Compound for treatment of female sexual dysfunction

Abstract

The disclosure relates treatment of female sexual dysfunction with a chromen-2-one compound.

Description

[0001] Compound for treatment of female sexual dysfunction

[0002] Technical field

[0003] The present disclosure relates to the treatment of female sexual dysfunction using a small-molecule drug.

[0004] Background

[0005] Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women and there are few treatment options (Allahdadi et al. 2009). FSD is more typical as women age and is a progressive and widespread condition. Female sexual dysfunction includes a heterogeneous group of sexual disorders, including difficulties with desire, arousal, lubrication, orgasm, or pain (dyspareunia) that may result in personal and interpersonal distress and impair a woman’s overall health and quality of life (Parish SJ et al.).

[0006] In comparison to the overwhelming research and treatment for erectile dysfunction in males, specifically with the development of phosphodiesterase type 5 inhibitors, significantly less has been explored regarding FSD. FSD is a more complex condition than male erectile dysfunction, with aspects relating to interest, arousal and desire being more relevant in FSD.

[0007] Common symptoms associated with FSD include diminished vaginal lubrication, pain and discomfort upon intercourse, decreased sense of arousal and difficulty in achieving orgasm. Only a small percentage of women seek medical attention. The treatment is primarily limited to psychological therapy, although different pharmacological modalities have been developed though with low efficacy and adverse effects (Miller et al., 2018).

[0008] Accordingly, there is an unmet need for therapies able to treat FSD effectively. Summary

[0009] The present disclosure addresses the above-mentioned need for candidates in the therapeutic treatment of female sexual dysfunction providing the use of a compound of formula I, as described herein. The inventors have surprisingly discovered that the compound of formula I is able to improve sexual behaviour in female animals having impaired sexual responses. The data demonstrates that the compound of formula I improves para-copulatory and copulatory behaviours in female animals. The behavioural studies reported herein highlight the ability of the compound to address key aspects of FSD related to interest, arousal and desire.

[0010] Thus, in one main aspect, a compound of formula (I) is provided: formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject.

[0011] One aspect provides for the use of a compound of formula (I), formula (I), for the manufacture of a medicament for the treatment of female sexual dysfunction.

[0012] One aspect provides for a method of treatment, prevention, or alleviation of 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), formula (I), or a pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides for a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment, prevention or alleviation of depression and / or anxiety in a subject, wherein said subject suffers from female sexual dysfunction.

[0013] In another aspect, a method of increasing sexual desire, sexual interest, sexual arousal, or a combination thereof, in a subject is provided, the method comprising administering a therapeutically effective amount of a compound of formula (I), formula (I), or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, a method of reducing sexual pain in a subject is provided, the method comprising administering a therapeutically effective amount of a compound of formula (I), formula (I), or a pharmaceutically acceptable salt thereof.

[0015] In one aspect, the present disclosure provides for a method of increasing the number of satisfying sexual events (SSE) in a subject, the method comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0016] In one aspect, the present disclosure provides for a compound of formula (I), formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of vulvodynia or progressive vulvodynia in a subject. Description of Drawings

[0017] Figure 1 : Protocol for the study in sexual dysfunction of FSL rats and the effects of

[0018] IP2018.

[0019] Figure 2: Effect of oestrus synchronization on paracopulatory sexual behaviour in female Sprague Dawley (SD) and Flinders Sensitive line (FSL) of rat. (A) Female rotation in her axis, (B) sniffing from male, (C) female for male sniffing position, (D) sniffing from female. The results are means±SD of 10-1 1 rats. *P<0.05, **P<0.01 , ***P<0.001 .

[0020] Figure 3: Effect of ketamine, IP2018, and fluoxetine (Fix) on paracopulatory behaviour in synchronized female Flinders sensitive line (FSL) rats. (A) Female for male sniffing position, (B) sniffing from male, (C) effect on number of hops, and (D) effect on darts in synchronized female rats. The results are means±SD of 10-12 rats. The parameters were recorded during a 30 min period. The one-way ANOVA was significant for darts, and post-test showed the number of darts were significant for IP2018 (0.5 mg / kg / day) compared to vehicle. *P<0.05.

[0021] Figure 4: Effect of two-weeks treatment with ketamine, IP2018, and fluoxetine (Fix) treatment on copulatory behaviour in synchronized female rats. (A) Male mounting female (B) Female rotation in her axis. The results are means±SD of 10-12 rats. *P<0.05, **P<0.01 , P<0.001.. The results are means±SD of 10-12 rats. The parameters were recorded during a 30 min period.

[0022] Definitions

[0023] As used herein, the terms "female sexual dysfunction" or "FSD" refer generally to the impairment of the sexual function in a female. Sexual dysfunction in females includes inhibited orgasm. Female sexual dysfunction includes but is not limited to, a number of categories of diseases, conditions and disorders including female hypoactive sexual desire disorder / dysfunction (FHSDD or HSDD, used interchangeably herein), female orgasmic disorder / dysfunction (FOD), sexual anhedonia, female sexual interest / arousal disorder / dysfunction (FSIAD), female sexual arousal disorder / dysfunction (FSAD), sexual pain disorder / dysfunction and dyspareunia.

[0024] As used herein, the terms "female sexual function index" or “FSFI” refer generally to the 19-item patient-reported outcome (PRO) instrument / questionnaire that has been used in clinical trials to measure overall sexual function (Rosen R, Brown C, et al., 2000) and grade the severity of FSD, wherein, individual domain questions from the FSFI have been used to measure specific components of sexual function, including:

[0025] A) Sexual desire domain (FSFI-D): (FSFI-; questions 1 -2 (frequency, level)

[0026] B) Sexual arousal domain: questions 3-6 (level, confidence, satisfaction)

[0027] C) Lubrication domain: questions 7-10 (frequency, difficulty, frequency of maintaining, difficulty in maintaining)

[0028] D) Orgasm domain: questions 1 1 -13 (frequency, difficulty, satisfaction)

[0029] E) Satisfaction domain: questions 14-16 (with amount of closeness with partner, with sexual relationship, with overall sex life)

[0030] F) Pain domain: questions 17-19 (frequency during vaginal penetration, frequency following vaginal penetration, level during or following vaginal penetration).

[0031] Responses are evaluated in a 5 point scale (1 to 5), where higher numbers indicate a higher level of said specific components of sexual function and lower numbers indicate a lower level of said specific components of sexual function. Thus, lower numbers indicate more severe levels of sexual dysfunction. Full-scale FSFI and / or domain-level scoring and interpretation can be utilised to measure overall sexual function and grade the severity of FSD.

[0032] As used herein, the terms " Female Sexual Distress Scale-Desire / Arousal / Orgasm " or “FSDS-DAO” refer generally to the 15-item patient-reported outcome (PRO) instrument / questionnaire that has been used in clinical trials to measure overall sexual function and grade the severity of female hypoactive sexual desire dysfunction (FHSDD) (Derogatis et al. 2008, Derogatis et al. 2021 ). The total score may be calculated as the sum of the responses and ranges from 0 to 60, with higher scores indicating a greater distress. The FSDS-DAO was 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 did you feel: Bothered by low sexual desire?”. Responses can be graded on a scale of 0 (never) to 4 (always). A decrease in the FSDS-DAO Q13 score over time denotes improvement in the level of distress associated with low sexual desire. Question 13 (Q13) of the FSDS-DAO questionnaire is identical to question 13 of the FSDS-R questionnaire. Detailed description

[0033] A compound for use

[0034] One embodiment of the present disclosure provides for a compound of formula (I), formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject. The compound of the present disclosure is a monoamine neurotransmitter re-uptake inhibitor. Compounds may be tested for their ability to inhibit reuptake of the monoamines dopamine, noradrenaline and serotonin in synaptosomes e.g. such as described in WO 97 / 30997 or WO 97 / 16451 .

[0035] The compound of formula (I) has been reported with the IC50 values in humans: 1 .8 nM (serotonin), 100 nM (dopamine), and 46 nM (noradrenaline) (WO 2021 / 023805).

[0036] In one embodiment, the compound of formula (I) has the structure of formula (la); formula (la), or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, the compound is exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen- 2-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one hydrochloride. In one embodiment, the name “IP2018” refers to the compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein.

[0038] In one embodiment, the pharmaceutically acceptable salt is of an organic or an inorganic counterion. In one embodiment, the pharmaceutically acceptable salt is hydrochloride. Other pharmaceutically acceptable salts are known to those of skill in the art. Such salts may be formed by procedures well known and described in the art. Female sexual dysfunction (FSD)

[0039] The compounds of the present disclosure have shown potential in the treatment of female sexual dysfunction (FSD).

[0040] Thus, one embodiment of the present disclosure provides for a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject.

[0041] Female sexual dysfunction can, for example, be of physiological or psychological origin.

[0042] In one embodiment, the female sexual dysfunction is selected from the group consisting of:

[0043] (i) female sexual interest / arousal disorder,

[0044] (ii) hypoactive sexual desire dysfunction,

[0045] (iii) female sexual arousal dysfunction

[0046] (iv) orgasmic dysfunction,

[0047] (v) sexual pain disorder,

[0048] (vi) sexual anhedonia and

[0049] (vii) dyspareunia.

[0050] In one embodiment, the female sexual dysfunction is selected from the group consisting of:

[0051] (i) female sexual interest / arousal disorder,

[0052] (ii) hypoactive sexual desire dysfunction,

[0053] (iii) female sexual arousal dysfunction

[0054] (iv) sexual pain disorder,

[0055] (v) sexual anhedonia and

[0056] (vi) dyspareunia.

