KR20060066094A - Succinate and malonate salt of trans-4-(ir,3s)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and the use as a medicament - Google Patents

Abstract

4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine hydrogen succinate or hadrogen malonat, pharmaceutical compositions containing these salts and the medical use thereof, including for the treatment of schizophrenia and other psychotic disorders. Also described are methods for the preparation of 4-((1R,3S)-6-Chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine and medical uses thereof.

Description

Trans-4- (IR, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine as succinate and malonate salts and uses as medicaments {SUCCINATE AND MALONATE SALT OF TRANS-4- (IR, 3S) -6-CHLORO-3-PHENYLINDAN-1-YL) -1,2,2-TRIMETHYLPIPERAZINE AND THE USE AS A MEDICAMENT}

The present invention relates to 4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine, in particular hydrogen succinate salts and hydrogen malonate thereof (hydrogen malonate) salt, 4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine and a process for preparing the salt thereof, a medicament containing the salt Pharmaceutical compositions, and their medical uses, including the treatment of other diseases including schizophrenia or psychotic symptoms.

The compound [4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin], which is the subject of the present invention, represents the formula (I) 638 073 is outlined:

.

.

[EP 638 073] deals with the group of trans isomers of 3-aryl-1- (1-piperazinyl) indane substituted at the 2- and / or 3-position of the piperazine ring. The compound is dopamine D ₁ and D ₂ Receptor and 5-HT ₂ It is described as having a high affinity for the receptor and has been suggested to be useful for treating various diseases in the central nervous system including schizophrenia. EP 638 073 does not disclose specific enantiomeric forms of these compounds of formula (I), but describes only the trans isomers in the form of racemates.

등의 J. Med. Chem., 1995, 38, page 4380-4392 (표 5, 화합물 (-)-38 참조)]에 기술되었다. The enantiomers of formula I are described in the form of fumarate salts [

J. Med. Chem., 1995, 38, page 4380-4392 (see 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 high affinity for α ₁ adrenergic receptor. It is also mentioned that the compound does not induce anxiety in rats.

의 Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds, 1998, ISBN 87-88085-10-4 (참고로, 예컨대, p47, 표 3 및 p101, 표 9A의 화합물 69)]에 기술되어 있다. Racemic and fumarate salts corresponding to the compounds of formula (I) are also described in Klaus P.

Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds, 1998, ISBN 87-88085-10-4 (see, eg, p47, Tables 3 and p101, Compound 69 of Table 9A). Described.

Thus, the compounds of formula I are mixed with D ₁ / D ₂ antagonist, 5-HT ₂ It is an antagonist and it also has an affinity for α ₁ adrenergic receptors. In the following, possible linkages between different diseases and each of the dopamine D ₁ and D ₂ receptors, the 5-HT ₂ receptor and the α ₁ adrenergic receptor are outlined.

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 (DNEder, 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 relaxant-induced parkinsonism. 5-HT ₂ receptor antagonism has also been proposed to reduce the incidence of adverse events induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979 , 62, 67-69).

[Brief Description of Drawings]

Figure 1 shows an X-ray powder diffractogram of the crystalline alpha form of the hydrogen succinate salt of compound I (obtained using copper K _a1 radiation (λ = 1.5406 kPa)).

Figure 2 shows an X-ray powder diffractogram of the crystalline beta form of the hydrogen succinate salt of compound I (obtained using copper K _a1 radiation (λ = 1.5406 kPa)).

3 shows the X-ray powder diffractogram of the hydrogen malonate salt of compound I (obtained using copper K _a1 radiation (λ = 1.5406 Hz))

Salt of the invention

It is now known that the water solubility of hydrogen succinate salts and hydrogen malonate salts of compounds of formula I is significantly greater than that of the corresponding fumarate salts.

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

As used herein, the “hydrogen malonate” salt of a compound of formula I refers to a malonic acid of 1: 1 and a salt of a compound of formula I.

Hydrogen succinate salts are known to be much more stable and non-hygroscopic than fumarate salts and hydrogen malonate salts.

Hydrogen malonate salts of Compound I have similar stability to fumarate salts when exposed to light and are much more stable when exposed to 60 ° C / 80% relative humidity (RH), but less stable than fumarate salts at 90 ° C. Known. However, 90 ° C is a very stressed condition and is not necessarily related to stability under normal conditions. Malonate gradually absorbs water up to 1% when the relative humidity rises to 95% but no hysteresis. It is thus considered to be non-absorbent but has good wettability indicating favorable solubility.

The invention also deals with solvates of the salts of the invention and crystalline salts of the invention, including, for example, anhydrates, hydrates. The term anhydrous hydrate means a salt of the present invention that does not contain crystal bound water. By hydrate is meant a salt of the present invention containing a crystal bond water molecule. Hydrates are usually prepared by the formation of salts in the presence of some water. Solvate means a salt of the invention containing a crystal binding solvent molecule. Solvates are usually prepared by the formation of succinate salts in the presence of a solvent. Solvent molecules in a single solvate may be one or more different solvents. Solvates may include water as one of two or more organic solvents or may be only non-aqueous solvents.

One embodiment of the invention provides succinic acid in the crystalline anhydrous form of 1: 1 and trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethyl Piperazine, ie, salts of compounds of formula (I).

We have found two crystalline forms (referred to as alpha and beta) of the hydrogen succinate salt of formula (I).

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

(i) an X-ray powder diffractogram as shown in FIG. 1;

(ii) the X-ray powder diffractogram pattern set forth in Table I obtained using copper K _a1 radiation (λ = 1.5406 Hz) showing the major peak at the provided 2θ-angle;

(iii) Have a DSC (differential scanning calorimeter) record showing warm-blooded animals with an onset temperature of 139-141 ° C.

