WO2025098307A1 - Use of 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-aryl propylamine compound in preparation of drug for treating sexual dysfunction - Google Patents

Abstract

Use of a [(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-aryl propylamine compound in the preparation of a drug for relieving and/or treating sexual dysfunction, especially sexual dysfunction that occurs before, concurrently with, or after a patient undergoes the treatment with antidepressant medications.

Description

Use of 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-arylpropylamine compounds in the preparation of drugs for treating sexual dysfunction

This application claims priority to Chinese patent application 202311468008.6, filed on November 7, 2023, the entire contents of which are hereby incorporated by reference.

Technical Field

The present invention belongs to the field of medicine and relates to the use of a 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-arylpropylamine compound in the preparation of a drug for treating sexual dysfunction, in particular for treating sexual dysfunction occurring before, simultaneously with or after a patient receives antidepressant treatment.

Background Art

Male physiological reproductive activities, including the maintenance of sexual function and male fertility, are all controlled and regulated by neuroendocrine glands. Any abnormality in any link of the entire male physiological reproductive activities can affect the maintenance of male sexual function and male fertility.

Normal male sexual function includes sexual desire, sexual excitement, penile erection, sexual intercourse ejaculation, sexual orgasm and other processes. Any change in any of these links that affects normal sexual life is collectively referred to as male sexual dysfunction. Male sexual dysfunction is a relatively common disease. The 2018 version of the European Guidelines for Male Sexual Dysfunction (EAU Guidelines. Edn. presented at the EAU Annual Congress Copenhagen 2018. ISBN 978-90-79754-91-5) mainly includes four aspects of male sexual dysfunction: erectile dysfunction (ED), premature ejaculation (PE), penile curvature (Penile curvature) and priapism. In addition, it is generally believed that male sexual dysfunction also includes low libido, retrograde ejaculation or sexual pain. The most common male sexual dysfunction is erectile dysfunction and premature ejaculation.

Erectile dysfunction, commonly known as impotence, refers to the inability of the penis to erect continuously or the erection hardness and duration are insufficient to complete satisfactory sexual life, and the course of the disease exceeds 3 months. ED can be divided into primary ED and secondary ED, and can be divided into functional (psychiatric or psychological) and organic (including vascular disorders, neurological disorders and endocrine disorders) according to the cause. The incidence of ED increases with age, about 7% under 55 years old and 18.6%-75% over 60 years old. Penile erection is regulated by the sexual center from the hypothalamus and the peripheral regulation of the sexual organs. For the drug treatment of ED, the drugs used include selective type 5 phosphodiesterase inhibitors, such as sildenafil, α receptor antagonists, such as phentolamine, etc.

The essence of premature ejaculation is that men continuously or frequently lack the ability to reasonably and voluntarily control ejaculation and orgasm during sexual activities. Ejaculation occurs before desire. The incidence rate accounts for about 20-30% of men aged 18 to 65. The cause is unknown. It is generally divided into primary premature ejaculation and secondary premature ejaculation. It is currently believed that the cause of premature ejaculation is mainly mental and psychological, and organic causes are relatively rare. The treatment of premature ejaculation includes antidepressants, sedatives and phenothiazines, which may prolong the duration of sexual intercourse, but the duration of action is relatively short.

It is generally believed that ejaculation is a reflex activity composed of receptors, motor central nerves and spinal nerves under the control of the neural network composed of the central nervous system and spinal nerves. At present, it has been reported that some antipsychotic drugs have the side effect of inhibiting ejaculation. Therefore, there have been relevant clinical studies involving the use of tricyclic antidepressants or SSRI (selective serotonin reuptake inhibitors) to treat premature ejaculation. However, because they are antipsychotic drugs, they have adverse reactions such as nausea, sweating, drowsiness and decreased libido, which limits their clinical use. Currently, the only SSRI on the market for the treatment of male premature ejaculation is Johnson &Johnson's Dapoxetine, which was originally studied for the treatment of depression. However, unlike other SSRIs, the pharmacokinetics of dapoxetine show that it has rapid oral absorption, short half-life and rapid excretion, making it a drug suitable for timely treatment of premature ejaculation. Its structure is shown below: However, dapoxetine is also accompanied by adverse reactions that cannot be ignored, such as headache (13.6%), dizziness (13.4%), diarrhea (11.3%), etc., which also constitute an obstacle to its popularization in clinical use.

Female sexual dysfunction (FSD) is a complex and multidimensional health problem that profoundly affects women's normal functions in key aspects such as sexual desire, sexual arousal, orgasm experience and sexual pleasure. These dysfunctions may occur alone or in combination, and have a significant impact on women's overall quality of life.

According to the 2015 guidelines of the International Society for the Study of Sexuality and Health (ISSWSH), female sexual dysfunction mainly includes four categories: hypoactive sexual desire disorder (HSDD), sexual arousal dysfunction, orgasmic dysfunction, and sexual pain disorder. Among them, hypoactive sexual desire disorder is particularly common, characterized by obstacles in the generation, maintenance and expression of sexual desire in women, which directly weakens the satisfaction of sexual life.

Female hypoactive sexual desire disorder can be specifically divided into three types: low sexual desire, sexual aversion and hypersexuality. Low sexual desire is the most common manifestation, which is manifested as a decrease in women's interest and desire for sexual activities, making it difficult for them to meet their own or their partners' sexual needs. Flibanserin is an FDA-approved drug for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Its structure is as follows:

Sexual dysfunction is also common in individuals with depression, who report decreased sexual interest and reduced levels of arousal, or as an adverse reaction to antidepressant medication. The incidence of sexual dysfunction varies among antidepressants, but in general, SSRIs (selective serotonin reuptake inhibitors) and SNRIs (norepinephrine and serotonin reuptake inhibitors) are associated with a higher incidence of sexual dysfunction, which can reach 60%-70%.

In view of the limitations and inadequacies of existing treatments, there is an urgent need in the current clinical field to develop a new drug to treat sexual dysfunction, including male and female sexual dysfunction, especially those that occur before, during or after antidepressant treatment.

Summary of the invention

International patent application WO2016101898A discloses a class of 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-arylpropylamine compounds, which are reported to have antidepressant activity. The present invention unexpectedly discovered for the first time that this series of compounds can also be used to treat and/or alleviate sexual dysfunction, including male and female sexual dysfunction, especially those sexual dysfunction that occurs before, during or after treatment with antidepressant drugs.

The technical problem to be solved by the present invention is to provide a compound represented by the following general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso-body, racemate or a mixture thereof for use in preparing a drug for alleviating and/or treating sexual dysfunction.

in:

_R1 and _R2 are each independently selected from hydrogen and _C1-5 alkyl;

R ₃ and R ₄ are each independently selected from hydrogen, halogen, optionally substituted C _1-5 alkyl, and optionally substituted C _1-3 alkoxy; the optional substituents are selected from halogen, C _1-5 alkyl, C _1-3 alkoxy, and -OH.

