Compounds for treating erectile dysfunction

Abstract

The present invention relates to compounds for the treatment of erectile dysfunction.

Description

[Technical Field]

[0001] The present invention relates to compounds for the treatment of erectile dysfunction. [Background technology]

[0002] Erectile dysfunction (ED), defined as the inability to achieve and maintain an erection sufficient for sexual activity, is a condition that affects many men and is on the rise. ED patients are known to experience reduced quality of life (QoL) caused by a variety of psychosocial reasons, including low self-esteem, depression, sadness, anger, frustration, anxiety, and relationship problems.

[0003] Although current treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, have shown improvement, approximately 30%-40% of men with ED still do not respond to PDE5i medications, and this patient population continues to experience poor quality of life. Additionally, patients with erectile dysfunction (ED) and comorbid conditions may be resistant to currently recommended treatment with phosphodiesterase type 5 (PDE5) inhibitors and / or their combination with other oral treatments.

[0004] Although injection therapy using a combination of drugs that can relax penile smooth muscle can achieve a higher success rate, there is currently no oral treatment. Therefore, ED can be effectively treated by correcting the signal transduction changes in reproductive tissues and the underlying pathophysiological mechanisms. However, coexisting neurological disorders, diabetes mellitus, and severe vascular disease can also adversely affect the central pathways that regulate erectile function. Furthermore, drugs for central nervous system disorders can affect function and libido, and tend to affect men more than women. Therefore, there is a significant unmet need for new treatments for ED that can address the issues discussed above. Summary of the Invention

[0005] As outlined above, compounds that can provide new treatments for erectile dysfunction are highly desirable. The present disclosure provides compounds that are useful in the treatment of erectile dysfunction, including various types of erectile dysfunction.

[0006] Thus, in one main aspect, the present disclosure provides a compound of formula (I) for use in treating, preventing, reducing or alleviating erectile dysfunction in a subject: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is administered at a dose of about 0.001 mg / kg to about 1 mg / kg.

[0007] The present inventors have demonstrated that the use of the compounds of formula I described herein is active in the treatment of erectile dysfunction. The present inventors have found that the compounds are effective in different animal models, including humans, and that the compounds for use described herein effectively treat the symptoms of erectile dysfunction. In humans, the present inventors have found that the compounds improve the duration, hardness, and swelling of the erectile phenomenon.

[0008] The inventors have surprisingly shown in studies in healthy volunteers that individual doses of the compound of 10 mg or less are associated with a lower incidence of treatment-emergent adverse events (TEAEs) compared to higher doses. Studies using subjects with erectile dysfunction have also shown that individual doses of 5 mg of IP2015 are effective in treating erectile dysfunction in human subjects compared to placebo.

[0009] Another aspect of the present disclosure is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount of from about 1 mg to about 10 mg.

[0010] Another aspect of the present disclosure is a compound of formula (I): [ka] and one or more PDE5 inhibitor(s). [Brief explanation of the drawings]

[0011] [Figure 1A] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (A) Vehicle administration does not alter the pressure, whereas (B-D) IP2015 administration induces a dose-dependent increase in intracavernous pressure (spontaneous erection, SE) without altering the response to EFS. [Figure 1B] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (A) Vehicle administration does not alter the pressure, whereas (B-D) IP2015 administration induces a dose-dependent increase in intracavernous pressure (spontaneous erection, SE) without altering the response to EFS. [Figure 1C] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (A) Vehicle administration does not alter the pressure, whereas (B-D) IP2015 administration induces a dose-dependent increase in intracavernous pressure (spontaneous erection, SE) without altering the response to EFS. [Figure 1D] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (A) Vehicle administration does not alter the pressure, whereas (B-D) IP2015 administration induces a dose-dependent increase in intracavernous pressure (spontaneous erection, SE) without altering the response to EFS. [Figure 1E]The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (E-G) Frequency, duration, and magnitude of spontaneous erections after intravenous injection of vehicle, IP2015 0.1 mg / kg, 1 mg / kg, or 10 mg / kg. IP2015 increased H) frequency, I) duration, and J) magnitude of spontaneous erectile responses in db / db mice (n=7). Results are mean ± se mean. *P<0.05 vs. vehicle control. [Figure 1F] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (E-G) Frequency, duration, and magnitude of spontaneous erections after intravenous injection of vehicle, IP2015 0.1 mg / kg, 1 mg / kg, or 10 mg / kg. IP2015 increased H) frequency, I) duration, and J) magnitude of spontaneous erectile responses in db / db mice (n=7). Results are mean ± se mean. *P<0.05 vs. vehicle control. [Figure 1G] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (E-G) Frequency, duration, and magnitude of spontaneous erections after intravenous injection of vehicle, IP2015 0.1 mg / kg, 1 mg / kg, or 10 mg / kg. Effects on EFS are reported in the Supplementary Data File. IP2015 increased H) frequency, I) duration, and J) magnitude of spontaneous erectile responses in db / db mice (n=7). Results are mean ± SE mean. *P<0.05 vs. vehicle control. [Figure 1H] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (H-J) Intravenous injection of vehicle and IP2015 (1 mg / kg) in diabetic db / db mice. IP2015 increased H) frequency, I) duration, and J) magnitude of spontaneous erectile responses in db / db mice (n=7). Results are mean ± se mean. *P<0.05 vs. vehicle control. [Figure 1I]The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (H-J) Intravenous injection of vehicle and IP2015 (1 mg / kg) in diabetic db / db mice. IP2015 increased H) frequency, I) duration, and J) magnitude of spontaneous erectile responses in db / db mice (n=7). Results are mean ± se mean. *P<0.05 vs. vehicle control. [Figure 1J] The original waveforms show the increase in intracavernous pressure induced by electrical field stimulation (EFS) of the cavernous nerve. (H-J) Intravenous injection of vehicle and IP2015 (1 mg / kg) in diabetic db / db mice. IP2015 increased H) frequency, I) duration, and J) magnitude of spontaneous erectile responses in db / db mice (n=7). Results are mean ± se mean. *P<0.05 vs. vehicle control. [Figure 2] Effect of IP2015 and its synergistic effect with sildenafil, a phosphodiesterase type 5 inhibitor, on erection. Mean increase in A) frequency, B) duration, and (C) magnitude of erectile responses induced by IP2015 in the absence (n=6) and presence (n=5) of sildenafil (1 mg / kg), a phosphodiesterase type 5 inhibitor, in rats. Results are mean ± se mean. *P<0.05 vs. control. [Figure 3] IP2015 induces relaxation mediated by dopamine D1 receptors and nitric oxide in isolated rat corpus cavernosum strips. A) Increasing concentrations of IP2015 at baseline tension induce relaxation, which is inhibited in the presence of the dopamine D1 receptor antagonist, SCH23390, and unchanged in the presence of the dopamine D2 receptor antagonist, clozapine (n=6). B) Mean relaxation induced by IP2015 in endothelium-containing and endothelium-free preparations (n=5). C) Concentration-response curves of IP2015 in the presence of NG-nitro-L-arginine (L-NOARG), guanethidine, and sildenafil at baseline tension (n=8). Results are mean ± SE mean. *P<0.05 vs. control. [Figure 4]Study design for a randomized, double-blind, placebo-controlled, group-sequential study to investigate ascending single oral doses of IP2015 in healthy male subjects. [Figure 5] Study design: A randomized, double-blind, placebo-controlled, two-period crossover study to evaluate a single oral dose of IP2015 in male patients with ED. [Figure 6] Stimulus-evoked test design. [Figure 7] Mean plasma concentrations of IP2015 (linear scale) after single ascending doses. [Figure 8] Mean plasma concentrations of IP2015 (semi-logarithmic scale) after single ascending doses. [Figure 9] Mean plasma concentrations of IP2015 for single doses (linear scale). [Figure 10] Mean plasma concentrations of IP2015 for single doses (semi-logarithmic scale). [Figure 11] Answer the following question Q3 of the International Institute for Erectile Function-15 (IIEF-15): When you attempted sexual intercourse, how often in the past week were you able to penetrate (insert) your partner? [Figure 12] Answer the following question Q4 of the International Institute for Erectile Function-15 (IIEF-15): How often were you able to maintain an erection after penetrating (entering) your partner during sexual intercourse? [Figure 13] Overall responses to the International Institute of Erectile Function 15 (IIEF-15) questions.

[0012] definition "Pharmaceutically acceptable" means generally safe, non-toxic, and useful in preparing biologically and otherwise undesirable pharmaceutical compositions, including pharmaceutical compositions that are acceptable for veterinary and human pharmaceutical use.

[0013] By "IP2015" or "Pudafensin" or "Compound I" is meant the compound of Formula I, which is [ka]

[0014] The term "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and preferably possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or formed with organic acids, or salts formed when an acidic proton present in the parent compound is replaced by a metal ion, or coordinate salts with organic or inorganic bases.

[0015] When a chiral carbon is present in a chemical structure, all stereoisomers associated with that chiral carbon are intended to be encompassed by the structure unless otherwise specified. Using the Cahn-Ingold-Prelog RS notation system, the asymmetric carbon atom may exist in either the (R) or (S) configuration, and the compound may exist as a mixture of stereoisomers, e.g., a racemic mixture, or as only one stereoisomer.

[0016] The compounds of the present invention may exist in tautomeric forms, and all such tautomers are considered to be within the scope of the present invention.

[0017] Also, in the compounds of formula I as defined herein, any hydrogen atom may be replaced with a deuterium ( 2 H), and such deuterated compounds of Formula I containing 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.

[0018] It is known in the art that prodrugs can be produced. Those skilled in the art will know what type of molecular moiety can be introduced into a drug to produce a prodrug. Prodrugs of the compounds of Formula I are considered to be within the scope of the present invention.

[0019] As used herein, the term "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, the alleviation or amelioration of one or more symptoms or pathological conditions, whether detectable or undetectable, attenuation of the extent of a disease or disorder, stabilization (i.e., not worsening) of the disease or disorder state, prevention of the disease or disorder state, delay or slowing of the progression of a disease or disorder, improvement or palliation of the disease state, and remission (partial or complete).

[0020] As used herein, "erectile dysfunction" refers to a disorder involving a male mammal's inability to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include the inability to achieve or maintain an erection, ejaculation disorders, premature ejaculation, or the inability to reach orgasm. Erectile dysfunction (hereinafter also referred to as "ED") is also called "impotence," "erectile dysfunction," or "erectile dysfunction." Depending on the cause, ED can be divided into organic factors (caused by or associated with other medical conditions such as arteriosclerosis, nerve damage, diabetes, etc.), psychological factors (caused by psychological stress), and mixed factors (caused by a combination of both organic and psychological factors).

