Compound for treating female sexual dysfunction

Abstract

The present disclosure relates to treating female sexual dysfunction with chromen-2-one compounds.

Description

Technical Field

[0001] The present disclosure relates to treating female sexual dysfunction using small molecule drugs.

Background Art

[0002] Female sexual dysfunction (FSD) is a common problem that affects approximately 40% of women and has few treatment options (Allahdadi et al. 2009). FSD becomes more typical and progressive and widespread as women age. Common symptoms associated with FSD include reduced vaginal lubrication, pain and discomfort during sexual intercourse, decreased sexual excitement, and difficulty achieving orgasm. Only a small percentage of women seek medical advice. There has been significantly less research on FSD compared to the active research and treatment of erectile dysfunction in men, specifically the research and treatment through the development of phosphodiesterase type 5 inhibitors. Its treatment is mainly limited to psychotherapy. Although various pharmacological modalities have been developed, their effectiveness is low and adverse effects are also seen (Miller et al., 2018).

Summary of the Invention

[0003] As outlined above, compounds that can treat FSD are highly desired. The present disclosure provides compounds and compositions useful for treating female sexual dysfunction.

[0004] The inventors have surprisingly found that compounds of formula (I) as described herein can improve parameters associated with improved sexual function and sexual behavior related to FSD in female animal models. In the examples of the present invention, it has unexpectedly been shown that compounds of formula (I) induce an increase in blood flow to the clitoris and an increase in clitoral temperature, thereby inducing an increase in genital temperature, similar to the stimulatory effect on the clitoral nerve. In addition, the inventors have shown that compounds of formula (I) induce an increase in mating - assisting behavior, i.e., "courtship," in female rats.

[0005] That is, the present invention shows that the compound of formula (I) can address both the physical and behavioral aspects of FSD and can change to a state where it is effective in sexual interest, sexual arousal, sexual desire, and dyspareunia associated with FSD.

[0006] Thus, in one main aspect, a compound of the following formula (I) for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject

Chemical formula

[0007] One aspect is a compound of the following formula (I) for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject

Chemical formula

[0008] One aspect is the use of a compound of the following formula (I) in the manufacture of a medicament for treating female sexual dysfunction

Chemical formula

[0009] In another aspect, there is provided a method for treating, preventing, or alleviating female sexual dysfunction, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0010] In yet another aspect, there is provided a method for increasing genital temperature in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, provided is a method for increasing blood flow to the genitalia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present disclosure provides a method for increasing sexual desire, sexual interest, sexual arousal, lubrication, sexual satisfaction, or combinations thereof in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present disclosure provides a method for reducing difficulty in reaching sexual stimulation or orgasm during sexual intercourse in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a last aspect, the present disclosure provides a method for reducing dyspareunia in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0014]

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[0015] Definitions As used herein, the terms "female sexual dysfunction" or "FSD" generally refer to disorders of sexual function in women. Female sexual dysfunction includes inhibition of orgasm. Female sexual dysfunctions include, but are not limited to, disorders / dysfunctions of decreased sexual desire in women (FHSDD or HSDD, used interchangeably herein), disorders / dysfunctions of female orgasm (FOD), frigidity, disorders / dysfunctions of female sexual interest / arousal (FSIAD), disorders / dysfunctions of female sexual arousal (FSAD), disorders / dysfunctions of dyspareunia, and dyspareunia pain syndrome, and a number of categories of diseases, conditions, and disorders.

[0016] As used herein, the term "female sexual function index", or "FSFI", generally refers to a 19 - item patient - reported outcome (PRO) document / questionnaire that measures overall sexual function (Rosen R, Brown C, et al., 2000) and is used in clinical trials to grade the severity of FSD, and measures specific elements of sexual function using questions in the following individual domains of the FSFI. A) Domain of sexual desire (FSFI-D): (FSFI-, Questions 1-2 (frequency, level)) B) Domain of sexual excitement: Questions 3-6 (level, confidence, satisfaction) C) Domain of lubrication: Questions 7-10 (frequency, difficulty, maintenance frequency, maintenance difficulty) D) Domain of orgasm: Questions 11-13 (frequency, difficulty, satisfaction) E) Domain of satisfaction: Questions 14-16 (intimacy with partner, sexual relationship, satisfaction with overall sex life) F) Domain of pain: Questions 17-19 (frequency during vaginal insertion, frequency after vaginal insertion, level during or after vaginal insertion)

[0017] Responses are evaluated on a 5-point scale (1-5 points), with higher numbers indicating a higher level of the specific element of sexual function and lower numbers indicating a lower level of the specific element of sexual function. That is, lower numbers indicate a more severe level of sexual dysfunction. The overall sexual function can be measured using the scoring and interpretation of all stages and / or domain levels of FSFI, and the severity of FSD can be graded.

[0018] As used herein, the term "Female Sexual Distress Scale-Desire / Arousal / Orgasm", or "FSDS-DAO", generally refers to a 15-item patient-reported outcome (PRO) document / questionnaire that measures overall sexual function and is used in clinical trials to grade the severity of female hypoactive sexual desire disorder (FHSDD) (Derogatis et al. 2008, Derogatis et al. 2021). Its total score can be calculated as the sum of the responses and ranges from 0 to 60, with higher scores indicating higher levels of distress. FSDS-DAO is a modification from the validated Female Sexual Distress Scale (FSDS-R) questionnaire. Question 13 of FSDS-DAO (FSDS-DAO Q13) asks the patient "How often did you feel bothered by low sexual desire?" The responses can be graded on a scale of 0 (never) to 4 (always). A decrease in the FSDS-DAO Q13 score over time indicates an improvement in the level of distress associated with low sexual desire. Question 13 (Q13) of the FSDS-DAO questionnaire is the same as question 13 of the FSDS-R questionnaire.

Mode for Carrying Out the Invention

[0019] Compounds and Compositions One embodiment of the present disclosure provides a compound of formula (I) below

Chemical Formula

[0020] In one embodiment, the compound of formula (I) is of the following formula (Ia) [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the compound is 7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, the name "IP2015" means a compound of formula I. In one embodiment, the name "IP2015" means a compound of formula Ia. In a specific embodiment of the present disclosure, "IP2015" means the hydrochloride salt of the compound of formula I.

[0022] In one embodiment, the pharmaceutically acceptable salt is a salt of an organic or inorganic counterion. In one embodiment, the pharmaceutically acceptable salt is selected from the list consisting of hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, nitrate, formate, acetate, aconitate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate. Other pharmaceutically acceptable salts are known to those skilled in the art. Such salts can be formed by well-known procedures and may be described in the art.

[0023] In one embodiment of the present disclosure, the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one hydrochloride.

[0024] The compounds of the present disclosure are monoamine reuptake inhibitors. The compounds can be tested for their ability to inhibit the reuptake of the monoamines dopamine, norepinephrine, and serotonin, for example, in synaptosomes as described in WO97 / 30997 or WO97 / 16451. The hydrochloride salts of the compounds of formula (I) have IC 50 values reported to be 0.0029 μM (serotonin), 0.07 μM (dopamine), 0.0038 μM (norepinephrine) (US9,133,184B1).

[0025] One embodiment of the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) below

Chemical formula

[0026] In one embodiment, the composition is a pharmaceutical composition. In one embodiment of the present disclosure, the composition is formulated for oral administration, rectal administration, bronchial administration, nasal administration, pulmonary administration, topical administration (including buccal and sublingual administration), transdermal administration, vaginal administration, or parenteral administration (including injection or infusion into the skin, mucosa, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, or intraocular), or for administration by inhalation or ventilation (including administration as a powder or liquid aerosol or by a sustained release system).

[0027] Female sexual dysfunction The compounds of the present disclosure have shown potential in the treatment of female sexual dysfunction (FSD).

[0028] Accordingly, one embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of female sexual dysfunction.

[0029] Female sexual dysfunction can be due to, for example, physiological or psychological causes.

[0030] In one embodiment, female sexual dysfunction is (i) female sexual interest / arousal disorder (FSIAD), (ii) hypoactive sexual desire disorder, (iii) female sexual arousal disorder, (iv) orgasm disorder, (v) dyspareunia disorder and (vi) coital pain disorder, selected from the group consisting of.

[0031] As shown in the examples, administration of the compound of formula (I) increases clitoral blood flow, similar to clitoral nerve stimulation. In addition, the compound of formula (I) can increase clitoral temperature or vaginal temperature. These effects are also indicators of normal sexual arousal, and when blood flow to the clitoral corpus cavernosum and labia increases, an increase in clitoral corpus cavernosum pressure, engorgement, protrusion of the glans clitoris, and eversion and swelling of the labia minora are observed (Bergman., 2005). Accordingly, the increased genital blood flow and temperature increase as shown in the examples are related to increased vaginal lubrication, increased sexual arousal, sexual satisfaction, and orgasm.

