HK1095595A - Trans-1(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine - Google Patents

Description

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

The present invention relates to trans-1- (6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine and salts thereof, in particular for medical use, including for the treatment of schizophrenia or other diseases involving psychotic symptoms.

Background

The subject of the present invention is the compound (compound I, trans-1- ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine) having the structure of the general formula (I).

A group of Compounds structurally Related to Compound I, namely the trans isomer of 3-aryl-1- (1-piperazinyl) indane substituted at the 2-and/or 3-position of the piperazine ring, has been described in EP 638073, Bges et al in J.Med.chem., 1995, 38, 4380-. These compounds are known as para-Dopamine (DA) D₁And D₂Receptors and 5-HT₂Receptors have high affinity and are proposed for the treatment of some diseases in the central nervous system, including schizophrenia.

The enantiomer corresponding to the compound of formula (I) has been disclosed in J.Med.chem., 1995, 38, 4380-4392 to B * ges * et al, see Table 5, the compound (-) -38, but with the difference of having a methyl group on the piperazine instead of a hydrogen. The conclusion of this disclosure is that the (-) -enantiomer of compound 38 is a potent D₁/D₂Antagonists, exhibiting certain D's in vitro₁As a D in vivo₁And D₂Antagonists are equivalent. This compound is described as para-alpha₁Potent 5-HT with high affinity for adrenergic receptors₂An antagonist.

None of the above references disclose the specific enantiomeric forms of the above (compound I) or their pharmaceutical use. B * ges * et al, in j.med.chem., 1995, 38, 4380-4392, disclose indirectly the trans isomer of compound I in the form of the racemate as an intermediate in the synthesis of compound 38, but do not describe the medical use of compound I or its corresponding racemate.

Although the etiology of schizophrenia is not known, the dopamine hypothesis of schizophrenia was set forth in the early 1960 s (Carlsson, am.j.psychiatry 1978)135, 164-. In its simplest form, the dopamine-postulated state of schizophrenia is associated with a state of dopamine overload, the view being that all antipsychotic drugs currently on the market exert some dopamine D₂The fact that the receptor antagonizes this activity is supported (Seeman Science and medicine 1995, 2, 28-37). However, it is generally accepted that dopamine D is present in the limbic regions of the brain₂Antagonism of the receptor plays a key role in the treatment of positive symptoms of schizophrenia, D in the striatal region of the brain₂Blockade of receptors causes extrapyramidal symptoms (EPS). Mixed dopamine D has been observed with several so-called "atypical" anti-psychotic compounds (in particular clozapine) for the treatment of schizophrenic patients, as described in EP 638073₁/D₂Outline of receptor inhibition. Now also proposed is the center alpha₁Antagonism contributes to the improvement of anti-psychotic traits (Millan et al, JPET, 2000, 292, 38-53).

In addition, selectivity D₁Antagonists have been associated with the treatment of sleep disorders and alcohol abuse (D.N. Eder, Current Opinion in Investigational Drugs, 20023 (2): 284-. 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).

In EP 638073 it is described which compounds have 5-HT₂Receptor affinities, in particular, have been proposed for the treatment of various diseases, such as schizophrenia, including negative symptoms in schizophrenic patients, depression, anxiety, sleep disorders, migraine attacks and antipsychotic-induced 5-HT of Parkinson's syndrome₂A receptor antagonist. Now also 5-HT has been proposed₂Receptor antagonism also reduces the incidence of extrapyramidal side effects induced by conventional antipsychotics (Balsara et al, psychopharmacogenology 1979, 62, 67-69).

Detailed description of the invention

The product of the invention and its medical use

The present inventors have found that compound I exhibits a high affinity for the dopamine D1 receptor, the dopamine D2 receptor and the α 1 adrenergic receptor. Furthermore, it has now been found that compound I is an antagonist of the dopamine D1 and D2 receptors and the serotonin 5-HT2a receptor. The pharmacological activity of compound I with respect to these receptors is believed to be similar to that of the compounds described above, with the structural difference that compound I has a methyl group on the piperazine rather than a hydrogen.

The present inventors have also found that several structurally related compounds, both racemates and enantiomers described in the above-mentioned references are CYP2D6 (cytochrome P4502D 6) inhibitors, whereas compound I is a relatively weak CYP2D6 inhibitor compared to other antipsychotics, such as risperidone. The racemate of the compound of the present invention is also quite effective against the CYP2D6 enzyme, compared to the enantiomer of the present invention (i.e., compound I).

The CYP2D6 enzyme is a liver enzyme important for metabolism. CYP2D6 is a mammalian enzyme, generally associated with the metabolism of pharmaceutical compounds, and inhibition of this metabolic drug enzyme can lead to clinically important drug-drug interactions, i.e., if two drugs are administered in combination and metabolized by the same enzyme, then competition for metabolism can lead to increased plasma concentrations, with the potential for side effects (see Lin et al, pharmaceutical Rev.1997, 49, 403-laid 449, Bertz and Granneman GR. clin Phacokinet 1997, 32, 210-laid 258).

Since more than 80 drugs (and particularly psychotherapeutic drugs) are metabolized by CYP2D6 in clinical use (Bertz RJ, Granneman gr. clin Pharmacokin1997, 32, 210-58, Rendic S, DiCarlo fj. drug Metab Rev 1997, 29, 413-580), inhibition of this enzyme by co-administered drugs Can cause dramatic increases in exposure levels and toxicity of the well-known CYP2D6 inhibitor feloxetine or paroxetine in combination with imipramine, desipramine or nortriptyline, leading to increased cardiotoxicity of these tricyclic compounds (erhefsky l. et al, J. clin. psychotherapeutic 1996, 57(suppl8), 17-25, shuman RW J psychiatristimatry, Vol 42, plet 1, 4S).

The fact that compound I has a low interaction with the liver enzyme CYP2D6 means that it has a reduced potential for drug-drug interactions, i.e. there may be fewer drug-drug interactions when treating a patient with the compound of the present invention together with other drugs metabolized by the major CYP2D6 enzyme. This is an important advantage, particularly for schizophrenic patients who are often treated with other drugs to control their disease.

The inventors have also found that compound I has a relatively low prolongation of the QT-interval in the electrocardiogram of "α -chloroaldose (chlorosulfose) anesthetized rabbits". Prolongation of the QT-interval and the appearance of fatal arrhythmias, distortion of spikes (TdP) in drug-induced Electrocardiograms (ECG) are believed to be indicated by the use of antiarrhythmic drugs including delayed repolarization [ C.L. Raehl, A.K. Patel and M.LeRoy, Clin Pharm 4(1985), 675-; yap and A.J.Camm, Clin Exp Allergy 29 supply 1(1999), 15-24), antipsychotics [ A.H.Glassman and J.T.Bigger, Am J Psychiatry 158(2001), 1774-1782] and antimicrobials [ B.Darpo, Eur Heart J3 supply K (2001), K70-K80 ]. The fact that compound I has a relatively low effect on the rabbit QT interval means that the compound has a reduced potential for introducing drug-induced prolongation of the QT interval and the occurrence of fatal cardiac arrhythmias, spiking of the heart (TdP) in humans compared to some commercial antipsychotics.

