RS20060083A - Trans-1(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine - Google Patents

Abstract

A compound 4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-2,2-dimethylpiperazine and salts thereof, pharmaceutical compositions comprising the compound and salts, and medical use thereof, including for treatment of schizophrenia and other psychotic disorders.

Description

r/?y\A/S-1-(6-CHLORO-3-PHENYLINDAN-1-YL)-3,3-DIMETHYLPIPERAZINE

The present invention relates to frans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine and salts thereof, particularly for medical 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 (Compound I,trans-{6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine) has the general formula (I).

A group of compounds structurally related to Compound I, that is, transisomers of 3-aryl-1-(1-piperazinyl)indanes substituted at the 2- and/or 3-position of piperazine prestene, is described in EP 638 073; Bogeso et al. in J. Med. Chem., 1995, 38, 4380-4392 and Klaus P. Bogeso in "Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindanes and Related Compounds", 1998, ISBN 87-88085-10-41. These compounds are described as having high affinity for dopamine (DA) D- and D2 receptors and 5-HT2 receptors. and have been suggested to be useful for the treatment of several central nervous system diseases, including schizophrenia.

An enantiomer corresponding to the compound of formula (I) but differing in having a methyl group instead of a hydrogen on the piperazine was discovered by Bogeso et al. in J. Med. Che., 1995, 38, 4380-4392, see Table 5, compound (-)-38. This publication concludes that the (-)-enantiomer of compound 38 is a potent D1/D2 antagonist that exhibits some disselectivity in vitro while being equipotent as a D1/D2 antagonist in vivo. The compound is described as a potent 5-HT2 antagonist, which has a high affinity for α-adrenoceptors.

None of the above references discloses the specific enantiomeric form mentioned above (Compound 1) or its medicinal use. The trans isomer in the racemate form of Compound 1 was only indirectly detected as an intermediate product in the synthesis of compound 38 by Bogeso et al. in J. Med. Chem., 1995, 38, 4380-4392) while the medicinal use of Compound I or its corresponding racemate is not described.

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 claims that schizophrenia is associated with a hyperdopaminergic state, a notion that is supported by the fact that all antipsychotic drugs on the market today exhibit some dopamine D2receptor antagonism (SeemanScience and Medicine1995, 2, 28-37). However, where it is generally accepted that antagonism of dopamine D2 receptors

in the limbic regions of the brain plays a key role in the treatment of positive symptoms of schizophrenia, blockade of D2 receptors in the striatal regions of the brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 mixed dopamine D 2 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 a-\ antagonist actions are also suggested to contribute to enhanced antipsychotic properties (Millanet al, JPET, 2000, 292, 38-53).

Furthermore, selective Diantagonists are associated with the treatment of sleep disorders and alcohol abuse (D.N.Eder, Current Opinion in Investigational Drugs, 20023(2):284-288). Dopamine may 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 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, sleep disorders, migraine attacks and neuroleptic-induced parkinsonism. 5-HT2 receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects caused by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

DETAILED DESCRIPTION OF THE INVENTION

Products of the invention and their medical use

The inventors found that Compound I exhibits high affinity for dopamine D1 receptors, dopamine D2 receptors and alpha 1 adrenoceptors. Moreover, compound I was found to be an antagonist at dopamine D1 and D2 receptors, and at serotonin 5HT2a receptors. The pharmacological activities of Compound I at these receptors were found to be similar to those of the above-described compound which differs structurally from Compound I in having a methyl group instead of a hydrogen on the piperazine.

The inventors also found that several structurally related compounds, both racemates and enantiomers, described in the aforementioned references are CYP2D6 (Cytochrome p450 2D6) inhibitors while Compound I is a relatively weak CYP2D6 inhibitor, also compared to other antipsychotics such as Haloperidol and Risperidone. The racemate of the compound of the present invention is also significantly more potent on the CYP2D6 enzyme compared to the enantiomer of the present invention, ie, Compound I.

The CYP2D6 enzyme is a liver enzyme important for metabolism. CYP2D6 is a mammalian enzyme commonly associated with the metabolism of pharmaceutical compounds and inhibition of this drug-metabolizing enzyme can lead to significant drug-drug interactions, i.e., if two drugs are given in combination and are metabolized by the same enzymes, a race for metabolism can lead to increased plasma concentrations and thus possible adverse effects (for review see Lin et al, Pharmacological Rev.1997, 49, 403-449, Bertz RJ and Granneman GR. Clin Pharmacokinet. 1997, 32, 210-258).

Since more than 80 drugs in clinical use (and especially psychotropic drugs) are metabolized by CYP2D6 (Bertz RJ, Granneman GR. Clin Pharmacokin1997, 32, 210-58, Rendic S, DiCarlo FJ. Drug Metab Rev1997, 29, 413-580), inhibition of this enzyme by co-administered drugs leads to dramatic increases in exposure levels and results in toxicity such as this is seen with the combination of the well-known CYP2D6 inhibitors fluoxetine or paroxetine in combination with Imipramine, Desimipramine or Nortriptyline, resulting in increased cardiac toxicity of these tricyclics (Ereshefskv L. et al. J. Clin. Psychiatry1996, 57(suppl8), 17-25, Shulman RWCan J Psychiatry, Vol 42, Supplement 1, 4S).

