Compounds for Combination Therapy

Abstract

The present invention relates to compounds for the treatment of diseases or disorders including depression, erectile dysfunction, anxiety, sexual dysfunction and / or ejaculatory disorders; or combinations thereof.

Description

[Technical field]

[0001] The present invention relates to compounds for use in the treatment of erectile dysfunction, depression, sexual dysfunction, ejaculatory disorders, and / or anxiety; and any combination thereof. [Background technology]

[0002] Anxiety and depression (also known as major depressive disorder, clinical depression, and recurrent depressive disorder) are mood disorders that cause fear and worry in anxiety or persistent feelings of sadness and loss of interest, which affect emotions, thoughts, and behaviors, resulting in a variety of emotional and physical illnesses. If left untreated, depression can greatly reduce the quality of life or even lead to premature death or suicide from the condition. Various factors can contribute to anxiety and depression, including inheritance of genetic traits, hormonal changes in the brain, and physical changes. Various brain regions show altered activity in patients with major depressive disorder, and these imbalances in the brain specifically affect the neurotransmitters serotonin, noradrenaline, and dopamine. In accordance with these findings, the primary current treatments for depression are drugs that selectively inhibit serotonin reuptake (SSRIs) and serotonin-norepinephrine reuptake (SNRIs) or that selectively inhibit the breakdown of serotonin, norepinephrine, and dopamine through inhibition of monoamine oxidase.

[0003] Sexual dysfunction or erectile dysfunction in men (sometimes referred to as erectile dysfunction, impotence, or male erectile dysfunction) is the persistent inability to achieve or maintain an erection sufficient enough to allow satisfactory sexual activity. Erection involves several different central and peripheral nervous mechanisms and / or humoral mechanisms. The central neurotransmitters and neuropeptides that control penile erection can promote (e.g., dopamine) or inhibit (e.g., opioid peptides) penile erection by acting in several brain regions. Serotonin can exert both promoting and inhibiting effects depending on the receptor subtype involved. Worsening sexual dysfunction is common in major depression, and one explanation is the decrease in the levels of monoamines in the brain regions involved in erectile function control. Functional magnetic resonance imaging studies have shown overlap of key brain regions (amygdala, dorsal thalamus, hypothalamus, caudate putamen, cingulate cortex, insular cortex, visual cortex, sensory cortex, and motor cortex) in depression and sexual dysfunction, which affects the ability to orgasm and sexual desire. Furthermore, antidepressants such as SSRIs and SNRIs have negative effects on male sexual function (desire-arousal-excitation-orgasm). Although the incidence of sexual dysfunction is lower with some atypical antidepressants, including bupropion, mirtazapine, and vortioxetine, compared to SSRIs, there is also a significant demand to treat sexual dysfunction (treatment-induced erectile dysfunction) induced by antidepressant administration with these drugs. Thus, a drug that can treat both erectile dysfunction and depression is an unmet need and of great clinical interest.

[0004] Major depressive disorder is one of the leading causes of physical and mental disability due to its high prevalence and associated disorders. The lifetime prevalence is 14.3% in high-income countries. The Global Burden of Disease Study showed a 37.5% increase in the burden of major depressive disorder between 1990 and 2010, and major depressive disorder is the second leading projected cause of disability-adjusted life years in 2020. The lifetime prevalence of anxiety, characterized by an excessive fear response and / or worry that inhibits activity or causes distress, is 16.6% worldwide, with women being twice as likely to be affected as men. Evaluation of treatment outcomes for anxiety and depression has traditionally focused on impairments related to mood symptoms. Thus, SSRIs and SNRIs are recommended as first-line treatments for anxiety and major depressive disorder in accordance with international guidelines. However, patients report that returning to normal levels of daily functioning is more important than symptom outcomes. Dysfunction may continue after resolution of mood symptoms, and dysfunction, including sexual dysfunction, may increase the risk of experiencing a future episode of major depressive disorder.

[0005] Ejaculatory disorders are classified as premature ejaculation and delayed ejaculation, the former defined as lifelong premature ejaculation (ejaculation less than 1 minute after vaginal penetration) and acquired premature ejaculation (ejaculation less than 3 minutes after vaginal penetration). The latter is defined as approximately 25 minutes after vaginal penetration, twice the normal average time to ejaculation. Ejaculatory disorders have various causes, including genetic, psychological, iatrogenic (pelvic surgery), and diseases that may affect prolactin and testosterone (diabetes, depression, etc.).

[0006] Erectile dysfunction is a common age-related global disease that is estimated to affect 300 million men by 2025. Ejaculatory disorders are primarily represented by premature ejaculation, with a global rate of 5% of men of all ages, and delayed ejaculation at 1-4%. Co-occurring sexual dysfunction is present in 68% of patients with major depressive disorder, with only 5%-30% of patients resolving with antidepressant treatment. Treatment of central nervous system disorders with antidepressants also tends to negatively affect erectile function, ability to achieve orgasm, and sexual desire, affecting men more than women. Current guidelines recommend phosphodiesterase type 5 (PDE5) inhibitors, sildenafil, vardenafil, tadalafil, and avanafil, as needed, as first-line treatment for erectile dysfunction, but approximately 30-40% of men with erectile dysfunction do not respond to PDE5 inhibitor therapy, and some men cannot take PDE5 inhibitors due to interactions with common cardiac medications (nitrates). There are few treatments for ejaculatory disorders. Premature ejaculation is treated with SSRIs or dapoxetine. There is no approved treatment for delayed ejaculation. In addition to mood disorders, antidepressants are also used to treat neuropathic pain, and therefore antidepressant-induced sexual dysfunction affects an even larger number of people. The better patients are treated for depression and sexual dysfunction, the healthier they will be and typically have a better quality of life.

[0007] The current treatment of sexual dysfunction in depressed patients is with one atypical antidepressant in addition to antidepressant treatment with SSRI or SNRI. An alternative is to switch the antidepressant treatment to vortioxetine monotherapy, but with the risk of reduced efficacy against depression. In patients with mild depression and erectile dysfunction, the recommended treatment is a type 5 phosphodiesterase inhibitor in addition to antidepressant treatment, with vardenafil, only 38% of patients achieved normal erectile function compared to 13% of the placebo group. Thus, there is still a large number of patients with comorbid depression and erectile dysfunction whose treatment needs are not met. However, in patients who respond positively, there is a correlation between improved erectile function and improved depression. Bupropion is a noradrenaline-dopamine reuptake inhibitor and nicotinic receptor antagonist, while mirtazapine antagonizes α2-adrenergic and serotonin receptors (5-HT2 and 5-HT3) and increases dopamine in the prefrontal cortex. Bupropion and mirtazapine are used as add-ons to enhance the antidepressant effect and counteract the severe effects of other antidepressants on sexual function. Vortioxetine is an atypical antidepressant that inhibits serotonin (5-hydroxytryptamine) reuptake and norepinephrine reuptake, as well as inhibiting some 5-hydroxytryptamine (5-HT 1A and 5-HT 1B ) and acts as an agonist on other 5-hydroxytryptamine receptors (5-HT 1D , 5-HT3, and 5-HT7) as antagonists. Although the incidence of sexual dysfunction is lower in patients treated with depression with vortioxetine compared to traditional SSRIs (e.g. paroxetine and escitalopram), there is also a significant demand for the treatment of antidepressant-induced sexual dysfunction (treatment-induced erectile dysfunction) with vortioxetine. Thus, there is a significant unmet need and market for antidepressants that improve sexual function in depressed patients rather than further worsening it. Summary of the Invention

[0008] As outlined above, compounds that can simultaneously affect penile erection and treat major depressive disorder, but without the adverse effects of conventional antidepressants, are highly desirable. In particular, the sedative effects of conventional SSRIs are undesirable for patients wishing to achieve and maintain an erection.

