UA110526C2 - Deuterated 1-piperazino-3-phenylindanes for the treatment of schizophrenia - Google Patents

Abstract

Vinakhid must be able to deuterate 1-pyrazine-3-phenylindane and salts; it is possible to have an active appearance of D- and D-receptors, and 5HT2 receptors must be activated, so that they should be activated of such compositions in case of a seizure of the central nervous system and before methods of seizure, such as include the introduction of such spoils.

Description

Priority is claimed to this application from U.S. Provisional Patent Application Mo. 61/498651, filed Jun. 20, 2011, and U.S. Provisional Patent Application Mo. 61/537103, filed Sep. 21, 2011, the entire content of each of which is incorporated herein by reference. description by reference.

All patents, patent applications and publications cited in this specification are therefore incorporated by reference in their entirety. The descriptions of these publications, in their entirety, are hereby incorporated by reference into this application in order to more fully describe the state of the art known to those skilled in the art as of the date of the present invention described and claimed in this application.

The field of technology to which the invention belongs

This invention relates to deuterated 1-piperazino-33-phenylindanes and their salts with activity against O.- and O-receptors of dopamine, as well as against 5HT"-receptors of serotonin in the central nervous system, to medicinal products that contain such compounds as active ingredients, and to the use of such compounds in the treatment of diseases of the central nervous system.

Prior art

References to various publications are made with reference to their full content elsewhere in this application.

The disclosures of these publications are therefore incorporated by reference in this application for a more complete description of the state of the art to which the present invention relates. 4-(18,35)-6-Chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and its salts, pharmaceutical compositions containing these salts, and medical uses of the foregoing, including the treatment of schizophrenia or other diseases that include psychotic symptoms described in

MO2005/016900. 4-(18,35)-6-Chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine has the general formula (X), hereinafter referred to as compound (X). rn, on which (Fk 7 (X) 25 .

EP 638073 describes a group of trans-isomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- or 3-position of the piperazine ring. These compounds are described as having high affinity for dopamine 0- and 12-receptors and 5-HT2-receptors and are believed to be useful in the treatment of certain central nervous system diseases, particularly

From schizophrenia.

The enantiomer of the above formula (X) was described by Vedeb5o et al. in 0 May. Spet., 1995, 38, pages 4380-4392, in the form of a fumarate salt, see Table 5, compound (-)-38. In this publication, it was concluded that the (-)-enantiomer of compound 38 is a potent O1/O2- antagonist, which exhibits some O-selectivity of the compound 38. This compound is also described as a potent 5-HT antagonist. It is also indicated that this compound does not induce catalepsy in rats.

The etiology of schizophrenia is unknown, but the dopamine hypothesis of schizophrenia (Sagi55op, At. ").

Rzusniaiu 1978, 135, 164-173), formulated in the early 1960s, provided a 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, a view supported by the fact that all antipsychotic drugs on the market today show some antagonism at the dopamine Y2 receptor (Zeetap Zsiepse apa Medisipe 1995, 2, 28-37). However, while it is generally accepted that antagonism of dopamine receptors in the limbic regions of the brain plays a key role in the treatment of positive symptoms of schizophrenia, blockade of the receptors in the striatal regions of the brain causes extrapyramidal symptoms (ERP). As described in EP

638073, a profile of mixed inhibition of O1/O2 dopamine receptors was observed with the use of some so-called "atypical" antipsychotic compounds, in particular clozapine (8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzoyl|p,e| P1,4|diazepine), used in the treatment of patients with schizophrenia.

In addition, selective antagonists O; were associated with the treatment of sleep disorders and alcohol addiction (OM Eaeg, Sigtepi Oripiop ip Ipmeziyadabnopai! Ogydv, 2002 3(2):284-288).

Dopamine can also play an important role in the etiology of affective disorders (R. UmMiipeg,

Why? Be5. Neu. 1983, 6, 211-224, 225-236 and 237-246; Vodezo ei ai., U Med. Spet., 1985, 28, 1817-1828).

EP 638073 describes how compounds having affinity for 5-HT receptors, in particular 5-HTα receptor antagonists, have been proposed for the treatment of various diseases such as schizophrenia, including negative symptoms in patients with schizophrenia, depression, anxiety, sleep disturbances, migraine attacks and neuroleptic-induced parkinsonism. It was also suggested that antagonism of 5-HTgda receptors reduces the frequency of extrapyramidal side effects caused by classic neuroleptics (Vaizaga ei a. Rhusporpagtasyodu 1979, 62, 67-69).

Isotopic substitution of one or more hydrogen (H) atoms by deuterium (0) atoms in a compound can cause a kinetic isotope effect that can affect the rate of a reaction, for example, the metabolism of the compound. This is especially true when the isotopic substitution is in a chemical bond that breaks or forms at the rate-limiting stage. In this case, the replacement is called the primary isotope effect. When the isotopic substitution(s) is not involved in one or more of the bonds being broken, then a smaller change in rate can be observed, called the secondary isotope effect.

The essence of the invention

This invention relates to compounds in which one or more hydrogen atoms (H) in one or more metabolic sites MI, M2 and M3 of compound (X) are replaced by deuterium (0) atoms.

In one aspect, the present invention relates to a compound of formula B: in b2 in pa

Be si | It's about ve

He v' ve (SO where K!-V'? independently represent hydrogen or deuterium and where at least one of K/-V'O

Zo contains at least about 5095 deuterium, or a pharmaceutically acceptable acid addition salt thereof.

In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (B) and one or more pharmaceutically acceptable carriers, diluents or excipients.

In another aspect, the present invention relates to the use of a compound of formula (U) or a pharmaceutical composition containing a compound of formula (U) in the treatment of psychosis, other diseases that include psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms.

In yet another aspect, the present invention relates to the manufacture of a medicament containing a compound of formula (U) for the treatment of psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms.

In yet another aspect, the present invention relates to methods of treating psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms, which comprise administering an effective amount of a compound of formula (B) or a pharmaceutical composition containing the compound formula (U), to a subject in need of such treatment.

In yet another aspect, this invention relates to a compound of formula (Fe)

SI C in; o o c) o (5)-(ХУ).

In yet another aspect, this invention relates to a method of obtaining a compound of formula (F)

SI S

Iv) o o c) o (5)-(XM), which includes the treatment of the compound (KHM) with the compound ((5)-VIMARIVN()VE i.

In yet another aspect, the present invention relates to a process for the preparation of the tartrate of compound (18,35)-(IM), which includes treatment of racemic trans-1-(b-chloro-3-phenyl(α5)-indan-1-yl)-1 (dz),2,2-trimethylpiperazine with 1--(--)-tartaric acid.

In addition, other objects and advantages of the invention will become apparent to those skilled in the art from the description of the invention provided herein, which is merely illustrative and not limiting of the invention.

Thus, specialists in this field of technology will recognize other implementation options that do not go beyond the essence and scope of the present invention.

Brief description of illustrative materials

On fitg. 1 shows the main metabolic sites of compound (X).

In fig. 2 shows compound (I) and compound (XI), each in the form of the (1K,35)-enantiomer.

In fig. C shows the NMR spectra of compound (II) and compound (M). Separate sections of the C NMR spectra with proton decoupling and proton and deuterium decoupling of compound (II) are shown in Fig. ZAI and compounds (M) Ifig. ZVI

In fig. 4 shows the mass spectrum of the compound (IM).

In fig. 5 shows the formation of a metabolite compound (XI) as a result of the metabolism of compound (X) and compound (ID (0.1 μM) in cryopreserved hepatocytes of a dog (p-2, vertical segments represent maximum and minimum results).

In fig. 6 shows the formation of a metabolite compound (XI) as a result of the metabolism of compound (X)

Zo and compounds (I) (1 µM) in cryopreserved dog hepatocytes (p-2, vertical segments represent maximum and minimum results).

In fig. 7 shows the formation of a desmethyl metabolite as a result of the metabolism of compounds (II), (IM) and (X) (1 μm) in human liver microsomes (p-3, vertical segments represent the standard deviation).

In fig. 8 shows the formation of a desmethyl metabolite as a result of the metabolism of compounds (II), (IM) and (X) (10 µM) in human liver microsomes (p-3, vertical segments represent the standard deviation).

In fig. 9 shows the formation of a desmethyl metabolite as a result of the metabolism of compound (II) (10

MKM) in human liver microsomes (p-3, vertical segments represent the standard deviation).

In fig. 10 shows the formation of a desmethyl metabolite as a result of the metabolism of compound (M) (10

MKM) in human liver microsomes (p-3, vertical segments represent the standard deviation).

In fig. 11 shows the formation of a desmethyl metabolite as a result of the metabolism of the compound (MI) (10 μM) in human liver microsomes (p-3, vertical segments represent the standard deviation).

In fig. 12 shows the formation of a desmethyl metabolite as a result of the metabolism of the compound (MII) (10 μM) in human liver microsomes (p-3, vertical lines represent the standard deviation).

In fig. 13 shows the chemical structure of compounds (I) - (MII), (X) - (XI) and (XIX) - (XXI).

In fig. 14 shows the formation of a desmethyl metabolite as a result of the metabolism of compounds (II) and (X) (10 μM) using recombinant SMUR2C19 human liver (n-3, standard deviation).

In fig. 15 shows the formation of a desmethyl metabolite as a result of the metabolism of compound (IM) and compound (X) (1 µM) using recombinant human liver SUR2C19 (p-3, vertical segments represent the standard deviation).

In fig. 16 shows PCP-induced hyperactivity in mice for compound (IM).

In fig. 17 shows the cataleptic response in rats for compound (IM).

In fig. 18 shows the X-ray diffractograms of two batches of the hydrotartrate salt of the compound (IM).

Detailed description of the invention

Atypical antipsychotics have been the subject of numerous studies in the pharmaceutical industry and have shown promise in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, dementia, anxiety disorder, and obsessive-compulsive disorder (OCD). The mechanism of action of these agents remains unknown; however, all antipsychotics act to some extent on the dopamine system. Most atypical antipsychotics show activity against dopamine receptors of subtypes 1 and 2 (0; and Ог, respectively) and against serotonin receptors of subtype 2 (5-HT2). In some cases, the definition of "atypical" has been assigned to antipsychotics that do not cause extrapyramidal side effects; however, it has been shown that

Some atypical antipsychotics still cause extrapyramidal side effects, although to a lesser extent than such effects are observed in typical antipsychotics (publication UUeidep, R.., "ERB rgoiyev: She aiurisai! apiirzusnoiszv age poi aiI She zate" U. Rzuspiaig 2007, 13(1): 13-24; this publication is incorporated herein by reference in its entirety). Approved atypical antipsychotics include, for example, amisulpride (5oiiiap), aripiprazole (Abiiu), asenapine (Zarpgi5), blonanserin (I opazep), clothiapine (Epishtipe), clozapine (Siolagi), iloperidone (Rapar)u, lurasidone (I ashaa), mozapramine (Stetip), olanzapine (7urgeha), paliperidone (Ipleda), perospirone (Pap), quetiapine (Zegodie!), remoxipride (Kohiat), risperidone (Kizhregaai), sertindole (Zegaoyesi), supliride (Ziirigid, Ediopui), ziprasidone ( Seodop, 7eiYidoh) and zotepin (MiroIer). Several other such antipsychotics are currently under development. Since the mechanism of action of atypical antipsychotics is not well known, the side effects associated with these drugs were difficult to plan. Thus, there is a need for additional antipsychotic therapies with the potential for reduced side effects and/or an improved therapeutic profile relative to existing therapies.

In one aspect, the present invention relates to compounds in which one or more hydrogen atoms (H) in one or more of the metabolic sites MI, M2 and M3 of compound (X) have been replaced by deuterium (0) atoms. Compound (X) and its variants are described, for example, in US patents MoMo 5807855; 7648991; 7767683; 7772240; 8076342; US patent publications MoMo 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; MO 2005/016900; ER 0638073 and U Med. Spent 1995, 38, 4380-4392; and each publication is incorporated herein by reference in its entirety.

The kinetic action of the isotope can potentially affect the rate of metabolism in one or more of the metabolic sites MI, M2 and M3 shown in Figure 1. The authors of the present invention have identified three main metabolic sites of 4-(1А8,35)-6-chloro-3-phenylindan -1-yl)-1,2,2-trimethylpiperazine (compounds (X)), designated as MI, M2 and M3 and shown in figure 1.

Deuteration of a compound at a site subject to oxidative metabolism may in some cases reduce the rate of metabolism of the compound due to the primary isotope effect. If the C-H bond cleavage step is the rate-limiting step, a significant isotope effect can be observed. However, if other steps affect the rate of metabolism of the compound, then the C-H bond cleavage step is not the rate-limiting step and the isotope effect may be of little importance. In addition, a negative isotope effect can be observed when the reaction rate increases with deuterium substitution. Thus, the incorporation of deuterium at a site subject to oxidative enzymatic metabolism has unpredictable effects on pharmacokinetic characteristics (see, for example, U.S. Pat.

USA Mo 7678914; Abomination Meiab. Oizrov5. 1986, 14, 509; Agsp Tohisoi! 1990, 64, 109; Yippee Atsp. Ossyr.

Epmigop. Neanky 1993, 65 (Zirri. 1): 5139, each publication incorporated herein by reference in its entirety). The effect of deuterium incorporation is unpredictable and does not exist in many drugs or classes of drugs. Reduced metabolic clearance was observed for some deuterated compounds relative to non-deuterated derivatives, while the metabolism of other compounds was not affected. Examples of studies indicating a lack of predictability regarding the inclusion of deuterium include US Pat. No. 6,221,335; 9. Rpagt.

All together. 1975, 64, 367-391; Hell Disgust Rev. 1985, 14, 1-40; In Med. Spent 1991, 34, 2871-2876; Sap. 9.

RNUzio!Y. Rnaptasoi 1999, 79-88; 5imeptap, V. V., Te Ogdapis Spetivigu oi Ogyd Oevzidp apa Ogpa

Asiip, 279 ha. (2004), 422; Sy. Orip. Oga Oeu. 2006, 9, 101-109; Spetis! Nev. Toh. 2008, 1672;

Nagbezop, 5.Yi. apa Tipo, K.O. "Oeshegisht ip Ogyd Oizsomegu apa OemeIortepi", in App. Ker. Mea.

Spent 2011, 46, 404-418; each publication is incorporated herein by reference in its entirety. Even the incorporation of deuterium into known metabolic sites has unpredictable effects on the metabolic profile. Metabolic switching can result in the metabolic profile of a particular drug changing as a result of deuterium incorporation, thus leading to different proportions of metabolites (or different metabolites) than the profile observed in the non-deuterated counterpart of the same drug.

The new metabolic profile may lead to a specific toxicological profile of the deuterated analogue. Adding to the potential complications of deuterium incorporation is the possibility of deuterium/hydrogen exchange in a physiological environment (Adu. Ogyd. Ke5. 1985, 14, 1-40; this publication is incorporated herein by reference in its entirety).

In some embodiments, isotopic substitution of one or more hydrogen atoms in compound (X) with deuterium atoms creates a kinetic isotope effect that affects metabolic rate.

Isotopic substitution of hydrogen atoms in compound (X) by deuterium atoms leads to less metabolism of the deuterated compound, which has been shown to occur in dog hepatocytes, in which,

For example, an approximately 5095-fold decrease in the formation of the desmethyl metabolite (compound (XI)) from compound (I) (Figure 2) was observed compared to the formation of compound (XI) due to the metabolism of compound (X).

Deuteration of free phenyl, optionally in combination with deuteration of the 1-methyl group (compounds (II) and (M)), unexpectedly reduces the amount of desmethyl metabolite produced in human liver microsomes, compared to the non-deuterated compound (compound (X)). Also, unexpectedly, deuteration of the 1-methyl group affected metabolism in dog hepatocytes, but not in human hepatocytes, thus indicating the unpredictability of the effect of deuteration on pharmacological properties.

The effect of reduced metabolism is higher bioavailability of the deuterated parent compound and less metabolite formation. Without being bound by any theory, based on the results described in the experimental part of this application, it is expected to see the same effect after several administrations of doses to humans, which allows to administer lower doses to humans, that is, to put less burden on the whole body, for example, the liver, and administer doses less often.