The fact that Compound I has a low level interaction with the liver enzyme CYP2D6 means that it reduces the potential of the drug to interact with another drug, that is, there is possibly less drug-to-drug interaction when a patient is treated with a compound of the present invention together with any other drug that is mainly metabolized by the CYP2D6 enzyme. This is a significant advantage, especially for patients with schizophrenia who are often treated with other medications to control their illness.

The inventors also found that Compound I had a relatively low prolonging effect on the QT-interval in the electrocardiogram (ECG) of the "alpha-chloroose anesthetized rabbit". Drug-induced QT-prolongation of the electrocardiogram (ECG) interval and occurrence of fatal cardiac arrhythmias, torsade de pointes (TdP), is becoming recognized as a potential risk during treatment with a wide range of drugs including repolarization-delayed antiarrhythmics [CL. Raehl, A.K. Patel and M. LeRoy, Clin Pharm 4

(1985), 675-690], various antihistamines [R.L. Woosley, Annu Rev Pharmacol Toxicol 36 (1996), 233-252; Y.G. Yap and A.J. Camm, Clin Exp Allergy 29 Suppl 1 (1999), 15-24], antipsychotics [A.H. Glassman and J.T. Bigger, Am J Psychiatry 158(2001), 1774-1782] and antimicrobial agents [B. Darpo, Eur Heart J3 Suppl K (2001), K70-K80]. The fact that Compound I has a relatively low-level effect on the QT interval in the rabbit means that this compound has a reduced potential to induce drug-induced QT prolongation and the occurrence of fatal cardiac arrhythmias, torsade de pointes (TdP), in humans compared to several commercialized antipsychotics.

Thus, in one aspect, the invention relates to a compound of formula I (Compound I) and a salt thereof. The salt of the invention, i.e. the compound of formula (I), can, for example, be selected from the fumarate or maleate salt of Compound I.

The properties of Compound I indicate that it will be particularly useful as a pharmaceutical agent. Accordingly, the present invention further relates to a pharmaceutical composition of Compound I of the invention or a salt thereof. The invention also relates to the medical use of such compounds, salts and compositions, such as for the treatment of diseases in the central nervous system, including psychosis, especially schizophrenia or other diseases that include psychotic symptoms, e.g., schizophrenia, schizophrenic form disorder, schizoaffective disorder, hallucination disorder, brief psychotic disorder, shared psychotic disorder as other psychotic disorders and diseases that present with psychotic symptoms, e.g., mania in bipolar disorder.

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

The present invention also relates to the use of Compound I of the invention, or a salt thereof for the treatment of diseases selected from the group consisting of anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced parkinsonism, cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders.

In an assumed embodiment, the present invention relates to a method of treating schizophrenic disorder, schizoaffective disorder, apparition disorder, brief psychotic disorder, shared psychotic disorder or mania in bipolar disorder, which consists of administering a therapeutically effective amount of Compound I of the invention or a salt thereof.

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 Compound I or its salt.

Another embodiment of the invention relates to a method of treating negative symptoms of schizophrenia, which consists of administering a therapeutically effective amount of Compound I or its salt.

A further embodiment of the invention relates to a method of treating depressive symptoms in schizophrenia, which consists of administering a therapeutically effective amount of Compound I or its salt.

A further aspect of the invention relates to a method of treating mania and/or . maintenance of bipolar disorder comprising administering a therapeutically effective amount of Compound I or a salt thereof.

A further aspect of the invention relates to a method of treating neuroleptic-induced parkinsonism comprising administering a therapeutically effective amount of Compound I or a salt thereof.

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 Compound I or a salt thereof.

In a broad aspect, the present invention relates to trans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine or a salt thereof for use as a medicament.

Accordingly, the present invention also relates to a method of treating a disease selected from the group consisting of a disease that includes psychotic symptoms, schizophrenia (e.g., one or more positive symptoms, negative symptoms, and depressive symptoms of schizophrenia), schizophrenic disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and mania in bipolar disorder, anxiety disorders, affective disorders including depression, sleep disorders, migraines, neuroleptic-induced parkinsonism, and abuse disorders, e.g., cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of the compound fra/?s-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine or a salt thereof.

As the term 7rans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine" is used herein, i.e., without any specific indication of the enantiomeric form (e.g., using (+) and (-), or using the R/S-convention), it is intended to refer to any enantiomeric form of this compound, i.e., either of the two enantiomers or a mixture of the two, e.g., a racemic mixture). However, in this context, it was assumed that the content of the enantiomer corresponding to that of Compound I was at least 5'%, that is, abr as a racemic mixture, but Compound I was assumed to be in enantiomeric excess.

In the present context for pharmaceutical uses it is understood that when the enantiomeric form is specified as is done in formula (I) for Compound I, then the compound is relatively stereochemically pure, assuming an enantiomeric excess of at least 70%, and more preferably at least 80% (80% enantiomeric excess means that the yield of I with 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 mac/s-1-((1S,3S)6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine is 95:5), at least 95%, at least 97%, or at least 98%.

A further aspect of the invention relates to a method of treatment as described herein, wherein the patient treated with Compound I or a salt thereof is also treated with at least one other medicament. A certain relevant embodiment in this connection is treatment with other drugs that are metabolized by CYP2D6.