[0009] The present disclosure thus provides a compound of formula (I) for use in the treatment of major depressive disorder and / or erectile dysfunction. In particular, the present disclosure provides a compound of formula (I) for use in the treatment of major depressive disorder and / or erectile dysfunction in patients suffering from both major depressive disorder and erectile dysfunction. The inventors have unexpectedly found that the compound has an effect on erection in rats. The inventors have found that both the duration and frequency of erectile response were higher in adult rats compared to young rats, while the magnitude of erectile response was higher in young rats compared to adult rats. The inventors have also unexpectedly found that the erectile response was stronger at lower doses, with lower doses of 0.001-0.1 mg / kg resulting in more frequent erectile responses than doses of 1.0 mg / kg. The inventors have also unexpectedly found that the compound has an antidepressant effect in two different animal models, namely mice and rats. These findings show a completely new way to treat erectile dysfunction and major depressive disorder with monotherapy using the compounds of the present disclosure.In contrast to current technology, the compounds of the present disclosure can treat both major depressive disorder and erectile dysfunction, ejaculation disorder, and anxiety.These findings can potentially bring about a greatly improved quality of life for patients suffering from major depressive disorder and erectile dysfunction, ejaculation disorder, and / or anxiety, erectile dysfunction caused by major depressive disorder treatment, or erectile dysfunction caused by major depressive disorder.

[0010] Thus, in one important aspect, there is provided a compound of formula (I) for use in the treatment, prevention, and / or alleviation of erectile dysfunction, sexual dysfunction, depression, anxiety, and / or ejaculatory disorder; or any combination thereof, in a subject: [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0011] In another aspect, there is provided a method for the treatment, prevention, or alleviation of a combination of erectile dysfunction and depression, erectile dysfunction and sexual dysfunction, erectile dysfunction and anxiety, erectile dysfunction and ejaculation disorder, sexual dysfunction and depression, sexual dysfunction and anxiety, sexual dysfunction and ejaculation disorder, depression and anxiety, depression and ejaculation disorder, and / or anxiety and ejaculation disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0012] In yet another aspect, there is provided a method for enhancing the magnitude of erectile response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0013] In another aspect, there is provided a method for increasing the duration of erectile response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0014] In yet another aspect, there is provided a method for increasing the frequency of erectile responses in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0015] In yet another aspect, there is provided a method for inducing relaxation of the corpus cavernosum in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0016] In a final aspect, there is provided a method for increasing penile blood flow in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0017] [Figure 1] Relationship between Compound (I) concentrations in plasma (closed diamonds) and brain (closed circles) and in vivo occupancy of DAT transporters in mouse striatum (open bars) 90 min after oral dosing at 3, 10 and 30 mg / kg. [Diagram 2] Inhibition of WIN binding in vitro and in vivo by compound (I). [Diagram 3] Time course of in vivo WIN binding in mice after oral administration of 20 mg / kg. [Figure 4] Effects of cocaine (black triangles, 25 mg / kg i.p., 0 min), bupropion (white triangles, 10 mg / kg s.c., 0 min), and Compound (I) at 30 mg / kg and 3 mg / kg at 0 min (white diamonds, black diamonds) on extracellular DA levels in the nucleus accumbens of anesthetized mice. Extracellular DA concentrations are expressed as a percentage of basal monoamine values ​​in three fractions taken before drug injection (mean ± standard error of the mean). [Diagram 5] Forced swimming in NMRI mice. Compound (I); oral, t=60 min. [Figure 6] Mouse tail suspension test. Male C57, 25-28g, Taconic, 16 / 8-06. Mice were acclimated to floor level for 5 days prior to testing. Mice were injected with saline twice, once per day, prior to testing. 22°C, N=7-8. [Figure 7] Effect of Compound (I) in nialamide-induced 5-HT syndrome test. 50mg / kg nialamide, subcutaneous, t=120min. Compound (I); oral, t=0. n=4. [Figure 8] Effect of Compound (I) on locomotor activity. Compound (I); Oral administration to NMRI mice. TSE motility. [Figure 9] Compound (I) in combination with WAY100635 (0.1 mg / kg) (subactive dose mFST). Compound (I) (oral, 60 min time point) + WAY100635 (subcutaneous, 60 min time point). [Figure 10]Compound (I) in combination with WAY100635 (1 mg / kg) in the mFST (active dose mFST). Compound (I) (oral, 60 min time point) + WAY100635 (subcutaneous, 60 min time point). [Figure 11] Compound (I) in combination with SCH23390 in the mFST (active dose mFST). Compound (I) (oral, 60 min time point) + SCH23390 (subcutaneous, 60 min time point). [Figure 12] Compound (I) in combination with SCH23390 (active dose), locomotor activity. Compound (I) orally + SCH23390 subcutaneously. [Figure 13] Marble hiding. In the marble hiding test, mice exposed to novel objects (marbles) hide them in sawdust bedding. Compounds exhibiting anxiolytic-like activity reduce the number of marbles hidden at non-sedative doses. Compound (I) (IP2018) was orally administered to NMRI mice (n=8) and showed a dose (0.1-1.0 mg / kg)-dependent increase in the number of visible marbles, suggesting an anxiolytic effect. The number of marbles covered in sawdust was counted at the end of a 60-min session. [Figure 14] Stress-induced hyperthermia. When mice face a stressful event, their body temperature increases. Vehicle and compound (I) (IP2018, 0.1 mg / kg, 1 mg / kg, and 3 mg / kg) were orally administered to NMRI mice (n=8 per group), which did not change their body temperature in the resting state (upper panel). When mice were exposed to stress, their body temperature increased in vehicle-treated mice, whereas the increase in body temperature was significantly prevented in compound (I)-treated mice at all three doses (lower panel). [Figure 15] Effect of Compound I in mouse zero maze. Mice were treated (orally) with vehicle, duloxetine (10mg / kg) and Compound I (0.1mg / kg, 1mg / kg and 3mg / kg) for 7 days (n=8 per group). The effect of Compound I at 3mg / kg was similar to that of duloxetine at 10mg / kg in mouse zero maze test. [Figure 16]Effects of Compound (I) on QT interval pacing data (90 bpm) in anesthetized beagle dogs. Data are expressed as mean ± standard error of the mean, where n=4 for all time points except D2t7 where n=3, D3t7 where n=2, and D4t7 and D4t26 where no data. Animals received 1, 3, 10, and 30 mg / kg of Compound (I) as four intravenous infusions (starting at t0, D1t30, D2t30, and D3t30, respectively). Each dose was administered over 5 minutes using an infusion pump, and the administration volume for each treatment was 2 ml / kg, except for the fourth dose, which was 3 ml / kg. Vertical lines represent the start of the infusion for each dose. [Figure 17] Effects of Compound (I) on QT interval pacing data (110 bpm) in anesthetized beagle dogs. Data are presented as mean ± standard error of the mean, where n=4 for all time points except D4t7 and D4t26, where no data were available. Animals received 1, 3, 10, and 30 mg / kg of Compound (I) as four intravenous infusions (starting at t0, D1t30, D2t30, and D3t30, respectively). Each dose was administered over 5 minutes using an infusion pump, and the administration volume for each treatment was 2 ml / kg, except for the fourth dose, which was 3 ml / kg. Vertical lines represent the start of the infusion for each dose. [Figure 18] Plasma pharmacokinetic (PK) profile of compound (I) in mouse plasma. [Figure 19] Plasma pharmacokinetic (PK) profile of compound (I) in rat plasma. [Figure 20] Plasma pharmacokinetic (PK) profile of Compound (I) in dogs. [Figure 21] Compound (I) administered orally to mice. Dose vs. AUC shows a slight trend towards sublinear kinetics. [Figure 22] Compound (I) administered subcutaneously to rats. Dose vs. AUC shows linear kinetics. [Figure 23] Compound (I) orally administered to mice. Plasma concentration at steady state versus dose. [Figure 24]Compound (I) orally administered to rats. Plasma concentration at steady state versus dose. [Diagram 25] Mean spontaneous increase in (A) intracavernous blood pressure, (B) duration of penile erection and (C) frequency of these events after infusion of compound (I) (1 mg / kg) in young (6-week-old male Wistar rats) and old (14-16-week-old male rats). Results are means ± standard error of the mean. [Figure 26] Mean increase in the number of spontaneous erections measured as intracavernous blood pressure (ICP) following infusion of 0.001 mg / kg, 0.01 mg / kg, 0.1 mg / kg, and 1 mg / kg of Compound (I) in anesthetized rats (n=4-6). [Figure 27] Average effects of vehicle (n=5) (A) and compound (I) on mean arterial pressure (MAP) and erectile response measured as peak intracavernous pressure (PICP) divided by mean arterial pressure (MAP) (PICP / MAP) in anesthetized 6-week-old male Wistar rats (n=6) (B) and 14-16-week-old male rats (n=6) (C). Vehicle and compound (I) were administered after establishing maximal (10 Hz, 1 ms, 6 V) and submaximal (submax) responses (10 Hz, 1 ms, 0.6-1.55 V) to 30 s of cavernous nerve stimulation. Submaximal stimulation was repeated 3, 13, 23, and 33 min after drug or vehicle administration. The top line indicates mean arterial pressure (MAP) and the bar graph indicates erectile response ((PICP / MAP)·100), where PICP is peak intracavernous pressure. [Figure 28] Compound (I) concentration in plasma over time following oral administration of Compound (I) in a Phase 1 study in men. The figure shows plasma concentrations following administration of 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, and 1 mg / kg in healthy volunteers. [Figure 29]Original charts showing the effect of Compound (I) on the resting state of rat corpus cavernosum strips. Increasing concentrations of Compound (I) (10-9 to 3x10-5M) were added. Compound (I) induced slight relaxation, while at the highest concentration (3x10-5M) contraction was also observed (bottom chart). These charts show Compound (I) response in the presence of vehicle, sildenafil (10-7M), guanethidine (10-5M), and L-NOARG (10-4M). [Diagram 30] Average results showing the effect of Compound (I) on the resting state of rat corpus cavernosum strips. Increasing concentrations of Compound (I) (10-9 to 3x10-5 M) were added. Compound (I) induced slight relaxation, while at the highest concentration (3x10-5 M) contraction was also observed (bottom chart). Compound (I) responses were obtained in the presence of vehicle, sildenafil (10-7 M), guanethidine (10-5 M), and L-NOARG (10-4 M). Results are the mean ± standard error of the mean of preparations from five rats. [Diagram 31] Original chart showing relaxation to Compound (I) in strips of rat corpus cavernosum contracted with phenylephrine (Phe). A representative chart shows Compound (I) relaxation in the presence of vehicle, guanethidine (10-5M), L-NOARG (10-4M), and sildenafil (10-7M) in a preparation contracted with phenylephrine. [Diagram 32] Average relaxation induced by Compound (I) in rat corpus cavernosum strips. Increasing concentrations (10-9 to 3x10-5 M) of Compound (I) in preparations contracted with phenylephrine. Compound (I) relaxation was obtained in the presence of vehicle, guanethidine (10-5 M), sildenafil (10-7 M), and L-NOARG (10-4 M). Results are the mean ± standard error of the mean of preparations from 5 rats. *P<0.05 compared to the control curve for Compound (I). [Diagram 33]Blood flow laser Doppler raw data from mouse erectile function (top panel) and average blood flow changes (EF) in mouse erectile tissue (bottom panel). The increase in penile blood flow induced by compound (I) (1 mg / kg) was highly significant, increasing 4.99-fold (n=2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present disclosure relates to a compound of formula (I) (Compound (I)) for use in treating a disease or disorder, or a group of diseases or disorders, including erectile dysfunction and / or depression, ejaculation disorder and / or anxiety. Treatment of such diseases or disorders by administration of the compound is described herein. More specifically, Compound (I) is shown to act as an antidepressant in mice and rats. Compound (I) is also shown to induce erections and have anxiolytic effects in rats.