It is known that the desmethyl metabolite (compound (XI)) has an affinity for PEX and, thus, potentially contributes to the prolongation of SS. As indicated above, deuteration of free phenyl, optionally in combination with deuteration of the 1-methyl group (compounds (II) and (IM)), unexpectedly reduces the amount of desmethyl metabolite produced in human liver microsomes, compared to the non-deuterated compound (compound (X )). Accordingly, and without being bound by any theory, it is believed that there will be less interaction with the PECOS channel and, consequently, lower cardiac burden when dosing deuterated variants of compound (X) (eg, compounds of formula (Y)) compared to dosing compounds (X).

This invention is further described in detail in the illustrative embodiments presented herein.

Definition

The term "compound(s) of the invention" as used herein means compounds (U), (I), (1), (11), (IM), (M), (MI) and/or (MI) and may include their salts, hydrates and/or solvates. The compounds of the present invention are obtained in various forms, such as salts, hydrates and/or solvates, and the invention includes compositions and methods covering all variant forms of these compounds.

The term "composition(s) of the invention", as used herein, means compositions that contain compounds (U), (), (1), (PI, (IM), (M), (MI) and/or (MII) or salts, hydrates and solvates thereof.The compositions of the invention may additionally contain one or more chemical components, such as, for example, excipients, diluents, fillers or carriers.

The term "method(s) of the invention" as used herein means methods involving treatment with compounds and/or compositions of the invention.

As used herein, the term "approximately" is used herein to mean approximately, around, near, near, or in the range. When the term "approximately" is used in conjunction with a numerical range, it modifies that range by extending above and below the specified numerical values. In general, the term "about" is used in this description of the invention to change the numerical values above and below the specified value by 20 percent up or down (higher or lower).

The term "effective amount", "sufficient amount" or "therapeutically effective amount", as used herein, means an amount of a compound that is sufficient to achieve beneficial or desired results, particularly clinical results. As such, an effective amount may be sufficient, for example, to reduce or alleviate the severity and/or reduce the duration of the lesion or disease or one or more of its symptoms, prevent the development of conditions associated with the lesion or disease, prevent recurrence, development or the occurrence of one or more symptoms associated with the lesion or disease, or the enhancement or otherwise improvement of the prophylactic or therapeutic action(s) of another therapy. An effective amount also includes that amount of the compound that prevents or substantially attenuates the undesirable side effects.

As used herein and well known in the art, the term "treatment" is an approach to obtain beneficial or desired results, including clinical results.

Beneficial or desired clinical results may include, but are not limited to, amelioration or reduction in the intensity of one or more symptoms or diseases, reduction in disease severity, stabilization (i.e., not worsening) of a disease state, prevention of disease progression, delay or slowing of disease progression, improvement or temporary alleviation of the pathological condition and remission (either partial or complete), detectable or not detectable. The term "treatment" can also mean prolonging survival compared to expected

With survival without treatment.

The term "in need thereof" refers to the need for symptomatic or asymptomatic relief of a disease such as, for example, psychosis or a psychotic disorder. A subject in need thereof may or may not be subject to treatment for diseases associated with, for example, psychosis or a psychotic disorder.

The term "carrier" refers to the diluent, adjuvant, excipient, or filler with which the compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids such as water, oils and oils, including oils derived from petroleum, animal fats, vegetable oils, or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like similar Pharmaceutical carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, and the like. In addition, you can use auxiliary, stabilizing agents, thickeners, lubricating agents and dyes. Other examples of suitable pharmaceutical carriers are described in the publication Keptipdiop: Te 5sieeepse apa

Rgasiise oi Rnaptasu, 2151 Ediiop (Opimegeiu oi Te Zsiepsevs ip Rpyadei!rnia, ed., Girripsoi M Patv a MMIKip5 2005), this publication is incorporated into this description by reference in its entirety).

The terms "animal", "subject" and "patient" as used herein include all members of the animal kingdom, including but not limited to mammals, animals (eg, cats, dogs, horses, pigs, etc.) and people

The term "isotopic variant", used in this description of the invention, means a compound obtained by replacing one or more hydrogen atoms in the original compound, which does not contain deuterium atoms, with deuterium atoms.

It is known that in most synthetic compounds the elements are present in the natural ratio of their isotopes, which leads to the inherent natural inclusion of deuterium.

However, the natural isotopic abundance of hydrogen isotopes such as deuterium is negligible (approximately 0.01595) relative to the degree of permanent isotopic substitution of the compounds described herein. Thus, as used herein, the designation of an atom as deuterium in a particular position indicates that the deuterium content is significantly greater than the natural deuterium content. Any atom not specified as a specific isotope is intended to be any stable isotope of that atom, as would be apparent to one of ordinary skill in the art. because Compounds (U) are isotopic variants of compound (X).

In some embodiments, compounds (1), (1), (I), (IM), (M), (MI) and (MI) are isotopic variants of compound (X).

MI is a site of compound (X) susceptible to metabolism; MI consists of -СНе- in the 6-position of piperazine of compound (X).

M2 is a site of the compound (X) susceptible to metabolism; M2 consists of methyl bonded to M piperazine compound (X).

M3 is a site of compound (X) susceptible to metabolism; MZ3 consists of the phenyl group of compound (X).

A parent compound is a chemical compound that is the basis for its derivatives obtained either by substitution or decomposition, for example, metabolic decomposition. In the context of the present invention, the starting compound is an active pharmaceutical ingredient (API).

In some embodiments, any hydrogen atom not labeled as deuterium has its natural isotopic abundance. In some embodiments, any hydrogen atom not labeled as deuterium has a deuterium isotopic abundance of less than 195.

In one aspect, this invention relates to a compound of formula (U) in y-v2 pa

Ky

SI | 09) wherein K'-B'E is independently hydrogen or deuterium, and at least one of K/-B'O contains at least about 5095 deuterium, or a pharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention relates to a pharmaceutical composition containing a compound of formula (U) and one or more pharmaceutically acceptable carriers, diluents or excipients.

In another aspect, the invention relates to the use of a compound of formula (Y) or a pharmaceutical composition containing a compound of formula (Y) in the treatment of psychosis, other diseases that include psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms.

In yet another aspect, the invention relates to the manufacture of a medicament containing a compound of formula (U) for the treatment of psychoses, other diseases involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms.

In yet another aspect, the present invention relates to methods of treating psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms, comprising administering an effective amount of a compound of formula (B) or a pharmaceutical composition comprising the compound formulas (7: shchi | i

In some embodiments, the compound is racemic. In some embodiments, the compound is enantiomerically enriched.

In some embodiments, the compound is selected from the group consisting of id , (1K,35)-(), Y ro (1K,35)-(01), , (1K,35)-(PT), Y | (1K,35)-(1X), u. (12.35)-(U), and | (1835)-SU1U,

t

Ku si | No

IV) c) c) c) c) (1K,35)-(MP).

In some embodiments, implementation of K' and K? represent deuterium, KZ-V? are deuterium or KU-VIE are deuterium.

In some variants of the implementation of K' and B? are deuterium. In some embodiments, the implementation of E! and KE? are deuterium and EZ-A? are hydrogen.

In some variants of the implementation of KZ-B? are deuterium. In some embodiments

VzZ-A? are hydrogen.

In some embodiments, the implementation of K-T? are deuterium. In some embodiments, K5-B'Z is deuterium and KZ-B" is hydrogen.

In some embodiments, K!-A" is deuterium.

In some embodiments, EC", B2 and K9-B/o are deuterium.

In some embodiments, the KZ-VE is deuterium.

In some embodiments, K!-VE is deuterium.

In some embodiments, the compound is a compound of formula

WITH

"M

SI | Her o or or or

Y (1K,35)-(P) o - ? or a compound of the formula o|B; in-

WITH

WITH"

SI | IS

IV),

IN);

IN); y y (15.35)-0U).

In some embodiments, the compound is a compound of the formula SE g

SI | AND

C)

C)

Ів) и о (18,35)-(P).

In some embodiments, the compound is a compound of formula c) on c| H ,, (12.35)-(P).

In some embodiments, the compound is a compound of the formula IV)

IN-

With them

SI | She

Iv);

Eve; o c) p (1K,35)-(1X).

In some embodiments, the compound is a compound of the formula p c) y-c) na

Ve

SI | No: (1K,35)-(X).

In some embodiments, the compound is a compound of the formula о IV) y-

IV) and /-

SI

C)

C)

C)

Iv) p (1K,35)-(M I).

In some embodiments, the compound is a compound of the formula: N

C)

C)

C)

Iv) c) (1K,35)- (MP).

In some embodiments, at least about 7595 of the compound has a deuterium atom at each position where it is labeled as deuterium, and any atom not labeled as deuterium is present in approximately the natural relative ratio of its isotopes.

In some embodiments, at least about 8595 compounds have a deuterium atom at each position where it is labeled as deuterium, and any atom not labeled as deuterium is present in approximately the natural relative ratio of its isotopes.

In some embodiments, at least about 9095 compounds have a deuterium atom at each position where it is labeled as deuterium, and any atom not labeled as deuterium is present in approximately the natural relative ratio of its isotopes.

In some embodiments, the compound is a salt selected from the group consisting of fumarate, maleate, succinate, and tartrate. In some embodiments, the compound is a fumarate salt. In some embodiments, the compound is a hydrofumarate salt. In some embodiments, the compound is a maleate salt. In some embodiments, the compound is a hydromaleate salt. In some embodiments, the compound is a succinate salt. In some embodiments, the compound is a hydrosuccinate salt. In some embodiments, the compound is a tartrate salt. In some embodiments, the compound is a hydrotartrate salt.

In some embodiments, the compound is a hydrotartrate salt of compound (1K,35)-(IM).

In some embodiments, the psychosis or disease comprising psychotic symptoms is schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, transient psychotic disorder, dissociated psychotic disorder, bipolar disorder, or mania in bipolar disorder. In some embodiments, the psychosis or disease including psychotic symptoms is schizophrenia.

In some embodiments, the methods additionally include administration of one or more antipsychotic agents.

In some embodiments, implementation of the application further includes the administration of one or more antipsychotic agents.

In some embodiments, the neuroleptic agent is selected from the group consisting of

Of sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and ozanetant.

In some embodiments, administration is oral, sublingual, or transbuccal. In some embodiments, administration is oral.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a rodent, cat, dog, monkey, horse, pig, bovine, or human. In some embodiments, the subject is a rodent, cat, dog, monkey, bovine, or human. In some embodiments, the subject is a mouse, rat, cat, dog, monkey, or human. In some embodiments, the subject is a mouse, rat, dog, monkey, or human. In some embodiments, the subject is a mouse, rat, dog, or human. In some embodiments, the subject is a mouse, rat, or human. In some embodiments, the subject is a dog or a human. In some embodiments, the subject is a human.

In some embodiments, designating a position as "OO" in a compound means that the minimum deuterium incorporation at that position is greater than about 4095. In some embodiments, designating a position as "SO" in the compound means that the minimum deuterium incorporation at that position is greater than about 5095. In some embodiments, designating a position as "O" in a compound means that the minimum deuterium incorporation at that position is greater than about 6095. In some embodiments, designating a position as "O" in a compound means that the minimum the deuterium incorporation at that position is greater than about 6595. In some embodiments, the designation of the position as "O" in the compound means that the minimum deuterium incorporation at that position is greater than about 7095. In some embodiments, the designation of the position as "OO" in the compound means that the minimum deuterium incorporation at this position is greater than about 7595. In in some embodiments, designating a position as "p" in a compound means that the minimum deuterium incorporation at that position is greater than about 8095. In some embodiments, designating a position as "0" in the compound means that the minimum deuterium incorporation at that position is greater , than about 8595. In some embodiments, designating a position as "O" in a compound means that the minimum incorporation of deuterium at that position is greater than about 9095. In some embodiments, designating a position as "OO" in the compound means that the minimum incorporation of deuterium at that position is greater than about 9595. In some embodiments, designating a position as "O" in a compound means that the minimum incorporation of deuterium at that position is greater than about 9795. In some embodiments, designating a position as "O" in compound means that the minimum deuterium incorporation at this position is greater than about 99965.

Pharmaceutically acceptable salts

This invention also includes salts of the compounds, usually pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid-addition salts include salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,

Picric, pyruvic, salicylic, amber, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pama, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, asparagine, stearic, palmitic, ethylenediaminetetraacetate (EOTA), glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p- toluenesulfonic acid, theophyllineacetic acid, as well as 8-halotheophyllines, for example, 8-bromotheophylline and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Wegde, 5.M. ей ай., In Rpagt.

All together. 1977, 66, 2, and Sosha, R.G.., Ipi. 9. Rpagptaseshiisv 1986, 33, 201-217; the contents of each are incorporated herein by reference.

In addition, the compounds of this invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, such solvated forms are considered equivalent to unsolvated forms for purposes of the present invention.

Headings and subheadings are used herein for convenience only and are not to be construed as limiting the invention in any way.

The use of any and all examples or expressions referring to examples (including "for example" (Chog ipeiapse), "for example" (og ehatrie), "for example" ("e.9.") and "such as" ("ab 5IySp)") in this description is intended only to better illustrate the invention and does not impose limitations on the scope of the invention, unless otherwise indicated.

The use of the singular and plural forms (the use of the terms with the articles "а", "ап" and "Те", and similar referents in the context of the description of the present invention should be interpreted as including both the singular form and the plural form, if in this description there is no other indication or unless the context clearly contradicts it.

Unless otherwise indicated, all exact values presented in this specification are representative of the respective approximate values (eg, all exact values from the examples given with respect to a particular factor or measurement may be assumed to also assume the corresponding approximate value of the measurement modified by "approximately" where appropriate).

In this description of the invention, the description of any aspect or aspect of the present invention, made using terms such as "comprising", "having", "comprising" or "comprising" with respect to an element or elements, is intended to confirm a similar aspect or aspect of the present invention made using the terms "consisting of," "consisting principally of," or "essentially being" in relation to a given particular element or elements, unless otherwise indicated in this description or clearly inconsistent with the context.

Illustrative syntheses of the compounds of the invention can be easily carried out by the methods described, for example, in US patents MoMo 5807855; 7648991; 7767683; 7772240; 8076342; US patent publications MoMo 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; MO 2005/016900; ER 0638073 and U. Med. Spent 1995, 38, 4380-4392; each source is incorporated herein by reference in its entirety. Such methods and similar methods can be carried out with the use of deuterated reagents and/or intermediate products and/or the introduction of deuterium atoms into the chemical structure according to the prescriptions known in this field of technology.

The following illustrative synthetic methods include the conversion of indanone A to intermediate C by treatment with 3-bromo-6b-chloroindan-1-one (A; for references on this substance, see publications Vbdeb5o EP 35363 A1 19810909 and Kepieg, Chiy, RabspI, MO 2008025361; each of these publications is incorporated herein by reference in its entirety) with a base such as triethylamine in a solvent such as tetrahydrofuran at ambient temperature (Scheme 1). Removal of the precipitated hydrobromide salt of the amine by filtration and concentration of the filtrate will give 6b-chloroinden-1-one (B). This substance can be reacted with phenyl-d"-boronic acid in the presence of about 1 equivalent of a base such as triethylamine and a catalytic amount of a mixture of IKp(par)2g|BE"bis(norbornadiene)rhodium(I) tetrafluoroborate) and racemic VIMAR ( 2,2'-bisidiphenylphosphino)-1,1-binaphthyl), 1:1, in a suitable solvent (for example, a mixture of about 10:1 solvents of 1,4-dioxane and water) in an argon atmosphere at an elevated temperature (for example, about 1007C ). Processing will allow to obtain racemic b-chloro-3-phenyl-az5-indan-1-one (C).

Scheme 1. An example of the synthesis of an intermediate product C (c) si; ; S si si - SU shcha r

Hg

And in r b

C (racemate)

Treatment of b-chloro-3-phenyl-d5-indan-io-one (C) with a reducing base, such as sodium borohydride (72 equivalents) in a solvent mixture of 10:11 tetrahydrofuran and water at a low temperature (approximately -157"C) will lead to the reduction of the carbonyl group to the corresponding alcohol

Zo (scheme 2). Workup will give racemic cis-b-chloro-3-phenylindan-1-ol (0). Treatment of this material with vinyl butyrate (approximately 5 equivalents) and Momolut 43585 in a solvent such as diisopropyl ether at ambient temperature will give (15,35)-6-chloro-3-phenylindan-1-ol (E) after workup.

Scheme 2. An example of the synthesis of the intermediate product Э и он ОН си С и с | si r r o goes r-- in; : o v o c)

В р б р ,

C govcemate) 2 (cis-racemate E (15,35)-hemenantiomer!

