Method of treating depressive disorders

Abstract

To provide a method for treating depressive disorders.SOLUTION: Provided is a method of treating a depressive disorder in a human in need thereof, comprising administering to the human a therapeutically effective amount of Compound A, wherein Compound A is N - [4 - (6-fluoro-3, 4-dihydro - 1H - isoquinolin-2-yl) - 2, 6-dimethylphenyl] - 3, 3-dimethylbutanamide.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Depressive disorders affect more than 20 million American adults. They are characterized by severe or persistent sadness that interferes with functioning and often leads to decreased interest or pleasure in activities. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classifies depressive disorders by specific symptoms, such as major depressive disorder (often called major depression) and persistent depressive disorder (dysthymia), and by etiology, such as premenstrual dysphoric disorder, depressive disorder due to other illnesses, or substance / drug-induced depressive disorder. Bipolar disorder (manic depression) is also a type of depression. The exact cause of depressive disorders is unknown, but genetic and environmental factors are known to play a role. [Background technology]

[0002] First-line treatments for depressive disorders typically include one or more of the following: support, psychotherapy, and antidepressants. Several drug classes and medications are available for the treatment of depressive disorders, including selective serotonin reuptake inhibitors (SSRIs), serotonin modulators (5-HT2 blockers), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors, atypical antidepressants, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), melatonergic antidepressants, and ketamine-like agents. SSRIs are often the first-line treatment. However, finding the right antidepressant treatment for depressive disorders can often involve a trial-and-error approach, as some antidepressants are only partially effective and have additional limitations, such as a slow onset of therapeutic action and unwanted side effects. Most approved antidepressants share the same serotonergic and noradrenergic pathways, limiting mechanistic diversity and leaving little opportunity for improved patient outcomes and personalized treatment approaches.

[0003] Due to the number of adults affected, the number and complexity of classes of disorders, and the frequent ineffectiveness and mechanistic homogeneity of first-line antidepressants, there remains a need in the art for new and effective treatments for depressive disorders, including major depression. The present disclosure addresses this need and offers other related advantages by providing compositions and methods and uses for treating depressive disorders. Summary of the Invention

[0004] The present disclosure describes the identification and use of the small molecule N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (referred to herein as "Compound A").

[0005] In one embodiment, the disclosure relates to a method of treating a depressive disorder in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of Compound A. In certain instances, the depressive disorder treated by administration of Compound A is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive response, or a combination thereof. In certain embodiments, the depressive disorder treated by administration of Compound A is major depressive disorder (MDD).

[0006] In an additional embodiment, the method of treating a depressive disorder comprising administering a therapeutically effective amount of Compound A further comprises enhancing the opening of Kv7 potassium channels in a human.

[0007] In another embodiment, the disclosure provides a method for opening or enhancing the opening of Kv7 potassium channels in a human, comprising administering to the human an effective amount of Compound A, wherein the human has a depressive disorder such as those described herein.

[0008] In some embodiments, the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. In certain instances, the opening or promoting of the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 potassium channels is selective over Kv7.1. In other instances, the method comprises the opening or promoting of the opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels.

[0009] In one embodiment, the disclosure provides a method of treating a depressive disorder in a human in need thereof, wherein Compound A is orally administered to the human. In certain examples, the oral administration to the human comprises a single dose of 2 to 200 mg of Compound A. In other examples, the oral administration to the human comprises a daily dose of 5 to 1000 mg.

[0010] Compound A is a small molecule currently being developed for the treatment of seizure disorders, and its use as a potassium channel modulator is disclosed in U.S. Pat. Nos. 8,293,911 and 8,993,593 and U.S. application Ser. Nos. 16 / 409,684 and 16 / 410,851, the disclosures of which are incorporated herein by reference in their entireties.

[0011] These and other aspects of the present disclosure will become apparent upon reference to the following detailed description, and to this end, various references are set forth herein which describe in more detail certain background information and procedures, each of which is incorporated herein by reference in its entirety. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the results of the mouse forced swim test, including a graphical representation of the mean immobility latency (seconds, y-axis) for vehicle, 1 mg / kg Compound A, 3 mg / kg Compound A, and imipramine administration (x-axis). [Figure 2] Figure 2 shows the results of the mouse forced swim test, including a graphical representation of the mean immobility time (2-6 min) (seconds, y-axis) for vehicle, 1 mg / kg Compound A, 3 mg / kg Compound A, and imipramine administration (x-axis). [Figure 3] Figure 3 shows the results of the mouse forced swim test, including a graphical representation of the mean immobility time (0-6 min) (seconds, y-axis) for vehicle, 1 mg / kg Compound A, 3 mg / kg Compound A, and imipramine administration (x-axis). [Figure 4]FIG. 4 contains a graphical representation of Compound A concentrations (μM, y-axis) in plasma and brain for 1 mg / kg and 3 mg / kg doses (x-axis). DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure relates to new and improved methods and uses for Compound A, particularly for the treatment of depressive disorders by administering Compound A to a human patient in need thereof, including by oral administration.

[0014] In the following disclosure, certain specific details are described to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in an open sense, i.e., meaning "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0015] Throughout this specification, references to "one embodiment" or "an embodiment" mean that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise. Also, please note that the term "or" is intended to include "and / or" unless the content clearly dictates otherwise.

[0016] 4.1.Definition In this specification and the appended claims, the following terms and abbreviations have the indicated meanings unless otherwise specified.

[0017] "Compound A" has the following formula

[0018] [ka] and refers to a compound having the chemical name N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. The preparation of Compound A and its use as a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener are disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593 and U.S. Application Serial Nos. 16 / 409,684 and 16 / 410,851. Compound A differs from most known AEDs in that it enhances and promotes the opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), which are important for controlling neuronal excitability. Compound A is used in the methods and applications described herein.

[0019] As used herein, "therapeutically effective amount" refers to an amount of Compound A sufficient to treat a disease, disorder, or condition described, or to have a desired, described effect on a disease, disorder, or condition, or one or more mechanisms underlying the disease, disorder, or condition, in a human subject. In certain embodiments, when Compound A is administered to treat a depressive disorder, a therapeutically effective amount refers to an amount of Compound A that, upon administration to a human, treats or improves the depressive disorder in a human, or shows a detectable therapeutic effect in a human with a depressive disorder. This effect can be detected, for example, by a reduction in the number of depressive attacks or a reduction in the severity of depressive attacks.

