Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia.

(54) Title: 1-PIPERAZINO-3-FENIL-IN DAMAGE DETERMINED FOR THE TREATMENT OF SCHIZOPHRENIA. (54) Title: DEUTERATED 1-PIPERAZINO-3-PHENYL INDANES FOR TREATMENT OF SCHIZOPHRENIA.

(57) Summary

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and their salts with activity at D1 and D2 dopamine receptors, as well as the 5HT2 receptor in the central nervous system, to drugs comprising such compounds as active ingredients, by use of such compounds in the treatment of diseases of the central nervous system and to treatment methods comprising the administration of such compounds.

(57) Abstract

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D1 and D2 as well as the 5HT2 receptors in the central nervous system, to medications comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

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Institute

Mexican Property

Industrial

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PATENT TITLE NO. 339552

Holder (s): H. LUNDBECK A / S

Address: Ottiliavej 9, DK-2500, Valby, DENMARK

Denomination: 1-PIPERAZINO-3-PHENYL-INDANOS DEUTERATED FOR THE TREATMENT OF SCHIZOPHRENIA.

Classification: IC.8: A61K31 / 495: A61P25 / 00; C07B59 / 00; C07D241 / 04

Inventor (s): MORTEN JORGENSEN; PETER HONGAARD ​​ANDERSEN; KLAUS GJERVIG

JENSEN: METTE GRAULUND HVENEGAARD; LASSINA BADOLO; MIKKEL FOG JACOBSEN

<td></td><td>rrajgSjasgajR.; ,, ;;. ί REQUEST</td><td></td>

<td>Number:</td><td colspan="2">International filing date!</td>

<td>MX / a / 2013/014849</td><td>June 19, 2012</td><td></td>

<td> |_; 1</td><td>PRIORITY</td><td></td>

<td>Country:</td><td>Date:</td><td>Number:</td>

<td>US</td><td>June 20, 2011</td><td> 61/498,651</td>

<td>US</td><td>September 21, 2011</td><td> 61/537,103</td>

<td>Validity: Twenty years</td><td></td><td></td>

Due date! 19th of 2032

The reference patent is duly granted with articles 1 », 2º fraction V, 6º fraction III, and 59 of the Industrial Property Law.

D (f in accordance with article 23 of the Industrial Property Law, this patent has a non-extendable term of twenty years, counted from the date of filing the non-valid application and will be subject to the payment of the fee to keep current debris iif

Whoever subscribes to this title, establishes it based on the provisions of sections 8 * (Factions III and 7 bis bis 2 of the Industrial Plippledad Law (Official Journal of the Federation (DOF) 06/27/1991, « formed «I 9» O871994, 10/25/1996, 12/26/1997, 05/17/1999, 2 & 1/2004, 06/16/2005, 01/25/2006, <# / 05 / 2009,06 / 01 / 2010, 06/18/2010, 06/28/2010; 01/27/2012 and 04/09/2012); articles 1, & section V ¹ 7 ¹¹¹ dál «Regulation of the Mexican Institute of Industrial PcogedacL (D.CLF, 12/14/1989, amended on 0l7oflz ™ 5, 'Τ5Μί ^> ί) ίΓΏΛ) 7/2004 and 7/09/2007); articles 1®, 3® ', 4 ”, 5' fraction V subsection a), TS fractions I and Di and 30 detEsfafuto Orgánica of the Mexican Institute of Industrial Property (DOF 12/27/1999, amended on 10/10/2002, 07/29/2004, 08/04/2004 and 09/13/2007); 1, 3 and 5 subsection a) of the Agreement that delegates powers to the Deputy Directors General, Coordinator, Divisional Directors, Holders of the Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

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Issue Date: May 31, 2016

THE DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

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MX / 2016/42741

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1-PIPERAZIN0-3-FENIL-1NDAN0S DEUTERAPOO FOR l = L TREATMENT OF SCHIZOPHRENIA

This application claims priority of US provisional applications

No. 61 / 498,651, filed on June 20, 2011, and 61 / 537,103, filed on September 21, 2011, thereby incorporating the entirety of each by reference herein.

All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entirety are hereby incorporated by reference into this application to further describe the state of the art as known to those of skill in the art as of the date of the invention described and claimed herein.

FIELD OF THE INVENTION

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and their salts with activity at dopamine Di and D receptors.₂as well as the 5HT serotonin receptor₂ in the central nervous system, to drugs comprising such compounds as active ingredients, and to the use of such compounds in the treatment of diseases in the central nervous system.

BACKGROUND OF THE INVENTION

In this application full reference is made to various publications. The disclosures in these publications are thus incorporated by reference in this application to describe in more detail the state of the art to which this invention relates.

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The 4 - ((1 R, 3S) —6-chloro-3-phenyl-indan-1-yl) —1, Ζ, 2 — ίηήή ^ ΤΙΓ— piperazine and salts thereof, pharmaceutical compositions containing these salts and their medicinal use, including the treatment of schizophrenia or other diseases comprising psychotic symptoms, are disclosed in WO 2005/016900. 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) 1,2,2-trimethyl-piperazine has the general formula (X), and is referred to below as compound ( X)

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(X)

EP 638 073 presents a group of trans isomers of

3-aryl-1— (1-piperazinyl) indanes substituted at position 2 and / or 3 of the piperazine ring. The compounds are described as having high affinity for D and D2 dopamine receptors and the 5-HT receptor.₂ and it is suggested that they are useful for the treatment of various diseases of the central nervous system, including schizophrenia.

The enantiomer of formula (X) mentioned above has been described by Bogeso et al. in J. Med. Chem., 1995, 38, pages 4380-4392, in the form of the fumarate salt, see Table 5, compound (-) - 38. This publication concludes that the (-) - enantiomer of compound 38 is a potent Dt / D antagonist.₂ that presents some Dt in vitro selectivity. The compound is also

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IMPI

MEXICAN INSTITUTE

J OF PROPERTY

1NDHSTWIAL describes as a potent 5-HT antagonist₂. It is also mentioned that the compound does not induce catalepsy in rats.

The etiology of schizophrenia is not known, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. Psychiatry 1978, 735, 164-173), formulated in the early 1960s, has provided a theoretical framework for understanding the mechanisms biological factors underlying this disorder. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion that is supported by the fact that all antipsychotic drugs on the market currently exert some antagonism to the dopamine D receptor.₂ (Seeman Science and Medicine 1995, 2, 28-37). However, while it is generally accepted that antagonism of dopamine D receptors₂ in the limbic regions of the brain it plays a key role in the treatment of positive symptoms of schizophrenia, the blockade of D receptors₂ in the striatal regions of the brain it causes symptoms ₁₅ extrapyramidal (EPS). As described in EP 638 073, a mixed inhibition profile of dopamine D- | / D receptors has been observed.₂ with some of the so-called "atypical antipsychotic compounds, in particular with clozapine (8-chloro-11- (4-met¡lp¡peraz¡n-1-¡l) -5H-d¡benzo [b, e] [1, 4] diazepine), used in the treatment of schizophrenic patients.

Furthermore, selective Di antagonists have been linked to the treatment of sleep disorders and alcohol abuse (DN Eder, Current Opinion in Investigational Drugs, 2002 3 (2 / 284-288).

Dopamine may also have an important role in the etiology of affective disorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 2252 5 236 and 237-246; Bogeso et al, J. Med. Chem., 1985, 28, 1817-1828).

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EP 638 073 describes how compounds that have an affinity for 5-HT receptors₂, in particular 5-HT receptor antagonists₂a, have been suggested for the treatment of different diseases, such as schizophrenia, including negative symptoms in schizophrenic patients, depression, anxiety, sleep disorders, migraine attacks and neuroleptic-induced parkinsonism. It has also been suggested that antagonism of 5-HT receptors₂a reduces the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

An isotopic substitution of one or more hydrogen (H) atoms for deuterlo (D) atoms in a compound can give rise to a kinetic isotopic effect that can influence the reaction rate, for example, the metabolism of the compound. This is particularly the case when the Isotopic replacement is found in a chemical bond that is broken or formed.₁₅ in a speed limiting step. In such a case, the change is called a primary isotopic effect. When the isotopic substitution or substitutions are not Involved in one or more bonds that are broken, a smaller change in velocity, called the secondary isotopic effect, can be observed.

THE INVENTION

The present invention provides compounds where one or more hydrogen (H) atoms at one or more M1, M2 and M3 metabolic sites of compound (X) have been replaced by deuterlo (D) atoms.

In one aspect, the invention provides a compound of the formula Y:

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MEXICAN INSTITUTE M LA MONEDAD INDUSTRIAL

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where, R¹ - R¹⁰ are independently hydrogen or deuterium, and where at least one of R¹-R¹⁰ comprises at least approx. 50% deuterium, or a pharmaceutically acceptable acid addition salt thereof.

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

In another aspect, the invention provides uses of a compound of formula (Y) or a pharmaceutical composition comprising a compound of formula (Y) in the treatment of psychoses, other diseases comprising psychotic symptoms, psychotic disorders, or diseases that they present with psychotic symptoms.

In yet another aspect, the invention provides for the manufacture of a medicament comprising a compound of formula (Y) for the treatment of psychoses, other diseases comprising psychotic symptoms, psychotic disorders, or diseases presenting with psychotic symptoms.

In yet another aspect, the invention provides methods of treatment

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of psychoses, other diseases comprising psychotic symptoms, psychotic disorders or diseases presenting with psychotic symptoms, comprising the administration of an effective amount of a compound of the formula (Y) or a pharmaceutically acceptable composition comprising a compound of the formula (Y) to a subject who needs it.

In yet another aspect, the invention provides a compound of the formula

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In yet another aspect, the invention provides a method for

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treating compound (XIV) with [(S) -BINAP] Rh (l) BF₄.

In another aspect, the invention provides a process for the preparation of compound (1 /? 3S) - (IV) tartrate comprising, the treatment of fraz7s-1- (6-chloro-3-phenyl (d5) -indan- 1-yl) -1 (d3), racemic 2,2-trimethyl-piperazine with L - (+) - tartaric acid.

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Other objects and advantages of the invention are apparent to those skilled in the art from the disclosure herein, which is merely illustrative and not restrictive. Therefore, other embodiments will be recognized by the person skilled in the art without departing from the spirit and scope of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows major metabolic sites of compound (X).

FIG. 2 shows compound (I) and compound (XI), each as the enantiomer (1R, 3S).

FIGS. 3A and 3B show the NMR spectra of compound (II) and compound (V). Selected regions of the spectra are displayed¹³C NMR decoupled protons and decoupled protons and deuterium of compound (II) [Fig. 3A] and of compound (V) [Fig. 3B],

FIG. 4 shows the mass spectrum of compound (IV).

FIG. 5 shows the formation of the metabolite of compound (XI) by metabolism of compound (X) and compound (I) (0.1 microM) in cryopreserved dog hepatocytes (n = 2 bars represent the max and min results).

FIG. 6 shows the formation of the metabolite of compound (XI) by metabolism of compound (X) and compound (I) (1 microM) in cryopreserved dog hepatocytes (n = 2 bars represent the max and min results).

FIG. 7 shows the formation of the desmethyl metabolite by metabolism of compound (II), (IV) and (X) (1 microM) in human liver microsomes (n = 3, bars represent standard deviation).

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MEXICAN INSTITUTE _n OF IA WORiedao and INDUSTRIAL

FIG. 8 shows the formation of the metabulilu doomotil poc. metabolism of compound (II), (IV) and (X) (10 microM) in human liver microsomes (n = 3, bars represent standard deviation).

FIG. 9 shows the formation of the metabolite desmethyl by metabolism of compound (lll) (10 microM) in human liver microsomes (n = 3, bars represent standard deviation).

FIG. 10 shows the formation of the desmethyl metabolite by metabolism of compound (V) (10 microM) in human liver microsomes (n = 3, bars represent standard deviation).

io FIG. 11 shows the formation of the desmethyl metabolite by metabolism of compound (VI) (10 microM) in human liver microsomes (n = 3, bars represent standard deviation).

FIG. 12 shows the formation of the desmethyl metabolite by metabolism of compound (Vil) (10 microM) in human liver microsomes.₁₅ (n = 3, bars represent standard deviation).

FIG. 13 shows the chemical structure of compounds (I) (VII), (X) - (XI) and (XIX) - (XXI).

FIG. 14 shows the formation of the desmethyl metabolite by metabolism of compound (II) and (X) (10 microM) by CYP2C19 from recombinant human liver (n = 3, standard deviation).

FIG. 15 shows the formation of the desmethyl metabolite by metabolism of compound (IV) and compound (X) (1 microM) by CYP2C19 from recombinant human liver (n = 3, bars represent standard deviation).

FIG. 16 shows PCP-induced hyperactivity in mice.

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for compound (IV).

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FIG. 17 shows the cataleptic response in rats for compound (IV).

FIG. 18 shows the X-ray diffractog branches in two batches of hydrogen tartrate salt of compound (IV).

DETAILED DESCRIPTION OF THE INVENTION

Atypical antipsychotics have been subjected to numerous studies by the pharmaceutical industry, and have shown promise for the treatment of mental disorders such as schizophrenia, bipolar disorder, dementia, anxiety disorder, and obsessive-compulsive disorder ( OCD). The mechanism of action of these agents is not yet known; however, all antipsychotics act to some degree on the dopamine system. The most atypical antipsychotics show activity in dopamine receptors subtypes 1 and 2 (D1 and D2, respectively), and in the ₁₅ serotonin receptor subtype 2 (5-HT2). In some cases, the name "atypical" was assigned to antipsychotics that did not induce extrapyramidal side effects; however, some atypical antipsychotics have been shown to still induce extrapyramidal side effects, albeit to a lesser extent than that observed with typical antipsychotics (Welden, PJ, “EPS proflles:

the atyplcal antipsychotlcs are not all the same J. Psychiatr. Pract. 2007, 13 (1): 13-24; Incorporated herein by reference in its entirety). Approved atypical antipsychotics include, for example, amisulprlda (Solian), arlplprazole (Ablllfy), asenaplna (Saphrls), blonanserlna (Lonasen), clotlaplna (Entumine), clozapine (Clozarll), iloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt), liloperldona (Fanapt) (Cremin), olanzapine (Zyprexa, paliperidone (Invega), perospirone

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INSTmiTU MEXICANO OE IA INDUSTRIAL PROPERTY

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(Lullan), quetiapine (Seroquel), remoxipride (Roxiam), r¡apg> r¡dona (Risperdal), sertindole (Serdolect), sulpiride (Sulpirid, Eglonil), ziprasidone (Geodon, Zeldox) and zotepine (Nipolept). Others are currently under development. As the mechanism of atypical antipsychotics is not yet well understood, the side effects associated with these drugs have been difficult to avoid. Therefore, a need exists for additional antipsychotic therapies with potential for reduced side effects and / or improved therapeutic profile over existing therapies.

In one aspect, the present invention provides compounds where one or more hydrogen (H) atoms at one or more of the M1, M2 and M3 metabolic sites of compound (X) have been replaced by deuterium (D) atoms. Compound (X) and its variants are described in, for example, US Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; US Patent Publications Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38,

4380-4392; each incorporated herein by reference in its entirety.

The kinetic isotopic effect can potentially influence the rate of metabolism in one or more of the metabolic sites M1, M2 and M3 indicated in Figure 1. The inventors of the present invention have identified three main metabolic sites of 4 - ((1 R, 3S) —6-chloro-3-phenyl-indan-1-¡ΟΙ, 2,2-trimethyl-piperazine (compound (X)) designated herein M1, M2, and M3 and indicated in Figure 1.

Deuteration of a compound at a site undergoing oxidative metabolism in some cases may reduce the rate of metabolism for a compound due to the primary isotopic effect. IF the passage of

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IMPI _η -, ΕΝΪΤΓΠΙΤΟ MKUCAno

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INDUSTRIAL CH bond cleavage is speed limiting, a significant isotopic effect must not be observed. However, if other steps direct the rate of metabolism for a compound, the CH bond cleavage step is not rate limiting and the isotopic effect may be of little significance.

Additionally, a negative isotopic effect can be observed where the reaction rate is increased after substitution with deuterium. Therefore, the incorporation of deuterium into a site subjected to oxidative enzyme metabolism does not impact pharmacokinetics in a way that can be predicted (See, for example, US Patent No. 7,678,914; Drug Metab.

