CN116847852A

CN116847852A - Use of neuroactive steroids for the treatment of sexual dysfunction

Info

Publication number: CN116847852A
Application number: CN202280012011.4A
Authority: CN
Inventors: V·博瑟阿帕利; E·苏特霍夫; H·贡杜兹-布鲁斯; R·阿诺德
Original assignee: Sage Therapeutics Inc
Current assignee: Sage Therapeutics Inc
Priority date: 2021-01-28
Filing date: 2022-01-27
Publication date: 2023-10-03

Abstract

The present application relates to methods of treating sexual dysfunction and/or maintaining sexual function in a patient by administering a neuroactive steroid to the patient.

Description

Use of neuroactive steroids for the treatment of sexual dysfunction

Cross Reference to Related Applications

The application claims the benefits of U.S. provisional application No. 63/142,840 filed on day 28 of 1 in 2021 and U.S. provisional application No. 63/142,833 filed on day 28 of 1 in 2021. The entire contents of the above-mentioned application are incorporated herein by reference in their entirety.

Technical Field

The present application relates to methods of treating sexual dysfunction, e.g., treatment-induced sexual dysfunction, and/or maintaining sexual function in a patient by administering compound (1) or compound (2) described herein.

Background

Sexual Dysfunction (SD) is a problem that can occur at any stage of the sexual response cycle. SD renders individuals unable to perceive satisfaction from sexual activity. Traditional sexual response cycles include excitation, stabilization, climax and regression. Both desire and arousal are part of the sexual response excitation phase. Sexual dysfunction can affect people of any age. Physical and/or medical conditions and psychological disorders may lead to sexual problems. Side effects of some drugs, including antidepressants, can also affect sexual function.

The sexual dysfunction caused by the treatment is an adverse reaction associated with the administration of various antidepressants. Tricyclic antidepressants, monoamine oxidase inhibitors, selective Serotonin Reuptake Inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are all associated with impairment at each stage of the sexual response cycle (arousal, arousal and climax) and effects on sexual frequency and pleasure. Studies have shown that citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, venlafaxine, imipramine and phenelzine are associated with significantly higher SD rates than placebo.

SD may be addressed by treating potential physiological, medical and/or psychological problems. Other methods of treating SD include drug therapy (e.g., sildenafilTadalafil->Vardenafil->Avanafil->Flibanserin->And Bramerlangdan->Mechanical assistance (e.g., vacuum device, penile implant), sexual therapy, behavioral therapy, psychological therapy, and education and communication are used. Current methods for treating or reducing therapy-induced SD include waiting for spontaneous remission or tolerance, reducing dose, drug holidays, non-drug intervention (e.g., motor, psychotherapy), switching to a different antidepressant, and/or adding drugs to treat adverse effects.

There is a need for new and improved methods of treating SD, including treatment-induced SD. Also needed are agents for the prevention and treatment of CNS related diseases that simultaneously exhibit reduced or no side effects, typically associated with antidepressants, in particular sexual dysfunction. The reagents and methods of using the reagents described herein are directed to this end.

Disclosure of Invention

The present invention provides a method of treating sexual dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

another aspect of the invention provides a method of treating sexual dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of:

in some embodiments, the compound administered is a compound of the formula:

in some embodiments, the pharmaceutically acceptable salt administered is a pharmaceutically acceptable salt of a compound of the formula:

in some embodiments, the compound administered is a compound of the formula:

In some embodiments, the patient has (or has) a CNS-related disorder. In some embodiments, the CNS-related disorder is selected from sleep disorders, mood disorders, schizophrenic lineage disorders, convulsive disorders, memory and/or cognition disorders, movement disorders, personality disorders, autism lineage disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and/or withdrawal syndrome, tinnitus and status epilepticus. In some embodiments, the CNS-related disorder is an mood disorder. In some embodiments, the mood disorder is major depressive disorder.

In certain aspects, the compound is administered at a dose of about 20mg to about 60mg once daily. In some embodiments, the compound is administered at a dose of about 50mg once daily for about 14 days. In some embodiments, the compound is administered at a dose of about 60mg once daily for about 14 days.

In certain aspects, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to 60mg of the free base compound once daily. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

In certain aspects, sexual dysfunction is assessed by a sexual function change questionnaire-14. In some embodiments, the day 42 sexual function change questionnaire-14 score is not greater than the baseline sexual function change questionnaire-14 score. In some embodiments, the patient is female and the sexual function change questionnaire-14 score is no greater than 41 days, 28 days, or 42 days after administration. In some embodiments, the patient is male and the sexual function change questionnaire-14 score is no greater than 47 days 15, 28, or 42 after administration.

In some embodiments, the sexual dysfunction includes a reduction or loss of one or more of sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement, and orgasm.

In another aspect, the invention provides a method of treating sexual dysfunction in a patient suffering from major depressive disorder, the method comprising administering a therapeutically effective amount of a compound selected from the following formulae:

in another aspect, the invention provides a method of treating sexual dysfunction in a patient suffering from major depressive disorder, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the following formulae:

in certain aspects, the compound administered is a compound of the formula:

In certain aspects, the pharmaceutically acceptable salt administered is a pharmaceutically acceptable salt of a compound of the formula:

in certain aspects, the compound administered is a compound of the formula:

in certain aspects, the compound is administered at a dose of about 20mg to 60mg once daily. In some embodiments, the compound is administered at a dose of about 50mg once daily for about 14 days. In some embodiments, the compound is administered at a dose of about 60mg once daily for about 14 days.

In certain aspects, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound once daily. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

In certain aspects, sexual dysfunction is assessed by the sexual function change questionnaire-14. In some embodiments, the day 42 sexual function change questionnaire-14 score is no greater than the baseline sexual function change questionnaire-14 score. In some embodiments, the patient is female and the sexual function change questionnaire-14 score is no greater than 41 days, 28 days, or 42 days after administration. In some embodiments, the patient is male and the sexual function change questionnaire-14 score is no greater than 47 days 15, 28, or 42 after administration.

Another aspect of the invention provides a method of maintaining sexual function in a patient suffering from a mood disorder comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

another aspect of the invention provides a method of maintaining sexual function in a patient having an mood disorder comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of:

in certain aspects, the compound administered is a compound of the formula:

in certain aspects, the mood disorder is major depressive disorder.

In some aspects, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound, once daily. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

In certain aspects, the sexual dysfunction is assessed by the sexual function change questionnaire-14. In some embodiments, the day 42 sexual function change questionnaire-14 score is no greater than the baseline sexual function change questionnaire-14 score. In some embodiments, the patient is female and the sexual function change questionnaire-14 score is no greater than 41 days, 28 days, or 42 days after administration. In some embodiments, the patient is male and the sexual function change questionnaire-14 score is no greater than 47 days 15, 28, or 42 after administration.

