JP2008150371A - Compound for treating sexual dysfunction - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for treating female sexual dysfunctions or a therapeutic agent perorally effective for the female sexual dysfunctions. <P>SOLUTION: The method for treating the female sexual dysfunctions with a selective antagonist of a μ opioid receptor and a treatment combined with other class of agents are disclosed. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to the use of selective mu opioid receptor antagonists to treat and / or prevent female sexual dysfunction (FSD), particularly female sexual arousal disorder (FSAD).

  Furthermore, the present invention relates to a method for treating and / or preventing FSD, in particular FSAD, using selective mu opioid receptor antagonists.

Sexual dysfunction Sexual dysfunction (SD) is a serious clinical problem that can affect both men and women. There are both organic and psychological causes of SD. Usually, the organic aspects of SD are caused by underlying vascular diseases such as those associated with hypertension or diabetes, by prescription drugs, and / or by mental illnesses such as depression. Physiological factors include fear, performance anxiety and interpersonal conflict. SD impairs sexual performance, reduces self-esteem, disrupts relationships and thereby causes personal distress. In the clinic, SD disorders are classified as female sexual dysfunction (FSD) disorder and male sexual dysfunction (MSD) disorder (Melman et al., J. Urology, 1999, 161, 5-11).

  FSD can be defined as the difficulty or inability of a woman to find satisfaction with sexual expression. In general, male sexual dysfunction (MSD) is associated with erectile dysfunction, also known as male erectile dysfunction (MED) (Benet et al., 1994-Male Electric dysfunction assessment and treatment options. Comp. Ther.20: 669-673).

  The present invention is particularly useful for the prevention and / or treatment of sexual dysfunction in women-female sexual dysfunction (FSD), such as female sexual arousal disorder (FSAD).

Female sexual dysfunction (FSD)
According to the present invention, FSD can be defined as the difficulty or inability for a woman to find satisfaction in sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, SR (1998)-Definition and classification of female sex disorders. Int. J. Impression Res., 10, S104-S106; JR, Berman, L. and Goldstein, I. (1999)-Female sex dysfunction: Incidence, pathology, evaluations and treatment options. Urology, 54, 385-39. Women may have a lack of desire, difficulty with arousal or orgasm, pain during intercourse, or a combination of these problems. Several types of diseases, medications, injuries or psychological problems can cause FSD, eg, antidepressant-induced female sexual dysfunction (Segreves RT., Antidepressant-induced sex function. J Clin Psychiatry). 1998; 59 Suppl 4: 48-54; Taylor MJ., Strategies for managing anti-depressant-induced sex dysfunction: a review, Curr Psychiatry Rep. 6; Therapies under development are aimed at treating specific subtypes of FSD, primarily craving disorders and arousal disorders.

  The categories of FSD are best defined by contrasting them with the stages of normal female sexual response: desire, arousal and orgasm (Leiblum, SR (1998)-Definition and classification of female sexors). Int. J. Impact Res., 10, S104-S106). Desire or libido is the driving force for sexual expression. The signs often include sexual imagination when being with a partner of interest or being exposed to other emotional stimuli. Excitement is the vascular response to sexual stimulation, an important component of which is genital congestion, including increased vaginal lubrication, vaginal elongation, and increased genital sensation / sensitivity. Orgasm is the release of sexual tension that has reached its peak during excitement.

  Thus, FSD occurs when a woman has an inadequate or unsatisfactory response at any of these stages, usually desire, arousal or orgasm. The FSD category includes hyposexual desire disorder, sexual arousal disorder, orgasm disorder and sexual pain disorder. The compounds of the present invention should restore genital response and improve subjective arousal in response to sexual stimulation (as in female sexual arousal disorder), so that the associated pain associated with sexual intercourse It can also improve pain and discomfort and thus treat other female sexual disorders.

  Sexual decline desire disorder exists when a woman has little or no desire to be sexual, and has little or no sexual imagination or fantasies. This type of FSD can be caused by low testosterone levels, either through natural menopause or surgical menopause. Other causes include illness, medication, fatigue, depression and anxiety.

