KR20060066104A - Trans-1 (6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine - Google Patents

Abstract

Compound 4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -2,2-dimethylpiperazine and salts thereof, pharmaceutical compositions comprising said compounds and salts, and schizophrenia and Its medical uses, including the treatment of other psychotic disorders.

Description

Trans-1 (6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazin {TRANS-1 (6-CHLORO-3-PHENYLINDAN-1-YL) -3,3-DIMETHYLPIPERAZINE}

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

Compounds of the present invention (compound I, trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine) have the formula (I):

등, J. Med. Chem., 1995, 38, 4380-4392] 및 문헌 [Klaus P.

, "Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds", 1998, ISBN 87-88085-10-4I]에 기재되어 있다. 상기 화합물들은 도파민(DA) D₁ 및 D₂ 수용체 및 5-HT₂ 수용체에 대해 고 친화력을 가진 것으로서 기재되어 있고, 정신분열증을 포함하는 중추신경계 내 여러 질환 치료용으로 유용한 것으로 제안되어있다. The trans isomer of the group of compounds structurally related to compound I, ie, 3-aryl-1- (1-piperazinyl) indan, substituted at the 2- and / or 3-position of the piperazine ring is described in EP 638 073. ;

Et al., J. Med. Chem., 1995, 38, 4380-4392 and Klaus P.

, "Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds", 1998, ISBN 87-88085-10-4I. The compounds are dopamine (DA) D ₁ and D ₂ receptors and 5-HT ₂ It has been described as having high affinity for the receptor and has been suggested to be useful for the treatment of various diseases in the central nervous system including schizophrenia.

등, J. Med. Chem., 1995, 38, 4380-4392, table 5, 화합물 (-)-38 참조]에 개시되어 있다. 상기 간행물에는 화합물 38 의 (-)-거울상체가 시험관 내 일정 D₁ 선택성을 보이는 강력한 D₁/D₂ 길항제인 반면, 생체 내에서의 그것은 D₁ 및 D₂ 길항제와 동등한 능력을 가진 것으로 결론내려져 있다. 상기 화합물은 또한 강력한 5-HT₂ 길항제로서 및 α₁ 아드레날린수용체에 대해 고 친화력을 가진 것으로서 기재되어 있다. Although there are differences with methyl groups in place of hydrogen on piperazine, enantiomers corresponding to compounds of formula (I) are described in [

Et al., J. Med. Chem., 1995, 38, 4380-4392, table 5, compound (-)-38. The publication concludes that the (-)-enantiomer of Compound 38 is a potent D ₁ / D ₂ antagonist that exhibits constant D ₁ selectivity in vitro, whereas in vivo it is concluded to have the same capacity as the D ₁ and D ₂ antagonists. have. The compound is also a potent 5-HT ₂ It is described as an antagonist and as having a high affinity for the α ₁ adrenergic receptor.

등, J. Med. Chem., 1995, 38, 4380-4392] 의 화합물 38 의 합성에서, 중간 물질로서 간접적으로만 개시된 반면, 화합물 I 의 의학적 용도 또는 그것에 상응하는 라세미체는 기재되지 않았다. None of the above references discloses the specific enantiomeric form (Compound I) or its medical use. The trans isomers of the racemate form of compound 1 are described in [

Et al., J. Med. Chem., 1995, 38, 4380-4392, while only indirectly disclosed as an intermediate, the medical use of Compound I or the corresponding racemates are not described.

The etiology of schizophrenia is unknown, but the dopamine hypothesis of schizophrenia, formulated in the early 1960s (Carlsson, Am. J. Psychiatry 1978 , 135, 164-173) laid the theoretical basis for understanding the biological mechanisms underlying this disorder. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, and all antipsychotic drugs on the market today have some dopamine D ₂ receptor antagonism (Seeman Science and Medicine). The concept is supported by the fact that it exercises 1995, 2, 28-37. However, antagonism of dopamine D ₂ receptors in the cerebral limbic area is generally accepted to play a major role in the treatment of benign symptoms of schizophrenia, while blocking of D ₂ receptors in the cerebral striatum is an extrapyramidal symptom Cause. As described in EP 638 073, the profile of mixed dopamine D ₁ / D ₂ receptor inhibition is witnessed using so-called some “atypical” antipsychotic compounds, in particular clozapine, used in the treatment of schizophrenic patients. It became. Central α ₁ antagonistic action is also suggested to contribute to improving antipsychotic properties (Millan et al., JPET, 2000 , 292, 38-53).

Selective D ₁ antagonists are also linked to treatment of sleep disorders and alcohol abuse (DN Eder, Current Opinion in Investigational Drugs, 2002 3 (2): 284-288). Dopamine may also play an important role in the pathogenesis of affective disorders (P. Willner, Brain. Res. Rev. 1983 , 6, 211-224, 225-236 and 237-246; J. Med. Chem., 1985 , 28, 1817-1828).

Literature [EP 638 073], the 5-HT ₂ compounds with affinity for receptors, in particular 5-HT ₂ receptor antagonists are different diseases, for example, negative symptoms of schizophrenia, depression, anxiety, sleep disturbance, migraine attacks and nerve A suggested process is described for the treatment of schizophrenia, including laxative-induced Parkinsonism. 5-HT ₂ receptor antagonism has also been suggested to reduce the incidence of adverse events induced by classical neuroleptics (Balsara et al., Psychopharmacology 1979 , 62, 67-69).

Products of the Invention and Medical Uses thereof

The inventors have found that Compound I exhibits high affinity for the dopamine D1 receptor, dopamine D2 receptor and alpha 1 adrenergic receptor. Furthermore, it was recognized that Compound I is an antagonist at the dopamine D1 and D2 receptors and the serotonin 5-HT2a receptor. The pharmacological activity of compound I relates to the receptor, which is structurally different from compound I in that it has a methyl group instead of hydrogen on piperazine, but similar to that of the compounds described above.

We also found that some of the structurally related compounds of both racemates and enantiomers described in the references cited above are CYP2D6 (cytochrome P450 2D6) inhibitors, while haloperidole and risperidone and Compared with other antipsychotics as well, it was also found that Compound I was a relatively weak inhibitor of CYP2D6. The racemates of the compounds of the invention are also significantly more potent on the CYP2D6 enzyme when compared to the invention, ie the enantiomers of the compounds.

CYP2D6 enzyme is an important liver enzyme for metabolism. CYP2D6 is a mammalian enzyme that is generally associated with the metabolism of pharmaceutical compounds, and inhibition of the drug that metabolizes the enzyme can lead to clinically important drug-drug interactions, ie, two drugs When provided in combination and metabolized by the same enzyme, competition for metabolism can lead to an increase in plasma concentrations and thus possible side effects (for review, see Lin et al., Pharmacological Rev. 1997, 49, 403-449, Bertz RJ and Granneman GR. Clin Pharmacokinet 1997, 32, 210-258] below).