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

The properties of compound I suggest that it would be a particularly useful drug. Accordingly, the present invention also relates to pharmaceutical compositions of compound I of the present invention or a salt thereof. The invention also relates to the pharmaceutical use of such compounds, salts and compositions, for example in the treatment of central nervous system disorders, including psychosis, particularly schizophrenia or other disorders involving psychotic symptoms, e.g., schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, Shared (Shared) psychotic disorder, and other psychotic disorders or diseases in which psychotic symptoms are present, e.g., mania in bipolar disorder.

Furthermore, the 5-HT2 antagonistic activity of the compounds of the invention suggests that the compounds or salts thereof have a relatively low risk of extrapyramidal side effects.

The invention also relates to the use of a compound I according to the invention or a salt thereof for the treatment of a disease selected from anxiety disorders, affective disorders including depression, sleep disorders, migraine, antipsychotic-induced parkinsonism, cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders.

In a preferred embodiment, the present invention relates to a method for the treatment of mania in schizophreniform disorders, schizoaffective disorders, delusional disorders, transient psychotic disorders, shared psychotic disorders or bipolar disorders, comprising administering a therapeutically effective amount of compound I or a salt thereof according to the invention.

Another embodiment of the present invention relates to a method for treating the positive symptoms of schizophrenia, which comprises administering a therapeutically effective amount of compound I or a salt thereof.

Another embodiment of the present invention relates to a method for treating negative symptoms of schizophrenia, which comprises administering a therapeutically effective amount of compound I or a salt thereof.

Another embodiment of the present invention relates to a method for treating the depressive symptoms of schizophrenia, which comprises administering a therapeutically effective amount of compound I or a salt thereof.

Another aspect of the invention relates to a method of maintenance for the treatment of mania and/or bipolar disorder comprising administering a therapeutically effective amount of compound I or a salt thereof.

Another aspect of the present invention relates to a method for the treatment of antipsychotic-induced parkinsonism, which comprises administering a therapeutically effective amount of compound I or a salt thereof.

The invention further relates to a method of treatment of substance abuse, such as 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.

Thus, the invention also relates to a method of treating a disease selected from the group consisting of a disorder comprising psychotic symptoms, schizophrenia (e.g. one or more of the positive, negative and depressive symptoms of schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder and mania in bipolar disorder, anxiety disorders, affective disorders including depression, sleep disorders, migraine, antipsychotic-induced parkinsonism, and abuse disorders, such as cocaine abuse, nicotine abuse or alcohol abuse, comprising administering a therapeutically effective amount of the compound trans-1- (6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine or a salt thereof.

The term "trans-1- (6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine" as used herein, i.e. without specific specification as to the form of the enantiomers (e.g. using (+) and (-) or using the R/S-convention to refer to any enantiomer formed from this compound, i.e. a mixture of either or both of the two enantiomers, e.g. a racemic mixture). However, in this context it is preferred that the content of the enantiomer corresponding to compound I is at least 50%, i.e. at least as a racemic mixture, but preferably compound I is in enantiomeric excess.

For medical use herein, it is to be understood that when an enantiomeric form is specified as the form of compound I in formula (I), then the compound is relatively stereochemically pure, preferably with an enantiomeric excess of at least 70%, more preferably at least 80% (80% enantiomeric excess means that the ratio of I to its enantiomer in the above mixture is 90: 10), at least 90%, at least 96%, or preferably at least 98% excess. In a preferred embodiment, the diastereomeric excess of compound I is at least 90% (90% diastereomeric purity means a ratio of compound I to trans-1- (1S, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine of 95: 5), at least 95%, at least 97%, or at least 98%.

Another aspect of the invention relates to a method of treatment as described herein, wherein the patient treated with the compound or salt thereof is also treated with at least one other drug. A particularly relevant embodiment in this regard is treatment with other drugs that are metabolized by CYP2D 6.

In a suitable embodiment, the other drug is an antipsychotic. Thus, one embodiment relates to the use of a compound, salt or pharmaceutical composition of the invention in the treatment of a patient suffering from schizophrenia or other psychotic disorder that is also treated with another drug, e.g., wherein such other drug is an antipsychotic.

In another embodiment, the invention relates to the use of a compound or salt of the invention for the treatment of patients suffering from schizophrenia or other psychoses as substance abusers, e.g. alcohol or narcotic abusers.

The compounds, salts or compositions of the invention may be administered in any suitable manner, for example orally, buccally, sublingually or parenterally, and for such administration the compounds or salts may be in any suitable form, for example in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. In one embodiment, the compounds or salts of the invention are administered in the form of a solid pharmaceutical entity, suitably in the form of a tablet or capsule.

Methods for preparing solid pharmaceutical formulations are well known in the art. Tablets may thus be prepared by mixing the active ingredient with conventional adjuvants, fillers and diluents and subsequently compressing the mixture in a suitable tabletting machine. Examples of adjuvants, fillers and diluents include corn starch, lactose, talc, magnesium stearate, gelatin, lactose gum and the like. Any other adjuvants or additives (e.g., colorants, fragrances, preservatives, etc.) may also be used provided they are compatible with the active ingredient.

Solutions for injection may be prepared by dissolving the salt of the invention and suitable additives in a portion of the solvent for injection (preferably sterile water), adjusting the solution to the desired volume, sterilizing the solution and filling in suitable ampoules or vials. Any suitable additive commonly used in the art may be added, such as osmotic agents, preservatives, antioxidants, solubilizing agents, and the like.

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

The term "treatment" as used herein in connection with a disease or condition also includes prophylaxis as appropriate.

Preparation method

The compounds of formula (I) in racemic form can be prepared, for example, by a process analogous to that set out in EP 638073 and B * ges * et al, page J.Med.chem., 1995, 38, 4380-4392, followed by optical resolution of the racemic compound by crystallization of the diastereomeric salt to give the enantiomer of formula (I).

The present inventors have now developed a synthetic route in which the enantiomer of formula (I) is obtained via a synthetic sequence starting from enantiomerically pure V, compound Va ((1S, 3S) -6-chloro-3-phenylindan-1-ol, see below). Thus, in this method, the intermediate of formula V is resolved, for example by chiral chromatography or enzymatic methods, to give the enantiomer of formula Va. This new synthetic route leads to compounds of formula (I) which are more efficient than the above mentioned crystallization of the diastereomeric salts of the final product I, e.g. when only the desired enantiomer is used in the following step, resolution of the intermediate instead of the final product leads to a more efficient synthesis, resulting e.g. in higher volumetric yields and less reagent consumption.

