EA044084B1 - METHODS FOR TREATING DEPRESSION USING OREXIN RECEPTOR-2 ANTAGONISTS - Google Patents

Description

Field of technology

The present description relates, among other things, to methods of treating depression.

Prerequisites for creating the invention

Orexins (also known as hypocretins) are neuropeptides expressed by neurons of the perifornical region, dorsomedial hypothalamus, and lateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al., 1998, Cell 92, 573-585). Orexinergic neurons project to many brain regions, including other hypothalamic nuclei, midline paraventricular thalamus, brainstem nuclei, ventral tegmental area, and shell accumbens. (Peyron et al., 1998, J. Neurosci. 18, 9996-10016) Orexin neuropeptides, either orexin-A or orexin-B, bind to receptors that have seven transmembrane domains and are coupled to G-proteins, which called orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R) (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al., 1998, Cell 92, 573-585). While orexin-A is not selective for OX1R and OX2R, orexin-B shows higher affinity for OX2R (Sakaurai et al., 1998, Cell 92, 573-585). Orexin receptor antagonists are classified as single-receptor antagonists (SORA) or dual-receptor antagonists (DORA).

Hypothalamic orexin neurons, which express discharge during active wakefulness, are essentially inactive during non-rapid eye movement sleep and exhibit episodic discharge during rapid eye movement sleep (Lee, 2005, J. Neuroscience 25(8): 6716-6720; Takahashi, 2008, Neuroscience, 153: 860-870). This pattern of activity supports the notion that orexins are potent endogenous peptides that promote activation (wakefulness). Single-neuron recording studies have also shown that OX-containing neurons are preferentially activated during rewarded foraging behavior (Hassani et al., 2016. J Neuroscience 36(5): 1747–1757). However, orexins are also hypothesized to play a role in hyperactivation (eg, hypervigilance, anxiety, somatic tension, arousal, and/or rumination) that is observed in subsets of patients with mood disorders. At this time, it is believed that the intrinsic antidepressant activity of a selective OXR2 antagonist has not been clinically tested.

As is known in the art, clinically significant improvement in depressive symptoms in subjects diagnosed with major depressive disorder (MDD) can take 4-6 weeks after initiation of treatment with currently available antidepressants. Therefore, subjects with MDD are not expected to benefit from shorter periods of antidepressant therapy, particularly 2 weeks or less. Thus, there remains an urgent medical need to provide effective treatment for depression.

Summary of the invention

The general description and detailed description provided below are for exemplary and illustrative purposes only and are not intended to limit the description as defined in the appended claims. Other aspects of the present disclosure will become apparent to those skilled in the art in the context of the detailed description as provided herein.

In one aspect, methods are provided for treating a subject suffering from depression or having been diagnosed with depression. These methods include administering to a subject requiring such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1- ^R4 are defined herein, wherein the compound is administered at night and before bedtime.

In another aspect, a subject treated in accordance with the methods described herein does not suffer from insomnia or has not been diagnosed with insomnia.

In a further aspect, a compound of formula (I) is administered at night in accordance with the methods described herein.

- 1 044084

Brief description of graphic materials

The present description will be better understood with reference to the following detailed description in conjunction with the accompanying figures and examples, which form a part of the present description. It should be understood that the present description is not limited to the specific devices, methods, applications, conditions or parameters described and/or shown herein, and that the terminology used herein is intended to describe specific embodiments by way of example only and is not intended to limit the claimed invention. Further, as used in this specification and the appended claims, the singular number includes a reference to the plural, and a reference to a particular numerical value includes at least that particular number unless the context clearly indicates otherwise. . When a range of values is expressed, another embodiment includes an interval from one particular value and/or to another particular value. Likewise, when values are indicated as approximate by using the prefix approximately, it is to be understood that the particular value constitutes another embodiment. All ranges are inclusive and combinable.

The foregoing summary of the invention, as well as the following detailed description, will be better understood when taken in conjunction with the accompanying drawings.

In fig. Figures 1-2 show the average plasma concentration profiles as a function of time for the compositions [5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2- [1,2,3]triazol-2ylphenyl)methanone (compound A).

In fig. Figures 3-8 show the composite plasma concentration profiles as a function of time for Compound A formulations.

In fig. Figures 9-11 present individual and average plasma pharmacokinetic parameters by treatment type for Compound A formulations.

In fig. Figure 12 shows a linear graph of sleep time (in minutes) from lights off to 10 minutes of sleep versus change on day 10/11 relative to baseline.

In fig. Figure 13 shows a line graph of total sleep time (in minutes) versus change on day 10/11 relative to baseline.

In fig. 14 is a line graph of the change in latency to onset of sustained sleep (LPS) as assessed by the Hamilton Depression Rating Scale (HAM-D6) from baseline on Day 10/11 versus the change in HAM-D6 score from baseline on Day 11.

In fig. Figure 15 is a line graph of the change in total sleep time (TST) HAM-D6 score from baseline on Day 10/11 versus the change in HAM-D6 score from baseline on Day 11.

In fig. 16 is a flow diagram of the tablets used in the present invention.

Detailed Description of Illustrative Embodiments

I. Definitions.

The term depression includes major depressive disorder, persistent depressive disorder, depression associated with bipolar disorder (i.e., bipolar depression), seasonal affective disorder, psychotic depression, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, depression midlife, late-life depression, depression due to identifiable stressors, treatment-resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, major depressive disorder is accompanied by characteristics of melancholia or an anxiety disorder.

The methods described herein are used in the treatment of core (or psychiatric) symptoms of depression. These symptoms include depressed mood and loss of interest or pleasure in almost any activity.

The term insomnia refers to a diagnosis made using criteria included in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, issued by the American Psychiatric Association (DSM-V), as well as the third edition of the International Classification of Mental Disorders. sleep disorders (ICSD-3) issued by the World Health Organization. In some embodiments, the term insomnia includes difficulty initiating or maintaining sleep, waking up too early and falling asleep too late, and/or lack of restorative sleep, in which difficulty sleeping results in any daytime disturbances.

Some quantitative expressions given herein are not qualified by the term about. It is understood that, whether the term about is used explicitly or not, each numerical value given herein is intended to refer to an actual given value and is also intended to refer to an approximation to

- 2 044084 such a given value as can be reasonably estimated by one of ordinary skill in the art, including approximations associated with the experimental and/or measurement conditions for such given value.

In this document, unless otherwise specified, the terms treating, treatment, etc. involve the management and care of a subject or patient (preferably a mammal, more preferably a human) to combat a disease, condition or disorder and include administering a compound described herein to prevent the occurrence of symptoms or complications, alleviate symptoms or complications or elimination of a disease, pathological condition or disorder. Likewise, the term treatment is used to cover (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delaying or preventing the development of additional symptoms and/or (d) delaying or preventing the development of a disorder or condition, or any combination thereof.

As used herein, unless otherwise indicated, the terms subject and patient may be used interchangeably and mean an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation or experiment. In some embodiments, the subject or patient has experienced and/or exhibited at least one symptom of a disease or disorder being treated and/or prevented. One skilled in the art will further appreciate that the treatments are directed to subjects or patients requiring such treatment, prophylaxis or regimen, and more particularly to subjects or patients who have been diagnosed with depression or who are experiencing at least one symptom of depression ( preferably meeting criteria for major depressive disorder or episode), regardless of type or underlying cause. In further embodiments, the subject does not suffer from insomnia or has not been diagnosed with insomnia.

Additionally, some of the quantitative expressions herein are specified as a range from about the X value to about the Y value. It is understood that when a range is specified, it is not limited to the specified upper and lower limits, but includes the entire range of values from about the X value to about Y values or any value or range of values within it.

As used herein, the terms including, containing, and consisting of are used herein in their open and non-limiting meaning.

II. Connections.

As described above, the compounds described herein are orexin receptor-2 antagonists and can be used to treat depression. In some embodiments, the compounds are administered such that they have a time to reach maximum plasma concentration of less than about 3 hours, less than about 2 hours, and preferably less than about 1 hour, i.e., without limitation, less than about 45 minutes, less than about 30 minutes, less than about 15 minutes. In other embodiments, the compound has a half-life of about 4 hours and typically less than about 4 hours. For example, certain compounds of the present disclosure have a half-life of about 2 to about 3 hours, for example, about 2 hours, about 2.1 hours, about 2.2 hours, about 2.3 hours, about 2.4 hours, about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8 hours or from about 2.9 hours to about 3 hours. Given the short half-life, the amount of compound remaining in the subject's body upon awakening is generally below the threshold required for pharmacodynamic effect. For example, the compounds of the present disclosure generally have pharmacodynamic effects at dose levels greater than about 5 mg.