A further embodiment relates to the crystalline form of the hydrogen succinate salt of compound I, which form is referred to as beta and is characterized by one or more of the following:

(i) an X-ray powder diffractogram as shown in FIG. 2;

(ii) an X-ray powder diffractogram pattern as described in Table I obtained using copper K _a1 radiation (λ = 1.5406 Hz) showing the major peak at the provided 2θ-angle;

(iii) have a DSC record showing warm-blooded animals with an onset temperature of 135-138 ° C.

Further embodiments relate to crystalline hydrogen malonate salts of compound I characterized by one or more of:

(i) an X-ray powder diffractogram as shown in FIG. 3;

(ii) X-ray powder diffractogram pattern set forth in Table I obtained using copper K _a1 radiation (λ = 1.5406 Hz) showing the major peak at the provided 2θ-angle.

TABLE 1

Characteristic X-ray powder diffractogram obtained using copper K _a1 radiation (λ = 1.5406 Hz) in the form of crystalline alpha and beta of crystalline hydrogen malonate salt of compound I and hydrogen succinate salt of compound I. Degree; 1, 2 and 3. which also provide representative XRPD forms of the polymorphic alpha and beta of the hydrogen succinate salt and malonate salt of Compound I, respectively. salt Characteristic reflex-major peak (expressed in diffraction angle 2θ) Succinate, Alpha 9.36; 10.23; 11.81; 13.45; 16.21; 16.57; 17.49; 18.89; 19.20; 19.63; 20.01; 20.30; 21.15; 21.53; 21.93; 22.34; 24.37; 25.34; 27.27; 29.65 Succinate, beta 8.1; 10.5; 11.4; 14.0; 14.6; 15.6; 15.7; 16.2; 17.2; 17.5; 17.9; 18.4; 18.9; 19.2; 20.3; 21.0; 21.9; 22.5; 23.3; 26.3 Malonate 8.3; 10.6; 11.5; 12.8; 14.2; 14.5; 14.7; 15.8; 16.5; 17.4; 17.6; 18.0; 18.6; 19.2; 21.2; 22.0; 22.9; 23.7; 24.7; 28.8

As used herein, the expression “crystalline form of a particular salt of Compound I characterized by the X-ray powder diffractogram shown in FIG. 1” is the crystalline form of the salt of Compound I having an X-ray powder diffractogram substantially similar to FIG. 1. Morphology, that is, substantially as shown in the figure and showing an X-ray powder diffraction pattern as measured under the comparative conditions described herein or by any comparison method.

In general, it should be understood that all data herein are approximate and may violate conventional measurement errors, for example, depending on the instrument used and other parameters affecting peak position and peak intensity.

The invention also relates to the solid hydrogen succinate salt of compound I, which solid salt consists mainly of alpha form when compared to the total amount of salt. In one embodiment, the term “mainly” means that when compared to the total hydrogen succinate salt of Compound I, the solid hydrogen succinate salt of Compound I is at least 75%, such as at least 80%, at least 90%, at least 95% It means a crystalline alpha form.

The present invention also relates to the solid hydrogen succinate salt of compound I, which solid salt consists mainly of beta form when the total amount of salts is compared. In one embodiment, the term “mainly” means that when compared to the total hydrogen succinate salt of Compound I, the solid hydrogen succinate salt of Compound I is at least 75%, such as at least 80%, at least 90% or at least 95% It means that the crystalline beta form.

The invention also relates to any mixture of crystalline forms of the hydrogen succinate salts of the invention, such as mixtures of alpha and beta crystalline forms of the hydrogen succinate salt of compound I.

Salt Preparation of the Invention

Succinate salts according to the invention can be obtained by treating the free base of the compound of formula (I) with succinic acid in an inert solvent followed by precipitation, isolation and optionally recrystallization. If desired, the crystalline salt may then be micronized by wet or dry milling or particle preparation from another convenient or solvent-emulsifying process.

Precipitation of the succinate salt of the invention preferably dissolves the free base of the compound of formula (I) in a suitable solvent such as acetone or toluene, after which the solution of succinic acid in a suitable solvent such as acetone, aqueous acetone or toluene By mixing in solution or suspension. In one embodiment, the solvent is a mixture of acetone and water, based on the weight of the mixture, such as a mixture essentially consisting of acetone and about 2% to 10%, preferably about 5% water. The solvent can be added until all the succinic acid has dissolved or the resulting suspension can be heated. The succinate salt of the compound of the invention precipitates, preferably upon cooling of the solution. The succinate salts of the present invention may optionally be isolated or washed, such as acetone, and dried by one or several times recrystallization, filtration.

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

Malonate salts can be obtained using similar procedures. Thus, the malonate salts according to the invention can be obtained by treating the free base of the compound of formula I with malonic acid in an inert solvent followed by precipitation, isolation and optionally recrystallization. If desired, the crystalline salt may then be micronized by wet or dry milling or particle preparation from another convenient or solvent-emulsifying process.

Precipitation of the malonate salts of the present invention is accomplished by dissolving the free base of the compound of formula I in a suitable solvent such as 2-propanol and then mixing the solution with a solution or suspension of malonic acid in a suitable solvent such as 2-propanol. Is carried out. The suspension can be heated until all malonic acid has dissolved. The malonate salt of the compounds of the invention precipitates, preferably upon cooling of the solution. The malonate salts of the present invention may be isolated, washed, such as washed with 2-propanol, and dried, optionally by recrystallization and filtration once or more times.