Dispos. 1986, 14, 509; Arch. Toxicol. 1990, 64, 109; Int. Arch. Occup. Environ. Health 1993, 65 (Suppl. 1): S139; each incorporated herein by reference in its entirety). The impact of deuterium incorporation is unpredictable, it does not work for many drugs or classes of drugs. Decreased metabolic clearance has been observed with some compounds₁₅ deuterated with respect to other non-deuterated derivatives; while the metabolism of other compounds has remained without impact. Examples of studies indicating lack of predictive ability with respect to deuterium incorporation include US Patent No. 6,221,335; J. Pharm. Sci. 1975, 64, 367-391; Adv. Drug. Res. 1985, 14, 1-40; J. Med. Chem.

1991, 34, 2871-2876; Dog. J. Physiol. Pharmacol. 1999, 79-88; Silverman, RB,

The Organic Chemistry of Drug Design and Drug Action, 2^gives Ed. (2004), 422; Curr. Opin. Drug Dev. 2006, 9, 101-109; Chemical Res. Tox. 2008, 1672; Harbeson, SL and Tung, RD "Deuterium in Drug Discovery and Development", in Ann. Rep. Med. Chem. 2011, 46, 404-418; each incorporated herein

5 by reference in its entirety. Still incorporating deuterium into sites

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known metabolism has an unpredictable impact on

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Metabolic change may result where the metabolic profile of a particular drug has been modified due to the incorporation of deuterium, thus leading to different proportions of (or different) metabolites than that observed with an un-deuterated analog of the same drug. The new metabolic profile may result in a different toxicological profile from that of a deuterated analog. In addition to the potential complications of deuterium incorporation is the possibility of deuterium / hydrogen exchange in the physiological environment (Adv. Drug. Res. 1985, 14, 1-40; incorporated herein by reference in its entirety).

In some embodiments, the isotopic substitution of deuterium atoms for one or more hydrogen atoms in compound (X) has resulted in a kinetic isotopic effect that influences the rate of metabolism.

The isotopic substitution of the hydrogen atoms in compound (X) by deuterium atoms results in less metabolism of the deuterated compound as shown to occur in dog hepatocytes where, for example, a decrease of about 50% in the formation of the metabolite desmethyl (compound (XI)) of compound (I) (Figure 2) compared to the formation of compound (XI) from the metabolism of compound (X).

Deuteration of free phenyl, optionally in combination with deuteration of 1-methyl group (compound (II) and (IV)), surprisingly reduces the amount of the desmethyl metabolite produced in human liver microsomes compared to the non-deuterated compound (compound (X )).

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Also surprisingly, the deuteration of the 1-metf metabolism in dogs but not in humans, thus indicating the inability to predict the deuteration in pharmacological properties.

The reduced metabolism effect is higher bioavailability of the deuterated, related compound, and less metabolite formation. Without intending to be limited by theory, based on the results described in the experimental section of this application, the same effect is expected to appear after multiple dosing in humans, allowing lower doses to be administered to humans, i.e. , less burden on the whole body, for example, the liver, and less frequent dose administration.

The metabolite desmethyl (compound (XI)) is known to have an affinity for hERG and therefore potentially contributes to QTc prolongation. As mentioned above, deuteration of free phenyl optionally in combination with deuteration of 1-metllo group (compound (II) and (IV)), reduces₁₅ surprisingly the amount of the desmethyl metabolite produced in human liver microsomes compared to the non-deuterated compound (compound (X)). Accordingly, it is anticipated that there will be less affinity for hERG and less resulting burden on the heart when doses of deuterated variants of compound (X) are administered [eg, compounds of formula (Y)] compared to dose administration of compound (X).

The invention is further detailed in the illustrative embodiments provided herein.

Definitions

The term "compound (s) of the invention" as used herein implies compounds (Y), (I), (II), (III), (IV), (V), (VI) and / or (Vil) and can

IMPI iNsrm rro mexicana Dt LA nonCDAC INDUSTRIA!

include its salts, hydrates and / or solvates. The compounds of the present invention are prepared in different forms, such as salts, hydrates, and / or solvates, and the invention includes compositions and methods that comprise all variant forms of the compounds.

The term "compositions of the invention" as used herein implies compositions comprising compounds (Y), (I), (II), (III), (IV), (V), (VI), and / o (Vil) or its salts, hydrates and solvates. The compositions of the invention may also comprise one or more chemical components such as, for example, excipients, diluents, vehicles or carriers.

The term "methods of the invention" as used herein implies methods that comprise treatment with the compounds and / or compositions of the invention.

As used herein, the term "approximately" is used herein to express approximately, nearly, around or in the region of. When the term "approximately" is used in conjunction with a numerical range, it modifies that range that extends the limits above and below the numerical values ​​set forth herein. In general, the term "approximately" is used herein to modify a numerical value above and below the value set by a 20% variance above or 2 or below (greater or lesser).

An "effective amount," "sufficient amount," or "therapeutically effective amount" as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, for example, to reduce or improve the severity and / or duration of a

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affliction or condition or one or more of its symptoms, pr

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conditions related to an affliction or condition, preventing the recurrence, development, or onset of one or more symptoms associated with an affliction or condition, or otherwise improving or improving the preventive or therapeutic effects of another therapy. An effective amount also includes the amount of the compound that prevents or substantially attenuates undesirable side effects.

As used herein, and as understood in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes may include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, decreased spread of the disease, a stabilized (i.e., not worsening) condition, prevention of disease spread the disease, delay or slowing down of the disease progress, improvement or palliation of the pathological state and remission (either partial or total), whether detectable or not detectable. "Treatment" can also mean prolonging survival compared to expected survival if you are not receiving treatment.

The term "in need" refers to the need for symptomatic or asymptomatic relief from a condition such as, for example, psychosis or a psychotic disorder. The subject in need may or may not be undergoing treatment for pathological conditions related to, for example, psychosis or a psychotic disorder.

The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Non-limiting examples of

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such pharmaceutical carriers include liquids, such cerne ° j^{i | g} and gadgets including those from petroleum, animal, vegetable, or synthetic oil, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical carriers can also be physiological solution, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and colorants can be used. Other examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin (incorporated herein 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 human.

The term "isotopic variant" as used herein implies a compound obtained by substituting one or more hydrogens in a major compound that does not comprise deuterlo atoms for deuterium atoms.

Elements are recognized to be present in natural isotopic abundances in most synthetic compounds and result in an inherent incorporation of deuterium. However, the natural isotopic abundance of hydrogen isotopes such as deuterium is immaterial (approximately 0.015%) with respect to the degree of stable isotopic substitution of compounds indicated herein. Thus, as used herein, the designation of an atom as deuterium in one position indicates that the

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Deuterium abundance is significantly greater than the natural deuterium abundance. Any atom not designated as a particular isotope is intended to represent any stable Isotope of that atom, as will be obvious to one skilled in the art.

Compounds (Y) are isotopic variants of compound (X).

In some embodiments, compounds (I), (II), (lll), (IV), (V), (VI) and (Vil) are isotopic variants of compound (X).

M1 is a site of compound (X) susceptible to metabolism; M1 consists of -CH₂- in position 6 of the piperazine of compound (X).

M2 is a site of compound (X) susceptible to metabolism; M2 consists of N-linked methyl of piperazine of compound (X).

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

The main compound is the chemical compound that is the basis for its derivatives obtained either by substitution or fracture, for example, metabolic fracture. In the context of the present invention, the main compound is the Active Pharmaceutical Ingredient (API).

In some embodiments, any atom not designated as deuterium is present at its natural isotopic abundance. In some embodiments, any atom not designated as deuterium is present in less than 1% deuterium isotopic abundance.

In one aspect, the invention provides a compound of formula (Y):

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Mexican Institute of Industrial Property

<img file="MX339552B_D0032.tif" />

where, R¹ - R¹⁰ they are independently hydrogen or deuterium, where at least one of R¹-R¹⁰ it comprises at least about 50% deuterium or one of its pharmaceutically acceptable acid addition salts.

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

In another aspect, the invention provides uses of a compound of formula (Y) or a pharmaceutical composition comprising a compound of formula (Y) in the treatment of psychosis, other diseases including psychotic symptoms, psychotic disorders, or diseases that are present with psychotic symptoms.

In yet another aspect, the invention provides for the production of a medicament comprising a compound of formula (Y) for the treatment of psychosis, other diseases including psychotic symptoms, psychotic disorders, or diseases presenting with psychotic symptoms.

<img file="MX339552B_D0033.tif" />

In yet another aspect, the Invention provides for treatment of psychosis, other illnesses including psychotic symptoms, psychotic disorders, or illnesses presenting with psychotic symptoms, comprising administering an effective amount of a compound of formula (Y) or a pharmaceutical composition comprising a compound of formula (Y).

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

<img file="MX339552B_D0034.tif" />

<img file="MX339552B_D0035.tif" />

<img file="MX339552B_D0036.tif" />

<img file="MX339552B_D0037.tif" />

(1R, 3S) - (IV), (1R, 3S) - (VI) and

<img file="MX339552B_D0038.tif" />

In some embodiments, R¹ and R² comprise deuterium,

<img file="MX339552B_D0039.tif" />

R³-R⁵ comprise deuterium or R⁶-R¹⁰ comprise deuterium ·· - · r,,

In some embodiments, R¹ and R² comprise deuterium. In some embodiments, R¹ and R² comprise deuterium and R³-R⁵comprise hydrogen.

In some embodiments, R³-R⁵ comprise deuterium. In some embodiments, R³-R⁵ comprise hydrogen.

In some embodiments, R⁶-R¹⁰ comprise deuterium. In some embodiments, R⁶-R¹⁰ comprise deuterium and R³-R⁵ comprise hydrogen.

In some embodiments, R¹-R⁵ comprise deuterium. In some embodiments, R¹, R² and R⁶-R¹⁰ comprise deuterium.

In some embodiments, R³-R¹⁰ comprise deuterium. In some embodiments, R¹-R¹⁰ comprise deuterium. In some embodiments, the compound is /

<img file="MX339552B_D0040.tif" />

(1R, 3S) - (IV).

In some embodiments, the compound is

<img file="MX339552B_D0041.tif" />

<img file="MX339552B_D0042.tif" />

In some embodiments, the compound is

<img file="MX339552B_D0043.tif" />

In some embodiments, the compound is

D.

<img file="MX339552B_D0044.tif" />

D

D

<img file="MX339552B_D0045.tif" />

In some embodiments, the compuestcres

<img file="MX339552B_D0046.tif" />

In some embodiments, the compound is

<img file="MX339552B_D0047.tif" />

In some embodiments, the compound is

<img file="MX339552B_D0048.tif" />

In some embodiments, at least about 75% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is present in approximately its natural isotopic abundance.

In some embodiments, at least about 85% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is present in approximately its natural isotopic abundance.

In some embodiments, at least about 90% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is present in approximately its natural isotopic abundance.

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 hydrogen fumarate salt. In some embodiments, the compound is a maleate salt. In some

ΙΜΡΙ ^>

MUICANC INSTITUTE

OE, r * IA FW? FtEDAD C ¿Z2Í35 ^J indi ISTWAÍ S ^ Tg embodiments, the compound is a salt of h ^^ genc m? l ?? ^

In some embodiments, the compound is a succinate salt. In some embodiments, the compound is a hydrogen succinate salt. In some embodiments, the compound is a tartrate salt. In some embodiments, the compound is the hydrogen tartrate salt.

In some embodiments, the compound is the hydrogen tartrate salt of (1R, 3S) - (IV).

In some embodiments, the psychosis or disease that includes psychotic symptoms is schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, bipolar disorder, or mania in bipolar disorder. In some embodiments, the psychosis or illness that includes psychotic symptoms is schizophrenia.

₁5 In some embodiments, the methods also comprise the administration of one or more neuroleptic agents.

In some embodiments, the uses also comprise the use of one or more neuroleptic agents.

In some embodiments, the neuroleptic agent is selected from the group consisting of sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, and osanetant.

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

In some embodiments, the subject is a mammal. In 2 5 some embodiments, the subject is a rodent, cat, dog, monkey, horse,

IMPI Institute of Mexicana

Dt THE INDUSTRY FROFIEDAD!

<img file="MX339552B_D0049.tif" />

pig, bovine or human. In some embodiments, e¹ cnj ^ tn 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, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 40% at that position. In some embodiments, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 50% at that position. In some embodiments, the designation of a position as "D" in a compound has a minimal Deuterium Incorporation of greater than about 60% at that position. In some embodiments, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 65% at that position. In some embodiments, designating a position as "D" in a compound has minimal deuterium incorporation of greater than about 70% at that position. In some embodiments, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 75% at that position. In some embodiments, the designation of a position as "D" in a compound has minimal deuterium incorporation of greater than

IMPI Mexican institute WW RROHFDAD INDUSTRIAL

<img file="MX339552B_D0050.tif" />

about 80% in that position. In some embodiments, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 85% at that position. In some embodiments, designating a position as "D" in a compound has minimal deuterium incorporation of greater than about 90% at that position. In some embodiments, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 95% at that position. In some embodiments, the designation of a position as "D" in a compound has a minimal deuterium incorporation of greater than about 97% at that position. In some embodiments, the designation of a position as "D in a compound has a minimal deuterium incorporation of greater than about 99% at that position. Pharmaceutically acceptable salts

The present invention also encompasses salts of the compounds, typically, pharmaceutically acceptable salts. These salts include pharmaceutically acceptable acid addition salts. Acid addition salts include inorganic acid salts as well as organic acids.

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

<img file="MX339552B_D0051.tif" />

methanesulfonic, maleic acid, malic acid, malonic acid. Mandelic Acid, Oxalic Acid, Picric Acid, Pyruvic Acid, Salicylic Acid, Succinic Acid, Methanesulfonic Acid, Ethanesulfonic Acid, Tartaric Acid, Ascorbic Acid, Pamoic Acid, Bismethylenesalicylic Acid, Ethanedisulfonic Acid, Gluconic Acid, Citraconic Acid, Aspartic Acid, Stearic Acid , palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acids, theophyllineacetic acid, as well as 8-haloteophyllins, for example, 8-bromoteofilina and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, SM et al., J. Pharm. Sci. 1977, 66, 2 and Gould, PL, Int. J. Pharmaceutics 1986, 33, 201-217; whose contents are incorporated herein by reference.

Furthermore, the compounds of this invention can exist in non-solvated forms, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered comparable to non-solvated forms for the purposes of this invention.

The titles and subtitles 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 illustrative examples or terms (including "for example", "for example" and "such as") in the present specification is merely intended to better illuminate the invention and does not impose a limitation on the scope of the invention, unless otherwise indicated.

The use of the terms “a” and “an” and “the” and “the” and similar referents

IMPI

MEXICAN INSTITUTE OF THE ΡΕΟΡΙΕΠΑΓ; INDUSTRIAL

<img file="MX339552B_D0052.tif" />

in the context of the description of the invention they are to be constructed to cover the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Unless otherwise stated, the exact values ​​provided herein are representative of the corresponding approximate values ​​(for example, all example exact values ​​provided for a particular factor or measurement may be considered to provide a corresponding, approximate, modified measurement. by "approximately", if appropriate).

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having", "including" or "containing" with reference to an element or elements is intended to provide support for an aspect similar or an aspect of the invention that "consists of", "consists essentially of" or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context.

Example syntheses of the compounds of the invention can be easily achieved by means of methods described, for example, in US Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; US Patent Publications Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem.

1995, 38, 4380-4392; each incorporated by reference in its entirety. These and similar methods and methods can be carried out using deuterated reagents and / or intermediates and / or introducing deuterium atoms to a chemical structure according to protocols known in the art.

IMPI

MIXICANC INSTITUTE I heard THE INDUSTRIAL currency

<img file="MX339552B_D0053.tif" />

Other example synthesis methods include the conversion of indanone A to intermediate C by treatment of 3-bromo-6-chloro-indan-1one (A; for references on this material, see: Bogeso EP 35363 A1 19810909 and Kehler , Juhl, Püschl, WO 2008025361; each incorporated by reference in its entirety) with a base such as triethylamine in a solvent such as tetrahydrofuran at room temperature (Scheme 1). Removal of the precipitated amine hydrobromide salt by filtration and concentration of the filtrate will give 6-chloro-inden-1-one (B). This material can be reacted with phenyl-os-boronic acid in the presence of about 1 equivalent of a base such as triethylamine and a catalytic amount of a 1: 1 mixture of [Rh (ndb) 2] BF₄ (Bis (Norbornadiene) Rhodium (I) tetrafluoroborate) and racemic BINAP (2,2-bis (diphenylphosphine) -1,1binaphthyl) in an appropriate solvent (eg approximately 10: 1 solvent mixture of 1,4-dioxane and water) under an argon atmosphere at elevated temperature (eg, about 100 ° C). Working up will give racemic 6-chloro-3-phenyl-d5-indan-1-one (C). Scheme 1. Example synthesis of intermediary C.