The present invention further provides the use of a drug comprising a compound represented by the above general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof and a second therapeutic agent in the preparation of a drug for alleviating and/or treating sexual dysfunction.

The present invention further provides a method for treating sexual dysfunction by administering an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof to a patient in need of treatment as a short-term or long-term treatment.

DETAILED DESCRIPTION

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms such as "comprising" encompass the meaning of "consisting of".

The terms "selected from...", "preferably..." and "more preferably..." mean that one or more elements in the group listed later are independently selected and may include a combination of two or more elements. In the present invention, one element in the group listed later is preferred.

The terms "optional", "optionally" or "optionally present" mean that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally including a second therapeutic agent" means that the second therapeutic agent may or may not be present.

The term "sexual dysfunction" includes male sexual dysfunction and female sexual dysfunction. In the present invention, the patient exhibits sexual dysfunction, regardless of whether he is in a depressed state or whether he receives antidepressant, especially antidepressant drug treatment, including both independent sexual dysfunction, especially male sexual dysfunction, and sexual dysfunction caused by being in a depressed state or diagnosed with depression, as well as sexual dysfunction occurring simultaneously or after receiving antidepressant drug treatment.

The term "male sexual dysfunction" also refers to male sexual dysfunction and male sexual disorder, which in the present invention includes disorders occurring in the stages of sexual arousal, penile erection, penile insertion into the vagina, sexual orgasm, ejaculation and sexual satisfaction, including but not limited to sexual desire loss dysfunction, sexual arousal dysfunction, erectile dysfunction, premature ejaculation, orgasm disorder, sexual pain disorder, post-orgasmic disorder, pelvic floor dysfunction and other rare male sexual dysfunctions.

The term "erectile dysfunction", also referred to as impotence, is a condition in which the penis is persistently unable to achieve or maintain an erection sufficient for sexual intercourse.

The term "premature ejaculation" refers to a disease in which the penis can erect but ejaculates too early and too quickly, causing the penis to become flaccid and unable to continue sexual intercourse.

The term "low or no sexual desire" refers to a disease in which the level of sexual behavior expression and sexual activity ability of men or women are reduced, and the sexual desire is suppressed to varying degrees.

The term "abnormal penile erection" refers to a disease in which the penis persists in the absence of stimulation and cannot return to normal after the stimulation is removed.

The term "ejaculation disorder" refers to the inability of a male to complete the normal ejaculation process during orgasm, or an abnormality in the ejaculation process, which in the present invention includes but is not limited to complete inability to ejaculate, delayed ejaculation, retrograde ejaculation, etc.

The term "female sexual dysfunction" refers to the abnormality or deficiency of one or more stages in the sexual response cycle of women, such as sexual desire, sexual excitement, orgasm, thereby affecting their sexual satisfaction. In the present invention, it includes but is not limited to decreased sexual desire, sexual arousal dysfunction, dyspareunia, and orgasm disorder.

The term "sensory disorder" refers to a condition in which men or women experience abnormal or absent sensations during sexual stimulation, which affects the quality and satisfaction of their sexual life.

The term "sexual arousal disorder" refers to a condition in which men or women have difficulty achieving or maintaining adequate levels of sexual excitement in response to sexual stimulation, thereby affecting the performance and satisfaction of their sexual activity.

For drugs, drug units or active ingredients, the "effective amount" of the present invention includes an amount sufficient to improve or prevent the symptoms or symptoms of the condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

As used herein, the term "treatment" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the development of a disease or symptom, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.

As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The present invention provides the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso-body, racemate or a mixture thereof in the preparation of a drug for alleviating and/or treating sexual dysfunction.

in:

_R1 and _R2 are each independently selected from hydrogen and _C1-5 alkyl;

_R3 and _R4 are each independently selected from hydrogen, halogen, optionally substituted _C1-5 alkyl and optionally substituted _C1-3 alkoxy;

According to the present invention, the substitution means that one or more hydrogen atoms of a given atom are replaced by a substituent, and the optional substituent is selected from halogen, C _1-5 alkyl, C _1-3 alkoxy and -OH.

In a preferred embodiment of the present invention, the C _1-5 alkyl group is methyl, ethyl or isopropyl.

In a preferred embodiment of the present invention, the halogen is fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, the substituted C _1-5 alkyl group is a C _1-5 alkyl group substituted by halogen, preferably a C _1-5 alkyl group substituted by fluorine, and more preferably a trifluoromethyl group.

In a preferred embodiment of the present invention, the C _1-3 alkoxy group is a methoxy group or an ethoxy group.

In one embodiment of the present invention, _R1 and _R2 are each independently hydrogen or _C1-5 alkyl; _R3 and _R4 are each independently hydrogen, halogen, methoxy, ethoxy, propoxy, methyl, ethyl or isopropyl.

In another embodiment of the present invention, _R1 and _R2 are each independently hydrogen, methyl, ethyl or isopropyl; and _R3 and _R4 are each independently hydrogen, halogen, methoxy, ethoxy, methyl, ethyl or isopropyl.

In a more preferred embodiment of the present invention, R ₁ is selected from hydrogen and methyl, R ₂ is selected from hydrogen and methyl, and R ₃ and R ₄ are each independently selected from hydrogen, fluorine, chlorine, methoxy and methyl.

In a preferred embodiment of the present invention, the compound represented by formula (I) is formula (Ia), formula (Ib) or a mixture thereof, preferably formula (Ia),

R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

In a preferred embodiment of the present invention, the compound of general formula (I) is a compound represented by general formula (II):

in:

_R1 is selected from hydrogen and _C1-5 alkyl, _R2 is selected from hydrogen and _C1-5 alkyl, and _R4 is selected from hydrogen and halogen.

In a preferred embodiment of the present invention, the R ₁ is selected from hydrogen, methyl, ethyl and isopropyl, preferably selected from hydrogen and methyl.

In a preferred embodiment of the present invention, the R ₂ is selected from methyl, ethyl and isopropyl, preferably methyl.

In a preferred embodiment of the present invention, R ₄ is selected from hydrogen, fluorine, chlorine and bromine, preferably selected from hydrogen and fluorine, more preferably hydrogen.

In one embodiment of the present invention, R ₁ is selected from hydrogen, methyl, ethyl and isopropyl, R ₂ is selected from methyl, ethyl and isopropyl, and R ₄ is selected from hydrogen, fluorine, chlorine and bromine.

In a more preferred embodiment of the present invention, R ₁ is selected from hydrogen and methyl, R ₂ is selected from methyl, and R ₄ is selected from hydrogen and fluorine.

In a preferred embodiment of the present invention, the compound represented by the general formula (II) is formula (II-a), formula (II-b) or a mixture thereof, preferably formula (II-a),

R ₁ , R ₂ and R ₄ are as defined above.

The present invention provides use of a compound represented by general formula (II) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof in the preparation of a drug for alleviating and/or treating sexual dysfunction.