[0019] definition "Pharmaceutically acceptable" means that it is useful in the preparation of pharmaceutical compositions that are normally safe, non-toxic and not biologically or otherwise undesirable, and includes that it is acceptable for veterinary use as well as human pharmaceutical use.

[0020] The term "pharmaceutically acceptable salt" of a compound, as defined herein, refers to a salt that is pharmaceutically acceptable and that retains the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed by the addition of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid); or with organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid); or salts formed upon replacement of an acidic proton present in the parent compound with a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed when an acidic proton present in the parent compound is coordinated to an organic or inorganic base. Acceptable organic bases include, for example, diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, morpholine, and tromethamine. Acceptable inorganic bases include, for example, ammonia, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0021] "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a condition, is sufficient to effect such treatment for the treatment of the condition. A "therapeutically effective amount" will vary depending on the condition of the disease or disorder being treated, the severity of the disorder being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, etc.

[0022] As used herein, the term "treatment" or "treating" refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, attenuation of the severity of a disease or disorder, stabilization of the state of a disease or disorder (i.e., not worsening), prevention of a disease or disorder, delay or slowing of the progression of a disease or disorder, improvement or palliation of the condition, and remission (either partial or complete remission).

[0023] Whenever an asymmetric carbon is present in a chemical structure, all stereoisomers associated with that asymmetric carbon are intended to be included in the structure unless otherwise specified. Using the Cahn-Ingold-Prelog (RS) notation, the asymmetric carbon atom may be represented in either the (R)- or (S)-configuration, and the compound may be represented as a mixture of its stereoisomers, e.g., a racemic mixture, or only one stereoisomer. With respect to the bicyclic moieties disclosed herein, the substituents may be attached in the endo configuration, the exo configuration, or both. All stereoisomers associated with the bicyclic moiety are intended to be included in the structure unless otherwise specified.

[0024] The compounds of the present invention may exist in tautomeric forms, and any such tautomers are considered to be within the scope of the present invention.

[0025] Also, in the compounds of formula (I) specified herein, any hydrogen atom may be replaced with a deuterium ( 2 Any such deuterated compounds of formula (I), which may be substituted with hydrogen (H) and contain one or more deuterium atoms in place of the corresponding number of hydrogen atoms, are considered to be within the scope of the present invention.

[0026] It is known in the art that prodrugs can be made. Those skilled in the art will understand what kind of molecular moieties can be introduced into drugs to make prodrugs. Prodrugs related to the compounds of formula (I) are considered to be within the scope of the present invention.

[0027] The terms "P2018," "Compound (I)," and "compound of formula (I)" are used synonymously herein.

[0028] Compounds for Use In one embodiment of the present disclosure, there is provided a compound of formula (I): [ka] The compound (Compound (I)) or a pharma- ceutically acceptable salt thereof is provided. The tests outlined in the Examples section reveal the positive effect of the compound on erectile function in rats, while the use of this compound for the treatment of depression is established.

[0029] In one embodiment of the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is used for the treatment, prevention, or alleviation of sexual dysfunction resulting from depression.

[0030] In one embodiment of the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is used for the treatment, prevention, or alleviation of erectile dysfunction resulting from depression.

[0031] In one embodiment of the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is used for the treatment, prevention, or alleviation of erectile dysfunction and / or depression, where the erectile dysfunction is treatment-induced erectile dysfunction. Treatment-induced erectile dysfunction refers to erectile dysfunction where the erectile dysfunction is due to the treatment of another disease, disorder, or condition.