<img file="MX339552B_D0054.tif" />

C (racemate)

Treating 6-chloro-3-phenyl-c / 5-indan-1-one (C) with a reductive base such as sodium borohydride (~ 2 equivalents) in a ~ 10: 1 mixture of tetrahydrofuran solvents and water at low temperature

<img file="MX339552B_D0055.tif" />

(approximately -15 ° C) will give the reduction of the carhnniin pn r | corresponding alcohol (Scheme 2). Work-up will yield racemic cis-6-chloro-3-phenylindan-1-ol (D). Treatment of this material with vinyl butyrate (approximately 5 equivalents) and Novozym 435® in a solvent such as di-os-propyl ether at room temperature will give (1S, 3S) -6-chloro-3-phenylindan-1- ol (E) after processing.

Scheme 2. Example synthesis of intermediate E.

<img file="MX339552B_D0056.tif" />

C (racemate) D (racemate D) E (enantiomer (1S.3S)

Alternatively, carrying out the sequence from A to E using phenylboronic acid or 4,4,5,5-tetramethyl-2-phenyl- [1,3,2] dioxaborolane instead of 4,4,5,5- tetramethyl-2-c /₅-phenyl- [1,3,2] dioxaborolane will lead to (1S, 3S) -6-chloro-3phenyl-indan-1-ol (E ') (Scheme 3).

Scheme 3. Example synthesis of Intermediate E '.

<img file="MX339552B_D0057.tif" />

TO

E '(enantiomer (1S.3S)

MUICANO INSTITUTE OE THE PROPERTY

INDUSTRIAL

Other alternative synthesis methods are revealed pdid ublener C ohla patent literature (Dahl, Wohlk Nielsen, Suteu, Robin, Brosen W02006 / 086984 A1; Bang-Andersen, Bogeso, Jensen, Svane, Dahl, Howells, Lingso, Mow W02005 / 016901 A1; each incorporated by reference in its entirety). These procedures are based on benzyl cyanide as one of the substrates. Using benzyl-dz cyanide (commercially available from Aldrich, catalog # 495840) or phenyl-cfe-acetonitrile (commercially available from Aldrich catalog # 495859 or CDN catalog No. D-5340 or Kanto catalog No. 49132-27) the same procedure can lead to E (Scheme 4). As alternatives to commercial sources, benzyl-c / 7-cyanide and phenyl-d5-acetonitrile can be prepared from sodium cyanide and benzyl-dz chloride (commercially available from Aldrich, catalog # 217336 ) and benzyl chloride2,3,4,5,6-d₅ (commercially available from Aldrich, catalog # 485764), respectively.

Scheme 4. Example synthesis of intermediaries E and E '.

<img file="MX339552B_D0058.tif" />

R = Q benzyl-d cyanide? E ((1S, 3S) enantiomer

R = R phenyl-ds-acetonitrile

Treatment of E with approximately 4 equivalents of di-isopropylethylamine and approximately 2 equivalents of methanesulfonic anhydride in tetrahydrofuran at approximately -18 ° C followed by slow heating to approximately -5 ° C and subsequent treatment with approximately 4 equivalents of 2,2-dimethyl -piperazine will lead to the formation of 1 - ((1R, 3S) -6chloro-3-phenyl-d5-iddan-1-yl) -3,3-d-methyl-piperazine (F) which can purify after reaction (Scheme 5). Alternatively, alcohol E can be converted to the corresponding chloride, predominantly with retention of the configuration at C1 leading to (1S, 3S) -1-chloro-3-d₅-phenyl-indane (E "; similarly, E 'can be converted to (1S, 3S) -1-chloro-3-phenyl-indane (E'")). Chloride E "can be reacted with 2,2-dimethyl-piperazine to obtain F. The final step can be carried out as described for the preparation of

IMPI fNSTnyno Mexican Dt LA INDUSTRIAL FRORIETY

<img file="MX339552B_D0059.tif" />

compound (l) * butandioic acid salt by use of iodomethane to dal * éT compound (II) or cfe-iodomethane to give compound (IV), respectively. Alternatively, as described below, the methyl group or the c / 3methyl group can be installed by refluxing in HCHO / HCOOH or DCDO / DCOOD, respectively.

Scheme 5. Example synthesis of intermediates F and compounds (II) and (IV).

R

<img file="MX339552B_D0060.tif" />

E (enantiomer (1S.3S))

F (enantiomer (1R.3S))

R = CH 3 compound (li) R = CD3. compound (, V)

(2-Amino-2-methyl-propyl) -carbamic acid tert-butyl ester (G) can be prepared from 2-methyl-propan-1,2-diamine and di-terbutyldicarbonate (alternatively G claimed as commercially available: Prime Catalog No. POI-1362-MB4; Rovatin Catalog No. NX45401). Reaction of G with a haloacetyl halide such as chloroacetyl chloride or bromoacetyl bromide will give [2- (2-chloro-acetylamino) -2-methylpropylj-carbamic acid ester or tert-butyl ester of [2 - (2-bromo-acetylamino) -2methyl-propylj-carbamic (H), respectively (Scheme 6). Treatment of an H variant with acid followed by base will lead to the formation of 6,6-dimethylpiperazin-2-one (I). This material can be reduced to 2,2-dimethyl-5,5-d₂35

<img file="MX339552B_D0061.tif" />

2-methylpropan-1,2diamine

<img file="MX339552B_D0062.tif" />

Piperazine (J) by treatment with lithium aluminum deuteride: Scheme 6. Example synthesis of intermediate J.

OR

<img file="MX339552B_D0063.tif" />

G

H

J

Alternatively, J can be prepared from 2-amino-2-methyl-propionic acid. The reaction of 2-amino-2-methyl-propionic acid and di-tert-butyldicarbonate will give 2-tert-butoxycarbonylamino-2-methyl-propionic acid (K) (Scheme 7). The acidic functionality can be converted to the corresponding Weinreb amide by reaction with O./V-dlmethyl-hydroxIlamine in the presence of an appropriate coupling reagent such as 2- (1H-7-azabenzotriazole-1-yl) methanamine phosphonate. ) -1,1,3,3-tetramethyluronium (HATU) or 1-ethyl-3— (3-dimethylaminopropyl) carbodimide (EDC) to obtain tert-butyl ester of [1- (methoxy-methyl- carbamoyl) -1-methyl-ethyl] -carbamic (L). Selective reduction of the Weinreb amide leads to (1,1-dimethyl-2-oxo-ethyl) -carbamic acid tert-butyl ester (M). Reductive amination including aldehyde M and amino-acetic acid methyl ester can be used to prepare (2-tert-butoxycarbonylamino-2-methyl-propylamino) -acetic acid methyl ester. Treatment of carbamate-N ester with an appropriate acid, such as trifluoroacetic acid, will lead to the formation of piperazinone I which, after treatment with lithium aluminum deuteride, gives piperazine J.

Scheme 7. Example alternative synthesis of Intermediate J.

<img file="MX339552B_D0064.tif" />

<img file="MX339552B_D0065.tif" />

<img file="MX339552B_D0066.tif" />

IMPI

MEXICAN INSTITUTE OF THE INDUSTRIAL RROEIEDAC

<img file="MX339552B_D0067.tif" />

<img file="MX339552B_D0068.tif" />

N

<img file="MX339552B_D0069.tif" />

<img file="MX339552B_D0070.tif" />

J

Using J instead of 2,2-dlmetll-plperazlna as described for the conversion of E into compounds (II) and (IV) will lead to compounds (VI) and compound (Vil), respectively. Similarly, using E 'and J instead of 2,2-dlmethyl-piperazine and E will lead to compound (lll) and compound (V). In another aspect, the Invention provides a process for preparing the

<img file="MX339552B_D0071.tif" />

D compound (S) - (XV) comprising the treatment of

7 MEXICAN INSTITUTE

OE THE PROPERTY

INDUSTRIAL compound (XIV) with [(S) -BINAP] Rh (l) BF₄. __

In another aspect, the invention provides a process for preparing compound (1R, 3S) - (IV) tartrate comprising the treatment of trans-ϊ - (6-chloro-3-phenyl (d5) -indan-1-yl) —1 (d3), racemic 2, 2-trimethyl-piperazine with L - (+) - tartaric acid.

In some embodiments, racemic frans-1- (6-chloro-3-phenyl (d5) indan-1-yl) —1 (d3), 2, 2-trimethyl-piperazine is generated from its corresponding salt succinate.

In some embodiments, racemic 1- (6-chloro-3-phenyl (d5) -indan-1-yl) -1 (d3), 2, 2-trimethyl-piperazine succinate is generated from the Racemic frans-1- (6-chloro-3-phenyl (d5) -indan-1-yl) -3,3-dimethyl-piperazine maleate salt.

In some embodiments, acetophenone-d5 is converted to an enol ether. In some embodiments, the enolic ether is an ether₁₅ silylenolic. In some embodiments, the acetophenone-d5 enol ether is converted to the corresponding vinyl boronate. In some embodiments, the acetophenone-d5 enol ether is treated with bis (pinacholate) diboro. In some embodiments, the vinyl boronate is treated with 2-halo-5-chlorobenzaldehyde.

In some embodiments, the compounds exist as racemates. In some embodiments, the compounds exist in more than about 70% enantiomeric excess. In some embodiments, the compounds exist in more than about 75% enantiomeric excess. In some embodiments, the compounds exist in more than about 80% enantiomeric excess. In some

<img file="MX339552B_D0072.tif" />

In embodiments, the compounds exist in more than about 85% enantiomeric excess. In some embodiments, the compounds exist in more than about 90% enantiomeric excess. In some embodiments, the compounds exist in more than about 92% enantiomeric excess. In some embodiments, the compounds exist in more than about 95% enantiomeric excess. In some embodiments, the compounds exist in more than about 97% enantiomeric excess. In some embodiments, the compounds exist in more than about 99% enantiomeric excess.

Pharmaceutical compositions

The present invention also provides pharmaceutical compositions comprising 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, either in single or multiple doses. Pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients according to conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. Other example compositions of the compounds of the invention are described, for example, in US Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; the publications

<img file="MX339552B_D0073.tif" />

IMPI of US Patent Nos. 2008/0269248; 2010 / 0069Ü70, 2011 / 01700Q4_r2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each incorporated by reference in its entirety.

The pharmaceutical compositions can be specifically formulated for administration by any appropriate route such as the oral, nasal, topical (including buccal and sublingual) and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route depends on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.

The daily dose of the compounds of the invention, calculated as the free base, is appropriately from about 1.0 to about 160 mg / day, more appropriately from about 1 to about 100 mg, for example preferably 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

IMPI

INST1PJTO MfcJUCAN »i PE LA ptOMIDAD industrial

<img file="MX339552B_D0074.tif" />

it is from about 1 mg to about 60 mg. In some embodiments, the daily dose is from about 2mg to about 30mg. In some embodiments, the daily dose is from about 2mg to about 15mg. 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 such as intravenous, intrathecal, intramuscular, and similar administration, typical doses are in the order of half the dose used for oral administration.

The compounds of this invention are generally used as the free substance or as one of its pharmaceutically acceptable salts. Examples of appropriate organic and inorganic acids are described herein.

In some embodiments, the composition comprises a cyclodextrin. In some embodiments, the composition comprises a cyclodextrin in water. In some embodiments, cyclodextrin is

IMPI 'ΝίΤίπΠ-Ο MEXICANO D € LA PROREDad industrial

<img file="MX339552B_D0075.tif" />

hydroxprop, H3-cyclodextrlna. In some embodiments, it comprises hldroxIpropll-P-cyclodextrin in water.

Treatment of disorders

The invention also relates to the medical use of compounds of the present invention, such as for the treatment of a disease in the central nervous system, including psychosis, in particular schizophrenia or other diseases that include psychotic symptoms, such as, for example, schizophrenia. , schulzofrenlforme disorder, esqulzoaffective disorder, delusional disorder, short psychotic disorder, shared psychotic disorder, as well as other psychotic disorders or diseases that present with psychotic symptoms, for example bipolar disorder, such as mania in bipolar disorder. Compounds and / or compositions of the invention can also be used in the treatment of disorders such as those described, for example, in US Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; US Patent Publications Nos. 2008/0269248; 2010/0069676; 2011/0178094;

2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each Incorporated by reference in its entirety. The invention also relates to the medical use of compounds of the present invention and as combination therapy together with other therapeutic agents such as those described, for example, in US Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; US Patent Publications Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each Incorporated by reference in its entirety.

It will be recognized that one or more characteristics of any of the

IMPI

INSTITUTO MEXICANO fl 9 OE IA Industrial Property Embodiments disclosed herein may be combined within the scope of the invention to produce other embodiments that are also within the scope of the invention.

Those skilled in the art will recognize or be able to determine, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These equivalents are intended to be within the scope of the present invention.

The invention is also described by means of the following non-limiting examples.

EXAMPLES

Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the example modes for making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these examples, which are for illustrative purposes only, since alternative methods can be used to obtain similar results.

Purification of compounds by chromatography refers to the application of silica gel chromatography using manual flash chromatography or automated flash chromatography, typically performed using elution gradients from heptanes in ethyl acetate or mixtures of ethyl acetate, triethylamine, and methanol. .

LCMS Methods Description

Compounds (I), (II), (lll), (IV), (V), (VI) and (Vil) were characterized by LCMS using the following methods (Table 1):

Table 1: Methods for LCMS analysis

<img file="MX339552B_D0076.tif" />

IMPI 'NSTTTUTO MEXICANO ^OF THE INDUSTRIAL FROFIFDaD

<td>equipment</td><td colspan="2">Agilent 1100 LCMS system with ELS detector</td>

<td></td><td colspan="2">[WuXyAB25 method Agilent 1200 LCMS system with</td>

<td></td><td>ELS detector]</td><td></td>

<td></td><td>Bomb</td><td>G1311A</td>

<td></td><td>Degasser</td><td>G1379A</td>

<td></td><td>Autosampler</td><td>G1367A</td>

<td></td><td>plates with cavities</td><td></td>

<td></td><td>Column oven</td><td>G1316A</td>

<td></td><td>DAD</td><td>G1315B</td>

<td></td><td>MSD</td><td>G1946C or G1956A [method</td>

<td></td><td></td><td>WuXyAB25 6110]</td>

<td></td><td>ELSD</td><td>Alltech ELSD 800 [method</td>

<td></td><td></td><td>WuXyAB25 Allgent1200]</td>

<td>Column</td><td colspan="2">YMC ODS-AQ [WuXyAB25 Agilent TC-C18 method]</td>

<td></td><td>Particle size</td><td>5 mlcrometers</td>

<td></td><td>Pore ​​size</td><td>12nm</td>

<td></td><td>Dimension</td><td>50 * 2.0mm ID [method</td>

<td></td><td></td><td>WuXyAB25 50 * 2.1mm ID]</td>

<td>Injection volume</td><td>2 mlcroL</td><td></td>

<td>Temperature of</td><td>50 ° C</td><td></td>

<td>column</td><td></td><td></td>

<td>Flow</td><td>0.8 mL / min</td><td></td>

<td>Mobile phases</td><td>TO</td><td>0.1% TFA in water</td>

B

0.05% TFA in acetonitrile

Run time 4.5 min

<img file="MX339552B_D0077.tif" />

total

<td>UV detection</td><td>Gradient Wavelength</td><td>linear 254 nm</td>

<td>ELSD detection</td><td>Temperature:</td><td>50 ° C</td>

<td></td><td>Gas pressure:</td><td>3.2 bar</td>

<td></td><td>Weather</td><td>Gradient</td>

<td>WXV-AB05</td><td>0 min</td><td>95% of A 5% of B</td>

<td></td><td>3.5 min</td><td>0% of A 100% of B</td>

<td></td><td>3.55 min</td><td>95% of A 6% of B</td>

<td>WXV-AB10</td><td>0 min</td><td>90% of A 10% of B</td>

<td></td><td>3.4 min</td><td>100% B</td>

<td></td><td>3.5 min</td><td>100% B</td>

<td></td><td>3.51 min</td><td>90% of A 10% of B</td>

<td>WXV-AB30</td><td>0 min</td><td>70% of A 30% of B</td>

<td></td><td>3.2 min</td><td>0% of A 100% of B</td>

<td></td><td>3.5 min</td><td>0% of A100% B</td>

<td></td><td>3.55 min</td><td>70% of A 30% of B</td>

<td>WuXyAB25</td><td>0 min</td><td>75% of A 25% of B</td>

<td></td><td>3.4 min</td><td>0% of A100% of B</td>

<td></td><td>4 min</td><td>0% of A100% of B</td>

<td></td><td>4.01 min</td><td>75% of A 25% of B</td>

<td></td><td>4.5 min</td><td>75% of A 25% of B</td>

Method 131

equipment

Sciex API150EX equipped with APPI source that operates

IMPI

INSTITUTO MtXICANO r »E LA MOMEDAfi industrial

<img file="MX339552B_D0078.tif" />

in positive ionic mode

LC-MS were run on a Sciex API150EX equipped with an APPI source operating in positive ionic mode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps, SPD-M20A PDA detector (operating at 254 nM) and SCL-10A system controller. The autosampler was

