Combination therapy for erectile dysfunction

Abstract

The present invention relates to a compound or a pharmaceutically acceptable salt thereof for use in the treatment of erectile dysfunction in combination with at least one second erectogenic agent.

Description

[0001] P7429PC00

[0002] 1

[0003] Combination therapy for erectile dysfunction

[0004] Technical field

[0005] The present invention relates to a compound or a pharmaceutically acceptable salt thereof for use in the treatment of erectile dysfunction in combination with at least one second erectogenic agent.

[0006] Background

[0007] Erectile dysfunction (ED), sometimes referred to as impotence or male erectile disorder, is a prevalent condition that is defined by the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. ED can have a substantial impact on an individual’s quality of life, affecting psychological well-being and personal relationships. It is frequently linked to underlying medical conditions such as cardiovascular disease, diabetes, and neurological disorders, as well as lifestyle factors including smoking, obesity, and insufficient physical activity. While there are various potential treatments for ED, phosphodiesterase type 5 inhibitors (PDE5 inhibitors) have emerged as the primary option for managing this condition.

[0008] PDE5 inhibitors are a class of medications that include sildenafil, tadalafil, vardenafil, avanafil, and udenafil. These agents function by elevating cyclic guanosine monophosphate (cGMP) levels in the corpus cavernosum, a sponge-like erectile tissue in the penis. The increase in cGMP promotes smooth muscle relaxation and vasodilation, facilitating greater blood flow into the penis. As a result, these medications enable men to achieve and maintain an erection in response to sexual stimulation, improving erectile function during intimate activity. While many men respond well to these treatments, a significant subset (40-50%) experiences inadequate results or incomplete efficacy. This is particularly true for the patient group known as ‘PDE5i non-responders’, who do not achieve sufficient improvement with typical PDE5 inhibitors, such as sildenafil or tadalafil. This patient group often includes men suffering from severe or chronic ED together with additional underlying conditions such as diabetes, cardiovascular disease, neurological disorders, and psychological factors. Non-response may stem from factors like low testosterone, improper medication use, or lifestyle influences, requiring alternative or adjunctive treatments. Treatment with higher dosages of PDE5 inhibitors is one P7429PC00

[0009] 2 approach often used in cases of reduced efficacy, but it is associated with an increased risk of adverse effects. Common side effects at elevated doses include: mild headaches, flushing, dyspepsia, altered colour vision, back pain, myalgias, hypotension, dizziness, and rhinitis. In rare instances, higher doses can increase the risk of cardiovascular events, and they are contraindicated in patients with chronic heart disease medicated with nitrates (Kloner et al., 2023) In addition, sildenafil inhibits drug-metabolizing liver CYP enzymes which poses a larger risk for drug-drug interactions with higher doses. As a result, these dose-dependent side effects frequently limit the maximum tolerable dosage of the drug (Kloner et al., 2023).

[0010] Alternative treatment options to phosphodiesterase type 5 (PDE5) inhibitors include, among others, alprostadil and nebivolol. Alprostadil is a synthetic form of prostaglandin E1 that directly stimulates the smooth muscle in the corpus cavernosum, resulting in increased blood flow and facilitating erections. This medication can be administered via intracavernosal injection or as a urethral suppository. Nebivolol is primarily known as a beta-blocker used for managing hypertension; however, it can also improve erectile function by stimulating the release of nitric oxide, which promotes vascular dilation and increases blood flow to the penis. While these and other oral treatments provide potential benefits, some patients may find these options ineffective (Munk et al., 2019).

[0011] Monoamine reuptake inhibitors (MRIs) are pharmaceutical agents that block the reuptake of neurotransmitters like serotonin, norepinephrine, and dopamine in the brain. They are commonly used to treat mental health disorders such as depression and anxiety. Erectile dysfunction is a known side effect of several monoamine reuptake inhibitors currently on the market (e.g., fluoxetine, sertraline, and paroxetine). As with other medications for ED, treatment efficacy with certain MRIs used as erectogenic agents is dose-dependent, and higher dosages are associated with an increased risk of developing side effects.

[0012] Consequently, there is an unmet need for improved methods of treating erectile dysfunction that address the limitations of existing therapies, particularly for patients who do not respond adequately to phosphodiesterase type 5 (PDE5) inhibitors or medications based on other peroral erectogenic agents. P7429PC00

[0013] Summary

[0014] The present disclosure provides a solution to the above-mentioned problem by providing a combination of an erectogenic agent, such as a PDE5i, nebivolol, or alprostadil, with a monoamine reuptake inhibitor. The combination benefits from the complementary therapeutic effects of a monoamine reuptake inhibitor and an erectogenic agent. Consequently, it allows for improved therapeutic outcomes through synergy and / or lower dosages of each component compared to their individual use in monotherapy, potentially reducing the risk of side effects.

[0015] Thus, in one main aspect, the present disclosure provides a compound of formula (I): , formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a second erectogenic agent in a method of treatment, prevention, or alleviation of erectile dysfunction in a subject in need thereof. For example, the erectogenic agent may be a PDE5 inhibitor, alprostadil, or nebivolol. If the erectogenic agent is a PDE5 inhibitor it may be sildenafil, tadalafil, vardenafil, or avanafil, without being limited to those.

[0016] The compound of formula (I), also known as ‘pudafensine’ or ‘IP2015’, offers a complementary mechanism of action to other erectogenic agents based on its effects on: (i) central effects on regulation of monoamine neurotransmitters dopamine, serotonin and noradrenaline, particularly dopamine; and (ii) peripheral effects on erectile tissue by inhibition of dopamine transporter (DAT) in tissue, followed by activation of dopamine Di-like receptors and nitric oxide release in the tissue. Thus, pudafensine strengthens the natural erection response by having a dual-action, both a central effect initiating erection and a peripheral effect potentiating erection through smooth muscle relaxation.

[0017] This mode of action may add particular advantages to therapies with known or standard-of-care erectogenic agents, particularly PDE5 inhibitors, which induce peripheral smooth muscle relaxation in erectile tissue. The combination of monoamine reuptake inhibitors presents with a differentiated mode of action. It can benefit ED by a combination of peripheral effects arising from the PDE5i, and the central and peripheral effects arising from the monoamine reuptake inhibitor. P7429PC00

[0018] 4

[0019] The inventors have demonstrated the advantage of combining sildenafil and pudafensine, in a validated animal model for ED, as the combination increased both magnitude and duration of erectile responses. These results support an unexpected advantage in the combination of PDE5i and monoamine reuptake inhibitor modalities of treatment, showing synergy in effective treatment of ED, dose sparing and reduction of toxicity and side effects compared to monotherapy; or ability to treat hard-to-treat patient groups.

[0020] As a result, the combination therapy described herein may permit the administration of a reduced dosage of pudafensine, or the second erectogenic agent compared to monotherapy to achieve equal or improved therapeutic effects. As an additional benefit, the combination therapy described herein reduces the risk or incidence of adverse effects caused by high dosages of such erectogenic agents, particularly PDE5 inhibitors.

[0021] Additionally, a combination therapy comprising pudafensine and a second known erectogenic agent as described herein, may be especially advantageous for patient groups identified as “non-responders” to PDE5 inhibitors, for whom treatment with a PDE5 inhibitor alone is insufficient. PDE5i “non-responders” constitute a mechanistically distinct population, since they respond inadequately to the peripheral cGMP preservation of PDE5L The central dopamine effects and peripheral nitric oxide release provided by pudafensine, provides a distinct mechanism to address this hard-to-treat population with the combination therapy of the present invention. It may also be possible to provide improved treatment for patients suffering from moderate-severe ED, and / or patients with contra-indication for PDE5i treatment.

[0022] By integrating pudafensine with a PDE5i inhibitor, enhanced treatment outcomes may be achieved for these challenging patient groups, as the combined therapeutic effect of pudafensine with a PDE5 inhibitor provides efficacy where traditional monotherapy may lack sufficient impact. Overall, this combined approach enables a safer, more effective ED treatment, optimizing therapeutic outcomes for a wider patient population by minimizing the risks associated with high-dose monotherapy.

[0023] A known issue with selective serotonin reuptake inhibitors (SSRIs) is that they induce a serotonergic inhibition of sexual drive. The dopaminergic activation provided by pudafensine, together with central effects, may help overcome the serotonergic imbalance in patients suffering from SSRI-induced ED. P7429PC00

[0024] The advantages arising from the central and peripheral effects of pudafensine may further complement therapy with erectogenic agent alprostadil. For example, by improving the erectogenic effects, reducing the side effects of alprostadil monotherapy, or allowing reduction of the required dose of alprotsadil.