In a suitable embodiment, the second medication is an antipsychotic. Accordingly, one embodiment relates to the use of a compound, salt, or pharmaceutical composition of the invention to treat a patient suffering from schizophrenia or other psychoses who is also being treated with another drug(s), eg, where the second drug is an antipsychotic.

In a further embodiment, the invention relates to the use of a compound or salt of the invention for the treatment of a patient suffering from schizophrenia or other psychosis who abuses substances, e.g., alcohol or narcotics.

The compound, salt or composition of the invention may be provided in any suitable manner, n. eg, oral, oral, sublingual or parenteral, and the compound or salt may be presented in any suitable form for such administration, n. eg in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. 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 imparting 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 the free base, is suitably between 1.0 and 160 mg/day, more suitably between 1 and 100 mg,n. eg, assumed to be 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.

Method of preparation

The compound of formula (I) in racemic form can, e.g., be prepared analogously to the procedures indicated in EP 638 073, and Bogeso et al. J. Med. Chem., 1995, 38, page 4380-4392 followed by optical separation of the racemic compound by crystallization of diastereomeric salts and thereby 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 enantiomerically pure V, i.e., compound Va ((fS,3S)-6-chloro-3-phenylindan-1-ol, see below). Thus, in this process, the intermediate product of formula V is separated,n. by pr.chiral chromatography or enzymatically, to obtain the enantiomer of the formula Va. This new synthetic route to obtain the compound of formula (I) is more efficient than the above-mentioned crystallization of the diastereomeric salts of the final rproduct I, e.g., 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 consumption of reagents.

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 a vessel-shaped formation of the compound of formula (II).

The compound of formula (II) is then subjected to acid hydrolysis to form the compound of formula (III), suitably 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 triethylamine or N-methyl pyrrolidin-2-one (NMP), to form the compound of formula

(IV).

The compound of formula (IV) is then reduced, conveniently with sodium borohydride (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. e.g., below 30°C, below 20°C, below 10°C, or presumably below 5°C, to form a compound of formula (V) of the configuration:

The compound of formula (V) is resolved to obtain the desired enantiomer (formula Va), i.e., also in the sac/s configuration ((7S,3S)-6-chloro-3-phenylindan-1-ol):

Separation (V) to (Va) can,n. eg, be performed using chiral chromatography, preferably liquid chromatography, preferably 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. A suitable solvent is used for chiral liquid chromatography, such as, n. eg, alcohol, nitrile, ether, or alkane, or mixtures thereof, suitable 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, simulating moving bed technology (SMB).

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, enantiomerically pure Compound Va can also be obtained by a process consisting of converting racemic Compound V into the corresponding ester derivative, i.e. the ester group at the hydroxyl position followed by enzymatic enantio-selective deacylation. 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 c/s-enantiomer of a compound of formula Va to the corresponding acetylated derivative Vb leaving the other c/s-enantiomer of Compound V, e.g., compound Va, as unconverted in the reaction mixture as indicated in the following:

where R,n. eg, acetate, propionate, butyrate, valerate, hexanoate, benzoate,

laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate, 3-methylvalerate, or 4-methylvalerate. Suitable for irreversible hardening, n. pr,vinyl-esters, 2-propenyl-esters or 2,2,2-trihalide-ethyl-esters. Alternatively, the other enantiomer is acetylated (ie acetylated Va is a product, not shown), and the alcohol Va can then be obtained by isolating the acetylated Va and subsequently removing the ester group.

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 effective to convert one of the esters of the compound of formula V (Vc), leaving the other cis-enantiomer of the ester of the compound of formula V (Vd) as unconverted in the reaction mixture.

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

where R<1>,n. eg, acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate, 3-methylvalerate, or 4-methylvalerate. Alternatively the Va ester is left unconverted in the reaction mixture (ie the acetylated Va is a product, not shown) and the Va alcohol can then be obtained by isolating the acetylated Va and subsequently removing the ester group by standard procedure.

Thus 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 (Vc), presumably leaving the other enantiomer of the compound of formula (Vc) unconverted in the reaction mixture.

Thus, one embodiment relates to a process for preparing the (S,S)- or (R,R)-enantiomer of a compound of formula V (ie sac/s configuration) comprising: a) subjecting racemic Compound V to enantio-selective enzymatic acylation using an acylating agent, or b) subjecting racemic Compound Va to enantio-selective enzymatic deacylation to form a mixture of deacylated Compound Va.

Mixtures obtained by enzymatic separation may not be completely pure, n. eg, they can contain a smaller amount of the second 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, for example, on the specific hydrolase used and the conditions under which the reaction is carried out. A characteristic of the enzymatic acylation/deacylation according to the invention is that a significantly larger part of one enantiomer is converted compared to the other. Enantio-selective acylation according to the invention thus results in a mixture containing the assumed 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 assumed compound of formula (Vb) in (S, S)-form and the compound of formula (Va) in (R, R)-form. In the same way, enantio-selective enzymatic deacylation may result in a mixture containing a putative compound of formula (Vd) in (S, S)-form and a compound of formula (Va) in (R, R)-form, or may result in a mixture putatively containing compound of formula (Vd) in (R, R)-form and compound of formula (Va) in (S, S)-form. The optical purity of Va obtained by the optical separation process of the present invention is typically at least 90% e.v., preferably at least 95% e.v., more preferably at least 97% e.v., and most preferably at least 98% e.v. However, lower optical purity values are also acceptable.