[0020] As used herein, "treatment" refers to therapeutic applications involving the administration of Compound A to improve the indicated disease, disorder, or condition, or one or more underlying mechanisms of said disease, disorder, or condition, including slowing or stopping the progression of the disease, disorder, or condition, or one or more underlying mechanisms, in a human subject. In certain embodiments, when Compound A is administered for the treatment of a depressive disorder, treatment refers to therapeutic applications to slow or stop the progression of the depressive disorder and / or to ameliorate the depressive disorder. Amelioration of a depressive disorder differs from therapeutic applications that slow or stop the depressive disorder in that it not only stops the progression of the depressive disorder, but also alters cellular behavior to a degree that would be observed in the absence of the depressive disorder. In some embodiments, treatment of a depressive disorder comprising administration of Compound A is accompanied by an alteration in the cellular activity of one or more Kv7 potassium channels (e.g., Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5, particularly Kv7.2 and / or Kv7.3, optionally in excess of Kv7.1) to normal levels that would be observed in the absence of a depressive disorder.

[0021] "Under fed conditions" refers to a state in which food is ingested between about 4 hours before oral administration of an effective amount (e.g., within a therapeutically effective amount range) of Compound A and about 4 hours after administration of Compound A. The food may be a solid, liquid, or a mixture of solid and liquid foods with sufficient bulk and fat content to avoid rapid dissolution and absorption in the stomach. In some examples, the food is a meal such as breakfast, lunch, or dinner, or alternatively, baby food (e.g., formula or breast milk). A therapeutically effective amount of Compound A may be orally administered to a subject, for example, between about 30 minutes before and about 2 hours after a meal; most preferably, a dosage unit of Compound A is orally administered during a meal or within 15 minutes after eating a meal.

[0022] "Under fasted conditions" refers to a state in which no food is consumed for at least 4 hours before oral administration of a therapeutically effective amount of Compound A until about 4 hours after administration of Compound A.

[0023] 4.2. Implementation Form In some embodiments, the present disclosure is directed to a method of treating a depressive disorder in a human in need thereof, comprising administering (e.g., orally) a therapeutically effective amount of Compound A to the human. In certain cases, the depressive disorder treated comprising administration of Compound A is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, or a combination thereof. In certain embodiments, the amount of Compound A administered is sufficient to reduce the severity of the depressive disorder, the frequency of the depressive disorder, or both. In certain embodiments, the depressive disorder treated comprising administration of Compound A is major depressive disorder (MDD).

[0024] In some embodiments, the method of treating a depressive disorder by administering a therapeutically effective amount of Compound A comprises promoting the opening of Kv7 potassium channels in a human.

[0025] In further embodiments, the present disclosure is directed to a method of treating obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, social phobia, agoraphobia, agoraphobia with panic disorder, hypochondriasis, post-traumatic stress disorder (PTSD), treatment-resistant bipolar disorder, generalized anxiety disorder, attention-deficit / hyperactivity disorder (ADHD), bipolar I disorder, bipolar II disorder, manic-depressive disorder, cyclothymic disorder and bipolar disorder not otherwise specified, dysthymic disorder not otherwise specified depressive disorder, minor depression, recurrent brief depressive disorder, depressive-type psychosis, impulse control disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, Parkinson's disease, dementia, Alzheimer's disease, Huntington's disease, Tourette's syndrome, aggression, and substance use and / or abuse, or a combination thereof, comprising administering a therapeutically effective amount of Compound A to a human being in need thereof.

[0026] In certain embodiments, the present disclosure provides methods or uses comprising administering an effective amount of Compound A to open or promote Kv7 potassium channels, such as Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 potassium channels, particularly Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels, in a human in need thereof, wherein in some such embodiments the human has a depressive disorder as described herein.

[0027] In certain examples, the methods or uses described herein include selectively opening or enhancing the opening of one or more of Kv7 potassium channels, Kv7.2, Kv7.3, Kv7.4, or Kv7.5, over Kv7.1. In some embodiments, the methods or uses are selective for Kv7.2 over Kv7.1. In other embodiments, the methods or uses are selective for Kv7.3 over Kv7.1. In still other embodiments, the methods or uses are selective for Kv7.4 over Kv7.1. In still other embodiments, the methods or uses are selective for Kv7.5 over Kv7.1. In certain embodiments, the methods or uses are selective for Kv7.2 and Kv7.3 over Kv7.1. In certain embodiments, the methods or uses are selective for Kv7.2 and Kv7.3 over other Kv7 potassium channels. In certain embodiments, the method or use is selective for Kv7.2 and Kv7.3 over Kv7.4 and Kv7.5.

[0028] In one embodiment, the methods and uses described herein, for example, methods for treating or uses in treating depressive disorders in humans in need thereof, are achieved by administering (e.g., orally) a therapeutically effective amount of Compound A, for example, about 0.05 mg / kg to about 2.0 mg / kg. More specific representative amounts include 0.05 mg / kg, 0.10 mg / kg, 0.20 mg / kg, 0.30 mg / kg, 0.40 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.80 mg / kg, 0.90 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, and 2.0 mg / kg, or any range of amounts created using two of the aforementioned amounts as endpoints. In some embodiments, the method or use comprises administering (e.g., orally) 0.1 to 1.0 mg / kg of Compound A, and in some embodiments, the method comprises administering (e.g., orally) 0.2 to 0.5 mg / kg of Compound A.

[0029] In some embodiments, the methods and uses described herein (e.g., treatment of or use in treating a depressive disorder in a human in need thereof) are accomplished by administering (e.g., orally) a therapeutically effective amount of Compound A (e.g., 2-200 mg of Compound A), in single or divided doses. For example, the methods include administering about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg About 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg , about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 1 07mg, approximately 108mg, approximately 109mg, approximately 110mg, approximately 111mg, approximately 112mg, approximately 113mg, approximately 114mg, approximately 115mg, approximately 116mg, approximately 117mg, approximately 118mg, approximately 119mg, approximately 120mg, approximately 121mg, approximately 122mg, approximately 123mg, approximately 124mg, approximately 125mg, approximately 126mg, approximately 127mg, approximately 129mg, approximately 130mg, approximately 131mg, approximately 132mg, approximately 133mg, approximately 134mg, approximately 135mg, approximately 136mg, approximately 137mg, approximately 138mg,About 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 ​​mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 1 The dose may include administering about 76 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, or about 200 mg, or any range created by using two of the foregoing amounts as endpoints. In some embodiments, the method or use includes orally administering 5 to 50 mg of Compound A in a single or divided dose. In some embodiments, the method or use includes orally administering 10, 20, or 25 mg of Compound A in a single or divided dose. In some embodiments, the method or use comprises orally administering 20 mg of Compound A in a single or divided dose.