  Female sexual arousal disorder (FSAD) is characterized by inadequate genital response to sexual stimulation. The genitals do not cause congestion, which is characteristic of normal sexual arousal. Intercourse is painful due to insufficient lubrication of the vaginal wall. Orgasm may be disturbed. Excitement disorders can be caused by decreased estrogen at menopause or after childbirth and during lactation, and by diseases related to vascular components such as diabetes, hypertension and atherosclerosis. Other causes are due to treatment with diuretics, antihistamines, antidepressants such as selective serotonin reuptake inhibitors (SSRIs), or antihypertensives.

  Sexual pain disorders (including sexual pain and vaginal spasticity) are characterized by pain caused by insertion, medications that reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems Can also be caused by nonsexual intercourse sexual pain.

  The prevalence of FSD is that this term encompasses several types of problems, some of which are difficult to measure, and such problems are usually reported by women who have experienced them It is difficult to grab correctly because of the low frequency and relatively recent interest in treating FSD. Many female sexual problems are directly related to either the female aging process or chronic illnesses such as diabetes and hypertension. Clinical evaluation and diagnostic tools are described in J. Sex Med 2005, 2 (Suppl. 3), pages 146-153, reviewed by Althof et al.

  Because FSD consists of several subtypes that develop symptoms at different stages of the sexual response cycle, there is no single treatment. Current treatments for FSD focus primarily on psychological or relationship issues. The treatment of FSD is gradually evolving as more clinical and basic science trials are dedicated to examining this medical problem. Female sexual complaints are not always psychological in pathophysiology, especially for individuals who may have an element of vascular dysfunction (eg, FSAD) that causes all female sexual complaints . At present, there are no drugs approved to treat FSD. Empirical medications include estrogen administration (locally or as hormone replacement therapy), androgens or tranquilizers such as buspirone or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects.

  Since interest in pharmacologically treating FSD is relatively recent, therapies include the following psychological counseling, over-the-counter sexual lubricants, and drugs approved for other conditions Including clinical trial candidates. These medications consist of hormonal agents, either testosterone or a combination of estrogen and testosterone, and more recently vascular drugs that have proven effective for male erectile dysfunction (MED). None of these agents has been proven to be effective in treating FSD so far.

  The present invention is particularly useful for the prevention and / or treatment of female sexual arousal disorder (FSAD).

Female sexual arousal disorder (FSAD)
The American Psychiatric Association's Diagnosis and Statistics Manual (DSM) IV defines female sexual arousal disorder (FSAD) as follows:
“… Not able to achieve or maintain a sufficient sexual arousal lubrication-swelling response until sexual activity is terminated, continuously or repetitively. This disorder causes significant distress or difficulty in interpersonal relationships Must be ... "

  The excitatory response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and expansion of the external genitalia. This disorder causes significant distress and / or difficulty in interpersonal relationships.

  Basson et al. (J. Urology, 2000, 163, 888-893, incorporated herein by reference) follow the same general structure as DSM IV and follow four major categories of dysfunction: desire disorders (sexual Describes a revised classification system that includes new categories of sexual pain, including decreased desire and sexual aversion disorders, arousal disorders, orgasmic disorders and sexual pain disorders, and nonsexual intercourse sexual pain ing. Nonsexual intercourse sexual pain disorder is recurrent or persistent genital pain caused by nonsexual intercourse sexual stimulation.

  FSAD is a highly prevalent sexual disorder that affects premenopausal, pre-menopausal and postmenopausal (± hormone replacement therapy (HRT)) women. FSAD is associated with concomitant disorders such as depression, cardiovascular disease, diabetes and genitourinary (UG) disorders.

  The primary consequences of FSAD are lack of congestion / inflation, lack of lubrication, and lack of pleasant genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during sexual intercourse and difficulty reaching orgasm.