[0021] As used herein, "organic" erectile dysfunction refers to erectile dysfunction caused by a condition that physically impairs the delivery of sufficient blood flow to the erectile tissue of the penis or prevents the maintenance of sufficient blood within the erectile tissue of the penis. Organic causes of ED can be, for example, vascular or neurological. Organic ED caused by a vascular condition is due to a malfunction of the vascular system, which is responsible for either achieving or maintaining an erection. Vascular causes of organic ED can be, for example, hypertension, diabetes, and heart disease, which can be caused by atherosclerosis or congestive heart failure. Any of these conditions can impair the delivery of blood necessary to achieve an erection. Fibrotic changes in penile tissue can also make it difficult to maintain adequate blood flow to an erectile penis. Neurological diseases affecting the central or peripheral nervous system, such as advanced diabetes, can also cause organic ED. Organic ED can be caused by prostate surgery, pelvic surgery, or other types of surgery, or by medication. Up to 90% of ED is explained by organic causes. The remaining 10% of ED is thought to be non-organic or psychogenic.

[0022] As used herein, the term "co-occurring" is used to refer to a disease or pathological condition that occurs simultaneously with another condition in a subject (regardless of the relationship between them).

[0023] The International Institute of Erectile Function (IIEF-15) questionnaire is a validated, multidimensional, self-administered survey that has been shown to be useful in the clinical assessment of erectile dysfunction and treatment outcome in clinical trials. A score of 0 to 5 is given for each of 15 questions that examine the major domains of male sexual function: erectile function, orgasmic function, sexual desire, and intercourse satisfaction. The domains according to specific questions are as follows: Domain A - Erectile Function (Q1, 2, 3, 4, 5, 15) Domain B - Orgasmic Function (Q9, 10) Domain C - Sexual Desire (Q11, 12) Domain D - Sexual Satisfaction (Q6, 7, 8) Domain E - Overall Satisfaction (Q13, 14)

[0024] The IIEF-5 is a five-item version of the IIEF-15. Possible scores on the IIEF-5 range from 5 to 25, and erectile dysfunction can be classified into five categories based on the score: severe (5-7), moderate (8-11), mild-moderate (12-16), mild (17-21), and no ED (22-25).

[0025] As used herein, a "formulation" is the result of combining different substances, including active ingredients, to produce a final product.

[0026] The term "about" as used herein to refer to an amount or percentage is to be interpreted as a variation of ±10%, such as ±5%, of the amount or percentage value to which it refers. DETAILED DESCRIPTION OF THE INVENTION

[0027] Compounds for Use One embodiment of the present disclosure provides a compound of formula (I) for use in treating, preventing, reducing or alleviating erectile dysfunction in a subject: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is administered at a dose of about 0.001 mg / kg to about 1 mg / kg. The compounds of the present disclosure are monoamine reuptake inhibitors. The compounds can be tested for their ability to inhibit the reuptake of the monoamines dopamine, noradrenaline, and serotonin in synaptosomes, for example, as described in WO97 / 30997 or WO97 / 16451.

[0028] In one embodiment, the compound of formula (I) has the structure of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, the compound is 7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the name "IP2015" refers to the compound of Formula I. In one embodiment, the name "IP2015" refers to the compound of Formula Ia. In a specific embodiment of the disclosure, "IP2015" refers to the hydrochloride salt of the compound of Formula I.

[0030] In one embodiment of the disclosure, the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one hydrochloride.

[0031] One embodiment of the present disclosure is a compound of formula I, as described herein, for use in treating, preventing, reducing or alleviating erectile dysfunction in a subject: [ka] or a pharmaceutically acceptable salt thereof.

[0032] In some cases, the erectile dysfunction is organic erectile dysfunction, such as erectile dysfunction associated with or resulting from metabolic syndrome, e.g., erectile dysfunction associated with or resulting from diabetes, erectile dysfunction associated with or resulting from vascular disease, e.g., cardiovascular disease, erectile dysfunction associated with or resulting from neurological damage.

[0033] Alternatively, the erectile dysfunction may be associated with or caused by a medical condition such as, for example, an injury, the effects of surgery or radiation therapy, or the erectile dysfunction may be associated with or caused by psychological or behavioral factors, including psychiatric disorders, or may be associated with or caused by drug use or the use of psychoactive substances.

[0034] One embodiment of the present disclosure provides a compound of formula I for use in treating, preventing, reducing or alleviating erectile dysfunction in a subject: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is administered at a dose of about 0.001 mg / kg to about 1 mg / kg.

[0035] In one embodiment, the compound of formula I is administered at a dose of from about 0.001 mg / kg to about 1 mg / kg per individual dose, for example, 0.005 mg / kg, for example, 0.01 mg / kg, for example, 0.015 mg / kg, for example, 0.02 mg / kg, for example, 0.025 mg / kg, for example, 0.03 mg / kg, for example, 0.035 mg / kg, for example, 0.04 mg / kg, for example, 0.045 mg / kg, for example, 0.05 mg / kg, for example, 0.055 mg / kg, for example, 0.06 mg / kg, for example, 0.065 mg / kg, for example, 0.07 mg / kg, 0.075 mg / kg, for example, 0.08 mg / kg, for example, 0.08 For example, 5mg / kg, 0.09mg / kg, for example, 0.095mg / kg, for example, 0.1mg / kg, for example, 0.15mg / kg, for example, 0.2mg / kg, such as, for example, 0.25mg / kg, for example, 0.3mg / kg, 0.35mg / kg, for example, 0.4mg / kg, for example, 0.45mg / kg, such as, for example, 0.5mg / kg, for example, 0.55mg / kg, such as, for example, 0.6mg / kg, for example, 0.65mg / kg, for example, 0.7mg / kg, for example, 0.75mg / kg, such as, for example, 0.8mg / kg, for example, 0.85mg / kg, for example, 0.9mg / kg, for example, 0.95mg / kg, for example, 1mg / kg.

[0036] In one embodiment, the compound is administered in an amount of about 0.05 mg / kg to about 1 mg / kg per individual dose.

[0037] In one embodiment, the compound is orally administered in an amount of about 0.01 mg / kg to about 1 mg / kg per individual dose, for example, 0.01 mg / kg, for example, 0.05 mg / kg, for example, 0.1 mg / kg, for example, 0.15 mg / kg, for example, 0.2 mg / kg, for example, 0.25 mg / kg, for example, 0.3 mg / kg, for example, 0.35 mg / kg, for example, 0.4 mg / kg, for example, 0.45 mg / kg, for example, 0.5 mg / kg, for example, 0.55 mg / kg, for example, 0.6 mg / kg, for example, 0.65 mg / kg, for example, 0.7 mg / kg, for example, 0.75 mg / kg, for example, 0.8 mg / kg, for example, 0.85 mg / kg, for example, 0.9 mg / kg, for example, 0.95 mg / kg, for example, 1 mg / kg per individual dose.

[0038] In one embodiment, the compound is administered at a dose of about 0.001 to about 0.1 mg / kg per individual dose, for example, 0.001 mg / kg, for example, 0.005 mg / kg, for example, 0.01 mg / kg, 0.015 mg / kg, for example, 0.02 mg / kg, for example, 0.025 mg / kg, for example, 0.03 mg / kg, for example, 0.035 mg / kg, for example, 0.04 mg / kg, for example, For example, the compound is administered intravenously in an amount of 0.045 mg / kg, 0.05 mg / kg, for example, 0.055 mg / kg, for example, 0.06 mg / kg, for example, 0.065 mg / kg, for example, 0.07 mg / kg, for example, 0.075 mg / kg, for example, 0.08 mg / kg, for example, 0.085 mg / kg, for example, 0.09 mg / kg, for example, 0.095 mg / kg, for example, 0.1 mg / kg.

[0039] In one embodiment, the compound is preferably administered orally in an amount of about 0.035 mg / kg to 0.135 mg / kg, such as 0.040 mg / kg to 0.110 mg / kg, for example, 0.042 mg / kg to 0.100 mg / kg, for example, 0.0450 mg / kg to 0.100 mg / kg, for example, 0.045 mg / kg to 0.091 mg / kg, for example, 0.050 mg / kg to 0.091 mg / kg, per individual dose.

[0040] In one embodiment, the compound is administered orally in an amount of about 0.050 mg / kg to 0.053 mg / kg, or 0.053 mg / kg to 0.056 mg / kg, or 0.056 mg / kg to 0.059 mg / kg, or 0.059 mg / kg to 0.063 mg / kg, or 0.063 mg / kg to 0.067 mg / kg, or 0.067 mg / kg to 0.071 mg / kg, or 0.071 mg / kg to 0.077 mg / kg, or 0.077 mg / kg to 0.083 mg / kg, or 0.083 mg / kg to 0.091 mg / kg per individual dose.

[0041] In one embodiment, the compound is orally administered in an amount of 0.075 mg / kg to 0.250 mg / kg, for example, 0.080 mg / kg to 0.222 mg / kg, for example, 0.083 mg / kg to 0.200 mg / kg, for example, 0.091 mg / kg to 0.185 mg / kg, for example, 0.100 mg / kg to 0.185 mg / kg, for example, 0.050 mg / kg to 0.185 mg / kg, per individual dose.

[0042] One embodiment of the present disclosure provides a compound of formula I for use in treating, preventing, reducing or alleviating erectile dysfunction in a subject: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is administered at a dose of about 0.5 mg to about 20 mg per individual dose, for example, about 1 mg to about 15 mg per individual dose, for example, about 5 to about 10 mg per individual dose, for example, about 5 mg per individual dose, for example, about 10 mg per individual dose.

[0043] In one embodiment, the compound is administered in an amount of about 0.5 mg to 20 mg per individual dose, e.g., about 0.5 mg, e.g., about 1 mg, 2 mg, 3 mg, 4 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.

[0044] This disclosure demonstrates for the first time that doses of 10 mg or less are associated with fewer side effects than doses of 16.2 mg in healthy volunteers. Thus, in one embodiment, the compound is administered in an amount of about 1 mg to 10 mg, e.g., about 3 mg to about 10 mg, e.g., about 5 mg or, e.g., about 10 mg, per individual dose.

[0045] In one embodiment, the compound is administered as described herein in an amount of about 1 mg to about 10 mg per individual dose, which administration results in fewer than 85 subjects per 100 experiencing adverse events, e.g., fewer than 84, 83, 82, 81, or 80 subjects per 100 experiencing adverse events.

[0046] In one embodiment, the compound is administered as described herein in an amount of about 5 mg per individual dose, which administration results in fewer than 80 subjects per 100 experiencing adverse events, e.g., fewer than 79, 78, 77, or 76 subjects per 100 experiencing adverse events.