[0025] Given the demonstrated peripheral effects of pudafensine via stimulation of nitric oxide release, it is plausibly expected that improved erectogenic effects may arise from combination with nebivolol, which is a beta-blocker that unlike other beta-blockers also induces smooth-muscle relaxation (vasodilation) via nitric oxide release.

[0026] The inventors have surprisingly demonstrated combining a monoamine reuptake inhibitor with a PDE5i increases the duration and magnitude of erectile responses compared to the monoamine reuptake inhibitor alone. However, administration of sildenafil alone in the tested model did not show an effect on baseline erectile response. These results indicate that the combination of pudafensine and PDE5i inhibitors is synergistic in improving erectile responses and treatment of ED.

[0027] Thus, in another aspect, the present disclosure provides a method of treatment, prevention, or alleviation of erectile dysfunction, said method comprising administration of a compound of formula (I): , formula (I) or a pharmaceutically acceptable salt thereof and at least one second erectogenic agent in a subject in need thereof.

[0028] In another aspect, the present disclosure provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in combination with at least one second erectogenic agent for the manufacture of a medicament for the treatment, prevention, or alleviation of erectile dysfunction in a subject. P7429PC00

[0029] 6

[0030] Description of Drawings

[0031] Figure 1 : Original traces show increased intracavernosal pressure induced by the cavernous nerve's electrical field stimulation (EFS). Administration of A) vehicle does not change the pressure, while B-D) IP2015 administration induces dose-dependent increases in intracavernosal pressure (spontaneous erections, SE) without changing the responses to EFS. E-G) Frequency, duration, and magnitude of spontaneous erections after intravenous infusion of vehicle, IP2015 0.1 mg / kg, 1 mg / kg, or 10 mg / kg. H-J) Intravenous infusion of vehicle and IP2015 (1 mg / kg) in diabetic db / db mice. IP2015 increased H) frequency, I) duration and J) the magnitude of spontaneous erectile responses in db / db mice (n = 7). K-M) Average rises in frequency, duration, and intracavernosal pressure in response to IP2015 1 mg / kg in the absence (n = 5) and in the presence of clozapine 1 mg / kg (n = 5). N-O) Average rises in frequency, duration, and intracavernosal pressure in response to IP2015 1 mg / kg in the absence (n = 9) and in the presence of (-)-sulpiride 1 mg / kg (n = 9). The results are means ± s.e. mean. *P<0.05 versus vehicle control.

[0032] Figure 2: Effect of IP2015 and synergy with the phosphodiesterase type 5 inhibitor, sildenafil, on erections. Average rises in A) frequency, B) duration, and C) magnitude of erectile responses induced by IP2015 in the absence (n = 6) and the presence (n = 5) of the phosphodiesterase type 5 inhibitor, sildenafil (1 mg / kg) in rats. The results are means ± s.e. mean. *P<0.05 versus control. D) Original traces showing in the upper trace stimulation of the cavernous nerve with maximal stimulation (6 V, 10 Hz) followed by administration of IP2015 (1 mg / kg), which 10 min later is followed by rises in intracavernous pressure (ICP). E) In the lower trace, sildenafil 1 mg / kg is administered without inducing spontaneous rises in ICP, while adding IP2015 1 mg / kg induces rises in ICP.

[0033] Figure 3: IP2015 induces relaxations mediated by dopamine D1 receptors and nitric oxide in isolated rat corpus cavernosum strips. A) At baseline tension, increasing IP2015 concentrations induces relaxations, which are inhibited in the presence of the dopamine Di receptor antagonist, SCH23390, and unaltered in the presence of the dopamine D2 receptor antagonist, clozapine (n = 6). B) Average relaxations induced by IP2015 in preparations with and without endothelium (n = 5). C) Concentration-response curves for IP2015 in the presence of NG-nitro-L-arginine (L-NOARG), guanethidine, and sildenafil at baseline tension (n = 8). The results are means ± s.e. means. *P<0.05 versus control. P7429PC00

[0034] 7

[0035] Definitions

[0036] The term ‘erectile dysfunction (ED)’ as used herein refers to a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm. Erectile dysfunction (hereinafter also referred to as "ED") is also called “impotence”, "erectile functional disorder" or "erectile disorder". ED is divided into the organic factors (caused by or associated with another medical condition such as arterial sclerosis, nerve damage, diabetes etc.), the psychological factors (caused by psychological stress), and the mixed factor (generated by combining both elements of the organic factor and the psychological factor).

[0037] The term ‘pharmaceutically acceptable salt’ of a compound as used herein refers to a salt that is pharmaceutically acceptable, i.e. that possesses the desired pharmacological activity of the parent compound. A pharmaceutically acceptable salt is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or formed 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, hydroxynaphtoic 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 when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include e.g. diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, morpholine, and tromethamine. Acceptable inorganic bases include e.g. ammonia, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0038] The terms ‘treatment’ or ‘treating’ as used herein refers to an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms P7429PC00

[0039] 8 or conditions, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, prevention of the disease or disorder, delay or slowing of disease or disorder progression, amelioration or palliation of the disease state, and remission (whether partial or total) whether detectable or undetectable.

[0040] The term ‘erectogenic agent' as used herein refers to any substance or compound that may promote, enhance, or facilitate the ability to achieve or maintain an erection sufficient for satisfactory sexual performance. Such agents typically act by modulating physiological processes, such as increasing blood flow to the penile tissue or affecting neural or hormonal pathways involved in erectile function.

[0041] The term phosphodiesterase 5 inhibitor (PDE5i)‘ as used herein refers to a compound or substance that inhibits the enzyme phosphodiesterase type 5, thereby increasing levels of cyclic guanosine monophosphate (cGMP) and promoting smooth muscle relaxation and vasodilation, particularly in the penile tissue. This action enhances blood flow and facilitates the achievement and maintenance of an erection.

[0042] The term monoamine reuptake inhibitor (MRI)’ as used herein refers to a compound that prevents or reduces the reuptake of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, into the presynaptic neuron following their release into the synaptic cleft. By blocking this reuptake process, MRIs increase the levels of these neurotransmitters in the synaptic cleft, thereby enhancing neurotransmission.

[0043] The term International Index of Erectile Function (IIEF-15)’ as used herein refers to a validated, multi-dimensional, self-administered questionnaire that has been found useful in the clinical assessment of erectile dysfunction and treatment outcomes in clinical trials. A score of 0-5 is awarded to each of the 15 questions that examine the main domains of male sexual function: erectile function, orgasmic function, sexual desire, and intercourse satisfaction. The domains according to specific questions are:

[0044] Domain A - Erectile function (01 ,2,3,4,5,15)

[0045] Domain B - Orgasmic Function (Q9,10)

[0046] Domain C - Sexual Desire (Q11 ,12)

[0047] Domain D - Intercourse Satisfaction (Q6,7,8)

[0048] Domain E - Overall Satisfaction (Q13, 14) P7429PC00

[0049] 9

[0050] The IIEF-5 is a 5-item version of the IIEF-15. The possible scores of IIEF-5 range from 5 to 25, and erectile dysfunction can be classified into 5 categories based on the scores: severe (5-7), moderate (8-11), mild to moderate (12-16), mild (17-21), and no ED (22- 25).

[0051] The term ’sildenafil' as used herein refers to a phosphodiesterase type 5 inhibitor (PDE5i) used to treat erectile dysfunction (ED) and pulmonary arterial hypertension by increasing blood flow to specific areas of the body. Sildenafil is the international nonproprietary name (INN) of the active ingredient 5-{2-Ethoxy-5-[(4-methylpiperazin-1- yl)sulfonyl]phenyl}-1-methyl-3-propyl-1 ,6-dihydro-6 / 7-pyrazolo[4,3-c(]pyrimidin-7-one (CAS Number - 139755-83-2) sold also under brand names Viagra® (for ED treatment) and Revatio® (for pulmonary hypertension treatment).

[0052] The term tadalafi I' as used herein refers to a phosphodiesterase type 5 (PDE5) inhibitor used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension by relaxing blood vessels and increasing blood flow. Tadalafil is the international non-proprietary name (INN) of the active ingredient (6R,12aR)-6-(1 ,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2- methylpyrazino[T, 2': 1 ,6]pyrido[3,4-b]indole-1 , 4-dione (CAS Number - 171596-29-5) sold also under brand names Cialis® (for ED and BPH treatment) and Adcirca® (for pulmonary hypertension treatment).

[0053] The term 'vardenafil' as used herein refers to a phosphodiesterase type 5 (PDE5) inhibitor used to treat erectile dysfunction (ED) by increasing blood flow to the penile tissue. Vardenafil is the international non-proprietary name (INN) of the active ingredient 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1 ,2,4]triazin-4-one (CAS Number - 224785-90-4) sold also under brand names Levitra® (for treatment of ED) and Staxyn® (for treatment of ED).