  In recent years, it has been hypothesized that vascularity exists for patients with at least some FSAD symptoms (Goldstein et al., Int. J. Impot. Res. 10, S84-S90, 1998) and animal data. Supports this view (Park et al., Int. J. Impot. Res., 9, 27-37, 1997).

Drug candidates for treating FSAD that are under investigation for efficacy are primarily erectile dysfunction therapies that promote circulation to the male genital organs. They are formulated into two types of oral or sublingual drug treatments (apomorphine, phentolamine, type 5 phosphodiesterase, which are injected or transurethrally administered in men and topically administered to the genitals in women. (PDE5) inhibitors, such as sildenafil, and prostaglandins (PGE ₁ ).

  R. J. et al. Levin argues that the structures of male and female genital organs are homologous to each other, as male and female genital organs develop developmentally from a common tissue primordium. The nucleus is the penile homologue and the labia is the scrotal homologue ... "(Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69).

Anorgasmia Anorgasmia may be classified as a psychiatric disorder and is a form of sexual dysfunction in which a patient cannot reach orgasm even with “sufficient” stimulation. However, anorgasmia can also be caused by medical problems such as diabetic neuropathy, multiple sclerosis, pelvic trauma, hormonal imbalance, total hysterectomy, spinal cord injury and cardiovascular disease. Anorgasmia is much more common in women than in men.

Opioid Receptors In the study of opioid biochemistry, a variety of endogenous and non-endogenous opioid compounds have been identified. In this effort, important research has been focused on understanding the mechanism of action of opioid drugs, particularly as it relates to the opioid receptors in cellular and differentiated tissues (Current Medicinal Chemistry, 2002, 1591-1603).

  Opioid drugs are usually classified according to their binding selectivity for receptors in cellular and differentiated tissues to which specific drug species bind as ligands. These receptors include mu (μ), delta (δ) and kappa (κ) receptors (Pharmacological Rev., 48, 1996, 567-592).

  All three receptors are present in the central and peripheral nervous systems of many species, including humans. In addition to causing antinociception in rodents and affecting gastrointestinal motility, delta receptor activation can induce analgesia in humans. (See "The Pharmacology of Opioid Peptides", edited by Tseng, LF, Burks, TF (1995) in Harwood Academic Publishers).

  Well-known narcotic opiates such as morphine and its analogs are selective for the opioid mu receptor. Mu receptors mediate analgesia, respiratory depression and gastrointestinal transit inhibition. The kappa receptor mediates analgesia and sedation.

  The presence of the opioid δ receptor (δ) [δ opioid receptor; DOR] is a relatively recent discovery, followed by the isolation and characterization of an endogenous enkephalin peptide that is a ligand for the δ receptor. This decade of research has produced important information about the δ receptor, but no clear picture of its function has yet emerged. The δ receptor mediates analgesia but does not appear to inhibit intestinal transit in a manner characteristic of the μ receptor.

Opiates and sexual function Opiates are involved in sexual function in the human and animal bodies, and effects on endocrine (hormone) function have been observed in human and animal studies.

  Opiates have a long history as drugs that slow sexual urges. In female rodents, centrally administered opioid agonists have been shown to inhibit or promote sexual behavior depending on receptor type, dose of drug used and brain area stimulated ing.

  Decreased sexual acceptability has been observed in animal studies with opiate agonists such as endogenous opiate or morphine, whereas non-selective opiate antagonists such as naloxone or naltrexone have been shown to be receptive to female sexual stimulation. It has been observed to increase sex.

  Naloxone and naltrexone are well known non-selective opioid antagonists. There are several suggestions for the role of naloxone or naltrexone in the treatment of male sexual dysfunction (impotence) (Psychoenuroendocrinology, 1979, 3, 231-236; Psychoeuroendocrinology 1989, 14, 103-111; Arch. Gen. Psych, 77. 34, 1179-1180; Arch. Med. Res., 2001, 32, 221-226; Arch. Gen. Psychiatry, 1986, 43, 1986).