[0030] In some embodiments, the methods and uses described herein (e.g., methods or uses for treating a depressive disorder in a human in need thereof) are achieved by administering (e.g., orally) at least 20 mg of Compound A, e.g., at least 25, 30, 35, 50, 75, or 100 mg. In some embodiments, the methods and uses described herein (e.g., methods or uses for treating a depressive disorder in a human in need thereof) are achieved by administering (e.g., orally) at least 50 mg of Compound A per day, e.g., at least 60, 75, 85, 100, 125, 150, 175, or 200 mg of Compound A per day.

[0031] In some embodiments, the methods and uses described herein, e.g., for treating a depressive disorder in a human in need thereof, are accomplished by administering (e.g., orally) a therapeutically effective amount of Compound A, e.g., 5-1000 mg per day, e.g., 5-500 mg or 5-250 mg per day. For example, the method or use may be administered in a range of about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 185 mg, about 190 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 300 mg, about 310 mg, about 315 mg, about 320 mg, about 32 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, About 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, This can include administering (e.g., orally) about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, or about 1000 mg of Compound A, or a range of amounts created by using two of the foregoing amounts as endpoints can be administered (e.g., orally) per day.In some embodiments, the method or use involves oral administration of 10 to 200 mg of Compound A per day, e.g., 10, 15, 20, 25, 30, 35, or 40 mg to 75, 100, 125, 150, 175, or 200 mg of Compound A per day, including 20 to 150 mg per day. In some embodiments, oral administration includes 50, 75, 100, or 125 mg of Compound A per day, e.g., 100 mg per day.

[0032] In certain instances, the above daily doses of Compound A are administered (e.g., orally) as multiple doses per day, such as two, three, four, or five doses per day. For example, a 100 mg daily dose may be administered as five 20 mg doses, four 25 mg doses, three 33.3 mg doses, or two 50 mg doses throughout the day.

[0033] In some embodiments, the above-mentioned daily doses of Compound A are administered as a single dose (e.g., orally). For example, about 5, 10, 15, 20, 25, or 30 mg to about 50, 65, 75, 100, 125, or 150 mg of Compound A per day can be orally administered as a single dose, including 10-25 mg, 10-30 mg, and 10-40 mg per day as a single dose, e.g., 10-25 mg per day as a single dose. Relatedly, any of the doses of Compound A discussed in the preceding paragraph can be included in a unit dosage form.

[0034] In certain embodiments, the methods and uses described herein achieve a steady state of Compound A within 6 to 9 days, e.g., within about 1 week, when using the daily dosing regimens disclosed herein.

[0035] In further embodiments, the above-described method or use of treating a depressive disorder by administering (e.g., orally) a therapeutically effective amount of Compound A comprises administering Compound A to a human under fed conditions. In some embodiments, oral administration of Compound A to a human under fed conditions (i.e., with food or in close temporal proximity to ingestion of food) significantly enhances the bioavailability and exposure of Compound A compared to oral administration of Compound A to a human under fasted conditions (i.e., without food or not in close temporal proximity to ingestion of food). In some embodiments, oral administration of Compound A to a human under fed conditions improves one or more pharmacokinetic parameters for Compound A (e.g., C) compared to oral administration of the same amount of Compound A to a human under fasted conditions. max , AUC inf , T max , t 1 / 2 λz, etc.)

[0036] In certain embodiments, the methods and uses described herein administer Compound A in the form of a pharmaceutically acceptable oral composition comprising Compound A and one or more pharmaceutically acceptable carriers or excipients. The amount of Compound A contained in these compositions can correspond to one or more of the amounts described herein. In some embodiments, the composition is a unit dose.

[0037] Examples of pharmaceutically acceptable oral compositions containing Compound A include solid formulations (such as tablets, capsules, lozenges, dragees, granules, powders, wafers, multiparticulates, and films), liquid formulations (such as aqueous solutions, elixirs, tinctures, slurries, suspensions, and dispersions), and aerosolized formulations (such as mists and sprays). In one embodiment, the pharmaceutically acceptable oral composition of Compound A comprises a pediatric suspension or granules. Capsules containing all of the above amounts of Compound A, for example, 5, 10, 15, 10, 25, 30, or 35 mg of Compound A, may be included in such formulations.

[0038] In another embodiment, a kit is provided for the oral administration of Compound A for the treatment of depressive disorders by oral administration. Such a kit includes a plurality of oral dosage unit forms of Compound A in combination with instructions for the oral administration of Compound A.

[0039] Further embodiments and examples of the present disclosure are described herein, which are illustrative and should not be construed as limiting the scope of the invention as claimed.

[0040] 5. Working Example Studies were conducted to determine the effects of Compound A in a rodent model of behavioral despair (i.e., the mouse forced swim test). Further analysis determined the total whole brain-to-plasma ratio of Compound A in the forced swim test. Further studies will be conducted to determine the effects, if any, of Compound A in recognized models of depression.

[0041] Example 1. Forced swimming test in mice Objective: A study was conducted to evaluate the potential efficacy of Compound A using the mouse forced swim test. The forced swim test is a model of behavioral despair and is sensitive to the detection of various classes of antidepressants (Can et al., The Mouse Forced Swim Test. J. Vis. Exp. 2012(59), e3638, DOI: 10.3791 / 3638).

[0042] Study Design: Forty male CD-I mice were acclimated to the testing facility for one week prior to the start of the study (Table 1 summarizes the events). Animals were housed five per cage, provided with free access to rodent chow and water (SOP ROD.03.01, SOP ROD.04.01, SOP ROD.18), and maintained on a 12-hour / 12-hour light / dark cycle; all experimental activities were conducted during the animal's light cycle. All animal use procedures were conducted in accordance with the principles of the Canadian Council on Animal Care (CCAC).

[0043] [Table 1]

[0044] Compound A formulation: Compound A (99.4% purity) was weighed (no correction for purity) and dissolved in DMSO at 20x the desired final concentration. The 20x DMSO stock solution of Compound A was diluted 20x with 0.5% aqueous methylcellulose to achieve the final desired concentration. If Compound A precipitated as a fine suspension, stirring or vortexing resulted in a homogenous suspension. The above formulation was kept at room temperature and continuously stirred or vortexed before each dose administration. The test substances are summarized in Table 2.

[0045] [Table 2]

[0046] Forced swim test: Forty male CD-I mice were administered the appropriate dose of vehicle, test substance, or positive control (treatments summarized in Table 3). After a predetermined pretreatment period (Can et al., 2012), the animals were gently placed into a tall glass cylinder filled with water (20–25°C). Mice exhibited vigorous activity followed by a characteristic, easily identifiable immobility posture. The swim test was timed to measure the duration of immobility. The latency to first immobility was recorded (in seconds) over a 6-minute test. The immobility time (in seconds) during the final 4 minutes of the test was also measured. Activity or inactivity between 0 and 2 minutes was not recorded.

[0047] [Table 3]

[0048] Results: The results of the forced swimming test are shown in Table 4 and Figures 1 to 3.