Since more than 80 drugs for clinical use (and especially psychotropic drugs) are metabolized by CYP2D6 (Bertz RJ, Granneman GR. Clin Pharmacokin 1997 , 32 , 210-58, Rendic S, DiCarlo FJ. Drug Metab Rev 1997 , 29 , 413-580), inhibition of this enzyme by coadministered drugs, in combination with imipramine, decimipramine, or nortriptyline, leading to increased presentation levels and tricyclic cardiac adverse events. As shown with a combination of the well-known CYP2D6 inhibitor fluoxetine or paroxetine, it can cause a sharp increase in hazard generation (Ereshefsky L. et al . , J. Clin . Psychiatry 1996 , 57 (suppl8), 17-25, Shulman RW Can J Psychiatry , Vol 42, Supplement 1, 4S).

The fact that Compound I has a low interaction with the liver enzyme CYP2D6 suggests that it has a reduced potential in drug-drug interactions, i.e., patients with compounds of the invention in combination with other drugs that are primarily metabolized by the CYP2D6 enzyme. When treated, it probably means less drug-to-drug interactions. This is a significant advantage, especially for patients with schizophrenia who are often treated with other drugs to control the disease.

We also found that Compound I has a relatively low prolonged effect on the QT-interval in the electrocardiogram (ECG) of "alpha-chloro anesthetized rabbit". The appearance of drug-induced QT-interval prolongation and fatal cardiac arrhythmias, ventricular tachycardia (TdP) in electrocardiograms (ECG) has been described as repolarization-smoker antiarrhythmic agents [C.L. Raehl, A. K. Patel and M. Le Roy, 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 antibacterial agents [B. Darpoe, Eur Heart J 3 Suppl K (2001), K70-K80] have been recognized as potential risks during treatment with a wide range of drugs. The relatively low effect of Compound I on rabbit QT intervals is that when compared to some commercialized antipsychotics, the compound appears to cause the death of human cardiac arrhythmias, ventricular tachycardia (TdP) and drugs. -Means that it has a reduced potential in introducing induced QT interval delays.

Thus, in one aspect, the invention relates to compounds of formula I (compound I) and salts thereof. Salts of the invention, ie salts of compounds of formula I, can be selected from, for example, fumarate or malate salts of compound I:

[Formula I]

The property of compound I is that it will be particularly useful as a pharmaceutical. Accordingly, the present invention further relates to the pharmaceutical compositions of the compounds I or salts thereof of the present invention. The invention also relates to the medical use of the compounds, salts and compositions, such as central nervous system diseases or psychiatric symptoms, including schizophrenia, in particular schizophrenia, such as schizophrenia, schizophrenic disorders, schizophrenia affect disorders, delusional disorders, short-term psychosis The present invention relates to the medical use of such salts and compositions for the treatment of other disorders, including psychiatric disorders, copsychotic disorders, as well as other psychotic disorders or diseases showing psychiatric symptoms such as mania among bipolar disorders.

In addition, the 5-HT ₂ antagonist activity of the compounds of the present invention suggests that the compounds or salts thereof may have a relatively less risk of side effects.

The invention also provides 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 And to the use of compounds I or salts thereof.

In a preferred embodiment, the present invention comprises administering a therapeutically effective amount of a compound I or a salt thereof of the present invention, a schizophrenic disorder, schizophrenia affect disorder, oblivion disorder, short-term psychotic disorder, copsychotic disorder or bipolar It relates to a method of treating mania among disorders.

A further embodiment of the invention relates to a method of treating positive symptoms of schizophrenia comprising administering a therapeutically effective amount of Compound I or a salt thereof.

Another embodiment of the invention is directed to a method of treating negative symptoms of schizophrenia comprising administering a therapeutically effective amount of Compound I or a salt thereof.

A further embodiment of the invention relates to a method for the treatment of depressive symptoms of schizophrenia 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 manic and / or sustained 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, 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.

Accordingly, the present invention also relates to psychotic symptoms comprising administering a therapeutically effective amount of the compound trans-1- (6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine or a salt thereof. Diseases, including schizophrenia (eg, one or more schizophrenia positive symptoms, negative symptoms, and depressive symptoms), schizophrenic disorders, schizophrenia affect disorders, forgetfulness disorders, short-term psychotic disorders, copsychotic disorders, and Methods of treating a disorder selected from the group consisting of manic disorders, anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced Parkinsonism, and abuse disorders such as cocaine abuse, nicotine abuse, or alcohol abuse It is about.

As used herein, the term “trans-1- (6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine”, ie (eg, (+) and (-) or R / The term without any specific indication of the enantiomeric form (using S-conversion) is meant to refer to any enantiomeric form of the compound, ie one of the two enantiomers, or a mixture thereof, such as a racemic mixture. . However, in this context, preferably the content of the enantiomer corresponding to that of compound I is at least 50%, ie at least as a racemic mixture, but preferably compound I is greater than the enantiomer.

In the present context for pharmaceutical use, when referring to enantiomeric forms as mentioned in Formula I for Compound I, the compounds are relatively stereochemically pure, preferably the enantiomeric excess is at least 70%, more preferably Is understood to be at least 80% (80% enantiomeric means that the compound I to enantiomer ratio is 90:10 in the present mixture), at least 90%, at least 96% or preferably at least 98%. In a preferred embodiment, the diastereomeric excess of Compound I is at least 90% (90% diastereomeric purity means Compound I vs. cis-1-((1S, 3S))-6-chloro-3-phenylindane-1 -Yl) -3,3-dimethylpiperazine ratio of 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 one or more agents. A particularly relevant embodiment in this regard is the treatment with other agents to be metabolized by CYP2D6.

In suitable embodiments, the other agent is an antipsychotic. Thus, one embodiment is a compound, salt of the invention, for the treatment of a patient suffering from schizophrenia or other psychosis, which is also treated with other medicament (s), such as other medicament (s) wherein the other medicament is an antipsychotic. Or to the use of a pharmaceutical composition.

In another 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 is a substance abuser such as an alcohol or nicotine abuser.

The compounds, salts or compositions of the present invention may be administered in a suitable manner, such as orally, orally, sublingually or parenterally and the compounds or salts may be in any form suitable for such administration, for example tablets, capsules, powders, It may be presented in the form of a syrup or injectable solution or dispersion. In one embodiment, the compound or salt of the present invention is administered in the form of a solid pharmaceutical, suitably tablet or capsule.

Methods of preparing solid pharmaceutical formulations are well known in the art. Tablets can thus be prepared by mixing the active ingredient with common auxiliaries, fillers and diluents and then compressing the mixture into a convenient tableting machine. Examples of auxiliaries, fillers and diluents include corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other auxiliaries or additives such as coloring, fragrances, preservatives and the like may also be used if compatible with the active ingredient.