[0032] In one embodiment of the present disclosure, the erectile dysfunction caused by treatment is drug-induced erectile dysfunction, where the drug used to treat other diseases, disorders or conditions in the subject causes erectile dysfunction as an adverse effect.The adverse effect of the drug may be, for example, psychological in nature (such as low libido), which may make it difficult to achieve or maintain an erection.Alternatively, the adverse effect of the drug may be physiological in nature (such as hormones), which may make it difficult to achieve or maintain an erection.It is also conceivable that the psychological aspects of mental disorders (such as sadness, anxiety, or apathy) may reduce the libido of the person suffering from depression, thereby adversely affecting the person's ability to achieve or maintain an erection.

[0033] In one embodiment, the present invention relates to treating depression and erectile dysfunction, erectile dysfunction due to treatment of depression or due to depression, anxiety associated with major depressive disorder, major depressive disorder with ejaculation disorder, anxiety with ejaculation disorder, anxiety due to sexual dysfunction, sexual dysfunction comorbid with anxiety due to major depression, major depression with sexual dysfunction comorbid with ejaculation disorder, and / or anxiety associated with sexual dysfunction with ejaculation disorder by administering a compound of Formula (I) to a subject in need thereof.

[0034] In one embodiment of the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is used for the treatment, prevention, or alleviation of erectile dysfunction, wherein the erectile dysfunction is treatment-induced erectile dysfunction caused by medications that are antidepressants, NSAIDs, finasteride, antiepileptics, or neuroleptics.

[0035] In one embodiment of the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is used for the treatment, prevention, or alleviation of erectile dysfunction, wherein the erectile dysfunction is treatment-induced erectile dysfunction caused by medications that are antidepressants.

[0036] In one embodiment of the present disclosure, the compound of formula (I) or its pharma- ceutically acceptable salt is used to treat, prevent or alleviate erectile dysfunction, where erectile dysfunction is treatment-induced erectile dysfunction caused by antidepressant treatment of depression.In one embodiment, the antidepressant is, for example, SSRI or SNRI.Because the compound of formula (I) is a serotonin / dopamine reuptake dual-action inhibitor, the compound is useful in treating both erectile dysfunction and depression.Therefore, in one embodiment, the treatment with the antidepressant is stopped, and the compound of formula (I) is administered instead to treat both erectile dysfunction and depression.In yet another embodiment, the treatment with the antidepressant is not stopped, but the compound of the present disclosure is administered to alleviate the symptoms of treatment-induced erectile dysfunction caused by the antidepressant.

[0037] In one embodiment of the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is used for the treatment, prevention, or alleviation of sexual dysfunction and / or depression resulting from said sexual dysfunction.

[0038] In one embodiment of the present disclosure, the compound of formula (I) or its pharma- ceutical acceptable salt is used for treating, preventing or alleviating erectile dysfunction and / or depression caused by said erectile dysfunction.Because it is a serotonin / dopamine reuptake dual action inhibitor, the compound is considered to be particularly useful for treating depression caused by erectile dysfunction.

[0039] In one embodiment, the compounds of formula (I) or pharma- ceutically acceptable salts thereof are used for the treatment, prophylaxis, or alleviation of a combination of sexual dysfunction and / or erectile dysfunction, and / or depression and / or anxiety.

[0040] In one embodiment of the disclosure, a composition is contemplated that includes a compound of formula (I). The composition further includes at least one pharma- ceutically acceptable carrier, excipient, or diluent.

[0041] In one embodiment of the present disclosure, the compound of the present disclosure is administered to the subject in need of treatment for sexual dysfunction, erectile dysfunction, and / or depression, or ejaculation disorder.In a preferred embodiment, the subject is a mammal.In a further preferred embodiment, the mammal is a human.In a further preferred embodiment, the human is a male.

[0042] The compound of formula (I) is a serotonin / dopamine reuptake dual action inhibitor.Therefore, in one embodiment of the present disclosure, the compound of formula (I) is used for treating, preventing, or alleviating erectile dysfunction, depression, sexual dysfunction, and / or ejaculation disorder; or any combination thereof; combination of erectile dysfunction and anxiety, sexual dysfunction and anxiety, depression and anxiety, or anxiety and ejaculation disorder.In a further embodiment, the compound of formula (I) is used for treating, preventing, or alleviating combination of erectile dysfunction and depression, erectile dysfunction and sexual dysfunction, erectile dysfunction and anxiety, erectile dysfunction and ejaculation disorder, sexual dysfunction and depression, sexual dysfunction and anxiety, sexual dysfunction and ejaculation disorder, depression and anxiety, depression and ejaculation disorder, and / or anxiety and ejaculation disorder.The compound of formula (I) is particularly useful for treating, preventing, or alleviating the above diseases or disorders and combinations thereof, since it is a serotonin / dopamine reuptake dual action inhibitor.

[0043] The compound of the present disclosure may be included in pharmaceutical compositions.The composition may be administered by any convenient route that is compatible with the desired treatment.Preferred administration routes include oral administration, particularly oral administration by tablet, capsule, sugar-coated, powder or liquid form, local administration such as by inhalation or patch, and parenteral administration, particularly cutaneous, subcutaneous, intramuscular or intravenous injection.

[0044] For topical administration to the epidermis, the compound of the present invention can be formulated as ointment, cream, or lotion, gel, or transdermal patch.Ointment and cream can be formulated, for example, with an aqueous or oily base, adding suitable thickening agent and / or gelling agent.Lotion can be formulated with an aqueous or oily base, and generally further comprises one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents, or coloring agents.

[0045] Treatment methods As shown in the examples below, the compound of formula (I) is useful for treating diseases or disorders such as erectile dysfunction, depression, sexual dysfunction, anxiety, and / or ejaculation disorder. That is, one embodiment of the present disclosure provides a method for treating, preventing, or alleviating erectile dysfunction, depression, sexual dysfunction, and / or ejaculation disorder; or any combination thereof, or a combination of erectile dysfunction and anxiety, sexual dysfunction and anxiety, depression and anxiety, or anxiety and ejaculation disorder, comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof. As shown in Example 25, compound (I) induces erection in both young and adult rats. As outlined in Figure 25, compound (I) can enhance the magnitude of erectile response, prolong the duration of erectile response, and / or increase the frequency of erectile response. Thus, one embodiment of the present disclosure provides a method for enhancing the magnitude of erectile response in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) to the subject. The enhanced degree of erectile response is particularly prominent in young test animals. That is, in a further embodiment of the present disclosure, the subject is a young male. In a particular embodiment of the present disclosure, the male is under 40 years old (such as under 35 years old, such as under 30 years old, such as under 25 years old, such as under 20 years old). Another embodiment of the present disclosure provides a method for prolonging the duration of erectile response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I). The prolongation of the duration of erectile response is particularly prominent in male adult test animals. That is, in a further embodiment of the present disclosure, the subject is an adult male. In certain embodiments, the subject is an adult male over 20 years of age (such as an adult male over 25 years of age, such as an adult male over 30 years of age, such as an adult male over 35 years of age, such as an adult male over 40 years of age, such as an adult male over 45 years of age, such as an adult male over 50 years of age, such as an adult male over 55 years of age, such as an adult male over 60 years of age, such as an adult male over 65 years of age, such as an adult male over 70 years of age, such as an adult male over 75 years of age).Another embodiment of the present disclosure provides a method for increasing the frequency of erectile response in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) to the subject.The increase in frequency of erectile response is particularly significant in male adult test animals.That is, in a further embodiment of the present disclosure, the subject is an adult male.In certain embodiments, the subject is an adult male over 20 years old (such as an adult male over 25 years old, such as an adult male over 30 years old, such as an adult male over 35 years old, such as an adult male over 40 years old, such as an adult male over 45 years old, such as an adult male over 50 years old, such as an adult male over 55 years old, such as an adult male over 60 years old, such as an adult male over 65 years old, such as an adult male over 70 years old, such as an adult male over 75 years old).