In certain embodiments, the compound has the structure of formula (I):

R ¹ represents C1_4alkyl. In some embodiments, R ¹ is CH3.

R ² represents C1_4alkyl. In some embodiments, R ² is CH3.

R ³ represents H or halogen. In some embodiments, R ³ is halogen. In other embodiments, R ³ is fluorine. In additional embodiments, R ³ is H.

_R ⁴ represents H or C _{1_4} alkoxy. In some embodiments, R ⁴ is

- 3 044084 is H. In additional embodiments, R ⁴ is C^alkoxy. In some embodiments, R ⁴ is methoxy.

Alkyl refers to a straight or branched chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and groups which, in light of the knowledge expected of one of ordinary skill in the art and the teachings herein, may be considered equivalent to any one of the above examples.

Alkoxy includes a straight or branched alkyl group with a terminal oxygen atom connecting the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.

Halogen is chlorine, fluorine, bromine or iodine.

When describing any formula provided herein, the selection of a particular functional group from the list of possible options for the specified variable does not imply the determination of such group selection for the variable in other formulas. In other words, if a variable appears in a formula in more than one place, then choosing an option for it from the list of those specified in one place does not depend on choosing an option for the same variable in another place in the formula, unless otherwise indicated.

The nomenclature C _i- j, where j>i, as used herein to designate a class of substituents, is intended to include embodiments for which each and all possible numbers of carbon atoms i to j, including i and j, are individually implemented. As an example, the term C1.3 refers independently to embodiments in which there is one carbon atom (C1), embodiments in which there are two carbon atoms (C ₂ ), and embodiments in which there are three carbon atoms (C ₃ ).

The term C _n -m alkyl means a linear or branched aliphatic chain with a total number of N carbon atoms in the chain satisfying the condition n < N < m, where m > n.

Any of the formulas given herein represents both the compound having the structure shown by the structural formula and certain variations or forms. In particular, a compound of any formula provided herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as mixtures thereof, are considered within the scope of the formula. Thus, any formula provided herein is intended to denote a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Additionally, certain structures may exist as geometric isomers (eg, cis and trans isomers), as tautomers, or as atropisomers.

Compounds may include those described in US Patent No. 8,653,263 and US Patent Publication No. 2014/0171430, both of which are incorporated herein by reference. In some embodiments, the compound is 5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2 -ylphenyl)methanone or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is 5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2ylphenyl )methanone. In further embodiments, the compound is 5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3] hydrochloride triazol2-ylphenyl)methanone. In other embodiments, the compound is (5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2, 3-triazol-2yl)phenyl)methanone or a pharmaceutically acceptable salt thereof. In further embodiments, the compound is (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol2(1H)-yl)(4-methoxy-2-(2H-1,2, 3-triazol-2-yl)phenyl)methanone. In certain embodiments, the compound is (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)yl)(4-methoxy-2-(2H-1,2 ,3-triazol-2-yl)phenyl)methanone hydrate. In other embodiments, the compound is (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1, 2,3-triazol-2-yl)phenyl)methanone. In further embodiments, the compound is (5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) hydrobromide hydrate (4-methoxy-2-(2H-1, 2,3-triazol-2-yl)phenyl)methanone.

In addition, any formula given herein is intended to also include hydrates, solvates and polymorphs of such compound, as well as mixtures thereof, even if such forms are not expressly stated. The compound of formula (I) or pharmaceutically acceptable salts of the compound of formula (I) may be prepared as solvates. Solvates include those forms that are formed by reacting or complexing a compound with one or more solvents, either as a solution or as a solid or crystalline form. In some embodiments, the solvent is water and the solvates are hydrates. In addition, crystalline forms of the compound of formula (I) or pharmaceutically acceptable salts of the compound of formula (I) can be obtained as co-crystals. In certain embodiments

- 4 044084 the compound of formula (I) is obtained in crystalline form. In other embodiments, the crystalline form of the compound of formula (I) is cubic in nature. In other embodiments, the pharmaceutically acceptable salts of the compounds of formula (I) are provided in crystalline form. In still other embodiments, the compounds of formula (I) are provided as one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or in an amorphous form. In other embodiments, the compound of formula (I) passes in solution between one or more crystalline and/or polymorphic forms.

Any of the formulas given herein also represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures shown by the formulas presented herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Examples of isotopes that may be included in the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ^PS , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²⁵ I, respectively. Such isotope-labeled compounds are used in studies of metabolism (preferably using ¹⁴ C), reaction kinetics (for example, using ² H or ³ H), detection or imaging modalities (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) )), including analysis of the distribution of a drug or substrate in tissues, or during radiotherapy of patients. In particular, compounds labeled with ¹⁸ F or 11 C may be particularly preferred for PET or I ¹²³ SPECT studies. Additionally, substitution with heavier isotopes such as deuterium (ie, ^2H ) may provide certain therapeutic benefits due to greater metabolic stability, such as longer half-life in vivo or reduced dosage requirements. The isotope-labeled compounds described herein and their prodrugs can be prepared substantially by following the procedures set forth in the Schemes or in the Examples and Preparation Methods described below by replacing a reagent not containing isotope-labeled atoms with an available isotope-labeled reagent atoms.

Also included are pharmaceutically acceptable salts of the compound of formula (I) and the specific compounds exemplified herein, as well as methods of treatment using such salts.

Pharmaceutically acceptable salt means a salt of the free acid or base of the compound represented by formula (I) that is non-toxic, biologically tolerable, or otherwise biologically acceptable for administration to a subject. See the merits of the publication by G.S. Paulekuhn, Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, Pharmaceutical Salts, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Pharmaceutical examples acceptable salts are those that are pharmacologically effective and acceptable for contact with patient tissue without causing an undue irritant, toxic or allergic reaction.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formats, isobutyrates, caproates, heptanoates , propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates , phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

The desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc. ., or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid, citric acid or tartaric acid, amino acid such as aspartic acid , glutaric or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, a sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids 044084 slot, such as those set forth in the examples herein, and any other acid or mixture of acids that are considered to be equivalent or acceptable substitutes in light of the usual state of knowledge in the art.

When the compound of formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, any compatible mixture of bases, such as those exemplified herein, and any other base, and mixtures thereof, which are considered to be equivalent or acceptable substitutes in light of the ordinary state of knowledge in the art. Illustrative examples of suitable salts include organic salts derived from amino acids such as N-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonium salts, carbonates, bicarbonates, primary, secondary and tertiary amine and cyclic amine salts, such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Also provided are pharmaceutically acceptable prodrugs of the compound of formula (I) and methods of treatment using such pharmaceutically acceptable prodrugs. The term prodrug means a precursor of the designated compound that, upon administration to a subject, provides the compound in vivo through a chemical or physiological process, such as solvolysis or enzymatic degradation, or under physiological conditions (e.g., the prodrug, when adjusted to a physiological pH, is converted to a compound of formula (I) ). A pharmaceutically acceptable prodrug is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically acceptable for administration to a subject. Exemplary procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue or polypeptide chain of two or more (eg, two, three or four) amino acid residues covalently linked by an amide or ester bond to a free amino, hydroxy or carboxy group of a compound of formula (I). Examples of amino acid residues include the twenty naturally occurring amino acids, which are usually designated by three letters, as well as 4hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine, and methionine sulfone .