Alternatively, carrying out the sequence of reactions from A to EE using phenylboronic acid or 4,4,5,5-tetramethyl-2-phenyl-(1,3,2|Idioxaborolan) instead of 4,4,5,5-tetramethyl-2-a5 -phenyl-P1,3,2|dioxaborolane will lead to the production of /(15,35)-6-chloro-3-phenylindan-1-ol (E (Scheme 3).

Scheme 3. An example of the synthesis of the intermediate product E"'

He (0 o

SI

----5 5083 - i t'' --Ш---

Ve (i

E((15,35)-enantiomer)

A c )

The following alternative methods of synthesis for obtaining E"' are described in the patent literature (Rani, UMepIK Miveizep, Zshchei, Kobip, Vgezep UUO2006/086984 A1; Vapd-Apaegzep, Vedezvo, Uepzep, zZmape, Bai, Nomeii5, Gupdb5e, Mom UMO2005/016901 At ; each of which is incorporated herein by reference in its entirety). In these procedures, benzyl cyanide is used as one of the substrates. The use of benzyl cyanide-d7 (commercially available from Algis, catalog number J 495840), or phenyl-d5"- of acetonitrile (commercially available from Algiers, catalog number Ж 495859, or from COM, catalog number Ж 0-5340, or from Capio, catalog number Ж 49132-27) and the same procedure can lead to intermediate product E ( scheme 4).As an alternative to the commercially available sources, benzyl cyanide-7 and phenyl-d5-acetonitrile, it is possible to use the obtained sodium cyanide and benzyl-d;7-chloride (commercially available from

Algisp, Mo catalog number 217336) and benzyl-2,3,4,5,6-d5-chloride (commercially available from

Aagisi, catalog number Mo 485764), respectively.

Scheme 4. An example of the synthesis of intermediate products E and E'

He

SI

5 pnnnnnnnnnnnnnnnnnifVs) benzyl cyanide E ((15,35)-enantiomer)

He

SM

E r r r nyny san --- 2 r r r s r r r r k-b:benzylcyanid-si7

B-H:phenyl-da-acetonitrile E (15.35) enantiomer)

Treatment of compound E with about 4 equivalents of diisopropylethylamine and about 2 equivalents of methanesulfonic anhydride in tetrahydrofuran at about -187C followed by slow heating to about -5"C and further treatment with about 4 equivalents of 2,2-dimethylpiperazine leads to the formation of 1-(1НА,35) -6-chloro-3-phenyl-d5-indan-1-yl)-3,3-dimethylpiperazine (P), which can be purified after the reaction (Scheme 5). Alternatively, alcohol E can be converted to the corresponding chloride, preferably with conservation configurations in

C1, thus obtaining (15,35)-1-chloro-3-d5-phenylindan (E"; analogously to E" can be converted into (15,35)-1-chloro-3-phenylindan (E")). Chloride E" can be reacted with 2,2-dimethylpiperazine to give E. The final step can be carried out as described for the preparation of the salt, compound (I)" butanedioic acid, using iodomethane, thus obtaining compound (I), or "from -iodomethane, thereby obtaining the compound (IM), respectively.

Alternatively, as described below, a methyl group or an az-methyl group can be introduced by heating under reflux in HCNO/HCOOH or OSRO/USCOOb, respectively.

Scheme 5. An example of the synthesis of intermediate products E and compounds (II) and (IM) / on M v s | and | No with | y r r r r r r-- r r r r r r B) B)

E C15,35 enantiomer) E CIC,35) enantiomer! (2-amino-2-methylpropyl)-carbamic acid tert-Butyl ester (C) can be prepared from 2-methylpropane-1,2-diamine and di-tert-butyl dicarbonate (alternatively, c is commercially available from : Rgite, catalog number ROI-1362-МВ4; Vomaitip, catalog number МХ45401). Reaction of C with a haloacetyl halide such as either chloroacetyl chloride or bromoacetyl bromide will give (2-(d-chloroacetylamino)-2-methylpropylcarbamic acid) tert-butyl ester or (|2-(2-bromoacetylamino)-2-methylpropylcarbamic acid) tert-butyl ester (H), respectively (Scheme 6). Treatment of any variant of compound H with an acid followed by treatment with a base will lead to the formation of 6,6-dimethylpiperazin-2-one (I). This substance can be reduced to 2,2-dimethyl-5 ,5-d2-piperazine (U) by treatment with lithium aluminum deuteride.

Scheme 6. An example of the synthesis of an intermediate product; and ) these N

Nam nm ho nm o M M ptn ry pnya rastyu i pnya IZ nzh o Z o a M m 2-methyplpranan-y,2. diamia (E! NN I z

Alternatively, compound B can be prepared from 2-amino-2-methylpropionic acid. The reaction of 2-amino-2-methylpropionic acid and di-tert-butyldicarbonate will give 2-tert-butoxycarbonylamino-2-methylpropionic acid (K) (Scheme 7). Functional acid group

Zo can be converted to the corresponding Weinreb amide by reaction with O,M-dimethylhydroxylamine in the presence of a suitable coupling reagent such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium (NATI) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EC), thereby obtaining tert-butyl ester (|1-(methoxymethylcarbamoyl)-1-methylethylcarbamic acid (). Selective reduction of Weinreb amide gives tert-butyl ester (1 ,1-dimethyl-2-oxoethyl)carbamic acid (M). Reductive amination using aldehyde M and aminoacetic acid methyl ester can be used to obtain (2-tert-butoxycarbonylamino-2-methylpropylamino)acetic acid methyl ester (M). Processing of carbamate ester M with an appropriate acid, such as trifluoroacetic acid, will lead to the formation of piperazinone I, which upon treatment with lithium aluminum deuteride gives piperazine ..

Scheme 7. An alternative example of the synthesis of an intermediate product from U z

In | V V Y I no (9) on and t v! H o 2-amino-2-methylirsthionic acid OMe

Kk I M a nN not o

MeO. M

M M and M i (c)

M I N!

The use of .) instead of 2,2-dimethylpiperazine as described for the conversion of E to compounds (I) and (M) will lead to compound (MI) and compound (MI), respectively. Similarly, the use of E and y) instead of 2,2-dimethylpiperazine and E will lead to compound (I) and compound (M).

In another aspect, this invention relates to a method of obtaining a compound of formula (9) but,

Iv) c) c) c) o (53-4ХУ). which includes the treatment of the compound (KHIM) with the compound ((5)-VIMARIVN()VE".

In another aspect, the invention relates to a method of obtaining the tartrate of the compound (1K,35)-(IM), which includes the treatment of racemic //thrano-1-(b-chloro-3-phenyl(a5)-indan-1-yl)-1 (dz),2,2-trimethylpiperazine with 1--(--)-tartaric acid.

In some embodiments, racemic trans-1-(6b-chloro-3-phenyl(di5)-indan-1-yl)-1(dz),2,2-trimethylpiperazine is prepared from its corresponding succinate salt.

In some embodiments, racemic trans-1-(b-chloro-3-phenyl(d5)-indan-1-yl)-1(d3),2,2-trimethylpiperazine succinate is obtained from the maleate salt of racemic trans-1-(b -chloro-3-phenyl(d5)-indan-1-yl)-3,3-dimethylpiperazine.

In some embodiments, acetophenone-d5 is converted to an enol ether. In some embodiments, the enol ether is a silyl enol ether. In some embodiments, the enol ether of acetophenone-d5 is converted to the corresponding vinyl boronate. In some embodiments, the enol ether of acetophenone-d5 is treated with bis(pinacolato)diboron. In some embodiments, the vinyl boronate is treated with 2-halo-5-chlorobenzaldehyde.

In some embodiments, these compounds exist as racemates. In some embodiments, these compounds exist in an enantiomeric excess greater than about 7095.

In some embodiments, these compounds exist at greater than about 7595 enantiomeric excess. In some embodiments, these compounds exist in an enantiomeric excess greater than about 8095. In some embodiments, these compounds exist at greater than about 8595 enantiomeric excess. In some embodiments, these compounds exist at greater than about 9095 enantiomeric excess. In some embodiments, these compounds exist in an enantiomeric excess greater than about 9295. In some embodiments, these compounds exist in an enantiomeric excess greater than about 9595. In some embodiments, these compounds exist in an enantiomeric excess greater than about 9795. In some embodiments, these compounds exist in greater than about 9995 enantiomeric excess.

Pharmaceutical compositions

This invention further relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of the present invention and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention can be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients in single or multiple doses.

The pharmaceutical compositions of the present invention can be prepared with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients according to generally accepted methods, such as the methods described in Ketipdiop: Te

Zsiepse apa Rgasiise oi Rpagtasu, 2151 Eaiyiop (Opimegeiu oi She Z5siepsez ip Rniiaae!rnia, ed.,

MPrripsoy UMiShate 4 UMiIKip5 2005). Further examples of compositions of compounds of the present invention are described, for example, in US patents MoMo 5807855; 7648991; 7767683; 7772240; 8076342; US patent publications MoMo 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744, UMO 2005/016900, ER 0638073 and 9. Med. Spent , 38, 4380-4392; each document is incorporated herein by reference in its entirety.

Pharmaceutical compositions can be specially formulated for administration by any suitable route, such as oral, nasal, topical (including transbuccal and

Sublingual) and parenteral (including subcutaneous, intramuscular, intramembranous, intravenous and intradermal) routes. It should be borne in mind that the route of administration will depend on the general condition and age of the subject being treated, the nature of the disease being treated, and the active ingredient.

A daily dose of the compounds of the invention on a free base basis is suitably from about 1.0 to about 160 mg/day, more suitably from about 1 to about 100 mg, for example preferably from about 2 to about 55, such as from about 2 to about 15 mg, for example, from about 3 to about 10 mg. In some embodiments, the daily dose is from about 0.1 mg to about 500 mg. In some embodiments, the daily dose is from about 1 mg to about 500 mg. In some embodiments, the daily dose is from about 1 mg to about 400 mg. In some embodiments, the daily dose is from about 1 mg to about 300 mg. In some embodiments, the daily dose is from about 1 mg to about 200 mg. In some embodiments, the daily dose is from about 1 mg to about 160 mg. In some embodiments, the daily dose is from about 1 mg to about 100 mg. In some embodiments, the daily dose is from about 1 mg to about 60 mg. In some embodiments, the daily dose is from about 2 mg to about 30 mg. In some embodiments, the daily dose is from about 2 mg to about 15 mg. In some embodiments, the daily dose is from about 3 mg to about 10 mg. In some embodiments, the daily dose is approximately 60 mg. In some embodiments, the daily dose is approximately 50 mg.

In some embodiments, the daily dose is approximately 40 mg. In some embodiments, the daily dose is approximately 30 mg. In some embodiments, the daily dose is approximately 20 mg. In some embodiments, the daily dose is approximately 10 mg.

In some embodiments, the daily dose is approximately 5 mg. In some embodiments, the daily dose is approximately 3 mg. In some embodiments, the daily dose is approximately 2 mg. In some embodiments, the daily dose is approximately 1 mg.

For parenteral routes of administration, such as intravenous, intrathecal, intramuscular, and similar, typical doses are about half the dose used for oral administration.

The compounds of the present invention are usually used in the form of a free substance or in the form of a pharmaceutically acceptable salt. Examples of suitable organic and inorganic acids are as described herein.

In some embodiments, the composition comprises cyclodextrin. In some embodiments, the composition comprises cyclodextrin in water. In some embodiments, the cyclodextrin is hydroxypropyl-VD-cyclodextrin. In some embodiments, the composition comprises hydroxypropyl-p-cyclodextrin in water.

Treatment of disorders

This invention also relates to the medical use of the compounds of the present invention, for example, for the treatment of diseases of the central nervous system, including psychosis, in particular schizophrenia, or other diseases that include psychotic symptoms, such as, for example, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, transient psychotic disorder, split psychotic disorder, and other psychotic disorders or illnesses that present with psychotic symptoms, such as bipolar disorder, such as mania in bipolar disorder. Compounds and/or compositions of the present invention can be additionally used in the treatment of disorders, such as disorders described, for example, in US patents MoMo 5807855; 7648991; 7767683; 7772240; 8076342; US patent publications MoMo 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; MO 2005/016900, ER 0638073 and U Med. Spent 1995, 38, 4380-4392; each document is incorporated herein by reference in its entirety. The invention also relates to the medical use of compounds of the present invention as a combination therapy in combination with other therapeutic agents, such as agents described, for example, in US patents MoMo 5807855; 7648991; 7767683; 7772240; 8076342; US patent publications MoMo 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; MO 2005/016900, ER 0 638 073 i) Med. Spent 1995, 38, 4380-4392; each document is incorporated herein by reference in its entirety.

It should be clear that one or more features of any of the embodiments described here can be combined and/or rearranged within the scope of the present invention to obtain additional embodiments that are also within the scope of the present invention.

Those skilled in the art will understand or be able to establish, using no more than ordinary experimentation, many equivalents to the specific embodiments of the invention described herein. It is assumed that such equivalents are in

Within the scope of this invention.

This invention is further described by the following non-limiting examples.

Examples

Examples are provided below to facilitate a more complete understanding of the present invention.

The following examples illustrate examples of methods of implementation and application of this invention in practice. However, the scope of the present invention is not limited to the specific implementation options described in these examples, which are intended only for illustration purposes, since alternative methods can be used to obtain similar results.

Purification of compounds by chromatography refers to the use of silica gel chromatography using either manual flash chromatography or automated flash chromatography, usually performed using eluent gradients from heptanes to ethyl acetate or a mixture of ethyl acetate, triethylamine and methanol.

Description of LC-MS methods

Compounds (I), (I), (1, (M), (M), (MI) and (MI) were characterized by LC-MS using the following methods (table 1).

Table 1

LC-MS analysis methods (method LLYHIIIIAV25, system LC-MS Adiyepi 1200 with detector ЕЙ 5) of nin NNYA ii visn tablets

M5O 6110

Table 1

LC-MS analysis methods alone A

Aiidepi 1200 ozmir mm IS

Objeminektsi| a mkl/////// HER 11111111 | 0 Temperature columns 5 o.s./:-/-/DZH/ | //:/:x(SS: SSS:

UNKNOWN with the PON of the flow in 0.0595 TEA in acetonitrile

Gradient Linear detection 000 Double 1000000

Wavelength 254 nm detection 11117711 pelvic pressure.//////// | 777777777777/IryurDrozabar77.7/7/7/77 11111111 time 77777111 Gradieet/:.//:/

Oh min 95965 А 595 В 3.5 min. 96 A 10095 V

MUKHU-AVOZ 3.55 min. 9595 A 695 V

Oh min 90965 А 1095 В 3.4 min. 10095 V

MUKHU-AUTO 3.5 min. 10096 V 3.51 min. 90965 A 1095 V

Oh min 70965 A 3095 B 3.2 min. 96 A 10095 V

MUHU-AVZO 3.5 min. 096 A 10095 B 3.55 min. 70965 A 3095 V

Oh min 75965 A 2595 V ! 3.4 min. 96 A 10095 V uihiAVg5 4 min. 096 A 10095 B 4.01 min. 75965 А 2595 В 4.5 min. 75965 A 2595 V neck of ions

IR-MS equipment was carried out on a 5-siekh ARI150OEH device equipped with an ARI-source operating in the mode of positive ions. HPLC equipment consisted of LC pumps

Ask and! C10-AYumr, ROA detector (operating at 254 nM) and system controller 5ХИ--10A. Automatic sampler - (from 5Op. 11111110 | Automatic sampler./ | /// Сйвоп2и5 //-/-/:/

Stove for speakers dope5 Spgotaiyoagarnu 799083 - shshn K

Column UMaiet5 Zutteigu 0-18 11111711 Size of particles.7/7//// | 77 Z5μm//

Re NN: ZNNNNNNYA NN PN

The injection volume is 10 μl of non-liquid NNNNNNNNNN NNYA KON column

Table 1

LC-MS analysis methods

Methods UUKHU-AV5, M/KhMU-AV10 and MUKHM-AVZO shk (3rd flow 0.0595 ТРА in water 1Г11в', 0.05965 ТРА in methanol no Duration of the experiment 11177711 Gradient // | 7777777 nonlinear///From detection

Detection at Temperature 50'C

Gas pressure is 4.4 bar

Time Gradient 0.01 min. 1796 VUA 0.27 min. 28955 VUA 0.53 min. ZO VUA 0.80 min. BO VUKHA 1.07 min. 599 VUA 1.34 min. 6895 VuUA 1.60 min. 718 VUA 1.87 min. 865 EARS 2.14 min. 9395 VUA 2.38 min. 10095 V 2.40 min. 1796 VUA

Description of chiral HPLC methods

Enantiomeric purity was analyzed on a NemlLei RasKaga series 1100 system equipped with a diode array detector and using a Spetbeijiaop for S Keum. A.08.03 |8471.