Injectable solutions can be prepared by dissolving the salts and possible additives of the invention in a portion of an injectable solvent, preferably sterile water, adjusting the solution to the desired volume, and sterilizing the solution and filling it with suitable ampoules and vials. Can be. Any suitable additive commonly used such as tonicity agents, preservatives, antioxidants, solubilizers and the like may be added.

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

The term "treatment" as used herein in connection with a disease or disorder also optionally includes preventative measures.

Manufacturing method

등. J. Med. Chem., 1995, 38, page 4380-4392]에 개괄된 방법과 유사하게 제조될 수 있고, 이어서 부분입체 이성질체 염의 결정화로 라세미 화합물의 광학분할이 수행될 수 있어, 그것에 의해 화학식 I 의 거울상체를 수득할 수 있다. The compounds of formula I in racemic form are described in EP 638 073 and in literature [

Etc. J. Med. Chem., 1995, 38, pages 4380-4392, which can be prepared in analogy with the crystallization of diastereomeric salts, followed by optical splitting of the racemic compound, thereby enantiomers of formula (I) Can be obtained.

The inventors have improved that the enantiomer of Formula I is obtained through a synthetic sequence starting from pure enantiomer V, ie compound Va ((1S, 3S) -6-chloro-3-phenylindan-1-ol, see below). Revealed a synthetic route. Thus, in this method, the intermediate of formula V is cleaved, for example by chiral chromatographic or enzymatic reaction, to obtain the enantiomer of formula Va. This novel synthetic route for obtaining compounds of formula I is much more effective than the above-mentioned crystallization of diastereomeric salts of the final product I, for example the partitioning of intermediates in place of the final product, for example high volume yields and While providing less wastage, only the desired enantiomer provides much more effective synthesis as it is used in subsequent steps.

Thus, enantiomers of formula I can be obtained by a process comprising the following steps:

Benzyl cyanide is reacted with 2,5-dichlorobenzonitrile in the presence of a base, suitably in a suitable solvent such as dimethyl ether (DME) in the presence of potassium tert-butoxide (t-BuOK), and further methyl chloro acetate ( Reaction with MCA) leads to spontaneous ring closure and one-pot formation of the compound of formula II.

The compound of formula II is then acid hydrolyzed to form a compound of formula III, suitably by heating in a mixture of acetic acid, sulfuric acid and water, after which the compound of formula III in a suitable solvent such as toluene is triethyl Decarboxylation by heating with amine or N-methyl pyrrolidone-2-one (NMP) forms a compound of formula IV:

Sodium borohydride, preferably at -30 ° C to + 30 ° C, such as below 30 ° C, below 20 ° C, below 10 ° C, or preferably below 5 ° C, suitably in a solvent such as an alcohol such as ethanol or iso-propanol The compound of formula IV is subsequently reduced with lead (NaBH ₄ ) to form a compound of formula V having a cis configuration:

The compound of formula V is cleaved to obtain the enantiomer having the desired enantiomer (formula Va), ie the cis configuration ((1S, 3S) -6-chloro-3-phenylindan-1-ol):

The cleavage of compound V into compound Va is appropriately, for example, silica gel coated with amylose tris- (3,5-dimethylphenylcarbamate) coated on chiral polymers such as modified amylose, preferably silica gel. It can be carried out using a chiral chromatograph on a chiral column of, preferably a liquid chromatograph. Suitable solvents such as alcohols, nitriles, ethers or alkanes, or mixtures thereof, suitably ethanol, methanol, iso-propanol, acetonitrile, or methyl tert-butyl ether or mixtures thereof, preferably methanol or acetonitrile are chiral Used in liquid chromatographs. Chiral liquid chromatographs can be scaled up using suitable techniques, such as simulated moving bed technology (SMB).

Alternatively, the compound of formula V is cleaved to obtain compound Va by enzymatic cleavage. Pure enantiomeric compound Va, or its acylated derivative, is prepared by enzymatic enantioselective acylation of the hydroxyl group in racemic compound V, resulting in compound Va or its acylated derivative with high optical purity It is known that can be obtained. Alternatively, pure enantiomer compound Va may also be obtained as a process comprising converting racemic compound V at the hydroxyl position to the corresponding ester derivative, ie, ester group, followed by enzymatically enantioselective deacylation. The use of enzymatic enantioselective deacylation has been reported for other compounds.

Thus, the cleavage of compound V into compound Va can be performed by selective enzymatic acylation. Selective enzymatic acylation means leaving other cis-enantiomers of compound V in the reaction mixture unconverted, such as leaving compound Va unconverted in the reaction mixture, as outlined below, Enzymatic acylation is preferentially effective in the conversion of one of the cis-enantiomers to the corresponding acylated derivative Vb.

[Wherein R is, for example, acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate , 3-methylvalerate or 4-methylvalerate]. Suitable irreversible acyl donors are, for example, vinyl-esters, 2-propenyl-esters or 2,2,2-trihalid-ethyl-esters. Alternatively, other enantiomers are acylated (ie, acylated Va is the product, but not shown) and alcohol Va is subsequently obtained by isolation of acylated Va and subsequent removal of ester groups. Can be.

Alternatively, cleavage of compound V into compound Va can be performed by selective enzymatic deacylation. Selective enzymatic deacylation refers to enzymatic activity in converting one of the esters of the compound of formula V (Vc), leaving unconverted the other cis-enantiomer of the ester of the compound of formula V (Vd) in the reaction mixture. Red deacylation means preferentially effective.

Suitable esters (Vc) of compounds of formula V are esters such as acetates, propionates, butyrates, valerates, hexanoates, benzoates, laurates, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate , 2-methyl valerate, 3-methyl valerate, 4-methyl valerate:

[Wherein R ¹ is, for example, acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate , 3-methylvalerate or 4-methylvalerate]. Alternatively, the ester of Va is left unconverted in the reaction mixture (ie acylated Va is not represented as a product) and alcohol Va is used for isolation of acylated Va and subsequent removal of ester groups by standard procedures. Subsequently obtained.

Thus, enantioselective enzymatic acylation means preferentially leaving the other enantiomer of the compound of formula V unconverted in the reaction mixture, and enzymatic acylation is preferential in the conversion of one of the enantiomers of the compound of formula V Means valid. Enantioselective enzymatic deacylation means preferentially leaving the other enantiomer of the compound of formula Vc unconverted in the reaction mixture, and in the conversion of one of the enantiomers of the compound of formula Vc, enzymatic deacylation is preferred. Means valid.

Thus, one embodiment relates to a process for the preparation of (S, S)-or (R, R) -enantiomers (ie, having a cis configuration) of a compound of Formula V comprising:

a) enantioselective enzymatic acylation of racemic compound V using an acylating agent, or

b) deacylating the racemic compound Vc by enantioselective enzymatic action to form a mixture of deacylated compound Va.