[0046] As shown in Example 27, compound (I) can induce relaxation of the corpus cavernosum. Thus, in one embodiment of the present disclosure, there is provided a method for inducing relaxation of the corpus cavernosum in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0047] As shown in Example 28, administration of compound (I) to mice increased penile blood flow in the test animals. Thus, one embodiment of the present disclosure provides a method for increasing penile blood flow in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0048] Any of the above methods for treating erectile dysfunction and / or related side effects (such as reduced degree of erectile response, shortened duration of erectile response, reduced frequency of erectile response, impaired relaxation of the corpus cavernosum, or reduced penile blood flow) may be further useful for treating subjects suffering from erectile dysfunction and / or the above related side effects complicated with depression, anxiety, and / or ejaculation disorder.That is, one embodiment of the present disclosure provides a method for treating, preventing, or alleviating erectile dysfunction, enhancing degree of erectile response, prolonging duration of erectile response, increasing frequency of erectile response, inducing relaxation of the corpus cavernosum, and / or increasing penile blood flow in a subject in need thereof, wherein the subject further suffers from depression, anxiety, or ejaculation disorder.

[0049] Working Example Example 1: Compound Stability Purity and stability tests were performed on exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one (Compound (I)) hydrochloride anhydrate, showing that the compound is chemically and thermodynamically stable in both the solid and solution states, but is light sensitive when in solution. The results are summarized in Table 1.

[0050] [Table 1]

[0051] conclusion Compound (I) exhibits good stability in solution over a range of pH values, but is sensitive to oxidation and light. In the solid state, Compound (I) is stable for over 26 days.

[0052] Example 2: In vitro efficacy Compound (I) has been characterized as a monoamine reuptake inhibitor based on its profile in a range of functional assays (Table 2). Good correlation between human and rat systems was observed in the 5-HT binding assay, but to a lesser extent for the NA transporter (Table 3).

[0053] [Table 2]

[0054] [Table 3]

[0055] conclusion In vitro, compound (I) is a potent inhibitor of the 5-HT transporter, with 26-fold and 56-fold lower affinity for the human NA and DA transporters, respectively. However, the ratio of 5-HT:NA:DA depends on the assay system utilized (see also Table 4).

[0056] Example 3: In vitro selectivity In the MDS LeadProfilingScreen (consisting of 67 different receptors, transporters and ion channels) supplemented with various in-house nicotine binding assays, compound (I) was found to be fairly selective for relevant molecular targets, with a few exceptions showing more than 50% inhibition at 10 μM (Table 4). 50 or K I Values ​​were then determined for targets for which >60% inhibition was observed in the initial screen.

[0057] [Table 4]

[0058] Compound (I) exhibited affinity for nicotinic acetylcholine receptors and 5-HT3 receptors in the micromolar range (Table 5).

[0059] [Table 5]

[0060] conclusion Compound (I) is highly selective for the intended receptors SERT, NET, and DAT, while binding only with substantially less inhibition to a few other receptors.

[0061] Example 4: Neurochemical mechanisms of action in vivo - Microdialysis The aim of this study was to investigate the effects of Compound (I) on the brain levels of serotonin, noradrenaline and dopamine after administration in the ventral hippocampus (Hipp), prefrontal cortex (PFC), striatum (STR) and nucleus accumbens (N.Acc) of anesthetized rats and mice by in vivo microdialysis technique. Compound (I) is a dual-acting serotonin / dopamine reuptake inhibitor and was tested in comparison with citalopram, a serotonin-selective reuptake inhibitor. Compound (I) was tested after subcutaneous injection at doses ranging from 0.25 to 30 mg / kg. Compound (I) dose-dependently increased serotonin (5-HT) in the prefrontal cortex (PFC) (area under the curve (AUC) in Table 6 below). 0-160分 )): A dose of 0.25 mg / kg induced an increase of 190 ± 15%, and at 1 mg / kg (AUC 0-160分 ) was the near-maximal increase to 252±48%, since the 10 mg / kg dose did not induce any further increase (i.e., 263±47%). 1A Pretreatment with the autoreceptor antagonist WAY-100635 further induced a modest increase in Compound (I) (0.25 mg / kg)-induced increases in 5-HT levels in the prefrontal cortex (PFC).

[0062] Compound (I) induced a small increase (132±9%) in dopamine (DA) levels in the prefrontal cortex (PFC) at 1 mg / kg and a further increase (211±40%) at 10 mg / kg.

[0063] At 10 mg / kg, Compound (I) increased noradrenaline (NA) (AUC 0-160分At 10-30 mg / kg, Compound (I) significantly increased DA levels in the nucleus accumbens (N.Acc) in a dose-dependent manner (192 ± 42 and 604 ± 88%, respectively). Compound (I) tested at 3 mg / kg and 10 mg / kg subcutaneously did not significantly increase DA (AUC 0-160分 ) had only a small effect on the schizophrenia (137 ± 21 and 134 ± 43%, respectively).

[0064] When tested in the ventral hippocampus (Hipp), Compound (I) at 3 mg / kg subcutaneously increased 5-HT levels (AUC 0-160分 ) significantly increased (433 ± 53%), but not noradrenaline levels (AUC 0-160分 ) (138 ± 13%) and dopamine levels (AUC 0-160分 ) (142±36%) was less effective.

[0065] Comparative data from a similar study was obtained with intraperitoneal administration of citalopram at 5 mg / kg. Results showed that the effect of citalopram administered at 5 mg / kg induced nearly identical effects to compound (I) at 3 mg / kg measured on 5-HT levels in the rat ventral hippocampus (Hipp). In the prefrontal cortex (PFC), both compound (I) and citalopram increased 5-HT levels, but only compound (I) induced effects on DA levels and slight effects on NA levels.

[0066] [Table 6]

[0067] conclusion Overall results showed that compound (I) was a potent inhibitor of serotonin and dopamine reuptake in vivo, producing a balanced increase in 5-HT and DA levels in the PFC with only minor effects on NA levels.

[0068] Example 5: Neurochemical mechanism of action in vivo - MPTP model of DAT inhibition Furthermore, the MPTP depletion model clearly shows that compound (I) has efficacy as an inhibitor of dopamine transporter (DAT) in the striatal tissue of C57 mice in vivo, with approximately 90% protection at a dose of 15 mg / kg and a slight additional effect at 30 mg / kg (Table 7). In this model, compound (I) induced protection against dopamine depletion induced by the influx of MPTP metabolite MPP+ into dopaminergic terminals in the striatal tissue of C57 mice.

[0069] [Table 7]

[0070] conclusion Compound (I) has potency as an inhibitor of the dopamine transporter (DAT) in striatal tissue of C57 mice.

[0071] Example 6: PD / PK studies in mice and rats The relationship between brain concentration of compound (I) and transporter occupancy was examined in mice in vivo. 3 H-WIN35.428 binding was investigated. The relationship between the increase in plasma and brain concentrations with each increase in dose level and the corresponding increase in in vivo DA transporter occupancy in the central nervous system 90 min after administration. In each case, there was a close correlation between plasma and brain concentrations and in vivo transporter occupancy in the brain, with brain-to-plasma ratios of approximately 4 at 3, 10 and 30 mg / kg (Figure 1). Compound (I) concentration-dependently inhibits WIN binding in vitro and in vivo in the striatum (Figure 2). Inhibition of in vivo WIN binding was measured 90 min after oral administration of the compound.

[0072] Example 7: Transporter occupancy in vivo The in vivo receptor occupancy (RO%) of compound (I) was calculated using the formula: RO% (estimated) = DOSE 100 / (ED 50 + DOSE) The MED values ​​(DOSE) were calculated using the mouse forced swimming test (mFST) and mouse motility test. The calculations were performed using the EDs for ex vivo uptake of 5-HT and NA and in vivo WIN binding. 50 The results are shown in Table 8.