[0047] In one embodiment, the compound is administered as described herein in an amount of about 1 mg to about 10 mg per individual dose, which administration results in fewer than 23 subjects per 100 experiencing moderate adverse events, e.g., fewer than 22, 21, 20, 19, 18, or 16 subjects per 100 experiencing moderate adverse events.

[0048] In one embodiment, the compound is administered as described herein in an amount of about 5 mg per individual dose, which administration results in fewer than 13 subjects per 100 experiencing moderate adverse events, e.g., fewer than 12, 11, 10, 9, or 8 subjects per 100 experiencing moderate adverse events.

[0049] In one embodiment, the compound is administered as described herein in an amount of about 1 mg to about 10 mg per individual dose, which administration results in fewer than 82 subjects per 100 experiencing mild adverse events, e.g., fewer than 81, 80, 79, 78, or 77 subjects per 100 experiencing mild adverse events.

[0050] In one embodiment, the compound is administered as described herein in an amount of about 5 mg per individual dose, which administration results in fewer than 75 subjects per 100 experiencing mild adverse events, e.g., fewer than 74, 73, 72, 71, or 70 subjects per 100 experiencing mild adverse events.

[0051] In one embodiment, the compound is administered as described herein in an amount of about 10 mg or less per individual dose, which administration results in a total of less than 15 moderate adverse events per 40-50 subjects, e.g., less than 12 moderate adverse events per 40-45 subjects, e.g., less than 10 moderate adverse events per 43 subjects.

[0052] In one embodiment, the compound is administered as described herein in an amount of about 5 mg or less per individual dose, and the administration results in a total of less than 10 moderate adverse events per 40-50 subjects, e.g., less than 7 moderate adverse events per 40-45 subjects, or less than 6 moderate adverse events per 42 subjects.

[0053] In one embodiment, the compound is administered as described herein in an amount of about 10 mg per individual dose, which administration results in fewer than 40 total mild adverse events per 40-50 subjects, e.g., fewer than 37 total mild adverse events per 40-45 subjects, e.g., fewer than 34 total mild adverse events per 43 subjects.

[0054] In one embodiment, the compound is administered as described herein in an amount of about 5 mg or less per individual dose, and the administration results in fewer than 35 mild adverse events per 40-50 subjects, e.g., fewer than 32 total mild adverse events per 40-45 subjects, or fewer than 30 mild adverse events per 42 subjects.

[0055] In one embodiment, the compound is administered as described herein in an amount of about 1 mg to about 10 mg per individual dose, which administration results in fewer than 58 subjects per 100 experiencing treatment-related adverse events, e.g., fewer than 57, 56, 55, or 54 subjects per 100 experiencing treatment-related adverse events.

[0056] In one embodiment, the compound is administered as described herein in an amount of about 5 mg per individual dose, which administration results in fewer than 28 subjects per 100 experiencing treatment-related adverse events, e.g., fewer than 27, 26, 25, or 24 subjects per 100 experiencing treatment-related adverse events.

[0057] A mild adverse event refers to an adverse event in which the subject experiences temporary or mild discomfort, does not limit activity, and does not require medical intervention. A moderate adverse event refers to an adverse event in which the subject experiences mild to moderate discomfort, which may (but does not necessarily) cause mild limitation in activity, and may require some assistance.

[0058] A treatment-related adverse event is an adverse event that may be either possibly or probably related to the treatment.

[0059] In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered more than once daily, such as twice daily, for example three times daily, for example four times daily.

[0060] In one embodiment, the compound is administered once per week. In one embodiment, the compound is administered twice per week.

[0061] In one embodiment, the total daily dose of the compound is from about 0.5 mg to about 100 mg, for example, 0.6, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 mg.

[0062] In one embodiment, the daily dose of the compound is from about 1 to about 10 mg, for example, from about 2 mg to about 10 mg, for example, from about 3 mg to about 10 mg, for example, from about 4 mg to about 10 mg, for example, about 5 mg or, for example, a total daily dose of about 10 mg.

[0063] In the present disclosure, it is shown for the first time that a 5 mg individual dose of the compound of formula I is effective in treating erectile dysfunction in subjects.A 5 mg individual dose of IP2015 results in a significant improvement in I compared with placebo.Therefore, in one embodiment, the compound of formula I is administered to a subject at about 5 mg per individual dose.In one embodiment, the compound of formula I is administered to a subject at an amount of 5 mg per individual dose.

[0064] In one embodiment, the compound of Formula I is administered to a subject at 5 mg per individual dose, wherein the subject weighs from about 55 kg to about 130 kg. In one embodiment, the compound of Formula I is administered to a subject at 5 mg per individual dose, wherein the subject weighs from about 60 kg to about 115 kg. In one embodiment, the compound of Formula I is administered to a subject at 0.041 mg / kg to about 0.083 mg / kg per individual dose.

[0065] In one embodiment, the compound for use is for the treatment, prevention, or alleviation of erectile dysfunction, wherein the erectile dysfunction is (i) associated with or resulting from a pathological condition, such as the effects of injury, surgery or radiation therapy; and / or (ii) related to or resulting from psychological or behavioral factors, including mental disorders; and / or (iii) Related to or resulting from the use of drugs or psychoactive substances.

[0066] In one embodiment, the compound for use is for treating, preventing or alleviating erectile dysfunction, and said erectile dysfunction is organic erectile dysfunction.Organic erectile dysfunction refers to the erectile dysfunction caused by the pathology that physically impairs the delivery of sufficient blood flow to the erectile tissue of the penis or prevents the maintenance of sufficient blood in the erectile tissue of the penis.The organic cause of ED can be, for example, due to blood vessels or nerves.

[0067] In one embodiment, the compound for use is for erectile dysfunction, which is congenital erectile dysfunction or acquired erectile dysfunction. Congenital erectile dysfunction is erectile dysfunction that the subject always experiences. Acquired erectile dysfunction is erectile dysfunction that follows a period in which the person does not experience erectile dysfunction. In one embodiment, the compound for use is for erectile dysfunction that is generalized erectile dysfunction or situational erectile dysfunction. Generalized erectile dysfunction is characterized by a lack, insufficiency, or absence of erectile response or erectile function in all situations and under all sexual stimuli. Situational erectile dysfunction is characterized by a lack, insufficiency, or absence of erectile response or erectile function under some situations, with some partners, or in response to some stimuli but not in other situations.

[0068] In one embodiment, the erectile dysfunction is coexistent in the subject with one or more condition(s) selected from the group consisting of: (i) diabetes; (ii) metabolic syndrome (iii) vascular diseases, such as cardiovascular disease, and (iv) Nervous system disorders.

[0069] In one embodiment, the erectile dysfunction is coexistent with diabetes in the subject. In one embodiment, the erectile dysfunction is coexistent with metabolic syndrome in the subject. In one embodiment, the erectile dysfunction is coexistent with vascular disease, such as cardiovascular disease, in the subject. In one embodiment, the erectile dysfunction is coexistent with nervous system disease in the subject.

[0070] In one embodiment, the compound for use is for erectile dysfunction associated with or caused by metabolic syndrome.

[0071] In one embodiment, the compound for use is for erectile dysfunction associated with or caused by diabetes.

[0072] In one embodiment, the compound for use is for erectile dysfunction associated with or caused by a vascular disease, such as a cardiovascular disease.

[0073] In one embodiment, the compound for use is for erectile dysfunction associated with or caused by neurological damage.

[0074] In one embodiment, the compound for use is for erectile dysfunction, which is treatment-induced erectile dysfunction associated with the use of medication. In one embodiment, treatment-induced erectile dysfunction is a side effect resulting from drug treatment. In a further embodiment, the drug is selected from the group consisting of antidepressants, NSAIDs, finasteride, antiepileptic drugs, and neuroleptics.

[0075] In one embodiment, the compound for use is for erectile dysfunction that is treatment-induced erectile dysfunction caused by treatment with an antidepressant.

[0076] The compounds for use according to the present disclosure may be used in combination with one or more additional therapeutic agent(s). Thus, in one embodiment, the subject is administered an additional therapeutic agent that is effective in treating erectile dysfunction.

[0077] In one embodiment, the additional therapeutic agent effective for treating erectile dysfunction is a phosphodiesterase-5 inhibitor (such as sildenafil, tadalafil, vardenafil, or avanafil), alprostadil.In one embodiment, the additional therapeutic agent effective for treating erectile dysfunction is testosterone.In one embodiment, the compound for use described herein is combined with cell therapy.In one embodiment, the compound for use described herein is combined with extracorporeal shock therapy.

[0078] In one embodiment, the subject is receiving another treatment for erectile dysfunction, hi one embodiment, the subject is receiving treatment with one or more phosphodiesterase 5 (PDE5) inhibitor(s), such as sildenafil, tadalafil, vardenafil, or avanafil.

[0079] In one embodiment, the subject is a non-responder to the treatment of erectile dysfunction with one or more PDE5 inhibitors.By the term " non-responder ", it should be understood that the subject does not respond to treatment as expected.Non-responder does not respond to the currently established and commercially available therapeutic drug as expected.For example, the non-responder to the treatment of erectile dysfunction with PDE5 inhibitors responds suboptimally to the treatment with PDE5, for example, the improvement of erectile dysfunction with the treatment with PDE5 inhibitors is absent or insufficient.

[0080] In one embodiment, the compounds for use described herein are capable of producing a central effect that initiates an erection and / or a peripheral effect that enhances an erection.

[0081] In one embodiment, the compounds for use described herein are capable of initiating and / or enhancing an erection through smooth muscle relaxation.

[0082] In one embodiment, the compounds for use described herein can initiate an erection by increasing central dopamine. In one embodiment, the compounds for use described herein can enhance an erection through the release of nitric oxide. In one embodiment, the compounds for use described herein can initiate an erection by increasing central dopamine and enhancing the peripheral effect of enhancing an erection through the release of nitric oxide.

[0083] In one embodiment, the compounds may increase the number and / or duration and / or frequency of erectile events, penile tumescence and / or penile hardness. Tumescence refers to the quality of being swollen or becoming swollen.

[0084] In one embodiment, the compound is capable of increasing the number and / or duration of erectile events, penile tumescence and / or penile hardness during sexual stimulation in a subject.

[0085] The number and duration of erectile events, penile swelling and tumescence events, and penile hardness are measured by techniques known in the art (e.g., Rigiscan device) and analyzed by Rigiscan Plus software. 1 .

[0086] In one embodiment, the compound may increase one or more of the parameters obtained in a Rigiscan assessment, such as, for example, duration of erectile episode, mean hardness of erectile episode, time to 80-100% hardness, apical hardness activity units (RAU), and basal tumescence activity units (TAU).

