Compounds for treating female sexual dysfunction

Abstract

The present disclosure relates to the treatment of female sexual dysfunction with chromene-2-one compounds.

Description

Technical Field

[0001] The present disclosure relates to the use of small molecule drugs to treat female sexual dysfunction. Background Art

[0002] Female sexual dysfunction (FSD) is a common problem that affects approximately 40% of women and for which few treatments are available (Allahdadi et al. 2009). FSD is more typical as women age and is a common, progressive disease. Common symptoms associated with FSD include decreased vaginal lubrication, pain and discomfort during intercourse, diminished arousal, and difficulty achieving orgasm. Only a small percentage of women seek medical attention. Compared to the extensive research and treatments that exist for male erectile dysfunction (particularly with the development of phosphodiesterase type 5 inhibitors), FSD has been significantly less explored. Treatment is primarily limited to psychotherapy, and although different pharmacological modalities have been developed, they have low efficacy and side effects (Miller et al., 2018). Summary of the invention

[0003] As mentioned above, there is a great need for a compound that can treat FSD. The present disclosure provides compounds and compositions that can be used to treat female sexual dysfunction.

[0004] The inventors have surprisingly discovered that compounds of formula (I) described herein are able to improve parameters associated with improved sexual function and sexual behavior associated with FSD in female animal models. The examples herein unexpectedly demonstrate that compounds of formula (I) cause increased blood flow to the clitoris, similar to the effects of clitoral nerve stimulation, and increased genital temperature by increasing clitoral temperature. In addition, the inventors have also demonstrated that compounds of formula (I) cause an increase in paracoital behavior or "courtship" in female rats.

[0005] Thus, the present invention demonstrates that compounds of formula (I) simultaneously address both the physical and behavioral components of FSD, which can translate into effects on sexual interest, arousal, desire and sexual pain associated with FSD.

[0006] Therefore, in one main aspect, there is provided a compound of formula (I)

[0007]

[0008] or a pharmaceutically acceptable salt thereof, for treating, preventing or alleviating female sexual dysfunction in a subject.

[0009] One aspect provides a pharmaceutical composition comprising a compound of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, for treating, preventing or alleviating female sexual dysfunction in a subject.

[0012] One aspect provides a compound of formula (I)

[0013]

[0014] Used for preparing medicine for treating female sexual dysfunction.

[0015] In another aspect, a method for treating, preventing or alleviating female sexual dysfunction is provided, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0016] In another aspect, provided is a method of 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.

[0017] In another aspect, provided is a method of increasing genital blood flow 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.

[0018] In another aspect, the present disclosure provides a method of increasing sexual desire, sexual interest, sexual arousal, lubrication, 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.

[0019] In another aspect, the present disclosure provides a method for reducing the difficulty of a subject to achieve orgasm during sexual stimulation or sexual intercourse, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] In a final aspect, the present disclosure provides a method of reducing sexual pain 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

[0021] Figure 1 : Preparation of female rat. A. Female genital region of interest. B. Positioning of laser Doppler. C. Positioning of thermal imaging camera.

[0022] Figure 2: Laser Doppler experimental data and averages of IP2015 infusion doses in female reproductive organs. A. Experimental visualization of the effect of IP2015 after administration. B. Changes in the average amplitude response of IP2015 due to different administration doses of IP2015. C. Changes in the average time response of IP2015 due to different administration doses of IP2015. D. Changes in the average frequency response of IP2015 due to different administration doses of IP2015.

[0023] Figure 3 : 4x magnified thermogram images of IP2015 infusion in rat female reproductive organs change. A. Thermogram view of control / basal. B. Thermogram view of IP2015 infusion at 0.3 mg / Kg. C. Thermogram view of IP2015 infusion at 10 mg / Kg. D. Anal / core temperature measured at IP2015 infusion doses.

[0024] Figure 4 : Thermogram averages of IP2015 infusion in rat female reproductive organs and related structures. A. Quantified chest / thoracic thermogram values ​​obtained during IP2015 dose infusion. B. Quantified vaginal thermogram values ​​obtained during IP2015 dose infusion. C. Quantified clitoral / urethra thermogram values ​​obtained during IP2015 dose infusion. Comparison by one-way ANOVA with Tukey post hoc test. P<0.05 * .

[0025] Figure 5 .A. Representative raw laser Doppler traces showing that IP2015 infusion increases clitoral blood flow in anesthetized female rats. A 1-minute infusion of a pulse dose of IP2015 (1 mg / kg) (shown as gray bars) was given into the jugular vein. IP2015 increases blood flow measured by laser Doppler in the clitoral cavernous tissue. The recording duration was 5 minutes. B. Representative raw laser Doppler traces showing that stimulation of the clitoral cavernous nerve increases blood flow in anesthetized female rats to a level comparable to the IP2015 infusion dose. The cavernous nerves were stimulated with electric field stimulation (EFS, 10 Hz, 1 ms pulses, 6 V, shown as gray bars). EFS increases flow measured by laser Doppler in the cavernous tissue. The recording duration was 5 minutes.

[0026] Figure 6.Average effects of increasing doses of IP2015 on clitoral blood flow in female rats. A. Average mean clitoral blood flow, and B. Peak clitoral blood flow. IP2015 dose-dependently increased both mean and peak blood flow in the clitoral region. Data are presented as mean ± SEM, n=6 and n=5 rats infused with IP2015 and vehicle, respectively. Statistical significance was defined as *p<0.05 compared to vehicle by two-way ANOVA.

[0027] Figure 7 Mean effects of increasing doses of IP2015 on heart rate and blood pressure in female rats. A. Heart rate and B. Mean arterial blood pressure (MAP) at baseline (b / l) and after infusion of increasing doses of vehicle and IP2015. Data are presented as mean ± SEM, n=6 and n=5 rats infused with IP2015 and vehicle, respectively. Statistical significance was defined as *p<0.05 compared to vehicle, by comparison by two-way ANOVA.

[0028] Figure 8 .IP2015 increases sexual behavior in female rats with synchronized estrus. Effects of a single dose of vehicle, IP2015 (1 mg / kg and 10 mg / kg), and apomorphine on sexual behavior parameters in female rats. Effects of (A) IP2015 on ear wiggling, (B) IP2015 on number of jumps, and (C) IP2015 on darts in synchronized female rats. Data are presented as mean ± se mean for n = 10-12 rats. One-way ANOVA showed that jumping was significant, and post hoc tests showed that IP2015 (10 mg / kg) had a significant increase in the number of jumps compared to apomorphine treatment. Number of darts in rats treated with IP2015 (10 mg / kg) compared to vehicle and apomorphine ** P<0.01.

[0029] definition

[0030] As used herein, the term "female sexual dysfunction" or "FSD" generally refers to impaired female sexual function. Female sexual dysfunction includes orgasm suppression. Female sexual dysfunction includes, but is not limited to, multiple categories of diseases, conditions and disorders, including female hypoactive sexual desiredisorder / dysfunction (FHSDD or HSDD, used interchangeably herein), female orgasmic disorder / dysfunction (FOD), lack of sexual pleasure, female sexual interest / arousal disorder / dysfunction (FSIAD), female sexual arousal disorder / dysfunction (FSAD), sexual pain disorder / dysfunction and dyspareunia.

[0031] As used herein, the term "Female Sexual Function Index" or "FSFI" generally refers to a 19-item patient-reported outcome (PRO) instrument / questionnaire used in clinical trials to measure overall sexual function (Rosen R, Brown C et al., 2000) and to grade the severity of FSD, where individual domain questions of the FSFI have been used to measure specific components of sexual function, including:

[0032] A) Sexual Desire Domain (FSFI-D): (FSFI-; Questions 1-2 (Frequency, Level)

[0033] B) Sexual arousal domain: Questions 3-6 (level, confidence, satisfaction)

[0034] C) Lubrication area: Questions 7-10 (frequency, difficulty, frequency of maintenance, difficulty of maintenance)

[0035] D) Orgasm area: Questions 11-13 (frequency, difficulty, satisfaction)

[0036] E) Satisfaction area: Questions 14-16 (intimacy with partner, sexual relationship, overall sex life)

[0037] F) Pain domain: Questions 17-19 (frequency during vaginal penetration, frequency after vaginal penetration, level during or after vaginal penetration).

[0038] Responses are assessed on a 5-point scale (1 to 5) where higher numbers indicate higher levels of that particular component of sexual function and lower numbers indicate lower levels of that particular component of sexual function. Thus, lower numbers indicate more severe levels of sexual dysfunction. The FSFI and / or domain-level scores and interpretations of the full scale can be used to measure overall sexual function and grade the severity of FSD.

