portion of one enantiomer is converted than the other. The enantioselective acylation according to the invention then results in a mixture that preferably contains the compound of formula (Vb) in the form (R, R) and the compound of formula (Va) in the form (S, S), or it may result in a mixture that preferably contains the compound of formula (Vb) in the form (S, S) and the compound of formula (Va) in the form (R, R). Similarly, enantioselective enzymatic deacylation can result in a mixture that preferentially contains the compound of formula (Vb) in the form (S, S) and the compound of formula (V) in the form (R, R), or it may result in a mixture that preferably contains the compound of formula (Va) in the form (R, R) and the compound of formula (Va) in the form (S, S). The optical purity of Va obtained by the optical resolution method of the present invention is usually at least 90% ee, preferably at least 95% ee, more preferably at least 97% ee and most preferably at least 98% of us However, lower values for optical purity are acceptable.

According to the invention, enantioselective enzymatic acylation is carried out under conditions that substantially suppress hydrolysis. Hydrolysis, which is the reverse reaction of the acylation reaction, takes place if water is present in the reaction system. Thus, enantioselective enzymatic acylation is preferably carried out in a water-free organic solvent or an almost 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 methyl acetate, ethyl acetate, ethyl butyrate, vinyl butyrate and ethyl benzoate; 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 dimethyl sulfoxide, N-methylpyrrolidone and hexamethyl phosphorus triamide. Preferred organic solvents for enzymatic acylation are organic solvents such as toluene, hexane, heptane, dioxane and tetrahydrofuran (THF).

Suitable irreversible acyl donors are, e.g. eg, acyl donors such as vinyl esters, 2-propenyl esters or 2,2,2-trihalide-ethyl esters.

Enantioselective enzymatic deacylation is preferably carried out in water or in a mixture of water and a suitable organic solvent in the presence of a buffer. They are suitable organic solvents, e.g. eg, water miscible solvents such as alcohols, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, DME and diglyme.

It has been found that enzymatic acylation according to the invention can be carried out using Novozym 435 (Candida Antarctica lipase B, from Novozymes A / S, Fluka Cat. No. 73940). In general, the enzymatic acylation or deacylation according to the invention is preferably carried out using a lipase, an esterase, an acylase or a protease. Enzymes useful according to the invention are enzymes capable of performing R-selective acylation or S-selective acylation of the hydroxy group in the racemic compound of formula (V) or enzymes that 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 the enzyme, including Cross-Linked Enzyme Crystal (CLEC), are useful according to the invention. A preferred embodiment refers to the use of a lipase to carry out the enzymatic resolution of Compound V. The most preferred lipase is Candida antarctica lipase (Fluka Cat.-No. 62299); Pseudomonas cepacia lipase (Fluka Cat.-No. 62309); lipase 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), preferably in immobilized form.

The alcohol group of the cis alcohol of formula (Va) is converted into a suitable labile group, such as, e.g. eg, a halogen, e.g. ex. Cl or Br, preferably Cl, or a sulphonate, e.g. ex. mesylate or tosylate, suitably by reaction with an agent such as thionyl chloride, mesyl chloride or tosyl chloride, in an inert solvent, e.g. ex. an ether, suitably tetrahydrofuran. The resulting compound has the formula (VI), in which LG is the labile group:

In a preferred embodiment, LG is Cl, that is, the cis-chloride of formula (VIa):

Compound VI, p. ex. with LG as chlorine, it is then reacted with 2,2-dimethylpiperazine in a suitable solvent, e.g. ex. a ketone such as, e.g. eg, methyl isobutyl ketone or methyl ethyl ketone, preferably methyl isobutyl ketone, in the presence of a base, such as p. eg potassium carbonate. The resulting compound of formula (VII):

it is methylated in the functionality of the secondary amine (suitably by reductive amination using suitable agents, such as, for example, formaldehyde, paraformaldehyde, trioxane, or diethoxy methane (DEM)) to obtain the free base of a 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, p. ex. when LG is Cl, thus shortening the synthesis in one stage.

In addition, the piperazine part of the molecule can be introduced by reacting Compound VI with a compound of formula (IX) below, wherein PG is a protective group such as, e.g. ex. and without limitation, phenylmethoxycarbonyl (which is often referred to as Cbz or Z), tert-butyloxycarbonyl (which is often called BOC), ethoxycarbonyl or benzyl, thus obtaining the compound of formula (X) that follows.

After deprotection of the product to give (VII), methylation as discussed above gives the final product, Compound I. Alternatively, the protective group such as p. ex. Ethoxycarbonyl can be converted directly into a methyl group using a suitable reducing agent, e.g. ex. lithium aluminum hydride.

During the synthesis some cis diastereoisomer of Compound I (ie 4 - ((1S, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine) is formed as an impurity in the final product. This impurity is mainly due to the formation of something of the trans form of (VI) (eg (1S, 3R) -3,5-dichloro-1-phenylindane when LG is Cl) at the stage in which form Compound VI. Therefore, the impurity can be minimized by the crystallization of the desired cis form of Compound VI, from the mixture of trans and cis (VI); in the case where LG is Cl in Compound VI, this can be done by stirring the mixture with a suitable solvent, e.g. ex. an alkane such as heptane, whereby the desired cis form of VI precipitates and the unwanted trans form of Compound VI passes into the solution. The cis form of the desired 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 the batch of (VI) used in the synthesis of Compound VII, this will result in the formation of the trans form of Compound VII (ie 4 - ((1S, 3S) -6 -chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine) as an impurity in (VII); This gives a second option of avoiding 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 a suitable salt of the compound of the formula of Compound VII, p. ex. an organic acid salt, such as an organic diacid, suitably the hydrogen fumarate salt or the hydrogen maleate salt of the compound of formula (VII), optionally followed by further recrystallization.