[0073] [Table 8]

[0074] Example 8: Abuse Liability In vivo binding time course studies showed that inhibition of WIN binding increased over time in mice orally dosed at 20 mg / kg, indicating a slower onset of in vivo inhibition of the DA transporter (Figure 3). Compound (I) at 30 mg / kg sc in rats shows a slower kinetic pattern in microdialysis (nucleus accumbens) compared to bupropion at 10 mg / kg sc and cocaine at 25 mg / kg i.p. In vivo binding data are shown in Figure 4. It is known that the primary factor in psychotomimetic side effects of dopamine agonists is the rate of inhibition of the DA transporter rather than an increase in DA release per se. This slower kinetic pattern may indicate a lower risk of abuse potential.

[0075] Example 9: Pharmacological activity in vivo - In vivo efficacy against depression and its mechanism Compound (I) was tested in two of the most widely used behavioral screening methods to predict the clinical efficacy of antidepressants: the mouse forced swim test (mFST) and the mouse tail suspension test (mTST). These paradigms show high pharmacological validity as evidenced by their sensitivity to the major types of antidepressant treatment (tricyclic compounds, monoamine oxidase inhibitors, atypical antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs)) and electroconvulsive shock. As summarized in Table 9 and Figures 5 and 6, Compound (I) significantly increased the swimming distance and decreased immobility time in the mFST and mTST, respectively, compared to vehicle-treated mice. These effects suggest potential antidepressant-like activity. In the mFST, the effect of Compound (I) was more potent than that after treatment with reference compounds (mFST: Compound (I) > citalopram > duloxetine). In the mTST, the effects of compound (I) were as potent or more potent than those following treatment with the reference compounds (compound (I) = citalopram > fluoxetine).

[0076] [Table 9]

[0077] Compound (I) was tested in a classical test often used to evaluate the ability of compounds to block 5-HT reuptake in vivo (nialamide-induced 5-HT syndrome (m5-HT)). In addition, compound (I) was tested in the locomotor activity paradigm (mLA) as a measure of the ability to block DA reuptake and thereby cause motility. It is generally accepted that >60% DA transporter inhibition is necessary to induce increased motility in this test. As summarized in Table 10 and Figures 7 and 8, compound (I) potently enhanced 5-HT syndrome-like behavior (activity indicative of in vivo 5-HT reuptake inhibition) in nialamide-pretreated mice. The effect of compound (I) was 100 times more potent than that of the reference compounds tested. In addition, compound (I) increased locomotor activity at 10 mg / kg (2-hour test) and 30 mg / kg (6-hour test), suggesting DA reuptake inhibitor properties. On the other hand, duloxetine and citalopram had no effect.The effect of Compound (I) on motility was slow to develop but long-lasting.

[0078] [Table 10]

[0079] To further characterize the role played by 5-HT and DAergic neurotransmission in the antidepressant-like effect of compound (I), the potential involvement of 5-HT1A and D1 receptors was examined in the mFST. Subactive / active doses of compound (I) were tested in combination with WAY1006351 (5-HT1A receptor antagonist) and SCH23390 (D1 receptor antagonist), respectively. As shown in Table 11 and Figures 9 and 10, the combination of a low dose of WAY100635 (most likely inhibiting presynaptic 5-HT1A receptors) with a normal subactive dose of compound (I) resulted in significant antidepressant-like activity in the mFST (MED: 0.1 mg / kg, 10-fold shift to the left in response to dose), suggesting increased 5-HT function in the mechanism of action of compound (I). These data also agree well with the microdialysis study showing that compound (I) enhances 5-HT in the PFC when combined with WAY100635. In contrast, higher doses of WAY100635 (pre- and postsynaptic 5-HT 1A Combining an active dose of compound (I) with SCH23390 (most likely blocking both D1 receptors) did not affect the activity of the compound (MED: 1 mg / kg). This result suggests that DA can contribute already at doses as low as 1 mg / kg. As shown in Figures 11 and 12, the antidepressant-like activity of compound (I) was attenuated when the active dose was combined with a non-sedative dose of SCH23390 in the mFST (MED: 10 mg / kg, 10-fold shift to the right in response to dose), suggesting increased DA function at the active dose (D1 receptor-mediated). This hypothesis is in good agreement with microdialysis studies showing enhanced DA release in the PFC at similar doses and may explain the data obtained with higher doses of WAY100635. Interestingly, the combination of compound (I) and SCH23390 did not affect the overall locomotor profile of compound (I), suggesting that the antidepressant-like activity of the compound is most likely mediated by 5-HT / DA interactions in the PFC and possibly the nucleus accumbens, but not the striatum.

[0080] [Table 11]

[0081] conclusion Compound (I) showed significant activity in the 5-HT syndrome (MED: 0.1 mg / kg) assay, consistent with this compound being a 5-HT reuptake inhibitor. The compound also induced a significant increase in locomotor activity at higher doses (10 and 30 mg / kg, orally administered) (corresponding to >60% DA transporter inhibition), suggesting potent DA reuptake inhibitor properties. Furthermore, when tested in simple efficacy assays (mFST, mTST), compound (I) showed potent antidepressant properties. Efficacy in these assays appeared to involve both 5-HT and DA mechanisms within the same dose range, as evidenced by combination studies with selective antagonists. In conclusion, compound (I) appears to be a novel 5-HT / DA reuptake inhibitor potentially with antidepressant-like properties.

[0082] Example 10: In vivo efficacy against anxiety Compound (I) was tested in three behavioral screening tests widely used to predict clinical anxiolytic efficacy: the mouse marble hiding test (mMB), the mouse zero maze (mZM) and the mouse stress-induced hyperthermia test (mSIH).

[0083] [Table 12]

[0084] As summarized in Table 12 and Figures 13, 14 and 15, Compound I, like duloxetine, significantly reduces hiding behavior in mMB test and increases the time spent in the open section in mZM test after repeated treatment.The anxiolytic effect of Compound I is more potent than duloxetine in mMB test and is equally potent in mZM test.Very interestingly, Compound I attenuates stress-induced hyperthermia in mSIH test, but does not have such effect after duloxetine treatment.In general, second and third generation antidepressants are inactive in this test, thus highlighting the unique properties of Compound I in animal models of anticipatory neurosis.

[0085] Example 11: Preclinical Safety Pharmacology - HERG Channel Studies A HEK293 cell line stably expressing Kv11.3 and KCNE1 (minK) for hERG was established. The effect of compound (I) on the amount of current carried by the hERG channel was assessed in whole-cell membrane patch clamp experiments. The channel was activated by a voltage protocol designed to mimic the human cardiac action potential. At 10 μM, compound (I) blocked the current with an estimated Ki of >10 μM.

[0086] Example 12: Preclinical Safety Pharmacology - Cardiovascular Safety in Anesthetized Dogs No consistent changes in arterial pressure (mean, systolic and diastolic) were observed following intravenous administration of 1, 3, 10 and 30 mg / kg of Compound (I) to α-chloralose-anesthetized dogs, except for an apparent dose-dependent decrease following administration of 10 and 30 mg / kg of Compound (I). A dose-dependent increase in heart rate was observed following administration of 1, 3, 10 and 30 mg / kg of Compound (I), which was accompanied by a concomitant dose-dependent shortening in the RR interval.

[0087] PR interval and QRS duration were relatively unaffected by Compound (I) administration at 1, 3, 10 and 30 mg / kg, with the exception of the PR interval, which was potentially shortened after Compound (I) was administered at 30 mg / kg. No consistent changes in QT interval were observed after Compound (I) administration at 1, 3, 10 and 30 mg / kg. When correction for changes in heart rate / RR interval was performed to obtain QTcF and QTcV intervals, a clear dose-dependent increase was noted. This was also noted after periods when the heart was beating at either 90 or 110 bpm (Figures 16 and 17), but as shown in Table 13, this occurred at plasma concentrations between 6500 and 15,000 ng / ml.