According to the invention, the enantio-selective enzymatic acylation is performed under conditions that essentially prevent hydrolysis. Hydrolysis, which is the reverse of the acylation reaction, is carried out in water if it is present in the reaction system. Thus enantio-selective enzymatic acylation is presumably carried out in a water-free or 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 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-methylpyrrolidin-2-one, and hexamethylphosphorus triamide. Presumed organic solvents for enzymatic acylation are organic solvents such as toluene, hexane, heptane, dioxane and tetrahydrofuran (THF).

Suitable for irreversible hardening, n. eg, acylating agents such as vinyl esters, 2-propenyl esters or 2,2,2-trihalide-ethyl esters.

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. 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 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, enzymatic acylation or deacylation according to the invention is presumably performed using a lipase, esterase, acylase or protease. Enzymes useful according to the invention are those enzymes capable of performing R-selective acylation or S-selective acylation of the hydroxy group in the racemic compound of formula (V) or such enzymes capable of performing the R-selective deacylation or S-selective deacylation of the acyl group in the racemic compound of formula (Vc). 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); Novozvm 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 c/'s-alcohol of formula (Va) is converted to the corresponding remaining group, such as,n. eg, halogen, n. pr.Cl or Br, assumed Cl, or sulfonate,n. eg, mesylate or tosylate, by suitable reaction with an agent, such as thionyl chloride, mesyl chloride or tosyl chloride, in an inert solvent, n. e.g., ether, suitable tetrahydrofuran u. The resulting compound has the formula (VI), where LG is the leaving group:

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

Compound VI, e.g., with LG as chloro, is then reacted 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. e.g., potassium carbonate, to obtain Compound I.

Further, the piperazine portion of the molecule may be introduced by reacting Compound VI with the following compound (VII), 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 to give the compound of formula (VIII) below. Compound VIII is then deprotected to Compound I.

During the synthesis, some diastereomers of Compound I (eg, 1-((7S,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine) are formed as impurities in the final product. This impurity is mainly due to the formation of some trans-form (VI) (eg, (7S,3ft)-3,5-dichloro-1-phenylindane when LG is Cl) in the step where Compound VI is formed. Therefore, the impurity can be minimized by crystallizing the desired form of Compound VI from a mixture of transic/s(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., with an alkane, such as heptane, whereby the desired/subform VI precipitates and the undesired transform of Compound VI goes into solution. The precipitate of Compound VI (eg, when LG is Cl) is isolated by filtration, washed with the solvent in question and dried.

This cis form of Compound I can also be removed by precipitation of the corresponding salt compound of the formula Compound I,n. e.g., salts of an organic acid, such as an organic dibasic acid, preferably a fumarate salt or a maleate salt of a compound of formula (I), optionally followed by one or more re-crystallizations.

The invention in further aspects also relates to intermediates as described herein for the synthesis of compounds of formula (I), i.e. in particular to intermediates Va and VI, including Compound Via. 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 is 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.

A further embodiment of the invention relates to a compound of formula (VI), 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%,

where LG is a potential leaving group, presumably made from a halogen-containing group, n. eg, chloride, or sulfonate. One embodiment relates to the diastereomeric purity of Compound VI; that is, a compound having a diastereomeric excess of assumed 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) is 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 relates 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 trans

diastereoisomer { n. eg, (1S,3R)-3,5-dichloro-1-phenylindane when LG=Cl) 55:45 in the mixture in question), at least 25% or at least 50%. One embodiment relates to substantially pure Compound VI wherein LG is Cl.

As indicated in the text above, the invention in a particularly interesting embodiment refers to:

- Compound I or its salt,

- pharmaceutical compositions as described herein containing Compound I or its salt, - medical use as described herein for Compound I or its salt,

where Compound I has an enantiomeric excess of at least 60% (60% enantiomeric excess means that the ratio of Compound I 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%.

One embodiment relates to Compound I or a salt thereof and uses as described herein, wherein Compound I has a diastereomeric excess of at least 10% (10% diastereomeric excess means that the ratio of Compound I to the macis-(1S, 3S) diastereoisomer is 55:45 in the mixture in question), at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, presumably at least 98%.

One embodiment relates to substantially pure Compound I or a salt thereof; also for medical use as described herein.

A further aspect relates to Compound I or a salt thereof, especially a fumarate or maleate salt, which can be obtained, especially obtained, by the process of the invention as described herein; also for medical use as described herein.

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

EXAMPLES

PHARMACOLOGY

Binding experiments

For all experiments: Results are expressed as percent inhibition of the specific binding control and IC50 values (concentration causing half-maximal inhibition of the specific binding control) determined by non-linear regression analysis using Hill's curve fitting equation. Inhibition constants (Kj) are calculated from the Cheng Prusoff equation (Kj= IC50/(1+(L/KD)), where L equals the concentration of radioactive ligand in the assay) and KD equals the affinity of the radioactive ligand for the receptor.