The parameters of the HPLC method are shown in the table below (Table 2). Compound (X) has a retention time of approximately 13.6-13.7 min, while its enantiomer, 4-(15,38)-6-chloro-3-phenylindan-1-yl)-1,2,2- trimethylpiperazine, eluted at 8.5-8.6 min.

Table 2

Chiral HPLC analysis methods

Sample preparation 1-3 ml in a mixture of hexane/2-propanol (80/20 vol./vol.)

Spigairak ARN, 5 μm, 250 x 4.6 mm

Column temperature (C)

Injection (µl) Peak (nm)

Duration of the experiment

Flow rate (ml/min) 11111106

Mobile phase Hexane/2-propanol/diethylamine/propionic acid,

In 90/10/0.2/2

Example 1. Preparation of 4-(18,35)-6-chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazine"butanedioic acid: (salt: compound (I)"butanedioic acid acid).

Scheme 8. Synthesis of compound (I)

in

NS in nn

OO OO

ММонсиНсицобо 0-05 is one hydrochloride 1-(18,35)-6-chloro-3- salt of compound (I) and butanedioic acid of phenylindan-1-yl)-3,3-dimethylpiperazine (hydrochloride of compounds (XI))

1-((18,35)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine hydrochloride (11.1 g) was dissolved in a mixture of toluene (74 ml) and water (74 ml). Preparation of 1-((18,35)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine hydrochloride is described in the patent literature (Yubapi, UMorIK Mieizep,

Zshivy, Kobrip, Vgozep M/O2006/086984 A1; Vapd-Apadegzep, Vedezo, Uepzep, Zmape, Bai, Nomei5,

Gupdzv, Mom UMO2005/016901 JSC; each document is incorporated herein by reference in its entirety). A 12.0 M solution of potassium hydroxide in water (5.38 ml), tetra-N-butylammonium bromide (1.42 g) and az-iodomethane (catalogue number AiYdgispy Zh 176036; 2.4 ml) were added and the mixture was stirred at at room temperature for 18 hours (scheme 8). The mixture was filtered through a glass filter into a separatory funnel. The solid on the filter was washed with toluene (50 ml) in a separatory funnel. The aqueous layer was extracted with toluene (100 mL) and the combined organic layers were washed with conc. aqueous ammonia (100 mL) and then with water (100 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow of olive oil The oil was cooled to -78"C in a vacuum, as a result of which the oil hardened.

After heating to room temperature, the oil became semi-solid.

This substance was dissolved in acetone (30 ml). In a separate flask, butanedioic acid (3.46 g) was suspended in acetone (30 mL) and heated to reflux (not all of the dibasic acid went into solution). An acid slurry was added to the crude product solution and additional acetone (50 mL) was added to the remaining butanedioic acid and then poured into the solution. The mixture was stirred overnight. Partial precipitation occurred overnight and the mixture was concentrated in vacuo. The residue was redissolved in acetone (70 mL) and heated to reflux and allowed to cool to room temperature and stirred for 2 hours.

The mixture was filtered to give 4-(18,35)-6-chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazinebutanedioic acid (salt: compound (I)"butanedioic acid ; 7.61 g).

LC-MS (method 131): CT(UV) 1.57 min.; purity according to UV/EI 5 was 10095/10095; the observed mass was 358.0. The inclusion of three deuterium atoms corresponded to »9995. 13Sb NMR spectrum with proton desolvation showed a heptet at approximately 36.4 ppm. (ppt), corresponding to deuterated

From the metabolic area M2; this signal was transformed into a singlet in the C NMR spectrum with proton and deuterium resolution. All other signals were singlets in both spectra. The optical purity of the isomer was »9595 ee.

Example 2. An alternative method of obtaining the salt 4-(1НА,35)-6-chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazinebutanedioic acid (salt: compound (I)"butanedioic acid ).

The free base of 1-((18,35)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine was obtained from the corresponding hydrochloride salt by partitioning 23.4 g of the salt between a mixture of water (100 mL), concentrated aq. of a solution of potassium hydroxide (40 ml) and toluene (250 ml). The organic layer was washed with a mixture of water (50 ml) and a concentrated aqueous solution of potassium hydroxide (10 ml).

The combined aqueous layers were extracted with toluene (75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the free base of 1-418.35)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine (21.0 d) in the form of colorless oil.

This substance was dissolved in a mixture of toluene (150 mL) and water (150 mL) before adding 12.0 M aqueous potassium hydroxide (11.3 mL), tetra-N-butylammonium bromide (2.98 g), and az-iodomethane

(4.9 ml) and the mixture was stirred at room temperature for 18 hours.

Processing and purification was carried out as described above, and the salt of 4-(1А8,35)-6-chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazine"butanedioic acid was obtained (salt: compound (I) "butanedioic acid; 14.34 g; 48.99).

Example 3. Preparation of 4-(1НА,35)-6-chloro-3-phenyl-α5-indan-1-yl)-1,2,2-trimethylpiperazine (compound (1)) its /4-(18,35 )-6-chloro-3-phenyl-di-indan-1-yl)-1-methyl-is-2,2-dimethylpiperazine (compound (IM)).

To a solution of compound A (57 g) in tetrahydrofuran (600 ml) was added dropwise triethylamine (30 ml) over 30 minutes. The reaction mixture was kept at room temperature for

From hours The precipitated solid was separated by filtration and the filtrate was concentrated in vacuo. The residue was re-precipitated from diethyl ether to give compound B (31 g) as a yellow solid. To a solution of the compound phenyl-α5-boronic acid (25 g) in a mixture of 1,4-dioxane/water (900 ml/90 ml) was added Ikp(par)g|VnEa (1.3 g), racemic VIMAR (2.1 d) and triethylamine (14 ml), then the reaction mixture was kept at room temperature for 2 hours in an M2 atmosphere. The indenone compound (19 g) was then added and the resulting mixture was heated to 100°C for 3 hours. The precipitated solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography to give indanone C (10 g).

Scheme 9. Synthesis of compound C (in; (in; si si in, ;

And after

And at 7 p.m.? o s z b r (c) r (c) r

C (racemate) р р

And in 13.4 kg of 3-bromo-6b-chloroindan-1-one (A; reference to this substance see: Vbdezb EP 35363 A1 19810909 and Kepieg, UyyI, Ra5spI, UMO 2008025361; each specified document is included in this description by reference in its entirety) was dissolved in tetrahydrofuran (170.8 L) and the solution was cooled to 0-57C (Scheme 9). Triethylamine (9.1 L) was added over 0.5 h. The mixture was stirred at 0-57C for 5 hours before an additional portion of triethylamine (248 L) was added for 0.5 hour and stirring was continued for 2 hours. The mixture was filtered and the filtrate was concentrated to 30 L before adding n-heptane (102 L). The volume was reduced to 60 l. More n-heptane (203 L) was added and the mixture was stirred for 1 hour.

Silica gel (17.2 kg) was added. The mixture was filtered and the residual solid was washed with

With heptane (100 l). The combined filtrates were concentrated to 30 L and stirred at 0-57 for 1 hour. The mixture was centrifuged and the residual solid was dried to give 6b-chloroinden-1-one (compound B; 2.42 kg), pure enough for the next step.

2-methyltetrahydrofuran (85 L) and M,M-dimethylacetamide (12.4 L) were added to the reactor, followed by the addition of potassium acetate (10.9 kg) and bis(pinacolato)diboron (14.8 kg). The resulting mixture is stirred for 0.5 hours. Ra(arr)CI--SUOSIM (0.91 kg) was added, followed by the addition of bromobenzene-sb (9.0 kg) and 2-methyltetrahydrofuran (12.2 L). The mixture was heated to 80-85°C for 3 hours, after which the temperature was reduced to ambient temperature. The crude mixture was filtered through kieselguhr and silica gel. The filter cake was washed with 2-methyltetrahydrofuran (31 L). The combined filtrates were concentrated to about 25 L , keeping the temperature below 35"C. n-heptane (52 L) and 796 aqueous solution were added

MansSOOz (31 L) and the resulting mixture were stirred for 0.5 hour. The organic layer was stirred with 7956 aqueous MnHsSOOz (31 L) for 0.5 h. The combined aqueous layers were extracted with n-heptane (22 L) for 0.5 h. The combined organic extracts were washed with 25% aqueous Masi solution (50 L) for 0.5 hour. The organic layer was concentrated,

maintaining the temperature below 357"C, thus obtaining 4,4,5,5-tetramethyl-2-d5-phenyl-

P,3,2Idioxaborolane (compound B"; 10.5 kg), pure enough for the next stage.

1,4-dioxane (85 l), b-chloroinden-1-one (compound B; 9.09 kg, obtained by a method similar to the method described above), 1,5-cyclooctadiene (0.2 l), bis(norbornadiene)rhodium(I) tetrafluoroborate (0.52 kg), triethylamine (5.5 l), 4,4,5,5-tetramethyl-2-45-phenyl-1,3,2|dioxaborolane (compound B'; 6.5 kg) and 1,4-dioxane (26 l). The mixture was heated to 48-537C and stirred at this temperature for 5 hours. The reaction was quenched by adding 2 M aqueous

NSIII (13 kg). Then n-heptane (110 L), methyl tert-butyl ether (32 L) and water (90 L) were added and the resulting mixture was stirred for 0.3 hours. The organic layer was washed with water (90 L) for 0.3 hours. The combined aqueous layers were extracted with a mixture of methyl tert-butyl ether (30 L) and n-heptane (57 L) for 0.3 hours. The combined organic layers were filtered through silica gel (13 kg). The precipitate on the filter was washed with a 2:1 mixture of n-heptane and methyl tert-butyl ether (19.5 kg). The filtrate was concentrated to approximately 25 l. n-heptane (45 L) was added and the volume of the mixture was reduced to about 25 L. n-heptane (45 L) was added and the volume of the mixture was reduced to about 35 L. The mixture was stirred at 0-5"C for 3 hours. The mixture was centrifuged and the remaining solid was dried, thereby obtaining racemic b-chloro-3-4x5-phenylindan-1-one (compound C; 8.4 kg), clean enough for the next stage.

Tetrahydrofuran (90 L) was added to the reactor, followed by the addition of water (10 L) and b-chloro-3-d5-phenylindan-1-one (compound C; 7.73 kg) (Scheme 10). The mixture was cooled to a temperature of -35 - -30"C. Sodium borohydride (1.5 kg) was added in portions, maintaining a temperature of -35 - -3076.

The resulting mixture was stirred at a temperature of -35 - -30"C for 5 hours, after which it was allowed to warm up to ambient temperature. The excess sodium borohydride was quenched by adding 2 M aqueous NSI (7.6 kg), maintaining the temperature below 4576.

Water (17 L) and methyl tert-butyl ether (67 L) were added and the mixture was stirred for 0.3 hour. The aqueous layer was extracted with methyl tert-butyl ether (39 L) for 0.3 hours.

The combined organic layers were washed with brine (36 kg) for 0.3 hours. The organic layer was filtered through silica gel (6.4 kg). The precipitate on the filter was washed with methyl tert-butyl ether (20 l). The combined filtrates were concentrated to about 30 L, maintaining the temperature below 45°C. n-heptane (55 L) was added and the resulting mixture was concentrated to about

Z to 30 L, maintaining the temperature below 457°C. The resulting mixture was stirred at 0-57 for 2 hours. The mixture was centrifuged and the filter cake was washed with n-heptane (12 L) before it was centrifuged again. The solid that remained, dried, thereby obtaining a crude substance 0. 4.87 kg of this substance was dissolved in methyl tert-butyl ether (20 L) and dried over NaCl 5 O1 (2 kg) for 0.25 h. The mixture was filtered and the precipitate on the filter was washed with methyl tert-butyl ether (4.4 L). The combined filtrate was concentrated to about 20 L, maintaining the temperature below 45"C. n-Heptane (32 L) was added and the mixture was concentrated to about 25 L, keeping the temperature below 45°C. n-Heptane (16 L) was added and the mixture was concentrated to about 20 L, keeping the temperature below 45°C. The solid was filtered and dried to give racemic cis-b-chloro-3-y5-phenylindan-1-ol (compound 0; 4.99 kg), pure enough for the next step.

Scheme 10. Synthesis and separation of compound E into isomers

EV. NO ІВ) o b C) i 0 y,

There are (racemate) 0 cis-racemate! BE Ts15,35) enanpomers

Vinyl butyrate (120 ml) and Novozym-435 (15 g) were added to a solution of racemic cis-b-chloro-3-d5-phenylindan-i-ol (compound 0.50 g) in 2-isopropoxypropane (200 ml). The mixture was kept at ambient temperature for 2 days. The solid was filtered off. The filtrate was evaporated and purified by silica gel chromatography to give (15,35)-6b-chloro-3-d5-phenylindan-i-ol (compound E; 13 g), pure enough for the next step.

A solution of (15,35)-6-chloro-3-d5-phenylindan-i-ol (compound E; 7 g) in THF (100 ml) was treated

ZOSI2 (6.6 g) at ambient temperature overnight. The mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution. The organic layer was dried over Ma»5O», filtered and concentrated in vacuo to give the intermediate chloride (7.5 g). 3.5 g of this substance was dissolved in 2-butanone (50 ml) and reacted with 2,2-dimethylpiperazine (1.7 g) in the presence of K»CO3 (2.7 g) under reflux overnight . The solid was filtered off.

The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC on a Zpitaid?2y EKS-10A instrument equipped with a C18 Bupegdi column (250 mm x 50 mm, 10 μm) using water and acetonitrile (containing 0.195 TEA, vol./06b .) as an eluent, thereby obtaining /1-(18,35)-6-chloro-3-d5-phenylindan-1-yl)y-3,3-dimethylpiperazine (compound EE; 26 g, pure enough for the next step .

Solution 1-41 of 8,35)-6-chloro-3-d5-phenylindan-1-yl)-3,3-dimethylpiperazine (compound E; 22 g) in

HSO/HSOOH (3 mL/3 mL) was refluxed overnight. Volatile substances were removed under vacuum. The residue was partitioned between ethyl acetate and 10956 aqueous Mahon. The organic layer was dried over Mag25O5, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, obtaining 4-((18,35)-6-chloro-3-d5-phenylindan-1-yl)-1,2,2-trimethylpiperazine (compound (I); 1.89 g ). LC-MS (MUHM-AVOB5 method): CT(UV) 2.43 min.; purity according to UV/EI 5 95.1965/99.695; observed mass 360.2. The inclusion of five deuterium atoms is »9595. 13 The proton decoupled NMR spectrum showed three triplets at approximately 126.1, 127.2, and 128.2 ppm, corresponding to the deuterated metabolic sites of the MUZ; this signal was transformed into three singlets in the "3 NMR spectrum with proton and deuterium resolution. All other signals were singlets in both spectra. The optical purity of the isomer is 9595 ee.

A solution of 1-41 8,35)-6-chloro-3-d5-phenylindan-1-yl)-3,3-dimethylpiperazine (compound E; 3.0 g) in sodium hydroxide (4 ml/4 ml) was boiled under reflux overnight. Volatile substances were removed under vacuum. The residue was partitioned between ethyl acetate and 10906 aqueous Mahon. The organic layer was dried over Mag25O5, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, thereby obtaining 4-(1НА,35)-6-chloro-3-d5-phenylindan-1-yl)-1-dz-methyl-2,2-dimethylpiperazine (compound (IM); 2 ,14 g). LC-MS (MUKHM-AVI10 method): CT(UV) 2.06 min.; purity according to UV/EI! 5 9895/10090; observed mass 363.3. Inclusion of eight atoms

Of deuterium is »9495. 73 The proton-decoupled NMR spectrum showed a heptet at approximately 36.4 ppm corresponding to the deuterated metabolic site M2; this signal is transformed into a singlet in the 730 NMR spectrum with proton and deuterium resolution. "The proton-desolved C NMR spectrum also showed three triplets at about 126.1, 127.2, and 128.2 ppm, corresponding to the deuterated metabolic sites of M3; these signals transform into three singlets in the C NMR spectrum with by proton and deuterium uncoupling. All other signals were singlets in both spectra. The optical purity of the isomer was x»9595 eV.