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

the reaction of phenylacetonitrile 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), and further with Methyl Chloroacetate (MCA), results in spontaneous ring closure and a one-pot formation of the compound of formula (II).

Acidic hydrolysis is then carried out to form the compound of formula (III), suitably by heating the compound of formula (II) in a mixture of acetic acid, sulphuric acid and water, followed by decarboxylation by heating the compound of formula (III) and triethylamine or N-methylpyrrolidin-2-one (NMP) in a suitable solvent, such as toluene, to form the compound of formula (IV).

The compound of formula (IV) is then reduced, suitably in a solvent such as an alcohol (e.g. ethanol or isopropanol), and preferably in the range-30 to +30 deg.C, for example below 30 deg.CAt a temperature of less than 20 ℃, less than 10 ℃, or preferably less than 5 ℃, with sodium borohydride (NaBH)₄) Reducing to form the compound of formula (V) having the cis configuration.

The compound of formula (V) is resolved to give the desired enantiomer (formula Va), i.e., (1S, 3S) -6-chloro-3-phenylindan-1-ol), which also has the cis configuration:

resolution of (V) into (Va) may be carried out, for example, using chiral chromatography, preferably liquid chromatography, suitably on a chiral silica gel column coated with a chiral polymer, such as a modified amylose, preferably amylose tris- (3, 5-dimethylphenyl carbamate) coated on silica gel. Suitable solvents are used for chiral liquid chromatography such as, for example, alcohols, nitriles, ethers or alkanes, or mixtures thereof, suitably ethanol, methanol, isopropanol, acetonitrile, or methyl tert-butyl ether or mixtures thereof, preferably methanol or acetonitrile. Chiral liquid chromatography can be scaled up using suitable techniques, such as simulated moving bed technology (SMB).

Alternatively, the compound of formula (V) is resolved by enzymatic resolution to give the compound Va. It has now been found that enantiomerically pure compound Va or an acylated derivative thereof can be prepared by the enzyme-catalysed enantioselective acylation of the hydroxyl group in racemic compound V to give compound Va or an acylated derivative thereof having high optical purity. Alternatively, enantiomerically pure compound Va can also be obtained by a process which comprises conversion of the racemic compound V into the corresponding ester derivative, i.e.subsequent enzymatic enantioselective deacylation of the ester group in the hydroxyl position. Enzyme-catalyzed enantioselective deacylation has been reported for other compounds.

Thus, resolution of compound V to compound Va can be carried out by selective enzymatic acylation. By selective enzymatic acylation is meant that the enzymatic acylation is preferentially effective for converting one of the cis enantiomers of the compound of formula V to the corresponding acetylated derivative while leaving the other cis enantiomer of compound V as the unconverted cis enantiomer (e.g. compound Va) in the reaction mixture, as listed below:

wherein R is, for example, an acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, valerate, 2-methylpentanoate, 3-methylpentanoate or 4-methylpentanoate. Suitable irreversible acyl donors are, for example, vinyl esters, 2-propenyl esters or 2, 2, 2-trihaloethyl esters. Alternatively, the other enantiomer is acetylated (i.e. acetylated Va is the product, not shown) and alcohol Va can be subsequently obtained by isolating the acetylated Va and subsequently removing the ester group.

Alternatively, resolution of compound V to compound Va can be carried out by selective enzymatic deacylation. Selective enzymatic deacylation means that the enzymatic deacylation is preferentially effective for converting one ester of the compound of formula V (Vc) while leaving the other cis enantiomer (Vd) in the reaction mixture as the ester of the compound of formula V unconverted.

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

Wherein R is¹Examples are acetate, propionate, butyrate, pentanoate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pentanoate, 2-methylpentanoate, 3-methylpentanoate, or 4-methylpentanoate. Alternatively, the ester of Va is left in the reaction mixture unconverted (i.e. acetylated Va is the product, not shown) and the alcohol Va can be subsequently obtained by isolating the acetylated Va and subsequently removing the ester group by standard methods.

Thus, enantioselective enzyme-catalyzed acylation means that the enzyme-catalyzed acylation is preferentially effective to convert one enantiomer of the compound of formula (V) while preferentially leaving the other enantiomer of the compound of formula (V) unconverted in the reaction mixture. Enantioselective, enzymatically catalyzed deacylation means that the enzymatically catalyzed deacylation is preferentially effective for converting one enantiomer of the compound of formula (Vc) while preferentially leaving the other enantiomer of the compound of formula (Vc) unconverted in the reaction mixture.

Accordingly, one embodiment relates to a process for preparing the (S, S) -or (R, R) -enantiomer of the compound of formula V (i.e., having the cis configuration), comprising:

a) the racemic compound V is subjected to enantioselective, enzymatically catalyzed acylation with an acylating agent, or

b) Racemic compound Vc is subjected to enantioselective enzymatic deacylation to form a mixture of deacylated compound Va.

The mixtures obtained by enzymatic resolution may not be completely pure, for example they may contain, in addition to a larger amount of the desired enantiomer (Va), a smaller amount of the other enantiomer. The mixture of components obtained after the acylation or deacylation according to the invention depends, for example, on the particular hydrolase used and the conditions under which the reaction is carried out. The enzymatic acylation/deacylation according to the invention is characterized in that a considerably larger part of one enantiomer is converted compared to the other enantiomer. Thus, enantioselective acylation according to the invention will result in a mixture which preferentially contains the (R, R) -form of the compound of formula (Vb) and the (S, S) -form of the compound of formula (Va), or may result in a mixture which preferentially contains the (S, S) -form of the compound of formula (Vb) and the (R, R) -form of the compound of formula (Va). Likewise, enantioselective enzyme-catalyzed deacylation may result in a mixture preferentially containing the (S, S) -form of the compound of formula (Vd) and the (R, R) -form of the compound of formula (Va), or may result in a mixture preferentially containing the (R, R) -form of the compound of formula (Vd) and the (S, S) -form of the compound of formula (Va). The optical purity of Va obtained by the optical resolution method of the present invention is usually at least 98% ee. However, lower values of optical purity are acceptable.

According to the invention, the enantioselective, enzymatically catalyzed acylation reaction is carried out under conditions which substantially inhibit the hydrolysis reaction. If water is present in the reaction system, hydrolysis is the reverse reaction of the acylation reaction. Thus, the enantioselective enzymatic acylation reaction is preferably carried out in an anhydrous organic solvent or in an almost anhydrous organic solvent (enzymes usually require some water to be present for activity). 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, methyl ethyl ketone and methyl ethyl ketone; esters such as methyl acetate, ethyl butyrate, vinyl butyrate, and ethyl benzoate; halogenated hydrocarbons such as dichloromethane, chloroform and 1, 1, 1-trichloroethane; secondary and tertiary alcohols, such as t-butanol; nitrogen-containing solvents such as dimethylformamide, acetamide, formamide, acetonitrile, and propionitrile; and aprotic polar solvents such as dimethyl sulfoxide, N-methylpyrrolidin-2-one, and hexamethyl phosphoric triamide. Preferred organic solvents for the enzyme-catalyzed acylation reaction are organic solvents such as toluene, hexane, dioxane, and Tetrahydrofuran (THF).