[0049] [Table 4-1] [Table 4-2]

[0050] Statistical analysis: The results in Table 4 were tested for significance using t-tests, univariate tests, and Dunnett's tests, as shown in Tables 5 to 14.

[0051] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0052] Tables 5-13 show that Compound A exhibited statistically significant effects in the mouse forced swim test model. For example, at a dose of 3 mg / kg, the two-tailed T-test scores for the latency to immobility, 2-6 minutes, and 0-6 minutes were 0.042, 0.015, and 0.007 (e.g., <0.05), respectively.

[0053] Blood and Brain Collection: Immediately after the forced swim test, all animals receiving the test substance were anesthetized with isoflurane inhalant and terminal blood collection (~1 ml) was performed via cardiac puncture into potassium EDTA blood collection tubes (SOP ROD.14.02). Plasma was isolated from whole blood by centrifugation at 3000 rpm at 4°C for 5 minutes. After isolation, the plasma was placed in cryovials and frozen at -80°C until shipment for bioanalysis. After blood collection, animals were decapitated, and whole brains were harvested according to standard operating procedures (SOP ROD.59). Brains were weighed, flash-frozen, and stored at -80°C until shipment. Blood and brain concentrations of Compound A are shown in Figure 4. The whole brain / plasma ratio (B / P ratio) was 2.2 at doses of 1 and 3 mg / kg, suggesting good central nervous system penetration in vivo.

[0054] 5.2. Example 2. Tail Suspension Test The tail suspension test (TST) has become one of the most widely used models for assessing antidepressant-like activity in mice. This test is based on the fact that animals subjected to a short period of inescapable stress, such as being suspended by their tail, develop an immobile posture. The protocol is described in Cryan, JF et al., Neurosci. Biobehav. Rev. 2005, 29:571-625.

[0055] Description: The device consists of two suspension devices in three cages, allowing six mice to be tested simultaneously. Each mouse is suspended by its tail with adhesive tape from a hook connected to a strain gauge. The strain gauge picks up all of the mouse's movements and transmits them to a central unit, where the signals are digitized. The signals are displayed visually using LEDs, allowing online confirmation that each unit is operating normally. The central unit has level filtering devices (1-9), which can be set to any sensitivity to maximize the discrimination of everything from minute movements of the animal or internal organs to entire body movements.

[0056] Parameters: "immobility duration" is the main parameter measured. It is calculated from the cumulative time during which the animal's movement does not exceed a threshold determined by a level filtering device. The "energy" consumed by the animal during the test measures the cumulative amplitude of individual movements in arbitrary units. The "power of movement" is calculated from the total energy consumed by the animal during the test divided by the total time the animal is active (in arbitrary units). For all three parameters, a computer provides data collection, generation of the experimental schedule (randomization), and grouping of results (mean, median, and SEM are automatically calculated for each treatment group).

[0057] Procedure: On the day of testing, mice are moved from the housing colony room to the testing room (cages are covered with a filter during transport). The filter cover is immediately removed, and the mice are allowed to remain undisturbed for at least 1 hour before testing. The mice are then administered the drug, and 1 hour (PO) or 30 minutes (IP) after administration, the mice are suspended by their tails (e.g., with adhesive tape) in the TST apparatus according to a randomized method. The test lasts 6 minutes to obtain measurements for all three parameters. The experiment is conducted between 08:00 and 12:30. Typically, 12 mice are used per treatment group.

[0058] Drug Treatment: Compound A and imipramine will be formulated at the concentrations listed in Table 2 of Example 1 above and administered 30 minutes prior to the TST. For each experiment, at least one control group will be included and run in parallel under strictly identical experimental conditions.

[0059] Statistics: For each experiment, statistical significance for the parameter "immobility time" was assessed using a one-way analysis of variance (ANOVA), with post-hoc analysis using Dunnett's test, if necessary. If tests of normality for the parameters "energy" and "power of movements" failed, intergroup comparisons were performed using a Kruskal-Wallis one-way analysis of variance on ranks, with post-hoc analysis using Dunnett's test, if necessary. For all three parameters, a value of p<0.05 was considered statistically significant.

[0060] 5.3. Example 3 Sucrose Preference and Intracranial Self-Stimulation Sucrose intake and intracranial self-stimulation (ICSS) are hedonic measures for chronic mild stress (CMS)-induced behavioral impairment in rodents. The protocol is described in Nielsen, CK et al., Behav. Brain Res. 2000, 107:21-33. A study will be conducted to evaluate the potential efficacy of Compound A using the CMS model.

[0061] Subjects: Male Wistar rats and male Piebor-Virol-Glaxo (PVG) hooded rats weighing 250-300 g and 220-240 g at the start of the study were used. Rats were housed individually or in pairs in polycarbonate cages and maintained on a 12-hour light:dark cycle (lights on at 06:00). Except when required by the study, animals had free access to food and water. Temperature (22 ± 1°C), relative humidity (55 ± 5%), and air exchange (16 times per hour) were automatically controlled. Body weights were measured weekly throughout all experiments.

[0062] Drug Treatment: Compound A and imipramine will be formulated and administered daily during the stress regime and / or intracranial self-stimulation at the concentrations described in Table 2 above in Example 1. For each experiment, at least one control group will be included, handled, and tested in parallel under strictly identical experimental conditions.

[0063] Stress Regime: Two different stress regimes (CMS-1 and CMS-2) were used. Each week in CMS-1 consisted of two periods of food deprivation (8 h and 19 h), three periods of water deprivation (6, 7, and 19 h), two periods of 45-degree cage tilt (7 and 16 h), two periods of 17-hour pair-housing, one period of 17-hour soiled cage (100 g sawdust bedding and 200 ml water), one period of 6-hour low-intensity strobe lighting (150 flashes per minute), and a 48-hour period of reversed light / dark cycle. Each week in CMS-2 consisted of 17-hour food and water deprivation followed by 2-hour food deprivation, 17-hour water deprivation followed by 1-hour empty bottle exposure, 17-hour pair-housing in soiled cage (100 g sawdust and 200 ml water), one-hour confinement to a small cage (25 x 10 x 10 cm), 1-hour light-on, and a 64-hour reversed light / dark cycle on weekends.

[0064] 5.3.1 Hedonic Measurement Sucrose intake: Rats (Wistar rats in some experiments, PVG-fed rats in others) are trained to consume a 1% sucrose solution twice weekly (Tuesdays and Fridays). This training consists of 8-10 1-h baseline trials in which the sucrose solution is presented in the rat's home cage after 20 hours of food and water deprivation. Sucrose intake is measured by weighing the bottle before and after the trial. After baseline levels have stabilized, sucrose consumption is measured at weekly (Wednesday) intervals for the duration of the experiment under similar conditions during the CMS protocol. The food and water deprivation prior to the sucrose test is the stressor upon which subsequent stressors included in the CMS regime are imposed; prior stressor history is not considered in subsequent analyses.