Example 4. Preparation of 4-(1A,35)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine-6,6-d2 (compound (1), 4-(18,35 )-6-chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazine-6,6-d2 (compound (M)), 4-(18,35)-6-chloro -3-phenyl-α5-indan-1-yl)-1-methyl-dz-2,2-dimethylpiperazine-6,6-d2 (compound (MI)) and 4-18,35)-6-chloro- 3-phenyl-di5-indan-1-yl)-1,2,2-trimethylpiperazine-6,6-di2 (compound (MI). 2-Amino-2-methylpropionic acid (50.0 g) was suspended in a mixture of methanol and triethylamine (9:11, 1.2 L) (Scheme 11). 1 M aqueous Mahon solution (450 mL) was added with stirring until all the solid had dissolved. Di-tert-butyl dicarbonate (Wosgo; 214) was added .0 g) and the mixture was stirred at ambient temperature overnight.

Organic volatiles were removed under vacuum. EOAc (500 ml) was added. The organic layer was washed with saturated saline solution and dried over Ma»5O»4, filtered, then concentrated, thereby obtaining 2-tert-butoxycarbonylamino-2-methylpropionic acid (compound K; 90 g) as a white solid, which was used directly on the next stage.

Scheme 11. Synthesis of the intermediate product U

Nam nm NM NM iepolvvavnvvvya ni iepopovavvvvnsya iepoplvvvvnvnia n poppolvvnnnnvny no o no o o i o N 9); 2-amino-g-methylpropionate OMe

Kk in M c

NM and; VI i i pen - yu « -- Sh

MeO. and (c)

M I N!

A mixture of the obtained 2-tert-butoxycarbonylamino-2-methylpropionic acid (compound K; 60.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EOS-HC; 86.4 g) in dichloromethane (900 ml) was stirred at ambient temperature, then M,O-dimethylhydroxylamine hydrochloride (35.3 g) and triethylamine (150 ml) were added. The resulting mixture was stirred at ambient temperature for three days. Water was added and most of the volatiles were removed under vacuum. The residue was distributed between OSM and an aqueous solution of MansSoOz. The organic layer was washed with 3 M aqueous HCl, then with saturated saline, then dried over Ma»5O»54, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, thereby obtaining tert-butyl ester (|1-(methoxymethylcarbamoyl)-1-methylethylcarbamic acid (compound I; 28.2 g)) in the form of a white solid, pure enough for the next stage.

Lithium aluminum hydride (7.8 g) was added to a stirred solution of tert-butyl ester | 1-(Methoxymethylcarbamoyl)-1-methylethylcarbamic acid (compound 1; 42.0 g) in anhydrous diethyl ether (1.5 L) at -40°C. Then the mixture was stirred at the same temperature for about 5 minutes. The excess of HyAIN was quenched potassium hydrosulfate solution in water.

The resulting mixture was distributed between E(Ac) and 3 M aqueous HCl. The organic layer was washed with a saturated aqueous solution of ManHsSoOz, dried over Ma»5O:, filtered and concentrated in a vacuum, thereby obtaining tert-butyl ester (1,1-dimethyl-2 -oxoethyl)-carbamic acid (compound M; 29 g), pure enough for the next stage.

Aminoacetic acid methyl ester hydrochloride (80.6 g) and EVM (160 ml) were dissolved in

OSM (1000 mL) and stirred for 15 min to separate the amine from the salt. Then a solution of tert-butyl ester of 1,1-dimethyl-2-oxoethyl)-carbamic acid (compound M; 29.0 g) in OCM (600 ml) was added. The resulting mixture was stirred for 0.5 hours at ambient temperature, then Mavn(OAc)z (102 g) was added and the mixture was stirred at ambient temperature overnight. Saturation was added. water solution

MansoOz. The aqueous layer was extracted by USM. The combined organic layers were dried over Ma»5oa,

Z was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, obtaining (2-tert-butoxycarbonylamino-2-methylpropylamino)-acetic acid methyl ester (compound M; 26.5 g) as a white solid, which was directly used in the next step.

A solution of (2-tert-butoxycarbonylamino-2-methylpropylamino)-acetic acid methyl ester (compound M; 26.5 g) in OCM (800 ml) was stirred at ambient temperature, TEA (180 ml) was added dropwise. The mixture was stirred at 30-407C for 5 hours, after which it was concentrated in a vacuum. The residue was partitioned between dissolved toluene and water. The organic layer was dried over NaCl5O, filtered and concentrated in vacuo. The remaining solid was dissolved in a mixture of ethanol (400 mL) and methanol (90 mL). They added

KSO" (207 g) and the mixture was refluxed overnight. The mixture was cooled to room temperature. OSM (2500 mL) was added and the mixture was stirred for 1 hour at ambient temperature. The solid was filtered off and the filtrate was concentrated in vacuo to give 6,6-dimethylpiperazin-2-one (compound I; 5.85 g) as a white solid, pure enough for the next step.

A solution of 6,6-dimethylpiperazin-2-one (compound I; 3.6 g) in THF (20 ml) is stirred at 0"C.

Lithium aluminum deuteride (PAY; 3.6 g) was added, then the mixture was refluxed overnight. The mixture was cooled to ambient temperature and Mag»5O5 was added. The mixture was stirred for 0.5 h before removing most of the volatiles in vacuo. The residue was suspended in a saturated solution of NSI in

EOAc at room temperature for 0.5 hours. The solid was filtered off and dried, thereby obtaining 2,2-O2-6,6-dimethylpiperazine in the form of a bis-hydrochloride salt (compound U"2HCl; 5.3 g), pure enough for the next stage.

5OCI2 (4.7 g) was added to a solution of compound E (5 g) in THF (50 ml) and the resulting mixture was stirred overnight at ambient temperature (Scheme 12). The mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with a saturated saline solution, dried over Mag5O54, filtered and concentrated in vacuo, thereby obtaining the corresponding chloride (5.3 g), which was used directly in the next stage. 3.3 g of this substance was dissolved in 2-butanone (50 ml) and subjected to interaction with 2,2-α02-6,6-dimethylpiperazine (compound .); From d) in the presence of K»CO3 (8.28 g) under reflux overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on a Zpitaadyl EKS-10A device equipped with a Bupegdu C18 column (250 mm x 50 mm, 10 μm) using water and acetonitrile (containing 0.195 TEA, vol./06 b.) as eluents, thus obtaining 1-(1А8,35)-6-chloro-3-phenylindan-1-yl)-3,3-d2-5,5-dimethylpiperazine (compound 0; 1.7 g).

Scheme 12. Synthesis of compound (III) and compound (M) in IV) Its M sho v-4 Io.

ОНоод- я 7 и т У Ве --- -О ши то шк ц та --

KZ sh - s s Ak u

EE 15.35) -enantomer: stock

About (1535 renannomer! speluka PT spotuka 2

1-((18,35)-6-chloro-3-phenylindan-1-yl)-3,3-d2-5,5-dimethylpiperazine solution (compound 0; 0.5 g)

Zo in HCNO/HCOOH (1 mL/1 mL) was refluxed overnight. Volatile substances were removed under vacuum. The residue was partitioned between EIOAc and 1095 aqueous Mahon. The organic layer was dried over NaCl5O, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, thereby obtaining 4-(1А,35)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine-6,6-d2 (compound (I); 0 ,33 g). LC-MS (MUHM-AVZO method): CT(UV) 1.42 min.; UV/EI purity! 5 10095/10095; observed mass 357.2. The inclusion of two deuterium atoms was x»9795. "3 The proton-desolved NMR spectrum showed a quintet at about 49.5 ppm corresponding to the deuterated metabolic site M1; this signal resolved into a singlet at 736

NMR spectra with proton and deuterium resolution. "3 The proton-desolved NMR spectrum additionally showed three triplets at about 126.1, 127.2, and 128.2 ppm corresponding to the deuterated metabolic sites of M3; these signals resolved into three singlets in the 3C NMR spectrum with by proton and deuterium uncoupling. All other signals were singlets in both spectra. The optical purity of the isomer was x»9595 eV.

A solution of 1-((18,35)-6-chloro-3-phenylindan-1-yl)-3,3-d2-5,5-dimethylpiperazine (compound 0; 0.7 g) in OSrO/USOOHO (1 ml /1 ml) was refluxed overnight. Volatile substances were removed under vacuum. The residue was partitioned between E(OAc) and 1095 aqueous Mn. The organic layer was dried over NaCl5O:, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 4-(18,35)-6-chloro-3-phenylindan -1-yl)-1-methyl-az-2,2-dimethylpiperazine-6,6-d2 (compound (M); 0.49 g). LC-MS (MUKMAV25 method): CT(UV) 2.13 min.; UV/EI purity! 5 10095/10095; observed mass 360.2. The inclusion of five deuterium atoms was x»9595. 13 The proton-decoupled NMR spectrum showed a heptet at approximately 36.4 ppm, corresponding to the deuterated metabolic site M2; this signal transforms into a singlet in the Cb proton-deuterium NMR spectrum. The C proton-decoupled NMR spectrum additionally showed a quintet at about 49.5 ppm corresponding to the deuterated metabolic site M1; this signal transformed to a singlet in the C NMR spectrum with proton and deuterium resolution. All other signals were singlets in both spectra. The optical purity of the isomer was »9595 ee.

A solution of (15,35)-6-chloro-3-d5-phenylindan-i-ol (compound E; 7 g) in THF (100 ml) was treated

ZOSI2 (6.6 g) at ambient temperature overnight (Scheme 13). The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution. The organic layer was dried over Na»5O», filtered and concentrated in vacuo to give the intermediate chloride (7.5 g).

Scheme 13. Synthesis of compound (MI) and compound (MI!)

M. E s i s N

Se No to 7 t y o

ЕВ) and 2nd x Ж І"; no P o 5-X - 35 p u. gu - - -sh o p

E (15.55 ananiyuMery E r y shchi shchi

RIV, C5 non-enantiomer compound (B compound (B 1.8 g of this substance was dissolved in 2-butanone (30 ml) and reacted with 2,2-d2-6,6-dimethylpiperazine (compound .); 1.4 g) in the presence of KgSO3 (5.5 g) under reflux overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on a 5pitala EKS-10A instrument equipped with a Bupegdu C18 column (250 mm x 50 mm, 10 μm) using water and acetonitrile (containing 0.195 TEA, vol./06 b.) as eluents, thus obtaining 1-(1А8,35)-6-chloro-3-y5-phenylindan-1-yl) -3,3-d2-5,5-dimethylpiperazine (compound P; 1.7 g).

A solution of 1-1 8,35)-6-chloro-3-a5-phenylindan-1-yl)-3,3-d2-5,5-dimethylpiperazine (compound P; 1 g) in OBSrO/USOOO (1.5 ml/1.5 ml) was refluxed overnight. Volatile substances were removed under vacuum. The residue was partitioned between E(OAc) and 1095 aqueous Mn. The organic layer was dried over Ma»5O:, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, thereby obtaining 4-(1НА,35)-6-chloro-3-д5- phenylindan-1-yl)-1-dz-methyl-2,2-dimethylpiperazine-6,6-d2 (compound (MI); 0.55 g). LC-MS (UMyKhiIAV25 method): CT(UV) 2.13 min.; UV/EI purity! 5 98.2956/10095; observed mass 365.2. The inclusion of ten deuterium atoms is »9195. 13 The proton-decoupled NMR spectrum showed a heptet at approximately 36.4 ppm, corresponding to the deuterated metabolic site M2; this signal turns into a singlet in the 3Sb NMR spectrum with proton and deuterium resolution. C NMR spectrum with proton decoupling additionally showed a quintet at about 49.5 ppm corresponding to the deuterated metabolic site

E; this signal was converted to a singlet in the 3C proton-deuterium NMR spectrum. 13; the proton-desolved NMR spectrum additionally showed three triplets at approximately 126.1, 127.2, and 128.2 ppm. , corresponding to the deuterated metabolic sites of M3; these signals were transformed into three singlets in the "3 NMR spectrum with proton and deuterium decoupling. All other signals were singlets in both spectra. The optical purity of the isomer was x»9595 ee.

Solution of 1-((18,35)-6-chloro-3-d5-phenylindan-1-yl)-3,3-d2-5,5-dimethylpiperazine (compound P; 0.7 g) in HCNO/HCOH (1 mL/1 mL) was refluxed overnight. Volatile substances were removed under vacuum. The residue was partitioned between E(OAc) and 1095 aqueous Mn. The organic layer was dried over Ma»5O:, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, thereby obtaining 4-(1НА,35)-6-chloro-3-d5 -phenylindan-1-yl)-1-methyl-2,2-dimethylpiperazine-6,6-d2 (compound (MI); 0.47 g). LC-MS (M/UHM-AVZO method): CT(UV) 1.33 min.; purity according to UV/EI 5 97.495/10095; observed mass 362.3. The inclusion of seven deuterium atoms was x»9395. "3 The proton-desolved NMR spectrum showed a quintet at about 49.5 ppm corresponding to the deuterated metabolic site M1; this signal was transformed into a singlet in the "Zb proton-deuterium NMR spectrum. "The proton desolvation NMR spectrum additionally showed three triplets at approximately 126.1, 127.2, and 128.2 ppm corresponding to the deuterated metabolic sites of M3; these signals resolved into three singlets at 730

NMR spectra with proton and deuterium resolution. All other signals were singlets in both spectra.

The optical purity of the isomer was 29595 ee.

Example 5. Description of NMR determination of position(s) containing deuterium instead of hydrogen.

NMR spectra were recorded on a VgyKeg 600-Amapse-P spectrometer equipped with a 5 mm TSI cryoprobe operating at 150.91 MHz for "ZS. The SOSiIz solvent was used as an internal standard for experiments with proton decoupling, while spectra with of protons and inversely regulated deuterium were recorded using controlled closure. The difference between the two spectra for the compounds of the invention determines the position of the deuterium atoms. When combining this information, summarized in the table below (Table 3), with the electrospray mass spectrometry data, which determined the degree of deuteration, it is possible to unambiguously establish the structures of the compounds of the invention.

Table C

C NMR data for compounds

M3Z (phenyl group at

From M.d.) -128.2 (26 syaMmRz | SYMRZ | zyamrz | SYMRZ | zyamra) /SYMRz

Compound!| solution solution solution solution solution solution solution proton runs | of protons ran | of protons and deuterium deuterium deuterium (0) | heptet | singlet | singlet | singlet | singlets | singlets: (0 | ssinglet | singlet | singlet | singlet | Triplets | Zsinglets (0) Ш| osinglet | singlet | o quintet | singlet | Zsinglets| Zsinglets

The table includes only NMR signals that "change" as a result of the presence of OH, and not H, in the compounds of the invention.

Corresponding sections of "3 NMR spectra with proton resolution (lower spectrum) and deuterium resolution (upper spectrum) of compound (II) and compound (M) are shown in figure C as representative examples. Selected sections of "3 NMR spectra with by uncoupling of protons and uncoupling of protons and deuterium of compound (II) fig. FOR| and compounds (M) | fig. ZVI

Example 6. Description of mass spectrometry with electrospraying to determine the degree of deuteration

Tools. Mass spectra of acidic and aqueous solutions of the compounds were obtained on a quadrupole mass spectrometer NeulLei RasKaga model 1100 1С-М50. Liquid chromatography was performed on an Adiyepi 1100 HPLC system coupled to a mass spectrometer.

Experiment. Sample solutions were obtained by dissolving approximately 2 mg of the substance in a mixture of 2 ml of methanol and 18 ml of a 10 mM ammonium formate solution, pH 3.0. The solutions were then diluted 100 times before analysis. In order to obtain a "pure" peak, the samples were chromatographed using a Umayeg5 X-rhydde C18 column, 3.5 μm (150 x 2.1 mm) and a mixture of 0.195 trifluoroacetate

Zo acid/acetonitrile, 50/50, as mobile phase. This procedure gives a single peak of the compound of interest that elutes after approximately 3.6 min. and contains both deuterated compounds of the invention and small amounts of deuterium-deficient compounds. The mass spectra obtained for these peaks were used to estimate the type of target molecules. The results were determined as a percentage of the total amount of the substance taken as 10095. The actual efficiency of the compounds was not analyzed, only the relative content of deuterium-deficient compounds was determined.