[0057] FSD is associated with personal distress, for example with frustration, grief, guilt, incompetence, loss, sadness, sorrow or worry; FSD can also be associated with interpersonal difficulty. The examples demonstrate that the compound of formula (I) is able to increase para- copulatory behaviours in a female rat model showing characteristics of FSD, in which the female demonstrates interest and desire for a sexual interaction. Thus, highlighting its ability to address a key aspects of FSD related to interest and desire.

[0058] In one embodiment, the female sexual dysfunction is selected from the group consisting of:

[0059] (i) female sexual interest / arousal disorder,

[0060] (ii) hypoactive sexual desire dysfunction, and

[0061] (iii) female sexual arousal dysfunction.

[0062] In one embodiment, the female sexual dysfunction is selected from the group consisting of: hypoactive sexual arousal dysfunction and female sexual interest / arousal disorder.

[0063] Subjects suffering from female sexual arousal disorder (female sexual interest disorder; sexual arousal disorder; FSAID) present with little or no interest in sex and do not respond subjectively or physically to sexual stimulation. The decrease in interest and ability to be sexually aroused is greater than what might be expected based on a subject’s age and the relationship duration. Lack of sexual interest and inability to be sexually aroused is considered a disorder if they cause distress in the subject and if interest is absent throughout the sexual experience.

[0064] In one embodiment of the disclosure, the female sexual dysfunction is female sexual interest / arousal disorder (FSIAD).

[0065] Hypoactive sexual desire dysfunction (HSDD) is the most common form of FSD and has been described as a driving factor of all FSDs. In some embodiments, hypoactive sexual desire dysfunction may also be referred to as hypoactive sexual desire disorder.

[0066] Hypoactive sexual desire dysfunction is characterised by absence or marked reduction in desire or motivation to engage in sexual activity as manifested by any of the following: 1 ) reduced or absent spontaneous desire (sexual thoughts or fantasies); 2) reduced or absent responsive desire to erotic cues and stimulation; or 3) inability to sustain desire or interest in sexual activity once initiated. HSDD can also be characterized by absence or marked reduction of libido. The pattern of diminished or absent spontaneous or responsive desire or inability to sustain desire or interest in sexual activity has occurred episodically or persistently over a period at least several months, and is associated with clinically significant distress.

[0067] It has been hypothesised that hypo-sexual desire disorder (HSDD) is associated with neuroendocrine dysregulation / imbalance leading to functional and structural neuroadaptations in these systems, resulting in decreased excitation, e.g., low levels of dopamine, increased inhibition, or a combination of both (Pfaus JG et al.; Goldstein I et al.). Thus, the compound of the present disclosure may be able to affect HSDD because it restores the dopamine and serotonin levels through amine re-uptake inhibition.

[0068] In one embodiment of the present disclosure, the FSD is hypoactive sexual desire dysfunction.

[0069] In one embodiment, the hypoactive sexual desire dysfunction is lifelong hypoactive sexual desire dysfunction or acquired hypoactive sexual desire dysfunction.

[0070] Lifelong, generalised hypoactive sexual desire dysfunction is characterised by the subject always having experienced hypoactive sexual desire dysfunction from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in all circumstances, including masturbation.

[0071] Lifelong, situational hypoactive sexual desire dysfunction is characterised by the subject always having experienced hypoactive sexual desire dysfunction, from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations.

[0072] Generalised, acquired hypoactive sexual desire dysfunction is characterised by an onset of hypoactive sexual desire dysfunction following a period of time during which the person did not experience it and the desired response is currently absent or diminished in all circumstances, including masturbation.

[0073] Situational, acquired hypoactive sexual desire dysfunction is characterised by an onset of hypoactive sexual desire dysfunction following a period of time during which the person did not experience it and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations. In one embodiment, the hypoactive sexual desire dysfunction is unspecified hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is lifelong, generalised 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, generalised hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is acquired, situational hypoactive sexual desire dysfunction. In one embodiment, the hypoactive sexual desire dysfunction is generalised hypoactive sexual desire dysfunction or situational hypoactive sexual desire dysfunction.

[0074] In yet another embodiment, the hypoactive sexual desire dysfunction is characterised by:

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

[0076] (ii) reduced or absent responsive desire to erotic cues and stimulation, and / or

[0077] (iii) inability to sustain desire or interest in sexual activity once initiated.

[0078] In one embodiment of the disclosure, the inability to sustain desire or interest in sexual activity has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

[0079] Sexual arousal dysfunctions include difficulties with the physiological or the subjective aspects of sexual arousal. In one embodiment of the disclosure, the FSD is sexual arousal dysfunction (female sexual arousal dysfunction).

[0080] Female sexual arousal dysfunction is characterised by the absence or marked reduction in response to sexual stimulation in women, as manifested by any of the following: 1 ) Absence or marked reduction in genital response, including vulvovaginal lubrication, engorgement of the genitalia, and sensitivity of the genitalia; 2) Absence or marked reduction in non-genital responses such as hardening of the nipples, flushing of the skin, increased heart rate, increased blood pressure, and increased respiration rate; 3) Absence or marked reduction in feelings of sexual arousal (sexual excitement and sexual pleasure) from any type of sexual stimulation. The absence or marked reduction in response to sexual stimulation occurs despite the desire for sexual activity and adequate sexual stimulation, has occurred episodically or persistently over a period of at least several months, and is associated with clinically significant distress. Lifelong, generalised female sexual arousal dysfunction is characterised by the subject having always experienced female sexual arousal dysfunction from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in all circumstances, including masturbation. Lifelong, acquired female sexual arousal dysfunction is characterised by the subject having always experienced female sexual arousal dysfunction from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations. Acquired, generalised female sexual arousal dysfunction is characterised by an onset of female sexual arousal dysfunction following a period of time during which the person did not experience it, and the desired response is currently absent or diminished in all circumstances, including masturbation. Acquired, situational female sexual arousal dysfunction is characterised by an onset of female sexual arousal dysfunction following a period of time during which the person did not experience it and the desired response is currently absent or diminished in all circumstances, including masturbation.

[0081] In one embodiment, the female sexual arousal dysfunction is lifelong female sexual arousal dysfunction or acquired female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is lifelong, generalised female sexual arousal dysfunction or situational female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is lifelong acquired female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is lifelong generalised female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is acquired, generalised female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is acquired, situational female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is generalised female sexual arousal dysfunction or situational female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is unspecified female sexual arousal dysfunction. In one embodiment, the female sexual arousal dysfunction is characterised by:

[0082] (i) absence or marked reduction in genital response, including vulvovaginal lubrication, engorgement of the genitalia, and sensitivity of the genitalia,

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

[0084] (iii) absence or marked reduction in feelings of sexual arousal, such as sexual excitement and sexual pleasure, from any type of sexual stimulation.

[0085] In one embodiment, the absence or marked reduction in response to sexual stimulation occurs despite the desire for sexual activity and adequate sexual stimulation, has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

[0086] Orgasmic dysfunctions refer to difficulties related to the subjective experience of orgasm. In one embodiment of the present disclosure, the FSD is orgasmic dysfunction.

[0087] In one embodiment, the orgasmic dysfunction is anorgasmia. Anorgasmia is characterised by the absence or marked infrequency of the orgasm experience or markedly diminished intensity of orgasmic sensations. In women, this includes a marked delay in orgasm, which in men would be diagnosed as Male Delayed Ejaculation. The pattern of absence, delay, or diminished frequency or intensity of orgasm occurs despite adequate sexual stimulation, including the desire for sexual activity and orgasm, has occurred episodically or persistently over a period of at least several months, and is associated with clinically significant distress.

[0088] Lifelong, generalised anorgasmia is characterised by the subject having always experienced anorgasmia from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in all circumstances, including masturbation. Lifelong, situational anorgasmia is characterised by the subject having always experienced anorgasmia from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations. Acquired, generalised anorgasmia is characterised by an onset of anorgasmia following a period of time during which the person did not experience it and the desired response is currently absent or diminished in all circumstances, including masturbation. Acquired, situational anorgasmia is characterised by an onset of anorgasmia following a period of time during which the person did not experience it and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations.

[0089] In another embodiment, the anorgasmia is lifelong anorgasmia or acquired anorgasmia. In another embodiment, the anorgasmia is generalised anorgasmia or situational anorgasmia. In another embodiment, the anorgasmia is lifelong, generalised anorgasmia. In another embodiment, the anorgasmia is lifelong, situational anorgasmia. In another embodiment, the anorgasmia is acquired, generalised anorgasmia. In another embodiment, the anorgasmia is acquired, situational anorgasmia.

[0090] In one embodiment, the anorgasmia is unspecified anorgasmia. In another embodiment, the anorgasmia is characterised by the absence or marked infrequency of the orgasm experience and / or markedly diminished intensity of orgasmic sensations.

[0091] In one embodiment, the absence or marked infrequency of the orgasm experience and / or markedly diminished intensity of orgasmic sensations occurs despite adequate sexual stimulation, including the desire for sexual activity and orgasm, has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

[0092] In one embodiment, the FSD is a sexual pain disorder. Sexual pain disorders refer to marked and persistent or recurrent difficulties related to the experience of pain during sexual activity in adults, which 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.

[0093] In one embodiment, the sexual pain disorder is sexual pain-penetration disorder. Sexual pain-penetration disorder is characterised by at least one of the following: 1 ) marked and persistent or recurrent difficulties with penetration, including due to involuntary tightening or tautness 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 about 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 stimulation, are not entirely attributable to a medical condition that adversely affects the pelvic area and results in genital and / or penetrative pain or to a mental disorder, are not entirely attributable to insufficient vaginal lubrication or post-menopausal / age-related changes, and are associated with clinically significant distress.