[0065] Intracranial self-stimulation: Rats (Wistar rats in some experiments, PVG-hooded rats in others) were pair-housed and allowed to acclimate for two weeks before surgery. They were anesthetized and mounted in a stereotaxic frame with an incisor bar set 2.7 mm below the interaural line. Stainless steel bipolar electrodes were implanted unilaterally in the ventral tegmental area (VTA), with the electrode tips 0.5 mm apart. The coordinates used were 3.2 mm anterior to the interaural line, 0.6 mm lateral to the midline, and 8.2 mm ventral from the skull surface. Five stainless steel screws and dental cement were used to secure the electrode assembly to the skull. Two weeks after surgery, each rat was trained to nose-poke for rewarding intracranial electrical stimulation in a test chamber placed inside a sound-attenuating box. By poking their nose into a hole (2.5 cm diameter) located 1 cm above the floor in the side wall, a focused light beam was interrupted and brain stimulation was initiated using a constant-current stimulator. Nosepokes deliver monophasic square-wave pulses (0.1 ms each) for 0.5 seconds. Stimulation is delivered on a 1-second fixed-interval reinforcement schedule to avoid excessively high stimulus density. Electrical stimulation and data recording are controlled by a computer and interface. Rats are initially trained at a fixed stimulation frequency of 70 Hz with individually selected current intensities (70-300 mA) to maintain the highest possible response rate without inducing motor impairment. Rats are trained for approximately 3 weeks in daily 40-minute sessions. Subsequently, rate-frequency curves are established by gradually changing the frequency while keeping the current intensity constant. Over 2-minute intervals, the frequency is decreased, then increased in 0.05-0.2 log steps within the range of 1.1-1.9 log Hz (10-85 Hz). Each session consists of 15 2-minute trials of each frequency, with a single priming stimulus at the beginning of each trial. The decreasing frequency series was used as a warm-up phase, meaning that only data obtained in the increasing series were used in subsequent calculations. The increasing frequency series was selected individually to obtain an ascending curve with at least two adjacent points at the maximum and minimum response rates, respectively. In this study, we employed the rate-frequency version of the curve shift method to evaluate the effect of CMS on reward.The properties of the rate-frequency function, particularly with regard to isolating the ICSS reward effect on operant motor performance, have been extensively examined and studied. ICSS behavior is measured at the frequency that supports 50% of the maximal response rate, known as the effective frequency (EF). 50 ) is evaluated by determining the EF 50 This method provides a reliable and stable EF. 50 On each test day, the observed response rate (nose poke (NP): 2 min test) is modeled as a function of the log10 of the imposed frequency (F), and an ascending rate-frequency curve is created for each rat. This function has three linear segments: the minimum response (NP), min ) through the horizontal lower asymptote, the maximum response (NP max ), and the linear transition between the asymptote (a+b * F). The last NP min and the first NP max Only data between (M) is included. This can be expressed as: 1.M={(F,NP(F)|max{F|NP(F)=NP min} ≦F≦min{F|NP(F)NP max Considering}}| 2.f(F)min(max(a+b * F,NP min ),NP max ) is fitted to the data in M ​​by the least squares method. In case of ambiguity, the function with the smallest b is used.

[0066] Effective frequency (EF), defined as the frequency that supports 50% of the maximum response rate 50 ) is determined. The horizontal curve shift along the simulation frequency axis, i.e., EF 50 Changes in EF reflect changes in the rewarding effect of the stimulus. Rate-frequency tests are conducted twice a week (Tuesdays and Fridays). If the maximum response does not show a tendency to increase or decrease, the EF 50A stable response is achieved when σ changes by less than 10-12%, after which the animals are assigned to two matched groups.

[0067] 5.3.2 Experimental Design Effects on sucrose intake in Wistar rats exposed to the CMS-1 regime (see above): Wistar rats are brought into the laboratory 4 weeks before the start of the experiment. Animals are housed individually, except as required by the stress protocol. Depending on their baseline sucrose intake, animals are assigned to two matched groups: one group is exposed to CMS-1 for 6 weeks, while the other group is maintained under standard laboratory conditions.

[0068] Effects on sucrose intake in PVG-fed rats exposed to the CMS-1 regime (see above): PVG-fed rats are brought into the laboratory 3 weeks before the start of the experiment. Animals are housed individually except as required by the stress protocol. Animals are assigned to two matched groups according to their baseline sucrose intake. One group of rats is exposed to CMS-1 for 9 weeks, while the other group is maintained under standard laboratory conditions.

[0069] Effects on ICSS in Wistar rats exposed to the CMS-2 regime (see above). Wistar rats were assigned to one group, housed individually, and exposed to CMS-2 for 10 weeks, while the other group (control group) was housed in pairs under standard laboratory conditions. Their EF 50 is measured twice weekly and a comparison is made for each individual rat to the mean of the last two baseline tests.

[0070] Effects of rat strain and stress regime on ICSS behavior (see above). Wistar rats were assigned to three matched groups: a control group and two groups exposed to 9 weeks of CMS-1 and CMS-2, respectively. PVG rats were assigned to two matched groups: one group was exposed to 9 weeks of CMS-2, while the other group (control group) was maintained under standard laboratory conditions. The control group was housed in pairs. Rats in the stress group were housed singly, except when required by the stress protocol. Their EF 50 is measured twice weekly and a comparison to the mean of the last two baseline tests is made for each individual rat.

[0071] Histology: After completion of the ICSS test, the animals are killed and the brains are removed and stored at 80°C. 12 mm cross sections are cut on a cryostat and stained with cresyl violet. The electrode tip is placed in the frontal lobe of the Paxinos and Watson stereotaxic atlas.

[0072] Statistical Analysis: In addition to comparing the control and stressed group tests for either normality or homogeneity of variance for both sucrose intake and ICSS data, data may also be evaluated by nonparametric statistics. Two-way ANOVAs are performed on ranks, with day and treatment (stress) as factors and animals nested within treatment, meaning that each set of parameters corresponds to only one observation. Therefore, all observations are independent. In ICSS experiments, there may be subclassification of stressed groups. If the grand mean response of stressed animals exceeds the maximum mean response of the control group, they are classified as belonging to a subgroup. Prior to comparing stress (subgroups and main group) with the control group, the responses of the stressed subgroups and main group are compared by a two-way ANOVA on ranks, with day and group as factors and animals nested within groups. A significant main effect for treatment (p<0.05) is followed by an unpaired t-test for each day. For clarity, both sucrose intake and ICSS data can be presented as mean ± SEM and still undergo nonparametric analysis. Body weight data that passed normality and homogeneity of variance tests were analyzed by one-way or two-way analysis of variance. Multiple comparisons were performed using Tukey's test and / or Kruskal-Wallis ANOVA on ranks.