In another aspect, the invention provides a method of treating a treatment-induced sexual dysfunction in a patient currently undergoing or having undergone a course of chemo-psychological therapy, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

In another aspect, the invention provides a method of treating a treatment-induced sexual dysfunction in a patient currently undergoing or having undergone a course of chemo-psychological therapy, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of:

in certain aspects, the compound administered is a compound of the formula:

in some embodiments, the chemopsychotherapy is an antidepressant. In some embodiments, the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a tricyclic, a monoamine oxidase inhibitor, or an atypical antidepressant.

In certain aspects, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound once daily. In some embodiments, the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days. In some embodiments, the pharmaceutically acceptable salt of the compound is administered at a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

Drawings

Fig. 1 is a schematic diagram showing a model study design according to example 1.

FIG. 2 is a graph showing the change in the total score of average functional change questionnaire-14 (CSFQ-14) from baseline (. + -. Standard error) for patients receiving 30mg of compound (1) or placebo at baseline and days 15, 28 and 42 according to example 1.

Fig. 3 is a graph showing the percentage of patients with sexual dysfunction across the treatment group (compound (1) and placebo) on baseline and days 15, 28 and 42 according to example 1.

Fig. 4 is a graph showing female odds ratios (odds ratios) on various CSFQ-14 score scales across treatment groups (compound (1) and placebo) on days 15, 28 and 42 according to example 1.

Fig. 5 is a graph showing male odds ratios on various CSFQ-14 score scales across treatment groups (compound (1) and placebo) on days 15, 28 and 42 according to example 1.

Detailed Description

The present invention relates generally to methods of treating sexual dysfunction and treatment-induced sexual dysfunction in a patient in need thereof by administering a compound selected from the group consisting of:

the invention also relates to methods of treating sexual dysfunction and treatment-induced sexual dysfunction in a patient in need thereof by administering a pharmaceutically acceptable salt of a compound selected from the group consisting of:

The invention also relates to a method of treating major depressive disorder in a patient in need thereof by administering to the patient a therapeutically effective amount of a compound (1) and a compound (2) selected from the following formulae, wherein the patient maintains sexual function during the treatment:

the invention also relates to a method of treating major depressive disorder in a patient in need thereof by administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt selected from compound (1) and compound (2) of the formula:

I. definition of the definition

As used herein, "compound (1)" refers to a compound having the following formula (or structure):

the compound (1), also known as zuranolone,3α -hydroxy-3β -methyl-21- (4-cyanopyrazol-1-yl) -5β -19-norpregnan-20-one, has the IUPAC name 1- (2- ((3 r,5r,8r,9r,10s,13s,14s,17 s) -3-hydroxy-3, 13-dimethylhexadeca-hydro-1H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (CAS registry number 1632051-40-1). The chemical synthesis of compound (1) is described in U.S. patent No. 9,512,165 and PCT application publication No. WO 2014/169833, each of which is incorporated herein by reference in its entirety. Several crystalline forms of compound (1) and methods of preparing the forms are described in U.S. patent application publication No. US2019/0177359 and PCT application publication No. WO 2018/039378, each of which is incorporated herein by reference in its entirety.

As used herein, "compound (2)" refers to a compound having the following formula (or structure):

compound (2) is also known as 3α -hydroxy-3β -methoxymethyl-21- (5-methyl-2H-tetrazol-2-yl) -19-nor-5α -pregnan-20-one, having the IUPAC name 1- ((3R, 5S,8R,9R,10S,13S,14S, 17S) -3-hydroxy-3- (methoxymethyl) -13-methylhexadechydro-1H-cyclopenta [ a ] phenanthren-17-yl) -2- (5-methyl-2H-tetrazol-2-yl) ethan-1-one (CAS registry number 1832596-09-4). The chemical synthesis of compound (2) is described in PCT application publication No. WO 2015/180679, which is incorporated herein by reference in its entirety.

Compound (1) and compound (2) are neuroactive steroids that have been shown to target synaptic and extrasynaptic GABA _A GABA of receptor _A Positive allosteric modulators of receptors. Compound (1) and compound (2) as GABA _A Positive allosteric modulators of receptors are useful as therapeutic agents for the treatment of CNS related disorders, such as depression, post-partum depression and major depressive disorders, and for the treatment of neurological disorders, such as essential tremor, epilepsy and parkinson's disease.

As used herein, the term "modulate" refers to GABA _A Inhibition or enhancement of receptor function. "modulators" (e.g., modulating GABA) _A A compound of receptor function or a pharmaceutically acceptable salt thereof) may be, for example, GABA _A Agonists, partial agonists, antagonists or partial antagonists of the receptor.

As used herein, unless otherwise indicated, the terms "treatment", "treatment" and "treatment" contemplate actions that occur when a subject has a particular disease, disorder or condition, which actions reduce the severity of the disease, disorder or condition (or any symptom thereof), or hinder or slow the progression of the disease, disorder or condition ("therapeutic treatment"), and also consider preventive actions that occur before the subject begins to have the particular disease, disorder or condition.

The terms "disease," "disorder," and "condition" are used interchangeably herein.

As used herein, an "effective amount" of a compound (or a pharmaceutically acceptable salt thereof) refers to an amount sufficient to elicit a desired biological response, e.g., to treat a sexual dysfunction caused by treatment. As will be appreciated by one of ordinary skill in the art, the effective amount of a compound of the invention (or a pharmaceutically acceptable salt thereof) may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. Effective amounts include therapeutic and prophylactic treatments.

As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound (or a pharmaceutically acceptable salt thereof) is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound (or pharmaceutically acceptable salt thereof) refers to an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

In alternative embodiments, the invention contemplates administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylaxis before a subject begins to suffer from a particular disease, disorder, or condition. As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence thereof. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent (alone or in combination with other agents) that provides a prophylactic benefit in preventing a disease, disorder or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

A "patient" is a human (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged, or elderly)).

As used herein, the term "about," when referring to a value or range, allows for some degree of variability in the value or range, for example, within 10% or within 5% of the limit of the specified value or specified range.

As used herein, the term "dose equivalent" refers to a bioequivalent dose. For example, the dose equivalent of compound (1) or a pharmaceutically acceptable salt of compound (2) to a 25mg dose of compound (1) or compound (2) is the amount (by weight) of pharmaceutically acceptable salt required to provide a 25mg dose of compound (1) or compound (2) free base bioequivalent dose.

As used herein, the term "unit dosage form" is defined to mean a form in which compound (1) or compound (2) is administered to a patient. In particular, the unit dosage form may be, for example, a pill, capsule or tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

As used herein, "solid dosage form" refers to a pharmaceutical dosage in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants, and chewable tablets.

By "pharmaceutically acceptable" is meant approved or approvable by a regulatory agency of the federal or a state government or a corresponding agency in a country other than the united states, or listed in the united states pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention which is pharmaceutically acceptable and which has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, hexadienedioic acid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts also include, by way of example only, salts of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; when the compound contains basic functional groups, non-toxic organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., berge, et al, j.pharm.sci. (1977) 66 (1): 1-79.