[0087] In one embodiment, the subject is a mammal. In one embodiment, the subject is a human. Preferably, the subject is a male, such as a male human. In some embodiments, the subject is an adult male. In some embodiments, the subject is an adult male. In some 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.

[0088] In one embodiment, the compound is for use in a subject as described herein, wherein the subject had an International Index of Erectile Function (IIEF-5) of less than 22 prior to treatment, for example, between 21 and 17, for example, between 12 and 16, for example, between 8 and 11, for example, between 5 and 7.

[0089] In one embodiment the compound is for use in a subject who had a pre-treatment International Index of Erectile Function (IIEF-5) of less than 22, such as 21, for example 20, for example 19, for example 18, for example 17, for example 16, for example 15, for example 14, for example 13, for example 12, for example 11, for example 10, for example 9, for example 8, for example 7, for example 6, for example 5.

[0090] In one embodiment, the subject had an International Institute for Erectile Function Score 5 (IIEF-5) of less than 17. In one embodiment, the subject had an International Institute for Erectile Function Score 5 (IIEF-5) of less than 12. In one embodiment, the subject had an International Institute for Erectile Function Score 5 (IIEF-5) of less than 8.

[0091] In one embodiment, the compound for use is capable of increasing the International Erectile Function Score in a subject. In one embodiment, the compound for use is capable of increasing the subject's IIEF-5 score by an amount of 1 to 20. In one embodiment, the compound for use is capable of increasing the subject's IIEF-5 score by an amount of 1 to 20, such as 1, for example, 2, for example, 3, for example, 4, for example, 5, for example, 6, for example, 7, for example, 8, for example, 9, for example, 10, for example, 11, for example, 12, for example, 13, for example, 14, for example, 15, for example, 16, for example, 17, for example, 18, for example, 19, for example, an amount of 20. In one embodiment, the compound for use described herein is capable of increasing the subject's IIEF-5 score by at least 1, for example, at least 2, for example, at least 3, for example, at least 4, for example, at least 5, for example, at least 6, for example, at least 7, for example, at least 8, for example, at least 9, for example, at least 10.

[0092] In one embodiment, the compounds for use described herein can increase the score of one or more questions in the International Institute for Erectile Function-15 (IIEF-15) in a subject. In one embodiment, the compounds for use described herein can increase the score of one or more questions in Domain A of the IIEF-15, for example, can increase the score of any of Questions 1, 2, 3, 4, 5, or 15 of the IIEF-15.

[0093] In one embodiment, the compounds for use described herein may improve one or more selected from erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction in different domains thereof as measured by the IIEF-15 questionnaire.

[0094] In one embodiment, the compound for use is administered orally.

[0095] In one embodiment, the compounds for use are administered parenterally, for example, by cutaneous, mucosal, subcutaneous, intramuscular, intraperitoneal, intravenous or intraarterial injection.

[0096] In one embodiment, the compound is formulated into a pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient.

[0097] In one embodiment, the compound is formulated as a solid dosage form such as a tablet, capsule, pill, granule, or powder.

[0098] In one embodiment, the compound according to Formula (I) and one or more additional therapeutic agent(s) described herein are administered in the same formulation.

[0099] One aspect of the present disclosure is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount of from about 1 mg to about 10 mg.

[0100] One aspect of the present disclosure is a compound of formula I: [ka] and one or more PDE5 inhibitor(s). In one embodiment, the one or more PDE5 inhibitor(s) are selected from the group consisting of sildenafil, tadalafil, vardenafil, and avanafil. In one embodiment, the compound of Formula (I) is present in an amount of about 0.5 mg to about 10 mg.

[0101] The present inventors have shown that administration of compounds of formula I described herein is useful for treating erectile dysfunction. Accordingly, the present disclosure provides uses of compounds of formula I as described in the "Compounds for Use" section.

[0102] One embodiment of the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating, preventing, alleviating, or ameliorating erectile dysfunction, wherein the compound is administered at a dose of about 0.001 mg / kg to 1 mg / kg. One embodiment of the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating erectile dysfunction.

[0103] One embodiment of the present disclosure provides a method for treating, preventing, reducing or alleviating erectile dysfunction in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

[0104] One embodiment of the present disclosure provides a method for increasing the frequency of erectile responses in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

[0105] One embodiment of the present disclosure provides a method for increasing the duration of an erectile response in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

[0106] One embodiment of the present disclosure provides a method for increasing the magnitude of the erectile response in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

[0107] One embodiment of the present disclosure provides a method for achieving a mean plasma concentration of IP2015 in a subject of about 1 ng / mL to 50 ng / mL, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.001 mg / kg to about 1 mg / kg.

[0108] item 1. A compound of formula (I) for use in treating, preventing, reducing, or alleviating erectile dysfunction in a subject; [ka] or a pharmaceutically acceptable salt thereof, wherein said compound is administered at a dose of about 0.001 mg / kg to about 1 mg / kg.

[0109] 2. The compound for use according to any one of items 1 and 2, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof.

[0110] 3. The compound for use according to any one of items 1 to 2, wherein the compound is administered at a dose of about 0.5 mg to about 10 mg.

[0111] 4. The compound for use according to any one of the preceding items, wherein prior to treatment, said subject had an International Institute for Erectile Function Score 5 (IIEF-5) of less than 17.

[0112] 5. The compound for use according to any one of the preceding items, wherein prior to treatment, said subject had an International Institute for Erectile Function 5 (IIEF-5) of less than 12.

[0113] 6. The compound for use according to any one of the preceding items, wherein said subject does not respond to treatment of erectile dysfunction with one or more PDE5 inhibitors.

[0114] 7. The compound for use according to any one of the preceding items, wherein said erectile dysfunction is organic erectile dysfunction.

[0115] 8. The erectile dysfunction in the subject: (i) diabetes; (ii) metabolic syndrome (iii) vascular diseases, such as cardiovascular disease, and (iv) Nervous system disorders The compound for use according to any one of the preceding items, wherein the compound is coexisting with one or more condition(s) selected from the group consisting of:

[0116] 9. The compound for use according to any one of items 1 to 8, wherein said erectile dysfunction is associated with or caused by diabetes or metabolic syndrome.

[0117] 10. The compound for use according to any one of items 1 to 8, wherein the erectile dysfunction is associated with or caused by a vascular disease, such as a cardiovascular disease.

[0118] 11. The compound for use according to any one of items 1 to 8, wherein the erectile dysfunction is associated with or caused by a disease of the nervous system.

[0119] 12. A compound for use according to any one of the preceding items, wherein said compound is capable of increasing the number and / or duration of erectile events, penile tumescence and / or penile hardness.

[0120] 13. The compound for use according to any one of the preceding items, wherein the compound is capable of improving one or more selected from erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction.

[0121] 14. The compound for use according to any one of the preceding items, wherein the compound is capable of increasing the score of one or more questions of the International Institute for Erectile Function-15 (IIEF-15) in the subject.

[0122] 15. The compound for use according to any one of the preceding items, wherein said compound is formulated as a solid dosage form, such as a tablet. [Example]

[0123] Example 1. Effects of IP2015 on erectile function in rats and diabetic mice. This study investigated whether IP2015 could improve erectile function.

[0124] Materials and Methods For in vivo erectile physiology studies, rats were anesthetized with intraperitoneal administration of sodium pentobarbital (Sygehus Apoteket, Aarhus, Denmark, 50 mg / kg). Rats breathed spontaneously throughout the experiment. Body temperature was continuously monitored and maintained at 37°C. A midline incision was made in the perineum to expose the base of the penis, surrounded by striated muscle. The ischiocavernosus muscle overlying the crus cavernosa was divided unilaterally, and an entrance to the underlying tunica albuginea was created. A 25-gauge needle attached to a heparinized (100 IE ml) polyethylene catheter was inserted into the crus cavernosa 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 using a transducer (Disposable BP Transducer, ADInstruments, UK) and were registered and analyzed with a computerized data acquisition system (PowerLab, ADInstruments).

[0125] A 20-30 min stabilization period was allowed before recording basal ICP and MAP. Through a lower abdominal incision, the cavernous nerve was isolated outside the prostate, and electrical stimulation was performed with a thin bipolar platinum electrode connected to a stimulator S48 (Grass Instrument Co., Boston, MA, USA). An initial stimulation of the cavernous nerve (6 V, 10 Hz, 1 ms pulse duration square wave pulse for 30 seconds) was performed to measure the maximum amplitude of the erectile response.

[0126] IP2015, sildenafil, clozapine, or vehicle was administered by injection into the jugular vein in a maximum volume of 200 μl. IP2015 was administered intravenously at doses of 0.1 and 1 mg / kg. The observation period for spontaneous erection after IP2015 injection was 30 minutes. Clozapine (1 mg / kg) or sildenafil (1 mg / kg) was administered 30 minutes or 10 minutes before the 1 mg / kg IP2015 injection, respectively. One group received vehicle injection only.

[0127] To investigate the involvement of proximal neuronal pathways in the effects of IP2015, mechanical denervation was performed. For mechanical denervation, the isolated cavernous nerve was severed distal to the greater pelvic ganglion. The lack of an erectile response to electrical stimulation demonstrated the effectiveness of mechanical denervation.

[0128] For functional testing in cavernosal strips, the penis was removed by cutting the corpora cavernosa at its attachment to the lower clavicle, and the corpora cavernosa was then dissected away. The penis was immediately immersed in ice-cold (4°C) PSS. The tunica albuginea was carefully opened from the proximal end of the corpus cavernosum toward the penile shaft, and the intracavernous erectile tissue was microsurgically dissected away. Changes in isometric tension in corpus cavernosum strips (0.5 × 0.5 × 3 mm) were investigated using a tissue organ bath system (750TOBS, Danish Myotechnology, Aarhus, Denmark). Suture connectors were attached to both ends of the strip preparation, which was then suspended between two L-shaped metal prongs in a thermostatically controlled organ bath (5 ml, 37°C) containing PSS aerated with a mixture of 5% CO2 in air (pH 7.4). The bath solution was routinely changed every 20 min, replaced with fresh PSS, and maintained at 37°C. During the 60 min equilibration period, tension was adjusted as described above until an average stable tension of 1.2 mN was obtained.

[0129] To test the contractility of the preparations, they were exposed to 125 mM potassium saline (KPSS) and phenylephrine (10 −6 M), and after each contraction, acetylcholine was administered to confirm endothelium-dependent relaxation.