The mass spectrum of the compound (IM) is shown as a representative example in Figure 4. The isotopic pattern of the protonated compound (M) MANI" corresponded to the mass of 363.1 (362.1--1.0), and isotopic ions 363.1, 364.1 , 365.1 and 366.1 were in the ratio 100:25.3:34.9:7.9; the calculation for SgoNggM»SiIiUv gives the ratio 100:25.2:34.9:8.3. In addition, 0О7 -analogues and UOz-analogues were observed at masses of 362.1 i

358.1, respectively. The signals in 364, 365 and 366 are caused mainly by protonated molecules containing isotopes "ZES and/or 9701 instead of 72C and SI (due to natural distribution).

These data show that the inclusion of eight deuterium atoms is more than 9495.

Example 7. Analyzes of experimental binding

Description of human Y2 binding analysis

The assay was performed as a competitive binding based on the 5RA complex in an assay buffer of 50 mM Tris, pH 7.4, containing 120 mM Masi, 5 mM KSI, 4 mM MasI, 1.5 mM Sasi, 1 mM EOTA. 1.5 nM ZN-raclopride (Regkip EIteg, MET 975) was mixed with the test compound before adding 20 μg of a homogenized membrane preparation of human Ug receptors and 0.25 mg of granules of the ZRA complex (MUZA KRMO 0001, Ategopat) in a total volume of 90 mcl Analytical tablets were incubated with agitation for 60 minutes at room temperature and then counted in a scintillation counter (TtgiYih, UmaiIas). Total binding, which was approximately 1595 added radioligand, was determined using assay buffer, while nonspecific binding was determined in the presence of 10 μM haloperidol. Nonspecific binding was approximately 1095 of total binding.

Data expressed as a percentage of the specific binding of H-raclopride and IC values (the concentration causing 50 percent inhibition of the specific binding of H-raclopride) were determined by non-linear regression analysis using a sigmoidal curve fit with variable slope. The constant dissociation (K) was calculated according to the Spepod Rgizoi equation (Ki - ISvo//1-4(/Ko)), where the concentration of the free radioligand H. is approximated to the concentration of ZN-racloprid added in the analysis. Ko of ZN-racloprid was determined up to 1.5 NM from two independent saturation assays, in each of which three determinations were performed.

Description of human Oi binding analysis

The assay was performed as a competitive binding based on the ZRA complex in assay buffer 50 mM Tris, pH 7.4, containing 120 mM Masi, 5 mM KSI, 4 mM Mosi, 1.5 mM Sasi, 1 mM

EOTA. Approximately 1 nm "H-5CH23390 (Regkip EIteg, MET 930) was mixed with the test compound before adding 2.5 μg of homogenized human O:-receptor membrane preparation and 0.25 mg of 5RA granules (M/SA KERMO 0001, Ategepat) in total volume of 60 μl.

Analytical tablets were incubated with stirring for 60 minutes at room temperature

From the temperature, after which the tablets were centrifuged, and then counting was carried out in a scintillation counter (Tgi ih, UmaIMas). Total binding, which was approximately 1595 added radioligand, was determined using assay buffer, while nonspecific binding was determined in the presence of 10 μM haloperidol.

Data were expressed as a percentage of specific binding, and IC values (concentration causing 50 percent inhibition of specific binding) were determined by non-linear regression analysis using variable slope sigmoidal curve fitting.

The dissociation constant (K) was calculated using the Spepud Rgizoi equation (Ki-ISvo/(1-(1/Ko)), where the concentration of the free radioligand is approximated to the concentration of the radioligand added in the analysis.

Description of human 5-HTgi binding

The experiment was carried out in Seger Sopias I arogayugies (Sai. Vei. 2 471).

Compound (I) was also tested ip mimo on the equipment, which demonstrates the main effects of the compound. With the help of ip mimo binding, the affinity of ip mimo compounds for ОХОг2-receptors was evaluated and the binding of 6095 targets was observed. Binding of Y2 receptors is closely related to antipsychotic effects in animal models and in patients.

Description of Ip binding to Og receptors in the brain of rats

Connection of ip mimo was carried out according to the publication of Apadegzep ei ai. (Eshig U) Rpaptasoi, (1987) 144:1-b; which is incorporated herein by reference in its entirety) with some modifications (published Karig 5.ei ai.,, U Rpapt Ehr Teg, 2003, 305, 625-631; which is incorporated herein by reference in its entirety) . Briefly, 6 rats (male Wistar strain, 180-200 g) were treated with a subcutaneous injection of 20 mg/kg of the test compound 30 minutes before intravenous administration of 9.4 microc of INI-raclopride via the tail vein.

Fifteen minutes after radioligand injection, the animals were killed by cervical dislocation, the brain was quickly removed, and the striatum and cerebellum were excised and homogenized in 5 ml (cerebellum in 20 ml) of ice-cold buffer (50 mM KzRO, pH 7.4). 1.0 ml of the homogenate was filtered through impregnated 0.195 REI UUpaytap CE/C filters. This procedure was completed within 60 seconds of decapitation. The filters were washed twice with 5 ml of ice-cooled buffer and counted in a scintillation counter. A group of vehicle-treated animals was used to determine the total binding (|"NO|)-raclopride in the striatum and non-specific binding in the cerebellum. The protein content in the homogenate was measured by the BCA protein analysis

Zo

(publication Ztiy R.K. ei ai. (1985) Apa! Viospet, 150: 6-85; the publication is incorporated into this description by reference in its entirety).

Example 8. Study of the metabolism of 4-(18,35)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine (compound (X)) and 4-(18,35)-6- chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazine (compound (1))

Cryopreserved hepatocytes from a dog (male short-legged hound) (1 million cells/ml in suspension, 50 μl/well) were pre-incubated for 15 minutes in 96-well plates at 37°C in a water bath in OMEM medium with a high concentration of glucose, buffered with 1 M 50 μl of test compounds (final concentration 01 or 1 μm 4-(18,35)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine (compounds (X)) were added to the cell suspension ) or 4-(18,35)-6-chloro-3-phenylindan-1-yl)-1-methyl-(z-2,2-dimethylpiperazine (compounds (I)) and additionally incubated for 0, 15, 45 , 75 and 120 minutes. The reaction was stopped by adding 100 μl of acetonitrile to the cell suspension and samples were then removed for analysis of the desmethyl metabolite (compound (XI)) by LC-MS. The data were expressed as plot M5 compared to the internal standard.

The results (figure 5 and figure 6) show that the amount of desmethyl metabolite (compound (XI)) produced in cryopreserved dog hepatocytes is lower in the deuterated form (compound (I)) than in the original compound (compound (X)), in both cases carried out at a concentration of 0.1

MKM (figure 5) and at a concentration of 1 µM (figure 6).

Example 9. Pharmacological testing of compounds 4-(18,35)-6-Chloro-3-phenylindan-1-yl)-1-dz-methyl-2,2-dimethylpiperazine (compound (I)) 4-(18,35 )-6-Chloro-3-phenylindan-1-yl)-1-dz-methyl-2,2-dimethylpiperazine (compound ()) was tested in three i.p. migo assays to determine the affinity for dopamine O1 receptor, dopamine Y2 receptor and 5-HTα receptor.

Experiments were performed as described in the Binding Assays section. Experimental results showed the following affinities for 4-(18,35)-6-chloro-3-phenylindan-1-yl)-1-methyl-dz-2,2-dimethylpiperazine: ri: average value of Ki-7.5 NM (pKi 0.88--/-0.15) reg: average value of Ki-34 nM (pKi 1.54--/-0.11)

Ko) B-NTga: ISvo - 1.14 NM.

These binding affinities indicate that compound (I) has biological activity suitable for providing antipsychotic activity.

Pharmacological testing of compound (II) and compound (IM)

Experiments were performed as described in the Binding Assays section. Experimental results for two compounds are shown below.

Compound (II) and compound (IM) were tested in two immunoassays for affinity for dopamine O-receptor: and dopamine O-receptor.

Compound (IM): ri: average value of Ki-26.1 nM (pKi 1.42-/-0.03) p2: average value of Ki-26.7 nM (pKi 1.43--/-0, 04).

Compound (I): рi: average value of Ki-23.2 NM (pKi 1.37-/-0.03) p2: average value of Ki-26.5 nM (pKi 1.42-/-0.03 ).

These binding affinities show that compounds (II) and (IM) have biological activity suitable for providing an antipsychotic effect.

Compounds (II) and (IM) were also tested on the equipment, which demonstrates the main effects of the compounds. With the help of ip mimo binding, the ip mimo affinity of compounds relative to ro-receptors was analyzed and the binding of 7090 target (compound IM) and 7595 target (compound (1Y)) was observed.

O2-receptor binding is closely related to antipsychotic effects in animal models and in patients.

Compounds (I) - (MI) and (X) were analyzed by sequential analysis in Seger Sopias I arogayugieez (Sai.

Ker and 44, 46 and 471). The results of receptor binding are presented in Table 4.

Table 4

Зв'язування сполук з О:, О» і 5-НТга полуки рецептора людини (К; рецептора людини (К; ЇСво (00 | 77771717 олонм7777771717771717171717171711л7бнм7777777 (Оз нм ли НМ (00 | 777 о2гонм777777 |7777717171717171ллб8нМ17777717 | линм (05 | 77777777 оз3бнм7777777 |777777717171711l7bnm7777 | lymn "In this analysis, compound (I) was tested twice.

Example 10. Study of metabolism in the pool of human liver microsomes (HIM)

A pool of human liver microsomes (50 donors, from Hepoiesi) was incubated with 1 μM or 10 μM of the compound at 37°C. The incubation mixture contained 50 mM Tris-HCII, 154 mM KSI, 5 mM Mosi" and the MAORN regeneration system (1 mM MAYUOR" , 5 mM of isocitric acid, 1 unit/ml of isolimonic dehydrogenase, from Zidt-Hiagisp). The protein concentration was 0.2 mg/ml and the final volume was 0.5 ml.

After a 10-minute pre-incubation, the reaction was initiated by adding the compound. After 0, 15, 30, 60, 90, 120, and 180 minutes, the reaction was terminated by transferring the intracellular fraction to 0.5 mL of reaction stop reagent containing the internal standard. Incubations were repeated three times. The samples were centrifuged at 4000 g (4°C, 15 min.) and the supernatants were analyzed using

HPLC-MS/MS. Data were expressed as the area of MC relative to the internal standard.

The results are shown as the mean of three determinations of 550. Figure 7 and Figure 8 show that the amount of desmethyl metabolite produced in human liver microsomes is lower in the case of the deuterated form (compound (II) and compound (IM)) than in the case of the non-deuterated compound ( compound (X)), both at a concentration of 1 μM (Figure 7) and at a concentration of 10 μM (Figure 8). The results for compound (II) are shown in Figure 9. The results for compounds (M) - (MI) are shown in Figures 10-12, respectively. Desmethyl metabolites of compounds (II), (IM) and (X) are compounds (XX) and (XI), respectively (see figure 13).

Research using recombinant SUR2C19 and SURZA4 human liver

Recombinant human liver isozymes SUR2C19 or SURZA4 (from VO Viozsiepsev) were incubated with 1 µM or 10 µM compound (X), compound (II) or compound (IM) at 37°C. The incubation mixture contained 50 mM Tris-HCI, 154 mM KSI , 5 mm Masi" and the MAORN regeneration system (1 mm

MAO RU, 5 mM of isocitric acid, 1 unit/ml of isolimonic dehydrogenase, from Zidt-Aiagisn).

The protein concentration was 0.5 mg/ml and the final volume was 0.5 ml. After 10 minutes of pre-incubation, the reaction was initiated by adding compound (X), compound (II) or compound (IM). After 0, 15, 30, 60, 90, 120 and 180 minutes, the reactions were stopped by transferring the intracellular fraction to 0.5 ml of reaction stop reagent containing the internal standard. Incubations were performed three times. The samples were centrifuged at 4000 rpm (4"C, 15 minutes) and the supernatants were analyzed by HPLC-

From MS/MS. Data were expressed as areas of MC relative to the internal standard.

The results (Figure 14 and Figure 15) show that the amount of desmethyl metabolite produced after incubation with recombinant human liver enzyme CUR2C19 is less in the case of deuterated forms (compound (II) and compound (IM)) than in the case of the non-deuterated compound (compound (X )), both at a concentration of 10 μM (Figure 14, compound (II)) and at a concentration of 1 μM (Figure 15, compound (IM)).

Corresponding results were obtained for compound (II) at a concentration of 1 μM and for compound (IM) at a concentration of 10 μM.

Accordingly, the amount of desmethyl metabolite produced by incubation with recombinant human liver SURZA4 enzyme is lower in the case of deuterated forms (compounds (II) and (IM)) than in the case of the non-deuterated compound (compound (X)), both at a concentration of 1 μM and 10 µM.

Example 11. Pharmacology of the compound (IM)

PCP-induced hyperactivity

The compound (IM) dose-dependently reverses PCR-induced hyperactivity in mice, which indicates its antipsychotic efficacy (Figure 16). Compound tartrate (IM) was injected subcutaneously (5.s.) 30 minutes before the start of the test. RSP hydrochloride (2.3 mg/kg) was injected subcutaneously immediately before the test. Motor activity was measured during 60 minutes as the number of beam interruptions (times). From eight to 16 male mice were used in each group.

Bonferroni). PCR blocks MMOA receptors and as such is used to model the hypoglutamatergic state associated with schizophrenia. RSP produces behavioral effects in animals that resemble positive, negative, and cognitive symptoms of schizophrenia in patients (Uepibsp publication, 9.0. apa Koii, EN MeigorhusporpagtasoiYodu 1999; 20: 201-225; incorporated herein by reference in its entirety ). PCR-induced hyperactivity is usually used as an assay for evaluating antipsychotic compounds (publication Chdaskzop, O.M. ei ai.,

Rpattasoi Viospet Vepamu. 1994; 48: 465-471; it is incorporated herein by reference in its entirety).

Catalepsy

Catalepsy is thought to reflect a drug-induced inhibition of the ability to initiate a behavioral response. The rat catalepsy test is a common and widely used preclinical screening test for EPR sensitivity of potential antipsychotic drugs. Although catalepsy is usually assessed after immediate drug administration, this test has been shown to be a reliable predictor of the propensity of an antipsychotic drug to induce EBRD (ie, pseudoparkinsonism, dystonia) in humans (EP, R. publication). ei ai, U. Meshgai. Thap5t. Ragk. beat

Oetepi 5 essays 1990; 2: 79-89; it is incorporated herein by reference in its entirety).

Compound (IM) dose-dependently induced catalepsy in rats, presumably with ERB sensitivity. The minimum effective dose inducing catalepsy was 10 mg/kg (Figure 17).

Compound tartrate (IM) was injected subcutaneously 30 minutes before the test. Eight male Zrgadcie YuaulLeu rats were used in each group. Mark Ж means p«0.05, ЖЭ means

Р«0.01 in comparison with the filler (one-factor analysis of variance was used

(IAMOMA), then Bonferroni's ro5i-pos criterion. This dose is 100 times higher than the dose indicated for

With antipsychotic activity (figure 16).

Example 12. Pharmacokinetic study with human participation

The pharmacokinetic characteristics of compound (IM) and compound (X) were compared in a multiple oral dose study in young healthy males. Study participants received daily doses of 3 mg of compound (IM) and 3 mg of compound (X) for 18 days, and blood samples were collected within 24 hours (one dosing interval) of the last dose to measure the effects of both compounds and their demethylated metabolites , compound (XX) and compound (XI), respectively.

For all study participants, the area under the plasma concentration-time curve for the dosing interval (AU 0-24) for compound (IM) was higher than the area for compound (X), averaging 104 hours "ng/mL compared to 98 hours" ng/ml A combined shift in the opposite direction was observed for demethylated metabolites with an average value of AC 0-24 of 117 hours"ng/ml and 120 hours"ng/ml for compound (XX) and compound (XI), respectively.

Example 13. Catalytic enantioselective synthesis of an intermediate ketone

This example describes the synthesis of (5)-6-chloro-3-phenyl-(α5)-indan-1-one, compound (ХМ), and (5)-β-chloro-3-phenylindan-1-one, compound (HM).

It turned out that (5)-6-chloro-3-phenyl(d5)-indan-1-one, compound (XM), is a valuable building block in the synthesis of deuterated variants of compound (X), where the free phenyl group is deuterated.