"sexual dysfunction" (or "SD") may include, but is not limited to, sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, reduction or loss of sexual excitement and orgasm, erectile difficulty, penile erectile dysfunction (priapism), orgasmic disorder (dysorgasmia), anorgasmia, dyspareunia, spontaneous orgasm, ejaculatory disorders (delayed, suppressed, retrograde, spontaneous, reduced in volume), sexual arrest relief (sexual disinhibition), and sexual satisfaction.

"sexual function" includes, but is not limited to, sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement and orgasm.

Sexual dysfunction is a problem that can occur at any stage of the sexual response cycle. SD may prevent an individual from feeling satisfied from sexual activity. The sexual response cycle traditionally involves excitement, stabilization, climax and regression. Both desire and arousal are part of the sexual response excitation phase.

Sexual dysfunction is a common symptom of Major Depressive Disorder (MDD) and antidepressant treatment, which usually occurs about 1 to about 3 weeks after initiation of treatment. Depending on the type of antidepressant taken, the prevalence is estimated to vary from 4% to 73%.

II therapeutic methods

Described herein are methods of treating sexual dysfunction and/or maintaining sexual function in a patient, and/or maintaining sexual function during treatment of major depressive disorder in a patient in need thereof, comprising administering to the patient a compound selected from compound (1) and compound (2); or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides a method of treating sexual dysfunction in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of compound (1) and compound (2).

In one aspect, the invention provides a method of treating sexual dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt selected from compound (1) and compound (2).

In one aspect, the invention provides a method of treating sexual dysfunction in a patient suffering from an mood disorder, the method comprising administering a therapeutically effective amount of a compound selected from the group consisting of compound (1) and compound (2).

In another aspect, the invention provides a method of treating sexual dysfunction in a patient suffering from an mood disorder, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt selected from compound (1) and compound (2).

In some embodiments, the mood disorder is major depressive disorder.

In one aspect, the invention provides a method of treating sexual dysfunction in a patient suffering from major depressive disorder, the method comprising administering a therapeutically effective amount of a compound selected from compound (1) and compound (2).

In another aspect, the invention provides a method of treating sexual dysfunction in a patient suffering from major depressive disorder, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt selected from compound (1) and compound (2).

In one aspect, the invention provides a method of treating major depressive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from compound (1) and compound (2), wherein the patient retains sexual function during the treatment.

In another aspect, the invention provides a method of treating major depressive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt selected from compound (1) and compound (2), wherein the patient retains sexual function during the treatment.

In one aspect, the invention provides a method of maintaining sexual function in a patient having an mood disorder comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of compound (1) and compound (2).

In another aspect, the invention provides a method of maintaining sexual function in a patient having an mood disorder comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt selected from compound (1) and compound (2).

In some embodiments, the mood disorder is major depressive disorder.

In some embodiments, the compound administered is compound (1).

In some embodiments, the pharmaceutically acceptable salt administered is a pharmaceutically acceptable salt of compound (1).

In some embodiments, the compound administered is compound (2).

In some embodiments, the pharmaceutically acceptable salt administered is a pharmaceutically acceptable salt of compound (2).

In some embodiments, the sexual function includes sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement, or orgasm.

In some embodiments, maintaining sexual function during treatment refers to the patient not having a loss of sexual function during treatment. In some embodiments, maintaining sexual function during treatment refers to the patient having no significant differences in sexual function during treatment. In some embodiments, maintaining sexual function during treatment refers to sexual dysfunction that the patient has not seen with treatment. In some embodiments, sexual function is maintained for the duration of the treatment for patients regardless of sex, e.g., female or male patients.

Sexual dysfunction assessment

Sexual Dysfunction (SD) can be assessed by the 14 item sexual function change questionnaire (CSFQ-14). CSFQ-14 gives three scale scores corresponding to the phases of the sexual response cycle (e.g., desire, arousal, and climax). CSFQ-14 has 5 score scales measuring pleasure, desire/frequency, desire/interest, arousal/excitement and climax/completion, respectively. In some embodiments, the CSFQ-14 total score is assessed at baseline, day 15, day 28, and/or day 42 after the start of the test.

In some embodiments, a total CSFQ-14 score of 41 or less for female patients indicates sexual dysfunction.

In some embodiments, a total CSFQ-14 score of less than or equal to 47 for a male patient indicates sexual dysfunction.

In certain embodiments, the total CSFQ-14 score on day 42 is no greater than the total CSFQ-14 score at baseline. In some embodiments, the patient is female and the patient has a total CSFQ-14 score of no more than 41 points 15 days after administration. In some embodiments, the patient is female and the patient has a total CSFQ-14 score of no more than 41 points at 28 days post-administration. In some embodiments, the patient is female and the patient has a total CSFQ-14 score of no more than 41 points at 42 days post-administration. In some embodiments, the patient is female and the patient has a total CSFQ-14 score of no more than 41 days 15, 28 or 42 days after administration. In some embodiments, the patient is male and the patient has a total CSFQ-14 score of no more than 47 points 15 days after administration. In some embodiments, the patient is male and the patient has a total CSFQ-14 score of no more than 47 points at 28 days post-administration. In some embodiments, the patient is male and the patient has a total CSFQ-14 score of no more than 47 points 42 days after administration. In some embodiments, the patient is male and the patient has a total CSFQ-14 score of no more than 47 points 15, 28, or 42 days after administration.

In some embodiments, the methods described herein provide a therapeutic effect measured by an increase in the total score of CSFQ-14. In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score relative to baseline after the onset of administration of compound (1) or compound (2). In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score from baseline of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 following administration of compound (1) or compound (2) in a female patient. In some embodiments, the therapeutic effect is an increase in the CSFQ-14 overall score from baseline of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5, following administration of compound (1) or compound (2) to a male patient.

In some embodiments, the methods described herein provide a therapeutic effect (e.g., as measured by an increase in the total score of CSFQ-14) for about 42 days, about 28 days, or about 15 days. In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score relative to baseline at the end of the treatment period (e.g., about 42 days, about 28 days, or about 15 days after starting administration of compound (1) or compound (2)). In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score from baseline of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 at the end of the treatment period in a female patient (e.g., about 42 days, about 28 days, or about 15 days after starting administration of compound (1) or compound (2)). In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score from baseline of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5 at the end of the treatment period for a male patient (e.g., about 42 days, about 28 days, or about 15 days after starting administration of compound (1) or compound (2)).

In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score relative to baseline following administration of compound (1) or a pharmaceutically acceptable salt of compound (2). In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score from baseline of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 after administration of compound (1) or a pharmaceutically acceptable salt of compound (2) to a female patient. In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score from baseline of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5, following administration of compound (1) or a pharmaceutically acceptable salt of compound (2) in a male patient.