Suitable irreversible acyl donors are, for example, those of vinyl esters, 2-propenyl esters or 2, 2, 2-trihaloethyl esters.

The enantioselective, enzymatically catalyzed deacylation is preferably carried out in water or a mixture of water and an organic solvent, suitably in the presence of a buffer. Suitable organic solvents are, for example, water-miscible solvents such as alcohols, acetonitrile, Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 4-dioxane, DME and diglyme.

It has now been found that the enzymatic acylation reaction according to the invention can be carried out using the novel enzyme 435 (Candida antarctica lipase B from the novel enzyme A/S, Fluka Cat. -No. 73940). In general, the enzymatic acylation or deacylation according to the invention is preferably carried out using lipases, esterases, acyltransferases or proteases. Enzymes useful according to the invention are enzymes capable of R-selective acylation or S-selective acylation of the hydroxyl groups in the racemic compound of formula (V) or of R-selective deacylation or S-selective deacylation of the acyl groups in the racemic compound of formula (Vc). In particular, immobilized forms of enzymes including cross-linked enzyme crystals (CLECs) may be used in the present invention. A preferred embodiment relates to the enzymatic resolution of compound V using lipase. The most preferred lipase is candida antarctica lipase (Fluka catalog No. 62299); pseudomonas cepacia lipase (Fluka catalog number 62309); neomycin CALB (Candida antarctica Lipase B) (neomycin A/S); neomycin 435 (Candida antarctica lipase B) (neomycin A/S); or the lipase TL IM (Thermomyces lanuginosus lipase) (Neomyces neoformans A/S, preferably in immobilized form.

The alcohol group of the cis-alcohol of formula (Va) is converted to a suitable leaving group, for example a halogen, such as Cl or Br, preferably Cl, or a sulphonic acid group, such as a methanesulphonic acid group or a toluenesulphonic acid group, suitably by reaction with a reagent such as thionyl chloride, methanesulphonyl chloride or p-toluenesulphonyl chloride in an inert solvent, such as an ether, suitably tetrahydrofuran. The resulting compound has the structure of formula (VI), wherein LG is a leaving group:

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

compound VI (e.g. bearing LG as chloro) is then reacted with 2, 2-dimethylpiperazine in a suitable solvent (e.g. a ketone such as methyl isobutyl ketone or methyl ethyl ketone, preferably methyl isobutyl ketone) in the presence of a base (e.g. potassium carbonate) to give compound I.

Further, the piperazine moiety in the molecule can be introduced by reacting compound VI with a compound of formula (VII) below, wherein PG is a protecting group such as, but not limited to, for example, benzyloxycarbonyl (often referred to as Cbz or Z), tert-butoxycarbonyl (often referred to as BOC), ethoxycarbonyl, or benzyl to give a compound of formula (VIII) below. Subsequent deprotection of compound VIII affords compound I.

During the synthesis, certain cis diastereoisomers of compound I (i.e., 1- ((1S, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine) are formed as impurities in the final product. This impurity is primarily due to the formation of some trans (VI) (e.g., (1S, 3R) -3, 5-dichloro-1-phenylindane when LG is Cl) during the step of forming compound VI. Thus, impurities can be minimized by crystallizing the desired cis compound VI from a mixture of trans and cis (VI); in this case LG is Cl in compound VI, which can be done by stirring the mixture with a suitable solvent (e.g. an alkane such as heptane) to precipitate the desired cis VI and bring the unwanted trans compound VI into solution. The desired cis-compound VI (e.g., when LG is Cl) is isolated by filtration, washed with the above solvent and dried.

The cis form of compound I may also be removed by precipitation of a suitable salt of compound I, e.g. an organic acid salt, such as an organic dibasic acid, suitably a fumarate or maleate salt of the compound of formula (I), followed by optional recrystallisation again.

The present invention also relates in another aspect to intermediates, i.e. in particular intermediates Va and VI, including compound VIa, as described herein, for the synthesis of compounds of formula (I). It is considered herein 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, the compound has an enantiomeric excess of said enantiomer.

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

Another embodiment of the invention relates to compounds 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%.

Wherein LG is a possible leaving group, preferably selected from halogen, e.g. chlorine, or sulfonic acid groups. One embodiment relates to diastereomerically pure compound VI; i.e. compounds having preferably a diastereomeric excess of at least 10% (10% diastereomeric excess means that the ratio of compound VI to the trans diastereomer (e.g. (1S, 3R) -3, 5-dichloro-1-phenylindane, when LG ═ Cl) in the mixture in question is 55: 45), at least 25% or at least 50%. One embodiment relates to substantially pure compound VI.

Accordingly, the present invention also relates to compounds having the following formula (VIa):

preferably with 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%. One embodiment relates to compounds that are diastereomerically pure, i.e., having preferably at least a 10% diastereomeric excess (a 10% diastereomeric excess refers to a ratio of the compound to the trans diastereomer (e.g., (1S, 3R) -3, 5-dichloro-1-phenylindane) in the mixture being 55: 45), at least 25%, or at least 50%. One embodiment relates to substantially pure compound VI, wherein LG is Cl.

As mentioned above, in a particularly interesting embodiment the invention relates to:

-a compound I or a salt thereof,

a pharmaceutical composition as described herein containing a compound or a salt thereof,

-a pharmaceutical use of compound I or a salt thereof as described herein, wherein compound I has an enantiomeric excess of at least 60% (60% enantiomeric excess means that the ratio of compound I to its enantiomer in said mixture is 80: 20), at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

One embodiment relates to compound I or a salt thereof and the use 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 cis- (1S, 3S) diastereomer in said mixture is 55: 45), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, preferably at least 98%.

One embodiment relates to substantially pure compound I or a salt thereof; it also relates to the medical use described herein.

Another aspect relates to compound I or a salt thereof, in particular a fumarate or maleate salt, obtainable, in particular, by the process of the invention as described herein; it also relates to the medical use as described herein.

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

Examples

Pharmacology of

Binding assays

For all assays: results are expressed as percent inhibition of specific binding over the control group and IC is determined by nonlinear regression analysis using Hill equation curve fitting₅₀Value (concentration that caused half of the maximal inhibition of specific binding to the control group). Constant of inhibition (K)_i) Is formed by Cheng Prusoff equation (K)_i＝IC₅₀/(1+(L/K_D) Calculated where L equals the concentration of radioligand in the assay and K_DEqual to the affinity of the radioligand for the receptor.