The present invention provides a method for alleviating and/or treating sexual dysfunction, which comprises administering a compound as represented by the general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof to an individual in need thereof (e.g., a mammalian individual, such as a human/patient).

In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, oxalate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate, preferably hydrochloride or oxalate.

In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is prepared by an acid-base neutralization reaction between the compound represented by formula (I) and its corresponding acid, such as dissolving the compound represented by formula (I) in a suitable organic solvent, optionally dissolving the corresponding acid in water or an organic solvent, adding the corresponding acid or acid solution to a solution of the compound represented by formula (I), and preparing the salt by an acid-base neutralization reaction, wherein the organic solvent is, for example, a saturated monohydric alcohol of C _1-3 , an ester of C _2-4 , etc.

In one embodiment of the present invention, in the pharmaceutically acceptable salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to its corresponding acid is 1:1.

In a further preferred embodiment of the present invention, the compound represented by formula (I) is selected from the following Table 1:

Table 1 Examples of compounds represented by formula (I)

In a specific embodiment of the present invention, the compound represented by general formula (I) is preferably or

In a specific embodiment of the present invention, the compound as shown in general formula (I) is preferably:

In a further preferred embodiment of the present invention, the compound 2 is preferably the following compound 2-a:

In a specific embodiment of the present invention, the compound as shown in general formula (I) is preferably:

In a further preferred embodiment of the present invention, the compound 3 is preferably the following compound 3-a:

In one embodiment of the present invention, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably a monohydrochloride.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably a monohydrochloride, preferably compound 2 monohydrochloride or compound 3 monohydrochloride, more preferably compound 2-a monohydrochloride or compound 3-a monohydrochloride, and further preferably compound 2-a monohydrochloride.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably a monooxalate, preferably a monooxalate of compound 2 or a monooxalate of compound 3, more preferably a monooxalate of compound 2-a or a monooxalate of compound 3-a, and further preferably a monooxalate of compound 3-a.

In one embodiment of the present invention, it relates to the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof in the preparation of a medicament for alleviating and/or treating sexual dysfunction, wherein the medicament optionally includes a second therapeutic agent.

In one embodiment of the present invention, the second therapeutic agent is selected from one or more of opium poppy alkaloids, phosphodiesterase type V (PDE5) inhibitors, dopamine receptor _D2 agonists, α-adrenaline receptor antagonists, prostaglandin E1 receptor agonists, 5- _HT1A receptor agonists and 5- _HT2A receptor antagonists, and more preferably one or more of phosphodiesterase type V (PDE5) inhibitors, 5- _HT1A receptor agonists and 5- _HT2A receptor antagonists.

In a preferred embodiment of the present invention, the PDE5 inhibitor is selected from sildenafil, fadanafil, tadalafil, mirodenafil, udenafil, avanafil and vardenafil; the dopamine receptor _D2 agonist is apomorphine; the α adrenaline receptor antagonist is selected from phentolamine and thymoxamine; the prostaglandin E1 receptor agonist is alprostadil; the 5- _HT1A receptor agonist or 5- _HT2A receptor antagonist is flibanserin.

In a preferred embodiment of the present invention, the sexual dysfunction is male sexual dysfunction. The male sexual dysfunction is preferably selected from the group consisting of sexual desire loss dysfunction, erectile dysfunction, ejaculation disorder and sensory disorder, further preferably selected from the group consisting of erectile dysfunction, premature ejaculation, delayed ejaculation, penis curvature deformity, abnormal penis erection, low libido, retrograde ejaculation or dyspareunia, more preferably selected from the group consisting of erectile dysfunction and/or premature ejaculation.

In a preferred embodiment of the present invention, the sexual dysfunction is female sexual dysfunction. The female sexual dysfunction is selected from one or more of sexual desire loss dysfunction, sexual arousal dysfunction, sexual intercourse pain, orgasm disorder and sensory disorder, preferably selected from one or more of low sexual desire, sexual arousal difficulty, orgasm loss and sexual discomfort, more preferably selected from low sexual desire.

In one embodiment of the present invention, the sexual dysfunction is selected from one or more of sexual desire dysfunction, erectile dysfunction, ejaculation disorder, sensory disorder, sexual arousal dysfunction, dyspareunia and orgasm disorder, preferably selected from one or more of sexual desire dysfunction, erectile dysfunction, ejaculation disorder, sensory disorder and sexual arousal dysfunction.

In one embodiment of the present invention, the erectile dysfunction is selected from erectile dysfunction (ED) and priapism, preferably erectile dysfunction.

In one embodiment of the present invention, the hyposexual dysfunction is selected from the group consisting of hyposexuality, anorexicism, sexual aversion, hypersexuality and paraphilia, preferably hyposexuality and anorexicism, such as hyposexuality.

In one embodiment of the present invention, the erectile dysfunction (ED) is selected from organic ED (e.g. vascular, neurological, surgical and traumatic, endocrine disease and/or chronic disease, drug-induced, caused by diseases of the penis itself, etc.), psychological ED and mixed ED (caused by both psychological factors and organic causes).

In one embodiment of the present invention, the ejaculation disorder is selected from premature ejaculation, anejaculation and retrograde ejaculation, preferably premature ejaculation.

In one embodiment of the present invention, the sensory disturbance is selected from the group consisting of dyspareunia, painful erection, painful ejaculation and orgasmic disorder.

In one embodiment of the present invention, the sexual arousal dysfunction is selected from the group consisting of decreased sexual desire, delayed sexual response and lack of sexual excitement.

In one embodiment of the present invention, the dyspareunia is selected from dull pain, sharp pain or burning pain in the male or female genitalia.

In one embodiment of the present invention, the orgasmic disorder is selected from the group consisting of decreased or absent sexual pleasure sensation and decreased or absent physiological and psychological responses during orgasm.

In one embodiment of the present invention, the priapism is selected from ischaemic (Low-Flow or Veno-Occlusive) priapism, non-ischaemic (high-flow or arterial) priapism, and stuttering (recurrent or intermittent) priapism. In a preferred embodiment of the present invention, the premature ejaculation is selected from primary premature ejaculation, secondary premature ejaculation, and situational premature ejaculation, wherein secondary premature ejaculation also includes secondary premature ejaculation caused by anxiety due to erectile dysfunction.

In a more preferred embodiment of the present invention, the male sexual dysfunction is selected from erectile dysfunction, priapism, low libido and/or asexuality, and premature ejaculation; preferably selected from erectile dysfunction, low libido and/or asexuality, and premature ejaculation; more preferably premature ejaculation.

In a more preferred embodiment of the present invention, the male sexual dysfunction is erectile dysfunction.

In a more preferred embodiment of the present invention, the male sexual dysfunction is priapism.

In a more preferred embodiment of the present invention, the male sexual dysfunction is low libido and/or no libido.