The mixture obtained by enzymatic cleavage may not be completely pure, for example it may comprise a small amount of other enantiomers in addition to a large amount of the desired enantiomer (Va). The composition mixture obtained after acylation or deacylation according to the invention depends on the specific hydrolase used and the conditions under which the reaction was carried out. A feature of enzymatic acylation / deacylation according to the invention is the conversion of a significantly larger portion of one enantiomer than the other. Thus, enantioselective acylation according to the invention preferentially provides a mixture comprising a compound of formula Vb in (R, R) -form and a compound of formula Va in (S, S) -form, or predominantly It is possible to provide a mixture comprising a compound of formula Vb in (S, S) -form and a compound of formula Va in (R, R) -form. Likewise, enantioselective enzymatic deacylation may preferentially provide a mixture comprising a compound of formula Vd in (S, S) -form and a compound of formula Va in (R, R) -form, or preferentially It is possible to provide a mixture comprising a compound of formula Vd in (R, R) -form and a compound of formula Va in (S, S) -form. The optical purity of Va obtained by the optical splitting method of the present invention is usually at least 90% ee, preferably at least 95% ee, more preferably at least 97% ee and most preferably at least 98% ee. However, lower values of optical purity are allowed.

According to the present invention, enantioselective enzymatic acylation is carried out under conditions that substantially inhibit hydrolysis. Hydrolysis, the reverse of the acylation reaction, occurs when water is present in the reaction system. Thus, enantioselective enzymatic acylation is preferably carried out in a water-free or almost anhydrous organic solvent (the enzyme usually requires the presence of some water 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, 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 protic polar solvents such as dimethylsulfoxide, N-methylpyrrolidone-2-one and hexamethylphosphorus triamide. Preferred organic solvents for enzymatic acylation are organic solvents such as toluene, hexane, heptane, dioxane and tetrahydrofuran (THF).

Suitable irreversible acyl donors are, for example, acyl donors such as vinyl-ester, 2-propenyl-ester or 2,2,2-trihalid-ethyl-ester.

Enantioselective enzymatic deacylation is preferably carried out in water or in a mixture of water and organic solvent, suitably in the presence of a buffer. Suitable organic solvents are, for example, water miscible solvents such as alcohols, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, DME, and digilyme. Enzymatic acylation according to the present invention can be carried out using Novozym 435 (Candida Antarctica lipase B, from Novozymes A / S, Fluka Cat. -No. 73940). In general, enzymatic acylation or deacylation according to the invention is preferably carried out using lipases, esterases, acylases or proteases. Useful enzymes according to the invention are enzymes capable of performing R-selective acylation or S-selective acylation of hydroxy groups in racemic compounds of formula V or R-selective deacylation of acyl groups in racemic compounds of formula Vc Or an enzyme capable of performing S-selective deacylation. In particular, according to the present invention, stationary phase forms of enzymes comprising cross-linked enzyme crystals (CLEC) are useful. Preferred embodiments relate to the use of lipases to effect enzymatic cleavage of compound V. Most preferred lipases include Candida antarctica lipase (Fluka Cat. -No. 62299); Pseudomonas cepacia lipase (Fluka Cat. -No. 62309); Novazym CALB L (Candida antarctica lipase B) (Novozymes A / S); Novazym 435 (Candida antarctica lipase B) (Novozymes A / S); Or Lipozyme TLug (Thermomyces lanuginosus lipase) (Novozymes A / S), preferably in stationary phase form.

Alcohol groups of the cis-alcohols of the formula Va are suitable leaving groups, for example by reacting appropriately with an agent such as thionyl chloride, mesyl chloride or tosyl chloride in an inert solvent such as ether, preferably tetrahydrofuran. , Halogen, eg Cl or Br, preferably Cl, or sulfonate such as mesylate or tosylate. The resulting compound has formula VI wherein LG is a leaving group:

In a preferred embodiment, LG is Cl, ie cis-chloride of formula VIa:

Compound VI, for example Compound VI with LG as chloro, is then used in a suitable solvent such as methyl isobutyl ketone or methyl ethyl ketone, preferably methyl isobutyl ketone, in the presence of a base such as potassium carbonate, 2,2 Reaction with dimethyl piperazine affords compound I.

Moreover, the piperazine portion of the molecule may be selected from the general formula VII, wherein PG is not limited thereto, for example, phenylmethoxycarbonyl (often referred to as Cbz or Z), tert-butyloxycarbonyl (often BOC). And a protecting group such as ethoxycarbonyl, or benzyl], and the compound VI may be introduced to obtain the following Formula VIII. The following compound VIII is subsequently deprotected to become compound I:

During the synthesis, some of the cis-diastereoisomers of Compound I (ie, 1-((1S, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine) are present in the final product. It is formed as an impurity. The impurity is mainly due to the formation of some of the trans forms of VI (eg, (1S, 3R) -3,5-dichloro-1-phenylindan when LG is Cl) at the stage where Compound VI is formed. Thus, impurities can be minimized from the mixture of trans and cis VI by crystallization of the desired cis form of compound VI; If LG in Compound VI is Cl, this can be done by stirring the mixture with a suitable solvent, for example an alkane such as heptane, whereby the desired cis form of Compound VI precipitates and the unwanted trans of Compound VI The form enters the solution. The desired cis form of compound VI (eg when LG is Cl) is isolated by filtration, washed with the present solvent and dried.

The cis form of compound I is also optionally one or more times after precipitation of suitable salts of compounds of formula I, for example salts of organic acids such as organic diacids, suitably fumarate salts or malate salts of compounds of formula I Can be recrystallized and removed.

In a further aspect the present invention also relates to a VI comprising an intermediate as described herein, in particular an intermediate Va, and a compound VIa for the synthesis of a compound of formula (I). In the present context, when specifying stereoisomeric forms, it is to be understood that stereoisomers are the main constituents of the compounds. In particular, when specifying the enantiomorphic form, it should be understood that the compound has an enantiomeric excess of the present enantiomer.

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

Further embodiments of the present invention provide a compound of formula VI, preferably at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98% It relates to a compound having:

[Formula VI]

Wherein LG is selected from the group consisting of latent leaving groups, preferably halogens such as chlorides or sulfonates. One embodiment relates to diastereomeric purity of Compound VI; That is, the compound is preferably at least 10% (10% diastereomeric excess is a compound VI to trans diastereomer (e.g., (1S, 3R) -3,5-dichloro-1- when LG = Cl) Phenylindan) in the present mixture of 55:45), having at least 25% and at least 50% diastereomeric excess. One embodiment relates to substantially pure compound VI.

Accordingly, the present invention also provides a compound having the formula VIa, preferably at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98% It relates to a compound having:

[Formula VIa]

One embodiment relates to the diastereomeric purity of the compound, ie the compound is preferably at least 10% (an excess of 10% diastereoisomer means that the compound to trans diastereomer, (1S, 3R)- Mean that the ratio of 3,5-dichloro-1-phenylindane is 55:45 in the present mixture), having at least 25% or at least 50% diastereomeric excess. One embodiment relates to substantially pure compound VI, wherein LG is Cl.