In addition, it has been found that impurities in the form of cis diastereoisomer in (I) (ie 4 - ((1S, 3S) -6-chloro-3phenylindan-1-yl) -1,2,2-trimethylpiperazine) can be removed effectively by precipitation of a suitable salt of the compound of formula (I), p. ex. an organic acid salt, such as an organic diacid, suitably a fumarate salt, e.g. ex. the hydrogen fumarate salt of the compound of formula (I), optionally followed by one or more recrystallizations.

The invention in other aspects also relates to intermediate products as described herein for the synthesis of the compound of formula (I), that is, in particular intermediate products (Va), VI, p. 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 main constituent of the compound. In particular, when the enantiomeric form is specified, the compound then has an enantiomeric excess of the enantiomer in question.

Accordingly, one embodiment of the invention relates to the compound of formula (Va), preferably having 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%, preferably at least 98%. In addition, the diastereomeric excess of the compound is preferably at least 70% (70% diastereomeric excess means that the ratio of Compound Va to (1R, 3S) -6-chloro-3phenylindan-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 refers to Compound Va substantially pure.

A further embodiment of the invention relates to the compound of formula (VI), preferably having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%,

5 where LG is a potential labile group, preferably chosen from the group consisting of a halogen, e.g. ex. chloride, or a sulphonate. One embodiment refers to the diastereomeric purity of Compound VI; that is, the compound having a diastereomeric excess of preferably at least 10% (10% diastereomeric excess means that the ratio of Compound VI to the cis diastereoisomer (eg (1S, 3R) -3,5-dichloro-1- phenylindane when LG = Cl) is 55:45 in the mixture in question), at least 25% or at least 50%. An embodiment, refers to Compound VI

10 substantially pure.

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

preferably having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%. An embodiment refers to purity

15 diastereomeric compound, that is, the compound having a diastereomeric excess of, preferably, at least 10% (10% diastereomeric excess means that the ratio of the compound to the cis diastereoisomer, (1S, 3R) -3,5-dichloro -1-phenylindane, is 55:45 in the mixture in question), at least 25% or at least 50%. One embodiment refers to Compound VI substantially pure in which LG is Cl.

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

preferably having 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%, preferably at least 98%, or a salt thereof, such as, e.g. eg, a fumarate salt, e.g. ex. hydrogen fumarate, or a maleate salt, e.g. ex. hydrogen maleate An embodiment refers to the

The diastereomeric purity of compound VII, that is, the compound having a diastereomeric excess of preferably at least 10% (10% diastereomeric excess means that the ratio of Compound VII to the cis- (1S, 3S) diastereoisomer is 55:45 in the mixture in question), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%. One embodiment refers to Compound VII substantially pure, or a salt thereof.

Another aspect relates to Compound I or a salt thereof, in particular the malonate or succinate salt, obtainable, and obtained in particular, by a method of the invention as described herein.

Another aspect refers to Compound VII or a salt thereof, e.g. ex. the fumarate salt, obtainable, and obtained in particular, by a method 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 product.

Accordingly, the present invention further relates to a pharmaceutical composition of the succinate salt, in particular the hydrogen succinate salt as described herein (eg the alpha or beta form as described herein), or of the malonate salt, in particular the hydrogen malonate salt, of the compound of formula (I). The invention also relates to the medical use of these salts and compositions, such as for the treatment of a disease in the central nervous system, including psychosis, in particular schizophrenia or other diseases that involve psychotic symptoms, such as, e.g. eg, schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, as well as other psychotic disorders or diseases that present with psychotic symptoms, e.g. ex. mania in bipolar disorder.

Additionally, the 5-HT2 antagonistic activity of the compound of the invention suggests that the compound may have a relatively low risk of extrapyramidal side effects.

The present invention also relates to the use of the succinate or malonate salt of the invention, preferably the hydrogen succinate salt (eg the crystalline alpha form) or hydrogen malonate, of the compound of formula (1) for the treatment of a disease , chosen from the group consisting of anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced parkinsonism, cocaine addiction, nicotine addiction, alcoholism and other addiction disorders.

In a broad aspect, the present invention relates to a method of treating schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder or mania in bipolar disorder, which comprises administering a therapeutically effective amount of the trans-compound. 4- (6-Chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt thereof.

As used herein, the expression "trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine", that is, without any specific indication of the form of the enantiomer (eg using (+) and (-), or using the R / S convention, means that it refers to any enantiomeric form of this compound, that is, either of the two enantiomers, 4 - ((1R, 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 a mixture of the two, eg the racemic mixture, however, in this context preferably the content of the enantiomer corresponding to that of Compound I is at least 50%, that is, at least as the racemic mixture, preferably Compound I is in enantiomeric excess.

In the present context, for pharmaceutical uses it is understood that when the enantiomer form of the compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (e.g. As has been done in formula (I)), the compound is then relatively pure stereochemically as described above, preferably the enantiomeric excess is at least 80% (80% enantiomeric excess means that the ratio of I to its enantiomer it is 90:10 in the mixture in question), at least 90%, at least 96%, or preferably at least 98%. In a preferred embodiment, the diastereomeric excess of Compound I is at least 90% (90% diastereomeric purity means that the ratio of Compound I to cis-4 - ((1S, 3S)) - 6-chloro-3-phenylindan- 1-yl) -1,2,2-trimethylpiperazine is 95: 5), at least 95%, at least 97%, or at least 98%.