Gilson 215,

Gilson 215 Autosampler

Jones Chromatography 7990R Column oven

ELSD Sedere Sedex 85

Column_Waters Symmetry C-18

<td>Injection volume</td><td>Particle size Dimension 10 microL</td><td colspan="2">3.5 micrometers 30 * 4.6mmID</td>

<td>Temperature of</td><td></td><td></td><td></td>

<td>column</td><td>60 ° C</td><td></td><td></td>

<td>Flow</td><td>3.0 mL / min</td><td></td><td></td>

<td>Mobile phases</td><td>TO</td><td>0.05% TFA in water</td><td></td>

<td></td><td>B</td><td>0.05% TFA in methanol</td><td></td>

<td></td><td>Total time of</td><td></td><td></td>

<td></td><td>run</td><td>2.8 min</td><td></td>

<td></td><td>Gradient</td><td>nonlinear</td><td></td>

<td>UV detection</td><td>Wavelength</td><td>254 nm</td><td></td>

<td>ELSD detection</td><td>Temperature:</td><td>50 ° C</td><td></td>

<td></td><td>Gas pressure:</td><td>4.4 bar</td><td></td>

MEXICAN INSTITUTE OF RRORIT.DAD

INDUSTRIAL

Gradient_Time

<td>0.01 min</td><td>17% of B in A</td>

<td>0.27 min</td><td>28% of B in A</td>

<td>0.53 min</td><td>39% of B in A</td>

<td>0.80 min</td><td>50% of B in A</td>

<td>1.07 min</td><td>59% of B in A</td>

<td>1.34 min</td><td>68% of B in A</td>

<td>1.60 min</td><td>78% of B in A</td>

<td>1.87 min</td><td>86% of B in A</td>

<td>2.14 min</td><td>93% of B in A</td>

<td>2.38 min</td><td>100% B</td>

<td>2.40 min</td><td>17% of B in A</td>

<td>2.80 min</td><td>17% of B in A</td>

Description of chiral HPLC methods

Enantiomeric purity was tested on a Hewlett system

Packard 1100 series equipped with a diode detector and using ChemStation for LC Rev. A.08.03 [847], The parameters of the HPLC method are described in the following table (Table 2). Compound (X) has a retention time of approximately 13.6-13.7 min while its enantiomer, 4 - ((1 S, 3R) -6-chloro-3-phenyl-indan-1-l) -1,2,2 -tr-methyl-piperazine, elutes at 8.5-8.6 min.

Table 2: Chiral HPLC analysis methods

<td>Sample preparation</td><td>1-3 mg / mL in hexane / 2-propanol (80/20 v / v)</td>

<td>Column:</td><td>Chiralpak ADH 5 microm 250 x 4.6 mm</td>

<td>Column temperature (° C):</td><td> 30</td>

<td>Injection (microL):</td><td> 5</td>

<td>Detection: wavelength, bandwidth (nm):</td><td> 240. 8</td>

<img file="MX339552B_D0079.tif" />

IMPI 'NSTETUTo MEXICANO DE LA PROPIEDAD industrial

<td></td><td></td><td></td>

<td>Total run time</td><td>30 min</td><td></td>

<td>Flow rate (mL.min^-1);</td><td> 0.6</td><td></td>

<td>Mobile phase</td><td>hexane / 2-propanol / diethylamine / acid 90/10 / 0.2 / 2</td><td>propionic</td>

Example 1 Preparation of 4 - ((1 R, 3S) -6-chloro-3-phenyl-ldan-1-l) -1-metyl-d32,2-dmemetll-praze Na * butandioic acid (compound (l) * butandloic acid salt).

Scheme 8. Synthesis of compound (I).

<img file="MX339552B_D0080.tif" />

1 - ((1 R, 3S) -6-Chloro-Butandioic Acid Salt Compound (I) 3-Phenyl-indan-1-yl) -1-methyl-3,3-d-methyl -piperazine (compound hydrochloride (XI)

1 - ((1 R, 3S) -6-Chloro-3-phenyl-indan-1-yl) -3,3-d-methyl-piperazine hydrochloride (11.1 g) was dissolved in a toluene mixture ( 74 mL) and water (74 mL). The preparation of 1 - ((1R, 3S) -6-chloro-3-phenyl-indan-1-yl) -3,3dimethyl piperazine hydrochloride is disclosed in the patent literature (Dahl, Wohlk Nielsen, Suteu, Robin , Brosen W02006 / 086984 A1; Bang-Andersen, Bogeso, Jensen, Svane, Dahl, Howells, Lingso, Mow W02005 / 016901 A1; each incorporated by reference in its entirety). 12.0 M potassium hydroxide in water (5.38 mL), tetra - / \ / - butylammonium bromide (1.42 g) and cfe-iodomethane (Aldrich Catalog # 176036; 2.4 mL) were added and the mixture was stirred at room temperature

IMPI

<img file="MX339552B_D0081.tif" />

for 18 hours (Scheme 8). The mixture was filtered through a dr virlrh__ filter in a separatory funnel. The solid on the filter was washed with toluene (50 mL) in the separating funnel. The aqueous layer was extracted with toluene (100 mL) and the combined organic layers were washed with concentrated aqueous ammonia (100 mL) and subsequently with water (100 mL) before drying over sodium sulfate, filtered and concentrated in vacuo to give a slightly yellow oil. The oil was cooled to -78 ° C under vacuum which solidified the oil. After warming to room temperature, the oil became a semi-solid.

This material was dissolved in acetone (30 mL); In a separate container, butandioic acid (3.46 g) was suspended in acetone (30 mL) and heated under reflux (not all of the diacid was dissolved). The acidic suspension was added to the crude product solution and additional acetone (50 mL) was added to the butandioic acid residue and then poured into solution. The mixture was stirred overnight. Partial precipitation occurred overnight and the mixture was₁₅ concentrated in a vacuum. The residue was redissolved in acetone (70 mL) and heated under reflux and allowed to cool to room temperature and stirred for 2 hours.

The mixture was filtered to give 4 - ((1 R, 3S) -6-chloro-3-phenyl¡ndan-1-l) -1-metyl-O3-2,2-dimethyl acid -piperazin'butandioic (compound (l) * butandioic acid salt; 7.61 g). LC-MS (method 131): RT (UV) 1.57 min; UV / ELS

0 100% / 100% purity; observed mass 358.0. Incorporation of three deuterium atoms> 99%. The spectre¹³Proton decoupled NMR showed a heptet of approximately 36.4 ppm corresponding to the deuterated M2 metabolic site; this signal collapsed into a singlet on the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra. Optical purity> 95% ee.

<img file="MX339552B_D0082.tif" />

IMPI

INSTITt 'TO MEXICANO

9 OF IA PROPERTY

INOUSTRIAI

Example 2 4-rru alternative preparation method? qq) -6-r.lnro-3-phenylindan-1-yl) -1-methyl-d3-2,2-dimethyl-piperazine * butandioic acid (compound (l) «butandioic acid salt )

The free base of 1 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) -3,3dimethyl-piperazine was prepared from the corresponding hydrochloride salt by dividing 23.4 g of the salt between a mixture of water (100 mL), concentrated aqueous potassium hydroxide (40 mL), and toluene (250 mL). The organic layer was washed with a mixture of water (50 mL) and concentrated aqueous 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 - ((1 R, 3S) -6-chloro-3-phenylindan-1-yl) -3.3 -dimethyl-piperazine (21.0 g) as a colorless oil. This material 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- / V-butylammonium bromide (2.98 g), and cfe-iodomethane (4.9 mL) and the mixture was stirred at room temperature for 18 hours.

Work-up and purification were performed as previously described and resulted in 4 - ((1 R, 3S) —6-chloro-3-phenyl-indan-1-yl) —1— methyl-c / 3- 2,2-Dimethyl-piperazine * butandioic acid (compound (l) -butandioic acid salt; 14.34 g; 48.9%).

Example 3 Preparation of 4 - ((1 R, 3S) -6-chloro-3-phenyl-c / 5-indan-1-yl) -1,2,2trimethyl-piperazine (compound (II)) and 4- ( (1 R, 3S) -6-chloro-3-phenyl-d5-indan-1-yl) 1-methyl-á3-2,2-dimethyl-piperazine (compound (IV)).

To a solution of compound A (57 g) in tetrahydrofuran (600 mL), triethylamine (30 mL) was added dropwise over 30 min. The reaction mixture

<img file="MX339552B_D0083.tif" />

it was kept at room temperature for 3 hours. The solids {SPéClplldilu ¿e fillféy the filtrate was concentrated in vacuo. The residue was reprecipitated in diethyl ether to obtain compound B (31 g) as a yellow solid. [Rh (ndb) 2] BF was added to a solution of phenyl-afeferonic acid compound (25 g) in 1,4-dioxane / water (900 ml_ / 90 mL)₄ (1.3 g), racemic BINAP (2.1 g) and triethylamine (14 mL), then the reaction mixture was kept at room temperature for 2 hours under N2. Then, the indenone compound (19 g) was added and the resulting mixture was heated to 100 ° C for 3 hours. The precipitated solid was filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography to obtain indanone C (10 g).

Scheme 9. Synthesis of compound C.

<img file="MX339552B_D0084.tif" />

D

<img file="MX339552B_D0085.tif" />

C (racemate)

<img file="MX339552B_D0086.tif" />

Ef

13.4 kg 3-Bromo-6-chloro-indan-1-one (A; for references to this material see: Bogeso EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO 2008025361; each incorporated by reference in its entirety ) were dissolved in tetrahydrofuran (170.8 L) and the solution was cooled to 0-5 ° C (Scheme 9). Triethylamine (9.1 L) was added over 0.5 h. The mixture was stirred at 0-5 ° C for

<img file="MX339552B_D0087.tif" />

hours before adding an additional portion of triethylamine (2.18 L) dumnta Q.5. hours 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 n-heptane (100 L). The combined filtrates were concentrated to 30 L and stirred at 0-5 ° C for 1 hour. The mixture was centrifuged and the residual solid was dried to obtain 6-chloro-inden-1-one (compound B; 2.42 kg) sufficiently pure for the next step.

2-Methyl-tetrahydrofuran (85 L) and A /./ V-dimethylacetamide (12.4 L) were added to a reactor followed by potassium acetate (10.9 kg) and bis (pinacholate) diboro (14.8 kg). The resulting mixture was stirred for 0.5 hour. Pd (dppf) CI₂-DCM (0.91 kg) was added followed by bromobenzene-cfe (9.0 kg) and 2-methyl-tetrahydrofuran (12.2 L). The mixture was heated to 80-85 ° C for 3 hours, before lowering the temperature to room temperature. The crude mixture was filtered by kieselguhr and silica gel. The filter cake was washed with 2-methyltetrahydrofuran (31 L). The combined filtrates were concentrated to approximately 25 L while maintaining the temperature below 35 ° C. n-Heptane (52 L) and NaHCO₃ 7% aqueous (31 L) were added and the mixture was stirred for 0.5 hour. The organic layer was stirred with 7% aqueous NaHCO3 (31 L) for 0.5 hours. The combined aqueous layers were extracted with nheptane (22 L) for 0.5 hour. The combined organic extracts were washed with 25% aqueous NaCI (50 L) for 0.5 hours. The organic layer was concentrated while maintaining the temperature below 35 ° C to obtain 4,4,5,5tetramethyl-2-d₅-phenyl- [1,3,2] dioxaborolane (compound B '; 10.5 kg)

ΙΜΡΙ &lt;«r_or 'MEXICAN PROPERTY Nrnnrro f * U

INDUSTRIAL ^^ 35 pure enough for the next stage. _______

1,4-dioxane (85 L), 6-chloro-inden-1-one (compound B; 9.09 kg prepared in a manner similar to that described above), 1,5-cyclooctadiene (0.2 L) were sequentially added to a reactor , bis (norbornadiene) rhodium (I) tetrafluoroborate (0.52 kg), triethylamine (5.5 L), 4,4,5,5-tetramethyl-2-c /₅phenyl- [1,3,2] dioxaborolane (compound B'¡ 6.5 kg) and 1,4-dioxane (26 L). The mixture was heated to 48-53 ° C and stirred at that temperature for 5 hours. The reaction was neutralized by the addition of 2M aqueous HCI (13 kg). Then, nheptane (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 filter cake was washed with a 2: 1 mixture of n-heptane and methyl tert-butyl ether (19.5₁₅ kg). The filtrate was concentrated to about 25L. N-Heptane (45L) was added and the volume was reduced to about 25L. N-Heptane (45L) was added and the volume was reduced to about 35L. The mixture was stirred at 0-5 ° C for 3 hours. The mixture was centrifuged and the residual solid was dried to obtain 6-chloro-3-d₅racemic -phenyl-indan-1-one (compound C; 8.4 kg) sufficiently pure for the next stage.

Tetrahydrofuran (90 L) was added to a reactor followed by water (10

L) and 6-chloro-3-c / 5-phenyl-indan-1-one (compound C; 7.73 kg) (Scheme 10). The mixture was cooled to -35 -30 ° C. Sodium borohydride (1.5 kg) was added portionwise while maintaining the temperature at -35 --30 ° C. The resulting mixture was stirred at -35 --30 ° C for 5 hours before allowing to warm

<img file="MX339552B_D0088.tif" />

up to room temperature. The excess of sodium borohydride was neutralized-poF. addition of 2M aqueous HCI (7.6 kg) while maintaining the temperature below 45 ° C. Water (17 L) and methyl tert-butyl ether (67 L) were added and the mixture was stirred for 0.3 hours. 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 filter cake was washed with methyl tert-butyl ether (20 L). The combined filtrates were concentrated to approximately 30 L while maintaining the temperature below 45 ° C. n-Heptane (55 L) was added and the resulting mixture was concentrated to approximately 30 L while maintaining the temperature below 45 ° C. The resulting mixture was stirred at 0-5 ° C for 2 hours. The mixture was centrifuged and the filter cake was washed with nheptane (12 L) before centrifuging it again. The residual solid was dried to obtain crude D. 4.87 kg of this material was dissolved in methyl tert-butyl ether (20 L) and dried over Na2SO₄ (2 kg) for 0.25 hours. The mixture was filtered and the filter cake was washed with methyl tert-butyl ether (4.4 L). The combined filtrate was concentrated to about 20 L while maintaining the temperature below 45 ° C. n-Heptane (32 L) was added and the mixture was up to about 25 L while maintaining the temperature below 45 ° C. n-Heptane (16 L) was added and the mixture was approximately 20 L while maintaining the temperature below 45 ° C. The solid was filtered and dried to obtain c / s-6-chloro-3-d5-fenll-indan-1-ol racemlco (compound D; 4.99 kg) sufficiently pure for the next step.

Scheme 10. Synthesis and resolution of compound E.

<img file="MX339552B_D0089.tif" />

C (racemate) D (cis racemate) E (1S, 3S enantiomer)

To a solution of c / s-6-chloro-3-d₅racemic -phenyl-indan-1-ol (compound D; 50 g) in 2-isopropoxypropane (200 mL), vinyl butyrate (120 mL) and Novozym-435 (15 g) were added. The mixture was kept at room temperature for 2 days. The solid was filtered. The filtrate was evaporated and purified by chromatography on silica gel to obtain (1S, 3S) -6-chloro-3-c / 5-phenyl-indan-1ol (compound E; 13 g) sufficiently pure for the next step.

To a solution of (1S, 3S) -6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7 g) in THF (100 mL) was treated with SOCb (6.6 g) at room temperature overnight. The mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over Na₂SW₄, filtered and concentrated in vacuo to obtain the intermediate chloride (7.5 g). 3.5 g of this material was dissolved in 2-butanone (50 mL) and reacted with 2,2-dimethyl-piperazine (1.7 g) in the presence of K₂CO₃ (2.7 g) at reflux overnight. The solid was filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC on a Shimadzu FRC10A instrument equipped with a Synergi C18 column (250mm * 50mm, 10 microm) using water and acetonitrile (0.1% TFA, v / v) as the eluent to obtain 1 ((1 R, 3S) -6-chloro-3-d₅-phenyl-indan-1-yl) -3,3-dimethyl-perazine (compound F;

IMPI

<img file="MX339552B_D0090.tif" />

2.6 g) pure enough for the next stage.