Subtypes of Alpha-1-Adrenoceptors

Chinese hamster ovary (CHO) cell lines expressing rat alpha1 and juvenile hamster kidney (BHK) cells expressing bovine alpha1ase were generated using standard stable transfection techniques. The rat-1 cell line expressing the hamster alpha1b receptor was obtained from the University of Utah, Salt Lake City, UT. Cell lines expressing the appropriate (alpha1a, alphaib, alpha1d) receptors are collected and homogenized in ice-cold 50 mM Tris pH 7.7 using an Ultra-Turrax homogenizer and either stored at -80°C or kept on ice until use. [<3>H]Prazosine (0.3-0.5 nM) is used as a radioactive ligand that assesses the affinity of alpha!receptor subtypes. Total binding is determined using assay buffer and non-specific binding is defined in the presence of 1jj.M

VVB-4101 for all alpha receptor subtypes. Aliquots are incubated for 20 minutes at 25°C. In all experiments, bound and free radioactivity is separated by vacuum filtration on GF/B filters pretreated with polyethyleneamine (PEI) and counted in a scintillation counter.

Alpha-1 Adrenoceptors (Inhibition of binding of [3HlPrazosin to rat alpha-1-receptors)

With this procedure, inhibition by drugs with bound [<3>H]Prazosin (0.5 nM) for alpha-1-receptors in rat brain membranes is determined in vitro. The procedure is modified in relation to Hvttel et al.J. Neurochem. 1985, 44, 1615-1622.

DA D1 receptors:

Affinities for human D1 receptors are determined in the Cerep laboratory under contract using the reference sample from catalog number 803-1 h. Membranes from CHO cells expressing human recombinant D1 receptors are used. 0.3 nM [<3>H]-SCH23390 is used as a radioactive ligand and compounds are tested in serial dilution simultaneously with the reference compound SCH23390 to assess suitability of the assay. Aliquots are incubated at 22°C for 60 minutes and bound radioactivity is measured with a liquid scintillation counter.

Control specific binding to D1 receptors is defined as the difference between the total binding determined in the absence of compound and the non-specific binding determined in the presence of 1 µM SCH 23390.

DA D2 receptors:

CHO cells expressing approximately 800 fmol/mg human recombinant D2 receptors are generated by standard stable transfection techniques. Membranes are harvested using standard protocols and affinities are measured by adding serial dilutions of compounds to a membrane preparation in 50 mM Tris-HCl, 120 mM NaCl, 4 mM MgCl 2 . 0.1 nM<3>[H]-Spiperone is used as a radioactive ligand to evaluate the affinity for the human D2 receptor. Total binding is determined in the presence of buffer and non-specific binding is determined in the presence of 10 µM haloperidol. The mixture is incubated for 30 minutes at 37°C, cooled briefly on ice. Bound and free radioactivity is separated by vacuum filtration on GF/C filters pretreated with 0.1% polyethyleneim (PEI) and the filters are counted in a scintillation counter.

Efficiency tests

DA D1 receptors:

The ability of a compound to inhibit D1 receptor-mediated cAMP formation in an in-house generated GHO cell line stably expressing human recombinant D1 receptor is measured as follows. Cells were seeded in 96-well plates at a concentration of 11,000 cells/well 3 days before the experiment. On the day of the experiment, cells are washed once with pre-warmed G buffer (1 mM MgCL2, 0.9 mM CaCL2, 1 mM IBMX in PBS) and the experiment is initiated by adding 100 (aL of a mixture of 30 nM A68930 and the test compound diluted in G buffer. Cells are incubated for 20 minutes at 37°C and the reaction is stopped by adding 100 (iL S buffer (0.1 M HCl and 0.1 mM CaCl2) and the plates are placed at 4°C for 1 hour. 68 µL of N buffer (0.15 M NaOH and 60 mM NaAc) are added and the plates are shaken for 10 min. |iL IC mix (50 mM NaAc pH 6.2, 0.1% NaAzide, 12 mM CaCl2, 1% BSA and 0.15 µCi/mL<125>1-cAMP). After an 18-hour incubation at 4 °C, the plates are washed once and counted in a VVallac Tril_ux counter.

DA D2 receptors:

The ability of compounds to inhibit D2 receptor-mediated inhibition of cAMP formation in CHO cells transfected with human D2 receptor is measured as follows. Cells are seeded in 96-well plates at a concentration of 8000 cells/well 3 days before the experiment. On the day of the experiment, cells are washed once with pre-warmed G buffer (1 mM MgCL 2 , 0.9 mM CaCL 2 , 1 mM IBMX in PBS) and the experiment is initiated by adding 100 µL of a mixture of 1 µM quinpirole, 10 µM forskolin and test compound in G buffer. Cells were incubated for 20 min at 37°C and the reaction was stopped by adding 100 µl S buffer (0.1 M HCl and 0.1 mM CaCl 2 ) and the plates were placed at 4°C for 1 hour. 68 µL of N buffer (0.15 M NaOH and 60 mM NaAc) was added and the plates were shaken for 10 min. 60 µL reactions are transferred to cAMP Flash Plates (DuPont NEN) containing 40 µL 60 mM NaAc pH 6.2 and 100 µL IC mix (50 mM NaAc pH 6.2, 0.1% NaAzide, 12 mM CaCl2, 1% BSA and 0.15 µCi/mL<125>l-cAMP) is added.