[0039] 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) instrument / questionnaire (Derogatis et al., 2008, Derogatis et al., 2021) used in clinical trials to measure overall sexual function and grade the severity of female sexual dysfunction (FHSDD). The total score can be calculated as the sum of the responses, ranging from 0 to 60, with higher scores indicating higher levels of distress. The FSDS-DAO is adapted from the validated, revised Female Sexual Distress Scale (FSDS-R) questionnaire. Question 13 of the FSDS-DAO (FSDS-DAO Q13) asks patients: "How often do you feel: bothered by low sexual desire?". Answers 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. DETAILED DESCRIPTION OF THE INVENTION

[0041] Compounds and compositions

[0042] One embodiment of the present disclosure provides a compound of formula (I),

[0043]

[0044] or a pharmaceutically acceptable salt thereof. The compounds disclosed herein are monoamine reuptake inhibitors. The ability of the compounds to inhibit the reuptake of monoamines dopamine, norepinephrine and serotonin in synaptosomes can be tested, for example, as described in WO 97 / 30997 or WO 97 / 16451. It is reported that the IC of the hydrochloride salt of the compound of formula (I) is 50 The values ​​are: 0.0029 μM (serotonin), 0.07 μM (dopamine), 0.0038 μM (norepinephrine) (US 9,133,184 B1).

[0045] In one embodiment, the compound of Formula (I) has the structure of Formula (Ia);

[0046]

[0047] or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the compound is 7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromene-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-chromene-2-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the name "IP2015" represents a compound of formula I. In one embodiment, the name "IP2015" represents a compound of formula Ia. In a specific embodiment of the present disclosure, "IP2015" represents the hydrochloride salt of a compound of formula I.

[0049] In one embodiment, pharmaceutically acceptable salts are salts of organic or inorganic counterions. In one embodiment, pharmaceutically acceptable salts are selected from the list consisting of: hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formates, acetates, aconates, ascorbates, benzenesulfonates, benzoates, cinnamates, citrates, embonates, enanthate, fumarates, glutamate, glycolate, lactate, maleate, malonate, mandelate, mesylate, naphthalene-2-sulfonate, phthalates, salicylates, sorbates, stearates, succinates, tartrates, toluene-p-sulphonate. Other pharmaceutically acceptable salts are known to those skilled in the art. This salt can be formed by the well-known methods described in the art.

[0050] 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.

[0051] The compounds disclosed herein are monoamine reuptake inhibitors. The ability of the compounds to inhibit the reuptake of the monoamines dopamine, norepinephrine and serotonin in synaptosomes can be tested, for example, as described in WO 97 / 30997 or WO 97 / 16451. It is reported that the IC of the hydrochloride salt of the compound of formula (I) is 50 The values ​​are: 0.0029 μM (serotonin), 0.07 μM (dopamine), 0.0038 μM (norepinephrine) ( US 9,133,184 B1 ).

[0052] One embodiment of the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)

[0053]

[0054] and at least one pharmaceutically acceptable carrier, excipient or diluent. In the context of the present disclosure, any reference to the administration or use of the disclosed compounds should be interpreted as also extending to the administration or use of the disclosed compositions.

[0055] In one embodiment, the composition is a pharmaceutical composition. In one embodiment of the present disclosure, the composition is formulated for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or in a form suitable for inhalation or inflation administration, including powder and liquid aerosol administration, or by a sustained release system.

[0056] Female sexual dysfunction

[0057] The compounds of the present disclosure show potential in the treatment of female sexual dysfunction (FSD).

[0058] Therefore, one embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating female sexual dysfunction.

[0059] For example, female sexual dysfunction may be of physiological or psychological origin.

[0060] In one embodiment, the female sexual dysfunction is selected from the group consisting of:

[0061] (i) Female sexual interest / arousal disorder (FSIAD),

[0062] (ii) Low libido and dysfunctional function,

[0063] (iii) Female sexual arousal dysfunction,

[0064] (iv) orgasmic dysfunction,

[0065] (v) sexual pain disorders, and

[0066] (vi) Dyspareunia.

[0067] As shown in the examples, the compound of formula (I) is applied, similar to stimulating the clitoral nerve, to increase clitoral blood flow. In addition, the compound of formula (I) can increase clitoral temperature or vaginal temperature. These effects are also signs of normal sexual arousal, where increased blood flow to the clitoral corpus cavernosum and labial arteries leads to increased pressure in the clitoral corpus cavernosum, swelling, clitoral protrusion, and eversion and congestion of the labia minora (Bergman., 2005). Therefore, as shown in the examples, the increase in genital blood flow and temperature is associated with increased genital lubrication, increased sexual arousal, desire satisfaction, and climax.

[0068] Subjects suffering from female sexual arousal disorder (female sexual interest disorder; sexual arousal disorder) have little or no interest in sex and no subjective or physical response to sexual stimulation. Depending on the age of the subject and the duration of the relationship, the decline in interest and ability to be sexually aroused is greater than expected. If the lack of sexual interest and the inability to be sexually aroused make the subject feel distressed, and if there is a lack of interest throughout the sexual experience, the lack of sexual interest and the inability to be sexually aroused are considered to be a disorder. In one embodiment, FSD is defined in the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the contents of which are incorporated herein by reference. In one embodiment of the present disclosure, FSD is female sexual interest / arousal disorder (FSIAD), which includes FSAD and FHSDD. FOD and FSIAD are defined in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the contents of which are incorporated herein by reference.

[0069] Diagnostic criteria for FSIAD include absent or significantly diminished sexual interest / arousal, as manifested by at least three of the following: (1) absent / diminished interest in sexual activity; (2) absent / diminished sexual / erotic thoughts or fantasies; (3) failure to initiate / diminished initiation of sexual activity and generally not accepting attempts initiated by a partner; (4) absent / diminished sexual excitement / pleasure during sexual activity in nearly all or all sexual encounters; (5) absent / diminished sexual interest / arousal in response to any internal or external sexual / erotic cues; and (6) absent / diminished genital or non-genital sensation during sexual activity in nearly all or all sexual encounters. In FSIAD, these symptoms persist for a minimum of about six months and cause the subject significant distress.

[0070] As shown in the examples, the compounds of formula (I) increased para-copulatory or courtship behavior in female rats, as evidenced by increased jumping and lunging in female rats. Thus, the ability of the compounds to increase sexual interest or the desire to engage in sexual activity is emphasized.

[0071] Female hyposexual desire disorder (FHSDD) is characterized by an absence or markedly reduced desire or motivation to engage in sexual activity, manifested by any of the following: 1) reduced or absent spontaneous desire (sexual thoughts or fantasies); 2) reduced or absent desire in response to sexual cues and stimuli; or 3) once initiated, the inability to sustain desire or interest in sexual activity. A pattern of reduced or absent spontaneous or responsive desire, or inability to sustain desire or interest in sexual activity, occurs intermittently or persistently over a period of at least several months and is associated with clinically significant distress. In one embodiment of the present disclosure, FSD is hyposexual desire disorder.

[0072] Hypoactive sexual desire disorder / function includes conditions in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties. Anorgasmia includes diminished or absent pleasure during sexual activity. Sexual arousal disorder / function may be caused by decreased estrogen, disease, or treatment with diuretics, antihistamines, antidepressants, or antihypertensives.

[0073] In one embodiment, hypoactive sexual desire dysfunction is lifelong hypoactive sexual desire dysfunction or acquired hypoactive sexual desire dysfunction. In one embodiment of the present disclosure, hypoactive sexual desire dysfunction is generalized hypoactive sexual desire dysfunction or situational hypoactive sexual desire dysfunction. Lifelong, generalized hypoactive sexual desire dysfunction is characterized in that the subject has been experiencing hypoactive sexual desire dysfunction since the initiation of sexual activity, and the desired response is currently lacking or diminished in all situations (including masturbation). Lifelong, situational hypoactive sexual desire dysfunction is characterized in that the subject has been experiencing hypoactive sexual desire dysfunction since the initiation of sexual activity, and the desired response is currently lacking or diminished in some cases, with certain partners or in response to certain stimuli, but not in other cases. Generalized, acquired hypoactive sexual desire dysfunction is characterized in that the patient develops hypoactive sexual desire dysfunction after a period of time without experiencing hypoactive sexual desire dysfunction, and the desired response is currently absent or diminished in all situations (including masturbation). Situational, acquired hypoactive sexual desire dysfunction is characterized in that the patient develops hypoactive sexual desire dysfunction after a period of time without experiencing hypoactive sexual desire dysfunction, and the desired response is currently absent or diminished in some cases, with certain partners or in response to certain stimuli, but not in other cases. In one embodiment, the hypoactive sexual desire dysfunction is unspecified hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is lifelong, generalized hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is lifelong, situational hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is acquired, generalized hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is acquired, situational hypoactive sexual desire dysfunction.