In a preferred embodiment, the present invention relates to a method of treating schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder or mania in bipolar disorder, which comprises administering a therapeutically effective amount of the compound of formula (I) [ie 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine] or a salt thereof.

An embodiment of the invention relates to a method of treating positive symptoms of schizophrenia, negative symptoms and depressive symptoms of schizophrenia, which comprises administering a therapeutically effective amount of the compound trans-4- (6-chloro-3-phenylindan-1- il) -1,2,2-trimethylpiperazine or a salt thereof, preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment a succinate salt or a malonate salt of the compound of formula (I), preferably the hydrogen succinate salt or the hydrogen malonate salt of the compound of formula (I).

A further embodiment of the invention relates to a method of treating positive symptoms of schizophrenia which comprises administering a therapeutically effective amount of the compound trans-4- (6-chloro-3-phenylindan-1-yl) 1,2,2- trimethylpiperazine or a salt thereof, preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment a succinate salt or a malonate salt of the compound of formula (I), preferably the hydrogen succinate salt or the hydrogen salt malonate of the compound of formula (I).

Another embodiment of the invention relates to a method of treating negative symptoms of schizophrenia which comprises administering a therapeutically effective amount of the trans-4- (6-chloro-3-phenylindan-1-yl) 1,2,2-trimethylpiperazine compound. or a salt thereof, or preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment a succinate salt or a malonate salt of the compound of formula (I), preferably the hydrogen succinate salt or the hydrogen salt malonate of the compound of formula (I).

Another embodiment of the invention relates to a method of treating depressive symptoms of schizophrenia, which comprises administering a therapeutically effective amount of the trans-4- (6-chloro-3-phenylindan-1-yl) 1,2,2 compound. trimethylpiperazine or a salt thereof, preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment the hydrogen succinate or malonate salt of the compound of formula (I).

Another aspect of the invention relates to a method of treating mania and / or maintaining bipolar disorder, which comprises administering a therapeutically effective amount of the trans-4- (6-chloro-3-phenylindan-1-yl) -1 compound. , 2,2-trimethylpiperazine or a salt thereof, preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment a succinate salt or a malonate salt of the compound of formula (I), preferably the hydrogen salt succinate or the hydrogen malonate salt of the compound of formula (I).

Another aspect of the invention relates to a method of treatment of neuroleptic-induced parkinsonism, which comprises administering a therapeutically effective amount of the trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2- compound. trimethylpiperazine or a salt thereof, preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment a succinate or malonate salt of the compound of formula (I), preferably the hydrogen succinate salt or the hydrogen malonate salt of the compound of formula (I).

The invention further relates to a method of treating substance addiction, e.g. ex. addiction to nicotine, alcohol or cocaine, which comprises administering a therapeutically effective amount of the compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt of the same, preferably the compound of formula (I) or a salt thereof, or in a preferred embodiment a succinate salt or a malonate salt of the compound of formula (I), preferably the hydrogen succinate salt or the hydrogen malonate salt of the compound of formula (I).

A salt or a composition of the invention can be administered in any suitable manner, e.g. ex. orally, orally, sublingually or parenterally, and salt may be presented in any form suitable for such administration, e.g. ex. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. In one embodiment, a salt of the invention is administered in the form of a solid pharmaceutical entity, suitably in the form of a tablet or a capsule.

Methods for the preparation of solid pharmaceutical preparations are well known in the art. Thus, tablets can be prepared by mixing the active ingredient with common adjuvants, fillers and diluents, and then pressing the mixture into a machine suitable for making tablets. Examples of adjuvants, fillers and diluents include corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvant or additive, such as dyes, flavors, preservatives, etc., can also be used, as long as they are compatible with the active ingredients.

Solutions for injection can be prepared by dissolving a salt of the invention and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution, and introducing it into suitable ampoules or vials. 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 compound of formula (I) above, calculated as the free base, is suitably between 1.0 and 160 mg / day, more suitably between 1 and 100 mg, e.g. ex. preferably between 2 and 55, or between 3 and 55 mg.

The term "treatment", as used herein in connection with a disease or disorder, also includes prevention when appropriate.

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

EXAMPLES

COMPOUND PREPARATION

Analysis

The enantiomeric excess of compound (Va) in Example 1a is determined by chiral HPLC using a CHIRALCEL® OD column, 0.46cm ID X 25 cm L, 10 μm at 40 ° C. N-hexane / ethanol 95: 5 (v / v) is used as the mobile phase at a flow rate of 1.0 ml / min, detection is carried out using a UV detector at 220 nm.

HPLC analysis for the conversion rate used for Examples 1b:

Column: a Lichrospher RP-8 column, 250 x 4 mm (5 μm particle size) Eluent: MeOH / buffered water prepared as follows: 1.1 ml of Et3N added to 150 ml of water, 10% H3PO4 (ac) is scratched at pH = 7 and water is added to a total of 200 ml. The mixture is screened at 1.8 L of MeOH.