[0094] In one embodiment the sexual pain-penetration disorder is lifelong sexual painpenetration disorder or acquired sexual pain-penetration disorder. In one embodiment, the sexual pain-penetration disorder is generalised sexual pain-penetration disorder or situational sexual pain-penetration disorder. In one embodiment, the sexual painpenetration disorder is generalised sexual pain-penetration disorder. In one embodiment, the sexual pain-penetration disorder is situational sexual pain-penetration disorder. In one embodiment, the sexual pain-penetration disorder is unspecified sexual pain-penetration disorder. Lifelong, generalised sexual pain-penetration disorder is characterised by the subject having always experienced genito-pelvic pain or penetration disorder from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in all circumstances, including masturbation. Lifelong, situational sexual pain-penetration disorder is characterised by the subject having always experienced genito-pelvic pain or penetration disorder from the time of initiation of relevant sexual activity and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations. Acquired, generalised sexual pain-penetration disorder is characterised by an onset of genito-pelvic pain or penetration disorder following a period of time during which the person did not experience it and the desired response is currently absent or diminished in all circumstances, including masturbation. Acquired, situational sexual pain-penetration disorder is characterised by an onset of genito-pelvic pain or penetration disorder following a period of time during which the person did not experience it and the desired response is currently absent or diminished in some circumstances, with some partners, or in response to some stimuli, but not in other situations. In one embodiment, the sexual pain-penetration disorder is a lifelong, generalised sexual pain-penetration disorder. In one embodiment, the sexual painpenetration disorder is a lifelong, situational sexual pain-penetration disorder. In one embodiment, the sexual pain-penetration disorder is acquired, generalised sexual painpenetration disorder. In one embodiment, the sexual pain-penetration disorder is acquired, situational sexual pain-penetration disorder. In one embodiment, the sexual pain-penetration disorder is characterised by:

[0095] (i) marked or persistent or recurrent difficulties with penetration, including due to involuntary tightening or tautness of the pelvis floor muscles during attempted penetration,

[0096] (ii) marked and persistent or recurrent vulvovaginal or pelvic pain during penetration, and / or

[0097] (iii) marked and persistent or recurrent fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of penetration.

[0098] In one embodiment, the sexual pain-penetration disorder has symptoms that:

[0099] (i) are recurrent during sexual interactions involving or potentially involving penetration, despite adequate sexual desire and stimulation,

[0100] (ii) are not entirely attributable to a medical condition that adversely affects the pelvic area and results in genital and / or penetrative pain or to a mental disorder,

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

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

[0103] Dyspareunia is a symptom of the genital system that affects females and is caused by physical determinants. This symptom is characterised by recurrent genital pain or discomfort that occurs before, during, or after sexual intercourse, or superficial or deep vaginal penetration that is related to an identifiable physical cause, not including lack of lubrication. Confirmation is by medical assessment of physical causes. In one embodiment, the FSD is dyspareunia. In one embodiment, the FSD presents with dyspareunia.

[0104] In one embodiment, the female sexual dysfunction is:

[0105] (i) associated with a medical condition, injury, or the effects of surgery or radiation treatment,

[0106] (ii) associated with psychological or behavioural factors, including mental disorders,

[0107] (iii) associated with use of psychoactive substance or medication,

[0108] (iv) associated with lack of knowledge or experience,

[0109] (v) associated with relationship factors,

[0110] (vi) associated with cultural factors, and / or

[0111] (vii)other specified aetiological considerations.

[0112] In one embodiment, the sexual pain disorders is vulvodynia or progressive vulvodynia. Vulvodynia is a persistent, unexplained pain in the vulva, which is the female genital area including the skin surrounding the opening of the vagina. In one embodiment, the female sexual dysfunction is associated with vulvodynia.

[0113] In one aspect, the present disclosure provides for a compound of formula (I), formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of vulvodynia or progressive vulvodynia in a subject.

[0114] In one embodiment, the vulvodynia induces and / or causes FSD in the subject. In one embodiment, the compound for use in the treatment, prevention, or alleviation of vulvodynia or progressive vulvodynia in a subject is as described in the above-mentioned section entitled “A compound for use”. In one embodiment, the subject is as described in the below-mentioned section entitled "assessment of FSD in subjects”. In one embodiment, the female sexual dysfunction is not caused by another disease, such as a psychiatric disorder. In one embodiment, the female sexual dysfunction is not caused by injury to the genitals. In one embodiment, the subject is not under treatment with a medicament known to cause female sexual dysfunction. In one embodiment, the female sexual disorder is not a hyperactive female sexual disorder, such as premature female orgasm.

[0115] FSD and depression

[0116] Subjects with FSD are frequently concomitantly associated and / or diagnosed with depression and / or anxiety, wherein either depression and / or anxiety can increase the risk of induction, incidence and / or diagnosis of FSD in a subject. Conversely, the presence of FSD can increase the risk of induction and / or diagnosis of depression and / or anxiety in a subject (Reddy et al.)

[0117] The inventors have surprisingly shown that the compound of formula I increases copulatory and paracopulatory behaviours in FSL rats, which show spontaneous depression. Thus, in one embodiment, the compound of formula I is provided for use in the treatment, prevention or alleviation of female sexual dysfunction in a subject, wherein the subject suffers from depression, anxiety, low mood or a combination thereof.

[0118] In one embodiment, the subject suffers from major depressive disorder. In one embodiment, the female sexual dysfunction is caused by depression, anxiety, major depressive disorder, low mood or a combination thereof. In one embodiment, the depression, anxiety, major depressive disorder or a combination thereof is caused by female sexual dysfunction.

[0119] In one embodiment, the female sexual dysfunction is treatment-emergent female sexual dysfunction. Treatment-emergent female sexual dysfunction is the induction of female sexual dysfunction following initiation, concurrent with, a result of and / or an adverse event related to a treatment. Said treatment can be utilised for the purpose of treating FSD per se or any other disease.

[0120] In one embodiment, the treatment-emergent female sexual dysfunction is caused by treatment with a medicament. When referring to treatment-emergent female sexual dysfunction caused by a medicament, it is also being referred to drug-induced female sexual dysfunction by said medicament. In one embodiment, the treatment-emergent female sexual dysfunction is caused by an adverse effect of the medicament. In one embodiment, the adverse event is psychological in nature, such as lower libido, or physiological, such as a hormonal or neurological adverse event. Different drugs known to induce or be associated with female sexual dysfunction are described in Conalgen et al. In one embodiment the treatment-emergent female sexual dysfunction is caused by treatment with a medicament, selected from the group consisting of: an antidepressant, a antihypertensive, a cardiovascular drug, a beta blocker and antiandrogens. In one embodiment, the treatment-emergent sexual dysfunction is caused by gabapentin or topiramate.

[0121] Female sexual dysfunction has been reported to be associated or induced by therapy with antidepressants (Lorenz et al. / Conlagen et al.). Thus, in one embodiment the treatment-emergent female sexual dysfunction is caused by treatment of depression with an antidepressant. In one embodiment the treatment-emergent female sexual dysfunction is caused by treatment of anxiety with an antidepressant. In one embodiment, the antidepressant is selected from: a tricyclic antidepressant, such as clomipramine or nortriptyline; a monoamine oxidase inhibitor; a selective serotonin reuptake inhibitor (SSRI), and a serotonin-norepinephrine reuptake inhibitor (SNRI).

[0122] In one embodiment, the antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). In one embodiment, the subject is under treatment with an antidepressant, such as an SSRI or an SNRI. In yet another embodiment, treatment with the antidepressant is not stopped, but the compound of the present disclosure is administered to alleviate the symptoms of the treatment-emergent female sexual dysfunction caused by the antidepressant.

[0123] The compound of formula I is a dual serotonin / dopamine re-uptake inhibitor that displays robust antidepressant properties (WO 2021 / 023805). Thus, in one embodiment, the compound for use as described herein is able to treat female sexual dysfunction and depression and / or anxiety.

[0124] In one embodiment, the compound for use as described herein is for use in the treatment, prevention or alleviation of female sexual dysfunction in combination with treatment, prevention or alleviation of depression and / or anxiety. In one embodiment, the compound for use as described herein, is for use in the treatment, prevention or alleviation of a combination of female sexual dysfunction as described herein with depression and / or anxiety.

[0125] Because FSD is associated with personal distress and interpersonal difficulty, FSD may lead to or increase low mood, depression and or anxiety. Thus, in one aspect, the present disclosure provides for a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention or alleviation of depression and / or anxiety in a subject, wherein said subject suffers from female sexual dysfunction. In one embodiment, the depression or anxiety is caused by female sexual dysfunction.

[0126] In one embodiment, the FSD and / or the subject are as described herein in the section “Female Sexual Dysfunction (FSD)”, “FSD and depression” and “Assessment of FSD in subjects”.

[0127] Assessment of FSD in subjects

[0128] The effect of a compound on FSD in animal models can be assessed through the study of sexual behaviour in animals. For example by measurement of paracopulatory or copulatory behaviours. Paracopulatory behaviours, also called solicitation or preceptive behaviours, is usually described as the species-specific behaviours displayed by an estrus female during sexual interaction in which she demonstrates sexual desire, arousal and interest and in turn initiates the establishment and maintenance of sexual interaction via encouraging the male to mate and regulates the pattern of copulation (Erskine, 1989).

[0129] In female rats, examples of paracopulatory behaviours include: ear wiggling, hops, darts, female for sniffing position, female mounting on male, sniffing from male and from female. Examples of copulatory behaviours in female rats include: male mounting female, thrusting from male, intromission, ejaculation, lordosis, orgasm, female rotation in her axis and female licking itself (Hegstad et al.).