Alpha-1 adrenergic receptor subtypes

Generation of expressed rat alpha Using Standard Stable transfection techniques_1dChinese Hamster Ovary (CHO) cell lines and expression of bovine alpha_1aBaby Hamster Kidney (BHK) cells. Expression of hamster α was obtained from the university of Utah (salt lake City, UT)_1bRat-1 cell line of the recipient. Harvesting expression-appropriate (. alpha.)_1a、α_1b、α_1d) Recipient cell lines were either homogenized in ice-cold 50mM Tris pH 7.7 using an Ultra-Turrax homogenizer, or stored at-80 ℃ and kept frozen until use. Will 2³H]Prazosin (0.3-0.5nM) was used as a radioligand to assess the affinity of the α 1 receptor subtype. Total binding was determined using assay buffer and non-specific binding to all α 1 receptor subtypes was determined in the presence of 1 μ M WB-4101. Aliquots were incubated at 25 ℃ for 20 minutes. In all assays, bound and free radioligand were separated by vacuum filtration on GF/B filters pretreated with Polyethyleneimine (PEI) and counted in a scintillation counter.

Alpha-1 adrenergic receptor (para [, ])³H]Inhibition of prazosin binding to rat alpha-1-receptor

By this method, the drug pair in the membrane derived from the brain of a rat is measured in vitro³H]Inhibition of the binding of prazosin (0.25nM) to the alpha-1 receptor. The method was modified by hyttel et al, J.neurochem, 1985, 44, 1615-.

DA D1 receptor:

the affinity for the human D1 receptor was determined at the contact laboratory Cerep using the catalog reference assay number 803-1 h. Membranes from CHO cells expressing the human recombinant D1 receptor were used. Mixing the particles of 0.3nM [ 2]³H]SCH23390 was used as radioligand and the compounds were tested in serial dilutions, while the reference compound SCH23390 was tested in order to evaluate the suitability of the assay. Aliquots were incubated at 22 ℃ for 60 minutes and bound radioactivity was measured with a liquid scintillation counter. The binding of the specific control to the D1 receptor was 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 μ M SCH 23390.

DA D2 receptor:

CHO cells expressing approximately 800fmol/mg human recombinant D2 receptor were generated using standard stable transfection techniques. Membranes were harvested using standard protocols and washed by washing in 50mM Tris-HCl, 120mM NaCl, 4mM MgCl₂Serial dilutions of the compounds were added to the membrane preparation in the mixture of (a) to determine affinity. Mixing the particles of 0.1nM [ 2]³H]-spirocyclic piperidones are used as radioligands to assess affinity for the human D2 receptor. Total binding was determined in the presence of buffer and nonspecific binding was determined in the presence of 10. mu.M haloperidol. The mixture was incubated at 37 ℃ for 30 minutes and briefly cooled on ice. Bound and free radioligand were separated by vacuum filtration on GF/C filters pretreated with 0.1% Polyethylenimine (PEI) and the filters counted in a scintillation counter.

Measurement of Effect

DA D1 receptor:

the inhibitory ability of this compound on D1 receptor mediated cAMP formation in an internally generated CHO cell line stably expressing human recombinant D1 receptor was determined as follows: cells were seeded in 96-well plates at a concentration of 11000 cells/well 3 days prior to the experiment. On the day of the experiment, in pre-warmed G buffer (1mM MgCl)₂、0.9mM CaCl₂1mM IBMX in PBS) and the assay was started by adding 100 μ l of a mixture of 30nM a68930 and test compound diluted in G buffer. Cells were incubated at 37 ℃ for 20 minutes and then incubated by adding 100. mu. l S buffer (0.1M HCl and 0.1mM CaCl)₂) The reaction was stopped and the plate was left at 4 ℃ for 1 hour. 68 μ l N buffer (0.15M NaOH and 60mM NaAc) was added and the plates were shaken for 10 minutes. Mu.l of the reaction was transferred to a cAMP flash plate (Flashplates) containing 40. mu.l of 60mM NaAc pH6.2, followed by addition of 100. mu.l of IC mix (50mM NaAc pH6.2, 0.1% Naazid, 12mM CaCl₂1% BSA and 0.15. mu. Ci/ml¹²⁵I-cAMP). After incubation at 4 ℃ for 18 hours, plates were washed once and counted in a Wallac TriLux counter.

DA D2 receptor:

the inhibitory ability of the compound on the inhibition of cAMP formation mediated by the D2 receptor in CHO cells transfected with the human D2 receptor was determined as follows. Cells were seeded on 96-well plates at 8000 cells/well 3 days before the experiment. On the day of the experiment, in pre-warmed G buffer (1mM MgCl)₂、0.9mM CaCl₂1mM IBMX in PBS) and the assay was started by adding 100. mu.l of 1. mu.M Kunpirole, 10. mu.M forskolin (forskolin) and test compound in G buffer. Cells were incubated at 37 ℃ for 20 minutes and then incubated by adding 100. mu. l S buffer (0.1M HCl and 0.1mM CaCl)₂) To stop the reaction and the plate was left at 4 ℃ for 1 hour. 68 μ l N buffer (0.15M NaOH and 60mM NaAc) was added and the plates were shaken for 10 minutes. Mu.l of the reaction was transferred to a cAMP flash plate (Flashplates) containing 40. mu.l of 60mM NaAc pH6.2, and then 100. mu. lIC mix (50mM NaAc pH6.2, 0.1% NaAzid, 12mM CaCl)₂1% BSA and 0.15. mu. Ci/ml¹²⁵I-cAMP). After incubation at 4 ℃ for 18 hours, plates were washed once and counted in a Wallac TriLux counter.

Serotonin 5-HT2A receptor

CHO cells expressing 250fmol/mg of 5-HT2A receptor were plated 2 or 3 days prior to the experiment at a density sufficient to obtain a single-fusion layer on the day of the experiment. 5% CO at 37 ℃ at 95% humidity₂The cells were loaded with dye (Ca from molecular sieves) in an incubator²⁺Kit and w/o phenol red as balanced salt with Hank's, 20 mhepes added and pH adjusted to 7.4 with 2M NaOH as assay buffer) for 60 min. The laser intensity was set to a suitable level to obtain a base value of approximately 8000-. The change in basal fluorescence should be less than 10%. EC is assessed using increasing concentrations of test compound covering at least thirty years₅₀The value is obtained. Evaluation of IC₅₀Value, the same concentration range of test substance as EC for 5-HT₈₅And (6) comparing. The test substance was added to the cells 5 minutes before 5-HT. Ki values were calculated using the Cheng-Prusoff equation. The percent challenge was determined for a concentration of test compound relative to the maximum concentration of 5-HT (100%). The% inhibition of a concentration of test compound was determined as the percentage of the decrease in response to EC85 for 5-HT. Maximum inhibition refers to the level of inhibition that the curve can achieve. It is expressed as the percentage inhibition at this levelThe scores were used to distinguish between full and partial antagonists.