Chemical formula Of I  Preparation of the compound

등. J. Med. Chem., 1995, 38, page 4380-4392]에 기재된 대로 제조될 수 있고, 라세미 화합물의 광학분할이 부분입체 이성질체 염의 결정화로 수행될 수 있고, 그것에 의해 화학식 I 의 거울상체를 수득할 수 있는 방법에 대해 기재했다. The compounds of formula I in racemic form are described in EP 638 073 and in literature [

Etc. J. Med. Chem., 1995, 38, page 4380-4392, wherein optical splitting of racemic compounds can be carried out by crystallization of diastereomeric salts, whereby an enantiomer of formula I can be obtained The method was described.

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). The synthetic route is currently revealed. Thus, in this process, 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 to obtain compounds of formula I is much more effective than the above-mentioned crystallization of diastereomeric salts of the final product I. In particular, the yield of this fraction is substantially above that when compared to the yield for the splitting of the final product I by crystallization of the diastereomeric salt (22% relative to the amount of racemic starting material, ie the maximum theoretical yield is 50%). High in the new method (45%, ie the maximum theoretical yield is 50% relative to the amount of racemic starting material). Another advantage of the present invention is that the enantiomeric purity of I is higher (higher than 99% ee) when synthesized according to the present invention compared to the synthesis using crystallization of diastereomeric salts (95.4% ee). In addition, the cleavage of the intermediates in place of the final product provides much more effective synthesis as only the right enantiomer is used in subsequent steps, for example providing a high volume yield and less consumption of reactants.

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 the presence of potassium tert-butoxide (t-BuOK) in a suitable solvent such as dimethyl ether (DME), and additionally 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 to form a compound of formula IV:

Preferably at -30 ° C to + 30 ° C, such as below 30 ° C, below 20 ° C, below 10 ° C, or preferably below 5 ° C, suitably NaBH ₄ in a solvent such as an alcohol such as ethanol or iso-propanol Is then used to reduce the compound of formula IV 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 division from V to Va is, for example, chiral of a silica gel coated with a chiral polymer such as modified amylose, preferably amylose tris- (3,5-dimethylphenylcarbamate) coated on silica gel. It can be carried out using a chiral chromatograph on the column, 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 cleavage of the enzymatic action. Pure enantiomeric compound Va, or its acylated derivative, is prepared by enantioselective acylation of the hydroxylation of hydroxyl groups 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 to the corresponding ester at the hydroxyl position followed by enantioselective deacylation of enzymatic activity. The use of enantioselective deacylation of enzymatic activity has been reported for other compounds.

Thus, the splitting of compound V into compound Va can be carried out by acylation of selective enzymatic action. Selective enzymatic acylation means that the acylation of the enzymatic action is preferentially effective in the conversion of one of the cis-enantiomers of the compound of formula V to the other, leaving the other cis-enantiomers of compound V in the reaction mixture unconverted. do.

Alternatively, cleavage of compound V into compound Va can be performed by deacylation of selective enzymatic action. Deacylation of selective enzymatic action means that deacylation of enzymatic action is preferred in converting one of the esters of the compound of formula V, leaving the other cis-enantiomer of the ester of the compound of formula V unconverted in the reaction mixture. Means valid.

Suitable esters of compounds of formula V (formula Vb) are esters such as acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate Pivalate, 2-methyl valerate, 3-methyl valerate, 4-methyl valerate:

[Wherein R is, for example, acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate, 2-methylvalerate , 3-methylvalerate, 4-methylvalerate].

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) acylating the racemic compound V with enantioselective enzymatic action, using an acylating agent, or

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

Acylation of enantioselective enzymatic action means that the other enantiomer of the compound of formula V is preferentially left unconverted in the reaction mixture and is preferentially effective in the conversion of one of the enantiomers of the compound of formula V. Deacylation of enantioselective enzymatic action means that the other enantiomer of the compound of formula Vb is preferentially left unconverted in the reaction mixture and is preferentially effective in the conversion of one of the enantiomers of the compound of formula Vb.

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 the acylation / deacylation of enzymatic activity 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, deacylation of enantioselective enzymatic reaction may preferentially provide a mixture comprising a compound of formula Vb in (S, S) -form and a compound of formula V in (R, R) -form, or preferentially It is possible to provide a mixture comprising a compound of formula Va 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 invention, acylation of enantioselective enzymatic action 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, acylation of enantioselective enzymatic action is preferably carried out in a water-free organic solvent or in 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; Hextones such as acetone, diethyl heptone, butanone and methyl ethyl heptone; 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 and hexamethylphosphorus triamide. Preferred organic solvents for the 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.

Deacylation of enantioselective enzymatic action 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.

Acylation of the enzyme action 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, the acylation or deacylation of the enzymatic activity 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 Vb 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 for carrying out the 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, such as Compound VI having LG as chloro, is then subjected to 2,2 in a suitable solvent such as methyl isobutyltonone or methyl ethyl buttone, preferably methyl isobutyl buttone in the presence of a base such as potassium carbonate. Reacts with dimethyl piperazine. The resulting compound of formula VII is:

Methylation in the secondary amine functionality (suitably by reductive amination with a suitable agent such as formaldehyde, paraformaldehyde, trioxane or diethoxy methane (DEM)) yields a free base of formula (I):

[Formula I]

Alternatively, the methyl group can be introduced by directly using 1,2,2-trimethyl piperazine (Formula VIII) instead of 2,2-dimethyl piperazine when reacting with compound VI, such as compound VI wherein LG is Cl. This reduces synthesis by one step:

Moreover, the piperazine moiety of the molecule can be prepared by the following formula IX, wherein PG is not limited to, for example, phenylmethoxycarbonyl (often referred to as Cbz or Z), tert-butyloxycarbonyl (often BOC). , And a protecting group such as ethoxycarbonyl, or benzyl, may be introduced to react Compound VI to yield Formula X:

After deprotection of the product with VII, methylation as discussed above gives the final product, Compound I. Alternatively, a protecting group such as, for example, ethoxycarbonyl, can be converted directly to the methyl group using a suitable reducing agent, for example lithium aluminum hydride.