[0074] In one embodiment of the present disclosure, hyposexual dysfunction is characterized by:

[0075] (i) Decreased or absent spontaneous desire,

[0076] (ii) decreased or absent sexual desire in response to sexual cues and stimuli, and / or

[0077] (iii) Inability to maintain desire or interest in sexual activity after initiation.

[0078] In one embodiment of the present disclosure, the inability to maintain desire or interest in sexual activity has occurred intermittently or persistently over a period of at least several months (e.g., 3, 4, 5, 6, 7, or 8 months) and / or is associated with clinically significant distress.

[0079] Sexual arousal dysfunction includes difficulties with the physiological or subjective aspects of sexual arousal. In one embodiment of the present disclosure, FSD is sexual arousal dysfunction (female sexual arousal dysfunction or FSAD). In one embodiment of the present disclosure, FSD is female sexual interest / arousal disorder / dysfunction (FSIAD). Female sexual arousal dysfunction (FSAD) is characterized by a lack or significant reduction in female response to sexual stimulation, manifested as any of the following: 1) lack or significant reduction in genital response, including vulvovaginal lubrication, genital congestion, and genital sensitivity; 2) lack or significant reduction in non-genital response, such as nipple hardening, skin flushing, increased heart rate, increased blood pressure, and increased respiratory rate; 3) lack or significant reduction in sexual arousal (sexual excitement and sexual pleasure) sensation from any type of sexual stimulation. Despite the desire for sexual activity and adequate sexual stimulation, the lack or significant reduction in response to sexual stimulation still occurs, occurs intermittently or persistently over a period of at least several months, and is associated with clinically significant distress.

[0080] In one embodiment, female sexual arousal dysfunction (FSAD) is lifelong female sexual arousal dysfunction or acquired female sexual arousal dysfunction. In one embodiment, female sexual arousal dysfunction is generalized female sexual arousal dysfunction or situational female sexual arousal dysfunction. In one embodiment of the present disclosure, female sexual arousal dysfunction is unspecified female sexual arousal dysfunction. Lifelong, generalized female sexual arousal dysfunction is characterized in that the subject has been experiencing female sexual arousal dysfunction since the initiation of the relevant activity, and the desired response is currently absent or diminished in all situations (including masturbation). Lifelong, acquired female sexual arousal dysfunction is characterized in that the subject has been experiencing female sexual arousal dysfunction since the initiation of related sexual activities, and the desired response is currently lacking or diminished in some cases, with certain partners or in response to certain stimuli, but not in other cases. Acquired, widespread female sexual arousal dysfunction is characterized in that the patient develops female sexual arousal dysfunction after a period of time without experiencing female sexual arousal dysfunction, and in all cases (including masturbation), the desired response is currently lacking or diminished. Acquired, situational female sexual arousal dysfunction is characterized in that the patient develops female sexual arousal dysfunction after a period of time without experiencing female sexual arousal dysfunction, and in all cases (including masturbation), the desired response is currently lacking or diminished. In one embodiment, female sexual arousal dysfunction refers to non-specific female sexual arousal dysfunction. In one embodiment, female sexual arousal dysfunction is lifelong, widespread female sexual arousal dysfunction. In one embodiment, female sexual arousal dysfunction is lifelong, situational female sexual arousal dysfunction. In one embodiment, female sexual arousal dysfunction is acquired, generalized female sexual arousal dysfunction. In one embodiment, female sexual arousal dysfunction is acquired, situational female sexual arousal dysfunction.

[0081] In one embodiment, female sexual arousal dysfunction (FSAD) is characterized by:

[0082] (i) absence or marked reduction in genital responsiveness, including vulvovaginal lubrication, genital engorgement, and genital sensitivity,

[0083] (ii) absence or marked reduction of non-genital responses such as hardening of the nipples, flushing of the skin, increased heart rate, blood pressure, and respiratory rate, and / or

[0084] (iii) Absence or marked reduction in feelings of sexual arousal (e.g., excitement and pleasure) from any type of sexual stimulation.

[0085] In one embodiment, the absent or significantly diminished response to sexual stimulation occurs despite desire for sexual activity and adequate sexual stimulation, occurs intermittently or persistently over a period of at least several months (e.g., 3, 4, 5, 6, 7, or 8 months), and / or is associated with clinically significant distress.

[0086] Orgasmic dysfunction or female orgasmic disorder / dysfunction (FOD) refers to difficulties associated with the subjective experience of orgasm. In one embodiment of the present disclosure, FSD is orgasmic dysfunction. In one embodiment, orgasmic dysfunction is not premature female orgasm.

[0087] In one embodiment, the orgasmic dysfunction is anorgasmia. Anorgasmia is characterized by the absence or significant infrequency of orgasmic experience, or a significant reduction in the intensity of orgasmic sensation. In women, this includes a significant delay in orgasm, while in men, this would be diagnosed as delayed ejaculation in men. A pattern of lack, delay, or reduced frequency or intensity of orgasm occurs despite adequate sexual stimulation, including desire for sexual activity and orgasm, occurs intermittently or persistently over a period of at least several months, and is associated with clinically significant distress.

[0088] In one embodiment, the anorgasmia is lifelong anorgasmia or acquired anorgasmia. In one embodiment, the anorgasmia is generalized anorgasmia or situational anorgasmia. In one embodiment, the anorgasmia is non-specific anorgasmia. Lifelong, generalized anorgasmia is characterized in that the subject has been experiencing anorgasmia since the initiation of the sexual activity, and the desired response is currently lacking or diminished in all situations (including masturbation). Lifelong, situational anorgasmia is characterized in that the subject has been experiencing anorgasmia since the initiation of the sexual activity, and the desired response is currently lacking or diminished in some cases, with certain partners or in response to certain stimuli, but not in other cases. Acquired, generalized anorgasmia is characterized in that the patient develops anorgasmia after a period of time without experiencing anorgasmia, and the desired response is currently lacking or diminished in all situations (including masturbation). Acquired, situational anorgasmia is characterized in that the patient develops anorgasmia after a period of not experiencing anorgasmia, and desired responses are currently absent or diminished in certain circumstances, with certain partners, or in response to certain stimuli, but not in other circumstances. In one embodiment, the anorgasmia is lifelong, generalized anorgasmia. In one embodiment, the anorgasmia is lifelong, situational anorgasmia. In one embodiment, the anorgasmia is acquired, generalized anorgasmia. In one embodiment, the anorgasmia is acquired, situational anorgasmia.

[0089] In one embodiment, anorgasmia is characterized by the absence or significant infrequency of orgasmic experiences and / or a significant reduction in the intensity of orgasmic sensations.

[0090] In one embodiment, the absence or marked infrequency of orgasmic experiences and / or marked reduction in the intensity of orgasmic sensations occurs despite adequate sexual stimulation, including desire for sexual activity and orgasm, occurs intermittently or persistently over a period of at least several months (e.g., 3, 4, 5, 6, 7, or 8 months), and / or is associated with clinically significant distress.

[0091] In one embodiment, the FSD is sexual pain disorder. Sexual pain disorder refers to marked and persistent or recurring difficulties associated with the experience of pain during sexual activity in adults that are not entirely attributable to an underlying medical condition, insufficient lubrication in women, age-related changes, or changes associated with menopause in women, and are associated with clinically significant distress.

[0092] In one embodiment, the sexual pain disorder is sexual pain-insertion disorder. Sexual pain-insertion disorder is characterized by at least one of the following: 1) marked and persistent or recurrent difficulty with penetration, including difficulty due to involuntary tightening or tightening of the pelvic floor muscles during attempted penetration; 2) marked and persistent or recurrent vulvovaginal or pelvic pain during penetration; 3) marked and persistent or recurrent fear or anxiety of vulvovaginal or pelvic pain in anticipation of, during, or as a result of penetration. The symptoms are recurrent during sexual interactions involving or potentially involving penetration, despite adequate sexual desire and sexual stimulation, are not entirely attributable to a medical condition or psychiatric disorder that adversely affects the pelvic region and causes genital and / or insertion pain, are not entirely attributable to insufficient vaginal lubrication or postmenopausal / age-related changes, and are associated with clinically significant distress.