[0130] The description of different sexual behaviours in female rats that can be used to assess female sexual function is described in Table 1 .

[0131] Table 1. Description of different behaviours in rats used to assess female sexual function.

[0132] In humans, FSD may be assessed through different reports by subject on sexual function. Methods to assess FSD include, but are not limited to, the questionnaires and self-report techniques described below. A person of skill in the art, such as a physician, will be aware of different methods that can assess and diagnose FSD, or an aspect thereof, based on the common general knowledge.

[0133] Female Sexual Function Index (FSFI) is a 19-item self-report inventory designed to assess female sexual function. It comprises six domains: desire (two items), arousal (four items), lubrication (four items), orgasm (three items), satisfaction (three items), pain (three items). The overall FSFI score through all domains is assessed on a scale from 2 to 36.

[0134] In one embodiment, the subject prior to treatment had a female sexual function index (FSFI) of less than 36, such from 32 to 35, such as from 28 to 32 such as from 26 to 32. In one embodiment, the subject prior to treatment had a female sexual function index of 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.

[0135] In one embodiment, the compound is capable of increasing the FSFI in the subject.

[0136] In one embodiment, 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. In one embodiment, the compound is capable of increasing FSFI to above 26.55, such as to above 28.00, such as to above 30.00, such as to above 32.00, such as to above 34.00, such as to 36.00. In one embodiment, the compound is able of increasing FSFI to a score between 26 and 36, such as between to 28 and 36, such as to between 30 and 36, such as to between 32 and 36.

[0137] The compound of the 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. being capable of increasing the FSFI in any one or more of the six domains ( desire, arousal, lubrication, orgasm, satisfaction and pain) or any one question of each domain. In one embodiment, the compound of the present disclosure is able to increase the score of any one question of the FSFI questionnaire by 1 , 2, 3, or 4 points.

[0138] The compound of the disclosure may 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), i.e. being capable of increasing the FSFI in any one or more of the other five domains (desire, arousal, lubrication, orgasm, and satisfaction).

[0139] The compound of the present disclosure may be especially efficient in improving the FSFI score of the desire domain (FSFI-D). The questionnaire contains 2 questions relating to sexual desire, each with a minimum score of 1 points and a maximum score of 5 points. In one embodiment, the compound is capable of increasing the FSFI score of a subject in the desire domain. In one embodiment, the compound is capable of increasing the FSFI score of a subject 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 compound of the disclosure is capable of increasing the score of FSFI question 1 (1stdesire question), such as increasing the score by 1 , 2, 3, or 4points. In one embodiment, the compound of the disclosure is capable of increasing the score of FSFI question 2 (2nddesire question), such as increasing the score by 1 , 2, 3, or 4, points. The FSFI-D domain may be assessed by multiplying the score of each question in the desire domain by 0.6 and adding them together, forming a FSFI-D domain score range from 1 .2 to 6.0. Thus, in one embodiment, the compound of the present disclosure is capable of increasing the score of the FSFI-D domain in a subject by 0.6 points, such as by 1.2, 1.8, 2.4, 3.0, 3.6, 4.2 or 4.8 points. In one embodiment, the compound is capable of increasing the score of the FSFI-D domain in a subject by 1 .2, 2.4, 3.6 or 4.8 points.

[0140] The compound of the present disclosure may be especially efficient in improving the FSFI score of the arousal domain. In one embodiment, the compound is capable of increasing the FSFI score of the arousal domain, or increasing the score of any one of the questions in the FSFI arousal domain, for example increasing the score of any one of questions 3 to 6 of the FSFI.

[0141] The compound of the present disclosure may able to improve the FSFI score of the pain domain. This is because the compound of the disclosure is a monoamine neurotransmitter reuptake inhibitor. The questionnaire contains 3 questions relating to pain, with a minimum score of 0 points and a maximum score of 6.0 points. In one embodiment, the compound of the present disclosure is capable of increasing the FSFI score of a subject in the pain domain. In one embodiment, the compound is capable of increasing the FSFI score of the pain domain by at least 0.3 points, at least 0.7 points, at least 1 .0 points, at least 1 .3 points, at least 1 .7 points, at least 2.0 points, at least 2.3 points, at least 2.7 points, at least 3.0 points, at least 3.3 points, at least 3.7 points, at least 4.0 points, at least 4.3 points, at least 4.7 points, at least 5.0 points, at least 5.3 points, at least 5.7 points, or 6.0 points. In one embodiment, the compound is capable of increasing the FSFI score question 17 (1stpain question), such as increasing the score by 1 , 2, 3, 4, or 5 points. In one embodiment, the compound is capable of increasing the FSFI score question 18 (2nd pain question), such as increasing the score by 1 , 2, 3, 4, or 5 points. In one embodiment, the compound is capable of increasing the FSFI score question 19 (3rd pain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

[0142] The compound of the present disclosure may be especially efficient in improving the FSFI score of the lubrication domain. In one embodiment, the compound is capable of increasing the FSFI score of the lubrication domain, or increasing the score of any one of the questions in the FSFI lubrication domain, for example increasing the score of any one of questions 7 to 10 of the FSFI.

[0143] The compound of the present disclosure may be especially efficient in improving the FSFI score of the orgasm domain. In one embodiment, the compound is capable of increasing the FSFI score of the orgasm domain, or increasing the score of any one of the questions in the FSFI orgasm domain, for example increasing the score of any one of questions 11 to 13 of the FSFI.

[0144] The compound of the present disclosure may be especially efficient in improving the FSFI score of the satisfaction domain. In one embodiment, the compound is capable is capable of increasing the FSFI score of the satisfaction domain, or increasing the score of any one of the questions in the FSFI satisfaction domain, for example increasing the score of any one of questions 14 to 16 of the FSFI.

[0145] One embodiment of the present disclosure provides for a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the disclosure, for use in increasing FSFI in a subject suffering from female sexual dysfunction.

[0146] One embodiment of the present disclosure provides for a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the disclosure, for the manufacture of a medicament for increasing the FSFI in a subject suffering from female sexual dysfunction.

[0147] One embodiment of the present disclosure provides for a method of increasing the FSFI in a subject suffering from female sexual dysfunction, said method comprising administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the disclosure.

[0148] General and specific aspects of FSD may be evaluated using the FSDS-DAO. The FSDS-DAO is a 15-item patient reported outcome (PRO) instrument / questionnaire that has be used in clinical trials to measure overall sexual function and grade the severity of female hypoactive sexual desire dysfunction (FHSDD) (Derogatis et al. 2021 ).

[0149] In one embodiment, the compound is capable of decreasing 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.

[0150] In one embodiment, the compound of the disclosure is capable of decreasing the question 13 score of the FSDS-DAO (FSDS-DAO Q13) in the subject. The compound of the present disclosure may be especially efficient in improving the question 13 of the FSDS-DAO (FSDS-DAO Q13) asks patients, “How often did you feel: Bothered by low sexual desire?”, with a minimum score of 0 points scale of 0 (never) to 4 points (always). A decrease in the FSDS-DAO Q13 score over time denotes improvement in the level of distress associated with low sexual desire. In one embodiment, the compound of the disclosure is capable of decreasing 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 compound of the disclosure is capable of decreasing the FSDS-DAO Q13 score by 1 , 2, 3, or 4 points.

[0151] In one embodiment, the subject prior to treatment had a female sexual function index FSDS-DAO of more than 10, such as more than 15, such as more than 20, such as more than 25, such as more than 30, such as more than 35, such as more than 40, such as more than 45, such as more than 50, such as more than 55.

[0152] General and specific aspects of FSD may be evaluated using the Elements of Desire Questionnaire (EDO). The EDO is a patient-reported outcome (PRO) developed to evaluate sexual desire. The EDO addresses attributes of desire such as sexual desire, thoughts / fantasies about sex, and receptivity to sexual requests, with an objective of measuring the effectiveness of drugs for this condition with regard to more facets of the pathology. The EDO is a 9-item PRO questionnaire intended to evaluate the efficacy of potential new treatments for women with FSD, HSDD or FSIAD. Items (questions) 1 , 2, 3, 4, 6, and 8 in the EDO is assessed on a 5 points scale with lower numbers indicating higher severity of dysfunction. Items 5 and 7 are assessed as a yes and no response.

[0153] In one embodiment, the compound of the present disclosure is capable of increasing the EDO score of a subject. In one embodiment, the compound of the present disclosure is capable of increasing the score of any one question of the EDQ, such as question 1 , 2, 3, 4, 5, 6, 7, 8 or 9. In one embodiment, one embodiment, the compound of the present disclosure is capable score of any one of questions 1 , 2, 3, 4, 6, and 8 of the EDQ by 1 , 2, 3, or 4 points.

[0154] In one embodiment, the subject is female. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human. In one embodiment, the subject is fertile.

[0155] In one embodiment, the subject is pre-menopausal. In one embodiment, the subject is menopausal. In one embodiment, the subject is post-menopausal.

[0156] In one embodiment, the subject is over the age of 18, such as over the age of 20, such as over the age of 25, such as over the age of 30, such as over the age of 35, such as over the age of 40, such as over the age of 45, such as over the age of 50, such as over the age of 55, such as over the age of 60, such as over the age of 65, such as over the age of 70, such as over the age of 75.

[0157] In one embodiment, the subject is below the age of 40, such as below the age of 35, such as below the age of 30, such as below the age of 25, such as below the age of 20.