During the synthesis, the cis-diastereomeric part of Compound I (ie 4-((1S, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin) It is formed as impurities in the product. 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 VI precipitates and the unwanted trans form of compound VI 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.

When the cis form of compound VI is present in one batch of VI used for the synthesis of compound VII, it is an impurity in VII that is a trans form of compound VII (ie, 4-((1S, 3S) -6-chloro-3- Phenylindan-1-yl) -3,3-dimethylpiperazine); This provides a secondary option to block the cis form of compound I in the final product: The cis form of compound VII is a suitable salt of a compound of formula VII, such as a salt of an organic acid, such as an organic diacid, suitably a compound of formula VII It has been found that after precipitation of the hydrogen fumarate salt or hydrogen maleate salt, it can be removed by recrystallization once more.

Moreover, impurities in the form of cis diastereomers in formula (ie, 4-((1S, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin) Suitable precipitation of compounds of formula (I), for example salts of organic acids such as organic diacids, suitably fumarate salts, for example hydrogen fumarate salts of compounds of formula (I), optionally by one or more recrystallizations It has been found that it can be effectively removed.

In a further aspect the present invention also relates to intermediates as described herein for the synthesis of compounds of formula (I), ie in particular the salts of intermediates Va, VI such as VIa and VII, or compound VII. 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) means that Compound VI to cis diastereomer (e.g., (1S, 3R) -3,5-dichloro-1 when LG = Cl) -Phenylindan) means 55:45 in this mixture), at least 25%, at least 50% of the diastereomer 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, i.e., the compound preferably comprises at least 10% (10% diastereomeric excess is said compound to cis 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.

The present invention also provides compounds VII, preferably at least 60% (60% enantiomeric means that the ratio of VII to its enantiomer is 80:20 in the present mixture), at least 70%, Compounds having an enantiomeric excess of at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%, or salts thereof such as fumarate salts such as hydrogen fumarate, or malate salts, For example hydrogen maleate:

[Formula VII]

One embodiment relates to the diastereomeric purity of compound VII, ie the compound preferably has a ratio of at least 10% (10% diastereomeric excess of compound VII to cis- (1S, 3S) diastereomer 55: 45), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98% of the diastereomer excess. One embodiment relates to substantially pure compound VII or salts thereof.

A further aspect relates to compound I or salts thereof, in particular fumarate, malonate or succinate salts, obtainable by the process of the invention described herein.

A further aspect relates to compound VII or a salt thereof, for example a fumarate salt, obtainable by the process of the invention described herein.

Pharmaceutical use

The physical characteristics of the Compound I salts of the invention refer to it as being particularly useful as a pharmaceutical.

Accordingly, the present invention further relates to succinate salts, in particular hydrogen succinate salts as described herein (for example alpha or beta forms described herein), or malonate salts, in particular hydrogen malonate salts of compounds of formula (I). It relates to a pharmaceutical composition. In addition, the present invention provides medical uses of the 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 psychotic disorders. To the medical use of such salts and compositions for the treatment of disorders, copsychotic disorders, as well as other disorders, including 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 may have a relatively less extracorporeal 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 To succinate or malonate salts, preferably to hydrogen succinate (eg crystalline form alpha) or hydrogen malonate salts of compounds of formula (I).

In a broad aspect, the present invention encompasses administering a therapeutically effective amount of compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt thereof. , Schizophrenic disorders, schizoaffective disorders, delusional disorders, short-term psychotic disorders, co-psychotic disorders or bipolar disorders.

As used herein, the term "trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine", ie (eg, (+) and (-) or The term without any specific indication of the enantiomeric form, using R / S-conversion, is 4-((1R, 3S) -6-chloro-3-phenyl, which is any enantiomeric form of the compound, ie two enantiomers. Indan-1-yl) -1,2,2-trimethylpiperazine (I) or 4-((1S, 3R) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethyl It is meant to refer to one or a mixture of piperazine, such as a racemic mixture. However, in the present context, preferably the content of the enantiomers corresponding to that of compound I is at least 50%, ie at least a racemic mixture, preferably compound I is above the enantiomer.

In the present context for pharmaceutical use, when referring to the enantiomeric form of the compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (eg , When referred to in formula (I), the compound is relatively stereochemically pure as described above, preferably the enantiomeric excess is at least 80% (the 80% enantiomeric ratio of compound I to its enantiomeric Meaning 90:10 in the 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-4-((1S, 3S))-6-chloro-3-phenylindane- 1-yl) -1,2,2-trimethylpiperazine means 95: 5), 95% or more, 97% or more, 98% or more.

In a preferred embodiment, the invention provides a therapeutically effective amount of a compound of formula I [ie 4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethyl Piperazine] or a salt thereof. The present invention relates to a method of treating mania in a schizophrenic disorder, schizophrenia affect disorder, delusional disorder, short-term psychotic disorder, copsychotic disorder or bipolar disorder.

One embodiment of the invention provides a therapeutically effective amount of compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin or a salt thereof, preferably of formula (I) Or a salt thereof, or in a preferred embodiment, of schizophrenia, comprising administering a succinate or malonate salt of a compound of formula I, preferably a hydrogen succinate or hydrogen malonate salt of a compound of formula It relates to the treatment of positive symptoms, negative symptoms of schizophrenia and depressive symptoms.