[0073] 5.4. Example 4 Novelty-Induced Hypophagia The inhibition of eating caused by novelty, termed "hyponeophagia," provides an anxiety-related measure that is sensitive to the effects of chronic, but not acute or subchronic, antidepressant treatment. The protocol is described in Dulawa, SC and Hen, R., Neurosci. Biobehav. Rev. 2005, 29:771-83.

[0074] Subject Selection: Male Balb / cJ mice were maintained on a 12 L:12 D schedule (lights on at 06:00) and housed in groups of 5 with identical mice. Food and water were provided ad libitum. Behavioral testing was performed during the light phase between 07:00 and 17:00.

[0075] Equipment and Procedure: Compound A and imipramine are formulated at the concentrations described in Table 2 of Example 1 above and administered at least 30 minutes prior to testing. Plasma concentrations of Compound A are determined by liquid chromatography with fluorescence detection.

[0076] Chronic testing: Male Balb / cJ mice are dosed (e.g., 1 and 3 mg / kg of Compound A per day). Separate groups of mice are used for subchronic versus chronic experiments. On day 23 of treatment, mice are housed singly. Mice are trained to drink sweetened condensed milk for three consecutive days (days 25–27). Mice are presented with diluted sweetened condensed milk (1:3, milk:water) for 30 minutes each day. Milk is presented in a 10 ml serological pipette with a parafilm-lined sipper. Milk is presented in a 10 ml serological pipette with a parafilm-lined sipper. The pipette is closed with a rubber stopper and placed through the lid of the wire cage. Home cage testing begins on day 28, when mice are briefly removed from their cage to place the milk-filled pipette. Testing begins when the mice are returned to their cage. Drinking latency and drinking volume are recorded every 5 minutes for 30 minutes. The home cage test was conducted in a dimly lit area (approximately 50 lux). On day 29, a novel cage test was conducted. Mice were placed in a clean cage of the same size but free of shavings, and a pipette containing milk was placed inside. The novel cage test was conducted under bright lighting (approximately 1200 lux), with white paper placed under the cage to enhance the aversive effect. Mice that did not drink during the 30-minute home cage test were excluded from the experiment, presumably because they had not learned to drink milk during training. Subchronic testing was conducted using separate groups of male Balb / cJ mice, administered with Compound A (e.g., 1 and 3 mg / kg per day). Mice were housed singly and trained to drink milk starting on day 1 of treatment. Mice were trained to drink sweetened condensed milk on days 1–3. After 4 days (home) and 5 days (novel) of subchronic treatment, they were then tested in the novelty-induced anorexia test.

[0077] 5.5. Example 5: Learning Helpless Model The learned helplessness paradigm is a depression model in which animals are exposed to unpredictable and uncontrollable stress, such as electric shock, and subsequently develop coping deficits in avoidable situations. The protocol is described in Chourbaji, S. et al., Brain Res. Protoc. 2005, 16:70-8.

[0078] Materials: The shock procedure was performed in a transparent Plexiglas shock chamber (18 x 18 x 30 cm) with a stainless steel grid floor (diameter of each grid: 0.5 cm, spacing: 0.6 cm). 3 The bidirectional avoidance test is performed in a shuttle box consisting of two compartments, each equipped with an infrared beam at the bottom, and the spontaneous movement and behavioral responses to a light stimulus (conditioned) and an aversive foot shock (unconditioned) are observed. The shuttle box is made up of compartments of equal size (18x18x30cm). 3 ) and separated by a small gate (6 cm wide, 7 cm high). Both compartments of the shuttle box are equipped with an electrically conductive grid floor (diameter of each grid: 0.5 cm, distance: 0.6 cm) and a signal light at the top of each compartment. Protocol charts for both the shock procedure and the shuttle box test are designed separately.

[0079] Hot Plate: To rule out altered pain sensitivity as a confounding factor, all mice are tested on a hot plate.

[0080] Pharmacological Treatment: The model is pharmacologically validated by administering Compound A and imipramine formulated at the concentrations listed in Table 2 of Example 1 above at least 30 minutes prior to testing. The dose of Compound A is assessed to restore helpless behavior in the shuttle box.

[0081] Animals: Ten-week-old male C57BL / 6N mice were purchased and acclimatized to single housing in polycarbonate cages (type II) under constant conditions of a 12-hour light-dark cycle and an average room temperature of 22°C, with food and water available ad libitum, for 2 weeks prior to the experiment.

[0082] Inevitable Shock Procedure: 1. Mice are exposed to an inescapable shock during their active phase (dark phase): Animals are transported to the experimental room in their home cages and then placed in the shock chamber. 2. The shock procedure included 360 scrambled footshocks (0.150 mA) over two consecutive days. The footshocks were unpredictable, varying in duration (1-3 seconds) and interval (1-3 seconds). The total session duration was approximately 52 minutes. The lights were off during the shock exposure. 3. Control animals undergo the same handling and contextual procedures without receiving the foot shock. Thorough cleaning with 70% ethanol ensures that non-shocked control animals can access the shock chamber without being overwhelmed by the odor of the shocked mouse. Daily washing with soap prevents the buildup of potential alarm substances.

[0083] Assessment of learned helplessness: Twenty-four hours after the second shock administration, learned helplessness was assessed by testing the animals' behavior in the shuttle box during the dark period. Each trial began with a 5-second light stimulus, followed by a footshock (intensity: 0.150 mA) of up to 10 seconds duration. The intertrial interval was 30 seconds. The following behavioral responses were defined: "Escape" was defined as a sufficient response to the light stimulus followed by immediate movement to the other compartment; "Escape" was defined as movement to the other compartment in response to the electric shock; and "Fail" was defined as no attempt to escape. Furthermore, the time it took for the animal to move to the other compartment after the footshock was administered was recorded as the escape latency parameter. General activity was determined by recording the number of trips before the first footshock (initial activity) and the activity between trials (intertrial activity or ITI). The total duration of the helplessness test was approximately 20–24 minutes, the exact duration depending on the animal's learning ability and ability to respond appropriately. Before each test, the apparatus was thoroughly cleaned with 70% ethanol. To emphasize the assessment of the effects of "true" learned helplessness, which relies on the uncontrollability of stress, an additional cohort of animals will be tested for immunization. These animals will be exposed to a pre-session identical to the learned helplessness test in the shuttle box, where they will experience a controllable shock condition. Furthermore, their initial activity before exposure will be monitored.