In some embodiments, the therapeutic effect is an increase in the total CSFQ-14 score relative to baseline at the end of the treatment period (e.g., about 42 days, about 28 days, or about 15 days after the beginning of administration of compound (1) or the pharmaceutically acceptable salt of compound (2)). In some embodiments, the therapeutic effect is that the total CSFQ-14 score increases from about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 from baseline at the end of the treatment period in a female patient (e.g., about 42 days, about 28 days, or about 15 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (2)). In some embodiments, the therapeutic effect is that the total CSFQ-14 score increases from about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5, relative to baseline at the end of the treatment period for a male patient (e.g., about 42 days, about 28 days, or about 15 days after the start of administration of compound (1) or a pharmaceutically acceptable salt of compound (2)).

In some embodiments, the methods described herein provide a therapeutic or prophylactic effect measured by a total CSFQ-14 score, wherein a patient treated with compound (1) or compound (2) has the same, similar, or no significant difference in the total CSFQ-14 score as a patient not treated with compound (1) or compound (2). In some embodiments, the methods described herein provide a therapeutic or prophylactic effect measured by a total CSFQ-14 score, wherein patients treated with compound (1) or a pharmaceutically acceptable salt of compound (2) have the same, similar (within about ±10%) or no significant difference (e.g., measured by p-value) total CSFQ-14 score compared to patients not treated with compound (1) or a pharmaceutically acceptable salt of compound (2).

CNS related disorders

In some embodiments, the patient has (or has) a CNS-related disorder. Exemplary CNS-related disorders include, but are not limited to, sleep disorders [ e.g., insomnia ], mood disorders [ e.g., depression (e.g., major Depressive Disorder (MDD) or postpartum depression (PPD)), dysthymic disorders (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized Anxiety Disorder (GAD), social anxiety disorder), stress, post Traumatic Stress Disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)) ] ], schizophrenic lineage disorders [ e.g., schizophrenia, schizoaffective disorder ], convulsive disorders [ e.g., epilepsy (e.g., status Epilepticus (SE)), seizures ], memory and/or cognitive disorders [ e.g., attention disorders (e.g., attention Deficit Hyperactivity Disorder (ADHD)), dementia (e.g., dementia of the Alzheimer's type, dementia of the Liu-SE type (Lewis body type dementia), vascular dementia), movement disorders [ e.g., huntington's disease, parkinson's disease ], personality disorders [ e.g., antisocial personality disorder, compulsive personality disorder ], autism Spectrum Disorders (ASD) [ e.g., autism, monogenic causes of autism, e.g., synaptic disorders, e.g., rett syndrome, fragile X syndrome, angelman syndrome ], pain [ e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain ], traumatic Brain Injury (TBI), vascular diseases [ e.g. stroke, ischemia, vascular malformation ], substance abuse disorders and/or withdrawal syndromes [ e.g. ***e, and/or alcohol in addition to opioids ], and tinnitus.

In certain embodiments, the CNS-related disorder is a sleep disorder, an mood disorder, a schizophrenic lineage disorder, a convulsive disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism lineage disorder, pain, traumatic brain injury, vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is an mood disorder. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is major depressive disorder.

Mood disorders

Mood disorders are, for example, clinical depression, postnatal depression (postnatal depression) or postnatal depression (postpartum depression), perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, tension depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar affective disorder or manic depression, depression caused by chronic medical conditions, treatment of resistant depression, refractory depression, suicidal tendency, suicidal ideation or suicidal behavior.

Clinical depression is also known as Major Depressive Disorder (MDD), major depressive disorder, unipolar depressive disorder, and recurrent depressive disorder, and refers to mental disorders characterized by generalized and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in generally pleasant activities. Some patients with clinical depression have difficulty sleeping and weight loss, and often experience anxiety and irritability. Clinical depression affects one's feel, thinking and behavior and can lead to various emotional and physical problems. People with clinical depression may have difficulty in daily activities, and feel as if life is not excessive.

In certain embodiments, the patient has major depressive disorder. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is major depressive disorder.

Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, sleep difficulties, extreme exhaustion (mood and/or body), appetite changes, difficulty concentrating, increased anxiety and/or anxiety, sense of distraction to the infant and/or fetus, and loss of interest in previously pleasurable activities.

Postnatal depression (postnatal depression, PND), also known as postnatal depression (postpartum depression, PPD), is a clinical depression affecting postnatal women. Symptoms include sadness, fatigue, changes in sleep and eating habits, hyposexuality, crying episodes, anxiety and irritability.

Atypical Depression (AD) is characterized by emotional reactions (such as contradictory lack of pleasure) and aggressiveness, a significant increase in body weight or an increase in appetite. AD patients may also have excessive or somnolence (hypersomnia), a feeling of heavy limbs, and severe social disorders, which are the result of being excessively sensitive to perceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (lack of pleasure) in most or all activities, lack of response to pleasant stimuli, a depressed mood that is more pronounced than sadness or injury, excessive weight loss, or excessive guilt.

Psychotic major depressive disorder (PMD) or psychotic depression refers to major depressive episodes, in particular having a depressed sex, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

Stress depression refers to major depressive disorder including dyskinesia and other symptoms. Individuals may become muted and comatose, or otherwise immobilized, or exhibit an unobtrusive or strange action.

Seasonal Affective Disorder (SAD) refers to a seasonal depression in which an individual has a depressive episode in the autumn or winter season in a seasonal pattern.

Dysthymia refers to symptoms associated with unipolar depression, where the same physical and cognitive problems are also apparent. They are less severe and often last longer (e.g., at least 2 years).

Double depression refers to a fairly depressed mood (dysthymia) that lasts at least 2 years, accompanied by a major depressive phase.

Depressive Personality Disorder (DPD) refers to personality disorders characterized by depression.

Recurrent transient depression (RBD) refers to a condition in which an individual has about one depressive episode per month, each episode lasting 2 weeks or less, typically less than 2-3 days.

Mild depressive disorder or mild depression refers to depression with at least two symptoms lasting for two weeks.

Bipolar disorders or manic-depressive disorders cause extreme mood swings, including elevated mood (mania or hypomania) and depressed mood (depression). During mania, an individual may feel or exhibit abnormal pleasure, vigour or irritability. They often make decisions that are considered for a small number of reasons. The need for sleep is generally reduced. During depression, patients may cry and have insufficient eye communication with others, with a negative attitude to life. Individuals with this disease are at high risk of suicide over 20 years, exceeding 6%, with a incidence of self-injury of 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder.

Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, etc.

Treatment resistant depression refers to the condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or psychological (psychological) counseling (psychotherapy) do not alleviate the symptoms of depression in patients with treatment-resistant depression. In some cases, the symptoms of treatment resistant depression patients are improved, but relapse. Refractory depression occurs in depressed patients who are resistant to standard drug therapies (including tricyclic antidepressants, MAOIs, SSRIs, dual and triple uptake inhibitors and/or anxiolytic drugs) as well as non-drug therapies (such as psychotherapy, electroconvulsive therapy, vagal nerve stimulation and/or transcranial magnetic stimulation).