  Less evidence is available regarding the role of such opiates in female sexual health, and one study of naloxone on a small number of sexually unresponsive women has shown no effect on sexual arousal. Naloxone has also been reported to enhance or inhibit orgasm (J. Sex Res., 1983, 19, 49-57). High doses of naloxone have been reported to produce immediate inhibition of sexual arousal (Neuroscience and Biobehavioral Reviews, 1987, 11, 1-34).

  Naltrexone has the ability to cause hepatocyte damage when given in overdose. Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects. The separation between the apparent safe dose of naltrexone and the dose that causes liver damage appears to be no more than 5 times. For this reason, naltrexone is accompanied by a “black border” warning on the package insert. Similarly, naloxone is associated with liver toxicity, which also has a black border warning.

  An issue that remains unresolved is the provision of treatments for female sexual dysfunction.

  Another problem that remains unsolved is the provision of an orally effective treatment for female sexual dysfunction.

  Surprisingly, it has now been found that μ selective opioid receptor antagonists are advantageous for treating FSD, preferably FSAD and / or female orgasmic disorder (FOD).

  According to a first aspect there is provided the use of a selective mu opioid receptor antagonist (MOR), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing female sexual dysfunction. The

According to a second aspect, of a selective mu opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing female sexual dysfunction
i) a compound that modulates the action of natriuretic factor, in particular atrial natriuretic factor,
ii) a compound that inhibits angiotensin converting enzyme,
iii) a substrate for NO synthase,
iv) cholesterol-lowering drugs,
v) estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists,
vi) phosphodiesterase (PDE) inhibitors,
vii) vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, VIP receptor agonists or VIP fragments, or a combination of an adrenergic receptor antagonist and VIP,
viii) serotonin receptor agonists, antagonists or modulators,
ix) testosterone supplements or testosterone implants,
x) selective androgen receptor modulators,
xi) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie in combination), or estrogen and methyltestosterone hormone replacement therapy,
xii) agonists or modulators of progesterone such as progesterone, gestodine, ethinylestradiol, ethinnodiol, etonogesterol implant, dihydrogesterone, progestogen, sekvens), norethinodrel or progesterone creams or gels such as MuProgest, Natragest and Fem-Gest,
xiii) modulators of noradrenaline, dopamine and / or serotonin transporters,
xiv) agonists or modulators of oxytocin / vasopressin receptors,
xv) a melanocortin receptor agonist or modulator,
xvi) monoamine transport inhibitors,
xvii) dopamine agonists (especially selective D2, selective D3, selective D4 and selective D2-like agents),
xviii) α-adrenergic receptor antagonists (also known as α-adrenergic receptor blockers, α-receptor blockers or α-blockers),
xix) use in combination with an antidiabetic agent, and xx) an adjuvant selected from one or more of NPY receptor modulators (agonists and / or antagonists), or a pharmaceutically acceptable salt thereof Is provided.

  According to a third aspect, there is provided a compound that is a selective mu opioid receptor antagonist (MOR), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of female sexual dysfunction. .

According to a fourth aspect, a selective mu opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of female sexual dysfunction,
i) a compound that modulates the action of natriuretic factor, in particular atrial natriuretic factor,
ii) a compound that inhibits angiotensin converting enzyme,
iii) a substrate for NO synthase,
iv) cholesterol-lowering drugs,
v) estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists,
vi) phosphodiesterase (PDE) inhibitors,
vii) vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, VIP receptor agonists or VIP fragments, or a combination of an adrenergic receptor antagonist and VIP,
viii) serotonin receptor agonists, antagonists or modulators,
ix) testosterone supplements or testosterone implants,
x) selective androgen receptor modulators,
xi) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie in combination), or estrogen and methyltestosterone hormone replacement therapy,
xii) agonists or modulators of progesterone such as progesterone, guestdin, ethinyl estradiol, ethinnodiol, etonogesterol implant, dihydrogesterone, progestogen, tetresecbens, norethinodrel or progesterone creams such as MuProgest, Natragest and Fem-Gest Agent or gel agent,
xiii) modulators of noradrenaline, dopamine and / or serotonin transporters,
xiv) agonists or modulators of oxytocin / vasopressin receptors,
xv) a melanocortin receptor agonist or modulator,
xvi) monoamine transport inhibitors,
xvii) dopamine agonists (especially selective D2, selective D3, selective D4 and selective D2-like agents),
xviii) α-adrenergic receptor antagonists (also known as α-adrenergic receptor blockers, α-receptor blockers or α-blockers),
ix) provided in combination with an antidiabetic agent, and xx) an adjuvant selected from one or more of NPY receptor modulators (agonists and / or antagonists), or a pharmaceutically acceptable salt thereof Is done.