[0084] Pain sensitivity: To exclude potential artifacts due to altered pain sensitivity that may affect the effectiveness of the electric shock, a subgroup of mice is tested on a hot plate at a temperature of 52 °C before the learned helplessness procedure. The latency to the first response (jumping or licking the hind paw) is monitored.

[0085] Definition of Helplessness: Following the evaluation of behavioral parameters, shocked animals are classified as "helpless" or "resistant" depending on their performance in the shuttle box test. Using failures and escape latencies as indicators of helplessness, a k-means (k = 2) clustering algorithm is applied to the data pool of mice subjected to the described protocol. The number of failures and escape latencies are used as performance scores for individual animals because they are the most commonly reported indicators of helplessness. These behavioral indicators are normalized (i.e., converted to Z-scores) to prevent bias due to differences in the distribution of each variable and to prevent them from being inadvertently used in the clustering process. This classification is further refined by means of two-step discriminant-canonical analysis, and a classification formula for distinguishing helpless / non-helpless mice according to this protocol is also provided.

[0086] Pharmacological validation: Additional C57BL / 6N mice are trained and tested with the protocol. Prior to any pharmacological treatment, these mice are classified as "helpless" or "non-helpless" using a previously derived classification formula (e.g., the definition of helplessness described above), taking into account the number of failures and escape latency. A helplessness period of approximately 10 days was determined, with brief Compound A treatment periods spaced 5–6 days apart. Thus, animals undergo a 5-day Compound A administration regimen. On day 6, animals are retested with the protocol. The classification formula is again used to classify each subject, but this time the value from the retest session is used in the calculation. The change in this categorization after Compound A administration (i.e., the transition of mice from the "helpless" group to the "non-helpless" group) is considered an indicator of the sensitivity of the given operational definition of helplessness. Because this analysis has a continuous rather than categorical indicator of Compound A effect, it is complemented by evaluating the change in squared Mahalanobis distance to the center of gravity of the non-helpless group before and after pharmacological treatment.

[0087] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein are hereby incorporated by reference in their entirety.

[0088] Although the foregoing compositions, methods, and uses have been described in some detail for ease of understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims. Accordingly, the described embodiments should be considered illustrative and not restrictive, and the claimed invention should not be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

[0089] Furthermore, the present invention includes the following aspects: Item 1. A method for treating a depressive disorder in a human in need thereof, comprising administering a therapeutically effective amount of Compound A to the human; The method wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. Item 2. The method according to Item 1, wherein the method comprises promoting the opening of Kv7 potassium channels in the human. Item 3. A method for promoting the opening of Kv7 potassium channels in humans, comprising administering an effective amount of compound A to a human, Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method, wherein the human has a depressive disorder. Item 4. The method according to Item 2 or 3, wherein the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. Clause 5. The method of clause 4, wherein the method is selective for promoting the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.1. Item 6. The method according to Item 2, wherein the method comprises opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels. Item 7. The method according to any one of Items 1 to 6, wherein the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression accompanied by agitation or anxiety, adjustment disorder accompanied by depressed mood, prolonged depressive reaction, or a combination thereof. Item 8. The method according to any one of Items 1 to 7, wherein the depressive disorder is major depressive disorder (MDD). Item 9. The method according to any one of Items 1 to 8, wherein compound A is orally administered to the human. Item 10. The method according to any one of Items 1 to 9, wherein compound A is administered to the human at a dose of 2 to 200 mg. Item 11. The method according to Item 10, wherein compound A is administered to the human at a dose of 2 to 100 mg. Item 12. The method according to Item 10, wherein compound A is administered to the human at a dose of 5 to 50 mg. Item 13. The method of Item 10, wherein Compound A is administered to the human at a dose of 10, 20, or 25 mg. Item 14. The method of Item 10, wherein Compound A is administered to the human at a dose of 20 mg. Item 15. The method according to any one of Items 1 to 9, wherein compound A is administered to the human in a dose of at least 20 mg. Item 16. The method of Item 15, wherein Compound A is administered to the human in a dose of at least 50 mg. Item 17. The method of Item 15, wherein compound A is administered to the human in a dose of at least 100 mg. Item 18. The method according to any one of Items 1 to 9, wherein compound A is administered to the human at a dose of 5 to 1000 mg / day. Item 19. The method according to Item 18, wherein compound A is administered to the human at a dose of 5 to 500 mg / day. Item 20. The method according to Item 18, wherein compound A is administered to the human at a dose of 5 to 250 mg / day. Item 21. The method according to Item 18, wherein compound A is administered to the human at a dose of 20 to 150 mg / day. Item 22. The method according to Item 18, wherein Compound A is administered to the human at a dose of 100 mg / day. Item 23. The method according to any one of Items 1 to 22, wherein compound A is administered to the human at a dose of 0.05 to 2.0 mg / kg. Item 24. The method according to Item 23, wherein compound A is administered to the human at a dose of 0.1 to 1.0 mg / kg. Item 25. The method according to Item 23, wherein compound A is administered to the human at a dose of 0.2 to 0.5 mg / kg. Item 26. Use of compound A in the manufacture of a medicament for treating a depressive disorder in a human in need thereof, Use of compound A, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. Item 27. The use according to Item 26, wherein treating a depressive disorder comprises promoting the opening of Kv7 potassium channels in the human. Item 28. Use of compound A in the manufacture of a medicament for promoting the opening of Kv7 potassium channels in humans, Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The use of Compound A, wherein the human has a depressive disorder. Item 29. The use according to Item 27 or 28, wherein the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. Item 30. The use of Item 29, wherein promoting the opening of Kv7 potassium channels is selective for promoting the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.1. Item 31. The use according to Item 27, wherein promoting the opening of Kv7 potassium channels includes the opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels. Item 32. The use according to any one of Items 26 to 31, wherein the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression accompanied by agitation or anxiety, adjustment disorder accompanied by depressed mood, prolonged depressive response, or a combination thereof. Item 33. The use according to any one of Items 26 to 32, wherein the depressive disorder is major depressive disorder (MDD). Item 34. The use according to any one of Items 26 to 33, wherein compound A is orally administered to the human. Item 35. The use according to any one of Items 26 to 34, wherein compound A is administered to the human at a dose of 2 to 200 mg. Item 36. The use according to Item 35, wherein compound A is administered to the human at a dose of 2 to 100 mg. Item 37. The use according to Item 35, wherein compound A is administered to the human at a dose of 5 to 50 mg. Item 38. The use of Item 35, wherein Compound A is administered to the human at a dose of 10, 20, or 25 mg. Item 39. The use according to Item 35, wherein Compound A is administered to the human at a dose of 20 mg. Item 40. The use according to any one of Items 26 to 34, wherein compound A is administered to the human in a dose of at least 20 mg. Item 41. The use according to Item 40, wherein compound A is administered to the human in a dose of at least 50 mg. Item 42. The use according to Item 40, wherein compound A is administered to the human in a dose of at least 100 mg. Item 43. The use according to any one of Items 26 to 34, wherein compound A is administered to the human at a dose of 5 to 1000 mg / day. Item 44. The use according to Item 43, wherein compound A is administered to the human at a dose of 5 to 500 mg / day. Item 45. The use according to Item 43, wherein compound A is administered to the human at a dose of 5 to 250 mg / day. Item 46. The use according to Item 43, wherein compound A is administered to the human at a dose of 20 to 150 mg / day. Item 47. The use according to Item 43, wherein compound A is administered to the human at a dose of 100 mg / day. Item 48. The use according to any one of Items 26 to 47, wherein compound A is administered to the human at a dose of 0.05 to 2.0 mg / kg. Item 49. The use according to Item 48, wherein compound A is administered to the human at a dose of 0.1 to 1.0 mg / kg. Item 50. The use according to Item 48, wherein compound A is administered to the human at a dose of 0.2 to 0.5 mg / kg.