Post-operative depression refers to the feeling of depression after surgery (e.g., due to having to face one's death). For example, individuals may feel sustained sadness or emotional absence, lose fun or interest in commonly liked hobbies and activities, or continue to feel worthless or desperate.

Mood disorders associated with a woman's health symptom or disorder refer to mood disorders (e.g., depression) associated with (e.g., caused by) a woman's health symptom or disorder.

Suicidal tendency, suicidal ideation, suicidal behavior refers to the individual's suicidal tendency. Suicidal ideation involves the idea of suicide or unusual concerns. The scope of suicidal ideation varies greatly from short ideation to broad ideation, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, obtaining means for suicide, exiting social connections, prejudicing about death, confusing or destinating for a situation, increasingly using alcohol or drugs, doing dangerous or self-destructive things, and the person saying to see as if they were not again visible.

Symptoms of depression include a feeling of persistent anxiety or sadness, helplessness, despair, pessimisty, futile, insensitivity, restlessness, sleep difficulties, insomnia, irritability, fatigue, exercise challenges, loss of interest in pleasant activities or hobbies, inattention, lack of self-esteem, lack of positive ideas or plans, hypersomnia, oversaturation, loss of appetite, insomnia, self-disability, suicidal thoughts, and suicidal attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Symptoms of depression and its relief may be determined by a physician or psychologist (e.g., through a mental state examination).

Depression and its associated behavioral patterns may lead to other disease processes, such as metabolic syndrome, thereby exacerbating female sexual dysfunction. Some adverse effects of women taking antidepressants include sexual desire and arousal problems.

Known depressive scales, such as the hamilton depression scale (HAM-D or HAMD-17), the clinical global impression improvement scale (CGI), and the montgomery-osberg depression scale (MADRS), can be used to identify patients with major depressive disorder.

In some embodiments, the total HAM-D score of the patient prior to treatment with compound (1) or compound (2) is at least 24 points. In some embodiments, the total HAM-D score of the patient prior to treatment with compound (1) or compound (2) is at least 22 points. In some embodiments, the total HAM-D score of the patient prior to treatment with compound (1) or compound (2) is at least 20 points. In some embodiments, the sum of the HAM-D scores of the patient prior to treatment with compound (1) or compound (2) is between 14 and 18 and comprises 14 and 18. In some embodiments, the total MADRS score of the patient prior to treatment with compound (1) or compound (2) is at least 32 points. In some embodiments, the total MADRS score of the patient prior to treatment with compound (1) or compound (2) is at least 28 points.

Another aspect of the invention provides a method of treating a therapy-induced sexual function in a patient currently undergoing or having undergone a course of chemotherapy, comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of compound (1) and compound (2).

In another aspect, the invention provides a method of treating a therapy-induced sexual function in a patient currently undergoing or having undergone a course of chemotherapy, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of compound (1) and compound (2).

In some embodiments, the compound administered is compound (1). In some embodiments, the pharmaceutically acceptable salt administered is a pharmaceutically acceptable salt of compound (1).

In some embodiments, the compound administered is compound (2). In some embodiments, the pharmaceutically acceptable salt administered is a pharmaceutically acceptable salt of compound (2).

"treatment-induced sexual dysfunction" or "treatment-induced sexual dysfunction" refers to sexual dysfunction resulting from receiving a drug for the treatment of CNS-related disorders. Tricyclic antidepressants, monoamine oxidase inhibitors, selective Serotonin Reuptake Inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are all associated with treatment-induced sexual dysfunction.

In some embodiments, the chemopsychotherapy is an antidepressant. In some embodiments, the antidepressant is selected from the group consisting of a Selective Serotonin Reuptake Inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (NERI), a tricyclic, a monoamine oxidase inhibitor, and an atypical antidepressant.

SSRIs drugs include antidepressants that increase the level of serotonin in the brain. Exemplary SSRIs include, but are not limited to, citalopram (celex), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

Exemplary NERIs include, but are not limited to, atomoxetine (Stratera), reboxetine (Edronate, vestra), bupropion (Wellbutrin, zyban), duloxetine, desipramine (Norpramin), amoxylin (UK-3540-1), dardamascin (UK-3557-15), edestin (LY-2216684), oxaplaxetine, clotalamine (LM-1404), nixoxetine (LY-94,939), talopram (Tasultopram) (Lu 3-010), tasulpran (Lu 5-005), tamdamine (AY-23,946), and viloxazine (Vivalan).

Exemplary tricyclic antidepressants include, but are not limited to, amitriptyline (elavidil, endep), amitriptyline (amixid, ambivalon, equilibrin), clomipramine (anafrail), desipramine (Norpramin, pertofrane), dibenzepine (Noveri, victoril), dimethrine (Istonil), dutasterine (Prothiaden), doxepin (Adapin, sinequan), imipramine (Tofranil), rofepamin (Lomot, gamanil), melitracin (Dixeran, melixeran, trausabin), nifedipine (Sintiaml), nortriptyline (Pamelor, aventyl), norcetirizine (Agedeal, elronon, nogedel), opiperidol (Instron), poisine (Azafen/Azafen), vapramine (Vahl) and trimeprazine (Sum).

Exemplary monoamine oxidase inhibitors include, but are not limited to, isocarbozine (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, zelapar, emsam), mei Qu Yinduo (Inkazan), molobelamide (Aurorix, manerix), pirlindol (Pirazidol), toloxadone (Humoryl), and benzphetamine (Alnert, celeport).

Dosage of

In some embodiments, compound (1) or compound (2) is administered at a dose of about 10mg to about 100 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 15mg to about 75 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 20mg to about 60 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, or about 60 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 60 mg.

In some embodiments, compound (1) is administered at a dose of about 10mg to about 100 mg. In some embodiments, compound (1) is administered at a dose of about 15mg to about 75 mg. In some embodiments, compound (1) is administered at a dose of about 20mg to about 60 mg. In some embodiments, compound (1) is administered at a dose of about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, or about 60 mg. In some embodiments, compound (1) is administered at a dose of about 50 mg. In some embodiments, compound (1) is administered at a dose of about 60 mg.

In some embodiments, compound (2) is administered at a dose of about 10mg to about 100 mg. In some embodiments, compound (2) is administered at a dose of about 15mg to about 75 mg. In some embodiments, compound (2) is administered at a dose of about 20mg to about 60 mg. In some embodiments, compound (2) is administered at a dose of about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, or about 60 mg. In some embodiments, compound (2) is administered at a dose of about 50 mg. In some embodiments, compound (2) is administered at a dose of about 60 mg.

In some embodiments, compound (1) is administered at a dose of about 50 mg.

In some embodiments, compound (2) is administered at a dose of about 60 mg.