[0130] To investigate the effects of IP2015 on corpus cavernosum strips, the drug (10 × 10 M) was administered as a preparation at baseline tension or contracted with phenylephrine (10 M) in the absence or presence of L-NOARG (10 M) (an NO synthase inhibitor), sildenafil (10 M) (a PDE5 inhibitor), a dopamine D1 receptor antagonist (SCH23390), and a dopamine D2 receptor antagonist (clozapine (10 M)). The effects of vehicle were also investigated.

[0131] result IP2015 induces spontaneous erections in rats and mice.

[0132] At the beginning of the experiment, 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. The maximum amplitude of erections induced by electrical stimulation of the cavernous nerve at the beginning of the experiment was 71.2 ± 1.5 mmHg (n = 24). In contrast to vehicle injection (Figure 1A), intrajugular administration of IP2015 at 0.1, 1, and 10 mg / kg induced transient increases in intracavernous pressure corresponding to erections (Figure 1B-D). The frequency, duration, and magnitude of these responses increased dose-dependently (Figure 1E-G). The magnitude of the erectile response was characterized by measuring the increase in intracavernous pressure (ICP), expressed as a percentage of mean arterial pressure (MAP), and was shown to be significantly increased compared to vehicle (Figure 1G).

[0133] To investigate the effects of IP2015 in a simple model of erectile dysfunction, we evaluated its effects in a mouse model of type 2 diabetes before further analyzing its underlying pharmacology in vivo. Type 2 diabetic db / db mice exhibit impaired erectile function compared with normal C57BL / 6 mice and heterozygous db / + control mice. Injection of IP2015 in diabetic db / db mice significantly increased the frequency, duration, and magnitude of erectile responses (Figure 1H-J).

[0134] Sildenafil, a phosphodiesterase inhibitor, improves erections by enhancing the erectile response. To investigate the effect of sildenafil on IP2015 administration, IP2015 was injected to induce erectile responses, and treatment with sildenafil significantly increased the duration of these responses (Figure 2). The magnitude of the erectile response induced by IP2015 (0.1 mg / kg) was also affected. These findings suggest that sildenafil enhances the effects of low doses of IP2015 on erections.

[0135] Effects of IP2015 on isolated rat erectile tissue IP2015, added at basal tension, induced concentration-dependent relaxation in corpus cavernosum strips. This effect remained unchanged in the presence of clozapine, but was translated into small IP2015-induced contractions in the presence of the dopamine D1 receptor antagonist SCH23390 (Figure 3A). IP2015 relaxation was observed in preparations containing endothelium but not in those without endothelium (Figure 3B). Incubation with the NO synthase inhibitor L-NOARG (10-4 M) abolished the relaxant effect of IP2015, whereas pretreatment with sildenafil (10-7 M) resulted in enhanced relaxation in response to IP2015 (Figure 3C). These findings suggest that endothelial dopamine D1 receptors and subsequent NO release are involved in IP2015-induced relaxation of the corpus cavernosum.

[0136] conclusion Measurement of intracavernous pressure in anesthetized rats revealed that IP2015 dose-dependently increased the number and duration of spontaneous erectile events. Pretreatment with the dopamine D2-like receptor antagonist, clozapine, or cavernous nerve sectioning suppressed the IP2015-induced erectile response, while the phosphodiesterase type 5 inhibitor, sildenafil, further enhanced the IP2015-mediated increase in intracavernous pressure. IP2015 also increased the number of erections in type 2 diabetic db / db mice. Direct intracavernous injection of IP2015 increased penile pressure, and in cavernous strips, IP2015 induced concentration-dependent relaxation. This was enhanced by sildenafil and by endothelial cell removal, the nitric oxide synthase inhibitor, NG-nitro-L-arginine, and the D1 receptor antagonist, SCH23390.

[0137] Example 2. Determination of the safety and tolerability of ascending single doses of IP2015 in healthy male subjects.

[0138] The objectives of this study were to determine the safety and tolerability of single ascending doses of IP2015 in healthy male subjects and to determine the pharmacokinetics (PK) of a single oral dose of IP2015 in healthy male subjects.

[0139] Materials and Methods Test Design This study was a Phase 1, randomized, double-blind, placebo-controlled, ascending single oral dose safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) study of IP2015 in healthy male subjects.

[0140] Each subject received a single oral dose of IP2015 or matching placebo. The starting dose of IP2015 was 0.01 mg in Cohort 1. Dose levels were escalated to a maximum of 0.05 mg in Cohort 2 and 0.2 mg in Cohort 3. Dose escalation criteria were used to determine doses for the remaining five cohorts. In all cohorts, no more than two subjects (one active, one placebo) were dosed on the first dosing day, such that no more than one subject at each dose level received active IP2015 for the first time.

[0141] Subjects were required to attend the Clinical Research Unit (CRU) for a screening visit within 28 days prior to dosing. Subjects were admitted to the CRU on Day -1 for baseline safety and pharmacodynamic (PD) assessments (RigiScan® [Cohorts 3-8 only] and central nervous system (CNS) assessments [saccadic eye movement measurements, visual analog scale [VAS], and prolactin level assessments; saccadic eye movement measurements were only assessed in Cohorts 3-8]) and received a dose of IP2015 or placebo in the fasted state on the morning of Day 1. Subjects in Cohorts 3-8 only self-applied a RigiScan Plus monitor to their penis on Day -1 and again before dosing on Day 1, where it remained in place for 10 hours between RigiScan assessments. All subjects remained in the CRU until Day 3 (48 hours post-dose) for collection of safety assessments, PK blood and urine samples, CNS assessments and RigiScan assessments.

[0142] Subjects attended a follow-up visit 5-7 days after discharge from the CRU, with each subject's participation period spanning approximately 5 weeks.

[0143] The study design is shown in Figure 1.

[0144] participants Healthy subjects were heterosexual men of any ethnicity, aged 18–59 years (inclusive), and had a BMI of 18–32 kg / m 2Participants were 6'11" (inclusive) and weighed 50 kg or more. They had a score of 17-25 on the International Institute for Erectile Function (IIEF-5) questionnaire at screening. Participants were determined by their physicians to be healthy based on medical history, physical examination, concomitant medications, vital signs, 12-lead ECG, and laboratory assessment. All participants provided written informed consent, including compliance with the requirements and restrictions described in the consent form.

[0145] Randomization and blinding In cohorts 1 and 2, a total of five subjects were randomly assigned to receive either IP2015 (three subjects) or placebo (two subjects). Of the first two subjects, one received placebo and one received IP2015. For all other cohorts 3–8, a total of eight subjects were randomly assigned to receive either IP2015 (six subjects) or placebo (two subjects). Of the first two subjects, one received placebo and one received IP2015. The randomization scheme was generated by a statistician using SAS PROC Plan.

[0146] The study was conducted in a double-blind fashion (investigator and subject / patient blinding). The randomization list was kept in a secure place until the end of the study.

[0147] The planned amount of either IP2015 or placebo was poured into blinded medication containers and provided to medication staff at the CRU.

[0148] Study drug, dose, and mode of administration IP2015 and matching placebo were provided as powders in bottles for oral solution. A 5% hydroxypropyl beta-cyclodextrin solution was reconstituted to form the placebo, which was used to dissolve IP2015. Reconstitution was performed by a pharmacist at the clinical site prior to dosing. IP2015 was stored at a controlled room temperature of 15-25°C until dispensed to subjects / participants.

[0149] IP2015 or matching placebo was administered as an oral solution in the fasted state once on the morning of Day 1. The dose was taken with 240 mL of water at room temperature. Subjects / participants fasted overnight from pre-dose until 4 hours post-dose. Water was available ad libitum except for 1 hour pre-dose and 1 hour post-dose.

[0150] The doses used in each cohort were as follows: Cohort 1 - 0.01 mg Cohort 2 - 0.05mg Cohort 3 - 0.2mg Cohort 4 - 0.6mg Cohort 5 - 1.8mg Cohort 6-5.4mg Cohort 7-16.2mg Cohort 8-10mg

[0151] evaluation This study evaluated clinical safety data from adverse event (AE) reports, 12-lead electrocardiogram (ECG), cardiac telemetry, vital signs (standing and supine blood pressure (BP), heart rate (HR), oral temperature), and clinical laboratory assessments (chemistry, hematology, urinalysis) and physical examination in healthy male subjects.

[0152] The study also evaluated plasma PK concentrations and parameters including, but not limited to, the area under the plasma concentration versus time curve (AUC), the time from time zero to the last quantifiable concentration (AUC), the AUC from zero to infinity (AUC), the maximum observed plasma concentration (C), the time to reach maximum plasma concentration (t), and the elimination half-life (T) in healthy male subjects. Blood samples for measuring IP2015 plasma concentrations were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours post-dose.

[0153] This study further evaluated the relationship between PK and PD data from CNS and RigiScan assessments in healthy male subjects, as well as the possible relationship between IP2015 dose and serum prolactin levels.

[0154] RigiScan assessments were performed on day -1 and from 1 hour pre-dose to 9 hours post-dose on day 1. CNS assessments (saccadic eye movements and visual analog scale [VAS] assessments) were performed pre-dose and 1, 2, 4, and 8 hours post-dose on day 1, and prolactin measurements were performed 24 and 48 hours post-dose.

[0155] A central nervous system evaluation was performed to determine the potential CNS effects of IP2015, which included the following: Saccadic eye movements (sedation study, Part A, Cohorts 3-8 only): Saccadic eye movements were measured using a saccademeter, a small, portable device for recording saccadic responses to visual stimuli. Eye movements were measured noninvasively using infrared reflectance; a small laser mounted on a transducer projected a small stimulus in front of the subject. 100 saccadic movements were recorded at each time point. Visual Analogue Scale: A VAS was used to rate a range of symptoms (drowsiness, hunger, dizziness, nausea, anxiety, irritability) on a scale ranging from "not at all" to "extremely." Prolactin levels: Serum prolactin levels were obtained via blood samples and analyzed.

[0156] Subjects self-applied the RigiScan Plus monitor to their penis before dosing on days -1 and 1, and left it in place for 10 hours each time.

[0157] The RigiScan Plus monitor consists of two loops, one placed around the base of the penis and one toward the tip. The portable monitor uses penile loops at the tip and base, adjusted by slight tightening at spaced time intervals, to measure and record penile hardness and swelling. Each loop contains a freely moving cable within a conduit. Each loop takes a measurement every 15 seconds. The loop is gently tightened with a linear force of 4 ounces (114 g) and then quickly released, allowing the tissue to return to its unloaded state. The RigiScan Plus monitor then takes a swelling measurement. After taking the swelling measurement, it is compared to the previous sample. If a 6 mm increase in swelling, indicating potential erectile function, is detected, the RigiScan Plus monitor takes a second measurement every 30 seconds. After measuring the swelling, the loop is tightened a second time around the circumference of the penis with a linear force of 10 ounces (283.5 g). The RigiScan Plus monitor takes measurements as this force is applied, recording the cross-section's response to radial compression, thus measuring hardness. 1 Data were recorded on a monitor strapped to the subject's / participant's thigh and downloaded to a computer after the recording session. Subjects / participants were instructed by the investigator on how to self-apply the RigiScan Plus monitor and were advised to wear loose-fitting clothing during their stay in the unit.