[0054] The term 'avanafil' as used herein refers to a phosphodiesterase type 5 (PDE5) inhibitor used to treat erectile dysfunction (ED) by enhancing blood flow to the penile tissue, facilitating erection. Avanafil is the international non-proprietary name (INN) of the active ingredient (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1- yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (CAS Number - 330784-47-9) sold also under brand names Stendra® (for treatment of ED) and Spedra® (for treatment of ED). P7429PC00

[0055] 10

[0056] The term udenafil' as used herein refers to a to a phosphodiesterase type 5 (PDE5) inhibitor used to treat erectile dysfunction (ED) by enhancing blood flow to the penile tissue, facilitating erection. Udenafil is the international non-proprietary name (INN) of the active ingredient 3-(1-Methyl-7-oxo-3-propyl-4,7-dihydro-1 / 7-pyrazolo[4,3- d]pyrimidin-5-yl)- / \ / -[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzene-1 -sulfonamide (CAS Number - 268203-93-6) sold also under brand names Zydena®.

[0057] The term ‘alprostadil’ as used herein refers to a prostaglandin E1 (PGE1) compound commonly utilized in the treatment of erectile dysfunction (ED). Alprostadil works by dilating blood vessels and increasing blood flow to penile tissue. Alprostadil is the international non-proprietary name (INN) of the active ingredient 7-[(1 R,2R,3R)-3- hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]heptanoic acid (CAS Number - 745-65-3) sold also under brand names Caverject® (for treatment of ED) and MUSE® (for treatment of ED).

[0058] The term ‘pudafensine’ or ‘IP2015’ refers to the compound exo-7-[(8- azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one (formula I). The compound of formula I is:

[0059] The term ‘nebivolol’ as used herein refers to a beta-1 selective adrenergic receptor antagonist primarily indicated for treating hypertension. However, due to its nitric oxidemediated vasodilatory effects, nebivolol may also exhibit benefits in treating erectile dysfunction by enhancing blood flow to erectile tissue. Nebivolol is the international non- proprietary name (INN) of the active ingredient rel-(aR,a'R,2R,2'S)-a,a'- [lminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (CAS Number - 118457-14-0) sold also under brand names Nebilet® (for treatment of hypertension) and Bystolic® (for treatment of hypertension).

[0060] The term ‘lifestyle factor' as used herein refers to any modifiable behavioural or environmental condition, such as, but not limited to, smoking, excessive alcohol consumption, poor diet, lack of physical activity, or stress, that may contribute to the development or exacerbation of erectile dysfunction (ED). P7429PC00

[0061] 11

[0062] The term ‘organic ED‘ as used herein refers to erectile dysfunction caused by underlying physiological factors, such as vascular, neurogenic, hormonal, or anatomical abnormalities, that may impair normal erectile function.

[0063] The term ‘psychogenic ED‘ as used herein refers to erectile dysfunction caused by psychological factors, such as stress, anxiety, depression, or emotional disturbances, that may interfere with normal erectile function in the absence of an underlying physiological cause.

[0064] The term ‘situational ED‘ as used herein refers to erectile dysfunction that may occur only in specific situations or under certain conditions, often triggered by temporary psychological or environmental factors, such as stress, anxiety, or specific circumstances, while normal erectile function may be present in other situations.

[0065] The term selective serotonin reuptake inhibitors (SSRIs)‘ as used herein refers to a class of compounds or substances that increase serotonin levels in the brain by inhibiting its reabsorption into neurons, primarily used to treat depression, anxiety, and related disorders. They are known to have potential side effects, including sexual dysfunction such as erectile dysfunction.

[0066] The term serotonin-norepinephrine reuptake inhibitors (SNRIs)‘ as used herein refers to a class of compounds or substances that increase the levels of serotonin and norepinephrine in the brain by inhibiting their reabsorption into neurons. They are primarily used to treat depression, anxiety, and certain pain disorders, with potential side effects that may include sexual dysfunction, such as erectile dysfunction.

[0067] The term ‘body mass index (BMI)‘ as used herein refers to a numerical value calculated by dividing a person’s weight in kilograms by the square of their height in meters (kg / m2). It is used as an indicator to categorize individuals into weight categories, such as underweight, normal weight, overweight, or obese, which can be associated with various health risks, including erectile dysfunction.

[0068] The term ‘diluent' as used herein refers to an inert substance used to dilute the active ingredient in a pharmaceutical formulation to achieve the desired concentration or volume.

[0069] The term ‘carrier' as used herein refers to a material that facilitates the delivery or absorption of the active pharmaceutical agent within the body. P7429PC00

[0070] 12

[0071] The term ‘excipient' as used herein refers to an inactive substance included in a pharmaceutical formulation to aid in the manufacturing process, improve stability, or enhance the delivery of the active ingredient, without having therapeutic effects of its own. Thus, excipients refer refers to any component other than the active therapeutic ingredient(s).

[0072] Detailed description for use

[0073] In one main aspect, the present disclosure provides a compound of formula (I): , formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a second erectogenic agent in a method of treatment, prevention, or alleviation of erectile dysfunction in a subject in need thereof. In one embodiment, the second erectogenic agent is a phosphodiesterase 5 inhibitor (PDE5i).

[0074] Pudafensine has been demonstrated in different animal models, including humans, that it effectively treats signs of erectile dysfunction. In humans, it has been found that the compound improves duration of erectile events, rigidity, and tumescence, as well as that it improves the IIEF-15 scoring.

[0075] The combination of pudafensine and a PDE5 inhibitor, such as sildenafil, enhances erectile response through additive or synergistic effects due to their complementary mechanisms of action. This approach enables effective dose sparing, as shown in Example 1 , where lower doses of both pudafensine and the PDE5 inhibitor, sildenafil produced longer-lasting and greater-magnitude of erectile responses. By reducing the required dose of the pudafensine and / or the PDE5 inhibitor, the combination treatment enhances safety by limiting adverse effects associated with higher doses, thereby offering an optimized therapeutic approach for erectile dysfunction through a more effective and tolerable dosing regimen. This may be beneficial for patients susceptible to side effects from current standard-of-care therapy with PDE5L P7429PC00

[0076] 13

[0077] By improving the effectiveness of the treatment of ED and adding a complementary mechanism of action, the present invention provides for the treatment of hard-to-treat patients such as PDE5i non-responders.

[0078] Thus, in one embodiment, the PDE5i is one or more PDE5 inhibitors selected from sildenafil, tadalafil, vardenafil, avanafil, and udenafil, or a pharmaceutically acceptable salt thereof.

[0079] In one embodiment, the PDE5i is sildenafil, or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the PDE5i is tadalafil, or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the PDE5i is vardenafil, or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the PDE5i is avanafil, or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the PDE5i is udenafil, or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment, the second erectogenic agent is alprostadil. In one embodiment, the second erectogenic agent is nebivolol or one or more stereoisomers thereof.

[0085] In one embodiment, the compound of formula (I) is exo-7-((8-azabicyclo[3.2.1]octan-3- yl)oxy)-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof.

[0086] In one embodiment, the compound of formula (I) is exo-7-((8-azabicyclo[3.2.1]octan-3- yl)oxy)-3-methoxy-chromen-2-one hydrochloride.

[0087] Based on the central and peripheral effects of pudafensine in ED, combined with the effects of PDE5i in smooth muscle relaxation and facilitating erectile responses, it is expected that the combination will be more efficacious than either treatment as monotherapy according to at least one of the following outcome measures, or any combination thereof:

[0088] • Increase in magnitude, frequency, and / or duration of erectile responses.

[0089] • Increase in intracavernosal pressure (ICP) required to facilitate erection.

[0090] • Increase in the ratio of peak intracavernosal pressure (pICP) and mean arterial pressure (MAP).

[0091] • The number and duration of erectile events, penile tumescence and tumescence events and penile rigidity. Said parameters can be measured by methods known P7429PC00

[0092] 14 in the art such as the Rigiscan device and analysed by the Rigiscan Plus Software3.

[0093] • Increase in the score in one or more questions, or domains, of the IIEF-15 or IIEF-5 questionnaire.

[0094] • Reduction of side effects compared to treatment with monotherapy of PDE5i, such as mild headache, flushing, dyspepsia, altered color vision, back pain and myalgias, hypotension and dizziness, or rhinitis.

[0095] In some embodiments, pudafensine produces a central effect initiating erection and / or a peripheral effect potentiating erection. In one embodiment, the compound of formula (I) or an acceptable pharmaceutical salt thereof initiates erection by increasing central dopamine and / or a peripheral effect potentiating erection through nitric oxide release.