To a solution of 1 - ((1R, 3S) -6-chloro-3-d₅-phenyl-indan-1-yl) -3,3dimethyl-piperazine (compound F; 2.2 g) in HCHO / HCOOH (3 mL / 3 mL) was heated under reflux overnight. Volatile substances were removed in vacuo.

The residue was partitioned between ethyl acetate and 10% aqueous NaOH. The organic layer was dried over Na2SO₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to obtain 4 - ((1 R, 3S) -6-chloro-3-d₅-phenyllandan-1-l) -1,2,2-tr-methyl-methylperazine (compound (II); 1.89 g). LC-MS (method WXV-AB05): RT (UV) 2.43 min; UV / ELS purity 95.1% / 99.6%; observed mass

360.2. Incorporation of five deuterium atoms> 95%. The spectrum of¹³Proton decoupled NMR showed three triplets around 126.1, 127.2 and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signals collapsed into three singles on the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra.

₁₅ Optical purity> 95% ee.

To a solution of 1 - ((1R, 3S) -6-chloro-3-d₅-phenyl-indan-1-yl) -3,3dimethyl-piperazine (compound F; 3.0 g) in DCDO / DCOOD (4 mL / 4 mL) was heated under reflux overnight. Volatile substances were removed in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous NaOH. The organic layer

0 Dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to obtain 4 - ((1 R, 3S) -6-chloro-3-d₅-phenylindan-1-l) -1-d₃-methyl-2,2-dimethylmethyl (compound (IV); 2.14 g). LC-MS (method WXV-AB10): RT (UV) 2.06 min; UV / ELS purity 98% / 100%; observed mass 363.3. Incorporation of eight deuterium atoms> 94%. The spectrum of¹³C NMR decoupled proton showed a heptet around 36.4 ppm Mexican Institute

DELAFROflEDAD C- · ..

INDUSTRIAL * corresponding to the deuterated M2 metabolic site; this signal collapse'eff ΌΙΤ ”singlet of the spectrum¹³C NMR decoupled of protons and deuterium. The spectrum of¹³Proton decoupled NMR also showed three triplets around 126.1, 127.2 and 128.2 ppm corresponding to metabolic sites

Deuterated M3; these signals collapsed into three singles on the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra. Optical purity> 95% ee.

Example 4: Preparation of 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1,2,2trimethyl-piperazin-6,6-c / 2 (compound (III) ), 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-110 ¡l) -1-methyl-d₃-2,2-dímet¡lp¡peraz¡n-6,6-í / 2 (compound (V)), 4 - ((1 R, 3S) -6chloro-3-phen¡l-d5-indan -1-¡l) -1-metíl-d3-2,2-d¡met¡lp¡peraz¡n-6,6-d2 (compound (VI)) y 4 - ((1R, 3S) - 6-chloro-3-phenyl-d5-indan-1-yl) -1,2,2-trimethylpiperazin-6,6-d₂ (compound (Vil).

2-Amino-2-methyl-propionic acid (50.0 g) was suspended in a ₁₅ methanol and triethylamine mixture (9: 1, 1.2 L) (Scheme 11). 1M aqueous NaOH (450 mL) was added with stirring until all the solid dissolved. Di-terbutyldicarbonate (Boc₂OR; 214.0 g) was added and the mixture was stirred at room temperature overnight. Volatile substances were removed in vacuo. EtOAc (500 mL) was added. The organic layer was washed with brine and dried over

Na₂SO4, filtered, then concentrated to obtain 2-terbutoxycarbonyllamine-2-methyl-propionic acid (compound K; 90 g) as a white solid which was used directly in the next stage.

Scheme 11. Synthesis of intermediary J.

<img file="MX339552B_D0091.tif" />

<img file="MX339552B_D0092.tif" />

2-araino-2methyl-propronieo acid

<img file="MX339552B_D0093.tif" />

ΙΜΡΙ MEXICAN INSTITUTE 0E LA FROPIBDAD industrial

<img file="MX339552B_D0094.tif" />

<img file="MX339552B_D0095.tif" />

go H

<img file="MX339552B_D0096.tif" />

A mixture to obtain 2-tert-butoxycarbonylamino-2-methylpropionic acid (compound K; 60.0 g) and 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCI; 86.4 g) in dichloromethane (900 mL) was stirred at room temperature, then N hydrochloride, Odimethylhydroxylamine (35.3 g) and triethylamine (150 mL) were added. The resulting mixture was stirred at room temperature for 3 days. Water was added and most of the volatiles were removed in vacuo. The residue was divided into DCM and NaHCO₃ aqueous. The organic layer was washed with 3M aqueous HCI, then with brine before drying over Na2SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give [1- (methoxy-methyl-carbamoyl) -l-methyl-ethyl] -carbamic acid tert-butyl ester (compound L; 28.2 g) as a sufficiently white solid pure for the next stage.

Lithium aluminum hydride (7.8 g) was added to a stirred solution

<img file="MX339552B_D0097.tif" />

IMPI of tert-butyl acid ester [1- (m^QtnYiHO^Qt¡lc^torham^nil) -i-mftt¡l-et¡Hcarbamic (compound L; 42.0 g) in dry diethyl ether (1.5 L) at -40 ° C. Then it was stirred at that temperature for about 5 min. Excess LiAIH₄ it was neutralized with a solution of potassium hydrogen sulfate in water. The resulting mixture was divided into EtOAc and 3M aqueous HCI. The organic layer was washed with saturated aqueous NaHCO3, dried over Na₂SW₄, filtered and concentrated in vacuo to obtain tert-butyl ester of (1,1-dimethyl-2-oxo-ethyl) -carbamic acid (compound M; 29 g) sufficiently pure for the next step.

Amino Acetic Acid Methyl Ester Hydrochloride (80.6g) and Et₃N (160 mL) were dissolved in DCM (1000 mL) and stirred for 15 min to release the amine from the salt. Next, a solution of 1,1-dimethyl-2-oxo-ethyl) -carbamic acid tert-butyl ester (compound M; 29.0 g) in DCM (600 mL) was added. The resulting mixture was stirred for 0.5 hours at room temperature before adding NaBH (OAc) 3 (102 g) and the mixture was stirred at room temperature overnight. NaHCCh sat was added. aqueous. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na₂SW₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain (2-tert-butoxycarbonylamino-2-methyl-propyllamine) -acetic acid methyl ester (compound N; 26.5 g) as a white solid which was used directly into the next stage.

A mixture of (2-tert-butoxycarbonylamino2-methyl-propylamine) -acetic acid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred at room temperature, TFA (180 mL) added drop by drop. The mixture was stirred at 30-40 ° C for 5 h before concentrating in vacuo. The residue was divided into

<img file="MX339552B_D0098.tif" />

dissolved toluene and water. The organic layer was dried over ΐ ° f^iltra and ^go concentrated in a vacuum. The residual solid was dissolved in a mixture of ethanol (400 mL) and methanol (90 mL). K2CO3 (207 g) was added and the mixture was heated under reflux overnight. The mixture was cooled to room temperature. DCM (2500 mL) was added and the mixture was stirred for 1 hour at room temperature. The solid was filtered and the filtrate was concentrated in vacuo to obtain 6,6-dimethyl-perazine-2-one (compound I; 5.85 g) as a sufficiently pure white solid for the next step.

A solution of 6,6-dimethyl-plperazin-2-one (compound I; 3.6 g) in THF (20 mL) was stirred at 0 ° C. Lithium Aluminum Deuteride (LIAID₄; 3.6 g) was then added, the mixture was heated under reflux overnight. The mixture was cooled to room temperature and Na was added₂SW₄. 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 HCI in EtOAc at room temperature for 0.5 hours. The solid was filtered and dried to obtain to give 2,2-d₂-6,6dlmetll-piperazine as bls-hydrochloride salt (compound J 2HCI; 5.3 g) sufficiently pure for the next step.

SOCI was added to a solution of compound E '(5 g) in THF (50 mL)₂ (4.7 g) and the resulting mixture was stirred overnight at room temperature (Scheme 12). The mixture was poured into ice-cold water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SW₄, filtered and concentrated in vacuo to obtain the corresponding chloride (5.3 g) which was used directly in the next step. 3.3 g of this material was dissolved in 2butanone (50 mL) and reacted with 2,2-c /₂-6,6-dlmetll-p¡perazína (compound J; 3 g) in the presence of K₂CO₃ (8.28 g) at reflux overnight. The

<img file="MX339552B_D0099.tif" />

solid leaked. The filtrate was concentrated in vacuo. The R^{Qoid |} 'ec? pnfírn pnr preparative HPLC on a Shlmadzu FRC-10A Instrument equipped with a column

Synergi C18 (250mm * 50mm, 10 microm) using water and acetonitrile (with 0.1% TFA, v / v) as the eluents to obtain 1 - ((1 R, 3S) -6-chloro-3-phen¡l -¡Ndan1-11) -3,3- ^ 2-5,5-dlmetll-plperazlna (compound O; 1.7 g).

Scheme 12. Synthesis of compound (lll) and compound (V).

<img file="MX339552B_D0100.tif" />

E '(1S, 3S enantlomer) OR (enantlomer (1R, 3S) compound (lll) compound (V)

A solution of 1 - ((1 R, 3S) -6-chloro-3-phenyl-ydan-1-yl) -3,3-cfe5,5-dimethyl-plperazine (compound O; 0.5 g) in HCHO / HCOOH (1 mL / 1 mL) was refluxed overnight. Volatile substances were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to obtain4 - ((1R, 3S) -6-chloro-3-phenil-indan-1l) -1,2,2-trimethyl-plperaz! n-6,6-d₂ (compound (lll); 0.33 g). LC-MS (method WXV-AB30): RT (UV) 1.42 min; UV / ELS purity 100% / 100%; observed mass

357.2. Incorporation of two deuterium atoms> 97%. The spectrum of¹³Proton decoupled NMR showed a quintet around 49.5 ppm corresponding to the deuterated M1 metabolic site; this signal collapsed into a slngle of the spectrum of¹³C NMR decoupled of protons and deuterium. The

<img file="MX339552B_D0101.tif" />

spectrum of ¹³C NMR decoupled proton tamhipn showed three triplets around 126.1, 127.2 and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signals collapsed into three singles on the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra. Optical purity> 95% ee.

A solution of 1 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) -3,3-d25,5-dimethyl-piperazine (compound O; 0.7 g) in DCDO / DCOOD (1 mL / 1 mL) was heated under reflux overnight. Volatile substances were removed in vacuo. The residue was divided into EtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SW₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to obtain 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1yl) —1-methyl-c /₃-2,2-dimethyl-piperazin-6,6-c / 2 (compound (V); 0.49 g). LC-MS (method WXVAB25): RT (UV) 2.13 min; UV / ELS purity 100% / 100%; observed mass 360.2. Incorporation of five deuterium atoms> 95%. The spectrum of¹³Proton decoupled NMR C showed a heptet about 36.4 ppm corresponding to the deuterated M2 metabolic site; this signal collapsed on a singlet the spectrum of¹³C NMR decoupled of protons and deuterium. The spectrum of¹³Proton decoupled NMR also showed a quintet around 49.5 ppm corresponding to the deuterated M1 metabolic site; this signal collapsed on a singlet the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra. Optical purity> 95% ee.

To a solution of (1S, 3S) -6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7 g) in THF (100 mL) was treated with SOCb (6.6 g) at room temperature overnight (Scheme 13). The mixture was poured into ice water and

IMPI

INSTITUTO MEXICANO de LA FRORIEDAD INDUSTRIAL

<img file="MX339552B_D0102.tif" />

it was extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over Na₂SO4 was filtered and concentrated in vacuo to obtain the intermediate chloride (7.5 g).

Scheme 13. Synthesis of compound (VI) and compound (Vil).

<img file="MX339552B_D0103.tif" />

E (1S, 3S enantiomer) P ((1R, 3S) enantiomer compound (VI) compound (Vil)

1.8 g of this material was dissolved in 2-butanone (30 mL) and reacted with 2,2-d₂-6,6-dimethyl-p-perazine (compound J; 1.4 g) in the presence of K₂CC> 3 (5.5 g) at reflux overnight. The solid was filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on a Shimadzu FRC-10A instrument equipped with a Synergi C18 column (250mm * 50mm, 10 microm) using water and acetonitrile (0.1% TFA, v / v) as the eluents to obtain 1 - ((1 R, 3S) -6-Chlorine-3-d₅-fen¡l-¡ndan-1-il) -3,3-d₂-5,5-dimethylpiperazine (compound P; 1.7 g).

A solution of 1 - ((1R, 3S) -6-Chloro-3-d5-phenyl-indan-1-yl) -3.3d₂-5,5-Dimethyl-piperazine (Compound P; 1 g) in DCDO / DCOOD (1.5 mL / 1.5 mL) was heated at reflux overnight. Volatile substances were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SW₄, filtered and concentrated in vacuo. The residue was purified by

IMPI iNSTrnrro muücano

OF THE INDUSTRIAL RRORBAD

<img file="MX339552B_D0104.tif" />

Silica gel chromatography to obtain ¿- // 1 R ^ sn-fi-r.loro-S-ck-phenyl¡ndan-1-¡l) -1-c / 3-methyl-2,2-dimet¡ lp¡perazin-6,6-d2 (compound (VI); 0.55 g). LC-MS (WuXyAB25 method): RT (UV) 2.13 min; UV / ELS purity 98.2% / 100%; observed mass 365.2. Incorporation of ten deuterium atoms> 91%. The spectrum of¹³Proton decoupled NMR C showed a heptet about 36.4 ppm corresponding to the deuterated M2 metabolic site; this signal collapsed on a singlet the spectrum of¹³C NMR decoupled of protons and deuterium. The spectrum of¹³Proton decoupled NMR also showed a quintet around 49.5 ppm corresponding to the deuterated M1 metabolic site; this signal collapsed into a singlet of the spectrum¹³C NMR decoupled of protons and deuterium. The spectrum of¹³Proton decoupled NMR also showed three triplets around 126.1, 127.2 and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signals collapsed into three singles on the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra. Optical purity> 95% ee.

A solution of 1 - ((1R, 3S) -6-chloro-3-d₅-fen¡l-¡ndan-1-il) -3,3d₂-5,5-dimethyl-piperazine (compound P; 0.7 g) in HCHO / HCOOH (1 mL / 1 mL) was heated under reflux overnight. Volatile substances were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SW₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to obtain 4 - ((1 R, 3S) -6-chloro-3-Ó5-phenylindan-1-yl) -1-methyl-2,2-dimethyl- piperazin-6,6-d₂ (compound (Vil); 0.47 g). LCMS (method WXV-AB30): RT (UV) 1.33 min; UV / ELS purity 97.4% / 100%; observed mass 362.3. Incorporation of seven deuterium atoms> 93% =. The spectrum of¹³Proton decoupled NMR showed a quintet around 49.5 ppm

<img file="MX339552B_D0105.tif" />

corresponding to the deuterated M1 metabolic site; egta &lt;? diaper cnapsed on a singlet of the spectrum of¹³C NMR decoupled of protons and deuterium. The spectrum of¹³Proton decoupled NMR also showed three triplets around 126.1, 127.2 and 128.2 ppm corresponding to metabolic sites

Deuterated M3; these signals collapsed into three singles on the spectrum of¹³C NMR decoupled of protons and deuterium. All other signals were singlets in both spectra. Optical purity> 95% ee.

Example 5: Description of NMR determination of ion (s) carrying deuterium instead of hydrogen io NMR spectra were recorded on a Bruker spectrometer

600-Advance-lll equipped with a 5mm TCI cryoprobe operating at 150.91 MHz to ¹³C. A CDCI3 solution was used as an internal reference for the uncoupled proton experiments, while the proton and reverse gate deuterium spectra were recorded by closed lock. ₁₅ per gate. The difference (s) between the two spectra for the compounds of the invention determine (s) the position (s) of the deuterium atoms. When this information summarized in the following table (Table 3) is combined with the electrospray mass spectrometry data determining the degree of deuteration, it is possible to unambiguously assign the structures of the compounds of the invention.

Table 3: Carbon NMR data for compounds.