As described above, the present invention, particularly the embodiments of interest, relates to the following:

Compound I or a salt thereof,

A pharmaceutical composition described herein comprising Compound I or a salt thereof,

The medical use as described herein of Compound I or a salt thereof

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

One embodiment relates to Compound I or salts and uses thereof, as described herein, wherein Compound I is at least 10% (10% diastereomeric excess is that of Compound I versus cis- (1S, 3S) diastereomers. Means that the ratio is 55:45 in the mixture), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, preferably at least 98% Has an excess of isomers.

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

Further aspects include, in particular, Compound I or a salt thereof, in particular a fumarate or malate salt, obtainable by the process of the invention as described herein; It also relates to the above for medical use as described herein.

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

Pharmacology

Combine black

For All Assays: Results are expressed as percentage inhibition of specific binding in control and IC ₅₀ values (concentrations that cause half inhibition at maximum of control specific binding) using non-linear regression analysis with Hill equation curve fitting Was measured. The inhibition constant (K _i ) is obtained from the Cheng Prusoff equation (K _i = IC ₅₀ / (1+ (L / K _D )) [where L is equal to the concentration of radioligand in the assay, and K _D is the radioligand for the receptor. Equal to the affinity of].

Alpha-1 Adrenergic Receptor Subtype

Chinese hamster ovary (CHO) cell lines expressing rat alpha _{1 d} and baby hamster kidney (BHK) cells expressing bovine alpha _{1 a} were prepared using standard stability transfection techniques. Rats 1 cell line expressing the hamster alpha _{1 b} receptor were obtained from the University of Utah (Salt Lake City, UT). Cell lines expressing the appropriate (alpha _1a , alpha _1b , alpha _1d ) receptors are harvested and homogenized in an ice-cold 50 mM Tris pH 7.7 using an Ultra-Turrax homogenizer and stored at -80 ° C on ice until either is used. did. [ ³ H] prazosin (0.3-0.5 nM) was used as a radioligand in assessing the affinity of subtypes of alpha ₁ receptor. Total binding was measured using assay buffer and nonspecific binding to all subtypes of alpha ₁ receptor was defined in the presence of 1 μM WB-4101. Aliquots were incubated at 25 ° C. for 20 minutes. In all assays, bound and free radioactivity was separated by vacuum filtration on GF / B filters pretreated with polyethyleneimine (PEI) and measured in scintillation counter.

Alpha-1 Adrenergic Receptor ([ ³ H] Prazosin Rat  Inhibition of binding to alpha-1-receptors)

As a method, inhibition by drugs binding to alpha-1 receptor on the membrane of rat brain of [ ³ H] prazosin (0.25 nM) was measured in vitro. See Hyttel et al., J. Neurochem . 1985 , 44 , 1615-1622.

DA D1  Receptor:

Affinity to the human D1 receptor was measured in the contract laboratory Cerep using the catalog reference assay 803-1h. Membranes derived from CHO cells expressing human recombinant D1 receptor were used. 0.3 nM [ ³ H] -SCH23390 was used as a radioligand and the compounds were tested in serial dilutions simultaneously with the reference compound SCH23390 to assess assay suitability. Aliquots were incubated at 22 ° C. for 60 minutes and bound radioactivity was measured with a liquid scintillation counter.

Specific control binding to the D1 receptor was defined as the difference between the total binding measured without the compound present and the non specific binding measured in the presence of 1 μM SCH 23390.

DA D2  Receptor:

CHO cells expressing about 800 fmol / mg human recombinant D2 receptor were prepared by standard stability transfection techniques. Membranes were harvested using standard protocols and affinity was measured by addition of serial dilutions of the compound to the membrane formulation in a mixture of 50 mM Tris-HCl, 120 mM NaCl, 4 mM MgCl ₂ . 0.1 nM ³ [H] -spiferon was used as a radioligand to assess affinity for the human D2 receptor. Total binding was measured in the presence of buffer and nonspecific binding was measured in the presence of 10 μM haloperidol. The mixture was incubated at 37 ° C. for 30 minutes and soon cooled on ice. Bound and free radioactivity was separated by vacuum filtration on GF / C filters pretreated with 0.1% polyethyleneimine (PEI) and the filters were counted in a scintillation counter.

Efficacy test

DA D1  Receptor:

In CHO cell lines expressing human recombinant D1 receptors that express safely in tissues, the ability of compounds to inhibit D1 receptor mediated cAMP formation was measured as follows. Three days before the experiment, cells were dispensed into 96-well plates at a concentration of 11000 cells / well. On the day of the experiment, the cells were washed once in pre-heated G buffer (1 mM IBMX, 1 mM MgCl ₂ , 0.9 mM CaCl ₂ in PBS) and 100 μl of a mixture of 30 nM A68930 and test compound diluted in G buffer. Addition began to assay. The cells were incubated at 37 ° C. for 20 minutes and the reaction was stopped by adding 100 μl S buffer (0.1 M HCl and 0.1 mM CaCl ₂ ) and the plate was placed at 4 ° C. for 1 hour. 68 μl N buffer (0.15 M NaOH and 60 mM NaAc) was added and the plate was stirred for 10 minutes. 60 μl of the reaction was transferred to cAMP FlashPlate (DuPont NEN) containing 40 μl 60 mM NaAc pH 6.2 and 100 μl IC mix (50 mM NaAc pH 6.2, 0.1% NaAzid, 12 mM CaCl ₂ , 1% BSA and 0.15 μCi). / ml ¹²⁵ I-cAMP) was added. After incubation at 4 ° C. for 18 hours, the plates were washed once and measured on a Wallac TriLux meter.

DA D2  Receptor:

The ability of compounds to inhibit D2 receptor mediated inhibition of cAMP formation in CHO cells transfected with human D2 receptor was measured as follows. Three days before the experiment, cells were dispensed into well plates at a concentration of 8000 cells / well. On the day of the experiment the cells were washed once in pre-heated G buffer (1 mM IBMX, 1 mM MgCl ₂ , 0.9 mM CaCl _{2 in} PBS) and of 1 μM quinpyrrole, 10 μM forskolin and reference compounds in G buffer. The assay was started by adding 100 μl of the mixture. Cells were incubated at 37 ° C. for 20 minutes and the reaction was stopped by adding 100 μl S buffer (0.1 M HCl and 0.1 mM CaCl ₂ ) and the plate was placed at 4 ° C. for 1 hour. 68 μl N buffer (0.15 M NaOH and 60 mM NaAc) was added and the plate stirred for 10 minutes. 60 μl of the reaction was transferred to cAMP FlashPlate (DuPont NEN) containing 40 μl 60 mM NaAc pH 6.2 and 100 μl IC mix (50 mM NaAc pH 6.2, 0.1% NaAzid, 12 mM CaCl ₂ , 1% BSA and 0.15 μCi / ml ¹²⁵ I-cAMP) was added. After 18 hours incubation at 4 ° C., the plates were washed once and measured on a Wallac TriLux meter.