  The female sexual dysfunction may be one or more disorders selected from hyposexual desire disorder, sexual arousal disorder, orgasm disorder and sexual pain disorder.

According to a fifth aspect, a selective mu opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, and i) a compound that modulates the action of natriuretic factor, in particular atrial natriuretic factor,
ii) a compound that inhibits angiotensin converting enzyme,
iii) a substrate for NO synthase,
iv) cholesterol-lowering drugs,
v) estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists,
vi) phosphodiesterase (PDE) inhibitors,
vii) vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, VIP receptor agonists or VIP fragments, or a combination of an adrenergic receptor antagonist and VIP,
viii) serotonin receptor agonists, antagonists or modulators,
ix) testosterone supplements or testosterone implants,
x) selective androgen receptor modulators,
xi) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie in combination), or estrogen and methyltestosterone hormone replacement therapy,
xii) agonists or modulators of progesterone such as progesterone, guestdin, ethinyl estradiol, ethinnodiol, etonogesterol implant, dihydrogesterone, progestogen, tetresecbens, norethinodrel or progesterone creams such as MuProgest, Natragest and Fem-Gest Agent or gel agent,
xiii) modulators of noradrenaline, dopamine and / or serotonin transporters,
xiv) agonists or modulators of oxytocin / vasopressin receptors,
xv) a melanocortin receptor agonist or modulator,
xvi) monoamine transport inhibitors,
xvii) dopamine agonists (especially selective D2, selective D3, selective D4 and selective D2-like agents),
xviii) α-adrenergic receptor antagonists (also known as α-adrenergic receptor blockers, α-receptor blockers or α-blockers),
a pharmaceutical composition comprising xix) an antidiabetic agent, and xx) one or more adjuvants selected from NPY receptor modulators (agonists and / or antagonists), or a pharmaceutically acceptable salt thereof. Provided.

  According to a sixth aspect, a method for treating and / or preventing female sexual dysfunction, wherein a therapeutic amount of a selective mu opioid receptor antagonist, or pharmaceutically, is administered to a subject in need thereof. There is provided a method comprising administering an acceptable salt thereof.

  According to a seventh aspect, a method for treating and / or preventing female sexual dysfunction, wherein a therapeutic amount of a selective mu opioid receptor antagonist, or pharmaceutically, is administered to a subject in need thereof. There is provided a method comprising administering an acceptable salt thereof together with an adjuvant selected from one or more of i) to xx) cited above, or a pharmaceutically acceptable salt thereof. .

Selective mu opioid receptor antagonist As used herein, the term "selective mu opioid receptor antagonist" inhibits physiological responses when acting on mu opioid receptors, and produces kappa and / or delta opioids. Refers to a compound that has a selectivity for the μ opioid receptor that is higher than the selectivity exhibited by naltrexone in a functional assay compared to the receptor.

  As used herein, the term “selectivity” is a measure of the relative potency of a drug between two receptor subtypes for the same ligand. Efficacy can be determined, for example, by an assay as described in the protocol. In addition, protocols for determining potency and ligand selectivity are described in Pharmacologic Reviews, 39, 1987, 197-249, the entire contents of which are hereby incorporated by reference.

  The selective mu opioid receptor antagonist preferably has a selectivity for the mu opioid receptor relative to the kappa opioid receptor that is higher than the selectivity exhibited by naltrexone in the functional assay.