[0093] In one embodiment, sexual pain-insertion disorder is lifelong sexual pain-insertion disorder or acquired sexual pain-insertion disorder. In one embodiment, sexual pain-insertion disorder is generalized sexual pain-insertion disorder or situational sexual pain-insertion disorder. In one embodiment, sexual pain-insertion disorder is non-specific sexual pain-insertion disorder. Lifelong, generalized sexual pain-insertion disorder is characterized in that the subject has been experiencing genital-pelvic pain or insertion disorder since the initiation of related activities, and in all cases (including masturbation), the desired response is currently lacking or weakened. Lifelong, situational sexual pain-insertion disorder is characterized in that the subject has been experiencing genital-pelvic pain or insertion disorder since the initiation of related activities, and in some cases, with certain partners or in response to certain stimuli, the desired response is currently lacking or weakened, but not in other cases. Acquired, generalized sexual pain-insertion disorder is characterized in that the subject develops genital-pelvic pain or insertion disorder after a period of time without experiencing genital-pelvic pain or insertion disorder, and in all cases (including masturbation), the desired response is currently lacking or weakened. Acquired, situational sexual pain-insertion disorder is characterized in that the subject develops genital-pelvic pain or insertion disorder after a period of not experiencing it, and the desired response is currently absent or diminished in some cases, with certain partners, or in response to certain stimuli, but not in other cases. In one embodiment, sexual pain-insertion disorder is lifelong, generalized sexual pain-insertion disorder. In one embodiment, sexual pain-insertion disorder is lifelong, situational sexual pain-insertion disorder. In one embodiment, sexual pain-insertion disorder is acquired, generalized sexual pain-insertion disorder. In one embodiment, sexual pain-insertion disorder is acquired, situational sexual pain-insertion disorder.

[0094] In one embodiment, sexual pain-insertion disorder is characterized by:

[0095] (i) marked, persistent or recurring difficulty with penetration, including difficulty due to involuntary tightening or tightening of the pelvic floor muscles during penetration attempts;

[0096] (ii) significant, persistent or recurring vulvovaginal or pelvic pain during penetration; and / or

[0097] (iii) marked, persistent, or recurring fear or anxiety of vulvovaginal or pelvic pain anticipated, during, or resulting from penetration.

[0098] In one embodiment, sexual pain-insertion disorder has the following symptoms:

[0099] (i) symptoms that occur repeatedly during sexual interactions that involve or could involve penetration, despite adequate sexual desire and stimulation,

[0100] (ii) symptoms that are not entirely attributable to a medical condition or psychiatric disorder that adversely affects the pelvic region and causes genital and / or penetration pain,

[0101] (iii) symptoms not entirely attributable to insufficient vaginal lubrication or postmenopausal / age-related changes, and

[0102] (iv) symptoms associated with clinically significant distress.

[0103] Dyspareunia is a reproductive symptom affecting women that is caused by physical determinants and is characterized by recurrent genital pain or discomfort (related to an identifiable physical cause, excluding lack of lubrication) that occurs before, during, or after sexual intercourse or superficial or deep vaginal penetration. Confirmed by medical evaluation of a physical cause. In one embodiment, FSD is dyspareunia. In one embodiment, FSD manifests as dyspareunia.

[0104] In one embodiment, the sexual pain disorder is vulvodynia or progressive vulvodynia. Vulvodynia is persistent, unexplained pain in the vulva, which is the female genital area including the skin around the vaginal opening.

[0105] In one embodiment, the female sexual dysfunction is:

[0106] (i) related to a medical condition, injury, or the effects of surgery or radiation therapy,

[0107] (ii) is associated with psychological or behavioural factors (including mental disorders),

[0108] (iii) is associated with the use of psychoactive substances or drugs,

[0109] (iv) related to lack of knowledge or experience,

[0110] (v) related to relationship factors,

[0111] (vi) related to cultural factors, and / or

[0112] (vii) Other specific etiological considerations.

[0113] In one embodiment, the female sexual dysfunction is female hypoactive sexual desire dysfunction.

[0114] In one embodiment, female sexual dysfunction is not caused by another disease (such as mental disorder). In one embodiment, female sexual dysfunction is not caused by genital injury. In one embodiment of the present disclosure, the subject is not in the treatment of a drug known to cause female sexual dysfunction.

[0115] In one embodiment of the present disclosure, the female sexual disorder is not female hypersexual disorder, such as premature female orgasm.

[0116] Patient population

[0117] In one embodiment of the present disclosure, the compound is capable of increasing the number of satisfying sexual events (SSE) in a subject. SSE is used as an outcome measure in clinical trials of female sexual dysfunction, see Kingsberg et al., 2011. SSE can be assessed as outlined in Derogatis et al., 2021 or Clayton et al., 2016.

[0118] In one embodiment of the present disclosure, the subject is a female. In one embodiment, the subject is a mammal. In one embodiment of the present disclosure, the subject is a human.

[0119] In one embodiment of the present disclosure, the subject is postmenopausal.

[0120] In one embodiment of the present disclosure, 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.

[0121] In one embodiment, the subject is less than 40 years old, such as less than 35 years old, such as less than 30 years old, such as less than 25 years old, such as less than 20 years old.

[0122] In one embodiment, the subject is aged between 20 and 25, or between 25 and 30, or between 30 and 35, or between 35 and 40, or between 40 and 45, or between 45 and 50, or between 50 and 55, or between 55 and 60, or between 60 and 65, or between 65 and 70, or between 70 and 75, or older.

[0123] Medical Uses

[0124] One embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating female sexual dysfunction. One embodiment of the present invention 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 for treating female sexual dysfunction.

[0125] One embodiment of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating, preventing or alleviating female sexual dysfunction. One embodiment of the present invention 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 for treating, preventing or alleviating female sexual dysfunction.

[0126] One embodiment of the present disclosure provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating female sexual dysfunction. One embodiment of the present disclosure provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing or alleviating female sexual dysfunction.

[0127] One embodiment of the present invention provides 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.

[0128] General and specific aspects of FSD can be assessed using the Female Sexual Function Index (FSFI). The FSFI is a 19-item self-rating scale designed to assess female sexual function. It includes six domains: desire (two items), arousal (four items), lubrication (four items), orgasm (three items), satisfaction (three items), and pain (three items). In one embodiment, the Female Sexual Function Index (FSFI) of the subject before treatment is less than 26.55, such as 25.00 to 26.55, such as 20.00 to 25.00, such as 15.00 to 20.00, such as 10.00 to 15.00, such as 5.00 to 10.00, such as 2.00 to 5.00.

[0129] In one embodiment, the compounds of the present disclosure are capable of increasing the FSFI of a subject. In one embodiment, the compounds are 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.

[0130] In one embodiment, the compounds of the present disclosure are capable of increasing the FSFI to above 26.55.

[0131] The compounds of the present disclosure may also have an effect, such as a positive effect on any one or more of the six domains of the FSFI (desire, arousal, lubrication, orgasm, satisfaction and pain), i.e., may increase the FSFI in any one or more of the six domains (desire, arousal, lubrication, orgasm, satisfaction and pain) or any one of the questions in each domain. In one embodiment, the compounds of the present disclosure may increase the score of any one of the questions in the FSFI questionnaire by 1 point, 2 points, 3 points or 4 points.

[0132] The compounds of the present disclosure may be particularly effective in improving the FSFI score in the field of pain. This is because the compounds of the present disclosure are monoamine neurotransmitter reuptake inhibitors. The questionnaire contains 3 questions related to pain, with a minimum score of 0 and a maximum score of 6.0. In some embodiments, the questions are graded according to a minimum score of 1 and a maximum score of 5. In one embodiment, the compounds of the present disclosure are able to improve the FSFI score of the subject in the field of pain. In one embodiment, the compounds of the present disclosure are able to improve the FSFI score in the field of pain 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 improve the score of FSFI question 17 (the first pain question), such as by increasing the score by 1 point, 2 points, 3 points, 4 points, or 5 points. In one embodiment, the compounds of the present disclosure can improve the score of FSFI question 18 (the second pain question), such as by increasing the score by 1 point, 2 points, 3 points, 4 points, or 5 points. In one embodiment, the compounds of the present disclosure can improve the score of FSFI question 19 (the third pain question), such as by increasing the score by 1 point, 2 points, 3 points, 4 points, or 5 points. The compounds of the present disclosure can also have an effect, such as a positive effect on any one or more of the other five domains (desire, arousal, lubrication, orgasm, and satisfaction), that is, can increase the FSFI in any one or more of the other five domains (desire, arousal, lubrication, orgasm, and satisfaction).