Additional types of prodrugs can be prepared, for example, by using the free carboxyl groups of the structures of formula (I) to produce amide or alkyl ether derivatives. Examples of amides include those derived from ammonium, primary C ₁ . ₆ αlkylamines and secondary di(C1_ ₆ alkyl)amines. Secondary amines include functional groups with 5- or 6-membered heterocycloalkyl or heteroaryl ring groups. Examples of amides include those derived from ammonium, C ₁ . ₃ alkyl primary amines and di(C1_2alkyl) amines. Examples of esters include C ₁ esters. ₇ alkyl, C ₅ _ ₇ cycloalkyl, phenyl and phenylAlkyl). Preferred esters include methyl esters. Prodrugs can also be prepared by using free hydroxy groups to derivatize with groups including hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, following procedures such as those described in Fleisher, Adv. Drug Delivery Rev. 1996, 19, 115-130. Prodrugs can also be prepared using carbamate derivatives of hydroxy and amino groups. Carbonate derivatives, sulfonate esters and hydroxy sulfate esters can also be used to prepare prodrugs. Hydroxy groups such as (acyloxy)methyl and (acyloxy)ethyl esters can also be used to prepare prodrugs, where the acyl group may be an alkyl ether optionally substituted with one or more ether, amine or carboxyl functional groups, or where the acyl group is an amino acid ester , as described above. Prodrugs of this type can be prepared as described in Robinson, J Med Chem. Chem. 1996, 39(1), 10-18. Free amines can also be obtained as amides, sulfonamides or phosphonamides. All of these prodrug functionalities may have groups including ether (-O-) groups, amino (-N-) and carboxyl (COO-) functional groups.

III. Compositions.

The compounds described herein, including the compounds of formula (I), can be formulated as a pharmaceutical composition for administration to a subject. Accordingly, the pharmaceutical composition may contain (a) an effective amount of at least one compound described herein, and (b) a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipient means a substance that is non-toxic, biologically tolerable and otherwise biologically acceptable for administration to a subject, such as an inert substance,

- 6 044084 added to and compatible with a pharmaceutical composition or otherwise used as a carrier, carrier medium or diluent to facilitate administration of the agent. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Delivery forms of pharmaceutical compositions containing one or more dosage units of the compounds described herein can be prepared using acceptable pharmaceutical excipients and preparation techniques now known or available to those skilled in the art in the future. The compositions can be administered by methods of the invention by any suitable route of delivery, for example orally, parenterally, rectally, topically, ocularly or by inhalation.

The drug can be presented in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, reconstitution powders or liquid preparations. In some embodiments, the compositions are formulated for intravenous infusion, topical administration, or oral administration. In certain embodiments, the compositions are formulated for immediate release.

For oral administration, the compounds may be provided in the form of tablets or capsules or as a solution, emulsion or suspension. In certain embodiments, the compounds may be taken with food.

Tablets for oral use may include the compound mixed with pharmaceutically acceptable excipients such as excipients, diluents, disintegrating agents, binding agents, lubricants, sweetening agents, flavoring agents, coloring agents, glidants and preservatives. Suitable excipients include sodium calcium carbonate, sodium calcium phosphate, lactose, lactose monohydrate, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, hypromellose, and the like. Examples of liquid excipients for oral use include ethanol, glycerin, water, etc. Acceptable disintegrants include starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinyl-K-pyrrolidone, or PVP), or alginic acid. Binding agents may include hypromellose (hydroxypropyl methylcellulose, or HPMC), starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid or talc. The glidant, if present, may be silica (SiO2), such as colloidal silica. If necessary, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay gastrointestinal absorption, or they may be enteric coated.

Capsules for oral administration may include hard and soft gelatin capsules. To prepare hard gelatin capsules, the compound may be mixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the compound with water, an oil such as peanut or olive oil, petrolatum, a mixture of mono- and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or they may be lyophilized or dried for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients such as suspending agents (eg, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous carrier media, such as oil (eg almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if necessary, flavoring or coloring agents.

The compounds described herein may also be administered by non-oral routes. For example, the compounds may be formulated for rectal administration. For parenteral use, including intravenous, intramuscular or intraperitoneal routes, the compound may be presented in the form of sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous carrier media include Ringer's solution and isotonic sodium chloride solution. Such forms will be in unit dosage form such as ampoules or single-use injection devices, in multidose dosage form such as vials from which the appropriate dose can be drawn, or in solid form or in concentrate form which can used to obtain injection formulations. Exemplary infusion doses may range from about 1 to 1000 μg/kg/minute of compound admixed with a pharmacological carrier over a period of time ranging from several minutes to several days.

For topical administration, the compounds can be mixed with a pharmaceutical carrier at a concentration of from about 0.1% to about 10% drug in the carrier medium. In another route of administration, the compound may be used in the form of a patch formulation to provide transdermal delivery.

The compounds may alternatively be administered by inhalation, through the nose or mouth, for example, as a spray formulation also containing a suitable carrier.

VI. Methods for treating depression.

As described herein, the authors found an unexpected and reliable antidepressant effect when using the described compounds in subjects diagnosed with depression. Without being limited by theory, it is believed that since the activity of orexin neurons is negligible during sleep (typically at night), the antidepressant efficacy of the compounds described herein is unexpected. As described herein, administration of the compounds as described before bedtime (typically at night) is associated with statistically significant antidepressant efficacy, and the efficacy is not due to effects on sleep components.

Accordingly, methods are provided for treating a subject suffering from depression or having been diagnosed with depression.

These methods include administering to a subject requiring such treatment an effective amount of a compound described herein. In certain embodiments, the compound is a compound of formula (I).

The compound is preferably administered to the subject once daily and administered to the subject at bedtime. For example, the compound is administered within about 2 hours of sleep, within about 1 hour, or within about 30 minutes before sleep. In other embodiments, the compound is administered at least 4 hours before the subject awakens or is scheduled to awaken from sleep, including about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours or about 12 hours before waking up or the subject's planned awakening from sleep. In certain embodiments, the compound is administered at least 6 hours to about 12 hours before the subject awakens or is scheduled to awaken from sleep. In preferred embodiments, the compound is administered at night.

Once a compound is administered, it undergoes at least one half-life before the subject awakens from sleep. In other embodiments, the compound undergoes at least two half-lives, and preferably at least three half-lives, before the subject is awakened from sleep.

Desirably, the concentration of the compound is below the threshold required for pharmacodynamic effect after about 6 to about 8 hours after administration of the compound. This differs from known antidepressants, which must achieve a stable concentration of the antidepressant in the patient's body. The methods described herein are characterized in that after a period of one to eight hours after drug administration, the concentration of the drug falls below pharmacodynamic levels and remains at these levels for the remainder of the 24-hour treatment period until the next dose of the drug is administered.

Therapeutically effective amounts of the compounds described herein include amounts that produce a biological or medical response from a tissue system in an animal or human expected by a researcher, veterinarian, physician, or other clinician, which includes alleviation of symptoms of a disease or disorder, which treatment is being carried out. Optimal dosages for administration can be readily determined by those skilled in the art and will depend on the route of administration, the concentration of the dosage form, and the development of the disease state. Such factors include the specific patient receiving treatment, including, but not limited to, patient gender, age, weight, diet, time of administration, and comorbidities. In certain embodiments, the effective amount of each dose of the compounds described herein is from about 0.001 to about 200 mg of compound per kg of subject body weight per day, from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day in single or divided dosage units (examples of such dosage units include 2.5 mg, 5 mg, 10 mg, and 20 mg tablets). For a 70 kg person, an exemplary acceptable dosage range is from about 0.05 to about 7 g/day, or from about 0.2 to about 2.5 g/day.

An effective amount of a compound described herein may also be described regardless of the weight of the subject. Accordingly, an effective amount of the compound is from about 10 to about 60 mg. In some embodiments, the effective amount of the compound is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg, or within the range formed by any two of these values.

An effective amount of the compound can be administered as a single daily dose. In further embodiments, the compound is administered daily and one or more symptoms of depression are reduced or alleviated for about 11 days after the first administration, i.e. day 1.

Frequency adjustment can be done by changing the frequency once, or it can be

- 8 044084 determine during two or more administrations. Thus, the attending physician or the like. will be able to determine the optimal frequency of administration and therefore tailor the administration regimen to the patient.

These methods also provide for the administration of reserve doses of the compounds described herein. As used herein, the term reserve dose means one or more additional doses of a compound described herein in addition to the regularly prescribed dose. The amount of a compound described herein in a reserve dose may be determined by the attending physician or clinician and will depend on any of the factors described herein. In certain embodiments, the reserve dose of the compounds described herein is the same as the effective dose used in the normal administration regimen. In other embodiments, the reserve dose is different from the effective dose that is used in the normal administration regimen.