[0032] Subjects suffering from female sexual arousal disorder (female sexual interest disorder, sexual arousal disorder) show little or no interest in sexual intercourse and do not subjectively or physically respond to sexual stimuli. The decrease in interest and the ability to become sexually aroused is more than expected based on the subject's age and relationship duration. The lack of sexual interest and the ability to become sexually aroused is considered a disorder when it causes distress to the subject and when there is a lack of interest throughout the sexual experience. In one embodiment, FSD is as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) Fourth Edition, the content of which is incorporated herein by reference. In one embodiment of the present disclosure, FSD is female sexual interest / arousal disorder (FSIAD), and FSD includes FSAD and FHSDD. FOD and FSIAD are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) Fifth Edition, the content of which is incorporated herein by reference.

[0033] The diagnostic criteria for FSIAD include a lack or significant decrease in sexual interest / arousal, which is recognized by at least three of the following: (1) lack / decrease in interest in sexual activity, (2) lack / decrease in sexual / sensual thoughts or fantasies, (3) lack / decrease in initiation of sexual activity, and typically, inability to accept attempts by a partner to initiate, (4) lack / decrease in sexual arousal / sexual pleasure during sexual activity in almost all or all sexual experiences, (5) lack / decrease in sexual interest / sexual arousal in response to either internal or external sexual / sensual signals, and (6) lack / decrease in genital or extra-genital sensations during sexual activity in almost all or all sexual experiences. In FSIAD, these symptoms persist for at least approximately six months and cause significant distress to the subject.

[0034] As shown in the examples, the compound of formula (I) increases copulatory or courtship behavior in female rats as seen by an increase in jumping and sudden movement in female rats. Thus, it is demonstrated that the compounds of the present invention can increase sexual interest or desire and enable sexual activity.

[0035] Female hypoactive sexual desire disorder (FHSDD) is characterized by the absence or marked decrease in the desire or incentive to engage in sexual activity, and this absence or decrease is recognized by one of the following: 1) a decrease or absence of spontaneous desire (sexual thoughts or fantasies), 2) a decrease or absence of responsive desire to sensory signals and stimuli, or 3) an inability to sustain desire or interest in sexual activity once sexual activity has been initiated. The pattern of decrease or absence of spontaneous or responsive desire, or the inability to sustain desire or interest in sexual activity, occurs either temporarily or persistently over a period of at least several months and is accompanied by clinically significant distress. In one embodiment of the present disclosure, FSD is hypoactive sexual desire disorder.

[0036] Disorders / deficiencies of low sexual desire include disorders in which sexual fantasies and desires for sexual activity are persistently or repeatedly decreased or absent, causing significant distress or difficulties in interpersonal relationships. Sexual frigidity includes a decrease or absence of pleasure in sexual activity. Disorders / deficiencies of sexual excitement may be caused by a decrease in estrogen, disease, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents.

[0037] In one embodiment, the hypoactive sexual desire disorder is a congenital hypoactive sexual desire disorder or an acquired hypoactive sexual desire disorder. In one embodiment of the present disclosure, the hypoactive sexual desire disorder is a general hypoactive sexual desire disorder or a situational hypoactive sexual desire disorder. Congenital general hypoactive sexual desire disorder is characterized by a subject who has always experienced hypoactive sexual desire disorder since the start of related sexual behavior, and currently, in any environment, including masturbation, the desired response is lacking or decreased. Congenital situational hypoactive sexual desire disorder is characterized by a subject who has always experienced hypoactive sexual desire disorder since the start of related sexual behavior, and currently, depending on the environment, the desired response is lacking or decreased by a partner or in response to some stimuli, but not lacking or decreased in other situations. General acquired hypoactive sexual desire disorder is characterized by the onset of hypoactive sexual desire disorder after a period when the person did not experience hypoactive sexual desire disorder, and currently, in any environment, including masturbation, the desired response is lacking or decreased. Situational acquired hypoactive sexual desire disorder is characterized by the onset of hypoactive sexual desire disorder after a period when the person did not experience hypoactive sexual desire disorder, and currently, depending on the environment, the desired response is lacking or decreased by a partner or in response to some stimuli, but not lacking or decreased in other situations. In one embodiment, the hypoactive sexual desire disorder is an unspecified hypoactive sexual desire disorder. In one embodiment, the hypoactive sexual desire disorder is a congenital general hypoactive sexual desire disorder. In one embodiment, the hypoactive sexual desire disorder is a congenital situational hypoactive sexual desire disorder. In one embodiment, the hypoactive sexual desire disorder is an acquired general hypoactive sexual desire disorder. In one embodiment, the hypoactive sexual desire disorder is an acquired situational hypoactive sexual desire disorder.

[0038] In one embodiment of the present disclosure, the hypoactive sexual desire disorder is (i) a decrease or lack of spontaneous desire, (ii) a decrease or lack of responsive desire to sensory signals and stimuli, and / or (iii) a state in which desire or interest in sexual behavior cannot be sustained when sexual behavior is initiated, characterized by.

[0039] In one embodiment of the present disclosure, a state in which desire or interest in sexual activity cannot be sustained occurs temporarily or persistently over a period of at least several months, for example, 3 months, 4 months, 5 months, 6 months, 7 months or 8 months, and / or is accompanied by clinically significant distress.

[0040] Sexual arousal disorder includes having difficulty with the physical or subjective aspects of sexual arousal. In one embodiment of the present disclosure, the FSD is female sexual arousal disorder (female sexual arousal disorder, i.e., FSAD). In one embodiment of the present disclosure, the FSD is female sexual interest / sexual arousal disorder / deficiency (FSIAD).

[0041] Female sexual arousal disorder (FSAD) is characterized by the absence or marked decrease in response to sexual stimuli in women, and this absence or decrease is 1) the absence or marked decrease in genital response, including vulvovaginal lubrication, genital congestion, and genital sensitivity, 2) the absence or marked decrease in responses other than genital responses, such as nipple erection, skin flushing, increased heart rate, increased blood pressure, and increased respiratory rate, 3) the absence or marked decrease in the feelings of sexual arousal (sexual arousal state and sexual pleasure) from any type of sexual stimuli. The absence or marked decrease in response to sexual stimuli, which occurs despite the desire for sexual activity and sufficient sexual stimuli, occurs temporarily or persistently over a period of at least several months and is accompanied by clinically significant distress.

[0042] In one embodiment, female sexual arousal disorder (FSAD) is either congenital female sexual arousal disorder or acquired female sexual arousal disorder. In one embodiment, the female sexual arousal disorder is generalized female sexual arousal disorder or situational female sexual arousal disorder. In one embodiment of the present disclosure, the female sexual arousal disorder is unspecified female sexual arousal disorder. Congenital generalized female sexual arousal disorder is characterized by an individual who has always experienced female sexual arousal disorder since the onset of related sexual activity, and currently lacks or has a diminished desired response, including masturbation, in any environment. Congenital acquired female sexual arousal disorder is characterized by an individual who has always experienced female sexual arousal disorder since the onset of related sexual activity, and currently lacks or has a diminished desired response depending on the environment, by a partner, or in response to some stimuli, but not in other situations. Acquired generalized female sexual arousal disorder is characterized by the onset of the sexual arousal disorder after a period during which the individual did not experience female sexual arousal disorder, and currently lacks or has a diminished desired response, including masturbation, in any environment. Acquired situational female sexual arousal disorder is characterized by the onset of the sexual arousal disorder after a period during which the individual did not experience female sexual arousal disorder, and currently lacks or has a diminished desired response, including masturbation, in any environment. In one embodiment, the female sexual arousal disorder is unspecified female sexual arousal disorder. In one embodiment, the female sexual arousal disorder is congenital generalized female sexual arousal disorder. In an embodiment, the female sexual arousal disorder is congenital situational female sexual arousal disorder. In one embodiment, the female sexual arousal disorder is acquired generalized female sexual arousal disorder. In one embodiment, the female sexual arousal disorder is acquired situational female sexual arousal disorder.

[0043] In one embodiment, the female sexual arousal disorder (FSAD) is (i) lack or marked decrease in genital response, including vaginal lubrication, engorgement of the genitals, and genital sensitivity, (ii) Absence or marked decrease in responses other than genitalia, such as nipple erection, skin flushing, increased heart rate, increased blood pressure, and increased respiratory rate, and / or (iii) Absence or marked decrease in feelings of sexual excitement from any type of sexual stimulation, such as sexual excitement state and sexual pleasure, characterized by.

[0044] In one embodiment, the absence or decrease in response to sexual stimulation, which occurs despite the desire for sexual activity and sufficient sexual stimulation, occurs temporarily or persistently over a period of at least several months, such as 3 months, 4 months, 5 months, 6 months, 7 months or 8 months, and / or is accompanied by clinically significant distress.

[0045] Anorgasmia or female orgasmic disorder / deficiency (FOD) refers to difficulty with the subjective experience of orgasm. In one embodiment of the present disclosure, the FSD is anorgasmia. In one embodiment, the anorgasmia is not female immature orgasm.