(and

After an 18-hour incubation at 4 °C, the plates are washed once and counted in a VVallac TriLux counter.

Serotonin5-HT2A receptors

2 or 3 days before the experiment, CHO cells expressing 250 fmol/mg 5-HT2A receptors are plated at a density sufficient to yield a monolayer on the day of the experiment. Cells were loaded with dye (Ca<2+->kit from Molecular Devices and using Hank's balanced salt w/o phenol red, added 20 mM HEPES and adjusted to pH 7.4 with 2M NaOH as assay buffer) for 60 min at 37 °C in a 5% CO2 incubator at 95% humidity. The tearing intensity is adjusted to a suitable level to obtain basal values of approximately 8000-10000 fluorescence units. Variations in basal fluorescence should be less than 10%. IC50 values are determined by challenging the same concentration range of test substances with the EC85 of 5-HT. K values are calculated using the Cheng-Prusoff equation. % Stimulation of the concentration of the test compound is measured according to the maximum concentration of 5-HT (100%). % Inhibition by the test compound concentration is measured as the percentage by which the EC85 response of 5-HT is reduced. Maximal inhibition is at that level and is used to distinguish between full and partial antagonists.

In vitro determination of the interaction of compounds with CYP2D6 (CYP2D6 inhibitor test)

Principle: Inhibition of human CYP2D6 is assessed using microsomes prepared from baculovirus/insect cell cDNA expressing CYP2D6 as sources of enzyme and the specific CYP2D6 substrate AMMC (3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin). AMMC is O-demethylated to AHMC (3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4-methylcoumarin) which is detected by measuring the appearance of fluorescence. The putative compounds of the present invention exhibit an IC50 of greater than 5 micromolar for CYP2D6 activity, the IC50 being at the concentration of the compound that provides 50% inhibition of CYP2D6 activity.

Materials and methods:

Microsomes prepared from baculovirus/insect cell cDNA expressing CYP2D6 were obtained from BD Biosciences (Gentest 456217). The measured fluorescence of Ex. (405 nm) Em. (465 nm) with SpectroFluor Plus plate reader (Liquid Nordic). Incubations with recombinant CYP2D6 microsomes containing 1.5 pmol recombinant CYP2D6 in 0.2 ml_ total volume of 100 mM phosphate buffer at pH 7.4 containing 1.5 AMMC (3-[2-(N,N-diethyl-N-methylammonium)-ethyl!]-7-methoxy-4-methylcoumarin) with a low NADPH-regenerating system consisting of 0.0082 mM NADP<+>, 0.41 mM glucose 6-phosphate, 0.41 mM magnesium chloride, and 0.4 units/mL glucose-6-phosphate dehydrogenase. The incubation time is 45 minutes and the incubations are quenched by adding 0.075 ml of 80% acetonitrile 20% 0.5 M Tris base. All chemicals were of analytical grade from Sigma (St. Louis, MO). IC50 curves are produced using 8 concentrations between 40 and 0.02 micromolar test compound dissolved in DMSO (dimethyl sulfoxide) - the final incubation concentration is below 1.0%

(Modified from N. Chauret et. al. DMD Vol. 29, Issue 9, 1196-1200, 2001). IC50 values are calculated by linear interpolation.

QT interval

Anesthetized rabbit:

The model described below was originally designed as a proarrhythmic model by Carlsson et al, [J Cardiovasc Pharmacol. 1990; 16:276-85.] and modified to fit the search setup as described below under "animal preparation".

Preparing the animal

Male rabbits (Hsdf:NZW, side breeding) weighing 2.0 - 2.8 kg are purchased from Harlan (Netherlands). Individual body weight is measured and recorded on the day of the experiment. General anesthesia is induced through the marginal ear vein via an intravenous infusion of pentobarbital (10 mg/mL, 18 mg/kg) followed by alpha-chloralose (100 mg/kg, infusion volume 4 mL/kg given over a 20-minute period). A cannula is inserted into the trachea and the rabbits are ventilated with air at 45 breaths per minute and a tidal volume of 6 mL/kg. A vascular catheter is implanted in the jugular vein to administer the test compound. Additional catheters are implanted in the left carotid artery for blood sampling and blood pressure monitoring. Electrode needles are placed subcutaneously to record a standard bipolar lead II: negative electrode is placed in front of the right shoulder, positive electrode near the left groin.

Experimental protocol

After a short equilibration period, previous dose values are obtained at -20, -10, and 0 minutes before IV bolus administration of vehicle or test compound. The effect of bolus administration is monitored over a period of 40 minutes.

Taking data from samples and calculating

ECG, blood pressure, and HR were recorded continuously on a Maclab 8/s using Chart software v3.6.1 for a Macintosh computer. The sample frequency is 1000 Hz. The effects of the electrocardiogram (PQ-, QRS-, QT-, QTc-intervals and heart rate) and mean arterial blood pressure (MAP) are recorded and measured electronically.

ANALYTICAL PROCEDURES

The enantiomeric excess of compound ( Va ) in Example 1a is determined by chiral HPLC using a CHIRALCEL ® OD column, 0.46 cm ID X 25 cm L, 10 µM at 40 °C. It is used as a mobile phase n-Hexane/ethanol 95:5 (v/v) 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 \ xm 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 added to a total of 200 mL. The mixture was added to 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 (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.