One skilled in the art will appreciate that for the methods described herein, maintenance of response in a patient may be determined, for example, by a clinician, physician, psychiatrist, psychologist, or other appropriate medical professional. In addition, maintenance of response to antidepressants may be defined, for example, by the absence of recurrence of depression (or one or more symptoms of depression), the absence of the need for additional or alternative treatment(s) for depression, or the absence of progression of depression. The therapist or treating clinician may use any technique known in the art, including, but not limited to, general assessment of the patient's condition, diagnostic questionnaires and assessments such as the Clinical Global Impression of Illness Severity Scale (CGI-S) score, the European Quality of Life Questionnaire (EuroQol); in 5 categories; 5-level (EQ-5D-5L), Patient Health Questionnaire 9-item (PHQ-9), Sheehan Disability Scale (SDS), Inventory of Depressive Symptoms - Clinical Rating 30-item scale (IDS-C ₃₀ ), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAM-D or HDRS), Beck Depression Inventory, or Quick Questionnaire of Depressive Symptoms (QIDS). The frequency of administration may be assessed and/or changed as the score on one or more of the above scales or questionnaires changes.

In addition, the compounds can be used in combination with additional active ingredients to treat the above conditions. Additional active ingredients may be administered simultaneously, separately or sequentially. In some embodiments, additional active ingredients are effective in treating a condition, disorder, or disease mediated by orexin activity, such as another orexin modulator or a compound active on another target associated with the particular condition, disorder, or disease. The combination may be used to enhance efficacy (eg, by including in the combination a compound that enhances the potency or effectiveness of a compound described herein), reduce one or more side effects, or reduce the required dosage of a compound described herein or an additional active agent. In certain embodiments, the additional active ingredient is an antidepressant. In other embodiments, the additional active ingredient is a monoaminergic antidepressant.

Accordingly, the compound of formula (I) can be used in combination with a second antidepressant. The second antidepressant may be a conventional drug used to combat depression, such as N-methyl-D-aspartate receptor antagonists, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMA), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSA), corticotropin-releasing hormone (CRF) antagonists, alpha-adrenergic receptor antagonists and atypical antidepressants. In some embodiments, the N-methyl-D-aspartate (NMDA) receptor antagonist is ketamine, including its racemates esketamine, arketamine, or combinations thereof. In additional embodiments, norepinephrine reuptake inhibitors include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, reboxetine, or pharmaceutically acceptable salts thereof. In other embodiments, selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, sertraline, or pharmaceutically acceptable salts thereof. In additional embodiments, monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranylcypromine, selegiline, and pharmaceutically acceptable salts thereof. In other embodiments, reversible monoamine oxidase inhibitors include moclobemide or pharmaceutically acceptable salts thereof. In other additional embodiments, serotonin and norepinephrine reuptake inhibitors include venlafaxine or pharmaceutically acceptable salts thereof. In other embodiments, atypical antidepressants include bupropion, lithium, nefazodone, trazodone, viloxazine, sibutramine, or pharmaceutically acceptable salts thereof. In additional embodiments, the second antidepressant includes adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, ati- pamezole, azamianserin, basinaprine, befuralin, bifemelan, binodalin, bipenamol, brofaromine, bupropion, caroxazone, cericlamine, cyanopramine, qi moxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexipteline, dibenzepine, dothiepin, droxidopa, enefexin, estazolam, etoperidone, femoxetine, fengabine, fesolamine, fluotracene, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofe pramin, medifoxamine, metapramine, metralindol, mianserin, milnacipran, minaprine, mirtazapine, monirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflosan, pinazepam, pirlindone, pizotiline, ritanserin, rolipram, cercloremin, setiptyline, sibutramine, sulbutiamine, sul pyride, teniloxazine, tosalinone, timoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualin, zimelidine, zometapine or their pharmaceutically acceptable salts; or St. John's wort, Hypericum perforatum, or its extracts.

In some embodiments, a compound of formula (I) is co-administered with esketamine. In additional embodiments, the compound of formula (I) is administered separately from esketamine, for example, sequentially. The compound of formula (I) can be administered before or after esketamine.

V. Sets.

Also disclosed herein are kits for administering one or more of the compounds described herein to a patient for the treatment of depression. Representative kits include one or more dosage units containing an effective amount of one or more compounds described herein for administration to a patient at a predetermined frequency.

The dosage unit may be formulated for delivery by any method. In certain embodiments, the dosage unit is formulated for oral, intravenous, intranasal, intramuscular, sublingual, intradermal, intraauricular, or rectal delivery. In certain embodiments, the dosage unit is formulated for oral delivery.

The dosage unit may be formulated to contain any amount of a compound described herein, depending on the route of administration. Therefore, each dosage unit may contain the required dose for the patient or may contain the portion of the compound described in the present invention required for one dose.

Also, the kits do not necessarily include a questionnaire for assessing symptoms of depression. The questionnaire can be intended for use by the patient alone or together with a doctor. The questionnaire can be used to determine the level of depression in a patient at any stage of administration of the compound. In one embodiment, the questionnaire is one or more of the questionnaires specified herein.

Instructions for performing the claimed methods and administering the compound may also be included in the kits described herein.

The kits may be organized to indicate a single formulation containing a compound described herein or a combination of formulations each containing a compound described herein. The composition may be divided and may contain appropriate amounts of a compound described herein. The dosage unit may be packaged compositions such as packaged powders, vials, ampoules, prefilled syringes, tablets, capsules, capsules or liquid sachets.

The compound described herein may be presented as a single dose or intended for continuous or periodic intermittent administration. For continuous administration, the kit may include a compound described herein in each dosage unit. In the event that the concentrations of a compound described herein, the components of a composition containing a compound described herein, or the relative ratios of a compound described herein or other agents within the composition need to be changed over time, the kit may contain a sequence of dosage units .

The kit may contain a package or container containing the compound described herein, formulated as required for the desired delivery route. The kit may also contain dosing instructions, package inserts for a compound described herein, instructions for monitoring circulating blood levels of a compound described herein, or combinations thereof. Additionally, materials for use of the compound described herein may be included, including, without limitation, reagents, well plates, containers, markers or labels, and the like. Such kits may be packaged in such a manner that they are suitable for the treatment of the desired indications.

Other suitable components for inclusion in such kits will be apparent to those skilled in the art based on the desired indication and route of delivery. The kits may also include or be provided with instruments to facilitate injection/administration of the compound to a patient. Such instruments include, but are not limited to, an inhaler, syringe, dropper, tweezers, measuring spoon, dropper, or any such medically approved delivery device. Other

- 10 044084 instruments may include a device that allows the results of reactions to be read or monitored in vitro.

The compound may be supplied in dry, lyophilized or liquid form. When reagents or components are supplied in dry form, reconstitution is essentially accomplished by adding a solvent. The solvent may be provided in other packaging and may be selected by one skilled in the art.

Many packages or kits for dispensing pharmaceutical agents are known to those skilled in the art. In certain embodiments, the package is a labeled blister pack, dial spray pack, or bottle.

Methods for optimizing the dosage of a compound for a patient suffering from or susceptible to depression are also provided. These methods may include (a) administering an effective amount of the compound to a patient, (b) analyzing the effects of the compound, and (c) administering an effective amount of the compound to the patient at a lesser frequency for a certain duration.

VI. Aspects of.

The present description includes at least the following aspects.

Aspect 1. A method of treating a subject suffering from depression or having been diagnosed with depression, comprising administering to the subject requiring such treatment an effective amount of a compound of formula (I):

where R ¹ represents C1_4alkyl; R ² represents C1_ ₄ alkyl; R ³ represents H or halogen; a R ⁴ is H or C _{1_4} alkoxy _; or a pharmaceutically acceptable salt or hydrate thereof.

Aspect 2. The method of Aspect 1, wherein the subject does not suffer from insomnia or has not been diagnosed with insomnia.

Aspect 3. A method according to any one of the preceding aspects, wherein R ³ is halogen.

Aspect 4. A method according to any one of the preceding aspects, wherein R ³ is fluorine.

Aspect 5. A method according to any one of the preceding aspects, wherein R ⁴ is H.

_Aspect 6. The compound of aspect 1 or 2, wherein R ⁴ is C _{1_4} alkoxy.