Serotonin 5- HT2A  Receptor

Two or three days before the experiment, CHO cells expressing 250 fmol / mg 5-HT _2A receptor were plated at a density sufficient to provide a mono-confluent layer on the day of the experiment. Cells was for 60 minutes at 95% humidity in a 5% CO ₂ thermostat to 37 ℃ dye treatment (Molecular Device of Ca ^{2 +} - a pH kits and phenol without the red, the addition of HEPES 20 mM, a 2M NaOH was adjusted to 7.4 Hank's balanced salt was used as assay buffer). The laser intensity is fixed at a suitable level to obtain a baseline of base units of about 8000 to 10,000 fluorescent units. The change in basic fluorescence should be less than 10%. EC ₅₀ Values were determined using increasing concentrations of test compounds over 30 years. IC ₅₀ values were evaluated in tests on test substances with EC ₈₅ of 5-HT in the same range of concentrations. Test substance was added to the cells 5 minutes before 5-HT. K _i values were measured using the Cheng-Prusoff equation. Test compound concentrate stimulation% was determined for 5-HT maximum concentration (100%). The percent inhibition of the test compound concentrate was determined as the percentage by which the reaction of EC ₈₅ of 5-HT is lowered. Maximum inhibition is the level of inhibition that the curve reaches. It is expressed as a percentage inhibition at this level and is used to distinguish between full and partial antagonists.

Compound and Of CYP2D6  Interactive In vitro  Measure( CYP2D6  Inhibitor assay)

Principle : Bacolo expressing CYP2D6 as a specific CYP2D6 substrate AMMC (3- [2- (N, N-diethyl-N-methylammonium) -ethyl] -7-methoxy-4-methylcoumarin) and an enzyme source Inhibition of human CYP2D6 was evaluated using microsomes prepared from virus / insect cell cDNA. AMMC is O-demethylated in AHMC (3- [2- (N, N-diethylamino) ethyl] -7-hydroxy-4-methylcoumarin) detected by measuring the appearance of fluorescence. Preferred compounds of the invention show an IC50 greater than 5 micromoles for CYP2D6 activity, wherein IC50 is the concentration of compound that provides 50% inhibition of CYP2D6 activity.

Material and method:

BD microsomes prepared from baculovirus / insect cell cDNA expressing CYP2D6 Obtained from Biosciences (Gentest 456217). Ex. (405 nm) Em. (465 nm) was measured with a SpectroFluor Plus Plate Reader (Tecan Nordic). Incubation with recombinant CYP2D6 microsomes was performed with a low NADPH-regeneration 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. In 100 mM phosphate buffer with a total volume of 0.2 ml at pH 7.4 containing AMMC (3- [2- (N, N-diethyl-N-methylammonium) -ethyl] -7-methoxy-4-methylcoumarin) It contained 1.5 pmol of recombinant CYP2D6. Incubation time was 45 min and incubation was stopped by addition of 0.075 mL 80% acetonitrile 20% 0.5 M Tris base. All chemicals were of analytical grade from Sigma (St. Louis, MO). IC50 curves were presented using eight concentrations of 40 to 0.02 micromoles of the compound to be tested dissolved in DMSO (dimethyl sulfoxide)-the final concentration in incubation was less than 1.0% (Modified from N. Chauret et al. DMD Vol 29, Issue 9, 1196-1200, 2001). IC ₅₀ values were calculated using linear interpolation.

QT-spacing

Anesthetized Rabbit:

The model described below is described in J Cardiovasc Pharmacol. 1990; 16: 276-85, which was originally designed as a proarrhythmic model and modified to fit the screening setup as described below under "Animal Preparation."

Animal manufacturing

Male rabbits (HsdIf: NZW, crossbreeding) from 2.0 to 2.8 kg were purchased from Harlan (Netherlands). Each weight was measured and recorded on the day of the experiment. General anesthesia was induced by intravenous infusion of pentobarbital through the marginal ear vein (afterwards with alpha chloraloose (100 mg / kg) at an injection volume of 4 ml / kg over 20 minutes). The cannula was inserted into the trachea and the rabbits were aerated at 45 strokes per minute and a periodic volume of 6 ml / kg. Vascular catheter was implanted into the jugular vein for test compound administration. Additional catheter was implanted into the left carotid artery and blood pressure was monitored for blood sampling. The precipitation pole was placed subcutaneously to record the standard anode lead II: the cathode was placed close to the right front shoulder and the anode close to the left waist.

Experimental protocol

After a short equilibrium, the existing pre-dose values were obtained before -20, -10 and 0 minutes prior to IV bolus administration of the excipient or test compound. The effect of bolus administration was followed for 40 minutes.

Material sampling and calculation

ECG, blood pressure and HR were recorded continuously on Maclab 8 / s using the chart software v3.6.1 on Macintosh computers. Sampling frequency was 1000 Hz. Electrocardiogram results (PQ-, QRS-, QT-, QTc-spacing and heart rate) and mean arterial blood pressure (MAP) were recorded and measured electronically.

Analytical Method

Example 1a In a 10㎛ enantiomer excess of the compound Va in 40 ℃, was measured by chiral HPLC using a CHIRALCEL ^® OD column of 0.46cm ID X 25 cm L. n-hexane / ethanol 95: 5 (vol / vol) was used as a mobile phase with a flow rate of 1.0 ml / min and detected 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 μm particle size)

Eluent: buffered MeOH / water prepared as follows: 1.1 ml of Et ₃ N was added to 150 ml of water, 10% H ₃ PO ₄ (aq) was added to pH = 7, and water was added in total 200 made in ml. The mixture was added to 1.8 L MeOH.

Example 1b In 10㎛ the enantiomer excess of the compound Va in 21 ℃, was measured by chiral HPLC using a CHIRALPAK ^® AD column of 0.46cm ID X 25 cm L. Heptane / ethanol / diethylamine 89.9: 10: 0.1 (vol / vol / vol) was used as a mobile phase with a flow rate of 1.0 ml / min and detected using a UV detector at 220 nm.

The enantiomeric excess of Compound I was determined by fused silica capillary electrophoresis (CE) using the following conditions: Capillar: 50 μm ID × 48.5 cm L, Operation Buffer: 25 mM Sodium Dihydrogen Phosphate, pH 1.25 mM β cyclodextrin in 1.5, voltage: 16 kV, temperature: 22 ° C., scan: 40 mbar for 4 seconds, detection: column diode assay detection 195 nm, sample concentration: 500 μg / ml. In this system, compound I has a residence time of about 10 minutes and the other enantiomer has a residence time of about 11 minutes.