[0046] In one embodiment, the anorgasmia is anorgasm. Anorgasm is characterized by the absence or markedly low frequency of orgasm experience, or a marked decrease in the intensity of orgasmic sensation. In women, anorgasm includes a marked delay in orgasm, and if male, would be diagnosed as male retarded ejaculation. The pattern of absence, delay or decrease in frequency or intensity of orgasm, which occurs despite sufficient sexual stimulation (including sexual activity and desire for orgasm), occurs temporarily or persistently over a period of at least several months and is accompanied by clinically significant distress.

[0047] In one embodiment, the anorgasmia is congenital anorgasmia or acquired anorgasmia. In one embodiment, the anorgasmia is global anorgasmia or situational anorgasmia. In one embodiment, the anorgasmia is unspecified anorgasmia. Congenital global anorgasmia is characterized by a subject who has always experienced anorgasmia since the start of related sexual behavior, and currently, in any environment, including masturbation, the desired response is absent or reduced. Congenital situational anorgasmia is characterized by a subject who has always experienced anorgasmia since the start of related sexual behavior, and currently, depending on the environment, the desired response is absent or reduced by the partner or in response to some stimuli, but not absent or reduced in other situations. Acquired global anorgasmia is characterized by the onset of the anorgasmia after a period when the person did not experience the anorgasmia, and currently, in any environment, including masturbation, the desired response is absent or reduced. Acquired situational anorgasmia is characterized by the onset of the anorgasmia after a period when the person did not experience the anorgasmia, and currently, depending on the environment, the desired response is absent or reduced by the partner or in response to some stimuli, but not absent or reduced in other situations. In one embodiment, the anorgasmia is congenital global anorgasmia. In one embodiment, the anorgasmia is congenital situational anorgasmia. In one embodiment, the anorgasmia is acquired global anorgasmia. In one embodiment, the anorgasmia is acquired situational anorgasmia.

[0048] In one embodiment, the anorgasmia is characterized by the absence or significantly low frequency of orgasm experience, and / or a significant decrease in the intensity of the orgasmic sensation.

[0049] In one embodiment, an absence of orgasm experience or a significantly low frequency and / or a significant decrease in the intensity of orgasmic sensation, which occurs despite sufficient sexual stimulation (including sexual behavior and desire for orgasm), and / or the decrease occurs temporarily or persistently over a period of at least several months, such as 3 months, 4 months, 5 months, 6 months, 7 months or 8 months, and / or is accompanied by clinically significant distress.

[0050] In one embodiment, the FSD is dyspareunia disorder. Dyspareunia disorder refers to a significant and persistent or recurrent problem associated with the experience of pain during sexual activity in adults that is not entirely due to underlying medical conditions, insufficient lubrication in women, age-related changes, or changes associated with menopause in women, and is accompanied by clinically significant distress.

[0051] In one embodiment, the dyspareunia disorder is dyspareunia - insertion disorder. Dyspareunia - insertion disorder is characterized by at least one of: 1) significant and persistent or recurrent difficulty in insertion, including cases due to involuntary tensing or rigidity of the pelvic floor muscles during insertion attempts; 2) significant and persistent or recurrent vulvovaginal pain or pelvic pain during insertion; 3) significant and persistent or recurrent fear or anxiety regarding vulvovaginal pain or pelvic pain in anticipation of, during, or as a result of insertion. The symptoms recur during sexual interactions involving or potentially involving insertion despite sufficient sexual desire and sexual stimulation, affect the pelvic region, and are not entirely due to a medical condition leading to genital pain and / or insertion pain, or a mental disorder, nor are they entirely due to insufficient vaginal lubrication or post - menopausal / age - related changes, and are accompanied by clinically significant distress.

[0052] In one embodiment, the dyspareunia and insertion disorder is a congenital dyspareunia and insertion disorder or an acquired dyspareunia and insertion disorder. In one embodiment, the dyspareunia and insertion disorder is a generalized dyspareunia and insertion disorder or a situational dyspareunia and insertion disorder. In one embodiment, the dyspareunia and insertion disorder is an unspecified dyspareunia and insertion disorder. Congenital generalized dyspareunia and insertion disorder is characterized by a subject who has always experienced genital pain, pelvic pain or insertion disorder since the start of related sexual behavior, and currently, in any environment, including masturbation, the desired response is lacking or decreased. Congenital situational dyspareunia and insertion disorder is characterized by a subject who has always experienced genital pain, pelvic pain or insertion disorder since the start of related sexual behavior, and currently, depending on the environment, the desired response is lacking or decreased by the partner or in response to some stimuli, but not lacking or decreased in other situations. Acquired generalized dyspareunia and insertion disorder is characterized by the onset of genital pain, pelvic pain or insertion disorder after a period when the person did not experience genital pain, pelvic pain or insertion disorder, and currently, in any environment, including masturbation, the desired response is lacking or decreased. Acquired situational dyspareunia and insertion disorder is characterized by the onset of genital pain, pelvic pain or insertion disorder after a period when the person did not experience genital pain, pelvic pain or insertion disorder, and currently, depending on the environment, the desired response is lacking or decreased by the partner or in response to some stimuli, but not lacking or decreased in other situations. In one embodiment, the dyspareunia and insertion disorder is a congenital generalized dyspareunia and insertion disorder. In one embodiment, the dyspareunia and insertion disorder is a congenital situational dyspareunia and insertion disorder. In one embodiment, the dyspareunia and insertion disorder is an acquired generalized dyspareunia and insertion disorder. In one embodiment, the dyspareunia and insertion disorder is an acquired situational dyspareunia and insertion disorder.

[0053] In one embodiment, the dyspareunia and insertion disorder is (i) including cases due to involuntary sclerosis or rigidity of the pelvic floor muscles during insertion attempts, significant and persistent or recurrent insertion difficulties, (ii) significant and persistent or recurrent vulvovaginal pain or pelvic pain during insertion, and / or (iii) Anticipation of, during, or as a result of insertion, marked and persistent or recurrent fear or anxiety regarding vulvovaginal pain or pelvic pain, characterized by.

[0054] In one embodiment, the dyspareunia and insertion disorder include (i) Symptoms that are recurrent during sexual interaction involving or potentially involving insertion, despite sufficient sexual desire and sexual stimulation, (ii) Conditions that affect the pelvic region and lead to genital pain and / or insertion pain, or symptoms not entirely due to mental disorders, (iii) Symptoms not entirely due to insufficient vaginal lubrication or changes associated with postmenopausal changes / aging, and (iv) Symptoms accompanied by clinically significant pain. There are.

[0055] Dyspareunia is a genital system symptom that affects women and is caused by physical determinants. This symptom is recurrent genital pain or discomfort that occurs before, during, or after sexual intercourse, or shallow or deep vaginal insertion, and is characterized by genital pain or discomfort related to identifiable physical causes (excluding lack of lubricity). Confirmation is by medical evaluation of physical causes. In one embodiment, the FSD is dyspareunia. In one embodiment, the FSD presents with dyspareunia.

[0056] In one embodiment, the dyspareunia disorder is vulvodynia or progressive vulvodynia. Vulvodynia is persistent unexplained pain in the vulva, which is the female genital area and includes the skin surrounding the vaginal opening.

[0057] In one embodiment, the female sexual dysfunction is (i) Associated with a condition, injury, or the effects of surgery or radiation therapy, (ii) Associated with psychological or behavioral factors (including mental disorders), (iii) Associated with the use of psychoactive substances or psychotropic drugs, (iv) associated with lack of knowledge or experience, (v) associated with relevant factors, (vi) associated with cultural factors, and / or (vii) other predetermined etiological reasons.

[0058] In one embodiment, the female sexual dysfunction is female hypoactive sexual desire disorder.

[0059] In one embodiment, the female sexual dysfunction is not caused by another disease, such as a mental disorder. In one embodiment, the female sexual dysfunction is not caused by genital injury. In one embodiment of the present disclosure, the subject is not under treatment with a drug known to be a cause of female sexual dysfunction.

[0060] In one embodiment of the present disclosure, the female sexual disorder is not female sexual hypoactive disorder, such as female immature orgasm.

[0061] Patient group In one embodiment of the present disclosure, the compound can increase the number of satisfactory sexual events (SSE) in a subject. SSE has been used as an outcome measure in clinical trials of female sexual dysfunction; see Kingsberg et al. 2011. SSE can be evaluated as outlined in Derogatis et al. 2021 or Clayton et al. 2016.

[0062] In one embodiment of the present disclosure, the subject is female. In one embodiment, the subject is a mammal. In one embodiment of the present disclosure, the subject is human.

[0063] In one embodiment of the present disclosure, the subject is postmenopausal.

[0064] In one embodiment of the present disclosure, the subject is over 18 years old, for example over 20 years old, over 25 years old, for example over 30 years old, for example over 35 years old, for example over 40 years old, for example over 45 years old, for example over 50 years old, for example over 55 years old, for example over 60 years old, for example over 65 years old, for example over 70 years old, for example over 75 years old.

[0065] In one embodiment, the subject is under 40 years old, for example under 35 years old, for example under 30 years old, for example under 25 years old, for example under 20 years old.