[0158] In one embodiment, the subject is 18 to 20 years of age, such as 20 to 25, such as 25 to 30, such as 30 to 35, such as 35 to 40, such as 40 to 45, such as 45 to 50, such as 50 to 55, such as 55 to 60, such as 60 to 65, such as 65 to 70, such as 70 to 75, such as 75 or older.

[0159] A composition

[0160] In one aspect, the present disclosure provides for a composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treatment, prevention or alleviation of female sexual dysfunction in a subject. In one embodiment, the FSD and / or the subject are as described herein in the section “Female Sexual Dysfunction (FSD)”, “FSD and depression” and “Assessment of FSD in subjects”.

[0161] In one embodiment, the composition comprises at least on pharmaceutically acceptable excipient.

[0162] 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, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration.

[0163] Improvement of sexual parameters and uses

[0164] One aspect of the present disclosure provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, for the manufacture of a medicament for the treatment of female sexual dysfunction.

[0165] One aspect of the present disclosure provides for a method of treatment, prevention, or alleviation of 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, or a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0166] The examples demonstrate that the compound of formula I is able to improve sexual behaviour in mammals. Therefore, the compound of formula I may be used to improve parameters associated with sexual desire, sexual arousal, sexual interest or combinations thereof.

[0167] In another aspect, the present disclosure provides for a method of increasing sexual desire, sexual interest, sexual arousal, 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.

[0168] In another aspect, a method of reducing sexual pain in a subject is provided, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another aspect, a method of treatment, prevention or alleviation of depression and / or anxiety in a subject is provided, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; wherein the subject suffers from female sexual dysfunction as described herein.

[0169] In one aspect, the present disclosure provides for a method of increasing the number of satisfying sexual events (SSE) in a subject, the method comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. SSEs are used as an outcome measure in clinical trials of female sexual dysfunction, see Kingsberg et al. 2011. SSE may be assessed as outlined in Derogatis et al. 2021 or Clayton et al. 2016.

[0170] In one embodiment, the FSD and / or the subject are as described herein in the section “Female Sexual Dysfunction (FSD)”, “FSD and depression” and “Assessment of FSD in subjects”.

[0171] Items A

[0172] A1 . A compound of formula (I), formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject.

[0173] A2. The compound for use according to item A1 , wherein the female sexual dysfunction is selected from the group consisting of: i. female sexual interest / arousal disorder, ii. hypoactive sexual desire dysfunction, ill. female sexual arousal dysfunction iv. orgasmic dysfunction, wherein the orgasmic dysfunction is not premature female orgasm, v. sexual pain disorder, vi. sexual anhedonia and vii. dyspareunia.

[0174] A3. The compound for use according to item A1 , wherein the compound has the structure of formula (la); formula (la), or a pharmaceutically acceptable salt thereof. A4. The compound for use according to any one of items A1 -A3, wherein the female sexual dysfunction is female sexual interest / arousal disorder (FSIAD) or hypoactive female sexual desire dysfunction (HSDD).

[0175] A5. The compound for use according to any one of items A1 -A4, wherein the sexual pain disorder is sexual pain-penetration disorder.

[0176] A6. The compound for use according to any one of items A1 -A5, wherein the subject suffers from depression and / or anxiety.

[0177] A7. The compound for use according to any one of items A1 -A6, wherein the compound is for use in treatment, prevention or alleviation of a combination of female sexual dysfunction with depression and / or anxiety.

[0178] A8. The compound for use according to any one of items A1 -A7, wherein the female sexual dysfunction is treatment-emergent female sexual dysfunction.

[0179] A9. The compound for use according to any one of items A1 -A8, wherein the female sexual dysfunction is caused by depression and / or anxiety.

[0180] A10. The compound for use according to any one of items A1 -A10, wherein the treatment-emergent female sexual dysfunction is caused by treatment with a further medicament.

[0181] A1 1 . The compound for use according to item A10, wherein the medicament is an antidepressant.

[0182] A12. The compound for use according to any one of the preceding items A1 -A1 1 , wherein the subject is under treatment with an antidepressant.

[0183] A13. The compound for use according to any one of items A11 -A12, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI). A14. A compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, for use in increasing sexual desire, sexual interest, sexual arousal, or a combination thereof, in a subject.

[0184] A15. A compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, for use in increasing the number of satisfying sexual events (SSE) in a subject.

[0185] Items

[0186] 1. A compound of formula (I), formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject.

[0187] 2. The compound for use according to item 1 , wherein the compound has the structure of formula (la); formula (la), or a pharmaceutically acceptable salt thereof.

[0188] 3. The compound for use according to any one of items 1 and 2, wherein the compound is exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one or a pharmaceutically acceptable salt thereof. The compound for use according to any one of the preceding items wherein the compound is exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one hydrochloride. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is selected from the group consisting of:

[0189] (i) female sexual interest / arousal disorder,

[0190] (ii) hypoactive sexual desire dysfunction,

[0191] (iii) female sexual arousal dysfunction

[0192] (iv) orgasmic dysfunction,

[0193] (v) sexual pain disorder,

[0194] (vi) sexual anhedonia and

[0195] (vii) dyspareunia. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is selected from the group consisting of:

[0196] (i) female sexual interest / arousal disorder,

[0197] (ii) hypoactive sexual desire dysfunction,

[0198] (iii) female sexual arousal dysfunction

[0199] (iv) sexual pain disorder,

[0200] (v) sexual anhedonia and

[0201] (vi) dyspareunia. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is selected from the group consisting of:

[0202] (i) female sexual interest / arousal disorder,

[0203] (ii) hypoactive sexual desire dysfunction, and

[0204] (iii) female sexual arousal dysfunction. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is is selected from the group consisting of: hypoactive sexual arousal dysfunction (HSDD) and female sexual interest / arousal disorder (FSIAD). 9. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is female sexual interest / arousal disorder (FSIAD).

[0205] 10. The compound for use according to any one of items 1 to 6, wherein the female sexual dysfunction is hypoactive sexual desire dysfunction (HSDD).

[0206] 1 1. The compound for use according to item 10, wherein the hypoactive sexual desire dysfunction is lifelong hypoactive sexual desire dysfunction or acquired hypoactive sexual desire dysfunction.

[0207] 12. The compound for use according to any one of items 10 to 11 , wherein the hypoactive sexual desire dysfunction is generalised hypoactive sexual desire dysfunction or situational hypoactive sexual desire dysfunction.

[0208] 13. The compound for use according to any one of items 10 to 12, wherein the hypoactive sexual desire dysfunction is unspecified hypoactive sexual desire dysfunction.

[0209] 14. The compound for use according to any one of items 10 to 13, wherein the hypoactive sexual desire dysfunction is characterised by:

[0210] (i) reduced or absent spontaneous desire,

[0211] (ii) reduced or absent responsive desire to erotic cues and stimulation, and / or

[0212] (iii) inability to sustain desire or interest in sexual activity once initiated.

[0213] 15. The compound for use according to item 14, wherein the inability to sustain desire or interest in sexual activity has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

[0214] 16. The compound for use according to any one items 1 to 6, wherein the female sexual dysfunction is female sexual arousal dysfunction (FSAD). 17. The compound for use according to item 16, wherein the female sexual arousal dysfunction is lifelong female sexual arousal dysfunction or acquired female sexual arousal dysfunction.

[0215] 18. The compound for use according to any one of items 16 to 17, wherein the female sexual arousal dysfunction is generalised female sexual arousal dysfunction or situational female sexual arousal dysfunction.

[0216] 19. The compound for use according to any one of items 16 to 18, wherein the female sexual arousal dysfunction is unspecified female sexual arousal dysfunction.

[0217] 20. The compound for use according to any one of items 16 to 19, wherein the female sexual arousal dysfunction is characterised by:

[0218] (i) absence or marked reduction in genital response, including vulvovaginal lubrication, engorgement of the genitalia, and sensitivity of the genitalia,

[0219] (ii) absence or marked reduction in non-genital responses such as hardening of the nipples, flushing of the skin, increased heart rate, increase blood pressure, and increased respiration rate, and / or

[0220] (iii) absence or marked reduction in feelings of sexual arousal, such as sexual excitement and sexual pleasure, from any type of sexual stimulation.

[0221] 21. The compound for use according to item 20, wherein the absence or marked reduction in response to sexual stimulation occurs despite the desire for sexual activity and adequate sexual stimulation, has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

[0222] 22. The compound for use according to any one of items 1 to 5, wherein the female sexual dysfunction is an orgasmic dysfunction.

[0223] 23. The compound for use according to item 22, wherein the orgasmic dysfunction is not premature female orgasm. 24. The compound for use according to any one of items 22 to 23, wherein the orgasmic dysfunction is anorgasmia.

[0224] 25. The compound for use according to any one of items 22 to 24, wherein the anorgasmia is lifelong anorgasmia or acquired anorgasmia.

[0225] 26. The compound for use according to any one of items 22 to 25, wherein the anorgasmia is generalised anorgasmia or situational anorgasmia.

[0226] 27. The compound for use according to any one of items 22 to 26, wherein the anorgasmia is unspecified anorgasmia.

[0227] 28. The compound for use according to any one of items 24 to 27, wherein the anorgasmia is characterised by the absence or marked infrequency of the orgasm experience and / or markedly diminished intensity of orgasmic sensations.

[0228] 29. The compound for use according to item 28, wherein the absence or marked infrequency of the orgasm experience and / or markedly diminished intensity of orgasmic sensations occurs despite adequate sexual stimulation, including the desire for sexual activity and orgasm, has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

[0229] 30. The compound for use according to any one of items 1 to 6, wherein the female sexual dysfunction is sexual pain disorder.

[0230] 31 . The compound for use according to item 30, wherein the sexual pain disorder is sexual pain-penetration disorder.