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

등, J. Med. Chem. 1995, 38, 4380-4392 (제 4388 면, 우측 칼럼)]에 기재된 바와 같이 ¹H NMR을 이용해 측정했다. 시스 이성질체에 대해서 5.3 ppm 에서의 신호 및 트랜스 이성질체에 대해서 5.5 ppm 에서의 신호의 적분을 이용한, 클로로포름 내 ¹H NMR으로 화합물 VI의 시스/트랜스 비율을 또한 측정했다. 일반적으로, 약 1% 의 원하지 않는 이성 질체의 함량이 NMR 에 의해 검출될 수 있다. Of compound I Cis / trans ratio

Et al., J. Med. Chem. 1995 , 38, 4380-4392 (p. 4388, right column)] was measured using ¹ H NMR. The cis / trans ratio of Compound VI was also determined by ¹ H NMR in chloroform using the integration of the signal at 5.3 ppm for the cis isomer and the signal at 5.5 ppm for the trans isomer. Generally, about 1% of the unwanted isomer content can be detected by NMR.

Melting points were measured using differential scanning calorimetry (DSC). The apparatus is a TA-Instrument DSC-2920 calibrated at 5 ° / min to provide the melting point as starting value. About 2 mg of sample was heated at 5 ° / min in a loosely closed pan under nitrogen flow.

synthesis

Synthesis of main starting materials

등 J. Med. Chem. 1983, 26, 935]에 기재된 방법을 적용하여, 화합물 V 를 나트륨 보로히드리드 (NaBH₄)를 이용해 환원함으로써 IV로부터 합성하고 에탄올을 용매로서 사용하고, 상기 반응을 약 0 ℃에서 실시했다. 양 화합물 모두 문헌[

등 J. Med. Chem. 1995, 38, 4380-4392]에 기재되어 있다. 화합물 IV 를, II 및 그의 합성을 기재한 문헌 [Sommer 등, J. Org. Chem. 1990, 55, 4822]에 기재된 일반적인 절차를 이용해 II로 부터 합성했다. Literature [

Et al. J. Med. Chem. 1983 , 26, 935] was applied, compound V was synthesized from IV by reduction with sodium borohydride (NaBH ₄ ), using ethanol as solvent and the reaction was carried out at about 0 ° C. Both compounds are described in [

Et al. J. Med. Chem. 1995, 38 , 4380-4392. Compound IV is described in II and J. Org. Chem. Synthesized from II using the general procedure described in 1990 , 55, 4822.

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

Digestion of racemic cis-6-chloro-3-phenylindan-1-ol (V) (492 g) with a preparative chromatograph using a CHIRALPAK ^® AD column of 10 μm, 10 cm ID × 50 cm L at 40 ° C. did. Methanol was used as the fluidized bed at a flow rate of 190 ml / min and detected using a UV detector at 287 nm. Racemic alcohol (V) is injected as a 50,000 ppm solution in methanol; 90 ml were injected at 28 minute intervals. All fractions containing the title compound with an enantiomeric excess of at least 98% were combined and evaporated to dryness using a rotary evaporator, followed by drying under " vacuum ". Yield 220 g as a solid. Elemental analysis and NMR correspond to the structure and the enantiomeric excess is at least 98%, according to chiral HPLC, [α] _D ²⁰ + 44.5 ° (c = 1.0, methanol).

Example  (1S, 3S) -6- Using 1b Enzymatic Degradation Chloro -3- Phenylindan Synthesis of -1-ol (Va)

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

Example  2 (1S, 3S) -3,5- Dichloro -One- Phenylindan  (VI, LG = Cl ) Synthesis

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

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

Potassium carbonate (390 g) and ethylene diamine (1001 g) were stirred with toluene (1.50 L). A solution of ethyl 2-bromoisobutyrate (500 g) in toluene (750 ml) was added. The suspension was heated to reflux overnight and filtered. The filter mass was washed with toluene (500 ml). The combined filtrates (vol. 4.0 L) were heated in a water bath and distilled at 0.3 atm using a Claisen apparatus; The first 1200 ml distillate was collected at 35 ° C (temperature in the mixture was 75 ° C). More toluene was added (600 ml) and another 1200 ml distillate was collected at 76 ° C (temperature in the mixture was 80 ° C). Toluene (750 ml) was added again and 1100 ml of distillate was collected at 66 ° C. (the temperature in the mixture was 71 ° C.). The mixture was stirred on an ice bath and inoculated to precipitate the product. The product was isolated by filtration, washed with toluene and dried overnight at 50 ° C. in a vacuum oven. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one. NMR matches 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. to give a slightly opaque solution. THF (50 kg) was stirred under nitrogen and LiAlH ₄ (250 g, in soluble plastic bag from Chemetall) was added to provide slow evolution of gas. After gas evolution had ceased, more LiAlH ₄ (3.0 kg total, using 79.1 mol) was added and the temperature rose from 22 ° C. to 50 ° C. due to exothermicity. A solution of 3,3-dimethylpiperazin-2-one was slowly added at 41-59 ° C. over 2 hours. The suspension was stirred at 59 ° C. (jacket temperature 60 ° C.) for another hour. The mixture was cooled, water (3 L) was added over 2 hours and the temperature kept below 25 ° C (cooling to jacket temperature of 0 ° C is mandatory). Sodium hydroxide (15%, 3.50 kg) was then added at 23 ° C (cooling required) over 20 minutes. More water (9 L) was added over 30 minutes (cooling required) and the mixture was stirred under nitrogen overnight. Filter Celit (4 kg) was added and the mixture was filtered. The filter mass was washed with THF (40 kg). The combined filtrates were concentrated in the reactor until the reactor temperature was 70 ° C. (distillation temperature 66 ° C.) at 800 mbar. The residue (12.8 kg) was further concentrated to about 10 L on a rotavapor. Finally, the mixture was fractionally distilled at atmospheric pressure and the product collected at 163-4 ° C. Yield 5.3 kg (72%). NMR matches the structure.

Example  5 trans-1-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3-dimethylpiperazine (Compound I) Hydrogen Malate  Salt synthesis

Cis- (1S, 3S) -3,5-dichloro-1-phenylindane (VI, LG = Cl) (240 g) was dissolved in butan-2-one (1800 ml). Potassium carbonate (272 g) and 2,2-dimethyl piperazine (prepared in Example 4) (113 g) were added and the mixture was heated at reflux for 40 hours. To the reaction mixture was added diethyl ether (2 L) and hydrochloric acid (1M, 6 L). The phases were separated and the aqueous phase pH was lowered from 8 to 1 with concentrated hydrochloric acid. The aqueous phase was used to wash the organic phase once more to ensure that all products were present in the aqueous phase. Sodium hydroxide (28%) was added until pH became 10, and the aqueous phase was extracted twice with diethyl ether (2 L). The diethyl ether extracts were combined, dried over sodium sulfate and evaporated using a rotary evaporator until dry. 251 g of the title compound were obtained as an oil. The cis / trans ratio according to NMR is 82:18. The crude oil (about 20 g) was further purified by silica gel (eluent: ethyl acetate / ethanol / triethylamine 90: 5: 5) flash chromatography and evaporated to dryness on a rotary evaporator. Yield: 12 g of the title compound (cis / trans ratio according to NMR 90: 10) as an oil. The oil was dissolved in ethanol (100 ml) and the solution of maleic acid in ethanol was added to pH 3. The resulting mixture was stirred for 16 hours at room temperature and the precipitate formed was collected by filtration. The ethanol volume was reduced and another batch of precipitate collected. Yield 3.5 g of the title compound solid (according to NMR, no cis isomer was detected). The enantiomeric excess is> 99%. Melting point 175-178 캜. NMR matches the structure.