In a more preferred embodiment of the present invention, the male sexual dysfunction is premature ejaculation.

In a more preferred embodiment of the present invention, the female sexual dysfunction is selected from the group consisting of low libido, difficulty in sexual arousal, vaginal dryness, anorgasmia and sexual discomfort.

In a more preferred embodiment of the present invention, the female sexual dysfunction is low sexual desire and/or no sexual desire.

The present invention also provides a method for treating sexual dysfunction by administering an effective amount of a compound of formula (I) to a patient in need of treatment as a short-term or long-term treatment.

wherein R ₁ and R ₂ are each independently selected from hydrogen and C _1-5 alkyl;

R ₃ and R ₄ are each independently selected from hydrogen, halogen, optionally substituted C _1-5 alkyl and optionally substituted C _1-3 alkoxy; the optional substituents are selected from halogen, C _1-5 alkyl, C _1-3 alkoxy and -OH.

In a preferred embodiment of the present invention, a method for treating sexual dysfunction by administering an effective amount of a compound of formula (II) to a person in need of treatment as a short-term or long-term treatment,

in:

_R1 is selected from hydrogen and _C1-5 alkyl, _R2 is selected from hydrogen and _C1-5 alkyl, and _R4 is selected from hydrogen and halogen.

In a preferred embodiment of the present invention, in the above-mentioned treatment method, the compounds represented by formula (I) and formula (II) are as defined above.

In a preferred embodiment of the present invention, in the above-mentioned treatment method, the sexual dysfunction is male sexual dysfunction.

In a preferred embodiment of the present invention, in the above-mentioned treatment method, the sexual dysfunction is female sexual dysfunction.

In a preferred embodiment of the present invention, in the above-mentioned treatment method, the male sexual dysfunction is selected from the group consisting of hypoactive sexual desire disorder, erectile dysfunction, ejaculation disorder and sensory disorder.

In a more preferred embodiment of the present invention, in the above-mentioned treatment method, the male sexual dysfunction is selected from one or more of erectile dysfunction, premature ejaculation, delayed ejaculation, penile curvature deformity, abnormal penile erection, low libido, retrograde ejaculation or dyspareunia.

In a more preferred embodiment of the present invention, the above-mentioned method of treatment, wherein the male sexual dysfunction is selected from erectile dysfunction and/or premature ejaculation;

In a preferred embodiment of the present invention, in the above-mentioned treatment method, the female sexual dysfunction is selected from the group consisting of hypoactive sexual desire disorder, sexual arousal disorder, dyspareunia, orgasmic disorder and sensory disorder.

In a more preferred embodiment of the present invention, in the above-mentioned treatment method, the female sexual dysfunction is selected from low libido and/or dyspareunia.

In a preferred embodiment of the present invention, the patient targeted by the drug use or treatment method also suffers from depression before or while being administered the drug or treatment.

In a preferred embodiment of the present invention, in the pharmaceutical use or treatment method, the sexual dysfunction occurs before, simultaneously with or after the patient receives antidepressant treatment.

In a preferred embodiment of the present invention, in the pharmaceutical use or therapeutic method, the sexual dysfunction occurs before the patient receives antidepressant treatment.

In a preferred embodiment of the present invention, in the pharmaceutical use or therapeutic method, the sexual dysfunction occurs while or after the patient receives antidepressant treatment.

The present invention further provides a pharmaceutical composition in unit dosage form comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof, wherein the pharmaceutical composition is used to alleviate and/or treat male or female sexual dysfunction.

The present invention also relates to a pharmaceutical composition comprising an active ingredient which is a compound as represented by the general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof, or a pharmaceutical composition comprising an active ingredient which is a compound as represented by the general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof and a second therapeutic agent, wherein the pharmaceutical composition comprises optionally one or more pharmaceutically acceptable carriers, excipients and/or diluents.

According to the present invention, the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form, including but not limited to tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays.

The present invention further relates to a compound as represented by the general formula (I) or its pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoforms, racemates or mixtures thereof, which are used for preparing drugs for alleviating and/or treating sexual dysfunction.

In the above embodiment of the present invention, the compound represented by the general formula (I) or its pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or its mixture is selected from compound 2-a or its pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or its mixture, compound 3-a or its pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or its mixture.

The compound of formula (I) or its pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoform, racemate or a mixture thereof of the present invention can be prepared according to the preparation method described in WO2016101898A.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Statistical chart of the comparative study of the number of riding and ejaculation between compound 2-a and dapoxetine. In the figure, * indicates a significant difference compared with the solvent group.

Beneficial Effects

Compared with sildenafil and duloxetine, the compound provided by the present invention has a significantly lower dosage while maintaining the same erectile effect, and has the potential clinical advantage of reducing the occurrence of adverse reactions such as nausea, sweating, drowsiness and decreased libido; compared with sildenafil and dapoxetine, the compound of the present invention has the effect of significantly increasing the incidence of erection in rats and improving premature ejaculation at a lower dosage, and can also enhance the sexual desire of rats; compared with ansofaxine and bupropion, the compound of the present invention can effectively increase the dopamine level in the rat brain and improve the low libido of rats. In summary, the compound of the present invention has high activity, can significantly improve male animal erectile dysfunction and premature ejaculation at a lower dose, has the effect of improving libido, can reduce the incidence of adverse reactions, and has a very high clinical application prospect.

Example

In the specification and claims of the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

The following provides an exemplary test scheme for the use of a compound as shown in formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating male or female sexual dysfunction, to show the favorable activity or beneficial technical effect of the compound of the present invention. However, it should be understood that the following test scheme is merely an example of the content of the present invention, rather than a limitation of the scope of the present invention. Those skilled in the art can make appropriate modifications or changes to the technical scheme of the present invention under the guidance of this specification without departing from the spirit and scope of the present invention.

Example 1. Preparation of R-3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine (Compound 2-a) oxalate

(1) 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine (Compound 2) oxalate was prepared according to the method described in Example 4 of Patent WO2016101898A.

(2) R-3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine (Compound 2-a) oxalate

2 g of the enantiomer was separated by Flash-Prep-HPLC under the chromatographic conditions (CHIRALCEL OD-H (250 mm × 4.6 mm, 5 μm) as the chromatographic column, n-heptane-anhydrous ethanol-diethylamine-trifluoroacetic acid (93:7:0.1:0.1) as the mobile phase; the detection wavelength was 230 nm; the flow rate was 1.0 ml per minute), and 464 mg of the R-configuration enantiomer was obtained. The yield was 23.2%.

The obtained product was dissolved in an appropriate amount of ethyl acetate, and an ethyl acetate solution of oxalic acid was slowly added, the pH was controlled at 4-5, and the mixture was stirred for 30 minutes. The solid was precipitated, filtered, and dried to obtain the target compound oxalate.