  More preferably, the selective mu opioid receptor antagonist has a selectivity for a mu opioid receptor that is at least three times higher than the selectivity exhibited by naltrexone in a functional assay compared to a kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for a mu opioid receptor that is at least 5 times higher than the selectivity exhibited by naltrexone in a functional assay compared to a kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 10 times higher than the selectivity exhibited by naltrexone in a functional assay compared to the kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for a mu opioid receptor that is at least 20 times higher than the selectivity exhibited by naltrexone in a functional assay compared to a kappa opioid receptor.

  A selective mu opioid receptor antagonist preferably has a selectivity for a mu opioid receptor that is higher than the selectivity exhibited by naltrexone in a functional assay compared to a delta opioid receptor.

  More preferably, the selective mu opioid receptor antagonist has a selectivity for a mu opioid receptor that is at least three times higher than the selectivity exhibited by naltrexone in a functional assay compared to a delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for a mu opioid receptor that is at least 5 times higher than the selectivity exhibited by naltrexone in a functional assay compared to a delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 10 times higher than the selectivity exhibited by naltrexone in the functional assay compared to the delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 20 times higher than the selectivity exhibited by naltrexone in the functional assay compared to the delta opioid receptor.

  The selective mu opioid receptor antagonist preferably has a selectivity for the mu opioid receptor relative to the kappa opioid receptor that is higher than the selectivity exhibited by naloxone in the functional assay.

  More preferably, the selective mu opioid receptor antagonist has a selectivity for a mu opioid receptor that is at least three times higher than the selectivity exhibited by naloxone in a functional assay compared to a kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 5 times higher than the selectivity exhibited by naloxone in the functional assay compared to the kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 10 times higher than the selectivity exhibited by naloxone in the functional assay compared to the kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 20 times higher than the selectivity exhibited by naloxone in the functional assay compared to the kappa opioid receptor.

  A selective mu opioid receptor antagonist preferably has a selectivity for a mu opioid receptor that is higher than the selectivity exhibited by naloxone in a functional assay compared to a delta opioid receptor.

  More preferably, the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least three times higher than the selectivity exhibited by naloxone in the functional assay compared to the delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for mu opioid receptors that is at least 5 times higher than the selectivity exhibited by naloxone in a functional assay compared to delta opioid receptors. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 10 times higher than the selectivity exhibited by naloxone in the functional assay compared to the delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has a selectivity for the mu opioid receptor that is at least 20 times higher than the selectivity exhibited by naloxone in the functional assay compared to the delta opioid receptor.

  Preferably, the selective mu opioid receptor antagonist has a Ki for mu opioid receptor of less than 100 nM in a binding assay. More preferably, the selective mu opioid receptor antagonist has a Ki of less than 10 nM for the mu opioid receptor in a binding assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the mu opioid receptor of less than 1 nM in the binding assay.

  The selective mu opioid receptor antagonist preferably has a Ki for the kappa opioid receptor of greater than 10 nM in the binding assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the kappa opioid receptor of greater than 100 nM in the binding assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the kappa opioid receptor of greater than 1000 nM in the binding assay.

  The selective mu opioid receptor antagonist preferably has a Ki for the delta opioid receptor of greater than 10 nM in the binding assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the delta opioid receptor of greater than 100 nM in the binding assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the delta opioid receptor of greater than 1000 nM in the binding assay.

  The selective mu opioid receptor antagonist preferably has a Ki for the mu opioid receptor of less than 100 nM in the functional assay. More preferably, the selective mu opioid receptor antagonist has a Ki of less than 10 nM for the mu opioid receptor in a functional assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the mu opioid receptor of less than 5 nM in the functional assay.

  The selective mu opioid receptor antagonist preferably has a Ki for the kappa opioid receptor of greater than 10 nM in the functional assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the kappa opioid receptor of greater than 50 nM in the functional assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the kappa opioid receptor of greater than 100 nM in the functional assay.