M3 (phenyl group a ~ 126.1

M2 (methyl group at -36.4 M1 (methylene group at ppm, -127.2 (2C) and -128.2 ppm) -49.5 ppm) (2C))

5 Compound ¹³C NMR

13,

C NMR

13,

C NMR

13,

C NMR

13,

C NMR

13,

C NMR

IMPI Mexican Institute γ> ε LA FROREDAD INDI ISTRIAL

<img file="MX339552B_D0106.tif" />

<td></td><td>protonic</td><td>protonic and</td><td>protonic</td><td>protonic and</td><td>protonic</td><td>preiuiiiuuy—</td>

<td></td><td>decoupling</td><td>deuterium</td><td>decoupling</td><td>deuterium</td><td>decoupled</td><td>deuterium</td>

<td></td><td>ado</td><td>disengaged</td><td>ado</td><td>disengaged</td><td> 0</td><td>disengaged</td>

<td>(I)</td><td>heptet</td><td>sinqulete</td><td>sinqulete</td><td>singlet</td><td>singlets</td><td>singlets</td>

<td>(II)</td><td>singlet</td><td>singlet</td><td>singlet</td><td>singlet</td><td>3 triplets</td><td>3 singlets</td>

(lll) _singulete singlet quintet singlet singlet 3 singlet

<td>(IV)</td><td>heptet</td><td>singlet</td><td>singlet</td><td>singlet</td><td>3 triplets</td><td>3 singlets</td>

<td>(V)</td><td>heptet</td><td>singlet</td><td>quintet</td><td>singlet</td><td>3 singlets</td><td>3 singlets</td>

<td>(SAW)</td><td>heptet</td><td>singlet</td><td>quintet</td><td>singlet</td><td>3 triplets</td><td>3 singlets</td>

<td>(Vile)</td><td>singlet</td><td>singlet</td><td>quintet</td><td>singlet</td><td>3 triplets</td><td>3 singlets</td>

Only NMR signals that change as a consequence of the presence of D rather than H in the compounds of the invention are included in the table.

The relevant rulers of the spectra of ¹³C decoupled proton NMR (Lower spectrum) and ¹³Disconnected proton and deuterlo NMR (upper spectrum) of compound (II) and compound (V) are shown in Figures 3A and 3B as representative examples. Selected lines of the spectra of¹³C decoupled proton NMR and ¹³Protonic C and decoupled deuterlo of compound (II) (Figure 3A) and compound (V) (Figure 3B). Example 6: Description of electrospray mass spectroscopy to determine the degree of deuteraclon

Instrumentation: mass spectra of solutions were obtained

<img file="MX339552B_D0107.tif" />

Aqueous acidic compounds were a Hewlett Packard Model 1100 LC-MSD Quadruple Maca Spectrometer. Liquid chromatography was performed using an Agilent 1100 HPLC system coupled to the mass spectrometer.

Experimental: solutions were prepared by dissolving approximately 2 mg of substance in 2 mL of methanol + 18 mL 10 mM ammonium pH 3.0 format. Subsequently, the solutions were diluted 100X before analysis. In order to obtain a clean peak, the samples were chromatographed using a Waters X-bridge C18 3.5 microm column (150 x 2.1 mm) and 0.1% trifluoroacetic acid / 50/50 acetonitrile was used as the mobile phase. This procedure allows obtaining a peak of the compound of interest that elutes at approximately 3.6 min, which contains both the deuterated compounds of the invention as well as small amounts of deuterium-deficient species. The mass spectra obtained from these peaks were used to evaluate the speciation of the target molecules. The results were analyzed as a percentage of the total amount of substance, completing up to 100%. The potency of the compounds was not analyzed, but only the relative content of the deuterium-deficient species.

By way of representative example, the mass spectrum of compound (IV) is shown in Figure 4. The isotopic pattern of the protonated compound (V) [M + H j⁺ with the mass 363.1 u (362.1 u + 1.0u) and the isotope ions 363.1u, 364.1u, 365.1u and 366.1u it was in the ratio 100: 25.3: 34.9: 7.9; the calculation for C20H22N2CID8 allows obtaining the ratio 100: 25.2: 34.9: 8.3. On the other hand, D2-analogs and D3-analogs were observed in masses 362.1u and 358.1u, respectively. Signals at 364u, 365u and 366u must be

<img file="MX339552B_D0108.tif" />

primarily protonated molecules that contain Tropic &amp; - ^ C_yZQ-2l £ L £ D. instead of¹²C and ³⁵CI (due to natural distribution). These data show that the incorporation of eight deuterium atoms was greater than 94%.

Example 7: Experimental binding tests

Description of the D binding assay₂ human

The assay was carried out in the form of a SPA-based competition binding in a 50 mM Tris assay buffer pH 7.4 containing 120 mM NaCl, MgCI₂ 4 mM, CaC l₂ 1.5mM, 1mM EDTA.

1.5 nM of ³H-raclopride (Parkin Elmer, NET 975) with test compound before addition of 20 microg of a D receptor membrane preparation₂ Homogenized human and 0.25 mg SPA beads (WGA RPNQ 0001, Amersham) in a total volume of 90 microL. The test plates are incubated with shaking for 60 minutes at room temperature and subsequently counted in a scintillation counter (TriLux, Wallac). Total binding, which comprised approximately 15% added radioligand, is defined by assay buffer, whereas non-specific binding is defined in the presence of 10 microM haloperidol. Non-specific binding made up about 10% of total binding.

Data points are expressed in percent of specific binding, and IC50 values ​​(the concentration that causes a 50 percent inhibition of specific binding) are determined by nonlinear regression analysis using a fit variable sigmoidal slope curve. The dissociation constant (Kj) is calculated using the Cheng Prusoff equation (Kj = IC50 / (1+ (L / K_d)), where the concentration of free radioligand L approaches the concentration of radioligand added in the assay.

<img file="MX339552B_D0109.tif" />

IMPI ^{, NST}'niTO MEXICANO PE «A FtOWEDAP' ^ PHSTRIAL

Description of the Human D-ι Union --—_.___

The assay was carried out as a SPA-based competition binding in a 50mM Tris assay buffer pH 7.4 containing 120mM NaCl, MgCI₂ 5 mM, CaC l₂ 4mM, 1mM EDTA. About 1 nM of³H-SCH23390 (Parkin Elmer, NET 930) with test compound prior to addition of 2.5 mlcrog of a homogenized human Di receptor membrane preparation and 0.25 mg SPA beads (WGA RPNQ 0001, Amersham) in a total volume of 60 microL.

The test plates are incubated with shaking for 60 minutes at room temperature before the plates are centrifuged, and subsequently counted in a scintillation counter (TriLux, Wallac). Total binding, which comprised approximately 15% added radioligand, is defined by assay buffer, whereas non-specific binding is defined in the presence of 10 microM haloperidol.

Data points are expressed in percent of specific binding and IC50 values ​​(the concentration that causes a 50 percent inhibition of specific binding) are determined by nonlinear regression analysis using a fit variable sigmoidal slope curve. The dissociation constant (Kj) is calculated using the Cheng Prusoff equation (K¡ = IC₅o / (1+ (L / K_D)), where the concentration of free radioligand L approaches the concentration of added radioligand

5-HT2 binding description_TO human

The experiment was carried out in Cerep Contract Laboratories (Cat. Ref. # 471).

Compound (I) was also tested in an in vivo set that

ΙΜΡΙ • «τπυτο MEXICAN Μ lR industrial RROREDAD

<img file="MX339552B_D0110.tif" />

demonstrated the central effects of the compound. MediaiTtC 'Id uiiiún in vivo, the in vivo affinity of compounds for D receptors₂ was evaluated, and an occupancy of 60% of the target was observed. The occupation of the D receptors₂It is closely related to antipsychotic effects in animal models and in patients.

Description of in vivo binding to D receptors₂ in the rat brain

The in vivo assay was carried out in accordance with Andersen et al (Eur J Pharmacol, (1987) 144: 1-6) incorporated herein by reference in its entirety) with a few modifications Kapur S. et al, J Pharm Exp Ther, 2003, 305, 625-631); incorporated herein by reference in its entirety. Briefly, 6 rats (male Wistar, 180-200 g) were treated with 20 mg / kg of test compound subcutaneously 30 minutes before receiving 9.4 micro [³H] -raclopride intravenously via the caudal vein.

minutes after injection of the radio ligand the animals are killed by cervical dislocation, the brain is removed quickly and the striatum and cerebellum are dissected and homogenized in 5 mL (cerebellum in 20 mL) frozen buffer (50 mM K₂PO₄, pH 7.4). 1.0 mL of the homogenized material is filtered through Whatman's GF / C filters soaked in 0.1% PEI. This is completed within 60 seconds after decapitation. Filters are washed twice with 5 mL of ice cold buffer and counted in a scintillation counter. A group of vehicle treated animals is used to determine the total binding of [³H] -raclopride in the striatum and unspecified junction in the cerebellum. Homogenized material was measured to establish protein content by the BCA protein determination assay (Smith PK et al (1985) Anal. Biochem., 150: 6-85), incorporated herein by way of

IMPI

<img file="MX339552B_D0111.tif" />

in its entirety - ...—

Example 8: Investigation of the metabolism of 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan1 — I) —1,2,2-trimethyl-piperazine (compound X)) and 4- ( (1 R, 3S) -6-chloro-3-phenylindan-1-yl) -1-methyl-d3-2,2-dimethyl-piperazine (compound (I))

A few hepatocytes from cryopreserved dog (male pack dog) (1 million cells / mL in suspension, 50 microL / well) were preincubated for 15 min in a 96 well plate in a 37 ° C water bath in high DMEM glucose buffered with 1M HEPES. The cell suspension was added with 50 microL test compounds (final concentration

0.1 or 1 microM of 4 - ((1R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1,2,2-trimethylpiperazine (compound (X)) or 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1-metildr-2,2-dimethyl-prazine (compound (I)) and subjected to further incubation for 0.15 , 45, 75 and 120 minutes. The reaction was stopped by adding 100 microL of acetonitrile to the cell suspension, and then₁₅ samples were removed for LC-MS analysis of the desmethyl metabolite (compound (XI)). Data is expressed as MS area with respect to an internal standard.

The results (Figures 5 and 6) show that the amount of desmethyl metabolite (compound (XI)) produced in cryopreserved dog hepatocytes 20 is lower than the deuterated form (compound (I)) than for the parent compound (compound (X )), both with a concentration of 0.1 micro M (Figure 5) and with a concentration of 1 micro M (Figure 6).

Example 9: Pharmacological test of the compounds.

4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1-d3-methyl-2,2-dimethyl-piperazine (compound (I)):

<img file="MX339552B_D0112.tif" />

4 - ((1R, 3S) -6-chloro-3-fe ni I — nd an-1 -il) -1 piperazine (compound (I)) was tested in three in vitro assays to establish affinity for dopamine Di , dopamine D₂ and serotonin 5-HT_2A.

The experiments were carried out as in the chapter on binding assays. The experimental results showed the following affinities for 4 - ((1 R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1-methyl-d3-2,2dimethyl-piperazine:

D &lt;K¡ log mean = 7.5 nM (pKi 0.88 +/- 0.15)

D₂: Ki log mean = 34 nM (pKi 1.54 +/- 0.11)

5HT2a: IC₅₀= 1.14 nM

These binding affinities indicate that compound (I) has a biological activity with a probability of exerting an antipsychotic effect.

Pharmacological tests of compound (II) and compound (IV)

The experiments were carried out as described in the chapter Binding tests. The experimental results for the two compounds are presented below.

Compound (II) and compound (IV) were infiltrated to establish affinity for dopamine D-ι and dopamine D₂. compound (IV):

Say: Ki log mean = 26.1 nM (pKi 1.42 +/- 0.03)

D₂ : Ki log mean = 26.7 nM (pKi 1.43 +/- 0.04) compound (II):

Dt Ki log mean = 23.2 nM (pKi 1.37 +/- 0.03)

D₂ : Ki log mean = 26.5 nM (pKi 1.42 +/- 0.03)

These binding affinities indicate that compounds (IUI) and (IV)

IMPI have a biological activity likely to exert an antipsychotic effect Compounds (II) and (IV) were also tested in an in vivo setting demonstrating the central effects of compounds (II) and (IV). By in vivo binding, the affinity of the compounds in vivo for D2 receptors was evaluated, and a 70% (compound (IV)) and 75% (compound (II)) target occupancy was observed. The occupation of the D receptors₂it is closely related to antlpslcotic effects in animal models and in patients.

Compounds (I) - (Vil) and (X) were tested in a side-by-side analysis at Cerep Contract Laboratories (Cat. Reis. 44 and 46). The results of receptor binding are listed in Table 4. Table 4. Binding of the compounds to D1, D2, and 5-HT2a.

(K¡): alternative binding to (K¡): alternative binding to 5-HT2A

Human D1 receptor compound human_human D2 receptor (IC₅₀)

<td>(I)</td><td>0.10 nM</td><td> 7.6</td><td>0.37 nM; 1.14 nM *</td>

<td>(II)</td><td>0.20 nM</td><td>6.8 nM</td><td>1.1 nM</td>

<td>(lll)</td><td>0.36 nM</td><td>7.6 nM</td><td>1.1 nM</td>

<td>(IV)</td><td>0.05 nM</td><td>10 nM</td><td>0.25 nM</td>

<td>(V)</td><td>0.10 nM</td><td>4.8 nM</td><td>0.61 nM</td>

<td>(SAW)</td><td>0.10 nM</td><td>3.7 nM</td><td>0.24 nM</td>

<td>(Vile)</td><td>0.14 nM</td><td> 5.2</td><td>0.33 nM</td>

<td>(X)</td><td>0.22 nM</td><td>7 nM</td><td>0.79 nM</td>

<td colspan="4">* Compound (I) was tested twice in this test</td>

IMPI 'NSTtTUTO MEXICANO DE LA PROPIEDAD industrial

<img file="MX339552B_D0113.tif" />

Example 10: Investigations on metabolism in the collected human liver ™ ia ™ nmas (HLM)

Pooled human liver microsomes (50 donors, from Xenotech) were incubated with 1 microM or 10 microM compound at 37 ° C. The incubation mix contained 50mM Tris-HCI, 154mM KCI, 5mM MgCb and a NADPH Regenerative System (1mM NADP⁺, 5 mM isocytric acid, 1 unit / mL isocytric dehydrogenase, from Sigma-Aldrich). The protein concentration was 0.2 mg / mL and the final volume was 0.5 mL. After a 10 minute preincubation, the relationship was started by adding the compound. After 0, 15, 30, 60, 90, 120 and 180 minutes, the reactions were terminated by transferring the subcellular fraction to 0.5 mL of internal reagent containing internal reagent. Incubations were carried out in triplicate. The samples were centrifuged at 4,000 g (4 ° C, 15 min) and the supernatant materials were analyzed by HPLC-MS / MS. The data were expressed as area of ​​M with respect to an internal standard.

The results show as the average of triplicate determinations ± SD. Figures 7 and 8 show that the amount of desmethyl metabolite produced in human liver microsomes is lower for the deuterated form (compound (II) and compound (IV)) than with respect to the non-deuterated compound (compound (compound (X) ), both with a concentration of 1 microM (Figure 7) and with a concentration of 10 microM (Figure 8) The results for compound (lll) are shown in Figure 9. The results for compounds (V) - (Vil) are shown in Figures 10-12, respectively. The desmethyl metabolites of compounds (II), (IV) and (X) are compounds (XX) and (XI), respectively (see Figure 13).

iNSTm to Mexican

OF IA EROFIEDAf)

ÍNTXjSTRIAL

<img file="MX339552B_D0114.tif" />

Research using human liver CYR?^P-19 and CYP3A4

Recombinant human liver isozymes CYP2C19 or CYP3A4 (from BD Biosciences) were incubated with 1 microM or 10 microM of compound (X), compound (II) or compound (IV) at 37 ° C. The incubation mixture contained 50mM Tris-HCI, 154mM KCI, 5mM MgCI₂ and a system for the regeneration of NADPH (1 mM NADP⁺, 5 mM isocytric acid, 1 unit / mL isocitric dhydrogenase, from Sigma-Aldrich). The protein concentration was 0.5 mg / mL and the final volume was 0.5 mL. After a 10 minute incubation, direction was started by the addition of compound (X), compound (II) and / or compound (IV). After 0, 15, 30, 60, 90, 120 and 180 minutes, the reactions were terminated by transferring the subcellular fraction to 0.5 mL of stop reagent containing internal standard. Incubations were carried out in triplicate. The samples were centrifuged at 4,000 g (4 ° C, 15 minutes) and the supernatant materials were analyzed by HPLCMS / MS. Data were expressed as the area of ​​MS referred to an internal standard.