A further embodiment of the invention provides a therapeutically effective amount of compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt thereof, preferably of formula I Of a positive symptom of schizophrenia, comprising administering a compound of formula I or a salt thereof, or a succinate or malonate salt of a compound of formula I, preferably a hydrogen succinate or hydrogen malonate salt of formula I To a method of treatment.

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

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

A further aspect of the invention provides a therapeutically effective amount of compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt thereof, preferably of formula (I) Manic and / or bipolar, comprising administering a compound or a salt thereof, or in a preferred embodiment, a succinate or malonate salt of a compound of formula I, preferably a hydrogen succinate or hydrogen malonate salt of a compound of formula I It relates to a method of sustained treatment of the disorder.

A further aspect of the invention provides a therapeutically effective amount of compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt thereof, preferably of formula (I) Neuroleptic-induced Parkinsonism comprising administering a compound or a salt thereof, or in a preferred embodiment, a succinate or malonate salt of a compound of formula I, preferably a hydrogen succinate or hydrogen malonate salt of a compound of formula I It relates to the treatment method of.

The present invention further provides a therapeutically effective amount of compound trans-4- (6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine or a salt thereof, preferably a compound of formula I Or a salt thereof, or a preferred embodiment thereof, comprising administering a succinate or malonate salt of a compound of formula (I), preferably a hydrogen succinate or hydrogen malonate salt of formula (I), such as nicotine, alcohol or A method of treating cocaine abuse.

The salts or compositions of the present invention may be administered in a suitable manner, such as orally, orally, sublingually or parenterally and the salts may be in any form suitable for such administration, for example tablets, capsules, powders, syrups or injections. It may be presented in the form of a solution or dispersion. In one embodiment, the salts of the present invention are administered in the form of a solid pharmaceutical, suitably a 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 or from 3 to 55 mg.

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

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

Compound manufacture

analysis

The enantiomeric excess of compound Va in Example 1a was determined by chiral HPLC at 40 ° C. using a CHIRALCEL® OD column of 10 μm, 0.46 cm ID × 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.

The enantiomeric excess of compound Va in Example 1b was determined by chiral HPLC at 205 ° C. with a CHIRALPAK® AD column of 10 μm, 0.46 cm ID × 25 cm L at 21 ° C. 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 × 64.5 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: 50 mbar for 5 seconds, detection: column diode assay detection 192 nm, sample concentration: 500 μg / ml. In this system, compound I has a residence time of about 33 minutes and the other enantiomer has a residence time of about 35 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 이성질체의 함량이 NMR 에 의해 검출될 수 있다. Of compounds I and VII 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.

X-ray powder diffractograms were recorded on a PANalyical X'Pert PRO X-ray diffractometer using CuKl _αl radiation. It measured by the reflection aspect in 2 (theta) -range 5-40 degrees.

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 of main starting materials

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 [

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 its synthesis by Sommer et al., 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 at least 98% enantiomeric excess were combined and evaporated to dryness using a rotary evaporator and then "at vacuum" and dried at 40 ° C. 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- with degradation of 1b enzymatic action 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.

Chemical formula Of I  Hydrogen Fumarate  By precipitation of salts Of I  Synthetic and Sheath  Removal of impurities in the form of diastereoisomers

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 in THF (500 ml) over 1 hour as a solution. 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 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 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 give the title compound as an oil. With a yield of 240 g, it is used directly in Example 5. The cis / trans ratio for 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 cake was washed with toluene (500 ml). The combined filtrate (volume 4.0 L) was 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 a 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. over 20 minutes and essentially cooled. 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 cake 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 Synthesis of -1-yl) -3,3-dimethylpiperazine (VII)

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. Yield is 251 g of the title compound as an oil, which is used directly in the following examples. The cis / trans ratio according to NMR is 82:18.

Example  6 trans-4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethylpiperazinium  (I) hydrogen Fumarate  synthesis

Crude trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (VII) (250 g) was added formaldehyde (37% in water, 300 ml ) And formic acid (366 g), and the mixture was slowly heated to reflux. The mixture was stirred at reflux for 3.5 h and cooled to rt before water (1200 ml) was added. The mixture was extracted twice with ether (1200 ml) and the aqueous phase was then made alkaline by adding sodium hydroxide (28%, about 500 ml). The aqueous phase was extracted three times with ether (900 ml). The organic phases were combined and washed with brine (650 ml) and twice with water (500 ml). The organic phase was dried over sodium sulfate, filtered and evaporated on a rotary evaporator until dry. Yield: 212 g of oil 19% cis diastere according to NMR with trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine free base (I) Has isomers. The compound was dissolved in 1-propanol (3.18 L) and the mixture was heated to 50 ° C. to give a clear solution. Fumaric acid (69.3 g) was added to provide a clear solution. The mixture was cooled to precipitate the title compound. The product was isolated by filtration, washed with 1-propanol and dried at 60 ° C. “in vacuum”. Yield: 182 g, containing cis diastereomer according to NMR of <1%. Elemental analysis and NMR correspond to the structure. According to chiral capillary electrophoresis (CE), the enantiomeric excess is higher than 99%. [a] _D ²⁰ = -22.8 ° (c = 1.0, methanol).

Hydrogen Fumarate  From salt Of I  freedom Amine  Glass and hydrogen Succinate  And reprecipitation as hydrogen malonate salt

Example  7 4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethylpiperazine  Synthesis of Free Base (I)

Trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) hydrogen fumarate (25.0 g) toluene (125 ml ) Was suspended. 25% ammonia water (75 ml) was added. The three phases were stirred until all solids disappeared. The organic phase was separated and the aqueous phase was washed with toluene (25 ml). The combined toluene phase was washed with water (25 ml). The aqueous phase was discarded and the organic phase was dried over dry sodium sulfate and the slurry filtered and evaporated on a rotary evaporator until the filtrate was dried to provide the title compound as an oil. Crude free base (15 g) was used without further purification.