[0231] 32. The compound for use according to any one of items 30 to 31 , wherein the sexual pain-penetration disorder is lifelong sexual pain-penetration disorder or acquired sexual pain-penetration disorder. 33. The compound for use according to any one of items 30 to 32, wherein the sexual pain-penetration disorder is generalised sexual pain-penetration disorder or situational sexual pain-penetration disorder.

[0232] 34. The compound for use according to any one of items 30 to 33, wherein the sexual pain-penetration disorder is unspecified sexual pain-penetration disorder.

[0233] 35. The compound for use according to any one of items 30 to 34, wherein the sexual pain-penetration disorder is characterised by:

[0234] (i) marked or persistent or recurrent difficulties with penetration, including due to involuntary tightening or tautness of the pelvis floor muscles during attempted penetration,

[0235] (ii) marked and persistent or recurrent vulvovaginal or pelvic pain during penetration, and / or

[0236] (iii) marked and persistent or recurrent fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of penetration.

[0237] 36. The compound for use according to any one of items 30 to 35, wherein the sexual pain-penetration disorder has symptoms that:

[0238] (i) are recurrent during sexual interactions involving or potentially involving penetration, despite adequate sexual desire and stimulation,

[0239] (ii) are not entirely attributable to a medical condition that adversely affects the pelvic area and results in genital and / or penetrative pain or to a mental disorder,

[0240] (iii) are not entirely attributable to insufficient vaginal lubrication or postmenopausal or age-related changes, and

[0241] (iv) are associated with clinically significant distress.

[0242] 37. The compound for use according to claim 30, wherein the sexual pain disorder is vulvodynia or progressive vulvodynia. 38. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is:

[0243] (i) associated with a medical condition, injury, or the effects of surgery or radiation treatment,

[0244] (ii) associated with psychological or behavioural factors, including mental disorders,

[0245] (iii) associated with use of psychoactive substance or medication,

[0246] (iv) associated with lack of knowledge or experience,

[0247] (v) associated with relationship factors,

[0248] (vi) associated with cultural factors, and / or

[0249] (vii) other specified aetiological considerations.

[0250] 39. The compound for use according to any one of items 1 to 6 and 30 to 38, wherein the female sexual dysfunction is dyspareunia.

[0251] 40. The compound for use according to any one of items 1 to 6, wherein the female sexual dysfunction is sexual anhedonia.

[0252] 41. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is not caused by another disease, such as a psychiatric disorder.

[0253] 42. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is not caused by injury to the genitals.

[0254] 43. The compound for use according to any one of the preceding items, wherein the subject is not under treatment with a medicament known to cause female sexual dysfunction.

[0255] 44. The compound for use according to any one of the preceding items, wherein the female sexual disorder is not a hyperactive female sexual disorder, such as premature female orgasm. 45. The compound for use according to any one of the preceding items, wherein the subject suffers from depression, anxiety, low mood or a combination thereof.

[0256] 46. The compound for use according to any one of the preceding items, wherein the subject suffers from depression and / or anxiety.

[0257] 47. The compound for use according to any one of the preceding items, wherein the subject suffers from major depressive disorder.

[0258] 48. The compound for use according to any one of items 1 to 40 and 42 to 47, wherein the female sexual dysfunction is caused by depression, anxiety, major depressive disorder, low mood or a combination thereof.

[0259] 49. The compound for use according to any one of items 1 to 41 and 44 to 47, wherein the female sexual dysfunction is treatment-emergent female sexual dysfunction.

[0260] 50. The compound for use according to item 49, wherein the treatment-emergent female sexual dysfunction is caused by treatment with a medicament.

[0261] 51. The compound for use according to any one of items 49 to 50, wherein the treatment-emergent female sexual dysfunction is caused by an adverse effect of the medicament.

[0262] 52. The compound for use according to item 51 , wherein the adverse event is psychological in nature, such as lower libido, or physiological, such as a hormonal or neurological adverse event.

[0263] 53. The compound for use according to any one of items 49 to 52, wherein the treatment-emergent female sexual dysfunction is caused by treatment with a medicament, selected from the group consisting of: an antidepressant, a antihypertensive, a cardiovascular drug, a beta blocker and antiandrogens. 54. The compound for use according to any one of the preceding items, wherein the female sexual dysfunction is caused by treatment of depression and / or anxiety with an antidepressant.

[0264] 55. The compound for use according to any one of the preceding items, wherein the subject is under treatment with an antidepressant, such as a SSRI or a SNRI.

[0265] 56. The compound for use according to any one of items 53 to 55, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor.

[0266] 57. The compound for use according to any one of the preceding items, wherein the compound is able to treat, prevent or alleviate a combination of female sexual dysfunction as described in any one of items 1 to 56, with depression and / or anxiety. 8. The compound for use according to any one of the preceding items, wherein the subject prior to treatment had a female sexual function index (FSFI) of 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. 9. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI in the subject. 0. The compound for use according to any one of the preceding items, 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 1 1 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. 61. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing FSFI to above 26.55.

[0267] 62. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of the pain domain by at least 0.3 points, at least 0.7 points, at least 1 .0 points, at least 1 .3 points, at least 1 .7 points, at least 2.0 points, at least 2.3 points, at least 2.7 points, at least 3.0 points, at least 3.3 points, at least 3.7 points, at least 4.0 points, at least 4.3 points, at least 4.7 points, at least 5.0 points, at least 5.3 points, at least 5.7 points, or 6.0 points.

[0268] 63. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score question 17 (1stpain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

[0269] 64. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score question 18 (2nd pain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

[0270] 65. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score question 19 (3rd pain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

[0271] 66. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of on any one or more of the other five domains (desire, arousal, lubrication, orgasm, and satisfaction).

[0272] 67. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of a subject in the desire domain.

[0273] 68. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of a subject 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. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of question 1 (1 st desire question) in a subject, such as increasing the score by 1 , 2, 3, 4, or 5 points. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of question 2 (2nddesire question) in a subject, such as increasing the score by 1 , 2, 3, 4, or 5 points. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of the arousal domain, or increasing the score of any one of the questions in the FSFI arousal domain, for example increasing the score of any one of questions 3 to 6 of the FSFI. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of the lubrication domain, or increasing the score of any one of the questions in the FSFI lubrication domain, for example increasing the score of any one of questions 7 to 10 of the FSFI. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI score of the orgasm domain, or increasing the score of any one of the questions in the FSFI orgasm domain, for example increasing the score of any one of questions 1 1 to 13 of the FSFI. The compound for use according to any one of the preceding items, wherein the compound is capable is capable of increasing the FSFI score of the satisfaction domain, or increasing the score of any one of the questions in the FSFI satisfaction domain, for example increasing the score of any one of questions 14 to 16 of the FSFI. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI-6 in the subject. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the FSFI-6 by at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points. The compound for use according to any one of the preceding items, wherein the compound is capable of decreasing 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 1 1 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. The compound for use according to any one of the preceding items, wherein the compound is capable of decreasing the FSDS-DAO question 13 (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. The compound for use according to any one of the preceding items, wherein the subject prior to treatment had a female sexual function index FSDS-DAO of more than 10, such as more than 15, such as more than 20, such as more than 25, such as more than 30, such as more than 35, such as more than 40, such as more than 45, such as more than 50, such as more than 55. The compound for use according to any one of the preceding items, wherein the subject is female.

[0274] The compound for use according to any one of the preceding items, wherein the subject is a mammal.

[0275] The compound for use according to any one of the preceding items, wherein the subject is a human.

[0276] The compound for use according to any one of the preceding items, wherein the subject is fertile.

[0277] The compound for use according to any one of the preceding items, wherein the subject is pre-menopausal.

[0278] The compound for use according to any one of the preceding items, wherein the subject is menopausal.

[0279] The compound for use according to any one of the preceding items, wherein the subject is post-menopausal. The compound for use according to any one of items 1 to 82, wherein the subject is over the age of 18, such as over the age of 20, such as over the age of 25, such as over the age of 30, such as over the age of 35, such as over the age of 40, such as over the age of 45, such as over the age of 50, such as over the age of 55, such as over the age of 60, such as over the age of 65, such as over the age of 70, such as over the age of 75. The compound for use according to any one of items 1 to 82, wherein the subject is below the age of 40, such as below the age of 35, such as below the age of 30, such as below the age of 25, such as below the age of 20. The compound for use according to any one of items 1 to 82, wherein the subject is 18 to 20 years of age, such as 20 to 25, such as 25 to 30, such as 30 to 35, such as 35 to 40, such as 40 to 45, such as 45 to 50, such as 50 to 55, such as 55 to 60, such as 60 to 65, such as 65 to 70, such as 70 to 75, such as 75 or older. 0. Use of a compound of formula (I), formula (I), for the manufacture of a medicament for the treatment of female sexual dysfunction. 1. A method of treatment, prevention, or alleviation of 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), formula (I), or a pharmaceutically acceptable salt thereof.

[0280] 92. A method of increasing sexual desire, sexual interest, sexual arousal, or a combination thereof, in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), formula (D, or a pharmaceutically acceptable salt thereof.

[0281] 93. A method of reducing sexual pain in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), formula (D, or a pharmaceutically acceptable salt thereof. 94. A method of increasing the number of satisfying sexual events (SSE) in a subject, the method comprising administering a therapeutically effective amount of a compound of formula I to the subject.

[0282] 95. A compound of formula (I),

[0283] / ^NHT X X^ formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention or alleviation of depression and / or anxiety in a subject, wherein the subject suffers from female sexual dysfunction.

[0284] 96. The compound for use according to item 95, wherein the compound or pharmaceutically acceptable salt thereof is as defined in any one of items 1 to 4.