In vitro assay of compound interaction with CYP2D6 (CYP2D6 inhibitor assay)

The principle is as follows: use of microsomes and a specific CYP2D6 substrate AMMC (3- [2- (N, N-diethyl-N-methylammonium) -ethyl]-7-methoxy-4-methylcoumarin) was evaluated for inhibition of human CYP2D6, and microsomes were prepared from baculovirus/insect cell cDNA expressing CYP2D6 as an enzyme source. Demethylation of AMMC O-to AHMC (3- [2- (N, N-diethylamino) ethyl)]-7-hydroxy-4-methylcoumarin), the latter being detected by measuring the appearance of fluorescence. Preferred compounds of the invention exhibit an IC for CYP2D6 of greater than 5 micromolar₅₀。IC₅₀Is the concentration of the compound that produces 50% inhibition of CYP2D6 activity.

Materials and methods:

microsomes prepared from baculovirus/insect cell cDNA expressing CYP2D6 were obtained from BD Biosciences (Gentest 456217). Fluorescence was measured by fluorescence spectroscopy plus a well plate reader (Tecan Nordic) (405nm) Em (465 nm). Cultured with recombinant CYP2D6 microsome containing 1.5pmol of recombinant CYP2D6 in a total volume of 0.2ml of 100mM phosphate buffer pH 7.4 containing 1.5AMMC (3- [2- (N, N-diethyl-N-methylammonium) -ethyl-ammonium) and a low NADPH-regenerating system]7-methoxy-4-methylcoumarin), low NADPH-regeneration system from 0.0082mM NADP⁺0.41mM glucose-6-phosphate, 0.41mM magnesium chloride and 0.4 unit/ml glucose-6-phosphate dehydrogenase. Incubation time was 45 minutes and the incubation was quenched by addition of 0.075ml 80% acetonitrile 20% 0.5M Tris base. All chemicals were analytical grade from Sigma (st. louis, MO). The IC50 curves (modified from N.Charret et al, DMD, Vol.29, Issue 9, 1196-1200, 2001) were generated using 8 concentrations (final concentration of culture broth less than 1.0%) of the compounds tested at 40-0.02 micromolar in DMSO (dimethylsulfoxide). Computing IC by linear interpolation₅₀The value is obtained.

QT-spacer

Anesthetized rabbits:

the model described below was originally described by Carlsson et al, [ J Cardiovasc pharmacol.1990; 16: 276-85] are designed as proarrhythmic models, but have now been modified to suit screening systems as described below under "animal specimens".

Animal specimen

Male rabbits (HsdIf: NZW, distant offspring) weighing 2.0-2.8kg were purchased from Harlan (Netherlands). Individual body weights were determined and recorded on the day of the experiment. General anesthesia was induced by intravenous infusion of pentobarbital (10mg/ml, 18mg/kg) followed by intravenous administration of alpha-chloroaldose (100mg/kg, infusion volume 4ml/kg, over 20 minutes) via the marginal ear vein. The trachea was cannulated and the rabbits were ventilated with air at 45 beats/minute and tidal volume of 6 ml/kg. A vascular catheter was implanted in the jugular vein for administration of the test compound. Additional catheters were implanted in the left carotid artery for blood sampling and monitoring. A needle electrode was placed subcutaneously to record a standard bipolar lead II: the cathode was placed in front of the right shoulder and the anode was placed near the left waist.

Experimental protocol

After a short period of equilibration, predose values were obtained at-20, -10 and 0 minutes prior to administration of the vehicle or IV bolus of test compound. The effect of the bolus administration was followed for 40 minutes.

Data sampling and computation

The ECG, blood pressure and HR were recorded continuously on Maclab 8/s using the graphic software v3.6.1 of the Macintosh computer. The sampling frequency is 1000 Hz. The effect on the electrocardiogram (PQ-, QRS-, QT-, QTc-interval and heart rate) and on the mean arterial blood pressure (MAP) was recorded and determined electronically.

Analytical method

The enantiomeric excess of compound (Va) in example 1a was determined by chiral HPLC (using a CHIRALCEL * OD column, 0.46cm ID. times.25 cm L, 10 μm at 40 ℃). N-hexane/ethanol 95: 5(vol/vol) was used as the mobile phase. Detection was performed at 220nm using a UV detector at a flow rate of 1.0 ml/min.

HPLC analysis of the conversion rate for example 1 b:

column: lichrospher RP-8 column, 250X 4mm (5 μm particle size)

Eluent: buffered MeOH/water prepared as follows: 1.1ml of Et₃N was added to 150ml of water, 10% H was added₃PO₄(aqueous solution) to pH 7 and water was added to a total of 200 ml. The mixture was added to 1.8L MeOH.

The enantiomeric excess of compound (Va) in example 1b was determined by chiral HPLC (using a CHIRALPAK * AD column, 0.46cm ID. times.25 cmL, 10 μm at 21 ℃). Heptane/ethanol/diethylamine 89.9: 10: 0.1(vol/vol/vol) was used as the mobile phase, and detection was performed at 220nm using a UV detector at a flow rate of 1.0 ml/min.

The enantiomeric excess of compound (I) was determined by fused silica Capillary Electrophoresis (CE) using the following conditions: capillar: 50 μm ID × 48.5cm L, flow buffer: 1.25mM solution of β -cyclodextrin in 25mM sodium dihydrogen phosphate, ph1.5, voltage: 16kV, temperature: 22 ℃, injection: 40mbar 4 seconds, detection: column diode array detection 195nm, sample concentration: 500. mu.g/ml. In this system, compound I has a retention time of about 10 minutes and the other enantiomer has a retention time of about 11 minutes.

Recording at 500.13MHz on a Bruker Avance DRX500 instrument or 250.13MHz on a Bruker AC 250 instrument¹H NMR spectrum. Chloroform (99.8% D) or dimethylsulfoxide (99.8% D) was used as solvent and Tetramethylsilane (TMS) was used as internal standard.

Using the same as described in J.Med.chem.1995, 38, 4380-4392 (page 4388, right column) of B * ges * et al¹H NMR determined the cis/trans ratio of the compound. By reaction in chloroform¹H NMR, using cisThe cis/trans ratio of compound VI was determined by integrating the signal at 5.3ppm for the isomer of formula VI and the signal at 5.5ppm for the trans isomer. Typically, the undesired isomer can be detected by NMR at a level of about 1%.

Melting points were determined using Differential Scanning Calorimetry (DSC). The apparatus was a TA-instruments DSC-2920, which was calibrated at 5 deg./min to obtain the melting point as the starting value. Approximately 2 mg of the sample was heated in a loosely closed pan at 5 deg./min under a stream of nitrogen. Synthesis of

Synthesis of key raw materials

Compound V was synthesized by reducing IV with sodium borohydride (NaBH4) by a method modified from B * ges * described in j.med.chem.1983, 26, 935, using ethanol as the solvent and the reaction was carried out at about 0 ℃. Both compounds are described in Med. chem.1995, 38, 4380-4392, B * ges * et al. Compound IV was synthesized from II using the general method described by Sommer et al in j.org.chem.1990, 55, 4822, wherein II and its synthesis are also described.