[0096] In some embodiment, pudafensine or an acceptable pharmaceutical salt thereof and / or the PDE5i initiates and / or potentiates erection through smooth muscle relaxation.

[0097] In some embodiments, the second erectogenic agent initiates or potentiates erection through smooth muscle relaxation. In some embodiments, the second erectogenic agent potentiates erection through nitric oxide release.

[0098] In some embodiment, the PDE5i potentiates erection through nitric oxide release.

[0099] In some embodiments, the method treatment as described herein increases the number of erectile events, the duration of erectile events, penile tumescence, and / or the penile rigidity. Said parameters can be measured by methods known in the art such as the Rigiscan device and analysed by the Rigiscan Plus Software3.

[0100] In some embodiment, the method treatment as described herein increases the number of erectile events, the duration of erectile events, penile tumescence, and / or the penile rigidity in the subject during sexual stimulation.

[0101] In some embodiment, the method treatment as described herein increases penile blood flow and / or achieves a faster onset of erection.

[0102] In some embodiment, the method treatment as described herein increases the International Index of Erectile Function 15 (IIEF-15) or IIEF-5 in the subject. For example, the method as described herein increases the score of one or more questions, or domains, of the IIEF-15 or IIEF-5. P7429PC00

[0103] 15

[0104] Erectile dysfunction

[0105] In one embodiment, the erectile dysfunction (ED) is associated with or caused by a cardiovascular condition, diabetes, a hormonal imbalance, a neurological disorder, a psychological condition, treatment with another medication, a lifestyle factor, and / or an injury.

[0106] In one embodiment, the erectile dysfunction is organic ED, psychogenic ED, or situational ED.

[0107] In one embodiment, the erectile dysfunction is organic ED. Pudafensine strengthens the natural erection response by having a dual-action, both a central effect initiating erection and a peripheral effect potentiating erection through smooth muscle relaxation. Accordingly, pudafensine may help subjects who have ED due to abnormalities of the penile arteries / and or veins.

[0108] The most common risk factors for organic ED are diabetes, overweight, lack of exercise, high cholesterol, high blood pressure, and cigarette smoking.

[0109] In one embodiment, the erectile dysfunction is organic ED caused by a cardiovascular disease, diabetes, a hormonal imbalance, a neurological disorder, a pelvic injury, chronic kidney disease, treatment with another medication, substance abuse, and / or obesity.

[0110] In one embodiment, the erectile dysfunction is psychogenic ED.

[0111] In one embodiment, the erectile dysfunction is psychogenic ED caused by anxiety, depression, stress, trauma, and / or a mental health disorder.

[0112] In one embodiment, the erectile dysfunction is antidepressant-induced ED.

[0113] In one embodiment, the erectile dysfunction is antidepressant-induced ED caused by treatment with one or more selective serotonin reuptake inhibitors (SSRIs) and / or with one or more serotonin-norepinephrine reuptake inhibitors (SNRIs).

[0114] In one embodiment, the erectile dysfunction is antidepressant-induced ED caused by treatment with one or more antidepressant(s) selected from fluoxetine, sertraline, escitalopram, paroxetine, citalopram, venlafaxine, duloxetine and desvenlafaxine.

[0115] In one embodiment, the erectile dysfunction is situational ED. P7429PC00

[0116] 16

[0117] In one embodiment, the erectile dysfunction is situational ED caused by performance anxiety and / or stress.

[0118] In one embodiment, the erectile dysfunction is associated with or caused by a lifestyle factor, such as obesity, smoking, excessive alcohol consumption, physical inactivity, nutritional deficiency, and / or stress.

[0119] In one embodiment, the subject is under one or more additional treatment(s) for ED.

[0120] In one embodiment, the subject is under treatment with a PDE5i for ED.

[0121] In one embodiment, the subject is under treatment with a PDE5i for antidepressant- induced ED.

[0122] In one embodiment, the subject is a PDE5i non-responder. In one embodiment, the subject achieves insufficient therapeutic effect with a PDE5i as monotherapy. In one embodiment, the subject is a non-responder to treatment for ED with one or more PDE5 inhibitor(s). For example, in one embodiment, the subject has inadequate response to therapy with maximum tolerated dosage of one or more PDE5 inhibitor(s), such as a PDE5i inhibitor as described herein.

[0123] In one embodiment, the subject is under treatment with sildenafil, tadalafil, vardenafil, avanafil, or udenafil.

[0124] In one embodiment, the subject is under treatment with a vasodilator for ED, such as alprostadil.

[0125] In one embodiment, the subject is under treatment with a beta-blocker, such as nebivolol.

[0126] In one embodiment, the subject is under treatment by hormone therapy for ED, such as testosterone replacement therapy.

[0127] In one embodiment, the subject has organic erectile dysfunction.

[0128] In one embodiment, the subject has organic erectile dysfunction and is a PDE5i non-responder.

[0129] In one embodiment, the subject is a mammal. In one embodiment, the subject is a human. In one embodiment, the subject is a male. In one embodiment, the subject is an adult male. In one embodiment, the subject is a male over the age of 20. P7429PC00

[0130] 17

[0131] In one embodiment, the subject is overweight or obese.

[0132] In one embodiment, the subject is a diabetic.

[0133] In one embodiment, the subject has a body-mass index (BMI) above 25 kg / m2.

[0134] In one embodiment, the subject has a body-mass index (BMI) above 30 kg / m2.

[0135] In one embodiment, the subject has a body-mass index (BMI) above 35 kg / m2.

[0136] In one embodiment, the subject prior to treatment had an international index of Erectile Function 5 (IIEF-5) of less than 17, such as between 12 and 16, such as between 8 and 11 , such as between 5 and 7.

[0137] In one embodiment, the subject has psychogenic erectile dysfunction.

[0138] In one embodiment, the subject is under treatment with one or more antidepressants, such as an SSRI or an SNRI.

[0139] In one embodiment, the subject suffers from antidepressant-induced erectile dysfunction. In one embodiment, the subject suffers from SSRI-induced erectile dysfunction.

[0140] Dosages and Administration

[0141] In one embodiment, pudafensine or a pharmaceutical acceptable salt thereof is administered in an amount from about 0.1 mg to about 20 mg per individual dose, such as about 0.1 mg, such as about 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per individual dose..

[0142] In one embodiment, pudafensine or a pharmaceutical acceptable salt thereof is administered in an amount from about 0.1 mg to 10 mg per individual dose, such as about 0.1 mg, such as about 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mgper individual dose.

[0143] In healthy volunteers, individual doses of pudafensine of 10 mg or below are linked to a lower incidence of treatment-emergent adverse effects (TEAEs) compared to higher doses. In dose escalation studies of 0.01 mg to 16.2 mg individual doses of pudafensine, P7429PC00

[0144] 18 the incidence of TEAEs at individual doses 10 mg or below was low, while all subjects in the 16.2 mg group reported at least 1 TEAE. No significant treatment- or dose-related trends in the mean or individual subject vital sign values over the 0.01 mg to 10 mg dose range were observed, but at 16.2 mg increases in baseline heart rate and tachycardia were observed in a few subjects.

[0145] In one embodiment, pudafensine or a pharmaceutical acceptable salt thereof is administered to the subject at about 5 mg per individual dose. Individual doses of 5 mg of IP2015 have been shown to produce statistically significant improvements in the IIEF-15 evaluation compared to placebo in a clinical trial enrolling 130 ED subjects.

[0146] In one embodiment, pudafensine or a pharmaceutical acceptable salt thereof is administered to the subject at 5 mg per individual dose.

[0147] In one embodiment, pudafensine or a pharmaceutical acceptable salt thereof is administered to the subject in an amount from 1 to 10 mg per individual dose.

[0148] In one embodiment, pudafensine or a pharmaceutical acceptable salt thereof is administered to the subject in an amount from 5 mg to 10 mg per individual dose.

[0149] In one embodiment, the total daily dose of pudafensine or a pharmaceutical acceptable salt thereof is from about 1 mg to about 10 mg.

[0150] In one embodiment, the PDE5i is one or more PDE5 inhibitors selected from sildenafil, tadalafil, vardenafil, avanafil, and udenafil, or a pharmaceutically acceptable salt thereof.

[0151] Example 1 has shown that pudafensine and the PDE5 inhibitor sildenafil, in combination, increases the duration and the magnitude of erectile responses. This result supports dose sparring of pudafensine and the PDE5 inhibitor, i.e. , the use of lower dosages in comparison to the dosages used in monotherapy can be achieved with the combination disclosed herein.