¹ H-NMR (400MHz, DMSO-d ₆ )δ:7.37(m,4H),7.28(t,J＝6.7Hz,1H),6.64(t,J＝8.1Hz,1H),6.50(d,J＝7.6Hz,2H),5.96(d, J＝11.0Hz,2H),5.53(m,1H),3.01(m,2H),2.55(s,3H),2.51(s,1H),2.27(m,1H),2.14(m,1H).

Referring to the above method, the hydrochloride of compound 2-a was prepared.

¹ H-NMR (400MHz, DMSO-d ₆ )δ:7.40-7.26(m,4H),7.28(t,J＝6.7Hz,1H),6.64(t,J＝8.1Hz,1H),6.50(d,J＝7.6Hz,2H),5.96(d,J＝ 11.0Hz,2H),5.54-5.51(m,1H),3.08-2.95(m,2H),2.55(s,3H),2.32-2.28(m,1H),2.25-2.10(m,1H).

Example 2, Preparation of R-3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine (Compound 3-a) oxalate

(1) 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine (Compound 3) oxalate

The preparation was carried out according to the method described in Example 7 of patent WO2016101898A.

(2) R-3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine (Compound 3-a) oxalate

2 g of the anti-rotator was separated by Flash-Prep-HPLC under the chromatographic conditions (silica gel coated with cellulose-tris(3,5-dimethylphenylcarbamate) as filler (4.6 mm×250 mm, 5 μm or chromatographic column of equivalent performance); n-heptane-anhydrous ethanol-diethylamine-trifluoroacetic acid (93:7:0.1:01) as mobile phase; column temperature of 35°C; detection wavelength of 210 nm; flow rate of 1.0 ml per minute), to obtain 572 mg of R-configuration enantiomer with a yield of 28.6%.

The obtained product was dissolved in an appropriate amount of ethyl acetate, and an ethyl acetate solution of oxalic acid was slowly added, the pH was controlled at 4-5, and the mixture was stirred for 30 minutes. The solid was precipitated, filtered, and dried to obtain the target compound oxalate.

¹ H-NMR (400MHz, DMSO-d ₆ )δ:7.46(dd,J＝8.1,5.8Hz,2H),7.21(t,J＝8.7,2H),6.67(t,J＝8.1Hz,1H),6.52(dd,J＝21.6,8.1Hz,2H), 5.99(d,J＝11.8Hz,2H),5.50(dd,J＝8.3,4.3Hz,1H),3.10(m,2H),2.73(s,6H),2.29(s,1H),2.14(s,1H).

Biological activity test

Test product

Compound 2-a (oxalate), compound 2-a (hydrochloride), and compound 3-a (oxalate) were prepared as described above; duloxetine, prepared by Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: A05-20130703; sildenafil, Damas-beta, batch number: P1120930; dapoxetine was synthesized according to the method described in patent application CN200610024697.1; paroxetine: Tianjin Tasly Group Co., Ltd.; amuoxetine was synthesized according to the method described in patent application CN200810127171.5, trazodone: Sigma, batch number: MKCM5195; ansofaxine, prepared by Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: 20230801; bupropion, prepared by Jiangsu Enhua Pharmaceutical Co., Ltd., batch number: BP220913W.

Estradiol benzoate injection (for veterinary use), diethylstilbestrol (for veterinary use) and progesterone injection (for veterinary use): Chifeng Born Pharmaceutical Co., Ltd.; Cefuroxime for injection: Suzhou Sinochem Pharmaceutical Industry Co., Ltd.

Solvent: pure drinking water (sterile water system, Hangzhou Yongjieda Purification Technology Co., Ltd.); soybean oil (for injection, Guangzhou Baiyunshan Hanfang Modern Pharmaceutical Co., Ltd.). The test compound was dissolved in pure drinking water, and estradiol benzoate and progesterone were dissolved in soybean oil. If the test sample is not well dissolved or unevenly suspended during the dissolution process, appropriate vortexing or ultrasound can be performed and it can be used immediately after preparation.

Example 3: Paroxetine-induced erectile dysfunction model test in rats

1. Experimental Animals

The experimental SD rats, SPF grade, male, purchased from Beijing Sibeifu, with a weight range of 220-250g; the above rats were raised in 6/cage. The temperature was controlled at 16-26℃; humidity: 40-70%; noise: below 60dB; light intensity: 60LUX. After the animals were purchased, they were adaptively raised for more than 3 days before the experiment began.

2. Experimental Methods

168 male rats were randomly divided into 21 groups. Except for the blank group (medication solvent), the rest groups were injected with paroxetine 10 mg/kg via tail vein to establish models. The test compound group was intragastrically administered with the designed dose, and the model group was intragastrically administered with an equal volume of distilled water. One hour later, the rat penis was stimulated with a stimulating electrode of a pharmacological and physiological experiment multi-instrument, and the stimulation mode was "continuous A, frequency of 64 Hz, wave width of 2 ms, voltage of 10 V". The time from the start of stimulation to penile erection (erection latency) of each group of rats was recorded respectively.

The experimental data were expressed as mean ± standard deviation (Mean ± SD) and SPSS 22.0 statistical software was used to perform a variance homogeneity test. If the variance was equal, a one-way analysis of variance was performed. The Dunnett test was used for pairwise comparisons, and P < 0.05 was considered statistically significant.

3. Experimental Results

Compared with the blank group, the erection latency of the paroxetine (10 mg/kg) model group was significantly prolonged, and the difference was statistically significant (##: P<0.01). The results of this experiment showed that under the experimental conditions, compared with the paroxetine model group, compound 2-a (2.5, 5, 10 mg/kg), compound 3-a (2.5, 5, 10 mg/kg), duloxetine (2.5, 5, 10 mg/kg), sildenafil (2.5, 5, 10 mg/kg), amuletine (5, 10 mg/kg), trazodone (5, 10 mg/kg) can significantly shorten the erection latency, and the difference is statistically significant (**: P<0.01). The experimental results are shown in Table 2.

Table 2 Test results of compounds on paroxetine-induced erectile dysfunction ( n＝8)

4. Experimental Conclusion

In this experiment, there was a significant difference between the paroxetine (10 mg/kg) model group and the blank group, proving that the modeling was successful and can be used for compound evaluation. The results of this experiment showed that compound 2-a, compound 3-a, duloxetine, sildenafil, amuletine, and trazodone all had certain effects, and the minimum effective doses were 2.5, 2.5, 2.5, 2.5, 5, and 5 mg/kg, respectively. From the experimental data, compound 2-a is superior to other compounds.

Example 4: Pharmacodynamics test on sexual function in rats

1. Experimental Animals

The experimental SD rats, SPF grade, half male and half female, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. The weight range of male rats was 291.4-397.3g, and the weight range of female rats was 180.3-246.9g; the above rats were kept in 6 per cage. The temperature was controlled at 20-26℃; humidity was controlled at 40-70%; noise was controlled at less than 60dB; automatic lighting was used, with light and dark alternation every 12h. On the mating test day, the working lighting was not turned on.