[0066] In one embodiment, the subject is 20 - 25 years old, 25 - 30 years old, 30 - 35 years old, 35 - 40 years old, 40 - 45 years old, 45 - 50 years old, 50 - 55 years old, 55 - 60 years old, 60 - 65 years old, 65 - 70 years old or 70 - 75 years old or older.

[0067] Pharmaceutical use One embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of female sexual dysfunction. One embodiment of the present disclosure provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, excipient or diluent, the composition for use in the treatment of female sexual dysfunction.

[0068] One embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment, prevention or alleviation of female sexual dysfunction. One embodiment of the present disclosure provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, excipient or diluent, the composition for use in the treatment, prevention or alleviation of female sexual dysfunction.

[0069] One embodiment of the present disclosure provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating female sexual dysfunction. One embodiment of the present disclosure provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing or alleviating female sexual dysfunction.

[0070] One embodiment of the present disclosure is a method for treating, preventing or alleviating female sexual dysfunction in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0071] The Female Sexual Function Index (FSFI) can be used to evaluate the overall and specific aspects of FSD. The FSFI is a 19-item self-report inventory designed to evaluate female sexual function. The FSFI includes six domains: desire (2 items), sexual arousal (4 items), lubrication (4 items), orgasm (3 items), satisfaction (3 items), and pain (3 items). In one embodiment, the subject before treatment had a Female Sexual Function Index (FSFI) of less than 26.55, such as 25.00 - 26.55, such as 20.00 - 25.00, such as 15.00 - 20.00, such as 10.00 - 15.00, such as 5.00 - 10.00, such as 2.00 - 5.00.

[0072] In one embodiment, the compound of the present disclosure can increase the FSFI in the subject. In one embodiment, the compound can increase the FSFI by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points or at least 26 points.

[0073] In one embodiment, the compound of the present disclosure can increase the FSFI to above 26.55.

[0074] The compounds of the present disclosure may affect, for example, favorably, any one or more of the six domains of the FSFI (desire, sexual excitement, lubrication, orgasm, satisfaction, and pain), that is, it may be possible to increase the FSFI in any one or more of the six domains (desire, sexual excitement, lubrication, orgasm, satisfaction, and pain), or in any one question of each domain. In one embodiment, the compounds of the present disclosure can increase the score of any one question of the FSFI questionnaire by 1 point, 2 points, 3 points, or 4 points

[0075] The compounds of the present disclosure may be particularly efficient in improving the FSFI score in the pain domain. This is because the compounds of the present disclosure are monoamine neurotransmitter reuptake inhibitors. The questionnaire includes three questions regarding pain, with a minimum score of 0 points and a maximum score of 6.0 points. In some embodiments, the questions are graded, with a minimum score of 1 point and a maximum score of 5 points. In one embodiment, the compounds of the present disclosure can increase the FSFI score of the subject in the pain domain. In one embodiment, the compounds of the present disclosure can increase the FSFI score in the pain domain by at least 0.3 points, at least 0.7 points, at least 1.0 points, at least 1.3 points, at least 1.7 points, at least 2.0 points, at least 2.3 points, at least 2.7 points, at least 3.0 points, at least 3.3 points, at least 3.7 points, at least 4.0 points, at least 4.3 points, at least 4.7 points, at least 5.0 points, at least 5.3 points, at least 5.7 points or 6.0 points. In one embodiment, the compounds of the present disclosure can increase the score of question 17 of FSFI (the first question about pain), for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points. In one embodiment, the compounds of the present disclosure can increase the score of question 18 of FSFI (the second question about pain), for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points. In one embodiment, the compounds of the present disclosure can increase the score of question 19 of FSFI (the third question about pain), for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points. The compounds of the present disclosure can also have an effect, for example, a beneficial effect, on any one or more of the other five domains (desire, sexual arousal, lubrication, orgasm and satisfaction), that is, the FSFI can be increased in any one or more of the other five domains (desire, sexual arousal, lubrication, orgasm and satisfaction).

[0076] The compounds of the present disclosure may be particularly efficient in improving the FSFI score in the desire domain (FSFI-D). The questionnaire includes two questions regarding sexual desire, each with a minimum score of 1 point and a maximum score of 5 points. In one embodiment, the compounds of the present disclosure can increase the FSFI score of the subject in the desire domain. In one embodiment, the compounds of the present disclosure can increase the FSFI score in the desire domain by at least 0.3 point, at least 0.7 point, at least 1.0 point, at least 1.3 point, at least 1.7 point, at least 2.0 point, at least 2.3 point, at least 2.7 point, at least 3.0 point, at least 3.3 point, at least 3.7 point, at least 4.0 point, at least 4.3 point, at least 4.7 point, at least 5.0 point. In one embodiment, the compounds of the present disclosure can increase the score of question 1 of FSFI (the first question of desire), for example, the score can be increased by 1 point, 2 points, 3 points or 4 points. In one embodiment, the compounds of the present disclosure can increase the score of question 2 of FSFI (the second question of desire), for example, the score can be increased by 1 point, 2 points, 3 points or 4 points. The FSFI-D domain can be evaluated by multiplying the score of each question in the desire domain by 0.6 and summing them up, and the range of the FSFI-D domain score is 1.2 - 6.0. Therefore, in one embodiment, the compounds of the present disclosure can increase the score of the FSFI-D domain in the subject by 0.6 point, for example, 1.2 points, 1.8 points, 2.4 points, 3.0 points, 3.6 points, 4.2 points or 4.8 points. In one embodiment, the compound can increase the score of the FSFI-D domain in the subject by 1.2 points, 2.4 points, 3.6 points or 4.8 points.

[0077] In one embodiment, the compounds of the present disclosure can increase the FSFI score in the sexual arousal domain or increase the score of any one of the questions in the sexual arousal domain of FSFI. For example, the score of any one of questions 3-6 of FSFI can be increased.

[0078] In one embodiment, the compounds of the present disclosure can increase the FSFI score in the lubrication domain or increase the score of any one of the questions in the lubrication domain of FSFI. For example, the score of any one of questions 7-10 of FSFI can be increased.

[0079] In one embodiment, the compounds of the present disclosure can increase the FSFI score in the orgasm domain or increase the score of any one of the questions in the orgasm domain of FSFI. For example, the score of any one of questions 11-13 of FSFI can be increased.

[0080] In one embodiment, the compounds of the present disclosure can increase the FSFI score in the satisfaction domain or increase the score of any one of the questions in the satisfaction domain of FSFI. For example, the score of any one of questions 14-16 of FSFI can be increased.

[0081] The overall and specific aspects of FSD can be evaluated using FSFI-6. FSFI-6 is a six-item questionnaire for measuring sexual function in women (Isidori et al. 2010).

[0082] In one embodiment, the compounds of the present disclosure can increase FSFI-6 in a subject. In one embodiment, the compounds of the present disclosure can increase FSFI-6 by at least 1 point, at least 2 points, at least 3 points, at least 4 points or at least 5 points.

[0083] One embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure for use in increasing FSFI in a subject suffering from female sexual dysfunction. One embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure for use in increasing FSFI-6 in a subject suffering from female sexual dysfunction.

[0084] One embodiment of the present disclosure provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure, in the manufacture of a medicament for increasing FSFI in a subject suffering from female sexual dysfunction. One embodiment of the present disclosure provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure, in the manufacture of a medicament for increasing FSFI-6 in a subject suffering from female sexual dysfunction.

[0085] One embodiment of the present disclosure provides a method for increasing FSFI in a subject suffering from female sexual dysfunction, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure. One embodiment of the present disclosure provides a method for increasing FSFI-6 in a subject suffering from female sexual dysfunction, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present disclosure.

[0086] Using the FSDS-DAO, the general and specific aspects of FSD can be evaluated. The FSDS-DAO is a 15-item patient-reported outcome (PRO) document / questionnaire that measures overall sexual function and has been used in clinical trials to grade the severity of female hypoactive sexual desire disorder (FHSDD) (Derogatis et al. 2008, Derogatis et al. 2021). In one embodiment, the subject before treatment had a Female Sexual Distress Scale - Desire And Arousal (FSDS-DAO) of less than 60, such as 55-60, such as 50-55, such as 45-50, such as 40-45, such as 35-40, such as 30-35, such as 25-30, such as 20-25, such as 15-20, such as 10-15, such as 5-10, such as 0-10. In one embodiment, the subject before treatment had a Female Sexual Distress Scale - Desire And Arousal (FSDS-DAO) of greater than 10, such as greater than 15, such as greater than 20, such as greater than 25, such as greater than 30, such as greater than 35, such as greater than 40, such as greater than 45, such as greater than 50, such as greater than 55.

[0087] In one embodiment, the compounds of the present disclosure can reduce FSDS-DAO in a subject. In one embodiment, the compound can reduce FSDS-DAO by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points, at least 26 points, at least 27 points, at least 28 points, at least 29 points, at least 30 points, at least 31 points, at least 32 points, at least 33 points, at least 34 points, at least 35 points, at least 36 points, at least 37 points, at least 38 points, at least 39 points, at least 40 points, at least 41 points, at least 42 points, at least 43 points, at least 44 points, at least 45 points, at least 46 points, at least 47 points, at least 48 points, at least 49 points, at least 50 points, at least 51 points, at least 52 points, at least 53 points, at least 54 points, at least 55 points, at least 56 points, at least 57 points, at least 58 points, at least 59 points or at least 60 points.