In some embodiments, compound (1) or compound (2) is administered at a dose of about 10mg to about 100mg once daily. In some embodiments, compound (1) or compound (2) is administered at a dose of about 20mg to about 60mg once daily. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg once daily. In some embodiments, compound (1) or compound (2) is administered at a dose of about 60mg once daily. For example, compound (1) is administered at a dose of about 10mg to about 100mg once daily. In other examples, compound (1) is administered at a dose of about 20mg to about 60mg once daily. In some examples, compound (1) is administered at a dose of about 50mg once daily. Also, in other examples, compound (1) is administered at a dose of about 60mg once daily. In other embodiments, compound (2) is administered at a dose of about 10mg to about 100mg once daily. In other examples, compound (2) is administered at a dose of about 20mg to about 60mg once daily. In some examples, compound (2) is administered at a dose of about 50mg once daily. Also, in other examples, compound (2) is administered at a dose of about 60mg once daily.

In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for less than 2 weeks. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for 1 day. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for 2 days. In some embodiments, compound (1) is administered at a dose of about 50mg once daily for about 14 days. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for about 28 days. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for about 42 days. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for at least 6 months. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for at least 1 year. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50mg or about 60mg once daily for a lifetime.

In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for less than 2 weeks. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for 1 day. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for 2 days. In some embodiments, compound (1) is administered at a dose of about 50mg once daily for about 14 days. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for about 28 days. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for about 42 days. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for at least 6 months. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for at least 1 year. In some embodiments, compound (1) is administered at a dose of about 50mg or about 60mg once daily for a lifetime.

In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for less than 2 weeks. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for 1 day. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for 2 days. In some embodiments, compound (2) is administered at a dose of about 50mg once daily for about 14 days. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for about 28 days. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for about 42 days. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for at least 6 months. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for at least 1 year. In some embodiments, compound (2) is administered at a dose of about 50mg or about 60mg once daily for a lifetime.

In some embodiments, the patient administers compound (1) or compound (2) at night. In some embodiments, compound (1) or compound (2) is administered no later than 1 hour before the patient sleeps. In some embodiments, compound (1) or compound (2) is administered no later than 15 minutes before the patient sleeps. In some embodiments, compound (1) or compound (2) is administered chronically.

In some embodiments, the patient administers compound (1) at night. In some embodiments, compound (1) is administered no later than 1 hour before the patient sleeps. In some embodiments, compound (1) is administered no later than 15 minutes before the patient sleeps. In some embodiments, compound (1) is administered chronically.

In some embodiments, the patient administers compound (2) at night. In some embodiments, compound (2) is administered no later than 1 hour before the patient sleeps. In some embodiments, compound (2) is administered no later than 15 minutes before the patient sleeps. In some embodiments, compound (2) is administered chronically.

In other embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 10mg to about 100mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 15mg to about 75mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 20mg to about 60mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, or about 60mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 50mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 60mg of the free base compound.

In some embodiments, the pharmaceutically acceptable salt of compound (1) is administered in a dose equivalent of about 50mg of the free base compound.

In some embodiments, the pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 60mg of the free base compound.

In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 10mg to about 100mg of the free base compound, once daily. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 20mg to about 60mg of the free base compound, once daily. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered in a dose equivalent of about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, or about 60mg of the free base compound once daily. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered at a dose equivalent of about 50mg of the free base compound once per day. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered at a dose equivalent of about 60mg of the free base compound once per day.

In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for less than 2 weeks. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for 1 day. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for 2 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for about 14 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for about 28 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for about 42 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for at least 6 months. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for at least 1 year. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered in a dose equivalent of about 50mg or about 60mg of the free base compound once daily for a lifetime.

In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered at night. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered no later than 1 hour before the patient sleeps. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (2) is administered no later than 15 minutes before the patient sleeps. In some embodiments, the pharmaceutically acceptable salt of compound (1) or compound (2) is administered chronically.

III pharmaceutical composition

Another aspect of the present disclosure provides a pharmaceutical composition comprising compound (1) or compound (2) (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient for use in treating sexual dysfunction and/or maintaining sexual function in a patient. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of an active ingredient and a pharmaceutically acceptable excipient for treating sexual dysfunction and/or maintaining sexual function in a patient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient or a pharmaceutically acceptable salt of the active ingredient.

The pharmaceutical compositions provided herein may be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In some embodiments, the pharmaceutical composition is administered orally.

The pharmaceutical compositions of the present invention may be further delivered using a variety of methods of administration. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. The location of the bolus dose depends on the desired systemic level of the active ingredient throughout the body, e.g., intramuscular or subcutaneous bolus doses allow slow release of the active ingredient, while direct bolus delivery to the vein (e.g., by IV infusion) allows faster delivery, thereby rapidly increasing the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of steady state concentration of the active ingredient in the subject. Furthermore, in still other embodiments, the pharmaceutical composition may be administered first as a bolus dose, followed by continuous infusion.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More often, however, the composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, and for solid compositions, pills, tablets, capsules or the like. In such compositions, the compound is typically the minor component (about 0.1 to about 50% by weight or more preferably about 1 to about 40% by weight), the remainder being the various vehicles or excipients and processing aids that aid in forming the desired dosage form.

Compositions of the above components for oral administration, injection or topical administration are merely representative. Other materials, as well as processing techniques, etc., are described in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, and are incorporated herein by reference.

The compositions of the present invention may also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

Compound (1) or compound (2) or a pharmaceutically acceptable salt thereof may be administered as the sole active agent, or they may be administered in combination with other active agents. In one aspect, the invention provides a combination of compound (1) or compound (2), or a pharmaceutically acceptable salt thereof, with another pharmacologically active agent. The combined administration may be by any technique apparent to those skilled in the art, including, for example, single, sequential, simultaneous, and alternating administration.

Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to a wide variety of animals. It is well understood that modifications are made to pharmaceutical compositions suitable for administration to humans to a variety of animals, and that ordinarily skilled veterinary pharmacologists can design and/or perform such modifications through routine experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in remington: the Science and Practice of Pharmacy 21st ed., lippincott Williams & Wilkins, 2005.

IV. examples

In order that the application described herein may be more fully understood, the following examples are set forth. The examples described in this disclosure are illustrative of the crystalline solid forms provided herein and should not be construed as limiting the scope thereof in any way.

Example 1 treatment-related sexual dysfunction in patients with major depressive disorder in a phase 3 randomized, double-blind, placebo-controlled MOUNTAIN study of Compound (1)

Introduction to the application

Sexual dysfunction is a common symptom of Major Depressive Disorder (MDD), and usually occurs 1-3 weeks after initiation of treatment. Depending on the type of antidepressant administered, the estimated prevalence varies from 4% to 73% (Jacobsen, et al cns spectra.2020;25 (1) 50-63; and Lorenz T, et al, mayo Clin Proc.2016;91 (9):1280-1286). Dysregulated gamma-aminobutyric acid (GABA) signaling can promote the development of depression by disrupting adaptation signals in critical neural networks, such as those controlling emotion, arousal, behavior and cognition (luccher B, et al, f1000research.2019;8:751;Maguire J.Front Cell Neurosci.2019;13:83;MV, et al front Cell neurosci.2019;13:87; fischer AS, et al biol Psychiatry Cogn Neurosci neuroimaging.2016;1 (3) 262-270; and Brown RE, et al front neurol 2015; 6:135). Binding of neuroactive steroids to GABAA receptors results in an enhancement of synaptic and extrasynaptic GABAA receptor populations and in increased GABAA receptor surface expression. The extra-synaptic GABAA receptor containing the delta subunit is not sensitive to benzodiazepines (Althaus AL, et AL neuropharmacology 2020;181:108333;and Martinez Botella G,et al.J Med Chem.2017;60 (18): 7810-7819).