2. Experimental Methods

Grouping method

Thirty SD male rats were divided into three experimental groups according to their body weight, namely, a blank control group (0 mg/ml), a compound 3-a (1 mg/kg) group, and a sildenafil (4 mg/kg) positive control group.

Dosage

After grouping, drug administration began, and male rats were intragastrically administered once a day for 5 consecutive days.

Experimental procedures

After the rat quarantine adaptive feeding was completed, female rats were subcutaneously injected with cefadroxil 25 mg/rat, and castration surgery was performed the next day. After 5 days of recovery, they were caged one-on-one with male rats for two days. When the male and female rats were caged together, the male rats were placed in the observation cage for 5 to 10 minutes before the female rats were placed. Rats were replaced in time when fighting occurred. Then the male and female rats were separated into cages, and the males were grouped and adaptively fed for 3 days before the drug administration began for 5 days, once a day. On the third day of drug administration (about 48 hours before the mating test), female rats were intramuscularly injected with estradiol benzoate 50 μg/rat. On the fifth day of drug administration (about 4.5 hours before the mating test), female rats were intramuscularly injected with progesterone 500 μg/rat. 0.5 hours after the last drug administration of male rats, a mating test was conducted for male and female rats, and the female rats caged with male rats were consistent with the previous adaptive cage. The behavior of the rats was recorded from the bottom of the cage with a camera for about 75 minutes. After the male and female rats are caged together, vaginal swabs are taken from female rats to check for sperm or to determine the estrous cycle of the female rats. If the female rat is not in estrus, the data of the male rat paired with it must be eliminated, or judged according to the actual situation. Read the experimental video records, collect the ejaculation animal ratio (the percentage of test animals that ejaculated to the total number of test animals), the sexual desire animal ratio (the percentage of sexual desire animals to the total number of test animals), the mounting latency (the time from the female rat being put into the male rat to the time the male rat first catches and mounts the female rat), and the ejaculation latency (the time from the female rat being put into the male rat, The time from the first time the male mouse mounted to the first successful ejaculation) and the number of mounts before the first ejaculation (from the time the female mouse threw herself onto the male mouse, the number of times the male mouse caught and mounted the female mouse before the first ejaculation).

Data presentation and statistical processing

Conduct statistical comparison and analysis on the collected indicators. SPSS 22.0 was used for statistical analysis. The variance homogeneity test of multiple groups was performed first. If the variance was homogeneous, the one-way ANOVA LSD test was performed. If the variance was not homogeneous among multiple groups, the two-sample t or t' test was performed directly. P < 0.05 indicated a significant statistical difference.

3. Experimental Results

Table 3 Comparison of ejaculation rate and ratio of animals with sexual desire in each experimental group (n=10)

Table 4 Comparison of the mounting latency and ejaculation latency of rats in each experimental group

Note: Compared with the blank control group, *P<0.05, there is a significant difference.

4. Experimental Conclusion

The ejaculation rate, the ratio of animals with sexual desire, the mounting latency period and the number of mounting times before the first ejaculation can be used to evaluate sexual desire. The higher the ratio of animals with sexual desire and the ratio of animals with ejaculation, the shorter the mounting latency period and the more the number of mounting times before the first ejaculation, indicating that the rats have stronger sexual desire. The ejaculation latency period can be used to evaluate premature ejaculation. The longer the ejaculation latency period, the better the premature ejaculation condition of the rats.

From the results of Table 3 and Table 4, it can be seen that compared with the blank control group, the test compound has an increased rate of ejaculation animals and a higher rate of animals with sexual desire, and a significantly reduced mounting latency, but the dosage of compound 3-a is only 1/4 of that of sildenafil, indicating that the compound of the present invention has a more significant efficacy and has a more excellent clinical therapeutic potential for improving sexual desire. In terms of ejaculation latency, compared with sildenafil and the blank control group, compound 3-a of the present invention can significantly prolong the ejaculation latency, indicating that the compound of the present invention has a better clinical therapeutic potential for improving premature ejaculation.

Example 5: Mating experiment of compound 2-a and dapoxetine in rats after single subcutaneous administration

1. Experimental Animals

The experimental SD rats, SPF grade, male, were purchased from Shanghai Jiesijie, with a weight range of 250-360g; the above rats were raised 6 per cage. The temperature was controlled at 20-26℃; humidity: 40-70%; noise: below 60dB; light intensity: 60LUX. After the animals were purchased, they were adaptively raised for more than 3 days before the experiment began.

2. Experimental Methods

Grouping method

First, the rats were randomly divided into 6 groups, 10 rats in each group, namely, vehicle group, compound 2-a (3 mg/kg) group, compound 2-a (6 mg/kg) group, dapoxetine (15 mg/kg) group, dapoxetine (30 mg/kg) group, and dapoxetine (60 mg/kg) group.

Dosage

Single subcutaneous/intraperitoneal administration, compound 2-a was administered subcutaneously, and dapoxetine was administered intraperitoneally; the corresponding dose was calculated based on body weight, and the administration time was 60 minutes before the behavioral test.

Experimental methods and steps

About 10 days after screening, formal behavioral tests were conducted. Female mice were subcutaneously injected with 25 μg of estradiol benzoate 48 hours before the behavioral test, and 4 hours before the test, 500 μg of progesterone was subcutaneously injected for aphrodisiac effect (0.1 mL/mouse). Sexual behavior observation was conducted about 16 to 21 hours before the test. Male mice were placed alone in an observation cage (42 cm × 27 cm × 19 cm) and kept quiet. The light was dimmed to allow observation and video recording. About 10 minutes later, the estrus female mice were gently placed in the male mouse cage, and the mating behavior of the mice was recorded within 30 minutes. The following parameters were recorded in combination with the video recording: (1) Mount frequency (MF): The number of times the male mice showed mounting behavior after being in the same cage, regardless of whether there was penetration; (2) Ejaculation frequency (EF): The number of times the male mice showed ejaculation behavior after being in the same cage.

Data presentation and statistical processing

Independent sample chi-square test was used, and p < 0.05 was considered statistically significant.

*, compared with the vehicle group, p<0.05, with significant difference.

3. Experimental Results

See Figure 1.

4. Experimental Conclusion

As shown in Figure 1, compound 2-a can significantly increase the number of ejaculations at a dose of 6 mg/kg compared with the vehicle group, and does not affect the number of mounting, indicating that the compound of the present invention not only does not affect the sexual desire of rats, but also significantly improves the sexual function of rats; while dapoxetine does not increase the number of ejaculations at a dose of up to 60 mg/kg, and there is a downward trend. In summary, the compound of the present invention has the effect of significantly improving the sexual function of rats at a low dose, and can reduce the possibility of adverse reactions while ensuring the efficacy.