Aspect 7. The method of any one of aspects 1, 2 or 6, wherein R ⁴ is methoxy.

Aspect 8. The method of any one of aspects 1, 2, 6 or 7, wherein R ³ is H.

Aspect 9. A method according to any one of the preceding aspects, wherein R ¹ is CH3.

Aspect 10. The method according to any one of the preceding aspects, wherein R ² represents CH3.

Aspect 11. The method of aspect 1 or 2, wherein the compound is 5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1 ,2,3]triazol-2ylphenyl)methanone or a pharmaceutically acceptable salt thereof.

Aspect 12. The method of aspect 1, 2 or 11, wherein the compound is 5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6- [1,2,3]triazol-2ylphenyl)methanone.

Aspect 13. The method of aspect 1, 2 or 11, wherein the compound is 5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro- 6-[1,2,3]triazol-2yl)phenyl)methanone.

Aspect 14. The method of aspect 1 or 2, wherein the compound is 5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2- (2H-1, 2,3-triazol-2yl)phenyl)methanone or a pharmaceutically acceptable salt thereof.

Aspect 15. The method of any one of aspects 1, 2 or 12, wherein the compound is (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl )(4-methoxy-2-(2H-1, 2,3-triazol-2-yl)phenyl)methanone.

Aspect 16. The method of any one of aspects 1-3, wherein the compound is 5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4- methoxy-2-(2H-1,2,3-triazole- 11 044084

2-yl)phenyl)methanone hydrate.

Aspect 17. The method of any one of aspects 1-3, wherein the compound is 5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl hydrochloride hydrate (4methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

Aspect 18. The method of any one of aspects 1-3, wherein the compound is 5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl hydrobromide hydrate (4methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

Aspect 19. The method of any one of the preceding aspects, wherein the compound is administered at night.

Aspect 20. The method of any one of the preceding aspects, wherein the compound is administered such that the time to reach maximum plasma concentration is less than about 1 hour.

Aspect 21. A method according to any one of the preceding aspects, wherein the compound has a half-life of about 2 to about 3 hours.

Aspect 22. A method according to any of the preceding aspects, wherein the compound is administered to a subject about at least 4 hours before the subject is scheduled to awaken from sleep.

Aspect 23. The method of any one of the preceding aspects, wherein the concentration of the compound is below the threshold required for pharmacodynamic effect after a period of about 6 to about 8 hours after administration of the compound.

Aspect 24. The method of any one of the preceding aspects, wherein the compound undergoes at least two half-lives before the subject is awakened from sleep.

Aspect 25. The method of any one of the preceding aspects, wherein a stable concentration of the compound is not achieved.

Aspect 26. The method of any one of the preceding aspects, wherein the compound is administered daily.

Aspect 27. The method of any one of the preceding aspects, wherein the compound is administered orally.

Aspect 28. The method of any one of the preceding aspects, wherein the effective amount is from about 0.05 to about 100 mg/kg/day.

Aspect 29. The method of any one of the preceding aspects, wherein the effective amount is from about 10 mg to about 40 mg.

Aspect 30. The method of any one of the preceding aspects, wherein the compound is administered daily and one or more symptoms of depression are reduced or alleviated for about 11 days after the first administration.

Aspect 31. A method according to any one of the preceding aspects, wherein depression includes major depressive disorder, persistent depressive disorder, depression associated with bipolar disorder, seasonal affective disorder, psychotic depression, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia , melancholia, midlife depression, late-life depression, depression due to identifiable stressors, treatment-resistant depression, or combinations thereof.

Aspect 32. The method of aspect 31, wherein the depression is major depressive disorder.

Aspect 33. The method of aspect 32, wherein the major depressive disorder is accompanied by characteristics of melancholia or an anxiety disorder.

Aspect 34. The method of any one of the preceding aspects, further comprising administering a second antidepressant.

Aspect 35. The method of aspect 34, wherein said second antidepressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a reversible monoamine oxidase inhibitor, a serotonin-norepinephrine reuptake inhibitor, a noradrenergic and specific serotonergic antidepressant, a corticotropin-releasing antagonist. hormone, alpha-adrenergic antagonists, atypical antidepressant, NMDA antagonist or combinations thereof.

Aspect 36. The method of aspect 35, wherein said NMDA antagonist is esketamine.

The following examples are provided to assist in understanding the description and are in no way intended or should be construed as limiting the invention described in the following claims.

- 12 044084

Examples

Example 1.

This example was implemented to determine the plasma pharmacokinetic (PK) properties and bioavailability of a solid dosage formulation of [5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4c]pyrrol-2-yl]-(2-fluoro-2 -[1,2,3]triazol-2-ylphenyl)methanone (compound A) after administration of a single dose tablet relative to the suspension composition. The effect of a semi-starved state on the rate and extent of bioavailability of solid dosage formulations and tolerability of solid and oral suspension formulations is also discussed.

(i) Reagents and test parameters.

[5(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2ylphenyl)methanone (compound A ) was prepared as described in Method B in Example 107 of US Pat. No. 8,653,263, except that the recrystallization was performed using ethanol rather than ethanol/2-propanol.

The internal standard was isotope-labeled [5(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2- ylphenyl)methanone having the following structure.

The internal standard was prepared as described in Method B in Example 107 of US Pat. No. 8,653,263, except that step b was performed using isotopically labeled intermediate 92, i.e. 2-(4,6-dimethylpyrimidin-2-yl)octadihydropyrrolo[3,4-c]pyrrole, bis-HCl salt, which was prepared using isotope-labeled 2-chloro-4,6-dimethylpyrimidine with the following structure:

C.I.

I ¹³ s ¹⁵ n *n ¹⁵

During each treatment period, blood samples were collected for FC measurements. Specifically, venous blood samples, 3 ml each, were collected to determine plasma concentrations of the compound. Using the actual time points of blood sampling, the following PK parameters of Compound A in plasma were assessed:

Cmax - peak plasma concentration.

t _max is the time until peak plasma concentration is reached.

AUC _last is the area under the plasma concentration curve from 0 to t hours after administration of the study drug, calculated by trapezoidal summation (time t represents the time of the last quantifiable concentration C _last ).

AUC, - AUC _last value extrapolated to infinity, calculated as AUChst+Chst/λζ.

λ _z is the elimination rate constant determined from linear regression of the end points of the logarithmic (In) plasma concentration-time curve.

t _1/2 is the final half-life, defined as 0.693/λ _z .

CL/F is the total elimination of the drug after extravascular administration, without correction for absolute bioavailability, calculated as dose/AUC^.

Vd/F is the apparent volume of distribution after extravascular administration, without correction for absolute bioavailability.

Compound A levels in plasma were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS), equipment and parameters presented in Table. 1-4.

- 13 044084

Table 1

HPLC system water pump LC-10 Advp (Shimadzu) with system controller SCL-10 Aur and in-line degasser DGI-14A Pressure Limits (MPa (psi)) 0-24 (0-3500) Pump mode Binary Total flow (ml/min) 0.350 Initial conc. pump B (%) 20, 0 Column heater Shimadzu STOYUASur Oven temperature (°C) 30, 0 Automatic sampler SIL NTs (Shimadzu) Injected Volume (µL) 2.00 Coolant temperature (°C) 4 Parameters of Shimadzu SIL-HTc Wash Volume (µL) 500 Needle stroke (mm) 47 Wash rate (µL/s) 35 Sampling speed (µl/s) 50 Purge time (min) 10 Immersion time wash solution (c) 5 Flushing mode Before and after aspiration Gradient Time (min) Module Events Parameter 1.50 Pumps Pump B END 50 1.51 Pumps Pump B END 90 2.50 Pumps Pump B END 90 2.51 Pumps Pump B END 20 3.00 Controller Limiter

- 14 044084

table 2

Detector Detector Mass spectrometer API 4000 (AB Sciex) Ion source Turbo ion sputtering Duration (min) 4.00 Polarity Positive MRM Resolution Q1 units Resolution Q3 units Intensity threshold (c/s) 0.00 CUR 30.0 CAD 5.00 GAS 1 (MPa (lbs per sq. inch)) 0.276 (40, 0) GAS 2 (MPa (lbs per sq. inch)) 0.345 (50.0) IS (B) 5000 Temperature (°C) 600 Ihe On