[0152] The present disclosure contemplates combination therapy of pudafensine and PDE5 inhibitor as described herein, wherein the PDE5i may be administered in any currently approved marketed dosage regime for use in humans, for example, any approved dosage regime of sildenafil, tadalafil, avanafil vardenafil, or udenafil, or any acceptable pharmaceutically acceptable salt thereof. However, lower doses may be used due to the enhanced therapeutic effects of the combination with pudafensine described herein. P7429PC00

[0153] 19

[0154] Thus, in one embodiment, the second erectogenic agent is sildenafil and is administered in an amount from 10 mg to 100 mg sildenafil per individual dose, such as 25-100 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg sildenafil per individual dose.

[0155] In one embodiment, the sildenafil is administered in an amount from about 25 mg to about 100 mg, and preferably of about 50 mg per individual dose.

[0156] In one embodiment, pudafensine is administered in an amount from 0.1 to 10 mg per individual dose, such as in an amount of 1 to 10 mg or 5 to 10 mg per individual dose, and sildenafil is administered in an amount from 25 mg to 100 mg per individual dose.

[0157] In one embodiment, the PDE5i is vardenafil, or a pharmaceutically acceptable salt thereof.

[0158] In one embodiment, the vardenafil is administered in an amount from 1 mg to 20 mg vardenafil per individual dose, such as 5-20 mg, 1-5 mg, 5-10 mg, 10-15 mg, or 15-20 mg vardenafil per individual dose.

[0159] In one embodiment, the vardenafil is administered in an amount from about 5 mg to about 20 mg, and preferably of about 10 mg per individual dose.

[0160] In one embodiment, pudafensine is administered in an amount from 0.1 to 10 mg per individual dose, such as in an amount of 1 to 10 mg or 5 to 10 mg per individual dose, and vardenafil is administered in an amount from about 5 mg to about 20 mg per individual dose.

[0161] In one embodiment, the PDE5i is tadalafil, or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment, the tadalafil is administered in an amount from 1 mg to 20 mg tadalafil per individual dose, such as 5-20 mg, 1-5 mg, 5-10 mg, 10-15 mg, or 15-20 mg tadalafil per individual dose.

[0163] In one embodiment, the tadalafil is administered in an amount from about 5 mg to about 20 mg, and preferably from about 10 mg to about 20 mg per individual dose.

[0164] In one embodiment, tadalafil is administered in an amount from 1 to 5 mg per individual dose, once daily. P7429PC00

[0165] 20

[0166] In one embodiment, pudafensine is administered in an amount from 0.1 to 10 mg per individual dose such as in an amount of 1 to 10 mg or 5 to 10 mg per individual dose, and tadalafil is administered in an amount from about 5 mg to about 20 mg per individual dose.

[0167] In one embodiment, the PDE5i is avanafil, or a pharmaceutically acceptable salt thereof.

[0168] In one embodiment, the avanafil is administered in an amount from 10 mg to 200 mg avanafil per individual dose, such as 50-200 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-110 mg, 110-120 mg, 120-130 mg, 130-140 mg, 140-150 mg, 150-160 mg, 160-170 mg, 170-180 mg, 180-190 mg, or 190-200 mg avanafil per individual dose.

[0169] In one embodiment, the avanafil is administered in an amount from about 50 mg to about 200 mg, and preferably of about 100 mg per individual dose.

[0170] In one embodiment, pudafensine is administered in an amount from 0.1 to 10 mg per individual dose, such as in an amount of 1 to 10 mg or 5 to 10 mg per individual dose and avanafil is administered in an amount from about 50 mg to about 200 mg per individual dose.

[0171] In one embodiment, the PDE5i is udenafil, or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment, the udenafil is administered in an amount from 10 mg to 300 mg udenafil per individual dose, such as 25-300 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-110 mg, 110-120 mg, 120-130 mg, 130-140 mg, 140-150 mg, 150-160 mg, 160-170 mg, 170-180 mg, 180-190 mg, 190-200 mg, 200-210 mg, 210-220 mg, 220-230 mg, 230-240 mg, 240-250 mg, 250- 260 mg, 260-270 mg, 270-280 mg, 280-290 mg, or 290-300 mg udenafil per individual dose.

[0173] In one embodiment, the udenafil is administered in an amount from about 25 mg to about 300 mg, and preferably of about 100 mg or 200 mg per individual dose.

[0174] In one embodiment, pudafensine is administered in an amount from 0.1 to 10 mg per individual dose and udenafil is administered in an amount from about 25 mg to about 300 mg per individual dose. P7429PC00

[0175] 21

[0176] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof is administered once daily.

[0177] In some embodiments, pudafensine or a pharmaceutically acceptable salt thereof is administered one time a week, two times a week, three times a week, four times a week, five times a week, six times a week or seven times a week.

[0178] In some embodiments, pudafensine or a pharmaceutically acceptable salt thereof is administered prior to sexual stimulation or before a sexual act.

[0179] For example, in one embodiment, pudafensine or a pharmaceutically acceptable salt thereof is administered 120, 90, 60, 40, 30, 20, or 15 minutes before sexual stimulation or before a sexual act. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered between 30 minutes and 60 minutes prior to sexual stimulation or prior to a sexual act.

[0180] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof is administered between 30 minutes and 24 hours prior to sexual stimulation or prior to a sexual act.

[0181] In some embodiments, the PDE5i as described herein, is administered once daily.

[0182] In some embodiments, the PDE5i is administered one time a week, two times a week, three times a week, four times a week, five times a week, six times a week or seven times a week.

[0183] In some embodiments, the PDE5i is administered prior to sexual stimulation or before a sexual act.

[0184] For example, in one embodiment, the PDE5i inhibitor as described herein, or a pharmaceutically acceptable salt thereof is administered 120, 90, 60, 40, 30, 20, or 15 minutes before sexual stimulation or before a sexual act. In one embodiment, the PDE5i as described herein is administered between 30 minutes and 60 minutes prior to sexual stimulation or prior to a sexual act.

[0185] In one embodiment, the PDE5i is administered between 30 minutes and 24 hours prior to sexual stimulation or prior to a sexual act. P7429PC00

[0186] 22

[0187] In some embodiments, pudafensine is administered prior to sexual stimulation or before a sexual act, as described herein (e.g. 15 minutes to 2 hours before sexual stimulation or a sexual act): and sildenafil is administered once daily.

[0188] In some embodiments, pudafensine is administered once daily, as described herein, and sildenafil is administered prior to sexual stimulation or sexual act (e.g. 15 minutes to 2 hours before sexual stimulation or a sexual act).

[0189] In some embodiments, pudafensine and sildenafil are administered prior to sexual stimulation or sexual act (e.g. 15 minutes to 2 hours before sexual stimulation or a sexual act).

[0190] In some embodiments, the pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are administered separately.

[0191] In some embodiments, the pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are administered together.

[0192] In one embodiment, the pudafensine or a pharmaceutically acceptable salt thereof and said PDE5i are administered separately by a delay period of about 0.5 to about 3 hours.

[0193] In one embodiment, the pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are administered separately, pudafensine or a pharmaceutically acceptable salt thereof being administered first and the PDE5i being administered second.

[0194] In one embodiment, the pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are administered separately, the PDE5i being administered first and pudafensine or a pharmaceutically acceptable salt thereof being administered second.

[0195] In one embodiment, the pudafensine or a pharmaceutically acceptable salt thereof is administered orally.

[0196] In one embodiment, the PDE5i is administered orally.

[0197] In one embodiment, the alprostadil is administered by intraurethral administration, such as by the commercially available MUSE trans urethral system, by which a pellet containing alprostadil is inserted into the urethra. Any conventional dosage or administration form alprostadil is envisioned within the present invention, however, due to enhanced effects arising from pudafensine lower dosages or less frequent dosing may be employed. P7429PC00

[0198] 23

[0199] In one embodiment, alprostadil is administered in an amount of 2.5 to 20 g per individual dose.

[0200] In one embodiment, alprostadil is administered intravenously. In one embodiment, the alprostadil is administered by intraurethral administration.

[0201] In one embodiment, alprostadil is administered intravenously in an amount of 2.5 pg to 20 pg per individual dose

[0202] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the alprostadil are administered by intraurethral administration, such as by the MUSE trans urethral system.

[0203] In one embodiment, the alprostadil is administered by topical administration.

[0204] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the alprostadil are administered by topical administration.

[0205] In one embodiment, the nebivolol is administered orally. Any conventional dosage or administration form of nebivolol is envisioned within the present invention, however, due to enhanced effects arising from pudafensine lower dosages or less frequent dosing may be employed for managing erectile dysfunction.

[0206] In one embodiment, the nebivolol is administered at a dose of 1.25 mg to 5 mg per individual dose, preferably orally in tablet form.

[0207] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof is administered by parenteral administration, such as cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous, or intraarterial injection.

[0208] In one embodiment, the PDE5i is administered by parenteral administration, such as cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous, or intraarterial injection.