[0158] PD parameters were derived from the PD assessments of RigiScan and CNS. The PD parameters shown in Table 1 were derived to evaluate the effects of IP2015.

[0159] [Table 1] JPEG2026502459000014.jpg79159

[0160] statistical methods Safety parameters were listed and summarized using descriptive statistics. Pharmacokinetic parameter estimates were calculated using non-compartmental methods. Pharmacokinetic data were listed for each subject / patient and summarized by descriptive statistics.

[0161] Dose proportionality in Part A was analyzed by a linear regression model using the logarithm of the PK parameter as the response variable and the logarithm of the dose as the independent variable. Log(y i )=α+β*log dose i +ε i It can be expressed as where α is the intercept and i is the actual dose of IP2015 for the i-th subject, and ε i is y i is the (within-subject) random error in observing

[0162] The above model was applied to the following PK parameters: AUC0-t, AUC0-∞, and Cmax. Based on the linear regression model, the dose-proportionality coefficient (slope) and its two-sided 90% confidence interval (CI) were estimated. Dose-proportionality was declared when the 90% CI of the slope was completely within the following range: 16:1 + log(0.5) / log(r), 1 + log(2) / log(r), where r is the high dose / low dose.

[0163] Pharmacodynamic data were described for each subject by time point and dose cohort, with summary statistics including arithmetic mean, SD, minimum, maximum, and median.

[0164] The effects of IP2015 on PD parameters were analyzed using a generalized mixed regression model with PD parameters as the response variable, dose cohort, time, and the interaction between dose cohort and time as mixed effects, baseline measurements as covariates, and subject as a random effect. This model was applied to each PD parameter. The least-squares (LS) mean differences between the two dose cohorts at different time points, along with 95% CIs, were derived from the generalized mixed regression model. For continuous outcomes, treatment differences were measured as LS mean differences. For dichotomous outcomes, treatment differences were measured as odds ratios. Additionally, the dose of study drug was introduced as a continuous variable into the generalized linear mixed model. If the model did not converge, several time points and dose cohorts could be pooled.

[0165] The relationship between plasma PK levels measured by RigiScan data and PD response was investigated using a generalized nonlinear mixed model.

[0166] result Single-dose pharmacokinetics of IP2015 The plasma concentrations of IP2015 at each dose level in Part A are shown in Figure 7 (linear scale) and Figure 8 (semi-logarithmic scale).

[0167] Plasma concentrations of IP2015 were below the LLOQ in all subjects receiving 0.01 mg and 0.05 mg IP2015 and in 3 / 7 subjects receiving 0.2 mg IP2015. The plasma concentration versus time profile for IP2015 doses of 0.6 mg and above was characterized by a relatively rapid absorption phase. Median tmax was generally similar for each dose, ranging from 2.25 to 5.00 hours post-dose, with tmax ranging from 1.00 to 6.00 hours post-dose across all dose levels. After reaching Cmax, IP2015 plasma concentrations appeared to decline in a biphasic manner. The mean T1 / 2 of IP2015 was generally similar across doses from 5.4 mg to 16.2 mg, ranging from 23.11 to 26.30 hours. At the lower dose levels of 0.6 mg and 1.8 mg, the mean t was shorter (14.49 hours and 16.09 hours, respectively), likely due to an incompletely defined elimination phase at these doses, as T could only be calculated for 1 / 6 subjects receiving 0.6 mg IP2015 and 3 / 6 subjects receiving 1.8 mg IP2015. Half-lives could not be calculated for any subjects at the 0.2 mg dose level.

[0168] The dose-proportionality analysis is shown in Table 2. The slope estimate (90% CI) from the regression analysis of Cmax was 1.1389 (1.1005-1.1773) for IP2015. The lower limit of the 90% CI was greater than 1, indicating a slightly greater than dose-proportional increase in Cmax over the 0.2-16.2 mg dose range. The slope estimates (90% CI) for AUC0-∞ and AUC0-t were 1.1884 (1.0721-1.3048) and 1.5579 (1.4007-1.7151) for IP2015, respectively. The lower limit of the 90% CI was greater than 1 for both parameters, indicating a slightly greater than dose-proportional increase in systemic exposure based on AUC0-∞ and a greater than dose-proportional increase in systemic exposure based on AUC0-t over the dose range of 0.2-16.2 mg.

[0169] [Table 2]

[0170] Adverse events: Overall, 24 subjects (42.1%) experienced 44 treatment-emergent adverse events (TEAEs). The incidence of TEAEs was relatively low across the 0.01 mg to 10 mg dose range. In the 16.2 mg dose group, all four subjects reported at least one TEAE. Most events were mild in severity, and no subjects discontinued due to a TEAE. Of the 40 subjects who received IP2015, 16 subjects experienced a total of 32 TEAEs during the study. Treatment-emergent AEs were reported in all dose groups except the 0.05 mg and 0.6 mg dose groups. Eight subjects in the placebo group experienced a total of 12 TEAEs.

[0171] There were no significant treatment- or dose-related trends in mean or individual subject hematology, serum biochemistry, or urinalysis data during the study, and no clinically significant findings were noted in the physical examinations performed. There were no significant treatment- or dose-related trends in mean or individual subject vital sign values ​​across the dose range of 0.01 mg to 10 mg. At the 16.2 mg dose level, increases from baseline in orthostatic pulse rate were observed at 2, 3, 4, 6, 8, 10, and 12 hours post-dose, respectively, while increases from baseline in supine pulse rate were observed at 6, 8, and 10 hours post-dose, respectively. These increases from baseline were the result of two subjects who exhibited sustained tachycardia for several hours.

[0172] There were no significant treatment- or dose-related trends in mean ECG parameters across the 0.01 mg to 10 mg dose range. At the 16.2 mg dose level, increases in heart rate from baseline were observed at 8 and 12 hours post-dose, respectively.

[0173] conclusion Plasma concentrations of IP2015 were below the LLOQ in all subjects receiving 0.01 mg and 0.05 mg IP2015 and in 3 / 7 subjects receiving 0.2 mg IP2015. After single oral doses of 0.2, 0.6, 1.8, 5.4, 10, and 16.2 mg, IP2015 was absorbed relatively rapidly, with median tmax values ​​ranging from 2.25 to 5.00 hours. Mean T1 / 2 values ​​ranged from 23.11 to 26.30 hours across the dose range of 5.4 mg to 16.2 mg. The elimination phase could not be fully defined across the dose range of 0.2 to 1.8 mg. Systemic exposure to IP2015 in plasma based on AUC0-∞ and Cmax values ​​increased slightly more than dose-proportionally across the single dose range of 0.2 to 16.2 mg and appeared to increase more than dose-proportionally based on AUC0-t. The incidence of TEAEs was relatively low across the 0.01 mg to 10 mg dose range. The incidence of adverse events increased at 16.2 mg compared with the 0.01 mg to 10 mg dose range. Most events were mild in severity, and no subjects discontinued due to TEAEs.

[0174] Example 3. Effect of a single oral dose of IP2015 on erectile dysfunction in men with erectile dysfunction This study investigated the effects of IP2015 on penile hardness and tumescence during visual stimulation in men with erectile dysfunction (ED), as well as the safety and tolerability of a single dose of IP2015 in men with ED.

[0175] Materials and Methods Test Design This study was an exploratory, phase II, randomized, placebo-controlled, double-blind, crossover study investigating the effect of a single oral dose of IP2015 on erectile function in men with ED. The 10 mg dose level was selected. Patients were enrolled in two cohorts. Both cohorts participated in two periods (Period 1 and Period 2) and received a single dose of IP2015 and a single dose of placebo. The study design is shown in Figure 2.

[0176] Twelve patients were enrolled in two cohorts (six patients per cohort). Both cohorts participated in two periods (Period 1 and Period 2) and received a single dose of IP2015 and a single dose of placebo. In both cohorts, patients were required to attend the CRU for a screening visit within 28 days prior to their first dose. Patients attended the CRU on the morning of Day 1 of Period 1 and underwent pre-dose safety, PK, and efficacy assessments. For efficacy assessments, patients were required to self-apply the RigiScan Plus monitor to their penis, which remained in place for approximately 20 minutes during each provocative assessment.

[0177] All patients received either placebo or IP2015 in a fasting state on Day 1. Patients remained in the CRU overnight until Day 2 (minimum 24 hours after dosing) to complete efficacy, safety, and PK assessments and were discharged from the CRU at the investigator's discretion. After a minimum 5-day washout period, patients returned to the CRU on Day 1 of Period 2 to receive the alternative treatment (either IP2015 or placebo). Patients returned for a follow-up visit 5–7 days after Period 2. Each patient's participation period was approximately 6 weeks.

[0178] participants Patients were heterosexual men of any ethnicity, aged 18–59 years (inclusive), and had a BMI of 18–32 kg / m 2 (inclusive) and weighed 50 kg or more. Patients had an IIEF-5 questionnaire score of less than 12 at screening. Other than the ED, patients were determined by their treating physician to have no other health problems based on medical history, physical examination, concomitant medications, vital signs, 12-lead ECG, and clinical laboratory evaluation. All participants provided written informed consent, including compliance with the requirements and restrictions described in the consent form.

[0179] Randomization and blinding Randomization numbers were assigned to subjects / patients in the order of recruitment. All screened subjects were identifiable throughout the study. The study was conducted in a double-blind manner (investigator and subject / patient blinded). The randomization list was kept in a secure place until the end of the study.

[0180] The planned amount of either IP2015 or placebo was poured into blinded medication containers and provided to medication staff at the CRU.

[0181] Study drug, dose, and mode of administration IP2015 and matching placebo were provided as powders in bottles for oral solution. A 5% hydroxypropyl beta-cyclodextrin solution was reconstituted to form the placebo, which was used to dissolve IP2015. Reconstitution was performed by a pharmacist at the clinical site prior to dosing. IP2015 was stored at a controlled room temperature of 15-25°C until dispensed to subjects / participants.

[0182] A 10 mg dose of IP2015 or matching placebo was administered once in the morning on Day 1 (Period 1 and Period 2) as an oral solution in the fasted state. The dose was taken with 240 mL of water at room temperature. Subjects / participants fasted overnight from pre-dose until 4 hours post-dose. Water was available ad libitum except for 1 hour pre-dose and 1 hour post-dose.