The enantiomeric excess of compound (Va) in example 1b is determined by chiral HPLC using a CHIRALPAK® AD column, 0.46 cm ID X 25 cm L, 10 μm at 21 ° C. Heptane / ethanol / diethylamine 89.9: 10: 0.1 (vol / vol / vol) 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 .

The enantiomeric excess of Compound I is determined by capillary fused silica electrophoresis (EC) using the following conditions: Capillary: 50 μm ID X 64.5 cm L, development buffer: � 1.25 mM cyclodextrin in 25 mM sodium dihydrogen phosphate , pH 1.5, voltage: 16 kV, temperature: 22 ° C, injection: 50 mbar for 5 seconds, detection: 192 nm column diode array detection, sample concentration: 500 μg / ml. In this system, Compound I has a retention time of approximately 33 min, and the other enantiomer has a retention time of approximately 35 min.

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

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

X-ray powder diffractograms are obtained on a PANalytical X'Pert PRO X-ray diffractometer using CuKa1 radiation. It is measured in reflection mode in the 28 range of 5 - 40 °.

Melting points are measured using differential scanning calorimetry (Differential Scanning Calorimetry (DSC)). The device is a TA-Instruments DSC-2920 device calibrated at 5 ° / min to give the melting point as the input value. Approximately 2 mg of sample is heated at 5 ° / min in a closed container not hermetically under nitrogen flow.

Synthesis of the key starting material.

Compound V was synthesized from IV by reduction with sodium borohydride (NaBH4) by adapting a method described in Bøgesø J. Med. Chem. 1983, 26, 935, using ethanol as solvent, and carrying out the reaction at about 0 ° C. Both compounds are described in Bøgesø et al. J. Med. Chem. 1995, 38, 4380-4392. Compound IV was synthesized from II using the general procedures described in Sommer et al., J. Org. Chem. 1990, 55, 4822, which also describes II and the synthesis thereof.

Example 1a Synthesis of (1S, 3S) -6-chloro-3-phenylindan-1-ol (Va) using chiral chromatography.

The racemic cis-6-chloro-3-phenylindan-1-ol (V) (492 grams) is resolved by preparative chromatography, using a CHIRALPAK® AD column, 10 cm ID X 50cm L, 10 μm at 40 ° C. Methanol is used as the mobile phase at a flow rate of 190 ml / min, detection is carried out using a 287 nm UV detector. Racemic alcohol

(V) is injected as a 50,000 ppm solution in methanol; 90 ml are injected with intervals of 28 min. All fractions containing the title compound with more than 98% enantiomeric excess are pooled and evaporated to dryness using a rotary evaporator, followed by drying under vacuum at 40 ° C. The yield is 220 grams in solid form. The elemental analysis and the NMR are consistent with the structure, the enantiomeric excess is greater than 98% according to the chiral HPLC, [alD20 +44.50 (c = 1.0, methanol).

Example 1b Synthesis of (1S, 3S) -6-chloro-3-phenylindan-1-ol (Va) using enzymatic resolution.

Compound V (5g, 20.4 mmol) is dissolved in 150 ml of anhydrous toluene. 0.5 g of Novozym 435 (Candida Antarctica lipase B) (Novozymes A / S, Fluka Cat.-No. 73940) are 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 a conversion of 54%, the mixture is filtered and concentrated under vacuum to obtain an oil containing an ester mixture (1R , 3R) -cis-6-chloro-3-phenylindan-1-ol-butyrate and the desired compound Va, with an enantiomeric excess of 99.2% (99.6% compound Va and 0.4% of (1R, 3R) - cis-6-chloro-3-phenylindan-1-ol).

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

Example 2 Synthesis of (1S, 3S) -3,5-dichloro-1-phenylindan (VI, LG = Cl)

The cis- (1S, 3S) -6-chloro-3-phenylindan-1-ol (Va) (204 grams) obtained as described in Example 1a is dissolved in THF (1500ml) and cooled to -5 ° C . Thionyl chloride (119 grams) is added dropwise as a solution in THF (500 ml) over a period of 1 h. The mixture is stirred at room temperature overnight. Ice (100 g) is added to the reaction mixture. When the ice has melted, 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 the water A phase, adjusted to pH 9 with sodium hydroxide (28%), and used to wash the 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 is combined with the organic phase B, dried with magnesium sulfate, and evaporated to dryness using a rotary evaporator, giving the title compound as an oil. Yield 240 grams, which are used directly in example 5. Cis / trans ratio 77:23 according to the NMR.

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

Potassium carbonate (390 grams) and ethylene diamine (1001 grams) are stirred with toluene (1.50 l). A solution of ethyl 2-bromoisobutyrate (500 grams) in toluene (750 ml) is added. The suspension is heated at reflux overnight and filtered. The filter cake is 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 (the temperature in the mixture is 75 ° C). More toluene (600 ml) is added, and another 1200 ml of distillate is collected at 76 ° C (the temperature in the mixture is 80 ° C). Toluene (750 ml) is added again, and 1100 ml of distillate are collected at 66 ° C (temperature in the mixture 71 ° C). The mixture is stirred in an ice bath and inoculated, whereby the product precipitates. The product is isolated by filtration, washed with toluene, and dried overnight in a vacuum oven at 50 ° C. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one. The NMR is consistent with the structure.

Example 4 Synthesis of 2,2-dimethylpiperazine.