[0209] Formulation

[0210] Each of pudafensine, or a pharmaceutically acceptable salt thereof, and the second erectogenic agent for use in treatment of ED according to the present disclosure may be administered either alone or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the pudafensine, the second erectogenic P7429PC00

[0211] 24 agent, and one or more pharmaceutically acceptable carriers, excipients and diluents, according to standard pharmaceutical practice.

[0212] Each of pudafensine, or a pharmaceutically acceptable salt thereof, and the second erectogenic agent in a combination therapy of the invention may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and / or are administered on different dosing schedules, e.g., a first therapeutic that is administered at least daily and a second therapeutic that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks.

[0213] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the second erectogenic agent are formulated in the same pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient.

[0214] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the second erectogenic agent are formulated in separate pharmaceutical compositions, each further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient.

[0215] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are formulated in the same pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient.

[0216] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are formulated separately.

[0217] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are formulated separately and independently as a pharmaceutical composition, a solid dosage form, and / or a liquid dosage form.

[0218] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are formulated in separate pharmaceutical compositions, each further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient. P7429PC00

[0219] 25

[0220] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are formulated as a solid dosage form, such as a tablet, a capsule, a pill, a pellet, a granule, or a powder.

[0221] In one embodiment, pudafensine or a pharmaceutically acceptable salt thereof and the PDE5i are formulated as a liquid dosage form, such as an oral solution, or an injectable solution.

[0222] In one embodiment, the alprostadil is formulated as a solid dosage form, such as a urethral suppository.

[0223] In one embodiment, the alprostadil is formulated as a liquid dosage form, such as an emulsion, such as a cream.

[0224] One embodiment of the present disclosure provides a method of treatment, prevention, or alleviation of erectile dysfunction, the method comprising administration of a compound of formula (I) , , fformula (I) or a pharmaceutically acceptable salt thereof and at least one second erectogenic agent in a subject in need thereof.

[0225] Examples

[0226] Example 1 : Effects of IP2015 on erectile function in rats and diabetic mice.

[0227] Aim

[0228] The study investigated whether IP2015 can improve erectile function.

[0229] Materials and Methods

[0230] For in vivo erectile physiology studies, rats were anaesthetized with pentobarbital sodium (Sygehus Apoteket, Aarhus, Denmark; 50 mg / kg) given intraperitoneally. During the experiment, the rats breathed spontaneously; the body temperature was monitored continuously and was maintained at 37 °C. With a midline incision in the perineum, the base of the penis, enclosed by striated muscles, was exposed. The ischiocavernous muscle covering the crus corpus cavernosum was divided on one side, and entrance to the underlying tunica albuginea was given. A 25-gauge needle attached to a heparinized P7429PC00

[0231] 26

[0232] (100 IE mL-1) polyethylene catheter was inserted into the crus corpus cavernosum to measure intracavernous pressure (ICP). A heparinized polyethylene catheter (PE 50) was introduced into the carotid artery to measure mean arterial pressure (MAP). Continuous direct measurements of MAP and ICP were performed with transducers (Disposable BP Transducer, ADInstruments, UK), and registered and analysed on a computerized data acquisition system (PowerLab, ADInstruments).

[0233] A stabilizing period of 20 - 30 min was allowed before registration of basal ICP and MAP. Through a lower abdominal incision, the cavernous nerve was isolated at the lateral aspect of the prostate, and electrical stimulation was performed with a slender bipolar platinum electrode, which was connected to a S48 stimulator (Grass Instrument Co., Boston, MA, U.S.A.). To measure the maximum amplitude of the erectile response, a first stimulation of the cavernous nerve (square wave pulses of 6 Volts, 10 Hz, 1 ms pulse duration for 30 s) was performed.

[0234] IP2015, sildenafil, clozapine or vehicle were administered by injection in the jugular vein in volumes of maximum 200 pL. IP2015 was injected at doses of 0.1 and 1 mg / kg intravenously. The observation period of spontaneous erection after injection of IP2015 was 30 min. Clozapine (1 mg / kg) or sildenafil (1 mg / kg) were administered 30 or 10 min prior to 1 mg / kg IP2015 injection, respectively. One group was injected with vehicle alone.

[0235] To investigate the involvement of proximal neuronal pathways in the effect of IP2015, mechanical denervation was performed. For mechanical denervation, the isolated cavernous nerve was cut distal to the major pelvic ganglion. The absence of erectile response to electrical stimulation verified the efficacy of mechanical denervation.

[0236] For functional studies in corpus cavernosum strips, the penis was removed by cutting the crura corpora cavernosa at the point of adhesion to the lower pubic bone, and the corpora cavernosa were then dissected free. The penis was submerged immediately in ice-cold (4 °C) PSS. The tunica albuginea was carefully opened from its proximal extremity of the corpus cavernosum towards the penile shaft and the erectile tissue within the corpus cavernosum was microsurgically dissected free. The change in isometric tension of corpus cavernosum strips (0.5 x 0.5 x 3 mm) was investigated in a tissue organ bath system (750TOBS, Danish Myotechnology, Aarhus, Denmark). Silk ligatures were applied at both ends of the strip preparations, which were then suspended between two L-formed metal prongs in thermostatically controlled organ baths (5 mL, 37 °C) P7429PC00

[0237] 27 containing PSS aerated with a mixture of 5% CO2 in air (pH 7.4). The bath fluid was routinely changed every 20 min and replaced with fresh PSS, also kept at 37 °C. During an equilibration period of 60 min, tension was adjusted until a mean stable tension of 1.2 mN was obtained, as described earlier.

[0238] To test the contractility of the preparations, they were exposed to a potassium physiological saline solution (KPSS) of 125 mM and phenylephrine (10-6M), after each contraction acetylcholine was administered to check endothelium-dependent relaxations.

[0239] To investigate the effect of IP2015 on corpus cavernosum strips, the drug (10-9- 3x10-4M) was administered either in preparations at baseline tension or contracted with phenylephrine (10-6M) in the absence or presence of NG-nitro-L-arginine (L-NOARG, 10-4M), a NO synthase inhibitor, sildenafil (10-7M), a PDE5 inhibitor, or guanethidine (10-5M) a blocker of adrenergic neurotransmission; a dopamine D1 receptor antagonist, SCH23390, and a dopamine D2 receptor antagonist, clozapine (10-6M). The effect of vehicle was also investigated.

[0240] Results

[0241] IP2015 induces spontaneous erections in rats and mice.

[0242] A mean basal intracavernous pressure of 10.2 ± 1.0 mmHg (n = 24) and a mean arterial blood pressure of 117.12 ± 3.2 mmHg (n = 24) were recorded at the beginning of the experiments. The maximal amplitude of erection evoked by electrical stimulation of the cavernous nerve at the beginning of the experiments was 71 .2 ± 1 .5 mmHg (n = 24).

[0243] In contrast to the vehicle infusion (Figure 1A), administration in the jugular vein of 0.1 , 1 , and 10 mg / kg IP2015 induced transient increases in intracavernosal pressure corresponding to erections (Figure 1 B-D). The frequency, duration, and magnitude of these responses were increased dose-dependently (Figure 1 E-G). The magnitude of erectile responses was characterized by measuring intracavernosal pressure (ICP) increases expressed as a percentage of mean arterial pressure (MAP) and showed they were significantly increased compared to vehicle (Figure 1G).

[0244] To investigate the effects of IP2015 in a simple model of erectile dysfunction, before dissecting its underlying pharmacology in vivo, its effects in a type-2 diabetic mouse model were assessed. Type 2 diabetic db / db mice have decreased erectile function compared to normal C57BL / 6 mice and heterozygous db / + control mice. Infusion of P7429PC00

[0245] 28

[0246] IP2015 in diabetic db / db mice significantly increased the frequency, duration, and magnitude of erectile responses (Figure 1 H-J).

[0247] Infusion of the dopamine D2 receptor-like antagonist, clozapine (1 rng kg"1), significantly reduced the frequency and magnitude, while there was no effect on the duration of erectile responses induced by IP2015 (Figure 1 K-M). Another D2 receptor antagonist, (-)-sulpiride, significantly inhibited the frequency of spontaneous erections, while the magnitude and duration were unaltered (Figure 1 N-P). These findings suggest that inhibition of DAT by IP2015, followed by activation of central dopamine D2 receptors, leads to erectile responses, although there can also be a contribution from peripheral dopamine receptors.

[0248] The phosphodiesterase inhibitor sildenafil improves erection by facilitating erectile responses. To investigate the effect of sildenafil on IP2015 administration, IP2015 was infused and induced erectile responses, and treatment with sildenafil markedly increased the duration of these responses (Figure 2). There was also an effect on the magnitude of erectile responses induced by IP2015 (0.1 mg / kg). In the model tested, sildenafil alone produced no increase in intracavernosal pressure (ICP), but only in combination with IP2015 an increase in ICP was observed (Fig. 2E). These findings suggest that sildenafil potentiates the effect on the erection of low doses of IP2015.