Claims

1. 1. A method of treating a depressive disorder in a human in need thereof, comprising administering to said human a therapeutically effective amount of Compound A; The method wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

2. 2. The method of claim 1, wherein the method comprises promoting the opening of Kv7 potassium channels in the human.

3. 1. A method for promoting the opening of Kv7 potassium channels in a human, comprising administering to the human an effective amount of Compound A, Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method, wherein the human has a depressive disorder.

4. 4. The method of claim 2 or 3, wherein the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.

5.

5. 5. The method of claim 4, wherein the method is selective for promoting the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.

1.

6. 3. The method of claim 2, wherein the method comprises opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels.

7. 7. The method of any one of claims 1 to 6, wherein the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive response, or a combination thereof.

8. The method of any one of claims 1 to 7, wherein the depressive disorder is major depressive disorder (MDD).

9. 9. The method of any one of claims 1 to 8, wherein Compound A is administered orally to the human.

10. 10. The method of any one of claims 1 to 9, wherein Compound A is administered to the human at a dose of 2 to 200 mg.

11. 11. The method of claim 10, wherein Compound A is administered to the human at a dose of 2 to 100 mg.

12. 11. The method of claim 10, wherein Compound A is administered to the human at a dose of 5 to 50 mg.

13. 11. The method of claim 10, wherein Compound A is administered to the human at a dose of 10, 20, or 25 mg.

14. 11. The method of claim 10, wherein Compound A is administered to the human at a dose of 20 mg.

15. 10. The method of any one of claims 1 to 9, wherein Compound A is administered to the human in a dose of at least 20 mg.

16. 16. The method of claim 15, wherein Compound A is administered to the human at a dose of at least 50 mg.

17. 16. The method of claim 15, wherein Compound A is administered to the human at a dose of at least 100 mg.

18. 10. The method of any one of claims 1 to 9, wherein Compound A is administered to the human at a dose of 5 to 1000 mg / day.

19. 19. The method of claim 18, wherein Compound A is administered to the human at a dose of 5 to 500 mg / day.

20. 19. The method of claim 18, wherein Compound A is administered to the human at a dose of 5 to 250 mg / day.

21. 19. The method of claim 18, wherein Compound A is administered to the human at a dose of 20 to 150 mg / day.

22. 19. The method of claim 18, wherein Compound A is administered to the human at a dose of 100 mg / day.

23. 23. The method of any one of claims 1 to 22, wherein Compound A is administered to the human at a dose of 0.05 to 2.0 mg / kg.

24. 24. The method of claim 23, wherein Compound A is administered to the human at a dose of 0.1 to 1.0 mg / kg.

25. 24. The method of claim 23, wherein Compound A is administered to the human at a dose of 0.2 to 0.5 mg / kg.

26. 1. Use of Compound A in the manufacture of a medicament for treating a depressive disorder in a human being in need thereof, comprising: Use of compound A, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

27. 27. The use of claim 26, wherein treating a depressive disorder comprises promoting the opening of Kv7 potassium channels in the human.

28. 1. Use of Compound A in the manufacture of a medicament for promoting the opening of Kv7 potassium channels in a human, comprising: Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The use of Compound A, wherein the human has a depressive disorder.

29. 29. The use of claim 27 or claim 28, wherein the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.

5.

30. 30. The use of claim 29, wherein promoting the opening of Kv7 potassium channels is selective for promoting the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.

1.

31. 28. The use of claim 27, wherein promoting the opening of Kv7 potassium channels comprises opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels.

32. 32. The use of any one of claims 26 to 31, wherein the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive response, or a combination thereof.

33. The use according to any one of claims 26 to 32, wherein the depressive disorder is major depressive disorder (MDD).

34. The use according to any one of claims 26 to 33, wherein compound A is administered orally to the human.

35. 35. The use according to any one of claims 26 to 34, wherein compound A is administered to the human at a dose of 2 to 200 mg.

36. 36. The use of claim 35, wherein compound A is administered to the human at a dose of 2 to 100 mg.

37. 36. The use of claim 35, wherein compound A is administered to the human at a dose of 5 to 50 mg.

38. 36. The use of claim 35, wherein Compound A is administered to the human at a dose of 10, 20, or 25 mg.

39. 36. The use of claim 35, wherein Compound A is administered to the human at a dose of 20 mg.

40. 35. The use according to any one of claims 26 to 34, wherein Compound A is administered to the human in a dose of at least 20 mg.

41. 41. The use of claim 40, wherein Compound A is administered to the human at a dose of at least 50 mg.

42. 41. The use of claim 40, wherein Compound A is administered to the human at a dose of at least 100 mg.

43. 35. The use according to any one of claims 26 to 34, wherein compound A is administered to the human at a dose of 5 to 1000 mg / day.

44. 44. The use of claim 43, wherein compound A is administered to the human at a dose of 5 to 500 mg / day.

45. 44. The use of claim 43, wherein compound A is administered to the human at a dose of 5 to 250 mg / day.

46. 44. The use of claim 43, wherein compound A is administered to the human at a dose of 20 to 150 mg / day.

47. 44. The use of claim 43, wherein Compound A is administered to the human at a dose of 100 mg / day.

48. 48. The use according to any one of claims 26 to 47, wherein compound A is administered to the human at a dose of 0.05 to 2.0 mg / kg.

49. 49. The use of claim 48, wherein compound A is administered to the human at a dose of 0.1 to 1.0 mg / kg.

50. 49. The use of claim 48, wherein compound A is administered to the human at a dose of 0.2 to 0.5 mg / kg.

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