[0133] The compounds of the present disclosure may be particularly effective in improving the FSFI score in the desire domain (FSFI-D). The questionnaire contains 2 questions related to 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 are capable of improving the FSFI score of the subject in the desire domain. In one embodiment, the compounds of the present disclosure are capable of improving the FSFI score in the desire 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. In one embodiment, the compounds of the present disclosure are capable of improving the score of FSFI question 1 (the first desire question), for example, by improving the score by 1 point, 2 points, 3 points, or 4 points. In one embodiment, the compounds of the present disclosure are capable of improving the score of FSFI question 2 (the second desire question), for example, by improving the score by 1 point, 2 points, 3 points, or 4 points. The FSFI-D domain can be assessed by multiplying the score of each question in the desire domain by 0.6 and adding them together to form a FSFI-D domain score ranging from 1.2 to 6.0. Thus, in one embodiment, the compounds of the present disclosure are capable of increasing a subject's FSFI-D domain score by 0.6 points, such as by 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 compounds are capable of increasing a subject's FSFI-D domain score by 1.2 points, 2.4 points, 3.6 points, or 4.8 points.

[0134] In one embodiment, the compounds of the present disclosure are capable of improving the FSFI score in the arousal domain, or improving the score of any one of the questions in the arousal domain of the FSFI, such as improving the score of any one of questions 3 to 6 of the FSFI.

[0135] In one embodiment, the compounds of the present disclosure are capable of improving the FSFI score in the lubrication domain, or improving the score of any one of the questions in the lubrication domain of the FSFI, such as improving the score of any one of questions 7 to 10 of the FSFI.

[0136] In one embodiment, the compounds of the present disclosure are capable of improving the FSFI score in the orgasm domain, or improving the score of any question in the orgasm domain of the FSFI, such as improving the score of any one of questions 11 to 13 of the FSFI.

[0137] In one embodiment, the compounds of the present disclosure are capable of improving the FSFI score for the Satisfaction domain, or improving the score for any one of the questions in the FSFI Satisfaction domain, such as improving the score for any one of questions 14 to 16 of the FSFI.

[0138] General and specific aspects of FSD can be assessed using the FSFI-6, a 6-item Female Sexual Function Index questionnaire that measures sexual function in women (Isidori et al., 2010).

[0139] In one embodiment, the compounds of the present disclosure are capable of increasing FSFI-6 in a subject. In one embodiment, the compounds of the present disclosure are capable of increasing FSFI-6 by at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

[0140] 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 improving 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 improving FSFI-6 in a subject suffering from female sexual dysfunction.

[0141] One embodiment of the present disclosure provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a composition of the present disclosure in the preparation of a medicament for improving FSFI in a subject suffering from female sexual dysfunction. One embodiment of the present disclosure provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a composition of the present disclosure in the preparation of a medicament for improving FSFI-6 in a subject suffering from female sexual dysfunction.

[0142] 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.

[0143] General and specific aspects of FSD can be assessed using FSDS-DAO. FSDS-DAO is a 15-item patient-reported outcome (PRO) instrument / questionnaire used in clinical trials to measure overall sexual function and grade the severity of female sexual dysfunction (FHSDD) (Derogatis et al., 2008, Derogatis et al., 2021). In one embodiment, the female sexual function index (FSDS-DAO) of the subject before treatment is less than 60, such as 55 to 60, such as 50 to 55, such as 45 to 50, such as 40 to 45, such as 35 to 40, such as 30 to 35, such as 25 to 30, such as 20 to 25, such as 15 to 20, such as 10 to 15, such as 5 to 10, such as 0 to 10. In one embodiment, the female sexual function index FSDS-DAO of the subject before treatment is 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.

[0144] In one embodiment, the compounds of the present disclosure are capable of reducing FSDS-DAO in a subject. In one embodiment, the compounds are 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 9 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.

[0145] In one embodiment, the compounds of the present disclosure are capable of reducing the FSDS-DAO Question 13 (FSDS-DAO Q13) score of the subject. The compounds of the present disclosure may be particularly effective in improving Question 13 (FSDS-DAO Q13) of the FSDS-DAO, which asks the patient "How often do you feel: bothered by low sexual desire?", with a minimum score of 0 points and a score scale of 0 (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 are capable of reducing the FSDS-DAO Q13 score 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, or at least 4.0 points. In one embodiment, the compounds of the present disclosure are capable of reducing the FSDS-DAO Q13 score by 1, 2, 3 or 4 points.

[0146] General and specific aspects of FSD can be assessed using the Elements of Desire Questionnaire (EDQ). The EDQ is a patient-reported outcome (PRO) developed to assess sexual desire. The EDQ addresses attributes of desire, such as sexual desire, thoughts / fantasies about sex, and receptivity to sexual requests, with the goal of determining the effectiveness of medications for this condition across multiple aspects of the pathology. The EDQ is a 9-item PRO questionnaire designed to assess the efficacy of potential new treatments for women with FSD, HSDD, or FSIAD. Items (questions) 1, 2, 3, 4, 6, and 8 in the EDQ are assessed on a 5-point scale, with lower numbers indicating greater severity of functional abnormalities. Items 5 and 7 are assessed as “yes” and “no” responses.

[0147] In one embodiment, the compounds of the present disclosure are capable of improving a subject's EDQ score.

[0148] In one embodiment, the compounds of the present disclosure are capable of improving the score of any one of the questions of the EDQ, such as questions 1, 2, 3, 4, 5, 6, 7, 8, or 9. In one embodiment, the compounds of the present disclosure are capable of improving the score of any one of questions 1, 2, 3, 4, 6, and 8 of the EDQ by 1 point, 2 points, 3 points, or 4 points.

[0149] One aspect of the present invention provides a method of increasing the genital temperature of a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0150] In one embodiment, the increase in genital temperature is an increase in the temperature of any 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 and / or clitoral temperature.

[0151] One aspect of the present invention 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.

[0152] In one embodiment, the increase in genital blood flow is an increase in blood flow to any 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.

[0153] In another aspect, the present disclosure provides a method of increasing sexual desire, sexual interest, sexual arousal, lubrication, 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.

[0154] In another aspect, the present disclosure provides a method for reducing the difficulty of a subject to achieve orgasm during sexual stimulation or sexual intercourse, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0155] One aspect of the present disclosure provides a method of alleviating sexual pain in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0156] item

[0157] 1. Compound formula (I)

[0158]

[0159] or a pharmaceutically acceptable salt thereof, for use in treating, preventing or alleviating female sexual dysfunction in a subject.

[0160] 2. The compound for use according to item 1, wherein the compound has the structure of formula (Ia);

[0161]

[0162] or a pharmaceutically acceptable salt thereof.

[0163] 3. A compound for use according to any one of the preceding items, wherein the female sexual dysfunction is selected from the group consisting of:

[0164] (i) Female sexual arousal disorder,

[0165] (ii) Low libido and dysfunctional function,

[0166] (iii) Female sexual arousal dysfunction,

[0167] (iv) orgasmic dysfunction,

[0168] (v) sexual pain disorders, and

[0169] (vi) Dyspareunia.

[0170] 4. The compound for use according to any one of the preceding clauses, wherein the female sexual dysfunction is sexual arousal disorder.

[0171] 5. A compound for use according to item 3 or any of the preceding items, wherein the hyposexual dysfunction is characterized by:

[0172] (i) Decreased or absent spontaneous desire,

[0173] (ii) decreased or absent sexual desire in response to sexual cues and stimuli, and / or

[0174] (iii) Inability to maintain desire or interest in sexual activity after initiation.

[0175] 6. The compound for use according to item 3, wherein the orgasmic dysfunction is anorgasmia.

[0176] 7. The compound for use according to item 3, wherein the sexual pain disorder is sexual pain-insertion disorder.

[0177] 8. The compound for use according to item 7, wherein the sexual pain-insertion disorder is generalized sexual pain-insertion disorder or situational sexual pain-insertion disorder.