Example  8 trans-4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethyl - Piperazinium  (I) hydrogen Succinate  synthesis

Crude trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin (I) (8,50) obtained as described in Example 7. g of oil) was dissolved in acetone (30 ml). A suspension of succinic acid (3,25 g) in acetone (32 ml) was prepared and trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2- Trimethylpiperazine (I) solution is added, succinic acid is dissolved and thereafter trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2- Trimethylpiperazinium (I) hydrogen succinate was precipitated. The suspension was cooled to 0 ° C. for 90 minutes before the precipitate was isolated by centrifuge. The supernatant was discarded and the precipitate was washed with acetone (20 ml). The slurry was centrifuged and the supernatant was discarded and the precipitate was dried at 50 ° C. under “vacuum”.

Yield 8.56 g.

When the procedure was performed for the first time, the isolated product was in beta form, which in turn produced a more stable alpha form of Compound I hydrogen succinate form.

In the experiments described above, acetone may also be substituted with aqueous acetone (95%) which also leads to the formation of the alpha form I of compound I hydrogen succinate.

Differential Scanning Calorimetry (DSC) shows warm blooded animals having an onset temperature of 140 ° C. and a peak at 141 ° C. corresponding to the alpha form. XRPD diffractograms depend on alpha morphology.

Example  9 Trans-4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethylpipera Zn (I) Hydrogen Malonate

Crude trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin (I) (1.0 g, obtained as described in Example 7) 2.81 mmol) was dissolved in 2-propanol (5 ml). Prepare a malonic acid solution (0.291 g, 2.46 mmol) in 2-propanol (5 ml) and trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2, 2-trimethylpiperazin solution was added to the mixture to thereby transform trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium hydrogen malonate. Precipitated. The suspension was cooled to room temperature until the precipitate was isolated by centrifugation. The supernatant was discarded and the precipitate was washed with 2-propanol (5 ml). The slurry was centrifuged and the supernatant was discarded and the precipitate dried at " vacuum " Yield: 0.98 g (84%). Elemental analysis fits the structure. The X-ray diffractogram corresponds to the diffractogram of the hydrogen malonate shown in FIG. 3.

(VII) Sheath  Salt formation of (VII) to remove diastereoisomers, synthesis of (I) and hydrogen from crude (I) Succinate  Salt formation

Example  10 trans-1-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -3,3- Dimethylpiperazinium  (VII) hydrogen Maleate  synthesis

Examples 2 and 5 were repeated to crude crude-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (VII) as an oil (about 20 g), which was further purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 90: 5: 5) 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 maleic acid solution was added to the solution to pH3 in ethanol. 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). Melting point 175-178 캜.

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

Trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazinium hydrogen maleate (VII) (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.

Example  12 trans-4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethylpiperazine  Preparation of free base (I)

Trans-1-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine (8.9 g) (VII) is dissolved in formic acid (10.5 ml) and the solution To formaldehyde (10.5 ml) was added. Heat to 60 ° C. and hold at this temperature for 2 hours 30 minutes. After cooling the reaction mixture, water (50 ml) and hexane (50 ml) were added. The pH was adjusted to pH> 12 with NaOH (27%, 33 ml). The hexane phase was washed with aqueous NaCl (20 ml) and water (20 ml). Hexane was azeotropically replaced with acetone (90 ml) and the mixture was concentrated. Crude free base in acetone (10 ml) was used without further purification.

Example  13 trans-4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethylpiperazinium  (I) hydrogen Succinate

Crude trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (I) in acetone solution (10 ml). A suspension of succinic acid (3.4 g) in acetone (20 ml) was prepared and trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpipepe Ragin (I) solution was added to heat the mixture to reflux (55 ° C.). Hydrogen succinate while dissolving succinic acid and cooling the solution trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium (I) Began to settle. The suspension was left to settle overnight. Trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazinium hydrogen succinate is isolated by filtration and washed with acetone (20 ml) did. The product was dried "in vacuum" at 60 ° C.

Yield: 7.9 g.

Differential scanning calorimetry represents warm-blooded animals with peaks at 141 ° C. corresponding to an onset temperature of 140 ° C. and alpha form. XRPD diffractograms depend on alpha morphology. [a] _D ²⁰ = -22.0 ° (c = 1.0, methanol).

1,2,2- Trimethylpiperazine  Used Of I  synthesis

Example  14 3,3,4- Trimethylpiperazine Synthesis of 2-one

3,3-dimethylpiperazin-2-one (50 g) was suspended in 1,2-dimethoxyethane (DME) (150 ml) and potassium carbonate (70 g) was added. Methyl iodide (66.4 g) is added for 30 minutes while the mixture is slowly cooled to reach a temperature of 50 ° C. The mixture was stirred for 9 h in a 40-45 ° C. oil bath and samples were taken for NMR which still showed 8% starting material (signal at 2.8 ppm). More methyl iodide (4.6 g) was added and the mixture was stirred at 40 ° C. for another 2 hours and 30 minutes so the new NMR sample showed complete conversion. The mixture was filtered and the filter cake was washed with DME. The filtrate was evaporated to dryness to give 41 g of the title compound. NMR matches the structure.