Compound (1) is a neuroactive steroid and GABA receptor positive allosteric modulator under investigation as an oral, once a day, 2 weeks old therapy for MDD, which is undergoing evaluation (Althaus AL, et AL neuropharmacology.2020;181:108333;Martinez Botella G,et al.J Med Chem.2017;60 (18): 7810-7819;Hoffmann E,et al.Clin Pharmacokinet.2020;59 (1): 111-120;Sage Therapeutics,Inc.Data on file.MLIB-2982;and Clayton,A.H.Presented at SOBP 2020Virtual Meeting).

The results of the multicenter, double blind, randomized, placebo-controlled phase 3 MOUNTAIN test (NCT 03672175) for evaluating the efficacy, safety and tolerability of treatment with 20mg or 30mg of compound (1) for 14 days compared to Placebo (PBO) have been previously provided (Clayton, A.H.present at SOBP 2020 visual Meeting).

This analysis evaluates the effect of treatment with 30mg of compound (1) on sexual function compared to PBO treatment, as measured by sexual function change questionnaire-14 (CSFQ-14) in the MOUNTAIN test.

Method

Adult outpatients (18-65 years; n=581) with MDD (HAMD-17 total score. Gtoreq.22 and MADRS total score. Gtoreq.32) were randomly grouped into 20mg of compound (1) (data not shown), 30mg of compound (1) or PBO at a 1:1:1 ratio, once a night for 2 weeks, followed up to day 42 (study design see FIG. 1). Standard-of-care antidepressants are allowed to be administered at equal doses for > 60 days prior to trial day 1. Exclusion criteria included suicidal paralysis associated with current episodes of depression, treatment resistant depression, bipolar disorder, schizophrenia, and/or history of schizoaffective disorder.

Exploratory, post hoc analysis included the use of 14 self-reported CSFQ-14 to assess sexual function at baseline, days 15, 28 and 42.

On baseline, day 15, day 28 and day 42, the verified 14, patient reported CSFQ-14 scores were used to assess male and female sexual function as exploratory endpoints. CSFQ-14 also has 5 component tables for measuring pleasure, desire/frequency, desire/interest, arousal/excitement and climax/completion, which were also evaluated. Sexual dysfunction is defined for women as CSFQ-14 _TS 41 or less and 47 or less for men. Patients with a baseline HAMD-17 total score of greater than or equal to 24 points (n=323) were analyzed using a repeated measure blend model and a generalized estimation equation.

Results

The analysis included 227 females and 96 males, e.g., a baseline HAMD-17 total score of 24. Mean baseline CSFQ-14 at baseline for Compound (1) 30mg and PBO in female patients _TS 31.7 (n=121) and 33.7 (n=105), respectively, mean baseline CSFQ-14 in male patients _TS 42.1 (n=45) and 40.9 (n=51), respectively. All groups met an effective level of sexual dysfunction at baseline.

No sexual function impairment compared to placebo was observed during the trial and on day 15 (+4.0 [ 0.83) in females ]And +2.7[0.74 ]]) Day 28 (+3.3 [ 0.80)]And +3.1[0.82 ]]) And day 42 (+3.6 [ 0.87)]And +2.9[0.88 ]]) At CSFQ-14 relative to baseline _TS Improved least squares mean (standard error) variation, 30mg of Compound (1) and PBO treatmentThere was no significant difference between patients. In men, on day 15 (+1.3 [1.28 ]) respectively]And +1.7[1.23 ]]) Day 28 (+1.7 [ 1.31)]And +2.0[1.30 ]]) And day 42 (+2.2 [ 1.33)]And +3.5[1.54 ]]) No statistically significant differences were observed between the treatment groups. (see FIG. 2).

For patients treated with Compound (1) 30 mg-and PBO-by CSFQ-14 _TS The percentage of all sexual dysfunction patients evaluated by the threshold was reduced to 66.5% (181/272) on day 42 relative to 82.4% (266/323) at baseline, respectively, with no significant difference in the odds ratio of sexual dysfunction between treatment groups. (see FIG. 3).

As shown in Table 1 below, no significant difference was observed in the odds ratio of sexual dysfunction (e.g., female CSFQ total score. Ltoreq.41 and male. Ltoreq.47 representative dysfunction) between compound (1) 30 mg-and PBO-treated patients.

The model used is a Generalized Estimation Equation (GEE) for a binary response model with interactions of therapeutic factors (compound (1) 30mg or placebo), baseline CSFQ-14 total score, use of antidepressants at baseline (yes or no), evaluation time points, and time point treatment with exchangeable covariance structure.

The odds ratio is an estimate of the likelihood that a subject treated with compound (1) will have CSFQ sexual dysfunction relative to a subject treated with placebo.

TABLE 1 odds ratio of sexual dysfunction

Furthermore, as assessed in the individual CSFQ-14 score scale, there was no significant difference between compound (1) 30mg and PBO for the percentage of patients with sexual dysfunction.

As shown in fig. 4, there was no significant difference between compound (1) 30mg and PBO on the whole individual CSFQ-14 score scale for the percentage of female patients with sexual dysfunction, except for libido/frequency on day 15 and orgasm/completion on day 28.

As shown in fig. 5, there was no significant difference between compound (1) 30mg and PBO, except for arousal/excitation on day 42, for the percentage of male patients with sexual dysfunction on the whole individual CSFQ-14 score scale.

Conclusion(s)

Such pair CSFQ-14 _TS Post hoc analysis of (a) shows that there is no difference in sexual function between female or male patients receiving 30mg or PBO of compound (1) in the MOUNTAIN test. Analysis of individual CSFQ-14 component scores also showed similar trends, with no consistent differences between patients receiving compound (1) 30mg or PBO, regardless of gender.

These data indicate that treatment with 30mg of compound (1) is not associated with the sexual dysfunction (antidepressant-related side effects) that appears to be treated. These general findings support the potential use of further development of compound (1) for MDD treatment, in the form of once daily, 2 week treatment, orally, as required.