Table 3

Mass-dependent parameters Compound Q1 Weight Q3 Weight D.P. (IN) SE (IN) SHR (B) Time (ms) Compound A 408.2 190.0 80 39 13 300 Interior 411.2 190.0 80 39 13 300 standard, connection B

- 15 044084

Table 4

Idle matrix Matrix View Anticoagulant Plasma Human ED TA Analytical column XBridge column VEN C18 Dimensions (mm) 50x2.1 Particle size (µm) 3.5 Typical back pressure 1500 Pre-column/filter Frit filter HPLC reagents Mobile phase A 0.1% formic acid in water Mixture of formic acid (2.00 ml) with water (2000 ml) Mobile phase B Acetonitrile Solvent for flushing 2-propanol:acetonitrile:water:formic acid (40:40:20:0.1 v/v/v/v) A mixture of propanol (400 ml) with acetonitrile (400 ml), water (200 ml) and formic acid (1 ml) Solvent for dilution 0.1% formic acid in water Mixture of formic acid (1.00 ml) with water (1000 ml) Solvent for breeding mother liquors dimethyl sulfoxide:acetonitrile (50:50, v/v) A mixture of dimethyl sulfoxide (50.0 ml) with acetonitrile (50.0 ml) Solvent for dilution for system checks 0.1% formic acid in the mixture water:acetonitrile (80:20, v/v) Mixture of 0.1% formic acid (80.0 ml) in water with acetonitrile (20.0 ml)

Two stock solutions of Compound A and one internal standard stock solution of Compound B were prepared as described below.

Compound A stock solution: This solution was prepared by dissolving Compound A (1.00 mg) in stock diluent (10.0 ml)

Compound A Superconcentrated Stock Solution: This solution was prepared by dissolving Compound A (2.00 mg) in 2.00 mL of Stock Diluent (2.00 mL)

Compound B Stock Solution: This solution was prepared by dissolving Compound B (1.00 mg) in 10.0 mL of Stock Dilution Solvent (2.00 mL)

Standard solutions of Compound A and the internal control were prepared as described below.

Compound A, Standard Solution 1 (10.0 μg/mL): Compound A stock solution (1000 μL) was combined with stock dilution solvent (10.0 mL).

Compound A, Standard Solution 2 (1.00 μg/mL): Compound A stock solution (100 μL) was combined with stock dilution solvent (10.0 mL).

Compound A, Standard Solution 3 (0.100 μg/mL): Compound A stock solution (10.0 μL) was combined with the stock dilution solvent (10.0 mL).

Compound B, working solution (200 mg/ml): Compound B stock solution (200 µl) was combined with the stock dilution solvent (100 ml).

Samples for the study were prepared using the protocol presented below:

i. Plasma samples were homogenized at room temperature.

ii. Samples were centrifuged for 5 minutes at about 2500 x g and 20°C.

iii. A plasma sample (50.0 μl) was pipetted into an assembly plate with 1.2 ml round-bottomed wells.

- 16 044084 iv. Solvent for diluting stock solutions (50.0 μl) was added to blank tubes, and working solution of internal standard was added to all others. After this, the test tubes were shaken for

With.

v. Acetonitrile (100 μl) was added to the tubes, and the tubes were again mixed on a shaker for 10 s.

vi. Additional acetonitrile (250 μL) was added to each tube, and the tubes were again mixed on a shaker for 60 s.

vii. Samples were centrifuged for 5 min at about 2500 x g and 20°C.

viii. The supernatant (50.0 μl) was transferred to a collection plate with 1.2 ml round-bottom wells using a liquidator.

ix. A solution of formic acid (0.1%; 400 μl) in water was added to each tube, and the tubes were shaken for 10 s.

Chromatogram plotting and peak area integration were performed using Analyst (version 1.6.2, MDS Sciex, Concord, Canada). Calculations were performed using bioanalytical LIMS Watson 7.3 (Thermo Fisher Scientific), (ii) Drug compositions.

A suspension containing Compound A was prepared by reconstituting the powder (100 mg of Compound A) in a hypromellose solution (5 mg/ml) to obtain an oral suspension of 5 mg/ml of Compound A. The hypromellose used for reconstitution was 0.5% solution of hypromellose in sterile water for injection.

The specific procedure for obtaining the suspension is given below:

(I) Powder containing compound A was added to the vial.

(ii) To achieve the desired concentration of the suspension, an appropriate amount of 0.5% HPMC solution was added to the vial.

(iii) A clean magnetic stirrer was placed in the vial.

(iv) Since it was necessary to suspend the drug substance, the stirrer vial was placed on a magnetic stirrer and the speed was adjusted to create a gentle vortex in the liquid. After a slight vortex appeared, the stirrer speed was increased to rapidly mix at 2500 rpm (from about 2400 to about 2600).

(v) The composition is stirred for at least about 24 to about 36 hours.

(vi) After mixing, the suspension was ready for use and the required volume was taken from it for dosing.

Tablets containing compound A contained the components presented in table. 5.

Table 5

Component Quantity/unit dose (in mg/tablet) (in % w/w) Compound A 20 13.3 Lactose monohydrate 80 53.3 Microcrystalline cellulose 40.5 27 Crospovidone 7.5 5 Colloidal silica 1 0.7 Magnesium stearate 1 0.7 Total 150 100

Tablets were prepared as described in FIG. 16, and according to the direct pressing process below:

A. Sifting and mixing.

1. All materials except magnesium stearate were passed through a Quadro Comil mill using screen 07L039R03125 at 1000 rpm. The following sequence was used to add material to the sieve:

(i) about ^1/2 _lactose monohydrate;

(ii) compound A;

(iii) colloidal silica;

(iv) crospovidone;

(v) microcrystalline cellulose;

(vi) about half lactose monohydrate.

2. The mixture was stirred for 20 minutes at 20 rpm.

3. Magnesium stearate was passed through a No. 40 sieve.

4. The mixture from step 3 was stirred for 5 minutes at 20 rpm.

B. Pressing.

- 17 044084

The tablets were compressed using a rotary press equipped with 7.0 mm D-type round slightly concave punches and associated dies. The technological process parameters are presented in table. 6.

Table 6

Tablet parameters Limits Description Round, biconvex tablets, white to off-white, unpatterned on both sides Fragility no more than (NMT) 1.0% Hardness 5.0-13.0 kilopounds (target 8.0 kilopounds) Time of destruction NMT 15 minutes Weight fluctuation separate tablet 150 mg ± 7.5% (139.0-161.0 mg) Total weight 10 tablets 1.5 g ± 5% (1.425 g - 1.575 g) Thickness 3.35 mm - 3.75 mm (target - 3.50 mm)

(iii) Measurement of PK parameters.

The study was conducted with the participation of eighteen male subjects, aged from 18 to 55 years inclusive. Subjects who have not received a strong inhibitor of cytochrome P45O(CYP)3A and CYP2C19 for 14 days or a period less than five times the half-life of the drug (whichever is greater), or a strong inducer of CYP3A or CYP2C19 for less than 30 days prior to study drug administration on day 1 of period 1 were excluded.

Subjects received a single oral dose of 20 mg of Compound A (suspension or solid dosage formulation) on Day 1 of each of 3 treatment periods. The total study duration for each subject (including the screening and follow-up visit) was to be 7 to 8 weeks.

This study consisted of 3 phases: an eligibility screening study (21 days to 2 days before the first dose), a 3-arm, open-label, single-dose treatment study that consisted of 3 treatment periods separated by a drug washout period. with at least 6 days between doses, as well as a follow-up visit (7 to 14 days after the last dose).

All participating subjects were randomly assigned to one of three treatment groups: Treatment A: 20 mg oral suspension formulation of Compound A (fasting), Treatment B: 20 mg solid formulation of Compound A (fasting), Treatment C: 20 mg solid formulation compounds A (half-starved state).

(iii) Results.

A mixed-effects model was applied to natural logarithm-transformed Cmax and AUC values. The model included sequence, period, and treatment as fixed effects and subject as a random effect. For each of the comparison parameters included:

solid dosage formulation (fasting) versus oral suspension formulation (fasting);

solid dose formulation (fasting) versus solid dose formulation (semi-fasted state).