General experimental section

Unless otherwise stated, all reactions were performed under a nitrogen atmosphere. Reactions were monitored using thin-layer chromatography (TLC, TLC) and LC-MSS analysis. All reagents were purchased and used without further purification. Spots were visualized by ultraviolet (UV) radiation (254 nm) or by staining with 595 solution of phosphomolybdic acid (PMA) in ethanol or alkaline aqueous solution of potassium permanganate (KMpO»5) followed by heating. Column chromatography was performed using Megok СбО silica gel (40-63 μm, 230-240 mesh). NMR spectra were recorded at 500 or 600

MHz CH NMR) and calibrated by the residual solvent peak. The following abbreviations were used for NMR data: c - singlet, d - doublet, t - triplet, m - multiplet. Coupling constants were rounded to the nearest 0.5 Hz. The enantiomeric excess of 0.50 cm was determined by chiral HPLC. 60 LC-MS method

An Asdiyu ORI C VEN, C18, 1.7 μm column was used; 2.1 x 50 mm, operating at 60"С with a flow rate of 1.2 ml/min. of a binary gradient consisting of water and - 0.195 formic acid (A) and acetonitrile and 595 water - 0.195 formic acid (B ).

Chiral HPLC method

The Rpepotepeh column was used, 5 in cellulose-2; 250 x 4.6 mm operating at 30" with a flow rate of 0.6 mL/min of a mixture of n-hexane:isopropanol:diethylamine, 90:10:0.1.

Synthesis of (5)-6-chloro-3-phenyl(d5")-indan-1-one (compound (XM)), (Scheme 14)

Scheme 14. Synthesis of the compound (KHM) (Pinacol) B)" y

RASIH (RIZR)" Fr. ro tio rot RAaR rov r OIREA r KORY r - 4-3 2- - --- --b9 522- ro OSM, Kt. in RyMe, vys vo r Stage A: 825 r Stage B

Vg si si (RAzR)Ra fi 2mole FO;

KSO, I(5)-VIMAR|VN(IV EX in ---in- - i - - i p

EON-NoO-RyMe r ro Acetone, kt. o t5o F Stage 0: her r

Stage C o o o 969 o

Stage B8-C: 7495 r 9695 ee (98:2 5:B) r

Total yield 5895 (KHIM) (ХУ) 1-Phenyl(a5)-vinyltrifluoromethanesulfonate (ХХХ)

Trifluoromethanesulfonic anhydride (2.52 ml, 15.0 mmol) was added to a solution of acetophenone-io5 (1.56 g, 12.5 mmol) in СНе2Си» (25.0 ml) at room temperature. Then M,M-diisopropylethylamine (3.04 mL, 17.5 mmol) was added dropwise, while the reaction mixture was cooled in an ice-water mixture bath. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Trifluoromethanesulfonic anhydride (0.63 mL, 3.74 mmol) was added followed by M,M-diisopropylethylamine (1.09 mL, 6.24 mmol). The reaction mixture was stirred for 2 hours at room temperature. Toluene (25 ml) and silica gel (5 g) were added. The mixture was concentrated in vacuo and the resulting suspension was filtered through a layer of celite. The filter cake was washed with toluene (10 mL) and the filtrate was evaporated to dryness in vacuo to give the crude compound (XII) (3.11 g, 82965, purity (NMR): ca. 8595) as a dark oil, which was used without further cleaning.

NMR NMR (600 MHz, SOSI) bn 5.38 (d, 1H, 9U-4.0 Hu), 5.62 (d, 1H, 9U-4.0 Hz).

B-Chloro-2-(1-phenyl(a5)-vinyl)benzaldehyde (KHIM) (publications TakKadi, 9.; Takanaezni, K.; Izpiuata,

T.; Miuaga, M. U. At. Spent boss. 2002, 124, 8001-8006; biteope, 9.R.; bBoma, u). V. uUg. Temanedgop 2007, 63, 12646-12654; each incorporated herein by reference in its entirety).

To a solution of compound (XII) (3.11 g, 10.3 mmol, purity (NMR) approximately 8595) in toluene was added triphenylphosphine (108 mg, 0.685 mmol), bis(pinacolato)diborone (2.61 g, 10.3 mmol),

Zo bis(triphenylphosphine)palladium(II) chloride (240 mg, 0.342 mmol) and potassium phenolate (1.92 g, 14.6 mmol). The reaction mixture was stirred at 50°C for 4 hours. This gave compound (XII) in the mixture, which was not isolated from the mixture. The mixture was cooled to room temperature and ethanol (10 mL) and water (5 mL) were added followed by tetrakis(triphenylphosphine) )palladium(0) (495 mg, 0.428 mmol), potassium carbonate (4.73 g, 34.2 mmol), and 2-bromo-5-chlorobenzaldehyde (1.88 g, 8.56 mmol). The reaction mixture was stirred at 80"C for 16 hours. The mixture was cooled to room temperature and partitioned between water (50 mL) and toluene (50 mL).

The organic phase was separated and washed with water (50 ml) twice and saturated saline. The organic phase was dried over Md5O5, filtered and evaporated to dryness under vacuum. The residue was purified by column chromatography eluting with a mixture of 80:1 n-heptane:E(Ac), thereby obtaining the compound (KHIM) (1.66 g, 7490) as an orange oil.

I"H NMR (600 MHz, SOS") bn 5.28 (d, 1H, 9U-0.5 Hz), 6.00 (d, 1H, 9U-0.5 Gu), 7.30 (d, 1H, 9U-8.0

Hz), 7.56 (dd, 1H, 9U-2.5, 8.0 Hz), 7.96 (d, 1H, 9-2.5 Hz); 3 NMR (150 MHz, SOSIi") and 118.7, 126.6 (t, U-24.0 Hz), 127.5, 128.2 (t, 9-24.0 Hz), 128.4 ( t, 9U-24.0 Gu), 132.5, 133.7, 134.7, 135.7, 1403, 143.9, 144.8, 190.8; LC-MS (ARRI): calculated m/e for C15H705C10 |MeNi 248.1, found 102481. (5)-6-Chloro-3-phenyl(a5)-indan-1-one (KHM) (published by Kypai, K .; MeSyPaodn, 9. M.; Mogepeaad, A. T.

UK U. At. Spent boss. 2005, 127, 16042-16043; incorporated herein by reference in its entirety).

Hydrogen was bubbled through a Ma-washed solution of ((K)-2,2- bisidiphenylphosphino)-1,1-binaphthyl)(norbornadiene)rhodium(I) tetrafluoroborate (37 mg, 0.0404 mmol) in acetone (7.5 mL) for 10 minutes at room temperature, during which time the color of the solution changed from orange to brownish-red. The flask containing the solution was then quickly washed with a jet of gaseous M". Then, at room temperature, a solution of (CHM) (526 mg, 2.02 mmol, purity (LC-MS) 9595) in acetone (7.5 mL) was added. The reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was mixed with silica gel and evaporated to dryness under vacuum. The obtained substance was loaded into a column with silica gel and the product was eluted with a mixture of 10:1 n-heptane:E(OAc), thereby obtaining compound (XM) (495 mg, 96905, isomer content 96.095 ee) as a solid. "H NMR (500 MHz, SOSIz) bn 2.72 (dd, 1H, 9U-4.0, 19.5 Hz), 3.27 (dd, 1H, 9-8.0, 19.5 Hz), 4.55 (dd , 1H, 9U-4.0, 8.0 Hz), 7.21 (d, 1H, U-8.0 Hz), 7.52 (dd, 1H, 9U-2.0, 8.0 Hz) . ), 127.3 (t, y-24.0 Hz), 128.7 (t, 9-24.0 Hz), 134.4, 135.1, 138.2, 142.9, 156.0, 206.4; LC-MS (ARRI): t/e calculated for

С15Н?Б5СИО (MANI 248.1, found 247.6.

Synthesis of (5)-6-chloro-3-phenylindan-1-one (HMI) (Scheme 15):

Zo Scheme 15. Synthesis of compounds (CHEMICALS) and 7 to su z schi Se maon Sto OR BA tya pn y om meon-nyo, CT. he is a Roma village

Stage A: 46 ohms) Stage B: 9795

REOASI o (VZ B-HYMEOVIRNER o ts Ruoiop vropde SI What, -- - - sl OmME, 8576 5 stage c: tt

MO 6495 ee(82:18 8:K) (MIV

Total yield: For (E)-1-(5-Chloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (HMI)

To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL) was added benzaldehyde (0.746 g, 7.03 mmol) followed by a solution of 5-chloro-2-hydroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The main part of the organic solvent was removed by evaporation in a vacuum. The aqueous residue was extracted with EtOAc (3 x 30 ml). The combined extracts were washed with water (50 ml) and saturated saline solution (50 ml), dried over

MBO", was filtered and evaporated in a vacuum to dryness. The residue was dissolved in a minimum volume of СНоСи» and n-pentane was added, resulting in the formation of a precipitate. The resulting suspension was filtered and the precipitate was washed with a small amount of cold pentane and dried in vacuo to give compound (XM!) (695 mg, 4695) as an orange solid.

IN NMR (500 MHz, SOSI»z) bn 6.22 (d, 1H, 9U-9.0 Hz), 6.80 (dd, 1H, 9U-3.0, 9.0 Hz), 7.33 (t, 1H,

In 7.5 Gu), 7.38-7.42 (m, 4H), 7.60 (d, 2H, 9U-7.5 Hz); 8.63 (d, 1H, 9U-16.0 Hz); C NMR (125 MHz,

SOPHIE") boss 110.6, 125.2, 127.8, 128.1, 128.8, 128.9, 129.4, 129.6 133.0, 136.4, 137.1, 174.5 , 188.2. 4-Chloro-2-(E)-(3-phenylacryloyl))-phenyl ester of trifluoromethanesulfonic acid (CHMII)

M,M-diisopropylethylamine (697 μl, 4.00 mmol) was added to a solution of the compound (HMI) (517 mg, 2.00 mmol) in СНоСи»g (10.0 mL). Then trifluoromethanesulfonic anhydride (437 μl, 2.60 mmol) was added dropwise at 0"C. The reaction mixture was stirred for 45 minutes at 0"C. A saturated aqueous solution of MNACI (5 ml) and water (10 ml) were added and the mixture was stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with SNeosSig (10 ml). The combined extracts were dried over Md5O", filtered and evaporated in vacuo to dryness. The residue was purified by column chromatography eluting with a mixture of 4:1 n-heptane-E(OAc), thereby obtaining the compound (CHMII) (757 mg, 9795) in the form of an oil.

IN NMR (500 MHz, SOSIz) bn 7.16 (d, 1H, 9U-16.0 Hz), 7.34 (d, 1H, 9U-9.0 Hz), 7.40-7.47 (m ) , 7.72 (d, 1H, U-2.5 Gy); ZS NMR (125 MGu, SOSI") because 124.1, 124.2, 129.0, 129.2, 130.7, 131.5, 132.8, 134.1, 134.6, 145.2, 147.8, 188.4. (5)-6-Chloro-3-phenylindan-1-one (KHM) (published by Mipatsyi, A.; 7pepod, H.; Vyspua!y, 5. H.. U. Oga.

Spent 2007, 72, 9253-9258, incorporated herein by reference in its entirety).

To a solution of compound (CHMII) (195 mg, 0.500 mmol) in DMF (2.0 mL) was added a proton sponge (rgoiop-zropde) (214 mg, 1.00 mmol), palladium acetate (b mg, 0.025 mmol) and ( K)-3,5-

HUIMEOVIRNER (35 mg, 0.05 mmol) at room temperature (rt). The reaction mixture was stirred at 85°C for 45 hours. The mixture was cooled to r.t. and diluted with TVME (15 mL). The mixture was washed three times with water (3 x 20 mL) and the organic phase was dried over Mo95OH, filtered and evaporated in vacuo to dry state. The residue was subjected to column chromatography eluting with a mixture of 10:1 n-heptane:ethyl acetate, thus obtaining the compound (CHMII) (94 mg, 7795, isomer content 6495 ee). "H NMR (600 MHz, SOCI3) bn 2, 71 (dd, 1H, 9U-4.0, 19.5 Hz), 3.25 (dd, 1H, 9-8.0, 19.5 Hz), 4.54 (dd, 1H, U-4, 0, 8.0 Hz), 7.10 (d, 2H, 9-7.0 Gy), 7.20 (d, 1H, 9U-8.0 Hz), 7.25 (t, 1H, 9U- 7.5 Hz), 7.391 (t, 2H, 9-7.5 Hz), 7.50 (dd, 1H, 9U-2.0, 8.0 Hz), 7.75 (d, 2H, 9U- 2.0 Hz); C NMR (150 MHz, SOSI") bs 441, 47.2, 123.3, 127.3, 127.6, 128.3, 129.1, 134.4, 135.2, 138.3, 143, 1, 156.1, 204.5.

Preparation of the enantiomer-enriched compound (HMIII) by reprecipitation

The compound (CHMII) (940 mg, 3.87 mmol, 9695 ee) was dissolved in a minimum volume of boiling ethanol (9995, vol./06.). The resulting solution was allowed to cool slowly to the boiling point. by exposing the glass flask containing the solution to air. The formed precipitate was separated from the solution by filtration, thus obtaining the compound (XMIII) (700 mg, 99.995 ee, 7495). The second portion of the compound (HM!) can be obtained by cooling the filtrate in a freezer (-8"C), thereby obtaining the compound (HMI) (80 mg, 98,695 ee, 990).

Analytical data (NMR and LC-MS) for compound (CHMII) were the same as above.

Example 14. Preparation of the compound (IM) in large quantities

The following method was developed to obtain the tartrate salt of the compound (IM) in large quantities.

Scheme 16. Synthesis of rac-trans-1-(b-chloro-3-phenyl(α)-indan-1-yl)-3,3-dimethylpiperazine maleate. obliquely. MIVK M IM the fate of the thief in s i s o Y si s i slot vo, But i ok IF, o

In Yu c) in and or; ! t I, E ikhhXV y (XX) I p still r; cis-racemate cis-racemate (51505 trane-isomer! schi o

Mop. mass 249.75 Mop. mass 258.20 Ikhi o (xx s.MSyuYur. blue, iikhhm) mapeat

Mol. mass 462.00 (3а5.53ж115.07) trans-racemate (1895 cis-isomer)

Methodology 1). 2.01 kg (16.9 mol) of thionyl chloride and 7.2 kg of tetrahydrofuran are mixed and the reaction mixture is cooled to 10-1576. 2). A solution of 2.76 kg (11.1 mol) (XXIII) in 7.2 kg of tetrahydrofuran (THF, TNE) is slowly added and after the addition is complete, 5.9 kg of THF is added. 3). The reaction mixture is stirred at 157C for about 90 hours. 4). 16.7 kg of water is cooled to 11"C and slowly added to the reaction mixture, after which 7.8 kg of 27.790 aqueous sodium hydroxide solution is slowly added, followed by the addition of 10 kg of ethyl acetate. 5). The mixture is stirred for 20-40 minutes. 6). The phases are separated and the volume of the organic phase is reduced to a volume of approximately 6 L. 7) 16 kg of methyl isobutyl ketone is added and the volume is reduced to approximately 8 L. 8) 1.58 kg (11.4 mol) of potassium carbonate is added 1.69 kg (14.8 mol) of 2,2-dimethylpiperazine and 13.6 kg of methyl isobutyl ketone. 9). The reaction mixture is stirred for 35 hours at 90-95760. 10). After cooling to room temperature, 11 kg of water is added and the mixture is stirred for 30-60 minutes. 11). The phases are separated. 13.7 kg of water is added to the organic phase and the mixture is slowly stirred for 30-60 minutes. 12). The phases are separated and the organic phase is filtered until a clear solution is obtained. 13). Add 5 kg of methyl isobutyl ketone, 7.8 kg of water and 5.9 kg of 3695 aqueous hydrogen chloride and the mixture is stirred at 507C for 30- 60 minutes. 14). The phases are separated, 8 kg of methyl isobutyl ketone is added to the aqueous phase and the mixture is cooled to 10-1576. 15). A mixture of 3.5 kg of methyl isobutyl ketone and 7.8 kg of 2595 aqueous ammonia solution is slowly added to the mixture and the reaction mixture is stirred at 20-257C for 60-90 minutes. 16). The phases are separated and the organic phase is washed with 10.5 kg of water. 17). The volume of the organic phase is reduced to 8 l. 18. Add 1.19 kg (10.25 mol) of maleic acid and 9 kg of methyl isobutyl ketone and the reaction

The mixture is then heated to 75-8070. 19). After cooling to 10-15", the precipitate is filtered and washed with 10 kg of methyl isobutyl ketone. 20). The solid is dried in a vacuum oven at 507"C for about 20 hours, obtaining 3.47 kg (yield 6895) of the compound maleate (XXM).