[0088] In one embodiment, the compounds of the present disclosure can reduce the score of question 13 of FSDS-DAO (FSDS-DAO Q13) in a subject. The compounds of the present disclosure may be particularly efficient in improving question 13 of FSDS-DAO (FSDS-DAO Q13) which asks patients "How often did you feel bothered by low sexual desire?" The point scale is from 0 points (never) to 4 points (always). A decrease in the FSDS-DAO Q13 score over time indicates an improvement in the level of distress associated with low sexual desire. In one embodiment, the compounds of the present disclosure can reduce the FSDS-DAO Q13 score by at least 0.3 points, at least 0.7 points, at least 1.0 point, at least 1.3 points, at least 1.7 points, at least 2.0 points, at least 2.3 points, at least 2.7 points, at least 3.0 points, at least 3.3 points, at least 3.7 points or at least 4.0 points. In one embodiment, the compounds of the present disclosure can reduce the FSDS-DAO Q13 score by 1 point, 2 points, 3 points or 4 points.

[0089] The overall and specific aspects of FSD can be evaluated using the Elements of Desire Questionnaire (EDQ). The EDQ is a patient-reported outcome (PRO) developed to evaluate sexual desire. The EDQ addresses desires such as sexual desire, thoughts / fantasies about sexual intercourse, and the trait of accepting sexual desires, and its purpose is to measure the effectiveness of drugs against this condition with respect to further aspects of the pathology. The EDQ is a 9-item PRO questionnaire intended to evaluate the effectiveness of potential new treatments for women with FSD, HSDD or FSIAD. Items (questions) 1, 2, 3, 4, 6 and 8 of the EDQ are evaluated on a 5-point scale, with lower numbers indicating higher severity of dysfunction. Items 5 and 7 are evaluated as "yes" and "no" responses.

[0090] In one embodiment, the compounds of the present disclosure can increase the EDQ score of a subject.

[0091] In one embodiment, the compounds of the present disclosure can increase the score of any one question of EDQ, for example, questions 1, 2, 3, 4, 5, 6, 7, 8 or 9. In one embodiment, the compounds of the present disclosure can increase the score of any one of questions 1, 2, 3, 4, 6 and 8 of EDQ by 1 point, 2 points, 3 points or 4 points.

[0092] One aspect of the present disclosure provides a method for increasing genital temperature in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0093] In one embodiment, the increase in genital temperature is an increase in the temperature of any one of the clitoris, vagina, labia or any combination thereof. In one embodiment, the increase in genital temperature is an increase in clitoral temperature. In one embodiment, the increase in genital temperature is an increase in vaginal temperature. In one embodiment, the increase in genital temperature is an increase in vaginal temperature and / or clitoral temperature.

[0094] One aspect of the present disclosure provides a method for increasing genital blood flow in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, the increase in genital blood flow is an increase in blood flow in any one of the clitoris, vagina, labia or any combination thereof. In one embodiment, the increase in genital blood flow is an increase in clitoral blood flow.

[0096] In another aspect, the present disclosure provides a method for increasing sexual desire, sexual interest, sexual arousal, lubricity, sexual satisfaction or a combination thereof in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0097] In another aspect, the present disclosure provides a method for reducing the difficulty in achieving orgasm during sexual stimulation or sexual intercourse in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098] One aspect of the present disclosure provides a method for reducing dyspareunia in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] Item 1. A compound of the following formula (I) for use in the treatment, prevention or alleviation of female sexual dysfunction in a subject

Chemical formula

[0100] 2. A compound for use according to item 1, having the structure of a compound of the following formula (Ia)

Chemical formula

[0101] 3. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is (i) female sexual arousal disorder, (ii) hypoactive sexual desire disorder, (iii) female sexual arousal insufficiency, (iv) anorgasmia, (v) dyspareunia disorder and (vi) coital pain disorder, and is selected from the group consisting of.

[0102] 4. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is female sexual arousal disorder.

[0103] 5. The hypoactive sexual desire disorder is (i) a decrease or absence of spontaneous desire, (ii) A decrease or absence of reactive desire for functional signals and stimuli, and / or (iii) When sexual activity is initiated, a state in which the desire or interest in sexual activity cannot be sustained, A compound for use according to any one of items 3 and the preceding items, characterized by

[0104] 6. A compound for use according to item 3, wherein the orgasm disorder is anorgasmia.

[0105] 7. A compound for use according to item 3, wherein the dyspareunia disorder is dyspareunia - insertion disorder.

[0106] 8. A compound for use according to item 7, wherein the dyspareunia - insertion disorder is generalized dyspareunia - insertion disorder or situational dyspareunia - insertion disorder.

[0107] 9. For the said dyspareunia - insertion disorder, (i) Symptoms that are recurrent during sexual interactions involving or potentially involving insertion, despite sufficient sexual desire and sexual stimulation, (ii) Conditions that affect the pelvic region and lead to genital pain and / or insertion pain, or symptoms not entirely attributable to mental disorders, (iii) Symptoms not entirely attributable to insufficient vaginal lubrication or changes associated with post - menopausal changes / aging, and (iv) Symptoms accompanied by clinically significant pain, A compound for use according to any one of items 7 and 8, having

[0108] 10. The female sexual dysfunction is (i) Associated with a disease state, injury, or the effects of surgery or radiotherapy, (ii) Associated with psychological or behavioral factors (including mental disorders), (iii) Associated with the use of psychoactive substances or psychotropic drugs, (iv) Associated with knowledge or experience, (v) Associated with relationship factors, (vi) associated with cultural factors and / or (vii) other predetermined etiological reasons, A compound for use according to any one of the preceding items, which is

[0109] 11. A compound for use according to any one of the preceding items, wherein the female sexual dysfunction is female hypoactive sexual desire disorder.

[0110] 12. A compound for use according to any one of the preceding items, wherein the female sexual function index (FSFI) of the subject before treatment is greater than 26.55, for example 25.00 - 26.55, for example 20.00 - 25.00, for example 15.00 - 20.00, for example 10.00 - 15.00, for example 5.00 - 10.00, for example 2.00 - 5.00.

[0111] 13. A method for increasing vaginal temperature in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) below

Chemical formula

[0112] 14. A method for increasing clitoral blood flow in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) below

Chemical formula

[0113] 15. A method for increasing clitoral temperature in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) below

Chemical formula

Example

[0114] Example 1: Efficacy in vitro Materials and Methods As described in WO97 / 16451 (NeuroSearch A / S), the ability of a compound to inhibit the reuptake of the monoamine neurotransmitters dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in synaptosomes was tested for the compound.

[0115] Results The test values are shown as IC 50 (the concentration (μM) at which the test substance inhibits 50% of the specific binding of 3 H-DA, 3 H-NA or 3 H-5-HT). See Table 1.

[0116] TIFF2025522944000012.tif23165

[0117] Example 2: Evaluation of the effect of the compound of formula (I) on the female rat genitalia Materials and Methods Animals: The experiment was set up in two different sets of measurement procedures to avoid the variations imposed on each other. The first set of experiments was performed on control female rats, and the second set was performed on a depression model called the Flint Sensitive Line (FSL), which shares molecular similarities with major depressive disorder patients.

[0118] Anesthesia and general surgical procedures: Rats were intraperitoneally injected with 50 mg / Kg of pentobarbital. After 10 minutes in the dark, the interdigital area was pinched to confirm that the reflex action was dull, and the rat was prepared on the table, where the legs were semi-extended with tape to fix the rat. The areas of interest (abdomen, inguinal region and neck) were shaved and cleaned and sterilized with water and ethanol. After each test was completed, the rat was euthanized by an overdose of pentobarbital, and the atlanto-occipital joint was severed to ensure a painless procedure in the rat.

[0119] Measurement of clitoral blood flow and genital temperature: Using a suture Nylon 4-0 and a needle, the urethral orifice was widened to expose the mucosa. To make the clitoris more visible, the two sides of the urethral wall were pulled with a thread, and then another thread was held at the proximal center of the urethral orifice to spread the skin cephalad, and in a better way, the mucosal area of the clitoris was exposed (Figure 1A). A calibrated laser Doppler blood flow probe (VP1T, Moor instruments-UK) was used to measure the anterior side of the clitoris, and this probe was connected to a laser Doppler blood flow monitor MOORVMS-LDF2 (Moor instruments-UK). The laser Doppler probe was placed and fixed to the bottom surface and the alligator clip so that it did not move at all. The tip of the calibrated probe was immersed in a water-based gel in the exposed area of the urethra-clitoris (Figure 1B). In addition, the right side was incised to clean the jugular vein, and another cannula was inserted using that jugular vein and used to perfuse IP2015 or vehicle at various doses (0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg, 10 mg / Kg) using a mechanical pump.