[0178] 9. The compound for use according to any one of items 7 and 8, wherein the sexual pain-insertion disorder has the following symptoms:

[0179] (i) symptoms that occur repeatedly during sexual interactions involving or potentially involving penetration, despite adequate sexual desire and stimulation,

[0180] (ii) symptoms that are not entirely attributable to a medical condition or psychiatric disorder that adversely affects the pelvic region and causes genital pain and / or painful penetration,

[0181] (iii) symptoms not entirely attributable to insufficient vaginal lubrication or postmenopausal / age-related changes, and

[0182] (iv) symptoms associated with clinically significant distress.

[0183] 10. A compound for use according to any one of the preceding items, wherein the female sexual dysfunction is:

[0184] (i) related to a medical condition, injury, or the effects of surgery or radiation therapy,

[0185] (ii) associated with psychological or behavioural factors including mental disorders,

[0186] (iii) is associated with the use of psychoactive substances or drugs,

[0187] (iv) related to lack of knowledge or experience,

[0188] (v) related to relationship factors,

[0189] (vi) related to cultural factors, and / or

[0190] (vii) Other specific etiological considerations.

[0191] 11. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is female hyposexual dysfunction.

[0192] 12. A compound for use according to any of the preceding items, wherein before treatment the subject's Female Sexual Function Index (FSFI) is greater than 26.55, such as 25.00 to 26.55, such as 20.00 to 25.00, such as 15.00 to 20.00, such as 10.00 to 15.00, such as 5.00 to 10.00, such as 2.00 to 5.00.

[0193] 13. A method of increasing vaginal temperature in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I)

[0194]

[0195] or a pharmaceutically acceptable salt thereof.

[0196] 14. A method of increasing clitoral blood flow in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I)

[0197]

[0198] or a pharmaceutically acceptable salt thereof.

[0199] 15. A method of increasing clitoral temperature in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I)

[0200]

[0201] or a pharmaceutically acceptable salt thereof. Example

[0202] Example 1: In vitro efficacy

[0203] Materials and methods

[0204] Compounds were tested for their ability to inhibit the reuptake of the monoamine neurotransmitter substances dopamine (DA), norepinephrine (NA) and serotonin (5-HT) in synaptosomes as described in WO 97 / 16451 (NeuroSearch A / S).

[0205] result

[0206] Test value is IC 50 (inhibition 3 H-DA, 3 H-NA, or 3 The concentration of the test substance at which 50% of the specific binding of H-5-HT is obtained is given in μM. See Table 1.

[0207] Table 1: Test results obtained by testing exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one.

[0208]

[0209] Example 2: Evaluation of the effect of the compound of formula (I) on female reproductive organs of rats

[0210] Materials and methods

[0211] Animals: The experimental setup was run in two different sets of measurement procedures to avoid differences between each other. The first set of experiments was performed in control female rats, and the second set of experiments was performed in a depression model called the Flint sensitive line (FSL), which has molecular similarities to patients with major depressive disorder.

[0212] Anesthesia and general surgical procedures: rats were injected intraperitoneally with 50 mg / Kg of pentobarbital. After 10 minutes under dark conditions, the pinch point in the interdigital area confirmed the lack of response to the reflex, and the animal was placed on the table and the legs were half extended with tape to fix the animal. The area of ​​interest (abdomen-groin and neck) was shaved and cleaned and disinfected with water and ethanol. After each study was completed, the animal was killed by an overdose of pentobarbital and the atlanto-occipital joint was cut to ensure painless surgery for the animal.

[0213] Measurement of clitoral blood flow and genital temperature: Nylon 4-0 sutures with a needle were used to extend the urethral opening and expose the mucosa. To obtain the best visualization of the clitoris, we pulled one suture on each side of the urethral wall and then another suture proximal to the medial side of the urethral opening to better extend the skin cranially and expose the clitoral mucosal area ( Figure 1 A). The anterior clitoris was measured using a calibrated laser Doppler flow probe (VP1T, Moor instruments UK) connected to a laser Doppler flow monitor: MOORVMS-LDF2 (Moor instruments-UK). The laser Doppler probe was placed and fixed to the base and alligator clip to avoid any movement. The tip of the calibrated probe was immersed in a water-based gel in the exposed area of ​​the urethra-clitoris ( Figure 1 B). In addition, right lateral dissection was performed to clean the jugular vein, which was used to insert another cannula for infusing different doses (0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg, 10 mg / Kg) of IP2015 or vehicle using a mechanical pump.

[0214] The anterior clitoris was measured using a calibrated laser Doppler flow probe (VP1T, Moor instruments UK) connected to a laser Doppler flow monitor: MOORVMS-LDF2 (Moor instruments-UK). After a stabilization period of 10-20 minutes, baseline control measurements were obtained 5 minutes before the jugular vein infusion of vehicle or increasing doses (0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg and 10 mg / Kg) of IP2015, and blood flow changes were recorded. The infusion protocol was performed as a group with 1 minute infusion + 4 minutes of further recording of blood flow changes recorded by the system. As described below, electric field stimulation of the cavernous nerve to the clitoris was used as a positive control.

[0215] The thermal image FLIR camera (E96, InfraTec, Germany, Figure 1 ) is located 50 cm from the area of ​​interest ( Figure 1 C). Three regions of interest (chest, vagina, and urethra-clitoris) were recorded by digital markers located using Research Studio-FLIR, and data were extracted and imported into Excel. After a 10-20 minute stabilization period, baseline control measurements were obtained 5 minutes before the jugular vein infusion of vehicle or increasing doses (0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg, and 10 mg / Kg) of IP2015, and changes in genital temperature were recorded.

[0216] Measurement of mean arterial pressure and heart rate: Anesthetized rats were breathing spontaneously, body temperature was continuously monitored, and they were kept on a heating blanket at 37.5°C. Heparinized (100IE mL) 1% BP was connected to a pressure transducer (disposable BP sensor, AD Instruments, UK). -1) Polyethylene (PE) catheters (PE-50) were 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 on a computerized data acquisition system (PowerLab, ADInstruments).

[0217] Measurement of clitoral blood flow after electrical stimulation of the clitoral cavernous nerve: The clitoral cavernous nerve was isolated through a lower abdominal incision and electrically stimulated with a thin bipolar platinum electrode connected to an S48 stimulator (Grass Instrument Co., Boston, MA, USA). To investigate whether nerve stimulation leads to changes in the hemodynamics of clitoral tissue, male rats were stimulated as described previously

[12] with parameters that elicited a maximal response amplitude (6 V, 10 Hz, 1 ms square wave pulses for 30 s), and flow was measured with laser Doppler. Clitoral blood flow was measured by laser Doppler as described above.

[0218] Genital Blood Flow Results

[0219] Laser Doppler measurements of the clitoral region of female Sprague Daley rats showed that infusion of IP2015 (0.3 mg / kg to 10 mg / kg) increased the frequency, duration, and amplitude of blood flow in the clitoral region ( Figure 2 In addition, compared with vehicle, mean clitoral blood flow ( Figure 6 A) and peak clitoral blood flow ( Figure 6 B) increased significantly.

[0220] Peak clitoral blood flow after IP2015 infusion ( Figure 2 A, 4.49V) and the peak blood flow of the clitoris after electrical stimulation of the clitoral cavernous nerve ( Figure 5 , 4.31V) equivalent.

[0221] Genital temperature

[0222] Sexual arousal and desire have been shown to increase genital temperature (Kukkonen et al., 2007). Thermal images at 4x magnification after infusion of IP2015 (0.3 mg / kg to 10 mg / kg) and control ( Figure 3 AC) and core temperature ( Figure 3 D). The extracted quantitative data are presented in histograms according to the different regions of interest (breast, vagina, and urethra-clitoris) ( Figure 4 AC).

[0223] Measurements of temperature using a thermographic camera showed that basal surface temperature varied depending on the area examined on the animal and changed during infusion of increasing doses of IP2015 ( Figure 3 AC, Figure 4 AC). Recording conditions were optimized by magnifying the region of interest. Quantification at 4x magnification showed that infusion of increasing doses of IP2015 in depressed FSL rats caused a dose-dependent increase in temperature in the vaginal and clitoral regions ( Figure 3 AC, Figure 4 AC). During the infusion of IP2015, there was no change in core temperature measured with a conventional rectal thermometer ( Figure 3 D). The increase in genital temperature observed after IP2015 treatment provides further evidence that IP2015 can cause an increase in sexual arousal and sexual desire. In addition, the increase in clitoral temperature observed after IP2015 treatment provides further evidence that IP2015 can cause an increase in sexual arousal and sexual desire, especially in FSD.