The enantiomeric excess of compound (I) is determined by fused silica capillary electrophoresis (CE) using the following conditions: Capillary: 50 µm 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: 40 mbar for 4 seconds, detection: array detection. diode column 195 nm, sample concentration: 500ng/mL. In this system, Compound I has a retention time of approximately 10 minutes, and the other enantiomer has a retention time of approximately 11 minutes.

<1>H NMR spectra were 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 dimethyl sulfoxide (99.8%D) are used as solvents, and tetramethylsilane (TMS) is used as an internal reference standard.

The cis / trans ratio of compound I was determined using <1>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 1H 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.

Melting points are measured using differential scanning calorimetry (DSC). The equipment was a TA-Instruments DSC-2920 calibrated at 5°/min to give the melting point as an initial value. About 2 mg of the sample is heated at 5°/min in a loosely closed vessel with a flow of nitrogen.

SYNTHESIS

Synthesis of key starting material

Compound V was synthesized from IV by reduction with sodium borohydride (NaBH4) by adapting the procedure described by BogesoJ. Med. Chem. 1983, 26, 935, using ethanol as a solvent, and performing the reaction at approximately 0 °C. Both compounds are described in Bogeso 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, where II and its synthesis are also described.

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

chiral non-chromatography

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 (am at 40°C. Methanol was used as the mobile phase at a flow rate of 190 mL/min, detection was performed using a UV detector at 287 nm. Racemic alcohol (V) is injected as a 50,000 ppm solution at 28 minute intervals. All fractions, containing more than 98% enantiomeric excess, are combined and evaporated to dryness using a rotary evaporator. The yield is 220 grams as a solid. enantiomeric excess is greater than 98% by chiral HPLC, [α]D<20>+44.5°

(c=1.0, methanol).

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

enzymatic cleavage

Compound V (5 g, 20.4 mmol) was dissolved in 150 mL of anhydrous toluene. 0.5 g of Novozvm 435 (Candida Antarctica lipase B) (Novozvmes 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 Novozvm 435 was added. After 4 days at 54% conversion, the mixture was 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).

Example 2 Synthesis of (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) over a period of 1 h. The mixture was stirred 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 the organic phase B, dried with 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.

Example 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 ethyl 2-bromoisobutyrate (500 grams) is added.

in toluene (750 mL). 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°C.

(temperature in the mixture is 71 °C). The mixture is stirred in an ice bath and coil, where the product settles. 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. 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) was heated to 50-60 °C, giving a slightly cloudy solution. THF (50 kg) was stirred under nitrogen, and LiAlH 4 (250 g, in a dissolvable plastic bag, from Chemetall) was added, giving slow gas evolution. After gas evolution is complete, more LJAIH4 is added (3.0 kg, 79.1 mol used in total), and the temperature rises from 22°C to 50°C due to exotherms. 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, cooling necessary. 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 was 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 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.

Example 5 Synthesis of frans-1-(1/?,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazinium (Compound I) hydrogen maleate salt C/s-(1S,3S)-3,5-dichloro-1-phenylindan (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) 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 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 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 1, and the aqueous phase was extracted twice with diethyl ether (2 L). The diethyl ether extracts were combined, dried with sodium sulfate, and evaporated to dryness using a rotary evaporator. Yield 251 g of the title compound as an oil.Cis/trans ratio, 82:18 by NMR. The crude oil (20 grams in total) is further purified 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 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 3.5 grams in solid form (no cis isomer detected by NMR) of the title compound. The enantiomeric excess is >99%. Melting point 175-178°C. NMR is consistent with the structure.

Example 6 Synthesis of Compound I

A mixture of trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazinium hydrogen maleate (I) (9.9 g), concentrated aqueous ammonia (100 mL), 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 brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. Yield 7.5 grams of oil. NMR is consistent with the structure.

Example 7 Synthesis of traAl7s-1-((1f?,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazinium (Compound I) fumarate salt

A solution of trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine (prepared as described in Example 6) (1 g) was dissolved in acetone (100 mL). Fumaric acid in ethanol is added to this solution until the pH of the resulting solution is 4. The resulting mixture is cooled in an ice bath for 1.5 hours, a precipitate forming. The compound was dried in vacuo to give a white solid (1.0 g). The enantiomeric excess is >99%. Melting point 193-196°C. NMR is consistent with the structure.