[0120] Using a calibrated laser Doppler blood flow probe (VP1T, Moor instruments-UK), measurements were taken on the anterior side of the clitoris, and this probe was connected to a laser Doppler blood flow monitor MOORVMS-LDF2 (Moor instruments-UK). After a stabilization period of 10 - 20 minutes, baseline control measurements were obtained for 5 minutes, and then vehicle or incremental doses (0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg, and 10 mg / Kg) of IP2015 were injected via the jugular vein, and changes in blood flow were recorded. The injection protocol was performed in multiple sets of injecting for 1 minute and further recording the blood flow changes recorded by this system for 4 minutes. As follows, electrical field stimulation of the cavernous nerves of the clitoris was used as a positive control.

[0121] A thermography camera FLIR (E96, InfraTec, Germany, Figure 1) was placed at a distance of 50 cm from the area of interest (Figure 1C). Three areas of interest (chest, vagina, and urethra / clitoris) were recorded using digital markers placed with Research Studio - FLIR, the data were extracted, and imported into Excel. After a stabilization period of 10 - 20 minutes, baseline control measurements were obtained for 5 minutes, and then vehicle or escalating doses (0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg, and 10 mg / Kg) of IP2015 were injected via the jugular vein, and changes in genital temperature were recorded.

[0122] Measurements of mean arterial pressure and heart rate: Anesthetized rats were allowed to breathe spontaneously, their body temperature was continuously monitored, and these rats were kept at 37.5 °C by placing them on a warming blanket. A heparinized (100 IE mL -1 ) polyethylene (PE) catheter (PE - 50) connected to a pressure transducer (Disposable BP Transducer, AD Instruments, UK) was introduced into the carotid artery to measure MAP. After a stabilization period of 10 - 20 minutes, continuous direct measurements of mean arterial pressure (MAP) and heart rate (HR) were obtained, registered, and analyzed using a computer - based data acquisition system (PowerLab, AD Instruments).

[0123] Measurement of clitoral blood flow after electrical stimulation of the cavernous nerve of the clitoris: Through a lower abdominal incision, the cavernous nerve of the clitoris was isolated, and electrical stimulation was performed using a slender bipolar platinum electrode, which was connected to a stimulator S48 (Grass Instrument Co., Boston, MA, U.S.A.). To examine whether the hemodynamics of the clitoral tissue changed due to nerve stimulation, the nerve was stimulated in male rats as described above

[12] with parameters that induced the maximum amplitude of the response (6 - volt square - wave pulses, 10 Hz, 1 ms every 30 seconds), and blood flow was measured with a laser Doppler. As described above, clitoral blood flow was measured with a laser Doppler.

[0124] Results of genital blood flow Laser Doppler measurements in the clitoral region of female Sprague Daley rats showed that after injection of IP2015 (0.3 - 10 mg / kg), the frequency, duration, and magnitude of blood flow in the clitoral region were improved (Figure 2). Furthermore, both the mean (Figure 6A) and peak (Figure 6B) of clitoral blood flow were significantly increased compared to the vehicle after injection of IP2015 (0.3 - 10 mg / kg).

[0125] The peak of clitoral blood flow after injection of IP2015 (Figure 2A, 4.49 V) corresponded to the peak of clitoral blood flow after electrical stimulation of the cavernous nerve of the clitoris (Figure 5, 4.31 V).

[0126] Genital temperature Sexual excitement and desire have been shown to increase genital temperature (Kukkonen et al., 2007). Thermographic images (Figure 3A - C) and central temperature (Figure 3D) at 4 - fold magnification after injection of IP2015 (0.3 - 10 mg / kg) and control. Extracted quantitative data are shown in histograms according to various regions of interest (chest, vagina, and urethra - clitoris) (Figure 4A - C).

[0127] When the temperature was measured using a thermography camera, it was revealed that the surface temperature of the base varied depending on the area examined in the rat and changed during the injection of incremental doses of IP2015 (Figs. 3A - C, Figs. 4A - C). The recording conditions were optimized by zooming in on the target area. When quantified under the condition of 4 - fold zoom, it was revealed that when incremental doses of IP2015 were injected into FSL rats with depression, the temperature in the vaginal and clitoral regions increased in a dose - dependent manner (Figs. 3A - C, Figs. 4A - C). During the injection of IP2015, the core temperature measured with a conventional rectal thermometer did not change (Fig. 3D). The increase in genital temperature observed after treatment with IP2015 provides further evidence that IP2015 can induce an increase in sexual excitement and desire. Furthermore, the increase in clitoral temperature observed after treatment with IP2015 provides further evidence that IP2015 can induce an increase in sexual excitement and desire, particularly in FSD.

[0128] Mean arterial pressure (MAP) and heart rate (HR) After the injection of IP2015 (0.3 - 10 mg / kg), the MAP of female Sprague - Daley rats was comparable to that of the vehicle (Fig. 7A). In contrast, after the injection of IP2015 (0.3 - 10 mg / kg), the HR of female Sprague - Daley rats increased significantly compared to the vehicle (Fig. 7B).

[0129] Conclusion In summary, IP2015 increases genital blood flow and raises the surface temperature of the genitals in a dose - dependent manner in control Sprague - Daley rats and the FSL rat strain that exhibits spontaneous decline. Furthermore, the increase in genital blood flow and the rise in clitoral temperature observed after treatment with IP2015 provide further evidence that IP2015 can induce an increase in sexual excitement and desire. Additionally, the increase in clitoral temperature observed after treatment with IP2015 provides further evidence that IP2015 can induce an increase in sexual excitement and desire, particularly in FSD. These findings support the idea that IP2015 may improve sexual health in women.

[0130] Example 3: Evaluation of the effect of the compound of formula (I) on the sexual behavior of female rats Materials and methods Animals: Female Sprague Dawley rats (12 - 15 weeks old) were housed in the animal facility in Universal Euro III type length-width cages, which had a standard wood bedding and space for two rats, with a clean environment and a comfortable temperature (22 - 23 °C), and a 12-hour:12-hour light-dark cycle starting at 11 am. The rats were allowed free access to food and tap water.

[0131] Synchronization of the estrous cycle during estrus in female rats: Female Sprague Dawley rats with an average body weight of 250 g were synchronized during the estrus phase of the estrous cycle by subcutaneous injection of 250 μg of prostaglandin F 2α (PGF 2α ) on days 0 and 3.

[0132] Comparative evaluation of the effects of apomorphine and IP2015 on sexual behavior: On day 4, 4 hours after injecting progesterone (1 mg / kg) into the rats, all tests were conducted. After randomly dividing the rats into groups for the second injection with vehicle (n = 10), apomorphine (0.25 mg / kg) (n = 10), and IP2015 (1 mg / kg and 10 mg / kg, n = 2 for each group), all tests were carried out. Apomorphine has been previously shown to increase, for example, lordosis (Hamburger-Bar R et al., 2011), and to decrease, for example, jumping and sudden movements (Snoeren et al., 2011) in female rats, and was included as a positive control treatment. To examine sexual behavior, the synchronized female rats were paired with conditioned male rats, and the behavior was recorded by two cameras. The videos were quantified by a skilled operator blinded to the treatment.

[0133] Data analysis and statistics: After one-way analysis of variance (ANOVA), Tukey's post hoc test was used to analyze the statistical differences among vehicle, apomorphine, and two different doses of IP2015. The assumptions of this model were examined by considering the Q-Q plot, and the data were logarithmically transformed as needed to create a dataset with a Gaussian distribution. When the data were skewed, the Brown-Forsythe test was applied. The ROUT method (Q = 1%) was used to exclude data from the analysis. P < 0.05 was considered statistically significant. When F was significant and there was no heterogeneity of variance, only the post hoc test was performed. All statistical analyses were performed using the software GraphPad Prism 9.5 (GraphPad Software, CA, USA).

[0134] Results To examine the effects of vehicle, IP2015, and apomorphine on the sexual behavior of rats with synchronized estrous cycles, female rats pretreated with 250 μg of PGF2α were examined for copulatory - supportive behaviors such as jumping, ear wiggling, and sudden movement.

[0135] The term "estrus" refers to the period of the estrous cycle during which a sexually mature non - pregnant female accepts sexual advances from a male. Prostaglandin F2α (PGF2α) is a natural luteinizing hormone that is also used to synchronize estrus through shortening the length of the luteal phase.

[0136] Copulatory - supportive behaviors (also called proceptive or estrous behaviors) are usually described as species - specific behaviors shown by estrous females during sexual interaction. During sexual interaction, the female shows sexual desire, sexual excitement, and sexual interest, and as a result, initiates and maintains sexual interaction by prompting the male to copulate, and regulates the pattern of copulation (Erskine, 1989).

[0137] In vehicle injection, the copulatory - assisting parameters did not change (Figure 8). When two different doses of IP2015 were injected, the ear vibration did not change (Figure 8A), but at 10 mg / kg of IP2015, the number of jumps increased compared to apomorphine (Figure 8B). IP2015 increased sudden movements in a dose - dependent manner compared to the vehicle and also compared to apomorphine (Figure 8C). The increase in jumps and sudden movements observed in female rats treated with IP2015 indicates that IP2015 induction increases desire, sexual arousal, and sexual interest. In apomorphine injection, the copulatory - assisting parameters did not change (Figure 8).