Example 6: Mating test of stress model mice

1. Experimental Animals

The mice used in the experiment were SPF grade, male, purchased from Shanghai Jiesijie, with a weight range of 25-30g; 8 mice were raised in a cage. The temperature was controlled at 16-26℃; humidity was controlled at 40-70%; noise was controlled at less than 60dB; light intensity was controlled at 60LUX. After the animals were purchased, they were adaptively raised for more than 3 days before the experiment began.

2. Experimental Methods

Grouping method

84 healthy male SPF mice were divided into normal control group, model control group, sildenafil 24mg/kg group, duloxetine 20mg/kg group, compound 2-a 1mg/kg group, compound 2-a 3mg/kg group and compound 2-a 10mg/kg group, with 12 mice in each group. Before the experiment, the mice were caged with feminized female mice (subcutaneously injected with diethylstilbestrol 1mg/kg) for 2-3 days to allow each group of mice to gain sexual experience. After caged, the male mice rested for 3-4 days before the formal experiment.

Dosage

The drugs were administered by intragastric gavage multiple times. Each group was given solutions of corresponding concentrations. The normal control group and the model control group were given solvent (pure water). The other test groups were given drugs according to the corresponding doses calculated according to body weight for 5 consecutive days.

Experimental methods and steps

Stress stimulation was performed on the 1st to 3rd day of the formal experiment in the shuttle box of MED. The stress condition was set to 0.3 mA current, 180 electric shocks, 2 to 4 seconds per shock, and a random interval of 4 to 10 seconds. Each mouse was electrically stimulated once a day for 3 consecutive days. The normal control group (No Inescapable Shock, NIS) animals were placed in the test box for the same time, but no foot shocks were given. The drug was administered once 1 hour after the electrical stimulation. The observation index was the mating experiment on the 5th day of drug administration.

Mouse mating test: A mating test was conducted 1 hour after multiple administrations. First, the male mice were placed in a cage alone for 5 minutes to familiarize them with the environment. Then, an adult feminized female mouse (injected with 1 mg/kg diethylstilbestrol 48 hours before the test) was placed in the cage with the male mouse. The video was recorded for 20 minutes and the following were observed and recorded: (1) capture and mounting latency (the time from the female mouse being put into the cage to the first time the male mouse mounted the female mouse with its forelimbs); (2) mounting latency (the time from the female mouse being put into the cage to the first time the male mouse mounted the female mouse with both forelimbs and failed mating); (3) mating latency (the time from the female mouse being put into the cage to the first time the male mouse mated); (4) capture times (the number of times each group of male mice captured the female mouse within 20 minutes); (5) mounting times (the number of times each group of male mice mounted the female mouse within 20 minutes); (6) mating times (the number of times each group of male mice mated within 20 minutes). The latency of the behavior that did not occur was calculated as 20 minutes.

Data presentation and statistical processing

The experimental data were expressed as mean ± standard deviation (Mean ± SD) and SPSS 20.0 statistical software was used to perform a variance homogeneity test. If the variance was equal, a one-way analysis of variance was performed. The Dunnett test was used for pairwise comparisons, and the chi-square test was used for counting data. The difference was considered statistically significant when p < 0.05.

3. Experimental Results

Table 5 Results of mating test on stressed mice after administration of compound 2-a for 5 days ( n＝12)

Note: ^# p<0.05, ^## p<0.01 vs blank control group; ^* p<0.05, ^** p<0.01 vs model control group.

4. Experimental Conclusion

As shown in Table 5, the model control group had significantly abnormal indicators in terms of capture latency, capture times, mount latency and mount times compared with the normal control group, and there were significant differences, indicating that the stress mouse model was successfully established.

Among the above-mentioned test drugs, compared with the model control group, sildenafil and compound 2-a of the present invention significantly improved the sexual desire indicators such as capture latency, capture times, mount latency and mount times of the mating test of model mice, while duloxetine not only had no improvement effect, but also tended to worsen.

The compound of the present invention not only has a dosage far lower than that of sildenafil (1-10 mg vs 24 mg), but also has a significantly better improvement in the mounting latency and mounting frequency than sildenafil, significantly increases the sexual desire of mice, and improves the sexual function of stressed mice. In summary, the compound of the present invention has a more prominent efficacy in improving the mating of stressed mice than sildenafil, and has a better and more excellent clinical application prospect.

Example 7. Microdialysis study of compound 2-a in rats

1. Experimental Animals

The experimental SD rats were SPF grade, both male and female, purchased from Beijing Sibeifu, with a weight range of 220-280g for males and 210-240g for females. The controlled temperature was 20-26℃; humidity was 40-70%; noise was below 60dB; light intensity was 60LUX. After the animals were purchased, they were adaptively raised for more than 3 days before the experiment began.

2. Experimental Methods

Grouping method

Twelve (2/sex) male and female SD rats were divided into 3 groups. The animals were given a single intraperitoneal injection of 10 mg/kg of compound 2-a, ansofacine, and bupropion. Dialysate samples were collected every 0.5 h before administration for a total of 2 hours; and every 0.5 h after administration for a total of 4 hours. The concentrations of DA, NE, and 5-HT in brain microdialysate were determined by LC MS/MS method.

Data presentation and statistical processing

The data were expressed as mean value or mean ± standard error, with the concentration of the test substance as the ordinate and each sampling end time point as the abscissa. The data were subjected to t-test using Excel to statistically analyze whether the brain dopamine concentration after administration was significantly different from that before administration in each group.

*, compared with before administration, p<0.05, with significant difference.

3. Experimental Results

The experimental results showed that compound 2-a could significantly increase the dopamine content in the brain 2h, 3h, and 4h after administration, with statistically significant differences (p<0.05, p<0.01); the highest increase was 5.6 times. Although ansufaxin and bupropion could increase the dopamine content in the brain, the difference was not statistically significant (p>0.05); the highest increase was 1.8 and 4.4 times, respectively.

Compound 2-a can significantly increase the content of NE in the brain 2h, 3h, and 4h after administration, with statistically significant differences (p<0.01); the highest increase is 4.2 times. Bupropion can significantly increase the content of NE in the brain 1h after administration, with statistically significant differences (p<0.05); the highest increase is 2.7 times. Ansufaxin failed to significantly increase the content of NE in the brain, with no statistically significant differences (p>0.05); the highest increase is 0.8 times.

Compound 2-a can significantly increase the content of 5-HT in the brain 4 hours after administration, the difference is statistically significant, p<0.05; the highest increase is 3.3 times. Ansufaxine and bupropion failed to significantly increase the content of 5-HT in the brain, the difference was not statistically significant, p>0.05; the highest increase was 1.8 and 0.8 times, respectively.