[0249] Added at basal tension, IP2015 concentration-dependently induced relaxation in corpus cavernosum strips, an effect that was unaltered in the presence of clozapine but converted to small contractions induced by IP2015 in the presence of the dopamine D1 receptor antagonist, SCH23390 (Figure 3A). IP2015 relaxation was observed in preparations with endothelium but not in preparations without endothelium (Figure 3B). Incubation with the NO synthase inhibitor, L-NOARG (10-4M), abolished the relaxant effect of IP2015, while pretreatment with sildenafil (10-7M) resulted in an enhanced relaxation to IP2015 (Figure 3C). These findings suggest endothelial dopamine D1 receptors followed by NO release are involved in the IP2015 relaxation of corpus cavernosum. P7429PC00

[0250] 29

[0251] Conclusion

[0252] Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose- dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2— like receptor antagonist, clozapine, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015 mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db / db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations, which were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG-nitro-L-arginine, and a D1 receptor antagonist, SCH23390.

[0253] References

[0254] 1 . Kloner RA, Burnett AL, Miner M, Blaha MJ, Ganz P, Goldstein I, Kim NN, Kohler T, Lue T, McVary KT, Mulhall JP, Parish SJ, Sadeghi-Nejad H, Sadovsky R, Sharlip ID, Rosen RC. Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health. J Sex Med. 2024 Jan 30;21 (2):90-116. doi: 10.1093 / jsxmed / qdad163. PMID: 38148297.

[0255] 2. Munk, C., Portnoy, A., Suharlim, C. et al. Systematic review of the costs and effectiveness of interventions to increase infant vaccination coverage in low- and middle-income countries. BMC Health Serv Res 19, 741 (2019). https : / / do i . org / 10.1186 / s 12913-019-4468-4

[0256] 3. GOTOP Medical. RigiScan PLUS Rigidity Assessment System [internet] 2014.

[0257] Available from: http: / / www.gotopmedical.eom / rigiscan@-plus.html

Claims

P7429PC00Claims, formula (I) or a pharmaceutically acceptable salt thereof, for use in combination with a second erectogenic agent in a method of treatment, prevention, or alleviation of erectile dysfunction in a subject in need thereof.

2. The compound for use according to any claim 1 , wherein said erectogenic agent is a phosphodiesterase 5 inhibitor (PDE5i), such as sildenafil, tadalafil, vardenafil, avanafil, or udenafil.

3. The compound for use according to claim 1 , wherein said erectogenic agent is alprostadil.

4. The compound for use according to claim 1 , wherein said erectogenic agent is nebivolol or one or more stereoisomers thereof.

5. The compound for use according to claim 1 , wherein the compound of formula (I) is exo-7-((8-azabicyclo[3.2.1]octan-3-yl)oxy)-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof.

6. The compound for use according to claim 5, wherein the compound of formula (I) is exo-7-((8-azabicyclo[3.2.1 ]octan-3-yl)oxy)-3-methoxy-chromen-2-one hydrochloride.

7. The compound for use according to any one of claims 1-2 and 5 to 6, wherein the compound and / or the PDE5i is able to produce a central effect initiating erection and / or a peripheral effect potentiating erection.

8. The compound for use according to any one of claims 1 to 2 and 5 to 7, wherein the compound and / or the PDE5i is able to initiate and / or potentiate erection through smooth muscle relaxation.P7429PC00319. The compound for use according to any one of the preceding claims, wherein the compound is able to initiate erection by increasing central dopamine and / or a peripheral effect potentiating erection through nitric oxide release.

10. The compound for use according to any one claims 2 and 5 to 9, wherein the PDE5i potentiates erection through nitric oxide release.

11. The compound for use according to any one the preceding claims, wherein the method increases the number of erectile events, the duration of erectile events, penile tumescence, and / or the penile rigidity.

12. The compound for use according to any one of the preceding claims, wherein the method increases the number of erectile events, the duration of erectile events, penile tumescence, and / or the penile rigidity in the subject during sexual stimulation.

13. The compound for use according to any one of the preceding claims, wherein the method increases penile blood flow and / or achieves a faster onset of erection.

14. The compound for use in a method of treatment according to any one of the preceding claims, wherein the method increases the International Index of Erectile Function in the subject.

15. The compound for use according to any one of the preceding claims, wherein the compound is administered in an amount from about 0.1 mg to about 20 mg per individual dose.

16. The compound for use according to any one of the preceding claims, wherein the compound is administered in an amount from about 0.1 mg to 10 mg per individual dose, such as about 0.1 mg, such as about 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.P7429PC003217. The compound for use according to any one of the preceding claims, wherein the compound is administered to the subject in an amount from 1 to 10 mg per individual dose.

18. The compound for use according to any one of the preceding claims, wherein the compound is administered to the subject in an amount of about 5 mg per individual dose.

19. The compound for use according to any one of the preceding claims, wherein the compound is administered to the subject in an amount of 10 mg per individual dose.

20. The compound for use according to any one of the preceding claims, wherein the total daily dose of said compound is from about 1 mg to about 10 mg.21 . The compound for use according to any one of claims 1 to 2 and 5 to 20, wherein said PDE5i is one or more PDE5 inhibitors selected from sildenafil, tadalafil, vardenafil, avanafil, and udenafil, or a pharmaceutically acceptable salt thereof.

22. The compound for use according to any one of claims 1 to 2 and 5 to 21 , wherein the PDE5i is sildenafil, or a pharmaceutically acceptable salt thereof.

23. The compound for use according to claim 22, wherein the sildenafil is administered in an amount from 10 mg to 100 mg sildenafil per individual dose, such as 25-100 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg sildenafil per individual dose.

24. The compound for use according to any one of the claims 22 to 23, wherein said sildenafil is administered in an amount from about 25 mg to about 100 mg, and preferably of about 50 mg per individual dose.

25. The compound for use according to any one of claims 1 to 2 and 5 to 21 , wherein the PDE5i is vardenafil, or a pharmaceutically acceptable salt thereof.P7429PC003326. The compound for use according to claim 25 , wherein the vardenafil is administered in an amount from 1 mg to 20 mg vardenafil per individual dose, such as 5-20 mg, 1-5 mg, 5-10 mg, 10-15 mg, or 15-20 mg vardenafil per individual dose.

27. The compound for use according to any one of claims 25 to 26, wherein said vardenafil is administered in an amount from about 5 mg to about 20 mg, and preferably of about 10 mg per individual dose.

28. The compound for use according to any one of claims 1 to 2 and 5 to 21 , wherein the PDE5i is tadalafil, or a pharmaceutically acceptable salt thereof.

29. The compound for use according to claim 28, wherein the tadalafil is administered in an amount from 1 mg to 20 mg tadalafil per individual dose, such as 5-20 mg, 1-5 mg, 5-10 mg, 10-15 mg, or 15-20 mg tadalafil per individual dose.

30. The compound for use according to any one of claims 28 to 29, wherein said tadalafil is administered in an amount from about 5 mg to about 20 mg, and preferably from about 10 mg to about 20 mg per individual dose.31 . The compound for use according to any one of claims 1 to 2 and 5to 21 , wherein the PDE5i is avanafil, or a pharmaceutically acceptable salt thereof.

32. The compound for use according to claim 31 , wherein the avanafil is administered in an amount from 10 mg to 200 mg avanafil per individual dose, such as 50-200 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60- 70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-110 mg, 110-120 mg, 120-130 mg, 130-140 mg, 140-150 mg, 150-160 mg, 160-170 mg, 170-180 mg, 180-190 mg, or 190-200 mg avanafil per individual dose.

33. The compound for use according to any one of claims 31 to 32, wherein said avanafil is administered in an amount from about 50 mg to about 200 mg, and preferably of about 100 mg per individual dose.P7429PC003434. The compound for use according to any one of claims 1 to 2 and 7 to 21 , wherein the PDE5i is udenafil, or a pharmaceutically acceptable salt thereof.

35. The compound for use according to claim 34, wherein said udenafil is administered in an amount from 10 mg to 300 mg udenafil per individual dose, such as 25-300 mg.

36. The compound for use according to any one of claims 34 to 35, wherein said udenafil is administered in an amount from 100 mg to 300 mg udenafil per individual dose.

37. The compound for use according to any one of the preceding claims, wherein the erectile dysfunction (ED) is associated with or caused by a cardiovascular condition, diabetes, a hormonal imbalance, a neurological disorder, a psychological condition, treatment with another medication, a lifestyle factor, and / or an injury.