[0285] 97. The compound for use according to any one of items 95 to 96, wherein the female sexual dysfunction is as described in any one of items 5 to 56.

[0286] 98. The compound for sue according to any one of items 95 to 97, wherein the subject is as described in any one of items 58 to 89.

[0287] 99. A compound of formula (I), NHT T X X^ formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention or alleviation of depression and / or anxiety in a subject, wherein said subject suffers from female sexual dysfunction.

[0288] 100. The compound for use according to item 99, wherein the depression or anxiety is caused by female sexual dysfunction

[0289] 101. The compound for use according to any one of items 99 to 100, wherein the female sexual dysfunction is as described in any one of items in any one of items 5 to 56. 102. A compound of formula (I), formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of vulvodynia or progressive vulvodynia in a subject.

[0290] 103. The compound for use according to item 102, wherein the compound or pharmaceutically acceptable salt thereof is as defined in any one of items 1 to 4.

[0291] 104. The compound for use according to item 103, wherein the subject is as described in any one of items 58 to 89.

[0292] 105. The compound for use according to any one of items 102-104, wherein the vulvodynia or progressive vulvodynia induces and / or causes female sexual dysfunction in the subject.

[0293] Examples

[0294] Example 1: Effect of IP2018 in sexual behaviour in female Flinders Sensitive Line (FSL) rats

[0295] Aim

[0296] To study the effects of IP2018 in the sexual behaviour in an animal model of female sexual dysfunction.

[0297] Materials and Methods

[0298] Testing protocol. Female Sprague Dawley rats were included to address whether Flinders Sensitive Line (FSL) rats have female sexual dysfunction. These two groups were treated with vehicle (15% beta-hydroxy-cyclodextrin) twice daily for two weeks (Figure 1 ). FSL rats were randomly allocated for treatment with IP2018 0.5 mg / kg / day and IP2018 2 mg / kg / day, twice daily, ketamine (15 mg / kg) once weekly, and fluoxetine (20 mg / kg / day) (Figure 1 ). The rats were treated for two weeks and the drugs were administered intraperitoneal. Day 3 and 1 before the terminal experiments, the rats were treated with PGF2a (250 pig / kg) to induce luteolysis and beginning of a new oestrus cycle, so the rats were synchronized in the oestrus cycle. Four hours before the final testing, the rats were injected progesterone (1 mg / kg). A vaginal cytology was performed to determine the point of the sexual cycle, and the rats underwent a sexual encounter profile testing.

[0299] Vaginal cytology. The oestrous cycle in the rat is generally divided into the four phases of proestrus, estrus, metestrus, and diestrus. The vaginal samples were collected early in the morning on day 4 of the protocol by vaginal lavage with 100 pl of NaCI 0.9% and drop slide smear as previously described in Cora et al. The smear was placed on a slide and stained with Giemsa. Pictures were taken, and the stage of the oestrus cycle was determined by two independent observers. In case of disagreement, the picture was discussed, and the animal allocated to one of the four phases of the oestrus cycle.

[0300] Sexual encounter profile. Sexual behaviour was determined by quantification of specific behaviours defined in table 1 in the section “Assessment of FSD in subjects”.

[0301] Oestrus cycle measurements and synchronization. Female Sprague Dawley rats with an average weight of 250 g were synchronized in the estrus phase of the sexual cycle by injecting with 250 pg prostaglandin F2a (PGF2a) subcutaneously at day 0 and day 3.

[0302] Oestrus cycle was assessed by vaginal cytology The vaginal samples were collected early in the morning on day 4 of the protocol by vaginal lavage with 100 pl of NaCI 0.9% and drop slide smear as previously described in Cora et al. The smear was placed on a slide and stained with Giemsa. Pictures were taken, and the stage of the oestrus cycle was determined by two independent observers. In case of disagreement, the picture was discussed, and the animal allocated to one of the four phases of the oestrus cycle.

[0303] Results

[0304] Female Flinders Sensitive Line (FSL) rats is a rat line exhibiting spontaneous depression. FSL rats show decreased sexual behaviour compared to Spargue Dawley (SD) rats, as shown by a reduction of copulatory behaviors. In oestrus synchronized rats, FSL rats showed decreased female rotation in her axis, female for male sniffling position, sniffling from male and sniffling from female (Figure 2). Thus, FSL rats are a model of female sexual dysfunction (FSD). The treatment of IP2018 restored the sexual behaviour of the FSL rats. Administration of IP2018 produced an increase in the paracopulatory behaviour and copulatory behaviours.

[0305] IP2018 increased paracopulatory behaviours compared to the control group, as shown by an increase in the average number of hops and a significant increase in the number of darts, the female for male sniffing position and sniffing from male (Figure 3).

[0306] In addition, IP2018 increased copulatory behaviours compared to vehicle, as shown by an increase of male mounting female events and an increase in female rotation in her axis behaviour (Figure 4).

[0307] Conclusion

[0308] The current study shows FSL rats with spontaneous depression exhibit decreased sexual behaviour compared to SD rats. These findings show FSL rats are a model of female sexual dysfunction. The treatment with IP2018 restored the sexual behaviour of the FSL rats, by improving aspects related to interest, desire and arousal. Thus, these results show that IP2018 is able to treat FSD.

[0309] References

[0310] WO 2021 / 023805

[0311] WO 97 / 30997

[0312] WO 97 / 16451

[0313] Allahdadi et al., Cardiovasc Hematol Agents Med Chem. 2009 Oct; 7(4): 260-269.

[0314] Parish SJ, Cottler-Casanova S, Clayton AH, McCabe MP, Coleman E, Reed GM. The Evolution of the Female Sexual Disorder / Dysfunction Definitions, Nomenclature, and Classifications: A Review of DSM, ICSM, ISSWSH, and ICD. Sex Med Rev 2021 ;9. https: / / doi.Org / 10.1016 / j.sxmr.2020.05.001 .

[0315] Miller MK, Smith JR, Norman JJ, Clayton AH. Expert opinion on existing and developing drugs to treat female sexual dysfunction. Expert Opin Emerg Drugs. 2018;23(3):223-230.

[0316] Pfaus JG, Sadiq A, Spana C, Clayton AH. The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women. CNS Spectr 2022;27. https: / / doi.Org / 10.1017 / S109285292100002X. Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, et al. Hypoactive Sexual Desire Disorder: International Society for the Study of Women’s Sexual Health (ISSWSH) Expert Consensus Panel Review. Mayo Clin Proc 2017;92. https: / / doi.Org / 10.1016 / j.mayocp.2016.09.018

[0317] Reddy RM, Saravanan RA, Praharaj SK, Thirunavukarasu M. Sexual Dysfunction in Women with Depression: A Hospital-Based Cross-sectional Comparative Study. Indian J Psychol Med. 2020 Jan 6;42(1):46-51. doi: 10.4103 / IJPSYM.IJPSYM_321_19.

[0318] Hegstad J, Huijgens PT, Houwing DJ, Olivier JDA, Heijkoop R, Snoeren EMS. Female rat sexual behavior is unaffected by perinatal fluoxetine exposure.

[0319] Psychoneuroendocrinology 2020 ; 120. https: / / d0i.0rg / l 0.1016 / j.psyneuen.2020.104796.

[0320] Isidori AM, Pozza C, Esposito K, Giugliano D, Morano S, Vignozzi L, Corona G, Lenzi A, Jannini EA. Development and validation of a 6-item version of the female sexual function index (FSFI) as a diagnostic tool for female sexual dysfunction. J Sex Med. 2010 Mar;7(3):1139-46.

[0321] Derogatis et al., J Patient Rep Outcomes, 2021 , 5:100

[0322] Kingsberg SA, Althof SE. Satisfying sexual events as outcome measures in clinical trial of female sexual dysfunction. J Sex Med. 2011 Dec;8(12).

[0323] Andersen FD, Joca S, Hvingelby V, Arjmand S, Pinilla E, Steffensen SC, et al. Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats. Addict Biol 2022;27. https: / / doi.org / 10.1111 / adb.13214.

[0324] Cora MC, Kooistra L, Travlos G. Vaginal Cytology of the Laboratory Rat and Mouse:Review and Criteria for the Staging of the Estrous Cycle Using Stained Vaginal Smears. Toxicol Pathol 2015;43. https: / / doi.org / 10.1177 / 0192623315570339

[0325] Conaglen HM, Conaglen JV. Drug-induced sexual dysfunction in men and women. Aust Prescr 2013;36:42-5.https: / / doi.org / 10.18773 / austprescr.2013.021

[0326] Lorenz T, Rullo J, Faubion S. Antidepressant-Induced Female Sexual Dysfunction. Mayo Clin Proc. 2016 Sep;91 (9):1280-6. doi: 10.1016 / j.mayocp.2016.04.033. PMID: 27594188; PMCID: PMC6711470.

Claims

Claims1. A compound of formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, or alleviation of female sexual dysfunction in a subject, wherein the female sexual dysfunction is hypoactive sexual arousal dysfunction (HSDD) or female sexual interest / arousal disorder (FSIAD).

2. The compound for use according to claim 1 , wherein the compound has the structure of formula (la);formula (la), 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-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one or a pharmaceutically acceptable salt thereof.

4. The compound for use according to any one of the preceding claims wherein the compound is exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one hydrochloride.

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

6. The compound for use according to any one of claims 1 to 4, wherein the female sexual dysfunction is hypoactive sexual desire dysfunction (HSDD).

7. The compound for use according to claim 6, wherein the hypoactive sexual desire dysfunction is lifelong hypoactive sexual desire dysfunction or acquired hypoactive sexual desire dysfunction.