[0138] Conclusion In summary, IP2015 dose - dependently increases sexual behavior in female rats (independent of the estrous cycle). The increase in jumps and sudden movements observed in female rats treated with IP2015 indicates that IP2015 induction increases desire, sexual arousal, and sexual interest. These findings support that IP2015 may improve sexual health in women through increasing sexual behavior and desire.

[0139] References WO97 / 30997 WO97 / 16451 US9,133,184B2 Allahdadi et al.,Cardiovasc Hematol Agents Med Chem.2009 Oct;7(4):260 - 269 Begrman,J.R.,2005.Physiology of female sexual function and dysfunction.International journal of impotence research,17(1),pp.S44 - S51 Clayton et al., Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Womens Health (Lond), 12:325-337 Derogatis et al., J Patient Rep Outcomes, 2021, 5:100 Erskine, M.S., 1989. Solicitation behavior in the estrous female rat: a review. Hormones and behavior, 23(4), pp.473-502 Hamburger-Bar R, Rigter H. Apomorphine: Facilitation of sexual behaviour in female rats. Eur J Pharmacol 1975;32. https: / / doi.org / 10.1016 / 0014-2999(75)90304-0 Kingsberg SA, Althof SE. Satisfying sexual events as outcome measures in clinical trial of female sexual dysfunction. J Sex Med. 2011 Dec;8(12) Isidori AM, Pozza C, Esposito K, Giugliano D, Morano S, Vignozzi L, Corona G, Lenzi A, Jannini EA. Development and validation of a 6-item version of the female sexual function index(FSFI)as a diagnostic tool for female sexual dysfunction. J Sex Med. 2010 Mar;7(3):1139-46 Miller MK, Smith JR, Norman JJ, Clayton AH. Expert opinion on existing and developing drugs to treat female sexual dysfunction. Expert Opin Emerg Drugs. 2018;23(3):223 - 230 Rosen R, Brown C, et al., 2000, The Female Sexual Function Index(FSFI): A Multidimensional Self-Report Instrument for the Assessment of Female Sexual Function, J Sex Marital Ther, 26(2):191 - 208 Snoeren EMS, Chan JSW, De Jong TR, Waldinger MD, Olivier B, Oosting RS. A New Female Rat Animal Model for Hypoactive Sexual Desire Disorder; Behavioral and Pharmacological Evidence. J Sex Med 2011;8. https: / / doi.org / 10.1111 / j.1743-6109.2010.01998.x T.M. Kukkonen, Y.M. Binik, R. Amsel, and S. Carrier, “Physiology: Thermography as a physiological measure of sexual arousal in both men and women,” J. Sex. Med. 4, 93 - 105(2007)

Claims

1. A compound of the following formula (I) for use in the treatment, prevention or alleviation of female sexual dysfunction in a subject 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. A compound for use according to claim 1, having the structure of the following formula (Ia) [Chemical Formula 2] or a pharmaceutically acceptable salt thereof.

3. A compound for use according to any one of claims 1 and 2, which is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof.

4. A compound for use according to any one of the preceding claims, which is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one hydrochloride.

5. wherein the female sexual dysfunction is (i) female sexual interest / arousal disorder (FSIAD), (ii) hypoactive sexual desire disorder, (iii) female sexual arousal disorder, (iv) orgasmic disorder, (v) dyspareunia disorder and (vi) coital pain disorder, A compound for use according to any one of the preceding claims, selected from the group consisting of.

6. A compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is female sexual interest / arousal disorder (FSIAD).

7. A compound for use according to any one of the preceding claims, wherein the hypoactive sexual desire disorder is congenital hypoactive sexual desire disorder or acquired hypoactive sexual desire disorder.

8. A compound for use according to any one of the preceding claims, wherein the hypoactive sexual desire disorder is generalized hypoactive sexual desire disorder or situational hypoactive sexual desire disorder.

9. A compound for use according to any one of the preceding claims, wherein the hypoactive sexual desire disorder is unspecified hypoactive sexual desire disorder.

10. The hypoactive sexual desire disorder is (i) a decrease or absence of spontaneous desire, (ii) a decrease or absence of responsive desire to sensory signals and stimuli, and / or (iii) a state in which desire or interest in sexual activity cannot be sustained when sexual activity is initiated, A compound for use according to any one of the preceding claims, characterized by.

11. A compound for use according to any one of the preceding claims, wherein the state of being unable to sustain desire or interest in said sexual behavior occurs temporarily or persistently over a period of at least several months, for example, 3 months, 4 months, 5 months, 6 months, 7 months or 8 months, and / or is accompanied by clinically significant distress.

12. A compound for use according to any one of the preceding claims, wherein said female sexual arousal disorder is female congenital sexual arousal disorder or female acquired sexual arousal disorder.

13. A compound for use according to any one of the preceding claims, wherein said female sexual arousal disorder is female generalized sexual arousal disorder or female situational sexual arousal disorder.

14. A compound for use according to any one of the preceding claims, wherein said female sexual arousal disorder is female unspecified sexual arousal disorder.

15. Said female sexual arousal disorder is (i) lack or marked decrease in genital response, including vulvovaginal lubrication, genital congestion, and genital sensitivity, (ii) lack or marked decrease in responses other than genital, such as nipple erection, skin flushing, increase in heart rate, increase in blood pressure, and increase in respiratory rate and / or (iii) lack or marked decrease in the feeling of sexual excitement, such as the state of sexual excitement and sexual pleasure from any kind of sexual stimulation, A compound for use according to any one of the preceding claims, characterized by the above.

16. A compound for use according to any one of the preceding claims, wherein the lack or decrease in response to sexual stimulation, which occurs despite the desire for sexual behavior and sufficient sexual stimulation, occurs temporarily or persistently over a period of at least several months, for example, 3 months, 4 months, 5 months, 6 months, 7 months or 8 months, and / or is accompanied by clinically significant distress.

17. A compound for use according to any one of the preceding claims, wherein said anorgasmia is anorgasmia.

18. A compound for use according to any one of the preceding claims, wherein said anorgasmia is congenital anorgasmia or acquired anorgasmia.

19. A compound for use according to any one of the preceding claims, wherein said anorgasmia is generalized anorgasmia or situational anorgasmia.

20. A compound for use according to any one of the preceding claims, wherein the anorgasmia is unspecified anorgasmia. **Claim 21** A compound for use according to any one of the preceding claims, wherein the anorgasmia is characterized by absence or significantly low frequency of orgasm experience and / or significantly reduced intensity of orgasm sensation. **Claim 22** A compound for use according to any one of the preceding claims, wherein the absence or significantly low frequency of orgasm experience and / or significantly reduced intensity of orgasm sensation, which occur despite sufficient sexual stimulation (including sexual behavior and desire for orgasm), occur temporarily or persistently over a period of at least several months, such as 3 months, 4 months, 5 months, 6 months, 7 months or 8 months, and / or are accompanied by clinically significant distress. **Claim 23** A compound for use according to any one of the preceding claims, wherein the dyspareunia disorder is dyspareunia / insertion disorder. **Claim 24** A compound for use according to any one of the preceding claims, wherein the dyspareunia / insertion disorder is congenital dyspareunia / insertion disorder or acquired dyspareunia / insertion disorder. **Claim 25** A compound for use according to any one of the preceding claims, wherein the dyspareunia / insertion disorder is generalized dyspareunia / insertion disorder or situational dyspareunia / insertion disorder. **Claim 26** A compound for use according to any one of the preceding claims, wherein the dyspareunia / insertion disorder is unspecified dyspareunia / insertion disorder. **Claim 27** The dyspareunia / insertion disorder is (i) significant and persistent or recurrent insertion difficulty, including cases due to involuntary sclerosis or rigidity of the pelvic floor muscles during insertion attempts, (ii) significant and persistent or recurrent vulvovaginal pain or pelvic pain during insertion, and / or (iii) significant and persistent or recurrent fear or anxiety regarding vulvovaginal pain or pelvic pain anticipated during, during, or as a result of insertion, A compound for use according to any one of the preceding claims, characterized by the above. **Claim 28** For the dyspareunia / insertion disorder, (i) symptoms that are recurrent during sexual interaction involving or potentially involving insertion, despite sufficient sexual desire and sexual stimulation, (ii) a pathological condition that affects the pelvic region and leads to genital pain and / or insertion pain, or a symptom that is not entirely due to a mental disorder. (iii) Symptoms that are not entirely due to insufficient vaginal lubrication or changes associated with postmenopausal or aging changes, and (iv) Symptoms accompanied by clinically significant pain, A compound for use according to any one of the preceding claims, wherein there is such a symptom.

29. A compound for use according to any one of the preceding claims, wherein the dyspareunia is vulvodynia or progressive vulvodynia.