38. The compound for use according to any one of the preceding claims, wherein the erectile dysfunction is organic ED, psychogenic ED, or situational ED.

39. The compound for use according to any one of the preceding claims, wherein the erectile dysfunction is organic ED.

40. The compound for use according to any one of the preceding claims, wherein the erectile dysfunction is organic ED caused by a cardiovascular disease, diabetes, a hormonal imbalance, a neurological disorder, a pelvic injury, chronic kidney disease, treatment with another medication, substance abuse, and / or obesity.41 . The compound for use according to any one of claims 1 to 38, wherein the erectile dysfunction is psychogenic ED.

42. The compound for use according to claims 1 to 38 and 39, wherein the erectile dysfunction is psychogenic ED caused by anxiety, depression, stress, trauma, and / or a mental health disorder.P7429PC003543. The compound for use according to any one of claims 1 to 38, wherein the erectile dysfunction is antidepressant-induced ED.

44. The compound for use according to claim 43, wherein the erectile dysfunction is antidepressant-induced ED caused by treatment with one or more selective serotonin reuptake inhibitors (SSRIs) and / or with one or more serotoninnorepinephrine reuptake inhibitors (SNRIs).

45. The compound for use according to any one of claims 43 to 44, wherein the erectile dysfunction is antidepressant-induced ED caused by treatment with one or more antidepressant(s) selected from fluoxetine, sertraline, escitalopram, paroxetine, citalopram, venlafaxine, duloxetine and desvenlafaxine.

46. The compound for use according to any one claims 1 to 38, wherein the erectile dysfunction is situational ED.

47. The compound for use according to claim 46, wherein the erectile dysfunction is situational ED caused by performance anxiety and / or stress.

48. The compound for use according to any one of claims 1 to 38, wherein the erectile dysfunction is associated with or caused by a lifestyle factor, such as obesity, smoking, excessive alcohol consumption, physical inactivity, nutritional deficiency, and / or stress.

49. The compound for use according to any one of the preceding claims, wherein the subject is under one or more additional treatment(s) for ED.

50. The compound for use according to any one of the preceding claims, wherein the subject is under treatment with a PDE5i for ED.51 . The compound for use according to any one of the preceding claims, wherein the subject is under treatment with a PDE5i for antidepressant-induced ED.P7429PC003652. The compound for use according to any one of the preceding claims, wherein the subject is a PDE5i non-responder.

53. The compound for use according to any one of the preceding claims, wherein the subject is under treatment with sildenafil, tadalafil, vardenafil, avanafil, or udenafil.

54. The compound for use according to any one of the preceding claims, wherein the subject is under treatment with a vasodilator for ED, such as alprostadil.

55. The compound for use according to any one of the preceding claims, wherein the subject is under treatment by hormone therapy for ED, such as testosterone replacement therapy.

56. The compound for use according to any one of the preceding claims, wherein the subject is a non-responder to treatment for ED with one more PDE5 inhibitor(s).

57. The compound for use according to any one of the preceding claims, wherein the subject has inadequate response to therapy with maximum tolerated dosage of one or more PDE5 inhibitor(s).

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

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

60. The compound for use according to any one of the preceding claims, wherein the subject is a male.61 . The compound for use according to any one of the preceding claims, wherein the subject is an adult male.

62. The compound for use according to any one of the preceding claims, wherein the subject is a male over the age of 20.P7429PC003763. The compound for use according to any one of the preceding claims, wherein the subject is overweight or obese.

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

65. The compound for use according to any one of the preceding claims, wherein the subject has a body-mass index (BMI) above 25 kg / m2.

66. The compound for use according to any one of the preceding claims, wherein the subject has a body-mass index (BMI) above 30 kg / m2.

67. The compound for use according to any one of the preceding claims, wherein the subject has a body-mass index (BMI) above 35 kg / m2.

68. The compound for use according to any one of the preceding claims, wherein the subject prior to treatment had an international index of Erectile Function 5 (I I EF- 5) of less than 17, such as between 12 and 16, such as between 8 and 11 , such as between 5 and 7.

69. The compound for use according to any one of the preceding claims, wherein the subject suffers from antidepressant-induced erectile dysfunction, such as SSRI- induced erectile dysfunction.

70. The compound for use according to any one of the preceding claims, wherein the compound is administered once daily.71 . The compound for use according to any one of the preceding claims, wherein the compound is administered one time a week, two times a week, three times a week, four times a week, five times a week, six times a week or seven times a week.P7429PC003872. The compound for use according to any one of the preceding claims, wherein the compound is administered prior to sexual stimulation or before a sexual act.

73. The compound for use according to any one of the preceding claims, wherein the compound is administered between 30 minutes and 60 minutes prior to sexual stimulation or prior to a sexual act.

74. The compound for use according to any one of the preceding claims, wherein the compound is administered between 30 minutes and 24 hours prior to sexual stimulation or prior to a sexual act.

75. The compound for use according to any one of claim 1 to 2 and , wherein the PDE5i is administered once daily.

76. The compound for use according to any one of the preceding claims, wherein the PDE5i is administered one time a week, two times a week, three times a week, four times a week, five times a week, six times a week or seven times a week.

77. The compound for use according to any one of the preceding claims, wherein said the PDE5i is administered prior to sexual stimulation or before a sexual act.

78. The compound for use according to any one of the preceding claims, wherein said the PDE5i is administered between 30 minutes and 60 minutes prior to sexual stimulation or prior to a sexual act.

79. The compound for use according to any one of the preceding claims, wherein the PDE5i is administered between 30 minutes and 24 hours prior to sexual stimulation or prior to a sexual act.

80. The compound for use according to any one of the preceding claims, wherein said compound and said PDE5i are administered separately.P7429PC003981 . The compound for use according to any one of the preceding claims, wherein the compound and the PDE5i are administered together.

82. The compound for use according to any one of the preceding claims, wherein said compound and said PDE5i are administered separately by a delay period of about 0.5 to about 3 hours.

83. The compound for use according to any one of the preceding claims, wherein said compound and said PDE5i are administered separately, said compound being administered first and said PDE5i being administered second.

84. The compound for use according to any one of the preceding claims, wherein said compound and said PDE5i are administered separately, said PDE5i being administered first and said compound being administered second.

85. The compound for use according to any one of the preceding claims, wherein the compound is administered orally.

86. The compound for use according to any one of the preceding claims, wherein the PDE5i is administered orally.

87. The compound for use according to any one of the preceding claims, wherein the alprostadil is administered by intraurethral administration, such as by the MUSE trans urethral system.

88. The compound for use according to any one of the preceding claims, wherein the compound and the alprostadil are administered by intraurethral administration, such as by the MUSE trans urethral system.

89. The compound for use according to any one of the preceding claims, wherein the alprostadil is administered by topical administration.

90. The compound for use according to any one of the preceding claims, wherein the compound and the alprostadil are administered by topical administration.P7429PC004091 . The compound for use according to any one of the preceding claims, wherein the nebivolol is administered orally.

92. The compound for use according to any one of the preceding claims, wherein the compound is administered by parenteral administration, such as cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous, or intraarterial injection.

93. The compound for use according to any one of the preceding claims, wherein the PDE5i is administered by parenteral administration, such as cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous, or intraarterial injection.

94. The compound for use according to any one of the preceding claims, wherein the compound and the PDE5i are formulated as a pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient.

95. The compound for use according to any one of the preceding claims, wherein the compound and the PDE5i are formulated as a solid dosage form, such as a tablet, a capsule, a pill, a pellet, a granule, or a powder.

96. The compound for use according to any one of the preceding claims, wherein the compound and the PDE5i are formulated as a liquid dosage form, such as an oral solution or an injectable solution.

97. The compound for use according to any one of the preceding claims, wherein the compound and the alprostadil are formulated as a solid dosage form, such as a urethral suppository.

98. The compound for use according to any one of the preceding claims, wherein the compound and the alprostadil are formulated as a liquid dosage form, such as an emulsion, such as a cream.P7429PC004199. The compound for use according to any one of the preceding claims, wherein the compound and the PDE5i are formulated separately.

100. The compound for use according to any one of the preceding claims, wherein the compound and the PDE5i are formulated separately and independently as a pharmaceutical composition, a solid dosage form, and / or a liquid dosage form.101 . A method of treatment, prevention, or alleviation of erectile dysfunction, said method comprising administration of a compound of formula (I)or a pharmaceutically acceptable salt thereof and at least one second erectogenic agent in a subject in need thereof.

102. Use of a compound of formula (I),, formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one second erectogenic agent for the manufacture of a medicament for the treatment, prevention, or alleviation of erectile dysfunction in a subject

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