[0183] evaluation This study evaluated efficacy data from RigiScan assessment in male patients with ED, and clinical safety data from AE reports, 12-lead ECG, vital signs, physical examination, and clinical laboratory assessment in male patients with ED.

[0184] Patients were assessed for efficacy on Day 1 of each dosing period using the RigiScan Plus monitor pre-dose and during provocation 1, 4, and 8 hours post-dose.

[0185] The study also evaluated plasma PK concentrations and parameters, including but not limited to AUC0-t, AUC0-∞, Cmax, tmax, and T1 / 2, in male patients with ED. Blood samples for measuring IP2015 plasma concentrations were collected pre-dose and 1, 4, 8 (post-challenge), and 24 hours post-dose for each treatment period. An exploratory endpoint was the potential relationship between plasma PK levels measured by RigiScan data and PD response.

[0186] Plasma samples for determination of IP2015 concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry method. A RigiScan Plus monitor was used for efficacy during challenge.

[0187] The design of the elicitation is outlined in Figure 3. Pre-dose and 1, 4, and 8 hours after dosing, patients were asked to watch a 20-minute video in a private room. The video consisted of a 10-minute neutral video followed by a 10-minute video of heterosexual pornography. Study staff started the video and then left the room, during which there was a 1-minute delay before the neutral video began. The neutral and AV videos were different for each assessment. RigiScan ratings were recorded throughout the assessment period. The RigiScan Plus monitor was worn for approximately 20 minutes during each run. Patients were in a semi-prone position during the assessment.

[0188] The RigiScan measurement parameters were treated as efficacy evaluation indexes and calculated in the same manner as in Example 2.

[0189] statistical methods Safety parameters were listed and summarized using descriptive statistics. Pharmacokinetic parameter estimates were calculated using non-compartmental methods. Pharmacokinetic data were listed for each subject / patient and summarized by descriptive statistics.

[0190] The effect of IP2015 on PD parameters was analyzed using a generalized mixed regression model with PD parameters as the response variable, treatment (active and placebo), time point, period (1 and 2), sequence (active-placebo, placebo-active), and the interaction between treatment and time point as mixed effects, baseline measurements as covariates, and subject as a random effect. This model was applied to each PD parameter. Treatment differences between active and placebo at different time points, along with 95% CIs, were derived from the generalized mixed regression model. For continuous outcomes, treatment differences were measured as LS mean differences. For dichotomous outcomes, treatment differences were measured as odds ratios. If the model did not converge due to small sample sizes at some time points, these time points may be pooled with adjacent time points.

[0191] The relationship between plasma PK levels measured by RigiScan data and PD response was investigated using a generalized nonlinear mixed model.

[0192] result Single-dose pharmacokinetics of IP2015 Plasma concentrations of IP2015 at the 10 mg dose level are shown in Figure 6 (linear scale) and Figure 7 (semi-logarithmic scale).

[0193] A limited PK profile was obtained, or plasma concentrations, of 10 mg of IP2015 (samples were taken pre-dose and 1, 4, 8, and 24 hours post-dose). The mean Cmax was 15.67 ng / mL, and the mean AUC0-t and AUC0-24 were 287.11 ng.h / mL. The median tmax occurred at 4.00 hours post-dose, ranging from 1.00 to 8.53 hours post-dose.

[0194] Efficacy evaluation For several RigiScan-assessed parameters, most notably, encouraging results were observed 4 hours post-dose in favor of 10 mg IP2015 treatment compared to placebo for total event duration, mean event firmness, time at 80%-100% firmness, mean swelling events, RAU, and TAU. Results for time at 80%-100% firmness at the tip, RAU at the tip, and TAU at the base were statistically significant compared to placebo (Table 3).

[0195] [Table 3] JPEG2026502459000017.jpg145159

[0196] One hour after administration, baseline apical circumference was significantly greater compared with placebo (LS mean difference 0.53 [95% CI: 0.02, 1.05]).

[0197] Based on individual RAU and TAU values, three patients appeared to be responding to treatment at 4 hours post-dose (patients 176, 177, and 191). At 4 hours post-dose, the RAU values ​​for patients 176, 177, and 191 at the proximal site were 21, 14, and 4, respectively, and at the distal site were 19, 13, and 5, respectively. At 4 hours post-dose, the TAU values ​​for patients 176, 177, and 191 at the proximal site were 14, 11, and 7, respectively, and at the distal site were 8, 9, and 7, respectively.

[0198] Adverse events: Overall, 9 (75.0%) patients experienced 19 TEAEs. No deaths or SAEs were reported, and no subjects discontinued due to TEAEs. All events were mild in severity.

[0199] There were no significant treatment- or dose-related trends in mean or individual subject hematology, serum biochemistry, or urinalysis data during the study, and no clinically significant findings were noted in the physical examinations performed. There were no significant treatment-related differences between IP2015 and placebo treatment for systolic blood pressure, diastolic blood pressure, and oral temperature. There was a clear treatment-related increase in pulse rate in both the upright and supine positions. There were no significant treatment-related differences between IP2015 and placebo treatment for PR.

[0200] PR interval, QRS interval, QT interval, and QTcF interval. For heart rate, an increase of 14.56 bpm from baseline was observed 8 hours after administration, compared with a change from baseline of 4.78 bpm at the corresponding time point during placebo administration.

[0201] conclusion PK profiles were obtained for plasma concentrations of 10 mg IP2015. The mean Cmax was 15.67 ng / mL, with a median tmax occurring at 4.00 hours post-dose. Promising results supporting 10 mg IP2015 treatment compared with placebo were observed 4 hours post-dose. Results for time to 80%-100% hardness at the tip, RAU at the tip, and TAU at the base were statistically significant compared with placebo.

[0202] Example 4. Effect of repeated single oral doses of IP2015 on the ability to form and maintain an erection in male subjects with erectile dysfunction (ED). This study investigated the effect of single and repeated oral doses of IP2015 on the ability to achieve and maintain an erection in male subjects with erectile dysfunction (ED), as well as the safety and tolerability of single oral doses of IP2015, its effect on penile hardness and tumescence during visual stimulation, its effect on semen count and motility, and any possible relationship between plasma levels of IP2015 and its efficacy and safety.

[0203] Materials and Methods Test Design The 130 subjects were divided into three parallel groups. Each subject received four doses of either 5 mg of IP2015, 10 mg of IP2015, or a matching placebo. Within each group, subjects were equally randomized to one of the three study treatments and received the same treatment at each visit.

[0204] The test lasted approximately eight weeks and consisted of: Screening visit (up to 21 days prior to the baseline visit) Baseline visit (day -7) Outpatient visits in weeks 1 (day 1), 2, 3, and 4 Follow-up visit at least 7-10 days after the last dose.

[0205] All groups were required to complete the IIEF-15 questionnaire on Day -7, and at Weeks 1 (Day 1), 2, 3, 4, and at the follow-up visit. Group 2 was required to complete a visual stimulation assessment using the RigiScan Plus monitor on Day -7, Week 1 (Day 1), and 4. Group 2 also had to provide blood samples for pharmacokinetic assessment on Weeks 1 (Day 1) and 4. Group 3 was required to provide semen samples on Day -7 and Week 4.

[0206] participants Patients were required to have an IIEF-5 score ≤16 and a body mass index of 18–35 kg / m 2 The subjects were otherwise healthy males of any ethnicity with erectile dysfunction (ED) as determined by ED (inclusive). Subjects were aged 18 to 59 years (inclusive).

[0207] [Table 4]

[0208] Dosage and Mode of Administration There were three study treatment possibilities: 5 mg IP2015, 10 mg IP2015, or matching placebo. Within each group, subjects were equally randomized to each of the three study treatments and received the same treatment at each visit. IP2015 or matching placebo was administered as an oral solution in the fasted state once in the morning during weeks 1 (day 1), 2, 3, and 4. Doses were taken with 240 mL of water at room temperature. Subjects fasted from 2 hours before dosing until 4 hours after dosing. Water was available ad libitum except for 1 hour before and 1 hour after dosing.

[0209] evaluation Efficacy was assessed using the International Institute for Erectile Function (IIEF)-15 questionnaire. Changes from baseline in responses to questions on the IIEF-15 questionnaire, including questions about erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction domain scores, were measured at various time points during the study. RigiScan assessment during stimulation assessment and semen sample collection for sperm count and motility were used to assess efficacy. Safety was assessed through AE reporting, 12-lead ECG, vital signs, physical examination, and clinical laboratory evaluations. Pharmacokinetics was assessed by blood sampling.

[0210] result Validity of IP2015 The results for IIEF-15 Q3: "When you attempted sexual intercourse, how often during the past week were you able to penetrate (insert) your partner?" are shown in Figure 11. The results for Q3 were significant for treatment with 5 mg IP2015 at week 3 versus placebo (p=0.034) and baseline (p=0.046). There was also a trend for a difference in the Q3 overall score versus placebo (p=0.07) and baseline (p=0.07).

[0211] The results for IIEF-15 Q4: "During attempted sexual intercourse, how often were you able to maintain an erection after penetrating (entering) your partner?" are shown in Figure 12. The results for Q4 show a trend toward a difference versus baseline for the 5 mg overall score (p=0.056), but no difference compared to placebo (p=0.44).

[0212] The overall response to the IIEF-15 questions is shown in Figure 13. Results were significant for IP2015 5 mg vs. baseline at follow-up (p=0.0046) with a trend vs. placebo (p=0.07), as well as for the 5 mg global score vs. baseline (p=0.0032) and trend vs. placebo (p=0.10).

[0213] In Figures 11, 12, and 13, results show change from baseline for patients treated with placebo at 4 doses (n=45), 5 mg (n=42), and 10 mg (n=43) of IP2015 administered concurrently on days 1, 8, 15, and 22. Results are mean ± SE. Statistical differences were performed using mixed model repeated measures (MMRM).

[0214] Adverse events Treatment-emergent adverse events with low-dose (5 mg) IP2015 were comparable to those in the placebo group. TEAEs were dose-dependent, mild to moderate, and slightly increased with the high dose compared with the low dose of IP2015. No serious adverse events were observed with any dose of IP2015 (Table 4).

[0215] Semen analysis results were complete, and treatment had no adverse effect on sperm count, motility, or morphology.

[0216] [Table 5]

[0217] conclusion There was a significant effect of the 5 mg dose of IP2015 (Pudafensine) on IIEF-15 score Q3 compared to baseline and placebo.

[0218] Regarding the overall IIEF-15 score, there was a trend towards a clinically significant score change of 2, which was significant for the low dose of IP2015 versus baseline, p=0.10 versus placebo.