A mixture of 3,3-dimethylpiperazin-2-one (8.28 kg, 64.6 mol) and tetrahydrofuran (THF) (60 kg) is heated to 50-60 ° C giving a slightly cloudy solution. The THF (50 kg) is stirred under nitrogen, and LiAlH4 (250 g, in a bag of soluble plastic material, from Chemetall) is added, which produces a slow gas evolution. Once the gas evolution has ceased, more LiAlH4 is added (a total of 3.0 kg, 79.1 moles is used), and the temperature rises from 22 ° C to 50 ° C because of the exothermic reaction. The 3,3-dimethylpiperazin-2-one solution is added slowly over 2 hours at 41-59 ° C. The suspension is stirred for another 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). After sodium hydroxide (15%, 3.50 kg) is added over 20 minutes at 23 ° C, it is necessary to cool. More water (9 l) is added over half an hour (it is necessary to cool) and the mixture is stirred overnight under nitrogen. Celit filter agent (4 kg) is added, and the mixture is filtered. The filter cake is washed with THF (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 (12.8 kg) is more concentrated in a rotary evaporator to approximately 10 l. Finally, the mixture is subjected to fractional distillation at atmospheric pressure, and the product is collected at 163-4 ° C. Yield 5.3 kg (72%). The NMR is in accordance with the structure.

Example 5 Synthesis of trans-1 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (VII)

Cis- (1S, 3S) -3,5-dichloro-1-phenylindane (VI, LG = Cl) (240 g) is dissolved in butan-2-one (1800 ml). Potassium carbonate (272 g) and 2,2-dimethyl piperazine (prepared in Example 4) (113 g) are added and the mixture is heated at reflux temperature for 40 h. To the reaction mixture is added diethyl ether (21) and hydrochloric acid (1M, 6 L). The phases are separated, and the pH of the aqueous phase is lowered from 8 to 1 with concentrated hydrochloric acid. The aqueous phase is used to wash the organic phase once more in order to ensure that the entire product is in the aqueous phase. Sodium hydroxide (28%) is added to the aqueous phase until the pH is 10, and the aqueous phase is 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. Yield 251 grams of the title compound in the form of an oil, which is used directly in the following example. Cis / trans ratio, 82:18 according to NMR.

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

Mix trans-1 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (VII) (250 grams) with formaldehyde (37% in water, 300 ml) and formic acid (366 grams), and the mixture is slowly heated to reflux. The mixture is stirred at reflux for 3.5 hours, and after cooling to room temperature water (1200 ml) is added. The mixture is extracted twice with ether (1200 ml), and then the aqueous phase is made alkaline by adding sodium hydroxide (28%, approximately 500 ml). The aqueous phase is extracted three times with ether (900 ml). The organic phases are combined and washed with brine (650 ml), and twice with water (500 ml). The organic phase is dried with sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. Yield: 212 grams of trans-4 - ((1R, 3S) -6-chloro-3phenylindan-1-yl) -1,2,2-trimethylpiperazine free base (I) in the form of an oil, with 19% of the diastereoisomer cis according to the NMR. The compound is dissolved in 1-propanol (3.18 l) and the mixture is heated to 50 ° C, which gives a clear solution. Fumaric acid (69.3 grams) is added, giving a clear solution. The mixture is allowed to cool, whereby the title compound precipitates. The product is isolated by filtration, washed with 1-propanol, and dried under vacuum at 60 ° C. Yield: 182 grams, contain <1% of the cis diastereoisomer according to NMR. The elementary analysis and the NMR conform to the structure. The enantiomeric excess is greater than 99% according to chiral capillary electrophoresis (EC). [alD20 = -22.80 (c = 1.0, methanol).

Free amine release of (I) from the hydrogen fumarate salt and reprecipitation as hydrogen succinate and hydrogen malonate salts.

Example 7 Synthesis of the free base 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (I).

Hydrogen fumarate of trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) (25.0 grams) is suspended in toluene (125 ml) ). 25% aqueous ammonia solution (75 ml) is added. The three phases are stirred until all solids disappear. The organic phase is separated, and the aqueous phase is washed with toluene (25 ml). The combined toluene phases are washed with water (25 ml). The aqueous phase is discarded and the organic phase is dried by sodium sulfate (35 grams), the suspension is filtered and the filtrate is evaporated to dryness on a rotary evaporator, giving the title compound as an oil. The raw free base (15 grams) is used without further purification.

Example 8 Synthesis of hydrogen trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) succinate (I).

The trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (I) (8.50 grams of oil) is dissolved in acetone (30 ml) ) obtained as described in Example 7. A suspension of succinic acid (3.25 grams) in acetone (32 ml) is prepared and the solution of trans-4 - ((1R, 3S) -6-chloro- 3-Phenylindan-1-yl) -1,2,2-trimethylpiperazine (I), succinic acid dissolves and shortly thereafter trans-4 hydrogen succinate precipitates ((1R, 3S) -6-chloro-3- phenylindan1-yl) -1,2,2-trimethylpiperazinium (I). The suspension is cooled to 0 ° C for 90 minutes before isolating the precipitate by centrifugation. The supernatant is discarded and the precipitate is washed with acetone (20 ml). The suspension is centrifuged, the supernatant is discarded and the precipitate is dried under vacuum at 50 ° C. Yield 8.56 grams.

When this procedure was performed for the first time, the isolated product was the beta form, the following repetitions resulted in the formation of the most stable alpha form of the hydrogen succinate of Compound I.