  The selective mu opioid receptor antagonist preferably has a Ki for the delta opioid receptor of greater than 10 nM in the functional assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the delta opioid receptor of greater than 100 nM in the functional assay. More preferably, the selective mu opioid receptor antagonist has a Ki for the delta opioid receptor of greater than 1000 nM in the functional assay.

  The selective mu opioid receptor antagonist preferably has at least 5 times the selectivity for the mu opioid receptor as compared to the kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has at least 10 times the selectivity for the mu opioid receptor as compared to the kappa opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has at least 50 times the selectivity for the mu opioid receptor as compared to the kappa opioid receptor. Furthermore, it is more preferable that the selective mu opioid receptor antagonist has at least 100 times the selectivity for the mu opioid receptor as compared to the kappa opioid receptor.

  The selective mu opioid receptor antagonist preferably has at least five times the selectivity for the mu opioid receptor as compared to the delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has at least 10 times the selectivity for the mu opioid receptor as compared to the delta opioid receptor. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has at least 50 times the selectivity for the mu opioid receptor as compared to the delta opioid receptor. Furthermore, it is more preferable that the selective mu opioid receptor antagonist has at least 100 times selectivity for the mu opioid receptor as compared to the delta opioid receptor.

  The selective mu opioid receptor antagonist preferably has at least 5 times as much selectivity for the mu opioid receptor as compared to the kappa and delta opioid receptors. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has at least 10 times the selectivity for the mu opioid receptor as compared to the kappa and delta opioid receptors. Furthermore, it is more preferred that the selective mu opioid receptor antagonist has at least 50 times selectivity for the mu opioid receptor as compared to the kappa and delta opioid receptors. Furthermore, it is more preferred that the selective μ opioid receptor antagonist has at least 100 times selectivity for μ opioid receptors compared to κ and δ opioid receptors.

  In a preferred embodiment, the selective mu opioid receptor antagonist inhibitor is a CNS permeable selective mu opioid receptor antagonist inhibitor.

  The term “antagonist” as used herein means any agent that reduces the action of another agent or target. Antagonism combines the substance being antagonized (chemical antagonism) or a combination of adverse effects via different targets (functional antagonism or physiological antagonism) or target activation linked to the observed effect It may occur as a result of competition for the binding site of the intermediate (indirect antagonism).

  The term “agonist” as used herein means any agent that enhances the action of another agent or target or activates another agent or target. The term agonist includes ligands that bind to receptors and thereby alter, usually increase, the proportion of receptors that are active, resulting in a biological response.

Preferred compounds Preferred compounds for use in the present invention include compounds of formula (I), or a pharmaceutically acceptable salt thereof,