8. The compound for use according to any one of claims 1 to 4 and 6 to 7, wherein the hypoactive sexual desire dysfunction is generalised hypoactive sexual desire dysfunction or situational hypoactive sexual desire dysfunction.

9. The compound for use according to any one of claims 1 to 4 and 6 to 8, wherein the hypoactive sexual desire dysfunction is unspecified hypoactive sexual desire dysfunction.

10. The compound for use according to any one of claims 1 to 4 and 6 to 9, wherein the hypoactive sexual desire dysfunction is characterised by: a. reduced or absent spontaneous desire, b. reduced or absent responsive desire to erotic cues and stimulation, and / or c. inability to sustain desire or interest in sexual activity once initiated.1 1 . The compound for use according to claim 10, wherein the inability to sustain desire or interest in sexual activity has occurred episodically or persistently over a period 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 claims 1 to 11 , wherein the female sexual arousal dysfunction is characterised by: a. absence or marked reduction in genital response, including vulvovaginal lubrication, engorgement of the genitalia, and sensitivity of the genitalia, b. absence or marked reduction in non-genital responses such as hardening of the nipples, flushing of the skin, increased heart rate, increase blood pressure, and increased respiration rate, and / or c. absence or marked reduction in feelings of sexual arousal, such as sexual excclaiment and sexual pleasure, from any type of sexual stimulation.

13. The compound for use according to claim 12, wherein the absence or marked reduction in response to sexual stimulation occurs despite the desire for sexual activity and adequate sexual stimulation, has occurred episodically or persistently over a period at least several months, such as 3, 4, 5, 6, 7, or 8 months, and / or is associated with clinically significant distress.

14. The compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is: a. associated with a medical condition, injury, or the effects of surgery or radiation treatment, b. associated with psychological or behavioural factors, including mental disorders, c. associated with use of psychoactive substance or medication, d. associated with lack of knowledge or experience, e. associated with relationship factors, f. associated with cultural factors, and / or g. other specified aetiological considerations.

15. The 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.

16. The compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is not caused by injury to the genitals.

17. The compound for use according to any one of the preceding claims, wherein the subject is not under treatment with a medicament known to cause female sexual dysfunction.

18. The compound for use according to any one of the preceding claims, wherein the female sexual disorder is not a hyperactive female sexual disorder, such as premature female orgasm.

19. The compound for use according to any one of the preceding claims, wherein the subject suffers from depression, anxiety, low mood or a combination thereof.

20. The compound for use according to any one of the preceding claims, wherein the subject suffers from depression and / or anxiety.

21. The compound for use according to any one of the preceding claims, wherein the subject suffers from major depressive disorder.

22. The compound for use according to any one of claims 1 to 21 , wherein the female sexual dysfunction is caused by depression, anxiety, major depressive disorder, low mood or a combination thereof.

23. The compound for use according to any one of claims 1 to 22, wherein the female sexual dysfunction is treatment-emergent female sexual dysfunction.

24. The compound for use according to claim 23, wherein the treatment-emergent female sexual dysfunction is caused by treatment with a medicament.

25. The compound for use according to any one of claims 23 to 24, wherein the treatment-emergent female sexual dysfunction is caused by an adverse effect of the medicament.

26. The compound for use according to claim 25, wherein the adverse event is psychological in nature, such as lower libido, or physiological, such as a hormonal or neurological adverse event.

27. The compound for use according to any one of claims 23 to 26, wherein the treatment-emergent female sexual dysfunction is caused by treatment with a medicament, selected from the group consisting of: an antidepressant, a antihypertensive, a cardiovascular drug, a beta blocker and antiandrogens.

28. The compound for use according to any one of the preceding claims, wherein the female sexual dysfunction is caused by treatment of depression and / or anxiety with an antidepressant.

29. The compound for use according to any one of the preceding claims, wherein the subject is under treatment with an antidepressant, such as a SSRI or a SNRI.

30. The compound for use according to any one of claims 27 to 29, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor.

31. The compound for use according to any one of the preceding claims, wherein the compound is able to treat, prevent or alleviate a combination of female sexual dysfunction as described in any one of claims 1 to 30, with depression and / or anxiety.

32. The compound for use according to any one of the preceding claims, wherein the subject prior to treatment had a female sexual function index (FSFI) of 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.

33. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI in the subject.

34. The 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 1 1 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.

35. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing FSFI to above 26.55.

36. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of the pain domain by at least 0.3 points, at least 0.7 points, at least 1 .0 points, at least 1 .3 points, at least 1 .7 points, at least 2.0 points, at least 2.3 points, at least 2.7 points, at least 3.0 points, at least 3.3 points, at least 3.7 points, at least 4.0 points, at least 4.3 points, at least 4.7 points, at least 5.0 points, at least 5.3 points, at least 5.7 points, or 6.0 points.

37. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score question 17 (1stpain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

38. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score question 18 (2nd pain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

39. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score question 19 (3rd pain question), such as increasing the score by 1 , 2, 3, 4, or 5 points.

40. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of on any one or more of the other five domains (desire, arousal, lubrication, orgasm, and satisfaction).41 . The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of a subject in the desire domain.

42. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of a subject 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 least3.0 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.

43. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of question 1 (1 st desire question) in a subject, such as increasing the score by 1 , 2, 3, 4, or 5 points.

44. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of question 2 (2nddesire question) in a subject, such as increasing the score by 1 , 2, 3, 4, or 5 points.

45. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of the arousal domain, or increasing the score of any one of the questions in the FSFI arousal domain, for example increasing the score of any one of questions 3 to 6 of the FSFI.

46. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of the lubrication domain, or increasing the score of any one of the questions in the FSFI lubrication domain, for example increasing the score of any one of questions 7 to 10 of the FSFI.

47. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI score of the orgasm domain, or increasing the score of any one of the questions in the FSFI orgasm domain, for example increasing the score of any one of questions 1 1 to 13 of the FSFI.

48. The compound for use according to any one of the preceding claims, wherein the compound is capable is capable of increasing the FSFI score of the satisfaction domain, or increasing the score of any one of the questions in the FSFI satisfaction domain, for example increasing the score of any one of questions 14 to 16 of the FSFI.

49. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI-6 in the subject.

50. The compound for use according to any one of the preceding claims, wherein the compound is capable of increasing the FSFI-6 by at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

51. The compound for use according to any one of the preceding claims, wherein the compound is capable of decreasing 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 1 1 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.

52. The compound for use according to any one of the preceding claims, wherein the compound is capable of decreasing the FSDS-DAO question 13 (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.

53. The compound for use according to any one of the preceding claims, wherein the subject prior to treatment had a female sexual function index FSDS-DAO of more than 10, such as more than 15, such as more than 20, such as more than 25, such as more than 30, such as more than 35, such as more than 40, such as more than 45, such as more than 50, such as more than 55.

54. The compound for use according to any one of the preceding claims, wherein the subject is female.

55. The compound for use according to any one of the preceding claims, wherein the subject is a mammal.

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

57. The compound for use according to any one of the preceding claims, wherein the subject is fertile.

58. The compound for use according to any one of the preceding claims, wherein the subject is pre-menopausal.

59. The compound for use according to any one of the preceding claims, wherein the subject is menopausal.

60. The compound for use according to any one of the preceding claims, wherein the subject is post-menopausal.61 . The compound for use according to any one of claims 1 to 56, wherein the subject is over the age of 18, such as over the age of 20, such as over the age of 25, such as over the age of 30, such as over the age of 35, such as over the age of 40, such as over the age of 45, such as over the age of 50, such as over the age of 55, such as over the age of 60, such as over the age of 65, such as over the age of 70, such as over the age of 75.

62. The compound for use according to any one of claims 1 to 56, wherein the subject is below the age of 40, such as below the age of 35, such as below the age of 30, such as below the age of 25, such as below the age of 20.

63. The compound for use according to any one of claims 1 to 56, wherein the subject is 18 to 20 years of age, such as 20 to 25, such as 25 to 30, such as 30 to 35, such as 35 to 40, such as 40 to 45, such as 45 to 50, such as 50 to 55, such as 55 to 60, such as 60 to 65, such as 65 to 70, such as 70 to 75, such as 75 or older.

64. Use of a compound of formula (I),formula (I), for the manufacture of a medicament for the treatment of female sexual dysfunction.

65. A method of treatment, prevention, or alleviation of 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),formula (I), or a pharmaceutically acceptable salt thereof.

66. A method of increasing sexual desire, sexual interest, sexual arousal, or a combination thereof, in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I),formula (I), or a pharmaceutically acceptable salt thereof.

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

68. A method of increasing the number of satisfying sexual events (SSE) in a subject, the method comprising administering a therapeutically effective amount of a compound of formula I to the subject.

69. A compound of formula (I),formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention or alleviation of depression and / or anxiety in a subject, wherein the subject suffers from female sexual dysfunction.

70. The compound for use according to claim 69, wherein the compound or pharmaceutically acceptable salt thereof is as defined in any one of claims 1 to .

71. The compound for use according to any one of claims 69 to 70, wherein the female sexual dysfunction is as described in any one of claims 1 to 30.

72. The compound for sue according to any one of claims 69 to 71 , wherein the subject is as described in any one of claims 1 to 63.

73. A compound of formula (I),formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention or alleviation of depression and / or anxiety in a subject, wherein said subject suffers from female sexual dysfunction.

74. The compound for use according to claim 73, wherein the depression or anxiety is caused by female sexual dysfunction75. The compound for use according to any one of claims 73 to 74, wherein the female sexual dysfunction is as described in any one of claims 1 to 30.

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