The acetone in the experiment described above can be substituted by aqueous acetone (95%), resulting in the formation of the alpha form of hydrogen succinate of Compound I. Differential scanning calorimetry (DSC) indicates an endothermic with an appearance temperature of 140 ° C and a peak at 141 ° C corresponding to the alpha form. The XRPD diffractogram conforms to alpha form.

Example 9 Hydrogen trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) malonate.

The trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (I) (1.0 gram, 2.81 mmol), obtained as described in Example 7 in 2-propanol (5 ml). A solution of malonic acid (0.291 grams, 2.46 mmol) in 2-propanol (5 ml) is prepared and the solution of trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1 is added -yl) 1,2,2-trimethylpiperazine, thereby precipitating hydrogen malonate from trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) 1,2,2-trimethylpiperazinium. The suspension is cooled to room temperature before isolating the precipitate by centrifugation. The supernatant is discarded and the precipitate is washed with 2-propanol (5 ml). The suspension is centrifuged, the supernatant is discarded and the precipitate is dried under vacuum at 50 ° C. Yield: 0.98 grams (84%). The elementary analysis conforms to the structure. The X-ray diffractogram conforms to the hydrogen malonate diffractogram as shown in Figure 3.

Synthesis of (I), salt formation of (VII) to remove the cis diastereoisomer of (VII), and formation of the hydrogen succinate salt from (I) crude.

Example 10 Synthesis of hydrogen trans-1 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium maleate (VII).

Examples 2 and 5 are repeated, yielding crude trans-1 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (VII) (about 20 grams) as an oil, which is purified more intensely by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 90: 5: 5) followed by evaporation to dryness on a rotary evaporator. Yield 12 grams of the title compound as an oil (cis / trans ratio, 90:10 according to the NMR). The oil is dissolved in ethanol (100 ml), and to this solution is added a solution of maleic acid in ethanol at pH 3. The resulting mixture is stirred at room temperature for 16 hours, and the precipitate that forms is collected by filtration. The volume of ethanol is reduced and another batch of precipitate is collected. Yield 3.5 grams of solid of the title compound (cis isomer is not detected according to NMR). Melting point 175-178 ° C.

Example 11 trans-1 - ((1R, 3S) -6-Chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (VII).

A mixture of hydrogen trans-1 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium (VII) (9.9 grams), concentrated aqueous ammonia solution (100 ml), brine (150 ml) and ethyl acetate (250 ml), stir at room temperature for 30 min. The phases are separated and the aqueous phase is extracted with ethyl acetate once more. The combined organic phases are washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. Yield 7.5 grams of oil.

Example 12 Preparation of the free base trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (I).

Trans-1 - ((1R, 3S) -6-Chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (8.9 grams) (VII) is 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 2½ hours. After cooling the reaction mixture, water (50 ml) and hexane (50 ml) are added. The pH is adjusted with NaOH (27%, 33 ml) at pH> 12. The hexane phase is washed with aqueous NaCl solution (20 ml) and water (20 ml). The hexane is changed azeotropic with acetone (90 ml) and the mixture is concentrated. The crude free base in acetone (10 ml) is used without further purification.

Example 13 Trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) succinate hydrogen.

trans-4 - ((1R, 3S) -6-Chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (I) crude in solution in acetone (10 ml). A suspension of succinic acid (3.4 grams) in acetone (20 ml) is prepared and the solution of trans-4 ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1, 2,2-trimethylpiperazine (I), and the mixture is heated to reflux (55 ° C). The succinic acid dissolves and during cooling the solution begins to precipitate hydrogen succinate from trans-4 ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I ). The suspension is left overnight to precipitate. The hydrogen trans-4- (1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium succinate is isolated by filtration and washed with acetone (20 ml). The product is dried under vacuum at 60 ° C. Yield: 7.9 grams.

Differential scanning calorimetry shows an endothermic with an appearance temperature of 140 ° C and a peak at 141 ° C corresponding to the alpha form. The XRPD diffractogram conforms to the alpha form. [alD20 = -22,040 (c = 1.0, methanol).

Synthesis of I using 1,2,2-trimethylpiperazine.

Example 14 Synthesis of 3,3,4-trimethylpiperazin-2-one.

3,3-Dimethylpiperazin-2-one (50 grams) is suspended in 1,2-dimethoxyethane (DME) (150 ml) and potassium carbonate (70 grams) is added. Methyl iodide (66.4 grams) is added for half an hour, while the mixture cools slightly, allowing the temperature to reach 50 ° C. The mixture is stirred 9 hours in an oil bath at 40-45 ° C, and a sample is taken for NMR, which indicates that there is still 8% starting material (signal at 2.8 ppm). More methyl iodide (4.6 grams) is added, and the mixture is stirred for a further 2½ hours at 40 ° C, and a new sample for NMR indicates total conversion. The mixture is filtered and the filter cake is washed with DME. The filtrate is evaporated to dryness giving 41 grams of the title compound. The NMR agrees with the structure.

Example 15 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 at 50 ° C in an oil bath. Raw 3,3,4-trimethylpiperazin-2-one (10 g) is suspended in THF and added slowly giving a gas evolution. The resulting mixture is stirred at 45-56 ° C for 4 hours, giving the total conversion in the title compound according to the NMR (there is no signal at 1.2 ppm from the starting material). The mixture is cooled and water (3.3 ml) is added giving gas evolution. Then a solution of sodium hydroxide in water (15%, 3.3 ml) is added, giving more gas, and finally water (10 ml) is added. The mixture is filtered and the filter cake is washed with THF (100 ml). The filtrates are concentrated in a rotary evaporator (0.3 atm and 60 ° C in the water bath). The residue is dissolved in THF (200 ml) and dried with sodium sulfate, then the mixture is filtered, and the filtrate is concentrated on a rotary evaporator (0.2 atm and 60 ° C in the water bath) giving 6, 4 grams of the title compound. The NMR is consistent with the structure, the substance contains some THF.