Example  15 1,2,2- Trimethylpiperazine  synthesis

Lithium aluminum hydride solution in tetrahydrofuran (THF) (1.0 M, Aldrich cat. No. 21,277-6, 90 ml) was heated to 50 ° C. on an oil batch. Crude 3,3,4-trimethylpiperazin-2-one (10 ug) was suspended in THF and slowly added to generate a gas. The resulting mixture was stirred at 45-56 ° C. for 4 hours and the title compound according to NMR (no 1.2 ppm signal from starting material) was converted completely. The mixture was cooled and water (3.3 ml) was added to generate a gas. Then water (15%, 3.3 ml), sodium hydroxide solution was added to provide more gas, and finally water (10 ml). The mixture was filtered and the filter cake was washed with THF (100 ml). The filtrate was concentrated on a rotary evaporator (60 at 0.3 atm. And water batch). The residue was dissolved in THF (200 ml) and dried over sodium sulfate, then the mixture was filtered and the filtrate was concentrated on a rotary evaporator (60 ° C. at 0.2 atm and water batch) to give 6.4 g of the title compound. NMR conforms to the structure and the material contains some THF.

Example  16 trans-4-((1R, 3S) -6- from compound VI Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethylpiperazinium  (I) hydrogen Fumarate  synthesis

Using the procedure described in Example 5, cis- (1S, 3S) -3,5-dichloro-1-phenylindane (VI with LG = Cl) (17.8 g) was distilled from 1,2,2-trimethylpiperazine. (VIII) (8.7 g). A raw material (15.7 g) of free amine containing 6% cis isomer was used to form the hydrogen fumarate salt using the procedure of Example 6. Yield 15.7 g of the title compound; NMR conforms to the structure and no cis isomers are observed.

Compound I Hydrogen Succinate  Synthesis of Crystalline Beta Forms of Salts

Example  17 trans-4-((1R, 3S) -6- Chloro -3- Phenylindan -1-yl) -1,2,2- Trimethyl - Piperazinium  (I) hydrogen Succinate , Beta form synthesis

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

Analysis Results: Differential Scanning Calorimetry (DSC) showed warm-blooded animals with peaks at 137.5 ° C, corresponding to an initiation temperature of 135.6 ° C and the beta form. XRPD follows the beta form.

Salt Features

Example  18 Chemical Formula Of I  Solubility of Salts in Compound

The solubility of salts in water was measured by adding excess (50 mg) of salt to 2 ml of water. The suspension was left in a rotarmix for at least 24 hours and subsequently the pH was measured and the concentration was determined by HPLC. The solid precipitate was isolated and left dry in the laboratory. The results are summarized in Table 1.

Solubility of salts in water at room temperature sample pH Solubility (mg / ml) Succinate 1: 1 Alpha 4.4 13 Malonate 1: 1 3.9 15 Fumarate 3.8 1.5

Example  19 Formula Of I  Solubility of Salts in Compound

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

Heat, 60 ° C./80% RH: Samples were stored at 60 ° C. at 80% RH for 1 week. It was then dissolved and analyzed by HPLC.

Heating, 90 ° C .: Samples (˜10 mg) were stored at 90 ° C. in a closed vessel containing 1 drop of water. It was then dissolved and analyzed by HPLC.

Light: Samples were placed in a light cabinet at 250 w / m ² for 24 hours. It was then dissolved and analyzed by HPLC.

The area of the peak in the chromatogram is summarized except for the peak corresponding to the substance or acid. The succinate salt of the present invention did not decompose at all.

sample Sum of Impurity Peak Area% 60 ℃ / 80% RH 90 ℃ Light Malonate 1: 1 Alpha 0 6.19 0.06 Succinate 1: 1 0 0 0 Fumarate 0.07 0.09 0.06

Example  20 Chemical Formula Of I  Hygroscopicity of Salts of Compounds

Hygroscopicity of fumarate salt, succinate salt (alpha form) and malonate salt was investigated by Dynamic Vapor sorption (DVS). Fumarate and succinate salts were found to be non-hygroscopic. Malonate gradually absorbed up to 1% water when the relative humidity rose to 95% but no hysteresis occurred.

Claims (46)

A succinate salt or malonate salt of a compound of formula [Formula I]

[Trans-4-((1R, 3S) -6-chloro-3-phenylindan-1-yl))-1,2,2-trimethylpiperazin].  The succinate salt of claim 1 which is a hydrogen succinate salt of the compound of formula (I). Crystalline hydrogen succinate salt of compound I as defined in claim 1. The salt according to claim 3, which is in crystalline form alpha. The salt according to claim 3 or 4, wherein the crystalline form is characterized by an X-ray powder diffractogram corresponding to FIG. 1. The salt according to any one of claims 3 to 5, characterized by the X-ray powder diffractogram obtained using CuK _αl radiation (λ = 1.5406 Hz) exhibiting a peak at the following 2θ-angles: 9.36; 10.23; 11.81; 13.45; 16.21; 16.57; 17.49; 18.89; 19.20; 19.63; 20.01; 20.30; 21.15; 21.53; 21.93; 22.34; 24.37; 25.34; 27.27; 29.65. The salt according to claim 3, wherein the crystalline form is characterized by having a DSC record indicating a warm blooded animal having an onset temperature of about 139-141 ° C. 8. The malonate salt of claim 1 which is a hydrogen malonate salt of a compound of formula (I). Crystalline hydrogen malonate salt of compound I as defined in claim 1. 10. The crystalline salt of claim 9, wherein the crystalline form is characterized by an X-ray powder diffractogram shown in FIG. The crystalline salt according to claim 9 or 10, characterized by the X-ray powder diffractogram obtained using CuK _αl radiation (λ = 1.5406 Hz) in which the crystalline form shows a peak at the following 2θ-angles: 8.3; 10.6; 11.5; 12.8; 14.2; 14.5; 14.7; 15.8; 16.5; 17.4; 17.6; 18.0; 18.6; 19.2; 21.2; 22.0; 22.9; 23.7; 24.7; 28.8. A pharmaceutical composition comprising a salt according to any one of claims 1 to 11 together with one or more pharmaceutically acceptable carriers, fillers or diluents. The salt according to any one of claims 1 to 11 for use in medicine. Disorders comprising psychiatric symptoms, anxiety disorders, affective disorders including depression, sleep disorders, migraine, neuroleptic-induced Parkinsonism, or abuse disorders such as cocaine abuse, nicotine abuse or alcohol abuse Use of a salt according to any one of claims 1 to 11 in the manufacture of a medicament for treatment. Use of a salt according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of schizophrenia or other psychiatric disorders. Claims 1 to 11 in the manufacture of a medicament for the treatment of diseases selected from the group consisting of schizophrenia, schizophrenic disorders, schizophrenia disorders, delusional disorders, short-term psychotic disorders, co-psychotic disorders, and bipolar disorders. Use of salts according to any of the preceding claims. Use of a salt according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of one or more schizophrenia, positive and negative symptoms. 4-((1R, 3S) -6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazine (Formula I) or a salt thereof, wherein the cis configuration A process comprising converting a compound of to a compound of formula (I) [Formula Va]