Following oral administration, Compound A was rapidly absorbed and reached Cmax with median _tmax values ranging from 0.5 to 1.0 hours. After reaching Cmax, Compound A concentrations fell rapidly in a monoexponential manner (up to 12 hours post-dose). The mean t ¹ / ₂ values for the suspension (fasting) and tablet (semi-fasting) were similar (~2 hours). However, the mean t1/ ₂ for the tablet taken on an empty stomach was longer than expected (~5 hours). Some subjects experienced prolonged low plasma levels during the latter phase, resulting in t1/ ₂ values ranging from 1.9 to 17.3 hours. See FIG. 1-11.

Example 2.

This example was implemented in a multicenter, double-blind, diphenhydramine-placebo controlled study. Men and women diagnosed with MDD aged 18 to 64 years, inclusive, were recruited to participate. At screening, subjects had a total IDS-C _3O score of 30, indicating moderate to severe depression.

Among other things, blood and saliva were collected for biomarker analysis. Venous samples

- 18 044084 blood (3 ml each) was taken on an empty stomach from 8:00 to 10:00 am to determine the concentrations of [5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2 -yl]-(2-fluoro-2-[1,2,3]triazol-2ylphenyl)methanone in plasma, and also measured biomarkers related to the activity of the immune system, activation of the hypothalamic-pituitary-adrenal axis (HPA), and neurotropic factors and metabolic factors. Blood samples were also collected for pharmacokinetic (PK) analysis. Plasma samples were analyzed to determine Compound A concentrations using LC-MS/MS. Saliva was collected to determine cortisol concentrations. Salivary cortisol concentrations were added as a biomarker.

Forty-eight subjects were randomly assigned (in a 2:1:1 ratio) to receive 20 mg of Compound A, 25 mg of diphenylhydramine, or placebo once daily (daily) in the evening - Women of Childbearing Potential (WOCBP) for 10 days or men and women of non-childbearing age (WONCBP) for 4 weeks. Subjects received the drug in the form of capsules containing 1 tablet of 20 mg of compound A, 1 tablet of 25 mg of diphenhydramine, or placebo. Men and WONCBP received 1 capsule each evening immediately before bed from day 1 to day 28. WOCBP received 1 capsule each evening immediately before bed from day 1 to day 10. 2 follow-up visits were made on days 3 and 14.

To analyze depressive symptoms, assessments were completed at screening and during the study. Specifically, depressive symptoms were assessed using the International Neuropsychiatric Interview (MINI) 6.0 or the 17-item Hamilton Depression Rating Scale (HDRS17). Polysomnography (PSG) was also performed to quantify sleep stages, including latency to stable sleep (LSP) and total sleep time (TST). Depressive symptoms were then analyzed on days 11 and 29 during treatment and on days 3 and 14 after treatment. PSG was recorded during the night following the administration of the first and tenth doses of study drug.

(i) Posology.

Compound A was found to be a selective orexin receptor2 antagonist that is orally active. Following oral administration of 20 mg, Compound A had a short time to maximum plasma concentration (T _max <1 hour) and a short half-life (2-3 hours). Daytime administration of Compound A induced drowsiness in healthy subjects, and nighttime administration decreased latency to onset of sustained sleep (LPS) and increased total sleep time (TST) in subjects with insomnia (ID). The magnitude of the effect of Compound A on LPS and TST was directly related to baseline levels of insomnia. See fig. 12-15.

Administration at night (30 minutes before bedtime) resulted in alternating plasma exposure of Compound A. Thus, it was demonstrated that repeated (10-day) daily dosing did not result in accumulation.

(ii) HDRS17/HAM-D6.

The HDRS17 total score was calculated by summing the scores on the 17 items assessed during the study. Total HDRS17 scores ranged from 0 to 52, with higher scores indicating higher severity of depression. To adjust for the possible effect of study medication on sleep, sleep-related items were excluded from the HDRS17 to calculate the (sleep-related) item-adjusted HDRS score. Accordingly, an adjusted HDRS17 total score was calculated by summing the scores of the items excluding the 3 insomnia questions (4 early insomnia, 5 moderate insomnia, and 6 late insomnia). Adjusted HDRS17 total scores ranged from 0 to 46. A subset of 6 items from the HDRS ₁₇ (HAM-D6) was analyzed to obtain information on major depressive symptoms and treatment sensitivity. The six items included depressed mood, guilt, work and interests, psychomotor inhibition, mental anxiety, and general somatic reactions (fatigue and pain).

- 19 044084 __________________________________________ Table 7

Mean score ± standard deviation (SD)

Study Time Compound Placebo (N=12) Compound A 20 mg (No. 22) Diphenhydramine 25 mg (No. 13) Total score HDRSiv Baseline 18.7 (5.71) 18.7 (4.65) 20.0 (5.12) Day 11 Change from baseline -3, 6 (4.03) -5.5 (3.86) -4.1 (3.66) Average Baseline 13.7 14.4 (3.36) 15.1 (4.41) adjusted HDRS17 score (4.98) Day 11 Change from baseline -2.3 (3.03) -4.5 (2.76) * -2.3 (2.81)

Results in table. 7 show that the improvements in HDRS17 total score observed after administration of 20 mg Compound A were largely unrelated to changes in sleep (-5.5 versus -4.5 points), whereas for diphenhydramine changes were associated with sleep were more significant (-4.1 compared to -2.3).

The HAM-D ₆ score was calculated by summing the scores of the 6 items, and the score ranged from 0 to 22. A higher score indicated greater severity of core symptoms.

Table 8

Mean scores ± standard deviation

Grade Time Compound Placebo (No. 12) Compound A 20 mg (No. 22) Diphenhydramine 25 mg (No. 13) Average HDRSiv Anxiety/Somatization Factor Score Baseline 4.3 (1.56) 4.8 (1.56) 5.1 (1.80) Day 11 Change from baseline -0.8 (1.40) -1.6 (1.50) -0.9 (1.12) Average HAM-Dg score Baseline 9, 0 (3.57) 10.4 (2.09) 10.6 (3.31) Day 11 Change from baseline -1.5 (2.15) -3, 8 (2.22)** -1.8 (2.01)

The results presented in table. 8 illustrate that changes from baseline in the anxiety/somatization factor were not associated with the observed improvement in depression scores in the Compound A group. However, core depressive symptoms (as measured by the HAM-D6 scale) were associated with the observed improvement in depression scores in the group receiving receiving compound A.

(iii) Polysomnography.

Study drug effects on polysomnography-related parameters (PSG) were assessed overnight on days 1/2 and 10/11. In addition, PSG was performed before and after forced awakening at night on days 5/6. Two PSG screening recordings were performed and raw values were calculated as the average of screenings 1 and 2.

(a) Total sleep time (TST).

TST is defined as the total number of minutes spent in rapid eye movement sleep

- 20 044084 (REM) and in the non-rapid eye movement (NREM) sleep phase. Compared to placebo, both Compound A and diphenhydramine increased overnight TST on day 1/2. Due to the increase in TST in placebo-treated subjects on day 10/11, the relative effects of Compound A and diphenhydramine were less pronounced. See table. 9. Although the entire study population did not meet criteria for insomnia (TST < 360 min), individual subjects had TST values of only 263 min. Thus, the population was mixed regarding the presence of insomnia.

Table 9

Time (min) Compound Placebo (No. 12) Compound A 20 mg (No. 22) Diphenhydramine 25 mg (No. 13) Baseline 376 (56.2) 380 (50.1) 382 (47.2) Day 1/2 Change from baseline 7.4 (52.07) 30, 9 (54.06) 28.3 (33.92) Day 10/11 Change from baseline 20, 7 (64.44) 26, 56 (56.11) 33, 92 (46, 01)

The effect of Compound A on TST is proportional to the duration of TST at baseline (Figure 13). However, there was no association between the magnitude of change in LPS and improvement in baseline depressive symptoms (Figure 15), supporting an antidepressant effect independent of the effect on insomnia.

(b) Latency to onset of sustained sleep.