Example 16 Synthesis of hydrogen fumarate of trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) from compound VI.

It binds cis- (1S, 3S) -3,5-dichloro-1-phenylindane (VI with LG = Cl) (17.8 grams) with distilled 1,2,2-trimethylpiperazine

(VIII) (8.7 grams), using the procedure described in Example 5. The crude product of the free amine (15.7 grams), which contains 6% of the cis isomer, is used to form the hydrogen fumarate salt, using the procedure of example 6. Yield 15.7 grams of the title compound; NMR satisfies the structure, cis isomer is not observed.

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

Example 17 Synthesis of hydrogen trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) succinate, beta form.

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

Analytical results: Differential scanning calorimetry (DSC) shows an endothermic with an appearance temperature of 135.6 ° C and a peak at 137.5 ° C corresponding to the beta form. The XRPD conforms to the beta form.

CHARACTERIZATION OF SALTS

Example 18 Solubility of the salts of the compound of formula (I).

The solubility of the salts in water was determined by adding an excess (50 mg) of salt to 2 ml of water. The suspensions were left in the rotary mixer for at least 24 hours, and then the pH was measured and the concentration was determined by HPLC. The solid precipitate was isolated and allowed to dry in the laboratory. The results are summarized in table 1.

Table 1: Solubility of salts in water at room temperature.

Sample

pH Solubility (mg / ml)

1: 1 alpha succinate

4.4 13

1: 1 malonate

3.9 fifteen

Fumarate

 3.8 1.5

Example 19 Stability of the salts of the compound of formula (I).

The stability of the salts was investigated under the following circumstances:

Heat, 60 ° C / 80% RH (relative humidity): Samples were stored at 60 ° C with 80% RH for one week. They were then dissolved and analyzed by HPLC.

Heat, 90 ° C: Samples (~ 10 mg) were stored at 90 ° C in closed containers containing 1 droplet of water. They were then dissolved and analyzed by HPLC.

Light: The samples were placed in a 250 w / m2 illuminated cabin for 24 hours. They were then dissolved and analyzed by HPLC.

The area of the peaks in the chromatograms was summarized next to the peaks corresponding to the substance or acid. The succinate salt of the invention does not show any degradation at all.

Table 2 Example 20 Hygroscopicity of the salts of the compound of formula (I)

Sample

Sum of the areas of the impurity peaks%

60 ° C / 80% RH

 90 ° C Light

Malonate 1: 1 alpha

0 6.19 0.06

1: 1 succinate

0 0 0

Fumarate

 0.07 0.09 0.06

The hygroscopicity of the fumarate salt, the succinate salt (the alpha form) and the malonate salt was investigated by dynamic steam absorption (Dynamic Vapor surprise: DVS). It was found that the fumarate and succinate salts were non-hygroscopic. The malonate gradually absorbs up to 1% of water when the relative humidity increases to 95%, but without hysteresis.

Claims (37)

1. A succinate salt or a malonate salt of the compound of formula (I) [trans-4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine].

2.

 The succinate salt according to claim 1, which is the hydrogen succinate salt of the compound of formula (I).

3.

 A crystalline hydrogen succinate salt of Compound I defined in claim 1.

Four.

 The salt according to any of claims 1 to 3, whose crystalline form is characterized by an X-ray powder diffractogram obtained using CuKa1 radiation (A = 1.5406 Å) showing peaks for the following angles 28: 9.36; 10.23; 11.81; 13.45; 16.21; 16.57; 17.49; 18.89; 19.20; 19.63; 20.01; 20.30; 21.15; 21.53; 21.93; 22.34; 24.37; 25.34; 27.27; 29.65.

5.

 The salt according to any of claims 3 to 4, whose crystalline form is characterized in that it has a DSC profile showing an endothermic with appearance at approximately 139-141 ° C.

6.

 The malonate salt according to claim 1, which is the hydrogen malonate salt of the compound of formula (I).

7.

 A crystalline hydrogen malonate salt of Compound I as defined in claim 1.

8.

 The crystalline salt according to claim 6 or 7, whose crystalline form is characterized by an X-ray powder diffractogram obtained using CuKa1 radiation (A = 1.5406 Å) showing peaks for the following angles 28: 8.3; 10.6; 11.5; 12.8; 14.2; 14.5; 14.7; 15.8; 16.5; 17.4; 17.6; 18.0; 18.6; 19.2; 21.2; 22.0; 22.9; 23.7; 24.7; 28.8.

9.

 A pharmaceutical composition comprising a salt according to any one of claims 1 to 8, together with at least one pharmaceutically acceptable carrier, filler or diluent.

10.

A salt according to any of claims 1 to 8, for use in medicine.

eleven.

The use of a salt according to any of claims 1 to 8, in the preparation of a medicament for the treatment of a disease chosen from the group consisting of a disease involving psychotic symptoms, anxiety disorders, affective disorders including depression, disorders of the sleep, migraine, neuroleptic-induced parkinsonism, or addiction disorders, e.g. ex. Cocaine addiction, nicotine addiction, or alcohol addiction.

12.