30. The female sexual dysfunction is (i) associated with a disease state, injury, or the effects of surgery or radiation therapy, (ii) associated with psychological or behavioral factors (including mental disorders), (iii) associated with the use of psychotropic substances or psychotropic drugs, (iv) associated with a lack of knowledge or experience, (v) associated with relationship factors, (vi) associated with cultural factors, and / or (vii) other predetermined etiological reasons, A compound for use according to any one of the preceding claims.

31. A compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is female hypoactive sexual desire disorder.

32. A compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is not caused by another disease, such as a mental disorder.

33. A compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is not caused by genital injury.

34. A compound for use according to any one of the preceding claims, wherein the subject is not being treated with a drug known to be a cause of female sexual dysfunction.

35. A compound for use according to any one of the preceding claims, wherein the female sexual disorder is female sexual hypoactive disorder, for example, not female premature orgasm.

36. A compound for use according to any one of the preceding claims, which can increase the number of satisfactory sexual events (SSE) in the subject.

37. A compound for use according to any one of the preceding claims, wherein the female sexual function index (FSFI) of the subject before treatment is less than 26.55, for example, 25.00 - 26.55, for example, 20.00 - 25.00, for example, 15.00 - 20.00, for example, 10.00 - 15.00, for example, 5.00 - 10.00, for example, 2.00 - 5.

00.

38. A compound for use according to any one of the preceding claims, which can increase FSFI in the subject.

39. A compound for use according to any one of the preceding claims, which is capable of increasing the FSFI by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points or at least 26 points.

40. A compound for use according to any one of the preceding claims, which is capable of increasing the FSFI to more than 26.

55.

41. A compound for use according to any one of the preceding claims, which is capable of increasing the FSFI score in the pain area by at least 0.3 point, at least 0.7 point, at least 1.0 point, at least 1.3 point, at least 1.7 point, at least 2.0 point, at least 2.3 point, at least 2.7 point, at least 3.0 point, at least 3.3 point, at least 3.7 point, at least 4.0 point, at least 4.3 point, at least 4.7 point, at least 5.0 point, at least 5.3 point, at least 5.7 point or 6.0 points.

42. A compound for use according to any one of the preceding claims, which is capable of increasing the score of question 17 (the first question about pain) of the FSFI score, for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points.

43. A compound for use according to any one of the preceding claims, which is capable of increasing the score of question 18 (the second question about pain) of the FSFI score, for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points.

44. The compound for use according to any one of the preceding claims, which can increase the score of FSFI question 19 (the third question about pain), for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points.

45. The compound for use according to any one of the preceding claims, which can increase the FSFI score of any one or more of the other five regions (desire, sexual excitement, lubrication, orgasm and satisfaction).

46. The compound for use according to any one of the preceding claims, which can increase the FSFI score of the subject in the region of desire.

47. The compound for use according to any one of the preceding claims, which can increase the FSFI score of the subject in the region of desire by at least 0.3 point, at least 0.7 point, at least 1.0 point, at least 1.3 point, at least 1.7 point, at least 2.0 point, at least 2.3 point, at least 2.7 point, at least 3.0 point, at least 3.3 point, at least 3.7 point, at least 4.0 point, at least 4.3 point, at least 4.7 point, at least 5.0 point.

48. The compound for use according to any one of the preceding claims, which can increase the FSFI score of question 1 (the first question about desire) in the subject, for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points.

49. The compound for use according to any one of the preceding claims, which can increase the FSFI score of question 2 (the second question about desire) in the subject, for example, the score can be increased by 1 point, 2 points, 3 points, 4 points or 5 points.

50. The compound for use according to any one of the preceding claims, which can increase the FSFI score in the region of sexual excitement or increase the score of any one of the questions in the region of sexual excitement of FSFI. For example, the score of any one of questions 3-6 of FSFI can be increased.

51. A compound for use according to any one of the preceding claims, which can increase the FSFI score of the lubricity domain or increase the score of any one of the questions in the lubricity domain of FSFI, for example, can increase the score of any one of questions 7 to 10 of FSFI.

52. A compound for use according to any one of the preceding claims, which can increase the FSFI score of the orgasm domain or increase the score of any one of the questions in the orgasm domain of FSFI, for example, can increase the score of any one of questions 11 to 13 of FSFI.

53. A compound for use according to any one of the preceding claims, which can increase the FSFI score of the satisfaction domain or increase the score of any one of the questions in the satisfaction domain of FSFI, for example, can increase the score of any one of questions 14 to 16 of FSFI.

54. A compound for use according to any one of the preceding claims, which can increase FSFI-6 in the subject.

55. A compound for use according to any one of the preceding claims, which can increase the FSFI-6 by at least 1 point, at least 2 points, at least 3 points, at least 4 points or at least 5 points.

56. A compound for use according to any one of the preceding claims, which is capable of reducing FSDS-DAO by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points, at least 26 points, at least 27 points, at least 28 points, at least 29 points, at least 30 points, at least 31 points, at least 32 points, at least 33 points, at least 34 points, at least 35 points, at least 36 points, at least 37 points, at least 38 points, at least 39 points, at least 40 points, at least 41 points, at least 42 points, at least 43 points, at least 44 points, at least 45 points, at least 46 points, at least 47 points, at least 48 points, at least 49 points, at least 50 points, at least 51 points, at least 52 points, at least 53 points, at least 54 points, at least 55 points, at least 56 points, at least 57 points, at least 58 points, at least 59 points or at least 60 points.

57. A compound for use according to any one of the preceding claims, which is capable of reducing the score of question 13 of FSDS-DAO (FSDS DAO Q13) by at least 0.3 point, at least 0.7 point, at least 1.0 point, at least 1.3 point, at least 1.7 point, at least 2.0 point, at least 2.3 point, at least 2.7 point, at least 3.0 point, at least 3.3 point, at least 3.7 point or at least 4.0 point.

58. For use according to any one of the preceding claims, the compound wherein the female sexual function index FSDS-DAO of the subject before treatment is less than 60, for example 55-60, for example 50-55, for example 45-50, for example 40-45, for example 35-40, for example 30-35, for example 25-30, for example 20-25, for example 15-20, for example 10-15, for example 5-10, for example 0-10.

59. For use according to any one of the preceding claims, the compound capable of increasing the EDQ score of the subject.

60. For use according to any one of the preceding claims, the compound capable of increasing the score of any one of the EDQ questions.

61. For use according to any one of the preceding claims, the compound wherein the subject is female.

62. For use according to any one of the preceding claims, the compound wherein the subject is a mammal.

63. For use according to any one of the preceding claims, the compound wherein the subject is a human.

64. For use according to any one of the preceding claims, the compound wherein the subject is fertile.

65. For use according to any one of the preceding claims, the compound wherein the subject is pre-menopausal.

66. For use according to any one of the preceding claims, the compound wherein the subject is in menopause.

67. For use according to any one of the preceding claims, the compound wherein the subject is post-menopausal.

68. For use according to any one of the preceding claims, the compound wherein the subject is over 18 years old, for example over 20 years old, for example over 25 years old, for example over 30 years old, for example over 35 years old, for example over 40 years old, for example over 45 years old, for example over 50 years old, for example over 55 years old, for example over 60 years old, for example over 65 years old, for example over 70 years old, for example over 75 years old.

69. For use according to any one of the preceding claims, the compound wherein the subject is over 40 years old, for example over 35 years old, for example over 30 years old, for example over 25 years old, for example under 20 years old.

70. For use according to any one of the preceding claims, the compound wherein the subject is 18-20 years old, 20-25 years old, 25-30 years old, 30-35 years old, 35-40 years old, 40-45 years old, 45-50 years old, 50-55 years old, 55-60 years old, 60-65 years old, 65-70 years old or 70-75 years old or older.

71. Use of a compound of the following formula (I) in the manufacture of a medicament for treating female sexual dysfunction 【Chemical Formula 3】 thereof.

72. A method for treating, preventing or alleviating female sexual dysfunction in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof.

73. A method for increasing vaginal temperature in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof.

74. A method for increasing genital blood flow in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof.

75. The method according to claim 74, wherein the increase in genital blood flow is an increase in blood flow in any one of the clitoris, vagina, labia or any combination thereof.

76. The method according to any one of claims 74 to 75, wherein the increase in genital blood flow is an increase in blood flow in the clitoris.

77. A method for increasing genital temperature in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) [Chemical Formula 7] or a pharmaceutically acceptable salt thereof.

78. The method according to claim 77, wherein the increase in genital temperature is an increase in temperature in any one of the clitoris, vagina, labia or any combination thereof.

79. The method according to any one of claims 77 to 78, wherein the increase in genital temperature is an increase in clitoral temperature.

80. The method according to any one of claims 77 to 79, wherein the increase in temperature is an increase in surface temperature.

81. A method for increasing sexual desire, sexual interest, sexual arousal, lubricity, sexual satisfaction or any combination thereof in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 【Chemical 8】 or a pharmaceutically acceptable salt thereof.

82. A method for reducing dyspareunia in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof.

83. A method for reducing difficulty in achieving sexual stimulation or orgasm during sexual intercourse in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) 【Chemical 10】 or a pharmaceutically acceptable salt thereof.

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