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

Racemic cis-6-chloro-3-phenylindan-1-ol (V) (492 g) was resolved by preparative chromatography using a CHIRALPAK * AD column, 10cm ID X50 cm L, 10 μm at 40 ℃. Methanol was used as the mobile phase and detection was carried out at a flow rate of 190ml/min using a UV detector at 287 nm. Racemic alcohol (V) was injected as a 50,000ppm solution in methanol; 90ml were injected at 28 minute intervals. All fractions containing the title compound in excess of 98% enantiomeric excess were combined and then evaporated to dryness on a rotary evaporator, followed by drying in vacuo at 40 ℃. 220 g of solid are obtained. Elemental analysis and NMR were consistent with their structures, with enantiomeric excesses higher than 98% according to chiral HPLC, [ alpha ]]_D ²⁰+44.5(c ═ 1.0, methanol).

Example 1b Synthesis of (1S, 3S) -6-chloro-3-phenylindan-1-ol (Va) by resolution Using an enzyme

Compound V (5g, 20.4mmol) was dissolved in 150ml of anhydrous toluene. 0.5g of the novel enzyme 435 (Candida antarctica lipase B) (novel enzyme A/S, Fluka cat # 73940) was added, followed by vinyl butyrate (13ml 102.2 mmol). The mixture was stirred at 21 ℃ using a mechanical stirrer. After 1 day, an additional 0.5g of new enzyme 435 was added. After 4 days when 54% conversion was reached, 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 and 99.2% enantiomeric excess of the desired compound Va (99.6% compound Va and 0.4% (1R, 3R) -cis-6-chloro-3-phenylindan-1-ol).

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

Cis- (1S, 3S) -6-chloro-3-phenylindan-1-ol (Va) (204 g) obtained as described in example 1a was dissolved in THF (1500ml) and cooled to-5 ℃. Thionyl chloride (119 g) in the form of a solution in THF (500ml) was added dropwise over a period of 1 h. The mixture was stirred at room temperature overnight. Ice (100g) was added to the reaction mixture. When the ice had melted, the aqueous phase (a) and the organic phase (B) were separated and the organic phase B was washed twice with saturated sodium bicarbonate (200 ml). The sodium bicarbonate phase was combined with the aqueous phase a, adjusted to pH9 with sodium hydroxide (28%), and the organic phase B was washed once more. The resulting aqueous phase (C) and organic phase B were separated and the aqueous phase C was extracted with ethyl acetate. The ethyl acetate phase was combined with the organic phase B, dried over magnesium sulphate and evaporated to dryness using a rotary evaporator to give the title compound as an oil. The yield was 240g, which was used directly in example 5. The cis/trans ratio was 77: 23 as determined by NMR.

Example Synthesis of 33, 3-dimethylpiperazin-2-one

Potassium carbonate (390 g) and ethylenediamine (1001 g) were stirred with toluene (1.501). A toluene solution (750ml) of ethyl 2-bromoisobutyrate (500 g) was added. The suspension was heated to reflux overnight and then filtered. The filter cake was washed with toluene (500 ml). The combined filtrates (volume 4.0l) were heated on a water bath and distilled at 0.3 atm using a Claisen apparatus; a first 1200ml of distillate was collected at 35 deg.C (the temperature in the mixture was 75 deg.C). 600ml more toluene was added) and an additional 1200ml distillate was collected at 76 ℃ (temperature in the mixture is 80 ℃). Toluene (750ml) was again added and 1100ml of distillate was collected at 66 deg.C (the temperature in the mixture was 71 deg.C). The mixture was stirred on an ice bath and seeded, whereby the product precipitated. The product was isolated by filtration, washed with toluene and dried in a vacuum oven at 50 ℃ overnight. 171g of 3, 3-dimethylpiperazin-2-one (52%) are obtained. NMR was consistent with the structure.

Example Synthesis of 42, 2-dimethylpiperazine

A mixture of 3, 3-dimethylpiperazin-2-one (8.28kg, 64.6mol) and Tetrahydrofuran (THF) (60kg) was heated to 50-60 ℃. A slightly less clear solution was obtained. THF (50kg) was stirred under nitrogen and LiAlH4(250g in a soluble plastic bag from Chemetall) was added, producing a slow evolution of gas. After the evolution of gas had ceased, more LiAlH4 (3.0 kg in total, 79.1mol) was added and the temperature increased from 22 ℃ to 50 ℃ due to the exotherm. The 3, 3-dimethylpiperazin-2-one solution was added slowly over 2 hours at 41-59 ℃. The suspension was stirred for an additional hour at 59 deg.C (jacket temperature 60 deg.C). The mixture was cooled and kept at a temperature below 25c (which had to be cooled with a jacket at a temperature of 0 c) water (3l) was added over a period of two hours. Sodium hydroxide (15%, 3.50kg) was then added over 20 minutes at 23 ℃ and cooled if necessary. More water (9l) was added over half an hour (cooling necessary) and the mixture was stirred under nitrogen overnight. The filtration reagent celite (4kg) was added and the mixture was filtered. The filter cake was washed with THF (40 kg). The combined filtrates were concentrated in the reactor at 800mbar until the temperature in the reactor was 70 ℃ (distillation temperature 66 ℃). The residue (12.8kg) was further concentrated on a rotary evaporator to about 10 l. Finally, the mixture was distilled stepwise at atmospheric pressure and the product was collected at 163-4 ℃. The yield was 5.3kg (72%). NMR was consistent with the structure.

Example 5 Synthesis of trans-1- ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazinium (Compound I) hydrogen maleate

Cis- (1S, 3S) -3, 5-dichloro-1-phenylindane (VI, LG ═ Cl) (240g) was dissolved in 2-butanone (1800 ml). Potassium carbonate (272g) and 2, 2-dimethylpiperazine (prepared in example 4) (113g) were added and the mixture was heated at reflux temperature for 40 hours. Diethyl ether (2l) and hydrochloric acid (1M, 6l) were added to the reaction mixture. The phases were separated and the pH of the aqueous phase was lowered from 8 to 1 with concentrated hydrochloric acid. The organic phase was again washed with the aqueous phase to ensure that all the product was in the aqueous phase. Sodium hydroxide (28%) was added to the aqueous phase until the pH was 10 and the aqueous phase was extracted twice with diethyl ether (2 l). The diethyl ether extracts were combined, dried over sodium sulfate and then evaporated to dryness using a rotary evaporator. 251 g of the title compound are obtained as an oil. The cis/trans ratio was 82: 18 as determined by NMR. The crude oil (approx. 20 g) is further purified by flash chromatography on silica gel (eluent: ethyl acetate/ethanol/triethylamine 90: 5) and then evaporated to dryness on a rotary evaporator. 12 g of the title compound are obtained as an oil (cis/trans ratio 90: 10, determined by NMR). The oil was dissolved in ethanol (100ml) and to this solution was then added an ethanol solution of maleic acid to pH 3. The resulting mixture was stirred at room temperature for 16 hours, and then the formed precipitate was collected by filtration. The volume of ethanol was reduced and another batch of precipitate was collected. 3.5 g of the title compound are obtained as a solid (no cis-isomer is detected by NMR). Enantiomeric excess is > 99%.