The use of a salt according to any of claims 1 to 8 in the preparation of a medicament for the treatment of schizophrenia or other psychotic disorders.

13.

The use of a salt according to any of claims 1 to 8 in the preparation of a medicament for the treatment of a disease chosen from the group consisting of schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and mania in bipolar disorder.

14.

The use of a salt according to any of claims 1 to 8 in the preparation of a medicament for the treatment of one or more of the following symptoms: positive symptoms, negative symptoms and depressive symptoms of schizophrenia.

fifteen.

 A method for preparing 4 - ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (formula I) or a salt thereof, which method comprises the conversion of the compound of formula Va in cis configuration in the compound of formula I, in which formulas I and Va are as follows:

16.

The method according to claim 15, which comprises the conversion of the alcohol group of the cis-alcohol of formula Va into a suitable suitable LG labile group in the compound of formula VI.

The method according to claim 16, wherein LG is a halogen, e.g. ex. Cl or Br, preferably Cl, or a sulphonate.

18.

The method according to claim 16 or 17, wherein Compound VI is precipitated in a suitable solvent.

19.

The method according to claim 18, wherein LG is a halogen, preferably Cl, and the solvent is an alkane, e.g. ex. heptane

The method of obtaining the free base of the compound of formula I according to any of claims 16 to 19, wherein

to.

Compound VI is reacted with 2,2-dimethylpiperazine to obtain the compound of formula VII

b.

Compound VII is methylated in the secondary amine to obtain the free base of the compound of formula I.

21. The method according to claim 20, wherein the compound of formula VII is precipitated as a suitable salt, e.g. ex. an salt of an organic acid, such as an organic diacid. 22. The method according to claim 21, wherein the salt formed is the hydrogen fumarate salt or the hydrogen maleate salt of Compound VII. 23. The method according to any of claims 17 to 21, wherein compound VI is reacted with 1,2,2,2-trimethylpiperazine (formula VIII) to obtain the free base of the compound of formula (I). 24. The method according to any of claims 17 to 20, which comprises

-

 reacting Compound VI with 1-protected 2,2-dimethylpiperazine (IX), wherein PG is a protecting group, thereby obtaining a compound of formula X; Y

-

 check out Compound X to obtain Compound VII or convert Compound X directly into Compound I,

wherein Compound IX and Compound X are as follows:

25.

The method according to claim 24, wherein the PG protecting group is selected from the group 10 phenylmethoxycarbonyl, tert-butyloxycarbonyl, ethoxycarbonyl, and benzyl.

26. A method for the preparation of the compound of formula I or a salt thereof, comprising reacting a compound of formula VIa (ie Compound VI for which LG is Cl) with 2,2-dimethylpiperazine, thereby obtaining the compound of formula VII, followed by methylation in the secondary amine.

27.

A method for the preparation of a compound of formula I or a salt thereof, comprising reacting a compound of formula VIa (ie Compound VI for which LG is Cl)

with 2,2-dimethylpiperazine, in the presence of a base, followed by reductive amination with suitable reagents, such as formaldehyde, paraformaldehyde, trioxane or diethoxymethane, followed by isolation of the compound of formula I as the free base or as a salt of the same. 20 28. A method for preparing 4 - ((1R, 3S) - (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (formula I) or a salt thereof, which The method comprises the conversion of the compound of formula VII into the compound of formula I, wherein formula VII is as defined in claim 20. 29. The method according to any of claims 15 to 25, wherein the compound of formula (I) is precipitated as a suitable salt, e.g. ex. an salt of an organic acid, such as an organic diacid, in order to eliminate the undesired cis diastereoisomer.

30

The method according to claim 29 wherein the salt formed is a hydrogen fumarate salt of Compound I.

31.

The method according to any of claims 15 to 27, which comprises preparing the succinate salt defined in any of claims 1 to 5.

32

The method according to claim 31, wherein the hydrogen succinate of Compound I is prepared in a ketone solvent, preferably acetone, e.g. ex. aqueous acetone

33.

The method according to any of claims 15 to 31, which comprises preparing the malonate salt defined in claim 1 or any of claims 6 to 8.

The method according to claim 33, wherein the hydrogen malonate of Compound I is prepared in an alcohol solvent, e.g. ex. 2-propanol.

35

The method according to any of claims 15 to 34, which comprises the conversion of the free base of the compound of formula (I) into a salt as defined in any one of claims 1 to 10.

36.

The method according to claim 35, wherein the base of formula (I) obtained is first isolated as the salt

10 fumarate thereof, which is optionally recrystallized one or more times, the fumarate salt is then treated with a base to release the free base of the compound of formula (I), which is then converted into the succinate or malonate salt thereof. . 37. The method according to any of claims 15 to 35 followed by isolation of the compound of formula I as the free base or as a salt thereof, p. ex. as a succinate salt as defined in any of 15 claims 1 to 5 or as a malonate salt as defined in any of claims 6 to 8.

38.

A compound (Va) that has the structure:

39.

A compound (VI) that has the structure:

20 in which LG is a potential labile group, p. ex. chosen from the group consisting of a halogen, e.g. ex. Br or Cl, preferably Cl, or a sulphonate. 40. A compound (VII) that has the following structure: or a salt thereof.

41.

A compound as defined in any one of claims 38 to 40, which compound is substantially pure.

42

The method according to any of claims 15 to 27 or any of claims 29 to 37, wherein Compound Va is obtained by enzymatic resolution of Compound V.