[0088] [Table 13]

[0089] Example 13: Bioavailability in mice and rats Bioavailability studies were performed in female NMRI mice and male Wistar rats (N=4). Plasma samples were collected up to 24 hours. These studies show that bioavailability is maximal in mice (74%). Bioavailability in rats is 3%, so subsequent studies in rats use subcutaneous administration. Compound (I) is rapidly absorbed. Plasma PK profiles in mice show first-order elimination kinetics (see Figures 18 and 19). T 1 The pharmacokinetic (PK) profiles of 0.1-fold increased with increasing doses of 0.1-fold in mice and rats, respectively.

[0090] [Table 14]

[0091] Example 14: Bioavailability in Dogs Bioavailability studies were also performed in dogs. One female and one male dog received oral doses of 2.5 mg / kg and intravenous doses of 0.5 mg / kg. Some central nervous system effects were observed in both male and female dogs after administration of the 2.5 mg / kg dose. The intravenous dose, performed 7 days later, was chosen at 0.5 mg / kg to prevent observable central nervous system effects. The difference between oral and intravenous administration may overestimate the bioavailability to some extent. Bioavailability was 84% ​​in male dogs and 114% in females. Plasma elimination kinetics showed first-order kinetics after intravenous administration (Figure 20). T 1 / 2 is in the same range (1.4 to 1.7 hours) in both dogs and after both oral and intravenous administration.

[0092] [Table 15]

[0093] Example 15: Linearity studies in mice and rats after single dose administration PK data from rats administered subcutaneously at relatively low doses show very clear linear kinetics when expressed as AUC vs. dose, whereas PK data from mice administered orally at relatively high doses showed a trend towards sublinear kinetics.

[0094] Compound (I) was orally administered to mice at 30 and 60 mg / kg. Plasma samples were collected up to 24 hours. The results are shown in Table 16 and Figure 21.

[0095] [Table 16]

[0096] Compound (I) was administered subcutaneously to rats at 1, 5 and 10 mg / kg. Two plasma samples were collected and analyzed up to 24 hours. The results are shown in Table 17 and Figure 22.

[0097] [Table 17]

[0098] Example 16: Linearity after repeated dosing in mice and rats Single time point data are available from two sets of 14-day repeat-dose studies in mice and rats dosed to both sexes. The three lowest doses were run together in one study, and the highest dose was run on a separate occasion as a single companion study.

[0099] Mice appear to show a trend towards less linear kinetics, whereas rats show a trend towards slightly more linear kinetics. This difference may be the result of inherent differences in the method of administration. Note that in these studies, compounds were administered in 5% glucose (clear solution) and not in Tween 80 as in the single dose studies.

[0100] Compound (I) was orally administered at 15, 30, 60 and 90 mg / kg for 14 days. Samples were taken 2 hours after the last dose. Mice appear to show a tendency towards sublinear kinetics after repeated dosing. Male mice in particular show a substantial increase in plasma concentrations at the last oral dose of 90 mg / kg. At doses between 15 and 60 mg / kg, female mice show higher plasma concentrations than males, but at 90 mg / kg the curves cross and male mice show higher concentrations (Figure 23).

[0101] Compound (I) was administered subcutaneously at 5, 10, 15 and 25 mg / kg for 14 days. Samples were taken 2 hours after the last dose. Both male and female rats showed slightly more linear kinetic trends after repeated dosing. Male rats showed higher plasma concentrations compared to females. This figure was consistent from 5 to 25 mg / kg (Figure 24).

[0102] Example 17: Tissue distribution after a single dose Compound (I) was orally administered at 10 mg / kg to female NMRI mice. Plasma was collected at 0.5, 1, 2, 4, 6 and 24 hours after administration. Brain, liver and lung were collected at 1, 4 and 24 hours after administration.

[0103] The plasma profile was essentially the same as in the bioavailability study (Table 20), with the same T 1 Although the data are very sparse for organs, the AUC and T 1 / 2 was calculated for plasma and organs. Compound (I) shows significant selectivity for liver and lung in mice, but the ratio to brain is optimal.

[0104] [Table 18]

[0105] Compound (I) was administered subcutaneously at 5 mg / kg to male Wistar rats. Plasma was collected at 0.5, 1, 2, 4, 6 and 24 hours after administration. Brain, liver and lung were collected at 1, 4 and 24 hours after administration.

[0106] The plasma profile was also essentially the same as in the single-dose study, with the same T of 0.8 hours. 1 Although the data are very sparse for organs, the AUC and T 1 / 2 was calculated for plasma and organs. In contrast to mice, compound (I) was not found in high concentrations in the liver (Table 19). This may be due to subcutaneous administration bypassing the liver and / or the rat's much higher ability to metabolize the compound. Distribution to the brain is the same as in mice. Distribution to the lungs is a little higher than in mice.

[0107] [Table 19]

[0108] Example 18: Tissue distribution after repeated administration Compound (I) was orally administered at 15, 30 and 60 mg / kg to male and female NMRI mice for 14 days. Plasma, brain and liver were harvested 2 hours after the last dose.

[0109] The brain ratio remains roughly the same for single and repeated doses. The liver ratio is also similar to the single dose, except for the low dose in male mice. There are no single dose data from male mice.

[0110] [Table 20]

[0111] Compound (I) was administered subcutaneously at 5, 10 and 15 mg / kg to male and female Wistar rats for 14 days. Plasma, brain and liver were harvested 2 hours after the last dose.

[0112] For rats, the brain ratio is higher after repeated dosing compared to a single dose. This is similar for the liver. Compared to mice, the liver ratio is also significantly lower. This may also be due to the higher metabolic capacity of the liver in rats. In contrast to mice, male rats showed higher concentrations than females, and the liver ratio was correspondingly lower.

[0113] [Table 21]

[0114] Example 19: Metabolism - Metabolic stability in liver microsomes The metabolic stability of compound (I) was tested in liver microsomes from all available species at 1 and 5 μM. One metabolite, 16 mass units higher than the parent compound, was detected in all incubations except human liver microsomes. This metabolite showed the same retention time in all species, suggesting that it is most likely the same metabolite. Compound (I) is relatively stable in all species tested except rats.

[0115] [Table 22]

[0116] Example 20: Metabolism - Metabolic stability in human hepatocytes The stability of compound (I) was tested in human hepatocytes by incubation at 10 μM for 120 minutes. The compound was stable in human hepatocytes.

[0117] Example 21: Metabolism - CYP Inhibition Compound (I) was tested for CYP450 inhibition using a cocktail of selective substrates. IC50 was evaluated as the concentration of compound (I) that inhibits metabolite formation by 50% (Table 23). Only CYP1A2 was significantly inhibited by compound (I). This may be a focus for clinical trials later.

[0118] [Table 23]

[0119] Example 22: Metabolism - In vivo metabolites By quantifying compound (I) in rat urine, it was estimated that the amount of parent compound transferred into the urine was 6-10% of the administered dose (0-24 hours).

[0120] Example 23: Protein Binding Plasma protein binding was tested in rat, mouse, dog and human plasma by equilibrium dialysis. Plasma protein binding of this compound is remarkably low (Table 24).

[0121] [Table 24]

[0122] Example 24: Toxicity Studies - Maximum Tolerated Dose and Repeated Dosing The following dose levels: Test 1: 3, 5, 15 mg / kg and Test 2: 30 and 60 mg / kg Compound (I), administered orally (non-GLP) to female mice for 5 days, produced increased activity (sedation and stereotypy) but no significant change in body weight.