NMR data for the compound maleate (XXM): "H-NMR (O0M50-a6, 600 MHz, ppm): 8.60 (shr.s, 2H, maleic acid), 7.39 (d, 1H, 9U -1.6 Hz), 7.29 (dd, 1H, 9U-8.0 Gu, 9U-1.8 Hz), 6.98 (d, 1H, 9-82

Hu), 6.04 (c, 2H, maleic acid), 4.56 (dd, 1H, 9U-8.1 Hz, U-4.9 Hu), 4.48 (dd, 1H, 9U-8, 6 Hz, 3-6.2 Hz), 3.37 (width s, 1H), 3.16 (width s, 2H), 2.77 (width s, 1H), 2.58-2, 50 (m, ZN), 2.31 (d, 1H, 912.0 Gu), 2.12 (ddd, 1H, 9U-13.8 Gu, 9U-8.0 Hz, U-6.0 Hz) , 1.33 (c, ZN), 1.31 (c, ZN).

Scheme 17. Synthesis of succinate rac-trans-1-(b-chloro-3-phenyl(d5)-indan-1-yl)-1 (dz),2,2- trimethylpiperazine n n I. MH aqueous MTBE so, sv ,

My 2 Sat. KOM, BUT. MTEE M M su su Z. MA, water S Su

M M 4. AssSi, MTBE M M in, 4 FI, -Burmtnic acid, zceta FI; o o an o o what r on o 5 b s o o o s o o ah t | he she t shchi p (xx o rok) PM) o (XM (XXM) Mapeate (XX sSuccinate

Mol. mass 462.00 1345 3115 07 Mol. mass 48107 (3655.88g118.09) trans-racemate 2995 cis) trans-racemate

Methodology 1). 1.1 kg (2.38 mol) of compound maleate (XXU), 11 l of methyl tert-butyl ester, 1.8 l of water and 1 l. 2595 of an aqueous solution of ammonia is stirred for 1-2 hours. 2). The phases are separated and the organic phase is washed twice with 2 liters of water.

3). A solution of 254 g (3.85 mol) of 8595 aqueous solution of potassium hydroxide and 1.5 l of water is added to the organic phase followed by the addition of 450 g (3.11 mol) of methyl(dz)iodide (CO). 4). The reaction mixture is stirred at 20-257C for 16-24 hours. 5). Add 2 liters of water and filter off the precipitated by-product. 6). 0.8 l of water and 0.2 l of 2595 aqueous ammonia solution are added to the filtrate and the mixture is stirred for 20-40 minutes. 7). The phases are separated and the organic phase is washed with 2 liters of water. 8). The phases are separated and 38 g (0.48 mol) of acetyl chloride is added to the organic phase and then it is stirred for 20-40 minutes. 9). Add 0.8 l of water and 0.2 l of 2595 aqueous ammonia solution and stir the mixture for 20-40 minutes. 10). The phases are separated and the organic phase is washed with 2 liters of water. 11). The organic phase is evaporated to dryness and acetone is added. 12). Add 225 g (1.91 mol) of succinic acid and acetone in such an amount that the volume of the reaction mixture is approximately 6-6.5 liters. 13). The reaction mixture is heated to reflux and then cooled to 5-1076. 14). The precipitate is filtered and washed with 1 liter of acetone. 153. The solid substance was dried in a vacuum oven at 50"C for more than 16 hours, obtaining 630 g (yield 5595) of compound succinate (XXMIII).

NMR data for the compound succinate (XXMI!): "H-NMR (0M50-ab6, 600 MHz, ppm): 7.33 (d, 1H, 9-1.9 Gsch, 7.26 (dd, 1H , 9U-8.1 Hz, uU-2.0 Hz), 6.95 (d, 1H, U-8.0 Hz), 4.46 (dd, 1H, 9U-8.0 Hz, 9U-5 ,1

Hz), 4.46 (dd, 1H, 9U-8.8 Hz, 9U-5.8 Hz), 2.65-2.56 (m, 4H), 2.46-2.41 (m, 1H ), 2.37 (s, 4H, succinic acid), 2.31 (shr.s, 1H), 2.13 (d, 1H, U-10.9 Hz), 2.02 (ddd, 1H, 9U -13.7 Hz, U-7.8 Hz, U-6.0 Hz), 1.04 (s, ZN), 1.02 (s, ZN).

Scheme 18. Synthesis of 4-(18,35)-6-chloro-3-phenyl(α)-indan-1-yl)-1(dz),2,2-trimethylpiperazine tartrate ,

M su SU Ya. MA. water EUDe su on

M M 2. it is - tartaric acid, acetone M no ; (os K z s Z EUN and recrystallization) si o v n i a -T15Zh(i ke ZM gives "300 8 AR o y o o o o on y I p o 0 b o schi (oh) (M) tartrate mol .mass 519.07 1362.95-150.09)

ХХУЙ Succinate сСНЕССИОЮ,, SO, mol. mass «8107 (362.98 118.05) t shi

Methodology 1). 1.0 kg (2.08 mol) of succinate compound (XXMII), 8 l of ethyl acetate, 2 l of water and 1 l of 2595 aqueous ammonia solution are mixed for 0.5-1 hour. 2). The phases are separated and the organic phase is washed with 2 liters of water. 3). The organic phase is reduced to approximately 1.5 l. 4). Add 10 liters of acetone and 312 g (2.08 mol) of I -(--.)-tartaric acid. 5). The reaction mixture is heated to reflux and then cooled to 5-1076. 6). The precipitate is filtered off, washed with 1.2 l of acetone. 7). Wet sediment on the filter is unloaded and 11 liters of absolute ethanol are added. 8). The reaction mixture is heated to reflux and then cooled to 5-1076. 9). The precipitate is filtered and washed with 1.2 l of absolute ethanol. 10). The solid substance was dried in a vacuum oven at 50"C for more than 16 hours, obtaining 395 g (yield 3790) of I -(--)-tartrate of compound (IM).

NMR data for compound I -(--)-tartrate (IM): "H-NMR (0M50-ab, 600 MHz, ppm): 7.36 (s, 1H), 7.27 (d, 1H , U-8.2 Hz), 6.96 (d, 1H, 9-8.2 Hz), 4.50 (dd, 1H, 9U-8.0 Hz, 95.1 Hz), 4.45 ( dd, 1H, 9U-8.5

Hz, U-5.8 Hu), 4.07 (s, 2H, tartrate), 2.95 (shr.s, 1H), 2.77 (shr.s, 1H), 2.61-2.50 (m, ZN), 2.31 (d, 1TN, 9-11.7 Gu), 2.04 (ddd, 1Н, 9У-13.7 Hz, 9У-27.8 Hz, 9У-6.0 Hz ), 1.21 (c, ZN), 1.18 (c, ZN).

Example 15. The physicochemical characteristics of the salts of the compound (IM) pKa and y0d R/O of the compound (IM) pKa were determined by potentiometric titration of the base at an ionic strength of 0.16 using

Meon as a co-solvent. Three series of three replicate titrations of the same sample solution were performed in a conventional manner from low to high pH and a difference curve was constructed for each of these titrations by subtracting the blank value.

The apparent pKa value at each MeOH:water ratio was calculated from the difference curves, and the pKa value was determined by extrapolation to zero MeOH content.

The lower value of pKa is too low to be determined by potentiometric titration, as values as low as "3 have been found to be reliable. It was determined that the highest pKa value is 8.901.

The lower value of pKa was determined by OiIR-Rhobe detection by absorption spectroscopy during titration of the base at an ionic strength of 0.16 using Meon as a cosolvent. The change in absorption spectra as a function of ionization was used to calculate the value of pKa. Two series of three replicate titrations of the same sample solution were performed from low to high pH with the photodiode array as additional detection. The apparent pKa value at each MeOH:water ratio was calculated by target factor analysis when the absorption spectrum changed, and the pKa value was determined by extrapolation to zero MeOH content.

Result: The lower pKa value was determined to be 2.5:50.1.

The IodO profile was determined by titration at 27"C and an ionic strength of approximately 0.16. A series of three repeated titrations of the same sample in a solution with a pH from low to high was carried out.

The first titration was performed with a small amount of n-octanol present in the solution, the second and third titrations were performed with increasing amounts of octanol.

A curve of differences was constructed from each value of these titrations by subtracting the value of a blind experiment, and imaginary values of pKa (roKa) were calculated from these curves of differences. Based on the change in the imaginary values of pKa (brKa) with the n-octanol:water ratio, in combination with the real value of pKa, the value of I odR was calculated and the Godot profile was established. The following values were determined: I 0d P--5.4--0.4 and Her 09 074-3.9--0.4.

Melting point determined by DSC

The melting point of the (K,K)-hydrotartrate salt of the compound (IM) was determined using differential scanning calorimetry (DSC) and using TA DSC 21000 instruments, which heat the sample at a rate of 5"7/min. The sample was placed in a closed cup with a perforated point hole

Melting is characterized by the initial and burn temperatures of endothermic melting, and the melting enthalpy was calculated from the peak area. Based on the DSC thermogram, the initial temperature of 187.4"C and the maximum peak at 189.47"C were determined. The enthalpy of fusion was 96 J/g, which corresponds to 49 kJ/mol, however, the thermogram is an indication that melting occurs during decomposition, which means that the enthalpy probably contains energy other than the fusion energy.

Solubility

The solubility of the (K,K)-hydrotartrate salt of compound (IM) was measured in aqueous solutions and in cyclodextrins with the following results (Table 5).

Table 5

Solubility of the (K.,K)-hydrotartrate salt of the compound (IM)

Hydrotartrate water, ZUE |Y777771711111111111111111l6b611111111111111111111111С|1508

BU NRASO priv /7777777777111111Ї7111111111111111111111т1а11Ї1

Polymorphism

A single crystalline form of the tartrate, containing no solvent, was isolated. An X-ray powder diffraction pattern (XPRD) of this form is shown in Figure 18, and this form is referred to in the description as "polymorphic modification A".

Salt compounds (IM)

Four salts were obtained by precipitation of compounds (IM) with 9995 ETON.

Analytical data are shown in the table below (table 6).

Table 6

Data for salts of the compound (IM)

DSK (Tpochatk "S

Decomposition at 250"C

Hydrofumarate 202.77 150.47C 145.0"C with subsequent decomposition

Hydrotartrate 187"C

Although the invention has been described and illustrated in the above illustrative embodiments, it is to be understood that this description of the invention has been presented by way of example only, and that numerous changes may be made in the details of the implementation of the present invention without departing from the spirit and scope of the present invention, which is limited only the formula of the invention given below. The features of the described embodiments can be combined and/or rearranged in various ways within the scope and essence of the present invention to make additional embodiments that are also within the scope of the present invention. Those skilled in the art will recognize or be able to establish, using no more than ordinary experimentation, numerous equivalents of the specific embodiments described specifically in this description of the invention. It is understood that such equivalents are included in the scope of the following claims.

Claims (31)

FORMULA OF THE INVENTION 1. The compound of the formula U: viv" v? v? pa Vi SI | Y v v? v i 8 i schi where V'-V'E are independently hydrogen or deuterium, where each of K9-HV'? represents deuterium, wherein at least one of K'!-B'O contains at least about 50 95 deuterium, or a pharmaceutically acceptable acid addition salt thereof. 2. Compound according to claim 1, where is each of KZ-B? is hydrogen. 3. The compound according to claim 1, where each of KZ-BA" represents deuterium. 4. The compound according to claim 2, where the compound is a compound of the formula C SI | Y y y y y y (18, 35)-(II). 5. The compound according to claim 2, where the compound is a compound of the formula Z / on 2» SI | Y y y y y y (18, 35)-(MI). 6. The compound according to claim 3, where the compound is a compound of the formula o |B) in C by si H р р р р р (18, 35)-(IM). 7. The compound according to claim 3, where the compound is a compound of the formula o |B) p IV) M SI | Y y y y y y (18, 35)-(MI). 8. The compound according to claim 1, where each of K' and Be is a deuterium. 9. The compound according to claim 8, where each of KZ-B" represents deuterium. 10. The compound according to claim 8, where each of KZ-NV" represents hydrogen. 11. A compound according to any one of claims 1-10, wherein at least about 85 95 of the compound has a deuterium atom in each position where it is designated as deuterium, and any atom not designated as deuterium is present in approximately its natural relative ratio isotopes 12. A compound according to any one of claims 1-11, wherein at least about 90 95 of the compound has a deuterium atom at each position where it is designated as deuterium, and any atom not designated as deuterium is present in approximately its natural relative ratio isotopes 13. The compound according to claim 1, where the compound is a hydrotartrate salt of the compound of the formula o |B) in С D/» SI | More (18, 35)-(IM). 14. The compound of claim 13, wherein the compound exists in a polymorphic form having an X-ray powder diffraction pattern (XPRD) shown in Figure 18. 15. The compound of claim 13, wherein at least about 85 95 of the compound has a deuterium atom at each position where it is labeled as deuterium, and any atom not labeled as deuterium is present in approximately the natural relative ratio of its isotopes. 16. A pharmaceutical composition comprising a compound according to any one of claims 1-15 and one or more pharmaceutically acceptable carriers, diluents or excipients. 17. Pharmaceutical composition according to claim 16, where the compound is a hydrotartrate salt of the compound of the formula o |B) in СМССИ | More (18, 35)-(IM). 18. The composition of claim 16 or 17, wherein the carrier comprises hydroxypropyl-B-cyclodextrin in a carrier wherein at least about 8595 of the compound has a deuterium atom at each position where it is labeled as deuterium and any atom not labeled as deuterium. present in approximately the natural relative ratio of its isotopes. 19. Use of a compound according to any of claims 1-15 or a composition according to any of claims 16-18 for the manufacture of a medicinal product for the treatment of psychosis, other diseases including psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms. 20. The use of claim 19, wherein the psychosis or disease comprising psychotic symptoms is schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, transient psychotic disorder, split psychotic disorder, bipolar disorder, or mania in bipolar disorder. 21. Use according to any one of claims 19-20, further comprising a compound selected from the group consisting of sertindole, olanzapine, resperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and ozanetant. 22. Use according to any one of claims 19-20, wherein the psychosis or a disease comprising psychotic symptoms is schizophrenia. 23. Use according to any one of claims 19-20, wherein the psychosis or the disease including psychotic symptoms is schizophrenia, wherein the pharmaceutical composition contains an effective amount of the hydrotartrate salt of the compound of the formula o|B) in C M SI | N y y y y y (18, 35)-(IM) and hydroxypropyl-B-cyclodextrin in water, and wherein at least about 85 95 of the compound (IM) has a deuterium atom at each position where it is labeled as deuterium, and any atom not labeled as deuterium is present in approximately its natural relative ratio isotopes 24. The compound of the formula (c) SI c) c) c) c) schi (8)-(XM). 25. The method of obtaining the compound of the formula (c) SI c) c) c) c) o; р р р р р (CHEMISTRY). 26. The method according to claim 25, where ((5)-VIMARIVN(I)VE" is used in a catalytic amount. 27. The method of obtaining the compound of the formula (c) SI Sheche i р р рр ро (ХМ) which includes a) treatment of the compound of the formula c) OT р р р р (XI) bis(pinacolato) diboron and 5) treatment with 2-bromo -5-chlorobenzaldehyde. 28. The method according to claim 27, where the treatment of the compound of the formula c) OT р р р р (Xi) bis(pinacolato) diboron also includes the addition of Ра). 29. The method according to claim 28, wherein the treatment with 2-bromo-5-chlorobenzaldehyde also includes the addition of Pa(O). 30. The method of obtaining the tartrate of the compound (18,35)-(IM), which includes the processing of racemic trans-1-(b-chloro-3-phenyl(α)-indan-1-yl)-1(dz),2, 2-trimethylpiperazine I -(--)-tartaric acid. 31. The method according to claim 30, where racemic trans-1-(b-chloro-3-phenyl(d5)-indan-1-yl)-1(dz),2,2-trimethylpiperazine is obtained from its corresponding succinate salt. M sh- pr no j 4 ZM Fig. 1