[0224] Mean arterial pressure (MAP) and heart rate (HR)

[0225] After infusion of IP2015 (0.3 mg / kg to 10 mg / kg), MAP in female Sprague Daley rats was comparable to that of vehicle ( Figure 7 However, after infusion of IP2015 (0.3 mg / kg to 10 mg / kg), the HR of female Sprague Daley rats increased significantly to vehicle ( Figure 7 B).

[0226] in conclusion

[0227] In summary, IP2015 dose-dependently increased genital blood flow and surface temperature in both control Sprague Daley rats and the spontaneously depressed rat strain FSL. Furthermore, the increases in genital blood flow and clitoral temperature observed after IP2015 treatment provide further evidence that IP2015 can cause increases in sexual arousal and desire. Furthermore, the increases in clitoral temperature observed after IP2015 treatment provide further evidence that IP2015 can cause increases in sexual arousal and desire, particularly in FSD. These findings support the potential of IP2015 to improve sexual health in women.

[0228] Example 3: Evaluation of the effect of the compound of formula (I) on the sexual behavior of female rats

[0229] Materials and methods

[0230] Animals: Female Sprague Dawley rats (12-15 weeks old) were housed in an animal facility in UniversalEuro III length-width cages with standard wooden bedding and room for 2 rats in a clean environment with a comfortable temperature (22-23°C) and a 12:12 h light-dark cycle starting at 11:00 AM. They had free access to food and tap water.

[0231] Synchronization of the estrus sexual cycle in female rats: 250 μg of prostaglandin F was injected subcutaneously on days 0 and 3. 2α (PGF 2α ), female Sprague Dawley rats with an average body weight of 250 g were synchronized at the estrus phase of the sexual cycle.

[0232] Evaluation of the effects of apomorphine versus IP2015 on sexual behavior: On day 4, rats were injected with progesterone (1 mg / kg) 4 h before any testing and randomly divided into 2 injection groups, including vehicle (n=10), apomorphine (0.25 mg / kg) (n=10) and IP2015 (1 mg / kg and 10 mg / kg, n=12 per group) before any testing. Apomorphine has previously been shown to increase, for example, lordosis in female rats (Hamburger-Bar R et al., 2011) and reduce, for example, jumping and lunging in female rats (Snoeren et al., 2011) and was included as a positive control treatment. To study sexual behavior, synchronized female rats were paired with trained male rats and their behavior was recorded with two video cameras. The videos were quantified by a trained operator blinded to the procedure.

[0233] Data analysis and statistics: Statistical differences between vehicle, apomorphine and two different doses of IP2015 were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post hoc test. The assumptions of the model were investigated by examining the QQ plots, and the data were logarithmically transformed when necessary to generate a Gaussian distributed data set. If the data were biased, 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. Post hoc tests were performed only when F was significant and there was no heterogeneity of variance. All statistical analyses were performed using GraphPad Prism 9.5 software (GraphPad Software, CA, USA).

[0234] result

[0235] To investigate the effects of vehicle, IP2015, and apomorphine on sexual behavior in rats with estrus-synchronized sexual cycles, we examined paracopulatory behaviors such as jumping, ear wiggling, and lunging in female rats pretreated with 250 μg of PGF2α.

[0236] The term "estrus" refers to the phase of the estrus cycle when sexually mature, non-pregnant females are receptive to male sexual advances. Prostaglandin F2α (PGF2α) is a naturally occurring luteolytic hormone that has also been used to synchronize estrus by shortening the length of the luteal phase.

[0237] Paracopulatory behavior, also known as courtship or active courtship behavior, is generally described as species-specific behavior displayed by estrous females during sexual interactions, during which females show sexual desire, arousal, and interest, and then establish and maintain sexual interactions by encouraging males to mate and regulating mating patterns ( Erskine, 1989 ).

[0238] Injection of vehicle did not alter paramour parameters ( Figure 8 Injection of two different doses of IP2015 did not alter ear wiggling ( Figure 8 A), but IP2015 at 10 mg / kg increased the number of jumps compared to apomorphine ( Figure 8 B). IP2015 dose-dependently increased the rush compared to vehicle and apomorphine ( Figure 8 C). The increase in jumping and lunging observed in female rats treated with IP2015 demonstrates the IP2015-induced increase in desire, arousal, and sexual interest. Apomorphine injection did not alter paracoital parameters ( Figure 8 ).

[0239] in conclusion

[0240] In summary, IP2015 increases sexual behavior in female rats in a dose-dependent manner, independent of the estrous cycle. The increase in jumping and lunging observed in female rats treated with IP2015 demonstrates the increase in desire, arousal, and sexual interest induced by IP2015. These findings support that IP2015 can improve sexual health by increasing sexual behavior and desire in women.

[0241] References

[0242] WO 97 / 30997.

[0243] WO 97 / 16451.

[0244] US 9,133,184 B2.

[0245] Allahdadi et al.,Cardiovasc Hematol Agents Med Chem.2009Oct;7(4):260–269.

[0246] Begrman,J.R.,2005.Physiology of female sexual functionanddysfunction.International journal of impotence research,17(1),pp.S44-S51.

[0247] Clayton et al.,Bremelanotide for female sexual dysunctionsinpremenopausal women:a randomized,placebo-controlled dose-findingtrial.Womens Health(Lond),12:325-337.

[0248] Derogatis et al.,J Patient Rep Outcomes,2021,5:100

[0249] Erskine,M.S.,1989.Solicitation behavior in the estrous female rat:areview.Hormones and behavior,23(4),pp.473-502.

[0250] Hamburger-Bar R,Rigter H.Apomorphine:Facilitation of sexualbehaviourin female rats.Eur J Pharmacol 1975;32.https: / / doi.org / 10.1016 / 0014-2999(75)90304-0.

[0251] Kingsberg SA,Althof SE.Satisfying sexual events as outcome measuresinclinical trial of female sexual dysfunction.J Sex Med.2011 Dec;8(12).

[0252] Isidori AM,Pozza C,Esposito K,Giugliano D,Morano S,Vignozzi L,CoronaG,Lenzi A,Jannini EA.Development and validation of a 6-itemversion of thefemale sexual function index(FSFI)as a diagnostic tool forfemale sexualdysfunction.J Sex Med.2010 Mar;7(3):1139-46.

[0253] Miller MK,Smith JR,Norman JJ,Clayton AH.Expert opinion on existinganddeveloping drugs to treat female sexual dysfunction.Expert OpinEmergDrugs.2018;23(3):223-230.

[0254] Rosen R,Brown C,et al.,2000,The Female Sexual Function Index(FSFI):AMultidimensional Self-Report Instrument for the Assessment of FemaleSexualFunction,J Sex Marital Ther,26(2):191-208.

[0255] Snoeren EMS,Chan JSW,De Jong TR,Waldinger MD,Olivier B,OostingRS.ANew Female Rat Animal Model for Hypoactive Sexual Desire Disorder;Behavioraland Pharmacological Evidence.J Sex Med 2011;8.https: / / doi.org / 10.1111 / j.1743-6109.2010.01998.x

[0256] T.M.Kukkonen,Y.M.Binik,R.Amsel,and S.Carrier,“Physiology:Thermographyas a physiological measure of sexual arousal in both men andwomen,”J.Sex.Med.4,93-105(2007).

Claims

1. A compound having the formula (I) or a pharmaceutically acceptable salt thereof, for use in treating, preventing or alleviating female sexual dysfunction in a subject.

2. The compound for use according to claim 1, wherein the compound has a structure of formula (Ia) or a pharmaceutically acceptable salt thereof.

3. The compound for use according to any one of claims 1 and 2, wherein 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.

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

5. A compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is selected from the group consisting of: (i) Female sexual interest / arousal disorder, (ii) Low libido and dysfunctional function, (iii) Female sexual arousal dysfunction, (iv) orgasmic dysfunction, (v) sexual pain disorders, and (vi) Dyspareunia.

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. The compound for use according to any one of the preceding claims, wherein the hyposexual dysfunction is lifelong hyposexual dysfunction or acquired hyposexual dysfunction.

8. The compound for use according to any one of the preceding claims, wherein the hyposexual dysfunction is generalized hyposexual dysfunction or situational hyposexual dysfunction.

9. The compound for use according to any one of the preceding claims, wherein the hyposexual dysfunction is non-specific hyposexual dysfunction.

10. A compound for use according to any one of the preceding claims, wherein the hyposexual dysfunction is characterized by: (i) a reduction or absence of spontaneous desire, (ii) a decrease in or absence of sexual desire in response to sexual cues and stimuli, and / or (iii) Inability to maintain desire or interest in sexual activity after initiation.