[0123] The following dose levels: Compound (I) administered orally (non-GLP) to female rats at 30, 60, or 90 mg / kg for 5 days resulted in increased activity but no changes in weight gain. Bioavailability in rats is low, so the rat studies described below were performed using subcutaneous dosing (~100% bioavailability).

[0124] In a 14-day repeated dose study, four groups of eight male and eight female NMRI mice were treated daily with Compound (I) at doses of 15, 30, and 60 mg / kg orally (Groups 2, 3, and 4) or with the vehicle 5% glucose subcutaneously (Group 1). A satellite group (Group 5) was administered orally at 90 mg / kg accordingly to enhance exposure and efficacy. Compound (I) administered at 60 mg / kg (Group 4) resulted in increased activity in both males and females, significant weight loss in the female group, and significant reductions in relative liver weight in both sexes. 90 mg / kg (Group 5) resulted in increased activity in both males and females, significant weight loss in both sexes, and significant reductions in relative liver weight. At termination, no treatment-related gross findings were noted in either males or females.

[0125] conclusion Male and female mice treated orally for 14 days at doses ranging from 15 to 90 mg / kg / day showed significant treatment-related changes in body weight and relative liver weight, but no treatment-related macroscopic findings were noted in either males or females.

[0126] In a 14-day repeated dose study, four groups of four male and four female Wistar rats were treated daily with Compound (I) at doses of 5, 10 and 15 mg / kg subcutaneously (Groups 2, 3 and 4) or vehicle 5% glucose subcutaneously (Group 1). A satellite group (Group 5) was administered 25 mg / kg subcutaneously accordingly to enhance exposure and efficacy. Compound (I) administered at 15 mg / kg (Group 4) resulted in increased activity in both males and females. No changes in body weight gain were observed in female rats, but there was a trend towards weight gain in Group 4 males. At termination, there were no treatment-related gross findings, but relative liver weight was decreased in Group 4 females and increased in Group 4 males. Group 5 (25 mg / kg) produced increased activity in both males and females, and minimal weight loss. No changes in liver weight were observed in Group 5.

[0127] conclusion Male and female Wistar rats were treated subcutaneously at doses ranging from 5 to 25 mg / kg / day for 14 days. The high dose group (25 mg / kg subcutaneously) showed minimal weight loss but increased activity in both male and female rats.

[0128] The compound was tested for genotoxicity in the Ames screening test using Salmonella typhimurium strains TA100 and TA98. Compound (I) was tested at dose levels ranging from 1.6 to 5000 μg / plate in the presence or absence of S-9 mix. It was concluded that compound (I) did not show any evidence of mutagenicity in this test.

[0129] Example 25: Induction of erection in rats Compound (I) was administered to rats at 1 mg / kg and resulted in improved erectile function as illustrated in Figure 25. Vehicle and Compound (I) were administered after establishing maximal (10 Hz, 1 ms, 6 V) and submaximal (submax) responses (10 Hz, 1 ms, 0.6-1.55 V) to 30 seconds of cavernous nerve stimulation. Submaximal stimulation was repeated 3, 13, 23, and 33 minutes after administration of drug or vehicle (Figure 27). Compound (I) was found to induce erections in both young and adult rats.

[0130] Example 26: Dose-dependent erectile frequency in rats Compound (I) was administered intravenously to rats at doses of 0.001, 0.01, 0.1, and 1.0 mg / kg, and the number of spontaneous erections was measured. The number of erections increased with increasing doses from 0.001 to 0.1 mg / kg, but suddenly decreased at a dose of 1.0 mg / kg (Figure 26). Thus, compound (I) is more efficient in inducing erections in rats at lower concentrations.

[0131] Example 27: Effect of Compound (I) on Corpus Cavernosum Contractility In resting corpus cavernosum strips, increasing concentrations of compound (I) (10 -9 ~3x10 -5 Addition of 100 mM resulted in slight relaxation (Figure 29). Very occasionally, contractions occurred at the highest concentration (3x10 -5 Relaxation was observed with compound (I) of the nitric oxide synthase inhibitor L-NOARG (10 -4 M) and was unchanged in the presence of sildenafil, an inhibitor of type 5 phosphodiesterase inhibitors, whereas treatment with guanethidine, which leads to noradrenaline depletion, inhibited contraction but did not alter relaxation (Figures 29, 30).

[0132] Phenylephrine (10 -6In strips contracted with 100 μg / mL of acetylcholine, low concentrations of compound (I) induced rapid relaxation followed by contraction, whereas concentration-dependent relaxations were observed at higher concentrations (Figure 31). Sildenafil significantly enhanced these relaxations, whereas the nitric oxide synthase inhibitor L-NOARG (3x10 -5 M) had a tendency to inhibit these relaxations (Figure 32). These findings suggest that low concentrations of Compound (I) relax rat corpus cavernosum tissue via nitric oxide release, and that this effect contributes to the erectile effects of the compound. These results strongly suggest that Compound (I) may be administered locally to or near the penis (such as transdermally or intracavernosally).

[0133] Example 28: Effect of Compound (I) on penile blood flow in mice Laser Doppler flow lobes were placed in situ in mouse erectile tissue for measurements of basal penile blood flow in the presence or absence of Compound (I). Penile blood flow was significantly increased by infusion of Compound (I) (1 mg / kg) (Figure 33). These results strongly suggest that Compound (I) may be administered locally to or near the penis (such as transdermally or intracavernosally).

Claims

1. A pharmaceutical composition for treating, preventing or alleviating erectile dysfunction in a subject, comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: 【Chemistry 1】 The pharmaceutical composition, wherein the subject is undergoing treatment with an antidepressant.

2. A pharmaceutical composition for treating, preventing or alleviating erectile dysfunction in a subject, comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: 【Chemistry 2】 The subject is characterized in that the subject suffers from depression or anxiety.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is for treating, preventing or alleviating erectile dysfunction and depression in a subject.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the erectile dysfunction is treatment-emergent erectile dysfunction.

5. 5. The pharmaceutical composition of claim 1, 3, or 4, wherein the erectile dysfunction is caused by depression, caused by adverse effects from drug treatment, or caused by treatment of depression with an antidepressant.

6. The adverse effect is difficulty in achieving or maintaining an erection; the adverse effect is psychological or physiological, or The adverse effect is decreased libido or hormonal The pharmaceutical composition according to claim 5.

7. 6. The pharmaceutical composition of claim 1 or 5, wherein the erectile dysfunction is due to adverse effects from drug treatment, the drug being selected from the group consisting of antidepressants, NSAIDs, finasteride, antiepileptics, and neuroleptics.

8. 8. The pharmaceutical composition of claim 1, 5 or 7, wherein the antidepressant is selected from the group consisting of serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs).

9. The pharmaceutical composition of any one of claims 1 to 3, 5 and 8, wherein the subject is suffering from major depression.

10. The pharmaceutical composition according to claim 2 or 3, wherein the depression is caused by erectile dysfunction.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the subject is a mammal.

12. The pharmaceutical composition described in any one of claims 1 to 11, wherein the subject is a human.

13. The pharmaceutical composition described in any one of claims 1 to 12, wherein the subject is a male.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the subject is a male under 40 years of age.

15. The pharmaceutical composition according to any one of claims 1 to 13, wherein the subject is an adult male.

16. The pharmaceutical composition of claim 2, wherein the subject is not being treated simultaneously with other anti-anxiety drugs or other anti-depressants.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the compound is administered systemically.

18. The pharmaceutical composition of claim 17 , wherein the compound is administered orally.

19. The pharmaceutical composition of any one of claims 1 to 16, wherein the compound is administered locally.

20. 20. The pharmaceutical composition of claim 19, wherein the compound is administered topically.

21. 21. The pharmaceutical composition of claim 20, wherein the topically administered is in the form of a lotion, cream, ointment, gel, or by a transdermal patch.

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