LPS is defined as the time (in minutes) from turning off the lights to 10 minutes of continuous sleep. Compared to placebo, both Compound A and diphenhydramine moderately reduced LPS overnight on day 1/2. Due to the decrease in LPS in placebo-treated subjects on day 10/11, the relative effects of Compound A and diphenhydramine were less pronounced. See table. 10. Overall, the study population was characterized by increased (>20 min) LPS. As with the TST, the population was mixed regarding the presence of insomnia at baseline, with LPS values of only 4.5 min.

Table 10

Time (min) Compound Placebo (No. 12) Compound A 20 mg (No. 22) Diphenhydramine 25 mg (No. 13) Baseline 53, 8 (40.12) 40.9 (22.62) 36, 0 (19, 20) Day 1/2 Change from baseline 3.4 (46, 39) 8.7 (36.04) 6, 7 (26, 40) Day 10/11 Change from baseline 17.5 (51.40) 9.2 (30.41) 0.3 (30.57)

The effect of compound A on LPS is proportional to the duration of LPS at baseline (Fig. 12). However, there was no association between the magnitude of change in LPS and improvement in baseline depressive symptoms (Figure 14), supporting an antidepressant effect independent of the effect on insomnia, (iv) Conclusion.

These results indicate that, compared with placebo and diphenhydramine, the antidepressant effect of Compound A was stronger and clinically significant. Surprisingly, it was found that the effect of Compound A was predominantly associated with its effect on core depressive symptoms and was generally unrelated to its effect on sleep-related items. The antidepressant effect was maintained for at least 14 days after cessation of treatment. Importantly, improvements were observed as early as day 11 (first assessment) and persisted after treatment was stopped.

- 21 044084

Example 3.

This example was implemented to illustrate that Compound A can be used during adjuvant therapy. Specifically, Compound A was administered to subjects diagnosed with MDD (i) as monotherapy and (ii) in combination with a known antidepressant, and the subjects' depressive symptoms were assessed using the HDRS17 and HAM-D6 scales.

In Group 1, thirty-seven subjects were randomly assigned (in a 2:1:1 ratio) to receive 20 mg of Compound A, 25 mg of diphenhydramine, or placebo once daily in the evening for 10 days. In Group 2, ten subjects were randomly assigned (in a 2:1:1 ratio) to receive 20 mg of Compound A, 25 mg of diphenylhydramine, or placebo once daily in the evening for 10 days. Each subject in Group 2 also took a quantity of an antidepressant selected from duloxetine, citalopram, paroxetine, or sertraline, as prescribed by their physician. To assess depressive symptoms in both groups, assessments were performed independently at screening and on day 11, i.e., one day after the study, using the HDRS ₁₇ and HAM-D6, as described in Example 2. The assessment results are shown in Table 1. 11 and 12. in table. 11-12 # indicates Cohen's effect size, * indicates P < 0.05 (statistical significance), and ** indicates P < 0.01.

Table 11

Average scores ± SD Group I Scale Time Placebo (No. 8) Compound A 20 mg (No. 18) Diphenhydram n 25 mg (No. 11) HDRS17 Baseline 19, 5 19, 4 21.5 (3.78)

- 22 044084

(5.40) (4.80) Day 11 Change from baseline -2.5 (4.14) -5, 1 (3.97) -4.2 (4.00) Effect size, Compound A versus placebo# -0.64 Adjusted HDRS Baseline 14.4 (4.50) 14.9 (3.37) 16.4 (3.35) Day 11 Change from baseline -1.4 (3.29) -4.3 (2.97) * -2.1 (3.02) Effect size, compound A versus placebo ^# -0.93 Anxiety factor of somatization Baseline 4.4 (1.41) 5.1 (1.53) 5.5 (1.51) Day 11 Change from baseline -0.8 (1.49) -16 (1.65) -0.8 (1.17) Effect size, compound A versus placebo ^# -0.51 HAM-D ₆ Baseline 9, 6 (3.70) 10, 8 (2.07) 11.7 (2.05) Day 11 Change from baseline -0.8 (2.25) -3, 6 (2.33)** -1.7 (2.15) Effect size, compound A versus placebo ^# -1.22

- 23 044084

Table 12

Group 2

Placebo (N=4) Compound A 20 mg (N=4) Diphenhydramine 2 5 mg (N=2) HDRS17 Baseline 17.0 (6.78) 15.5 (2.08) 11.5 (0.71) Day 11 Change from baseline -5, 8 (3.20) -7.0 (3.37) -3.5 (0.71) Effect size, Compound A versus placebo# -0.37 Adjusted HDRS Baseline 12.3 (6.29) 11, 8 (1.89) 8.0 (1.41) Day 11 Change from baseline -4.3 (0.96) -5, 5 (1.29) -3.5 (0.71) Effect size, Compound A versus placebo# -1.06 Anxiety factor Baseline 4.3 (2.06) 3.5 (1.00) 2.5 (0.71) somatization Day 11 Change from baseline -1.0 (1.41) -Ι,θ (0.50) -1.5 (0.71) Effect size, Compound A versus placebo# -0.76 HAM-D ₆ Baseline 7.8 (3.40) 8.8 (1.26) 4.5 (0.71) Day 11 Change from baseline -thirty (0.82) -4.8 (1.50) -2.0 (1.41) Effect size, Compound A versus placebo# -1.49

These results illustrate that Compound A exhibits antidepressant activity in untreated and antidepressant-treated subjects with MDD, supporting its effectiveness as monotherapy and adjuvant therapy.

The disclosures of each patent, patent application, and publication cited or described herein are incorporated herein by reference in their entirety.

It will be apparent to those skilled in the art that the preferred embodiments of the disclosure are susceptible to many changes and modifications, and that such changes and modifications can be made without departing from the spirit of the disclosure. Thus, the appended claims are intended to cover all such equivalent variations as fall within the spirit and scope of the specification.

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Claims (26)

CLAIM 1. A method of treating depression, comprising administering to a subject requiring such treatment an effective amount of a compound of formula (I): ^r2 (I), where R ¹ represents C _1-4 alkyl; R ² represents C _1-4 alkyl; R ³ represents H or halogen; A R ⁴ represents H or C _1-4 alkoxy; or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is administered at night and before bedtime. 2. The method of claim 1, wherein the subject does not suffer from insomnia. 3. The method according to claim 1, in which R ³ represents a halogen. 4. The method according to claim 3, in which R ³ represents fluorine. 5. The method according to claim 1, in which R ⁴ represents H. 6. The method according to claim 1, in which R ⁴ represents C _1-4 alkoxy. 7. The method according to claim 6, in which R ⁴ represents methoxy. 8. The method according to claim 1, in which R ³ represents H. 9. The method according to claim 1, in which R ¹ represents CH ₃ . 10. The method according to claim 1, in which R ² represents CH ₃ . 11. The method according to claim 1, in which the compound is [5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1, 2,3]triazol-2-ylphenyl)methanone or a pharmaceutically acceptable salt thereof. 12. The method according to claim 1, in which the compound is [5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1, 2,3]triazol-2-ylphenyl)methanone. 13. The method according to claim 1, in which the compound is [5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1) hydrochloride ,2,3]triazol-2ylphenyl)methanone. 14. The method according to claim 1, in which the compound is (5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-( 2H-1,2,3-triazol-2-yl)phenyl)methanone or a pharmaceutically acceptable salt thereof. 15. The method according to claim 1, in which the compound is (5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-( 2H-1,2,3-triazol-2-yl)phenyl)methanone. 16. The method of claim 1, wherein the compound is administered daily. 17. The method according to claim 1, wherein the compound is administered orally. 18. The method of claim 1, wherein the effective amount of the compound is from about 10 to about 40 mg. 19. The method of claim 1, wherein the depression includes major depressive disorder, depression associated with bipolar disorder, or treatment-resistant depression. 20. The method of claim 19, wherein the depression is major depressive disorder. 21. The method of claim 19, wherein the depression is treatment-resistant depression. 22. The method of claim 1, further comprising administering a second antidepressant that is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof. 23. The method according to claim 2, where the compound is [5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2 ,3]triazol-2-ylphenyl)methanone or a pharmaceutically acceptable salt thereof. 24. The method of claim 23, wherein the depression is major depressive disorder. 25. The method of claim 24, further comprising administering a second antidepressant that is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof. 26. The method according to claim 1, where the compound is [5-(4, 6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2 ,3]triazol-2-ylphenyl)methanone or its pharmaceutical -