The melting point was 175 ℃ and 178 ℃. NMR was 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-dimethylpiperazine hydrogen maleate (I) (9.9 g), concentrated aqueous ammonia 100ml), brine (150ml) and ethyl acetate (250ml) was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. 7.5 g of oil are obtained. NMR was consistent with the structure.

Example 7 Synthesis of trans-1- ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazinium (Compound I) fumarate

Trans-1- ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine (obtained as described in example 6) (1g) was dissolved in acetone (100 mL). To this solution was added an ethanol solution of fumaric acid until the pH of the resulting solution was 4. The resulting mixture was cooled in an ice bath for 1.5 hours, whereby a precipitate was formed. The solid compound was collected by filtration. The compound was dried in vacuo to give a white solid compound (1.0 g). Enantiomeric excess is > 99%. The melting point was 193-196 ℃. NMR was consistent with the structure.

Claims (33)

1. A compound of the formula (Compound I, trans-1- ((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine)

Or a salt thereof.

2. The compound of claim 1, or a salt thereof, which is substantially pure.

3. A pharmaceutical composition comprising a compound of claim 1 or 2, or a salt thereof, and at least one pharmaceutically acceptable carrier, filler or diluent.

4. A pharmaceutical composition according to claim 3, wherein the enantiomeric excess of the compound is at least 90%, at least 96%, or at least 98%.

5. A compound according to claim 1 or 2 for use in medicine.

6. Use of a compound or salt according to claim 1 or 2 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, antipsychotic-induced parkinsonism, and abuse disorders, such as cocaine abuse, nicotine abuse or alcohol abuse.

7. Use according to claim 6 for the preparation of a medicament for the treatment of schizophrenia or other psychotic disorders.

8. Use according to claim 7 for the preparation of a medicament for the treatment of one or more of the positive symptoms, negative symptoms and depressive symptoms of schizophrenia.

9. The use of a salt of a compound according to claim 1 or 2 or in the manufacture of a medicament for the treatment of a disease selected from the group consisting of schizophrenia, schizophreniform 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 to 9, wherein the compound or salt thereof is in the form of a pharmaceutical composition as defined in claim 4.

11. A method of treatment of a disease selected from psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, antipsychotic-induced parkinsonism, or abuse disorders, e.g. cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of a compound or salt as defined in claim 1 or 2.

12. A method according to claim 11 for the treatment of schizophrenia or other psychotic disorders.

13. The method of claim 12 for treating one or more of the positive symptoms, negative symptoms, and depressive symptoms of schizophrenia.

14. A method for the treatment of a disease selected from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and mania in bipolar disorder, comprising administering a therapeutically effective amount of a compound or salt as defined in claim 1 or 2.

15. A method according to any one of claims 11-14, wherein the patient being treated with compound I or a salt thereof is also being treated with another drug.

16. The method according to claim 12, wherein the patient treated with compound I or a salt thereof is also treated with at least one other drug.

17. A method according to any one of claims 11 to 16, wherein the compound or salt thereof is in the form of a pharmaceutical composition as defined in claim 4.

18. The compound trans-1- (6-chloro-3-phenylindan-1-yl) -3, 3-dimethylpiperazine compound or a salt thereof for use in medicine.

19. A pharmaceutical composition comprising a compound or salt of claim 18 and at least one pharmaceutically acceptable carrier, filler or diluent.

20. Use of a compound of claim 18 or a salt thereof in the manufacture of a medicament for the treatment of a disease selected from the group consisting of psychotic symptoms, schizophrenia (e.g., one or more of schizophrenia' positive symptoms, negative symptoms, and depressive symptoms), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, mania in bipolar disorder, anxiety disorders, affective disorders including depression, sleep disorders, migraine, antipsychotic-induced parkinsonism, abuse disorders, e.g., cocaine abuse, nicotine abuse, or alcohol abuse.

21. A method of treatment of a disease selected from the group consisting of psychotic symptoms, schizophrenia (e.g. one or more of positive symptoms, negative symptoms and depressive symptoms of schizophrenia), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, mania in bipolar disorder, anxiety disorders, affective disorders including depression, sleep disorders, migraine, antipsychotic-induced parkinsonism, abuse disorders, e.g. cocaine abuse, nicotine abuse or alcohol abuse, comprising administering a therapeutically effective amount of a compound or salt as defined in claim 18.

22. A method of preparing a compound of formula I (compound I) or a salt thereof, which method comprises converting a compound of formula Va (compound Va) in the cis configuration to a compound of formula I, wherein I and Va are as follows:

23. the method of claim 22, comprising converting the alcohol group of the cis-alcohol of formula Va to a suitable leaving group LG to give the compound of formula VI.

24. The method of claim 23, wherein LG is a halogen, such as Cl or Br, preferably Cl, or a sulfonate group.

25. The process of any one of claims 22-24, wherein compound VI is precipitated from a suitable solvent.

26. The method of claim 25, wherein LG is a halogen, preferably Cl, and the solvent is an alkane, such as heptane.

27. The process of any one of claims 22-26, wherein compound VI is reacted with 2, 2-dimethylpiperazine to give compound I.

28. The process according to claim 27, wherein compound I is precipitated as a suitable salt, such as a salt of an organic acid (e.g. an organic dibasic acid).

29. The method of claim 28, wherein the salt formed is the fumarate salt or the maleate salt of compound I.

30. The method of any of claims 22-26, comprising:

-reacting compound VI with 1-protected 2, 2-dimethylpiperazine (VII), wherein PG is a protecting group, for example selected from benzyloxycarbonyl, tert-butoxycarbonyl, ethoxycarbonyl and benzyl, to give a compound of formula VIII; and

-deprotecting compound VIII to give compound I, wherein compounds VII and VIII are as follows:

31. a process for the preparation of compound I or a salt thereof, which process comprises reacting a compound of formula VIa (i.e. compound VI wherein LG is Cl) with 2, 2-dimethylpiperazine.

32. A process for the preparation of compound I or a salt thereof, which process comprises reacting a compound of formula VIa

With 2, 2-dimethylpiperazine in the presence of a base.

33. The method of any one of claims 22-32, wherein compound Va is obtained by enzymatic resolution of compound V.