The results (Figure 14 and Figure 15) show how the amount of desmethyl metabolite produced after incubation with recombinant human liver enzymes CTP2C19 is lower for the deuterated forms (compound (II) and compound (IV)) than with respect to the compound not deuterated (compound (X)), both with a concentration of 10 microM (Figure 14, compound (II)) and with a concentration of 1 microM (Figure 15, compound (IV)). Corresponding results for compound (II) were obtained with a

IMPI

<img file="MX339552B_D0115.tif" />

concentration of 1 micro M and for compound (IV) with l

<img file="MX339552B_D0116.tif" />

micro M.

Correspondingly, the amount of desmethyl metabolite produced by incubation with the recombinant human liver enzymes 5 CYP3A4 is lower for the deuterated forms (compound (II) and (IV)) than for the non-deuterated compound (compound (X)), both with a concentration of 1 micro M and 10 micro M.

Example 11: Pharmacology of compound (IV).

PCP-induced hyperactivity

Compound (IV) reverses PCP-induced hyperactivity in mice as a function of dose, indicative of its antipsychotic efficacy (Figure 16). Compound IV tartrate was administered subcutaneously (sc) 30 minutes prior to testing. PCP hydrochloride (2.3 mg / kg) was administered sc sc just prior to the assay. Locomotor activity was measured for 60 minutes based on₁₅ of the beam break amount (counts). 8 to 16 male mice were used in each group. ## indicates P &lt;0.01 versus Vehicle -PCP (one-way analysis of variance [ANOVA] followed by Bonferroni post hoc test). PCP is blocking NMDA receptors and as such are used to modernize the hypoglutamatergic state related to schizophrenia. PCP produces behavioral effects in animals that suggest positive, negative, and cognitive symptoms in schizophrenia patients (Jentsch, JD, and Roth, RH Neuropsychopharmacology 1999; 20; 201-225; incorporated herein in its entirety by way of reference). Hyper activity induced by PCP is commonly used as an assay for the evaluation of antipsychotic compounds (Jackson, DM et al., Pharmacol Biochem Behav. 1994; 48: 465IMPI

MKXICANO INSTITUTE

OE LA MONíOad industrial

<img file="MX339552B_D0117.tif" />

471; incorporated herein in its entirety by way of referonoia) Catalepsy

Catalepsy is considered to reflect the suppression, drug-induced, of the ability to initiate a behavioral response. The catalepsy test in rats is a widely used and widely used systematic screening test for EPS reliability of potentially antipsychotic drugs. Although catalepsy is usually evaluated after acute drug administration, the trial has proven to be a reliable editor regarding the propensity of an antipsychotic drug to induce EPS (i.e. pseudo parkinsonism, dystonia) in humans (Elliott , PJ et al, J. Neural. Transm. Park. Dis. Dement. Sect. 1990; 2: 79-89; incorporated herein by reference in its entirety).

Compound (IV) induced dose-dependent catalepsy in rats, suggesting EPS reliability. The minimum effective dose inducing catalepsy was 10 mg / kg (Figure 17). Compound (IV) tartrate was administered sc Prior to testing. Eight male Sprague Dawley rats were used in each group. # indicates P &lt;0.05, ## indicates P &lt;0.01 versus vehicle (one-way ANOVA followed by Bonferroni's post hoc assay). This dose is 100 times higher than the indicator dose of antipsychotic activity (Figure 16).

Example 12: Human Pharmacokinetic Studies

The symmetric drug effects of compounds (IV) and compound (X) were compared in a multiple oral dose study in healthy young men. Study participants received daily doses of 3 mg of compound (IV) and 3 mg of compound (X) for 18 days, and samples were drawn

IMPI

DE M / ROPISrMfi INDUSTRIAL

<img file="MX339552B_D0118.tif" />

of blood for 24 hours (interval of one Hr> g¡f¡ran¡ón) -rioQpi es of the last dose to measure the exposure to both compounds and their demethylated metabolites, compound (XX) and compound (XI), respectively.

For all study participants, the area under the plasma-time concentration curve for the dosing interval (AUC 0-24) for compound (IV) was greater than for compound (X), mean 104 h * ng / ml_ vs 98 h * ng / mL. A consistent shift in the opposite direction was observed for the demethylated metabolites with a mean AUC 0-24 of 117h * ng / mL and 120h * ng / ml for compound (XX) and compound (XI), respectively.

Example 13: Catalytic enantioselective synthesis of the ketone intermediate

In this example, the synthesis of (S) -6-chloro-3-phenyl (d5) indan-1-one, compound (XV), and (S) -6-chloro-3-phenyl-indan- is revealed. 1-one, compound (XVIII).

(S) -6-Chloro-3-phenyl (d5) -indan-1-one, compound (XV), has proven to be a valuable building block in the synthesis of deuterated variants of compound (X) where the phenyl group free is deuterated. Experiment Overview

Unless otherwise indicated, all reactions were carried out under nitrogen. Reactions were monitored by TLC analysis (thin layer chromatography) and LC-MS. All reagents were purchased and used without further purification. Spots were observed by exposure to ultraviolet (UV) light (254 nm), or by staining with a 5% aqueous solution of phosphomolybendenic acid (PMA) in ethanol or basic aqueous potassium permanganate (KMnO₄), followed by

<img file="MX339552B_D0119.tif" />

Heating, Merck C60 mediaete ^ eLde-silica column chromatography (40-63 pm, 230-240 mesh) was performed. NMR spectra are recorded at 500 or 600 MHz (¹H NMR), and calibrated with respect to the residual solvent peak. The following abbreviations were used for the ML data: s, singlet; d, doublet; t, triplet; m, multiplet. Coupling constants were rounded to the nearest 0.5 Hz. The enantlomeric excess was determined by chiral HPLC.

LC-MS method:

Acqulty UPLC BEH C18, 1.7 pm column; 2.1 x 50 mm operating at 60 ° C with a flow of 1.2 mL / mln of a binary gradient consisting of water + 0.1% formic acid (A) and acetonitrile + 5% water + 0.1% formic acid (B) .

Chiral HPLC method

Phenomenex Lux 5p Cellulose-2 column; 250 x 4.6 mm operating at 30 ° C with a flow rate of 0.1 mL / mln of n-hexane: IsopropaneLdletlIamlna, 90: 10: 0.1 Synthesis of (S) -6-chloro-3-fenll (d5) -lndan-1 -one (compound (XV)) (Scheme 14)

Scheme 14. Synthesis of compound (XV)

<img file="MX339552B_D0120.tif" />

<img file="MX339552B_D0121.tif" />

'X

<img file="MX339552B_D0122.tif" />

EtGH-M / EPWa

EtB3? C

EtaosBCiM

<img file="MX339552B_D0123.tif" />

2R »i% tí> 8« Wl »tOBF <

acetone, ta

Baopík gg%

O »&lt;W {OB: 2 S. R)

<img file="MX339552B_D0124.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX339552B_D0125.tif" />

<img file="MX339552B_D0126.tif" />

(XV) —phenyl (d5) —vinyl trifluoromethanesulfonate (XII):

To a solution of acetophenone-d₅ (1.56 g, 12.5 mmol) in CH2CI2 (25.0 mL) trifluoromethanesulfonic anhydride (2.52 mL, 15.0 mmol) was added at room temperature. Then, / V, / V-diisopropylethylamine (3.04 mL, 17.5 mmol) was added dropwise while the reaction mixture was cooled in an ice-water bath. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. Trifluoromethanesulfonic anhydride (0.63 mL,

3.74 mmol) was added followed by N, N-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 pad of celite. The filter cake was washed with toluene (10 mL) and the filtrate was evaporated to dryness in vacuo to

<img file="MX339552B_D0127.tif" />

obtain the crude compound (XII) (3.11 g, 82%, pnro-zT- ^ nnn) j | j_orv aw pp form of a dark oil, which was used without further purification.

¹H NMR (600 MHz, CDCI₃) δ_Η 5.38 (d, 1H, J = 4.0 Hz), 5.62 (d, 1H,

J = 4.0 Hz).

5-chloro-2- (1-fenll (d5) -v¡n¡l) benzaldehyde (XIV) (Takagi, J .; Takahashl, K .; Ishiyama, T .; Mlyaura, NJ Am: Chem. Soc. 2002 , 124, 80018006; Slmeone, JP; Sowa, JR Jr. Tetrahedron 2007, 63, 12646-12654; each incorporated by reference in its entirety).

To a solution of compound (XII) (3.11 g, 10.3 mmol, purity (NMR): approx. 85%) in toluene was added tfenfenphosflna (108 mg, 0.685 mmol), bis (plnacholate) diboro (2.61 g, 10.3 mmol) , 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 (XIII) in the mixture, which was not isolated. The mixture was cooled to room temperature and ethanol (10 mL) and water (5 mL) were added, followed by tetrakls (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 divided into water (50 mL) and toluene (50 mL).

The organic phase was separated and washed with water (50 mL) twice and brine. The organic phase was dried over MgSO₄, filtered and evaporated to dryness in vacuo. The residue was subjected to purification by column chromatography eluting with 80: 1 n-heptane: EtOAc mixture to obtain compound (XIV) (1.66 g, 74%) as an orange oil.

¹H NMR (600 MHz, CDCI₃) δ_Η 5.28 (d, 1H, J =, 5 Hz), 6.00 (d, 1H, J

<img file="MX339552B_D0128.tif" />

= 0.5 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.56 (dd, 1H; J = 2.5, «(wy thuijh, ./ = 2.5 Hz); ¹³C NMR (150 MHz, CDCI₃) or_c 118.7, 126.6 (t, J = 24.0 Hz), 127.5, 128.2 (t, J = 24.0 Hz), 128.4 (t, J = 24.0 Hz), 132.5, 133.7, 134.7, 135.7, 140.3, 143.9,

144.8, 190.8; LC-MS (APPI); m / e cale, for C₁₅H₇D₅CIO [M + H]⁺ 248.1, exp.

248.1.

(S) -6-Chloro-3-phenyl (d5) -indan-1-one (XV) (Kundu, K .; McCullagh, JV; Morehead, AT Jr. J. Am. Chem. Soc. 2005, 127, 16042-16043; incorporated herein by reference in its entirety).

Hydrogen was bubbled through a solution flooded with N₂ ((R) -2,2'-b¡s (diphenylphosphino) -1, T-binaftil) (norbornadian) rhodium (I) (37 mg, 0.0404 mmol) tetrafluoroborate in acetone (7.5 mL) for 10 min at room temperature, during which the color of the solution changed from orange to more brownish red. The container containing the solution was subsequently briefly flooded with N gas₂. Next, a solution of (XIV) (526 mg, 2.02₁₅ mmol, purity (LC-MS): 95%) in acetone (7.5 mL) was added at room temperature. The reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was mixed with silica gel and evaporated to dryness in vacuo. The obtained material was loaded on a silica gel column and the product was eluted with 10: 1 mixture of n-heptane: EtOAc to obtain compound (XV) (495 mg, 96%, 96.0% ee) as a solid.

¹H NMR (500 MHz, CDCI₃) δ_Η 2.72 (dd, 1H, J = 4.0, 19.5 Hz), 3.27 (dd, 1H, J = 8.0, 19.5 Hz), 4.55 (dd, 1H, J = 4.0, 8.0 Hz), 7.21 (d, 1H; J = 8.0 Hz), 7.52 (dd, 1H, J = 2.0, 8.0 Hz), 7.77 (d, 1H, J = 2.0 Hz); ¹³C NMR (125 MHz, CDCI₃) oc 44.0, 47.2, 123.2, 126.8 (t, J = 24.0 Hz), 127.3 (t, J = 24.0 Hz), 128.7 (t,

J = 24.0 Hz), 134.4, 135.1, 138.2, 142.9, 156.0, 206.4; LC-MS (APPI): m / e cale.

for C₁₅H₇D₅CIO [M + Hf 248.1, exp. 247.6.

IMPI 'ΝίΤΤη / ΤΟ MEXICANO or * LA FROHÍDAD industrial

Synthesis of (S) -6-chloro-3-fenll-lndan-1-one (XVIII) (Scheme 15)

Scheme 15. Synthesis of compound (XVIII) or

<img file="MX339552B_D0129.tif" />

to

<img file="MX339552B_D0130.tif" />

Oh

NaOH

MeOH-HsO. Stage A: 46%

<img file="MX339552B_D0131.tif" />

UNCLE

DiPEA

- »DCM, 0®C

Stage B: 97%

<img file="MX339552B_D0132.tif" />

Pd (0Ac)₂ (R> 3,5-XyMeOBiPHEP proton sponge

DMF, 85 ° C

Stage C:

77%

64% ee (82:18 S: R)

<img file="MX339552B_D0133.tif" />

General yield: 34% (E) -1- (5-chloro-2-hdrroxlfen¡l) -3-phen¡lprop-2-en-1-one (XVI):

To an ice cold solution of sodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL), benzaldehldo (0.746 g, 7.03 mmol) was added, followed by a solution of 5-chloro-2-hldroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. The bulk of the organic solvent was removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO₄, filtered and evaporated to dryness in vacuo. The residue was dissolved in a minimal volume of CH2CI2 and n-pentane was added, which resulted in precipitation. The suspension obtained was filtered and the precipitate was washed with a little cold pentane and dried under vacuum to obtain compound (XVI) (695 mg, 46%) as an orange solid.

<img file="MX339552B_D0134.tif" />

¹H NMR (500 MHz, CDCI₃) δ_Η 6.22 (d, 1H, J = -9.9 W 1H

J = 3.0, 9.0 Hz), 7.33 (t, 1H, J = 7.5 Hz), 7.38-7.42 (m, 4H), 7.60 (d, 2H, J = 7.5 Hz); 8.63 (d, 1H, J = 16.0 Hz);¹³C NMR (125 MHz, CDCI₃) or_c 110.6, 125.2,

127.8, 128.1, 128.8, 128.9, 129,4, 129.6, 1 '33.0, 136.4, 137.1, 174.5, 188.2.

4-Chloro-2 - ((E) - (3-phenll-acrylyl)) - trifluoromethanesulfonic acid phenolic ester (XVII):

To a solution of compound (XVI) (517 mg, 2.00 mmol) in CH2CI2 (10.0 mL) was added A /, ñ / -dl¡sopropylethylelamine (697 pL, 4.00 mmol). Trlfluoromethanesulfonic anhydride (437 pL, 2.60 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred for 45 min at 0 ° C. NH₄CI sat. Aqueous (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 CH2CI2 (10 mL). The combined extracts were dried over MgSO₄, filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography eluting with 4: 1 n-heptane: EtOAc to obtain (XVII) (757 mg, 97%) as an oil.

¹H NMR (500 MHz, CDCI3) δΗ7.16 (d, 1H, J = 16.0 Hz), 7.34 (d, 1H, J = 9.0 Hz), 7.40-7.47 (m, 3H), 7.57 (dd, 1H, J = 2.5, 9.0 Hz), 7.60-7.62 (m, 2H), 7.69 (d, 1H, 16.0 Hz), 7.72 (d, 1H, J = 2.5 Hz); ¹³C NMR (125 MHz, CDCI3) or_c124.1, 124.2, 129.0, 129.2, 130.7, 131.5, 132.8, 134.1, 134.6, 145.2, 147.8,

188.4.

(S) -6-Chloro-3-fenll-indan-1-one (XVIII) (Minatti, A .; Zheng, X .; Buchwald, SLJ Org. Chem. 2007, 72, 9253-9258; Incorporated herein by reference in its entirety).

To a solution of compound (XVII) (195 mg, 0.500 mmol) in DMF

IMPI ^INST,£ 7P μμιοκνο ra INDUSTRIAL PROPERTY

<img file="MX339552B_D0135.tif" />

(2.0 mL) Proton sponge (214 mg, 1.00 mmol), palladium acetate (6 mg, 0.025 mmol) and (R) -3.5-XylMeOBIPHEP (35 mg, 0.05 mmol) were added at room temperature. The reaction mixture was stirred at 85 ° C for 45h. The mixture was cooled to room temperature and diluted with TBME (15 mL). The mixture was washed three times with water (3 x 20 mL) and the organic phase was dried over MgSO₄, filtered and evaporated to dryness in vacuo. The residue was subjected to column chromatography eluting with 10: 1 n-heptane: EtOAc to obtain compound (XVII) (94 mg, 77%, 64.0% ee).