Example  6 compound Of I  synthesis

Trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium hydrogen maleate (VI) (9.9 g), concentrated ammonia water (100 ml ), Brine (150 ml) and ethyl acetate (250 ml) were stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated under vacuum until dry. Yield 7.5 g of oil. NMR matches the structure.

Example  7 trans-1-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpiperazinium (Compound I) Fumarate  Salt synthesis

A solution of acetone (1 g) of trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (obtained as described in Example 6) was obtained Dissolved in (100 mL). To the solution was added a solution of fumaric acid in ethanol until the pH of the resulting solution became 4. The resulting mixture was cooled in an ice bath for 1.5 hours to form a precipitate. The solid compound was collected by filtration. The compound was dried under vacuum to give a white solid compound (1.0 g). The enantiomeric excess is> 99%. Melting point 193-196 ° C. NMR matches the structure.

Claims (33)

A compound of formula (compound I, trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine) or a salt thereof: [Formula I]

. The compound or salt according to claim 1, which is substantially pure. A pharmaceutical composition comprising a compound or salt of claim 1 or 2 together with one or more pharmaceutically acceptable carriers, fillers or diluents. 4. A pharmaceutical composition according to claim 3, wherein the enantiomeric excess of Compound I is at least 90%, at least 96% or at least 98%. The compound or salt according to claim 1 or 2 for medical use. A disorder comprising psychiatric symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced parkinsonism, and abuse disorders such as cocaine abuse, nicotine abuse or alcohol abuse Use of a compound or salt of claim 1 in the manufacture of a medicament for the treatment of a disease. Use according to claim 6 in the manufacture of a medicament for the treatment of schizophrenia or other psychiatric disorders. Use according to claim 7 in the manufacture of a medicament for the treatment of positive, negative and depressive symptoms of schizophrenia. Claim 1 or 2 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of schizophrenia, schizophrenic disorder, schizophrenia disorder, oblivion disorder, short-term psychotic disorder, copsychotic disorder, and bipolar disorder Use of the compound or salt of claim.  Use according to any of claims 6 to 9, wherein the compound or salt thereof is in the form of a pharmaceutical composition as defined in claim 4. Diseases involving psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disorders, migraine, nerves, comprising administering a therapeutically effective amount of a compound or salt as defined in claim 1 or 2 Relaxant-induced parkinsonism or a method for treating a disease selected from the group consisting of abuse disorders such as cocaine abuse, nicotine abuse or alcohol abuse. The method of claim 11, wherein the schizophrenia or other psychotic disorder is treated. The method of claim 12, wherein the positive symptoms of one or more schizophrenia, negative symptoms depressive symptoms. Manic schizophrenia, schizophrenic disorders, schizophrenia affect disorders, oblivion disorders, short-term psychotic disorders, copsychotic disorders and bipolar disorders, comprising administering a therapeutically effective amount of a compound or salt of claim 1 or 2 Method of treating a disease selected from the group consisting of. The method of claim 11, wherein the patient treated with Compound I or a salt thereof is also treated with other agent (s). The method of claim 12, wherein the patient treated with Compound I or a salt thereof is also treated with one or more other agents.  The method of claim 11, wherein the compound or salt thereof is in the form of a pharmaceutical composition as defined in claim 4. Compound trans-1- (6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine or a salt thereof for medical use. A pharmaceutical composition comprising a compound or salt of claim 18 together with one or more pharmaceutically acceptable carriers, fillers or diluents. Diseases including schizophrenia, schizophrenia (eg, one or more positive symptoms of schizophrenia, negative symptoms and depressive symptoms), schizophrenic disorders, schizophrenic disorders, oblivion disorders, short-term psychotic disorders, co-mental disorder Medications for the treatment of diseases selected from the group consisting of bipolar disorders, disorders such as mania, anxiety disorders, affective disorders including depression, migraine, neuroleptic-induced Parkinsonism, cocaine abuse, nicotine abuse, or alcohol abuse Use of the compound or salt of claim 18 in the preparation. Diseases, including schizophrenia (eg, one or more positive symptoms of schizophrenia, negative and depressive symptoms), schizophrenia, comprising administering a therapeutically effective amount of a compound or salt as defined in claim 18 Type disorders, schizophrenic disorders, oblivion disorders, short-term psychotic disorders, shared psychotic disorders, manic disorders among bipolar disorders, anxiety disorders, affective disorders including depression, sleep disorders, migraines, neuroleptic-induced parkinsonism, cocaine abuse, A method of treating a disease selected from the group consisting of abuse disorders such as nicotine abuse or alcohol abuse. A process for preparing a compound of formula I (compound I) or a salt thereof, the method comprising converting a compound of formula (Va) in the cis-array to a compound of formula [Formula I]

[Formula Va]

. The method of claim 22 comprising converting the alcohol group of the cis-alcohol of formula Va to a suitable leaving group LG to produce a compound of formula VI: [Formula VI]

. The method according to claim 23, wherein LG is halogen, such as Cl or Br, preferably Cl, or sulfonate. The method of any one of claims 22-24, wherein compound VI is precipitated from a suitable solvent. The process according to claim 25, wherein LG is halogen, preferably Cl, and the solvent is an alkane, such as heptane. 27. The method of any one of claims 22-26, wherein compound VI is reacted with 2,2-dimethylpiperazine to afford compound I. 28. The process of claim 27, wherein compound I is precipitated as a suitable salt, such as a salt of an organic acid such as organic diacid. 29. The method of claim 28, wherein the salt formed is a fumarate salt or maleate salt of Compound I. 27. The method of any one of claims 22 to 26, comprising the following steps: Compound VI is 1-protected 2,2-dimethylpiperazine (Formula VII) wherein PG is a protecting group selected from protecting groups such as phenylmethoxycarbonyl group, tert-butyloxycarbonyl group, ethoxycarbonyl group and benzyl group Reacting to obtain a compound of formula VIII; Deprotecting formula (VIII) to give compound (I): [Formula VII]

[Formula VIII]

. A process for preparing Compound I or a salt thereof, comprising reacting a compound of Formula VIa (ie Compound VI wherein LG is Cl) with 2,2-dimethylpiperazine. A process for preparing Compound I or a salt thereof, comprising reacting a compound of Formula VIa with 2,2-dimethylpiperazine in the presence of a base: [Formula VIa]

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