[0219] Treatment did not adversely affect sperm count, motility, or morphology. Plasma concentrations were linearly related to IP2015 dose.

[0220] Treatment-emergent adverse events (TEAEs) for the 5 mg dose of IP2015 were similar to those in the placebo group. TEAEs were dose-dependent, with only mild and moderate effects observed. There were no serious TEAEs.

[0221] Overall, these results indicate that the 5 mg dose of IP2015 is effective and safely tolerated in the treatment of erectile dysfunction.

[0222] References WO 97 / 30997 GOTOP Medical. RigiScan PLUS Rigidity Assessment System [internet] 2014. Available at: http: / / www.gotopmedical.com / rigiscan®-plus.html

Claims

1. A compound of formula (I) for use in the treatment, prevention, reduction or alleviation of erectile dysfunction in a subject. 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein said compound is administered in an amount of about 0.1 mg to about 10 mg per individual dose.

2. The compound has the structure of formula (Ia): 【Chemistry 2】 3. The compound for use according to any one of claims 1 and 2, wherein:

3. 10. The compound for use according to any one of the preceding claims, wherein said compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxy-chromen-2-one or a pharmaceutically acceptable salt thereof.

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

5. 10. The compound for use according to any one of the preceding claims, wherein the compound of formula I is administered in an amount of about 0.5 mg to about 10 mg per individual dose.

6. 10. The compound for use according to any one of the preceding claims, wherein the compound of formula I is administered in an amount per individual dose of about 0.1 mg to 20 mg, for example 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 per individual dose.

7. 10. The compound for use according to any one of the preceding claims, wherein the compound of formula I is administered to the subject at about 5 mg per individual dose.

8. 10. The compound for use according to any one of the preceding claims, wherein the compound of formula I is administered to the subject at 5 mg per individual dose.

9. 10. The compound for use according to any one of the preceding claims, wherein the compound is administered once daily.

10. 10. The compound for use according to any one of the preceding claims, wherein the compound is administered multiple times daily, such as twice daily, for example three times daily, for example four times daily.

11. 10. The compound for use according to any one of the preceding claims, wherein the compound is administered once a week or twice a week.

12. 10. The compound for use according to any one of the preceding claims, wherein the total daily dose of said compound is about 1 to 10 mg.

13. 10. The compound for use according to any one of the preceding claims, wherein the compound is administered orally in an amount per individual dose of about 0.035 mg / kg to 0.135 mg / kg, such as 0.040 mg / kg to 0.110 mg / kg, for example 0.042 mg / kg to 0.100 mg / kg, for example 0.0450 mg / kg to 0.100 mg / kg, such as 0.045 mg / kg to 0.091 mg / kg, for example 0.050 mg / kg to 0.091 mg / kg.

14. 10. The compound for use according to any one of the preceding claims, wherein the compound is administered orally in an amount per individual dose of about 0.075 mg / kg to 0.250 mg / kg, such as 0.080 mg / kg to 0.222 mg / kg, for example 0.083 mg / kg to 0.200 mg / kg, for example 0.091 mg / kg to 0.185 mg / kg, such as 0.100 mg / kg to 0.185 mg / kg, for example 0.050 mg / kg to 0.185 mg / kg.

15. 10. The compound for use according to any one of the preceding claims, wherein said compound is administered to said subject at 5 mg per individual dose, and said subject weighed from about 60 kg to about 115 kg.

16. The erectile dysfunction is (i) associated with or resulting from a pathological condition such as an injury, the effects of surgery or radiation therapy, and / or (ii) associated with or resulting from psychological or behavioral factors, including mental disorders; and / or (iii) A compound for use according to any one of the preceding claims, which is associated with or results from drug use or psychotropic substance use.

17. 10. A compound for use according to any one of the preceding claims, wherein said erectile dysfunction is organic erectile dysfunction.

18. 10. The compound for use according to any one of the preceding claims, wherein said erectile dysfunction is congenital erectile dysfunction or acquired erectile dysfunction.

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

20. The erectile dysfunction is characterized in that, in the subject: (i) diabetes; (ii) metabolic syndrome (iii) vascular diseases, such as cardiovascular diseases, and (iv) diseases of the nervous system 10. A compound for use according to any one of the preceding claims, wherein the compound is coexisting with one or more condition(s) selected from the group consisting of:

21. 21. The compound for use according to any one of claims 1 to 20, wherein said erectile dysfunction is associated with or caused by metabolic syndrome.

22. The compound for use according to any one of claims 1 to 20, wherein said erectile dysfunction is associated with or caused by diabetes.

23. The compound for use according to any one of claims 1 to 20, wherein said erectile dysfunction is associated with or caused by a vascular disease, such as a cardiovascular disease.

24. The compound for use according to any one of claims 1 to 20, wherein said erectile dysfunction is associated with or caused by a disease of the nervous system.

25. 21. The compound for use according to any one of claims 1 to 20, wherein said erectile dysfunction is treatment-induced erectile dysfunction associated with or resulting from the use of said drug.

26. 26. The compound for use according to claim 25, or a pharmaceutically acceptable salt thereof, wherein said treatment-induced erectile dysfunction is a side effect resulting from drug treatment.

27. 27. The compound for use according to any one of claims 25 or 26, wherein the drug is selected from the group consisting of antidepressants, NSAIDs, finasteride, antiepileptics, and neuroleptics.

28. The compound for use according to any one of claims 25 to 26, wherein the erectile dysfunction is treatment-induced erectile dysfunction caused by treatment with an antidepressant.

29. 10. The compound for use according to any one of the preceding claims, wherein the subject is administered a further therapeutic agent effective in the treatment of erectile dysfunction.

30. 30. The compound for use according to claim 29, wherein the subject is administered with an additional therapeutic agent effective in treating erectile dysfunction selected from the group consisting of a phosphodiesterase 5 (PDE5) inhibitor such as sildenafil, tadalafil, vardenafil or avanafil, alprostadil, testosterone.

31. 30. The compound for use according to claim 29, wherein said treatment is combined with cell therapy.

32. 30. The compound for use according to claim 29, wherein said treatment is combined with extracorporeal shock therapy.

33. 10. The compound for use according to any one of the preceding claims, wherein the subject is undergoing another treatment for erectile dysfunction.

34. 34. The compound for use according to claim 33, wherein the subject is undergoing treatment with one or more phosphodiesterase 5 (PDE5) inhibitor(s), such as sildenafil, tadalafil, vardenafil, or avanafil.

35. 10. The compound for use according to any one of the preceding claims, wherein the subject does not respond to treatment of erectile dysfunction with one or more PDE5 inhibitors.

36. 10. A compound for use according to any one of the preceding claims, wherein the compound is capable of producing a central effect that initiates an erection and / or a peripheral effect that enhances an erection.

37. 10. A compound for use according to any one of the preceding claims, wherein the compound is capable of initiating and / or enhancing an erection by relaxation of smooth muscles.

38. 10. A compound for use according to any one of the preceding claims, wherein the compound is capable of initiating an erection by increasing central dopamine and / or producing a peripheral effect that enhances erection by the release of nitric oxide.

39. 10. A compound for use according to any one of the preceding claims, wherein said compound is capable of increasing the number of erectile episodes, the duration of erectile episodes, penile tumescence and / or penile hardness.

40. 10. A compound for use according to any one of the preceding claims, wherein said compound is capable of increasing the number of erectile events, the duration of erectile events, penile tumescence and / or penile hardness in said subject during sexual stimulation.

41. 10. The compound of any one of the preceding claims, wherein the subject is a mammal.

42. 10. The compound of any one of the preceding claims, wherein the mammal is a human.

43. 10. The compound of any one of the preceding claims, wherein the human is a male.

44. 10. The compound for use according to any one of the preceding claims, wherein the subject is male.

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

46. 10. The compound for use according to any one of the preceding claims, wherein the subject is a male over 20 years of age.

47. 10. The compound for use according to any one of the preceding claims, wherein the subject has a body weight of from about 55 kg to about 130 kg, such as from 60 kg to about 115 kg.

48. The subject has a body weight of about 19.5 kg / m ２ ~Approx. 35.5kg / m ２ 10. The compound for use according to any one of the preceding claims, having a body mass index (BMI) of

49. 10. The compound for use according to any one of the preceding claims, wherein prior to treatment the subject had an International Erectile Function Score 5 (IIEF-5) of less than 17, for example between 12 and 16, such as between 8 and 11, for example between 5 and 7.

50. 10. The compound for use according to any one of the preceding claims, wherein the subject prior to treatment had an International Erectile Function Score 5 (IIEF-5) of less than 12.

51. 10. The compound for use according to any one of the preceding claims, wherein said compound is capable of increasing the International Erectile Dysfunction Score in said subject.

52. 10. The compound for use according to any one of the preceding claims, wherein said administration of said compound is oral administration.

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

54. 10. The compound for use according to any one of the preceding claims, wherein the compound is formulated into a pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier and / or excipient.

55. 10. The compound for use according to any one of the preceding claims, wherein the compound is formulated as a solid dosage form such as a tablet, capsule, pill, granule, or powder.

56. A compound of formula I, 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein said compound is present in an amount of from about 0.5 mg to about 10 mg.

57. A compound of formula (I), 【Chemistry 4】 and one or more PDE5 inhibitor(s).

58. 58. The composition of claim 57, wherein the one or more PDE5 inhibitor(s) is selected from the group consisting of sildenafil, tadalafil, vardenafil, and avanafil.

59. 59. The composition of any one of claims 57 to 58, wherein the compound of formula (I) is present in an amount of from about 0.5 mg to about 10 mg.

60. 1. Use of a compound of formula (I) for the manufacture of a medicament for treating, preventing, alleviating or alleviating erectile dysfunction in a subject in need thereof, comprising: 【Transformation 5】 The above uses, wherein the compound is administered at a dose of about 0.001 to about 1 mg / kg mg.

61. 1. A method for treating, preventing, alleviating or ameliorating erectile dysfunction in a subject in need thereof, comprising administering to said subject in need thereof a compound of formula I in an amount of from about 0.001 to about 1 mg / kg; 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

62. 1. A method of increasing the frequency of erectile responses in a subject, comprising administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

63. 1. A method of increasing the duration of erectile response in a subject, comprising administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

64. 1. A method of increasing the magnitude of the erectile response in a subject, comprising administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg / kg to about 1 mg / kg.

65. 1. A method of achieving a mean plasma concentration of the compound of formula (I) of about 1 ng / mL to 50 ng / mL in a subject, comprising administering to the subject the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.001 mg / kg to about 1 mg / kg.

66. 66. The method of claim 65, wherein the subject is administered the compound of formula (I) in an amount of about 0.5 mg to about 10 mg.

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