11. A compound for use according to any one of the preceding claims, wherein the inability to maintain desire or interest in sexual activity has occurred intermittently or persistently over a period of at least several months, such as 3, 4, 5, 6, 7 or 8 months, and / or is associated with clinically significant distress.

12. The compound for use according to any one of the preceding claims, wherein the female sexual arousal dysfunction is lifelong female sexual arousal dysfunction or acquired female sexual arousal dysfunction.

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

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

15. A compound for use according to any one of the preceding claims, wherein the female sexual arousal dysfunction is characterized by: (i) absence or marked reduction in genital responsiveness, including vulvovaginal lubrication, genital engorgement, and genital sensitivity, (ii) absence or marked reduction of non-genital responses such as hardening of the nipples, flushing of the skin, increased heart rate, blood pressure, and respiratory rate, and / or (iii) Absence or markedly diminished feelings of sexual arousal, such as excitement and pleasure, from any type of sexual stimulation.

16. A compound for use according to any of the preceding claims, wherein the lack of or markedly reduced response to sexual stimulation occurs despite desire for sexual activity and adequate sexual stimulation, occurs intermittently or persistently over a period of at least several months, such as 3, 4, 5, 6, 7 or 8 months, and / or is associated with clinically significant distress.

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

18. The compound for use according to any one of the preceding claims, wherein the anorgasmia is lifelong anorgasmia or acquired anorgasmia.

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

20. The compound for use according to any one of the preceding claims, wherein the anorgasmia is non-specific anorgasmia.

21. Compound for use according to any of the preceding claims, wherein the anorgasmia is characterized by the absence or marked infrequency of orgasmic experiences and / or by a marked reduction in the intensity of orgasmic sensations.

22. A compound for use according to any one of the preceding claims, wherein the absence or marked infrequency of orgasmic experience and / or marked reduction in the intensity of orgasmic sensation occurs despite adequate sexual stimulation, including desire for sexual activity and orgasm, occurs intermittently or persistently over a period of at least several months, such as 3, 4, 5, 6, 7 or 8 months, and / or is associated with clinically significant distress.

23. A compound for use according to any one of the preceding claims, wherein the sexual pain disorder is sexual pain-insertion disorder.

24. The compound for use according to any one of the preceding claims, wherein the sexual pain-insertion disorder is lifelong sexual pain-insertion disorder or acquired sexual pain-insertion disorder.

25. A compound for use according to any one of the preceding claims, wherein the sexual pain-insertion disorder is generalized sexual pain-insertion disorder or situational sexual pain-insertion disorder.

26. A compound for use according to any preceding claim, wherein the sexual pain-insertion disorder is non-specified sexual pain-insertion disorder.

27. A compound for use according to any one of the preceding claims, wherein the sexual pain-insertion disorder is characterized by: (i) marked, persistent or recurring difficulty with penetration, including difficulty due to involuntary tightening or tightening of the pelvic floor muscles during penetration attempts; (ii) significant, persistent or recurring vulvovaginal or pelvic pain during penetration; and / or (iii) marked, persistent, or recurring fear or anxiety of vulvovaginal or pelvic pain anticipated, during, or resulting from penetration.

28. A compound for use according to any one of the preceding claims, wherein the sexual pain-insertion disorder has symptoms of: (i) symptoms that occur repeatedly during sexual interactions that involve or could involve penetration, despite adequate sexual desire and stimulation, (ii) symptoms that are not entirely attributable to a medical condition or psychiatric disorder that adversely affects the pelvic region and causes genital and / or penetration pain, (iii) symptoms not entirely attributable to insufficient vaginal lubrication or postmenopausal / age-related changes, and (iv) symptoms associated with clinically significant distress.

29. A compound for use according to any preceding claim, wherein the sexual pain-insertion disorder is vulvodynia or progressive vulvodynia.

30. A compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is: (i) related to a medical condition, injury or the effects of surgery or radiation therapy, (ii) associated with psychological or behavioural factors including mental disorders, (iii) is associated with the use of psychoactive substances or drugs, (iv) related to lack of knowledge or experience, (v) related to relationship factors, (vi) related to cultural factors, and / or (vii) Other specific etiological considerations.

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

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 psychiatric 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 preceding claim, wherein the subject is not on medication known to cause female sexual dysfunction.

35. A compound for use according to any one of the preceding claims, wherein the female sexual disorder is not hypersexual disorder in women, such as premature female orgasm.

36. A compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the number of satisfying sexual events (SSE) in a subject.

37. A compound for use according to any one of the preceding claims, wherein the subject's Female Sexual Function Index (FSFI) before treatment is less than 26.55, such as 25.00 to 26.55, such as 20.00 to 25.00, such as 15.00 to 20.00, such as 10.00 to 15.00, such as 5.00 to 10.00, such as 2.00 to 5.

00.

38. A compound for use according to any preceding claim, wherein the compound is capable of increasing the FSFI of the subject.

39. A compound for use according to any one of the preceding claims, wherein the compound is capable of increasing 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, wherein the compound is capable of increasing the FSFI to above 26.

55.

41. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving the FSFI score in the painful area 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.

42. A compound for use according to any preceding claim, wherein the compound is capable of improving the FSFI score for question 17 (first pain question), such as by 1, 2, 3, 4 or 5 points.

43. A compound for use according to any preceding claim, wherein the compound is capable of improving the FSFI score for question 18 (second pain question), such as by 1, 2, 3, 4 or 5 points.

44. A compound for use according to any preceding claim, wherein the compound is capable of improving the FSFI score for question 19 (third pain question), such as by 1, 2, 3, 4 or 5 points.

45. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving FSFI scores in any one or more of the other five domains (desire, arousal, lubrication, orgasm and satisfaction).

46. ​​A compound for use according to any one of the preceding claims, wherein the compound is capable of increasing a subject's FSFI score in the desire domain.

47. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving a subject's FSFI score in the desire 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.

48. A compound for use according to any preceding claim, wherein the compound is capable of improving a subject's FSFI score for question 1 (the first desire question), for example by 1, 2, 3, 4 or 5 points.

49. A compound for use according to any preceding claim, wherein the compound is capable of improving a subject's FSFI score for question 2 (the second desire question), for example by 1, 2, 3, 4 or 5 points.

50. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving the FSFI score in the arousal domain, or improving the score of any one of the questions in the arousal domain of the FSFI, such as improving the score of any one of questions 3 to 6 of the FSFI.

51. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving the FSFI score in the area of ​​lubrication, or improving the score of any question in the area of ​​lubrication of the FSFI, such as improving the score of any one of questions 7 to 10 of the FSFI.

52. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving the FSFI score in the orgasm domain, or improving the score of any one of the questions in the orgasm domain of the FSFI, such as improving the score of any one of questions 11 to 13 of the FSFI.

53. A compound for use according to any one of the preceding claims, wherein the compound is capable of improving the FSFI score in the Satisfaction domain, or improving the score of any one of the questions in the FSFI Satisfaction domain, such as improving the score of any one of questions 14 to 16 of the FSFI.

54. A compound for use according to any preceding claim, wherein the compound is capable of increasing FSFI-6 in a subject.

55. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing 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 of the preceding claims, wherein the compound 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, wherein the compound is capable of reducing the score of FSDS-DAO Question 13 (FSDSDAO Q13) 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 or at least 4.0 points.

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

59. A compound for use according to any preceding claim, wherein the compound is capable of improving a subject's EDQ score.

60. A compound for use according to any preceding claim, wherein the compound is capable of improving the score on any question of the EDQ.

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

62. A compound for use according to any preceding claim, wherein the subject is a mammal.

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

64. A compound for use according to any preceding claim, wherein the subject is fertile.

65. A compound for use according to any preceding claim, wherein the subject is premenopausal.

66. A compound for use according to any preceding claim, wherein the subject is postmenopausal.

67. A compound for use according to any preceding claim, wherein the subject is postmenopausal.

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

69. The compound for use according to claim 15, wherein the subject is less than 40 years old, such as less than 35 years old, such as less than 30 years old, such as less than 25 years old, such as less than 20 years old.

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

71. Use of a compound of formula (I) for preparing a medicament for treating female sexual dysfunction, 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): or a pharmaceutically acceptable salt thereof.

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

74. A method of 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.

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

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

77. A method of increasing the genital temperature of a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

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

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

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

81. A method of increasing sexual desire, sexual interest, sexual arousal, lubrication, 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.

82. A method of reducing sexual pain in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

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

Images