[Formula I]

19. The process of claim 18 comprising converting the alcohol group of the cis-alcohol of formula Va to a suitable leaving group LG to provide a compound of formula VI. [Formula VI]

20. The process according to claim 19, wherein LG is halogen, such as Cl, Br, preferably Cl or sulfonate. 21. The method of claim 19 or 20, wherein compound VI is precipitated from a suitable solvent. 22. The process according to claim 21, wherein LG is halogen, preferably Cl and the solvent is an alkane such as heptane. 23. The method of any one of claims 19-22, wherein compound VI is reacted with 2,2-dimethylpiperazine to yield a compound of formula [Formula VII]

The method of claim 23 comprising methylating in secondary amines to obtain free base of the compound of formula (I). The method of claim 23 or 24, wherein the compound of formula VII is precipitated as a suitable salt, such as a salt of an organic acid such as organic diacid. The method of claim 25, wherein the salt formed is a hydrogen fumarate salt or hydrogen maleate salt of compound VII. 23. The method of any one of claims 19-22, wherein compound VI is reacted with 1,2,2-trimethylpiperazine (VIII) to give the free base of the compound of formula (I): [Formula VIII]

The method of claim 20, wherein the method comprises the following steps: Reacting compound VI with 1-protected 2,2-dimethylpiperazine (compound IX below), wherein PG is a protecting group to obtain a compound of formula (X); Deprotecting compound X to afford compound VII or converting compound X directly to compound I: [Formula IX]

[Formula X]

29. The process of claim 28, wherein the protecting group PG is selected from the group of phenylmethoxycarbonyl, tert-butyloxycarbonyl, ethoxycarbonyl and benzyl. A compound of formula (I) comprising reacting a compound of formula (VIa) (ie, a compound VI wherein LG is Cl) with 2,2-dimethylpiperazine to give a compound of formula (VII), followed by methylation in a secondary amine Or a method for preparing the salt thereof. In the presence of a base, a compound of formula VIa (i.e., compound VI wherein LG is Cl) is reacted with 2,2-dimethylpiperazine, followed by a suitable reagent such as formaldehyde, paraformaldehyde, trioxane or diethoxymethane A process for preparing a compound of formula (I) or a salt thereof, comprising reductive amination and then isolating the compound of formula (I) as a free base or salt thereof. [Formula VIa]

A process for preparing 4-((1R, 3S)-(6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperazin (Formula I) or salts thereof, as defined in claim 23. A method comprising converting a compound of Formula VII to a compound of Formula I. 33. The process according to any one of claims 18 to 32, in which the compounds of formula (I) are precipitated as suitable salts, such as salts of organic acids such as organic diacids, in order to remove unwanted cis-diastereomers. 35. The process of claim 34, wherein the salt formed is the hydrogen fumarate salt of compound I. 35. The method of any one of claims 18 to 34 comprising preparing a succinate salt as defined in any of claims 1-7. 36. The process of claim 35, wherein the compound I hydrogen succinate is prepared in a tonton solvent, preferably acetone, such as aqueous acetone. 35. A method according to any one of claims 18 to 34 comprising preparing a malonate salt as defined in any one of claims 1 or 8 to 11. 38. The process of claim 37, wherein compound I hydrogen malonate is prepared in an alcoholic solvent such as 2-propanol. 39. The method of any one of claims 18 to 38, comprising converting the free base of the compound of formula (I) to a salt as defined in any one of claims 1-14. 40. The free base of the compound of formula (I) according to claim 39, wherein the base of formula (I) obtained is first isolated as its fumarate salt, optionally recrystallized one or more times, and then the fumarate salt is treated with a base to Liberation and then converting it to its succinate or malonate salt. 30. A free base or salt thereof, such as a succinate salt as defined in any one of claims 1-7 or any of claims 8-11. The method of following isolation of a compound of formula I as a malonate salt as defined in A compound having the structure

Compound VI having the structure:

Wherein LG is a latent leaving group selected from the group consisting of, for example, halogen, eg Br or Cl, preferably Cl or sulfonate. Compound VII or a salt thereof having the structure as follows.

45. The compound of any one of claims 42-44, wherein the compound is substantially pure. 42. The method of any one of claims 18-31 or 33-41, wherein compound Va is obtained by cleavage of the enzymatic action of compound V.

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