Table 6 Detection results of DA content in the brain after administration of each compound (Mean±SD)

Table 7 Results of NE content in the brain after administration of each compound (Mean±SD)

Table 8 Results of 5-HT content in the brain after administration of each compound (Mean ± SD)

4. Experimental Conclusion

From the results of Table 6, Table 7 and Table 8, it can be seen that compound 2-a can significantly increase the levels of DA, 5-HT and NE in the brain. In comparison, bupropion can significantly increase DA and NE in the brain, while ansofaxine cannot significantly increase the content of DA, 5-HT and NE in the brain. Combined with the test results of compound 2-a in rat microdialysis test, mouse stress model test and rat mating test, compound 2-a can increase the level of dopamine in the brain to improve sexual dysfunction, so it is expected that it also has an improvement effect on sexual dysfunction such as female sexual dysfunction.

The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (17)

Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso-body, racemate or a mixture thereof in the preparation of a medicament for alleviating and/or treating sexual dysfunction, in: _R1 and _R2 are each independently selected from hydrogen and _C1-5 alkyl; R ₃ and R ₄ are each independently selected from hydrogen, halogen, optionally substituted C _1-5 alkyl and optionally substituted C _1-3 alkoxy; the optional substituents are selected from halogen, C _1-5 alkyl, C _1-3 alkoxy and -OH. The use according to claim 1, characterized in that R ₁ and R ₂ are each independently selected from hydrogen and C _1-5 alkyl, each independently preferably selected from hydrogen, methyl, ethyl and isopropyl, and further each independently preferably selected from hydrogen and methyl; Said R ₃ and R ₄ are each independently selected from hydrogen, halogen, methoxy, ethoxy, propoxy, methyl, ethyl and isopropyl, each independently preferably selected from hydrogen, halogen, methoxy, ethoxy, methyl, ethyl and isopropyl, further each independently preferably selected from hydrogen, fluorine, chlorine, methoxy and methyl. The use according to any one of claims 1 to 2, characterized in that the compound represented by formula (I) is formula (Ia), formula (Ib) or a mixture thereof, preferably formula (Ia), wherein R ₁ , R ₂ , R ₃ and R ₄ are as described in any one of claims 1-2. The use according to claim 1, characterized in that the compound of general formula (I) is as shown in general formula (II): in: R ₁ is selected from hydrogen and C _1-5 alkyl, preferably selected from hydrogen, methyl, ethyl and isopropyl, more preferably selected from hydrogen and methyl; R ₂ is selected from hydrogen and C _1-5 alkyl, preferably selected from methyl, ethyl and isopropyl, more preferably methyl; R ₄ is selected from hydrogen and halogen, preferably selected from hydrogen, fluorine, chlorine and bromine, more preferably selected from hydrogen and fluorine, and further preferably hydrogen. The use according to claim 4, characterized in that the compound represented by the general formula (II) is formula (II-a), formula (II-b) or a mixture thereof, preferably formula (II-a), wherein R ₁ , R ₂ and R ₄ are as described in claim 4. The use according to any one of claims 1 to 5, characterized in that the compound represented by formula (I) is selected from: 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-N,N-dimethyl-3-phenylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-chlorophenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-chlorophenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-chlorophenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-chlorophenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-fluorophenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-fluorophenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-methoxyphenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-methoxyphenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-methylphenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3-methylphenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(2-fluorophenyl)-N,N-dimethylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(2-fluorophenyl)-N-methylpropylamine; 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3,4-dichlorophenyl)-N,N-dimethylpropylamine; and 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(3,4-dichlorophenyl)-N-methylpropylamine. The use according to any one of claims 1 to 5, characterized in that the compound represented by formula (I) is selected from 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine, R-3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine, 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine, R-3-[(benzo[d][ R-3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine, preferably selected from R-3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine and R-3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-(4-fluorophenyl)-N,N-dimethylpropylamine, more preferably R-3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine. The use according to any one of claims 1 to 7, characterized in that the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from one or more of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, oxalate, benzoate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate, preferably hydrochloride or oxalate, more preferably oxalate. The use according to any one of claims 1 to 8, characterized in that the drug comprises a second therapeutic agent, which is selected from one or more of a phosphodiesterase type V (PDE5) inhibitor, a dopamine receptor _D2 agonist, an α-adrenaline receptor antagonist, a prostaglandin E1 receptor agonist, a 5-HT1A receptor agonist and a 5-HT2A receptor antagonist. The use according to claim 9, characterized in that the PDE5 inhibitor is selected from sildenafil, Fadanafil, Tadalafil, Mirodenafil, Udenafil, Avanafil and vardenafil; the dopamine receptor D2 agonist is apomorphine; the α-adrenaline receptor antagonist is phentolamine; the prostaglandin E1 receptor agonist is alprostadil; the 5-HT _1A receptor agonist or 5-HT _2A receptor antagonist is flibanserin. The use according to any one of claims 1 to 10, characterized in that the sexual dysfunction includes male sexual dysfunction and female sexual dysfunction, preferably selected from the group consisting of sexual dysfunction, erectile dysfunction, ejaculation disorder, sensory disorder, sexual arousal dysfunction, sexual intercourse pain and orgasm disorder, further preferably selected from the group consisting of erectile dysfunction, premature ejaculation, delayed ejaculation, penis curvature deformity, abnormal penis erection, low libido, retrograde ejaculation, sexual intercourse pain, sexual arousal difficulty, vaginal dryness, orgasm loss and sexual discomfort, more preferably selected from the group consisting of erectile dysfunction, premature ejaculation and low libido. The use according to any one of claims 1 to 11, characterized in that the sexual dysfunction occurs before, simultaneously with or after the patient who receives the drug for relief and/or treatment receives antidepressant treatment. A method for treating sexual dysfunction by administering an effective amount of a compound of formula (I) to a patient in need of treatment as a short-term or long-term treatment, wherein the sexual dysfunction includes male sexual dysfunction and female sexual dysfunction, preferably one or more selected from the group consisting of sexual desire dysfunction, erectile dysfunction, ejaculation disorder, sensory disorder, sexual arousal disorder, dyspareunia and orgasm disorder; The compound represented by formula (I) is as described in any one of claims 1 to 8. The method of claim 13, wherein the patient in need of treatment suffers from depression before or while being given treatment. The method of any one of claims 13-14, characterized in that the sexual dysfunction occurs before, during or after the patient receives antidepressant treatment. [Corrected 18.11.2024 in accordance with Rule 26]
The treatment method according to any one of claims 13 to 15, characterized in that the male sexual dysfunction is selected from the group consisting of hypoactive sexual desire disorder, erectile dysfunction, ejaculation disorder and sensory disorder, preferably selected from one or more of erectile dysfunction, premature ejaculation, delayed ejaculation, penile curvature deformity, abnormal penile erection, low libido, retrograde ejaculation and dyspareunia, more preferably erectile dysfunction and/or premature ejaculation. The treatment method according to any one of claims 13 to 15, characterized in that the female sexual dysfunction is selected from one or more of hypoactive sexual desire disorder, sexual arousal disorder, dyspareunia, orgasm disorder and sensory disorder, preferably selected from one or more of low sexual desire, difficulty in sexual arousal, loss of orgasm and sexual discomfort, more preferably low sexual desire.