Claims (33)

1. A compound indicated by having the formula (Compound 1,trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine) or his sp. 2. A compound or salt according to claim 1, characterized in that it is substantially pure. 3. A pharmaceutical composition, characterized in that it consists of a compound or salt according to claim 1 or 2 together with at least one pharmaceutically acceptable carrier, filler or diluent. 4. Pharmaceutical composition according to claim 3, characterized in that the enantiomeric excess of Compound I is at least 90%, at least 96%, or at least 98%. 5. A compound or salt according to claim 1 or 2, indicated by the fact that it serves for use in medicine. 6. Use of a compound or salt according to claim 1 or 2 in the preparation of a medicament for the treatment of a disease selected from the group consisting of diseases including psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced parkinsonism, and abuse disorders, e.g., cocaine abuse, nicotine abuse, or alcohol abuse. 7. Use according to claim 6 in the preparation of medication for the treatment of schizophrenia or other psychotic disorders. 8. Use according to claim 7 in the preparation of a medicament for the treatment of one or more: positive symptoms, negative symptoms and depressive symptoms of schizophrenia. 9. Use of a compound or salt according to claim 1 or 2 in the preparation of a medicament for the treatment of an entity selected from the group consisting of schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and mania in bipolar disorder. 10. Use according to any one of claims 6-9, wherein said compound or a salt thereof is in the form of a pharmaceutical composition as defined in claim 4. 11. A method of treating a disease selected from the group consisting of diseases including psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced parkinsonism, and abuse disorders, e.g., cocaine abuse, nicotine abuse, or alcohol abuse, characterized by administering a therapeutically effective amount of a compound or salt as defined in claim 1 or 2. 12. The method according to claim 11, characterized by the fact that it serves for the treatment of schizophrenia or other psychotic disorders. 13. The method according to claim 12, characterized by the fact that it serves to treat one or more: positive symptoms, negative symptoms and depressive symptoms of schizophrenia. 14. A method of treating a disease selected from the group consisting of schizophrenia, schizophrenic disorder, schizoaffective disorder, apparition disorder, brief psychotic disorder, shared psychotic disorder, and mania in bipolar disorder, characterized by the administration of a therapeutically effective amount of a compound or salt as defined in claim 1 or 2. 15. The method according to any one of claims 11-14, characterized in that the patient treated with Compound I or a salt thereof is also treated with other medication(s). 16. The method according to claim 12, characterized in that the patient treated with Compound I or its salt is also treated with at least one other medication. 17. The method according to any of claims 11-16, characterized in that the said compound or its salt is in the form of a pharmaceutical composition as defined in claim 4. 18. The compound trans-(-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine or its salt, indicated by the fact that it serves for use in medicine. 19. A pharmaceutical composition comprising a compound or salt according to claim 18 together with at least one pharmaceutically acceptable carrier, filler or diluent. 20. Use of a compound or salt according to claim 18 in the preparation of a medicament for the treatment of a disease selected from the group consisting of diseases that include psychotic symptoms, schizophrenia (e.g., one or more of the positive symptoms, negative symptoms, and depressive symptoms of schizophrenia), schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, mania in bipolar disorder, anxiety disorder, affective disorder including depression, sleep, migraine, neuroleptic-induced parkinsonism, abuse disorders, n. eg, cocaine abuse, nicotine abuse, or alcohol abuse. 21. A method for treating diseases selected from the group consisting of diseases that include psychotic symptoms, schizophrenia (eg, one or more of positive symptoms, negative symptoms, and depressive symptoms of schizophrenia), schizophrenic disorder, schizoaffective disorder, apparition disorder, brief psychotic disorder, shared psychotic disorder, mania in bipolar disorder, anxiety disorder, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced parkinsonism, abuse disorders, n. e.g., cocaine abuse, nicotine abuse, or alcohol abuse, as indicated by the administration of a therapeutically effective amount of the compound or salt as defined in claim 18. 22. A process for the production of a compound of formula I (Compound I) or its salt, characterized in that the process consists in the conversion of a compound of formula Va (Compound Va) in the c/s-conformation into a compound of formula I, wherein I and Va are as follows: 23. The process according to claim 22, characterized in that it consists in the conversion of the alcohol group of the cis-alcohol of formula Va into the corresponding leaving group LG, resulting in the compound of formula VI. 24. The method according to claim 23, characterized in that LG is a halogen, e.g. Cl or Br, presumably Cl, or sulfonate. 25. A process according to any one of claims 22-24, characterized in that Compound VI is precipitated from a suitable solvent. 26. The method according to claim 25, characterized in that LG is a halogen, presumably Cl, and the solvent is an alkane, n. eg, heptane. 27. A process according to any one of claims 22-26, characterized in that Compound VI is reacted with 2,2-dimethylpiperazine to give Compound I. 28. The procedure according to claim 27, characterized by the fact that Compound I is precipitated as the corresponding salt, n. eg, a salt of an organic acid such as an organic dibasic acid. 29. The method according to claim 28, characterized by the fact that it is formed with a fumarate salt or a maleate salt of Compound I. 30. The method according to any one of claims 22-26, characterized in that it consists of - reacting Compound VI with 1-protected 2,2-dimethylpiperazine (VII), wherein the PG protecting group is, e.g., selected from the group of phenylmethoxycarbonyl, tert-butyloxycarbonyl, ethoxycarbonyl and benzyl, thereby giving a compound of formula VIII; and - deprotection of Compound VIII to obtain Compound I, where Compounds VII and VIII are as follows: 31. A process for the preparation of Compound I or its salt, characterized in that it consists in reacting a compound of formula Via (ie Compound VI for which LG=CI) with 2,2-dimethylpiperazine. 32. Procedure for the preparation of Compound I or its salt, indicated by which consists of reacting a compound of formula Via with 2,2-dimethylpiperazine in the presence of a base. 33. The method according to any one of claims 22-32, characterized in that Compound Va is obtained by enzymatic cleavage of Compound V.