¹H NMR (600 MHz, CDCI₃) δ_Η 2.71 (dd, 1H, J = 4.0, 19.5 Hz), 3.25 (dd, 1H, J =

8.0, 19.5 Hz), 4.54 (dd, 1H, J = 4.0, 8.0 Hz), 7.10 (d, 2H, J = 7.0 Hz), 7.20 (d, 1H, J = 8.0 Hz), 7.25 (t, 1H, J = 7.5 Hz), 7.31 (t, 2H, J = 7.5 Hz), 7.50 (dd, 1H, J = 2.0, 8.0 Hz), 7.75 (d, 2H, J = 2.0 Hz); ¹³C NMR (150 MHz, CDCI₃) or_c 44.1,47.2, 123.3,

127.3, 127.6, 128.3, 129.1, 134.4, 135.2, 138.3, 143.1, 156.1, 204.5.

Enantioenrichment of compound (XVIII) by reprecipitation

Compound (XVII) (940 mg, 3.87 mmol, 96% ee) was dissolved in a minimal volume of boiling ethanol (99% v / v). The resulting solution was allowed to cool slowly to room temperature by replacing the glass container containing the solution in air. A precipitate formed which was filtered from the solution to obtain compound (XVIII) (700 mg, 99.9% ee, 74%). A second batch of compound (XVIII) could be obtained by cooling the filtrate in the freezer (-8 ° C) to obtain compound (XVIII) (80 mg, 98.6% ee, 9%).

Analytical data (NMR and LC-MS) for compound (XVIII) were the same as previously reported.

Example 14: Large-scale production of compound (IV)

The following process was developed for large-scale production

<img file="MX339552B_D0136.tif" />

of the tartrate salt of compound (IV) '——

Scheme 16: Synthesis of rac-trans-1- (6-Chloro-3-phenyl (d5) -dandan1 —i I) —3,3 — d metomet I — pi perazi na

<img file="MX339552B_D0137.tif" />

c, ^₈croo₅ c ^ cijDj (XXV) maleate M w «2.00 (3« 53 * 116.07} trans racemate (+ 8% is)

Process:

one. ) 2.01 kg (16.9 mol) of thionyl chloride and 7.2 kg of tetrahydrofuran are mixed and the reaction is cooled to 10-15 ° C

2. ) a solution of 2.76 kg (11.1 mol) of (XXII) in 7.2 kg of THF is added slowly and after completion 5.9 kg of tetrahydrofuran are added

3. ) the reaction is stirred at 15 ° C for about 90 hours

Four. ) 16.7 kg of water is cooled to 11 ° C and slowly added to the reaction, then 7.8 kg of aqueous sodium hydroxide is added to the TI.7% slowly, followed by 10 kg of ethyl acetate

5. ) the mixture is stirred for 20-40 minutes

6. ) the phases are separated and the organic phase is reduced to a volume of approximately 6 L

7. ) 16 kg of methyl isobutyl ketone are added and the volume is reduced to approximately 8 L

8. ) 1.58 kg (11.4 mol) of potassium carbonate, 1.69 kg (14.8 mol) of 2,2-dimethylpiperazine and 13.6 kg of methyl isobutyl ketone are added

<img file="MX339552B_D0138.tif" />

IMPI

<img file="MX339552B_D0139.tif" />

9. ) the reaction is stirred for 35 hours at 90-95 ° C -

10. ) After cooling to room temperature, 11 kg of water are added and the mixture is stirred for 30-60 minutes

eleven. ) the phases are separated. 13.7 kg of water are 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 in white

13. ) 5 kg of metllsobutyl ketone, 7.8 kg of water and 5.9 kg of 36% aqueous hydrogen chloride are added and the mixture is stirred at 50 ° C for 30 - 60 minutes

14.) The phases are separated. 8 kg of methyl isobutyl ketone are added to the aqueous mixture and the mixture is cooled to 10-15 ° C

15.) A mixture of 3.5 kg of methyl isobutyl ketone and 7.8 kg of 25% aqueous ammonia is slowly added to the mixture and the reaction is stirred at 20-25 ° C for 60-90 minutes ₁₅ 16.) the phases are separated and the organic phase is washed with 10.5 kg of water

17. ) the organic phase is reduced to 8 L

18. ) 1.19 kg (10.25 mol) of maleic acid and 9 kg of methyl isobutyl ketone are added and the reaction is then heated to 75-80 ° C

19. ) After cooling to 10-15 ° C, the precipitate is filtered and washed with 10 kg of methyl isobutyl ketone

twenty. ) The solid is dried in a vacuum oven at 50 ° C for approximately 20 hours to give 3.47 kg (68% yield) of (XXV) maleate.

NMR data for (XXV) maleate:

1H-NMR (dmso-d6, 600 MHz, ppm): 8.60 (bs, 2H, maleic acid),

7.39 (d, 1H, J = 1.6 Hz), 7.29 (dd, 1H, J = 8.0 Hz, J = 1.8 Hz), 6.98 (d, 1H, J = 8.2

<img file="MX339552B_D0140.tif" />

IMPI

QT ^{, W}k7¡T * &lt;* &lt;CANO

7 ”L *,« orntcAo »N» 1ISTR,_AI

Hz), 6-04 (s, 2H, maleic acid), 4.56 (dd, 1H, J = 8.1 Hz, .l = -A-9 Hz). 4.48 (dd, 1H, J = 8-6 Hz, J = 6.2 Hz), 3.37 (bs, 1H), 3.16 (bs, 2H), 2.77 (bs, 1H), 2.58-2.50 (m, 3H), 2 -31 (d, 1H, J = 12.0 Hz), 2.12 (ddd, 1H, J = 13.8 Hz, J = 8.0 Hz, J = 6.0 Hz), 1.33 (s, 3H), 1.31 (s, 3H).

Scheme 17: Synthesis of rac-trans-1- (6-chloro-3-phenyl (d5) -indan1-yl) —1 (d3), 2,2-trimethyl-piperazine succinate

I.NHjac, MTBE 2Cq, i.K0H, H, 0, MTBE

3. NH¡ ac.

Four. Ac «, MTBE

5. NH, ac. _C1

6. succMco acid, acetone

<img file="MX339552B_D0141.tif" />

(XXVI) succinate Mw 481.07 (36298 + 118 09) trans racemate

<img file="MX339552B_D0142.tif" />

(XX) (XXIV) (XXV) maléate Mw 462.00 (345.93 + 118.07) trans racemate (+ 8% as)

Process:

one. ) 1.1 kg (2.38 mol) of (XXV) maleate, 11 L of methyl tert-butyl ether, 1.8 L of water and 1 L of 25% aqueous ammonia are stirred for 1-2 hours

2. ) the phases are separated and the organic phase is washed twice with 2 L of water

3. ) a solution of 254 g (3.85 mol) of 85% aqueous potassium hydroxide and 1.5 L of water are added to the organic phase, followed by the addition of 450 g (3.11 mol) methyl iodide (d3) (CD₃I)

Four. ) the reaction is stirred at 20-25 ° C for 16-24 hours

5. ) 2 L of water are added and the precipitated by-product is filtered

6. ) 0.8 L of water and 0.2 L of 25% aqueous ammonia 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 L of water

IMPI ^wstIÜT^Om«JCam) otLAieontonn industrial

<img file="MX339552B_D0143.tif" />

8. ) the phases are separated and 38 g (0.48 mol) of acetyl chloride sg'üffctden to the organic phase which is stirred for 20 - 40 minutes

9. ) 0.8 L of water and 0.2 L of 25% aqueous ammonia are added and the mixture is stirred for 20 - 40 minutes

10.) the phases are separated and the organic phase is washed with 2 L of water

eleven. ) the organic phase is reduced to dryness and acetone is added

12. ) 225 g (1.91 mol) of succinic acid and acetone are added so that the reaction volume is approximately 6 - 6.5 L

13. ) The reaction is heated to reflux and then cooled to 5-10 ° C

14.) The precipitate is filtered and washed with 1 L of acetone

15.) The solid is dried in a vacuum oven at 50 ° C for more than 16 hours to give 630 g (55% yield) of (XXVII) succinate NMR data for (XXVII) succinate:

¹H-NMR (dmso-d6, 600 MHz, ppm): 7.33 (d, 1H, J = 1.9 Hz), 7.26 ₁₅ (dd, 1H, J = 8.1 Hz, J = 2.0 Hz), 6.95 (d, 1H, J = 8.0 Hz), 4.46 (dd, 1H, J = 8.0 Hz,

J = 5.1 Hz), 4.46 (dd, 1H, J = 8.8 Hz, J = 5.8 Hz), 2.65-2.56 (m, 4H), 2.46-2.41 (m, 1H), 2.37 (s, 4H, succinic acid) , 2.31 (bs, 1H), 2.13 (d, 1H, J = 10.9 Hz), 2.02 (ddd, 1H, J = 13.7 Hz, J = 7.8 Hz, J = 6.0 Hz), 1.04 (s, 3H), 1.02 (s, 3H).

Scheme 18: Synthesis of 4 - ((1 R, 3S) -6-chloro-3-phenyl (d5) 20 indan — 1 — yl) —1 (d3), 2,2 (L) —Trimethyl! Piperazine

<img file="MX339552B_D0144.tif" />

XXVII succinate

Mw 481.07 (352.98 + 118.09)

one. NHjac ..., BOAc

2. tartaric acid L {+), acetone

3. EtOH (recrystallization) j

<img file="MX339552B_D0145.tif" />

Yield to start of íu Arasior -ÍJXfJÍOSMda ~ 30QgA «;

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L (+) (IV) tartrate Mw 513.07 (362.98 + 150.09) C₁₅H_gCIOD₅, C₄H ^ 5_g

Process:

one. ) 1.0 kg (2.08 mol) of (XXVII) succinate, 8 L of ethyl acetate, 2 L of water and 1 L of 25% aqueous ammonia are stirred for 0.5 - 1 hour

2. ) the phases are separated and the organic phase is washed with 2 L of water

3. ) the organic phase is reduced to approximately 1.5 L

Four. ) 10 L of acetone and 312 g (2.08 mol) of L (+) - tartaric acid are added

5. ) the reaction is heated to reflux and then cooled to 5-10 ° C

6. ) the precipitate is filtered, washed with 1.2 L of acetone

7. ) the wet filter cake is recharged and 11 L of absolute ethanol are added

8. ) the reaction is heated to reflux and then cooled to 5-10 ° C

9. ) the precipitate is filtered and washed with 1.2 L of absolute ethanol

10. ) the solid is dried in a vacuum oven at 50 ° C for more than 16 hours to give 395 g (37% yield) of (IV) L (+) - tartrate

NMR data for (IV) L (+) - tartrate:

¹H-NMR (dmso-d6, 600 MHz, ppm): 7.36 (s, 1H), 7.27 (d, 1H, J =

8.2 Hz), 6.96 (d, 1H, J = 8.2 Hz), 4.50 (dd, 1H, J = 8.0 Hz, J = 5.1 Hz), 4.45 (dd, 1H, J = 8.5 Hz, J = 5.8 Hz), 4.07 (s, 2H, tartrate), 2.95 (bs, 1H), 2.77 (bs, 1H), 2.61-2.50 (m, 3H), 2.31 (d, 1H, J = 11.7 Hz), 2.04 (ddd, 1H, J = 13.7 Hz, J = 7.8

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Hz, J = 6.0 Hz) 1.21 (s, 3H), 1.18 (s, 3H). ----- Example 15: Physicochemical characterization of salts of compound (IV) pK_to and log P / D of compound (IV)

PK was determined_to by potentiometric titration of the base with an ionic intensity of 0.16, for which MeOH was used as a cosolvent. Three series of three repeated titrations were carried out on the same sample solution in a conventional low to high pH manner, and a difference curve was created from each of these titrations by blank subtraction. The apparent value of pK is calculated._to for each MeOH: water ratio from the difference curves, and the pK value is determined_to by extrapolation to zero MeOH content.

The lower value of pK_to it is too low to be determined by potentiometric titration, since reliable values ​​were found only less than about 3. pK was found to be_to high was 8.9+ 0.1.

PK_to Lower was determined by detection of spectroscopy by absorption of sample in immersion during the titration of the base with an ironic intensity of 0.16 for which MeOH was used as cosolvent. The change in absorption spectra as a function of ionization is used to calculate the pK value._to. Two series of three repeated titrations were carried out on the same sample solution, from low to high pH, ​​with an ordered set of photodiodes as additional detection. The apparent value of pK is calculated_to for each MeOH.water ratio using objective factor analysis on the change in absorption spectra, and the pK value is determined_to by extrapolation to zero MeOH content.

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Result: by calculation, the pK_to lower turned out to be 2.5 + 0.1

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The logD profile was determined by titration at 27 ° C and a

Ionic intensity of approximately 0.16. A series of three repeated titrations was carried out on the same sample in solution, from low to high pH. The first titration was carried out with a small amount of n-octanol present in the solution, and the second and third titration with increasing amounts.

A difference curve was created from each of these titrations by blank subtraction, and the apparent values ​​of pK were calculated from these difference curves._to (p₀K_to). From the change in the apparent values ​​of pK_to (ApK_to) with the n-octanol: water ratio combined with the actual value of pK_to, the LogP value was calculated, and the LogD profile was derived. The following values ​​were determined: Log P = 5.4+ 0.4 and Log D₇₄ = 3.9+ 0.4.

Melting point determined by DSC ₁₅ The melting point of the hydrogen tartrate salt (R, R) of compound (IV) was determined by DSC (dlfferentlal scanning calorlmetry, differential scanning calorimetry), for which a TA Instruments DSC Q1000 was used to heat the sample to ratio of 5 ° / mlnuto. The sample was placed in a frying pan covered with a drilled pinhole.

The fusion is characterized by initiation and peak temperatures of the fusion endothermic, and the enthalpy is calculated from the area of ​​the peak. Based on the DSC thermogram, an Initiation temperature of 187.4 ° C and a peak temperature of 189.4 ° C were found. The enthalpy of the fusion was 96 J / g corresponding to 49 kJ / mol, however, this program indicates that the fusion takes place under decomposition, which means that the enthalpy is probably

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contains energy in addition to that of fusion

Solubility

The solubility of the (RR) -hydrogen tartrate salt of compound (IV) in aqueous solutions and in cyclodextrins was measured, with the following results (Table 5):

Table 5. Solubility of the (RR) -hydrogen tartrate salt of compound (IV).

<td>Solvent</td><td>Measured concentration (mg base / ml)</td><td>PH</td>

<td>Hydrogen tartrate in water, 5 ° C</td><td> 3.1</td><td> 3.25</td>

<td>Hydrogen tartrate in water, temperature environment</td><td> 4.0</td><td> 3.15</td>

<td>Hydrogen tartrate in water, 37 ° C</td><td> 6.6</td><td> 3.08</td>

<td></td><td></td><td></td>

<td>Solvent</td><td>Measured concentration (mg base / ml)</td><td>PH</td>

<td>10% HPpCD</td><td> 25.2</td><td> 3.59</td>

<td>5% HP3CD, at room temperature</td><td> 15.5</td><td> 3.61</td>

<td>5% HPPCD, at 5 ° C</td><td> 12</td><td></td>

Polymorphism

A solvent free crystalline form of tartrate has been isolated. The XRPD in this way is shown in Figure 18, and is here referred to as "A" polymorph.

Salts of compound (IV)

Four salts were prepared by precipitation of compound (IV) at ^{, nst}ÍÜ'7^{0mex, can}&lt;’

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Analytical data is given in the following table (Table 6). Table 6. Data for the salts of compound (IV)

<td>Salt</td><td>DSC (T_in¡c¡₀° C)</td><td>Solubility (mg / ml)</td><td>pH</td>

<td>Dihydrogen phosphate</td><td>Degradation to 250 ° C</td><td> 1.4</td><td> 4.67</td>

<td>Hydrogen fumarate</td><td>202.7 ° C</td><td> 1.2</td><td> 4.10</td>

<td>Hydrogen maleate</td><td>150.4 ° C</td><td> 1.2</td><td> 4.94</td>

<td>Hydrogen malonate</td><td>145.0 ° C followed by degradation</td><td> 9.5</td><td> 4.08</td>

<td rowspan="2">Hydrogen tartrate</td><td>187 ° C</td><td> 4.0</td><td> 3.15</td>

<td></td><td></td><td></td>

<td>Base</td><td> 59.9</td><td> 0.1</td><td> 7.6</td>

While the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made by way of example only, and that numerous changes are possible in the details of implementation of the invention. , without departing from the spirit and scope of the invention, which is limited only by the claims that follow. The features of the disclosed embodiments can be combined and rearranged in various ways within the scope and spirit of the invention, so as to produce other embodiments that are also within the scope of the invention. The

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INDUSTRIAL skilled persons will recognize, or podfáh arres ninai, on the basis of simple routine experimentation, numerous equivalents to the embodiments specifically described in this disclosure. Said equivalents are intended to be encompassed within the scope of the following claims.

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