Equivalent forms and scope

In the claims, articles such as "a" and "the" may refer to one or more than one unless indicated to the contrary or clear from the context. Unless indicated to the contrary or apparent from the context, claims or descriptions that include "or" between "one or more group members are considered satisfactory if one, more than one, or all group members are present, used, or otherwise associated with a given product or process. The present invention includes embodiments in which exactly one group member is present, used, or otherwise associated with a given product or process. The present invention includes embodiments in which more than one or all of the group members are present, employed, or otherwise associated with a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same underlying claim. Where elements are presented in a list (e.g., in Markush group format), each sub-group of the elements is also disclosed, and any elements may be removed from the group. It should be understood that, in general, certain embodiments of the invention or aspects of the invention consist of or consist essentially of the particular elements and/or features when referred to as comprising those elements and/or features. For simplicity, those embodiments are not explicitly set forth in these words herein. It is further noted that the terms "comprising" and "comprises" are intended to be open-ended and to allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understood by those of ordinary skill in the art, values expressed as ranges in different embodiments of the invention may take any particular value or subrange within the range to one tenth of the unit of the lower limit of the range unless the context clearly indicates otherwise.

The present application is directed to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If a conflict exists between any of the incorporated references and this specification, the present specification will control. In addition, any particular embodiment of the application that falls within the prior art may be expressly excluded from any one or more of the claims. Because these embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not explicitly set forth herein. Any particular embodiment of the application may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Other embodiments

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited by the foregoing description, but rather is set forth in the following claims. It will be understood by those skilled in the art that various changes and modifications may be made to the present description without departing from the spirit or scope of the application as defined in the following claims.

Claims

1. A method of treating sexual dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

2. the method of claim 1, wherein the compound is a compound of the formula:

3. the method of claim 1, wherein the compound is a compound of the formula:

4. a method of treating sexual dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of:

5. the method of claim 4, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

6. the method of claim 4, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

7. the method of any one of claims 1-6, wherein the patient has a CNS-related disorder.

8. The method of claim 7, wherein the CNS-related disorder is selected from the group consisting of sleep disorders, mood disorders, schizophrenic lineage disorders, convulsive disorders, memory and/or cognition disorders, movement disorders, personality disorders, autism lineage disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and/or withdrawal syndrome, tinnitus and status epilepticus.

9. The method of claim 8, wherein the CNS-related disorder is an mood disorder.

10. The method of claim 9, wherein the mood disorder is major depressive disorder.

11. The method of any one of claims 1-3, wherein the compound is administered at a dose of about 20mg to about 60mg once daily.

12. The method of claim 11, wherein the compound is administered at a dose of about 50mg once daily for about 14 days.

13. The method of claim 11, wherein the compound is administered at a dose of about 60mg once daily for about 14 days.

14. The method of any one of claims 4-6, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound once daily.

15. The method of claim 14, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days.

16. The method of claim 14, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

17. The method of any one of claims 1-16, wherein the sexual dysfunction comprises a reduction or loss of one or more of sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement, and orgasm.

18. A method of treating sexual dysfunction in a patient suffering from major depressive disorder, the method comprising administering a therapeutically effective amount of a compound selected from the following formulas:

19. the method of claim 18, wherein the compound is of the formula:

20. the method of claim 18, wherein the compound is of the formula:

21. a method of treating sexual dysfunction in a patient suffering from major depressive disorder, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the following formulas:

22. the method of claim 21, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

23. the method of claim 21, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

24. the method of any one of claims 18-20, wherein the compound is administered at a dose of about 20mg to about 60mg once daily.

25. The method of claim 24, wherein the compound is administered at a dose of about 50mg once daily for about 14 days.

26. The method of claim 24, wherein the compound is administered at a dose of about 60mg once daily for about 14 days.

27. The method of any one of claims 21-23, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound once daily.

28. The method of claim 27, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days.

29. The method of claim 27, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

30. The method of any one of claims 18-29, wherein the sexual dysfunction comprises a reduction or loss of one or more of sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement, and orgasm.

31. A method of maintaining sexual function in a patient suffering from a mood disorder comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

32. the method of claim 31, wherein the compound is of the formula:

33. the method of claim 31, wherein the compound is of the formula:

34. a method of maintaining sexual function in a patient suffering from a mood disorder comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of:

35. The method of claim 34, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

36. the method of claim 34, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

37. the method of any one of claims 31-36, wherein the mood disorder is major depressive disorder.

38. The method of any one of claims 31-33, wherein the compound is administered at a dose of about 20mg to about 60mg once daily.

39. The method of claim 38, wherein the compound is administered at a dose of about 50mg once daily for about 14 days.

40. The method of claim 38, wherein the compound is administered at a dose of about 60mg once daily for about 14 days.

41. The method of any one of claims 34-36, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound once daily.

42. The method of claim 41, wherein the pharmaceutically acceptable salt of the compound of formula (I) is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days.

43. The method of claim 41, wherein the pharmaceutically acceptable salt of the compound of formula (I) is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

44. The method of any one of claims 31-43, wherein the sexual function comprises one or more of sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement and orgasm.

45. A method of treating a treatment-induced sexual dysfunction in a patient currently receiving or having received a course of chemo-psychotherapy comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

46. the method of claim 45, wherein the compound is of the formula:

47. the method of claim 45, wherein the compound is of the formula:

48. a method of treating a treatment-induced sexual dysfunction in a patient currently receiving or having received a course of chemo-psychotherapy comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound selected from the group consisting of:

49. the method of claim 48, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

50. The method of claim 48, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound of the formula:

51. the method of any one of claims 45-50, wherein the chemopsychotherapy is an antidepressant.

52. The method of claim 51, wherein the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a tricyclic, a monoamine oxidase inhibitor, and an atypical antidepressant.

53. The method of any one of claims 45-52, wherein the patient has a CNS-related disorder.

54. The method of claim 53, wherein the CNS-related disorder is selected from the group consisting of sleep disorders, mood disorders, schizophrenic lineage disorders, convulsive disorders, memory and/or cognition disorders, movement disorders, personality disorders, autism lineage disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and/or withdrawal syndrome, tinnitus and status epilepticus.

55. The method of claim 54, wherein the CNS-related disorder is an mood disorder.

56. The method of claim 55, wherein the mood disorder is major depressive disorder.

57. The method of any one of claims 45-47, wherein the compound is administered at a dose of about 20mg to about 60mg once daily.

58. The method of claim 57, wherein the compound is administered at a dose of about 50mg once daily for about 14 days.

59. The method of claim 57, wherein the compound is administered at a dose of about 60mg once daily for about 14 days.

60. The method of any one of claims 48-50, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 20mg to about 60mg of the free base compound once daily.

61. The method of claim 60, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 50mg of the free base compound once daily for about 14 days.

62. The method of claim 60, wherein the pharmaceutically acceptable salt of the compound is administered in a dose equivalent of about 60mg of the free base compound once daily for about 14 days.

63. The method of any one of claims 41-62, wherein the sexual dysfunction comprises a reduction or loss of one or more of sexual pleasure, libido, sexual frequency, sexual interest, sexual arousal, sexual excitement, and orgasm.