式中、
Ｘは、Ｈ、ハロゲン、−ＯＨ、−ＣＮ、１〜３個のハロゲン原子で置換されている−Ｃ_１〜Ｃ_４アルキル、または−Ｏ（Ｃ_１〜Ｃ_４アルキル）であり、−Ｏ（Ｃ_１〜Ｃ_４アルキル）のＣ_１〜Ｃ_４アルキルは、１〜３個のハロゲン原子で置換されていてもよく、
Ｑは、ハロゲン、−ＯＨ、−Ｏ（Ｃ_１〜Ｃ_４アルキル）、−ＮＨ_２、−ＮＨ（Ｃ_１〜Ｃ_４アルキル）、−Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）、−Ｃ（＝Ｏ）ＮＨ_２、−Ｃ（＝Ｏ）ＮＨ（Ｃ_１〜Ｃ_４アルキル）、−Ｃ（＝Ｏ）Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）、−ＮＨＳ（＝Ｏ）_２Ｈ、または−ＮＨＳ（＝０）_２Ｒ^１１であるか、
または、Ｑは、それが結合している炭素原子に隣接するどちらかの炭素原子と共に５または６員シクロアルキルまたはヘテロシクロアルキル環を形成し、それによってそれが結合しているフェニルと二環式縮合環系を形成することができ、前記ヘテロシクロアルキルは、Ｏ、Ｓ、−Ｃ（＝Ｏ）、およびＮから選択される１〜３個のヘテロ部分を含み、前記シクロアルキルまたはヘテロシクロアルキルは、１または２個の二重結合を含んでいてもよく、
Ｒ^１およびＲ^２は、それらが結合している炭素と共に、結合してＣ_３〜Ｃ_７シクロアルキルまたはＯ、Ｓ、−Ｃ（＝Ｏ）、およびＮから選択される１〜３個のヘテロ部分を含む４〜７員ヘテロシクロアルキルを形成し、前記シクロアルキルまたはヘテロシクロアルキルは、１または２個の二重結合を含んでいてもよく、前記シクロアルキルまたはヘテロシクロアルキルは、Ｃ_６〜Ｃ_１４アリールまたは５〜１４員ヘテロアリール基と縮合していてもよく、
Ｒ^１およびＲ^２によって形成される前記Ｃ_３〜Ｃ_７シクロアルキルまたは４〜７員ヘテロシクロアルキルは、各々、１〜３個のＲ^１２基によって置換されていてもよく、前記縮合していてもよいアリールまたはヘテロアリールは、各々独立して、１〜６個のＲ^１２基で置換されていてもよく、Ｒ^１２基は、Ｒ^１３、Ｒ^１６、１または２個の不飽和結合を含む−Ｃ_１〜Ｃ_４アルキル、ハロゲン、−ＯＲ^１３、−ＮＯ_２、−ＣＮ、−Ｃ_３〜Ｃ_６シクロアルキル、−ＮＲ^１３Ｒ^１４、−ＮＲ^１３Ｃ（＝Ｏ）Ｒ^１４、−Ｃ（＝Ｏ）ＮＲ^１３Ｒ^１４、−ＯＣ（＝Ｏ）Ｒ^１３、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＮＲ^１３Ｃ（＝Ｏ）ＯＲ^１４、−ＮＲ^１３Ｃ（＝Ｏ）ＮＲ^１４Ｒ^１５、−ＮＲ^１３Ｓ（＝Ｏ）_２Ｒ^１４、および−Ｓ（＝Ｏ）_２Ｒ^１３から選択され、
Ｒ^３は、Ｃ_１〜Ｃ_４アルキルであり、前記Ｃ_１〜Ｃ_４アルキルは、１または２個の不飽和結合を含んでいてもよく、
Ｒ^４は、１または２個の不飽和結合を含んでいてもよい−Ｃ_１〜Ｃ_４アルキル、−ＯＨ、−ＣＮ、−ＮＯ_２、−ＯＲ^１６、−ＮＨ_２、−ＮＨＲ^１６、−ＮＲ^１６Ｒ^１７、または−ＮＨＣ（＝Ｏ）Ｒ^１６であり、
Ｒ^５およびＲ^８は、各々独立して、Ｈまたはメチルであり、
Ｒ^６、Ｒ^７、Ｒ^９およびＲ^１０は、Ｈであり、
Ｒ^１１は、Ｃ_１〜Ｃ_４アルキル、−（Ｃ_１〜Ｃ_４アルキレン）−Ｏ−（Ｃ_１〜Ｃ_４アルキル）、４−（１−メチルイミダゾール）、−（Ｃ_１〜Ｃ_４アルキレン）−ＮＨ_２、−（Ｃ_１〜Ｃ_４アルキレン）−ＮＨ（Ｃ_１〜Ｃ_４アルキル）、−（Ｃ_１〜Ｃ_４アルキレン）−Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）から選択され、
各Ｒ^１３、Ｒ^１４、およびＲ^１５は、独立して、Ｈ、Ｒ^１６、Ｃ_１〜Ｃ_４アルキル、ハロゲン、−ＯＨ、−ＳＨ、−ＮＨ_２、−ＮＨ（Ｃ_１〜Ｃ_４アルキル）、−Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）、−Ｏ（Ｃ_１〜Ｃ_４アルキル）、−Ｓ（Ｃ_１〜Ｃ_４アルキル）、−ＣＮ、−ＮＯ_２、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_４アルキル）、−Ｃ（＝Ｏ）ＯＨ、−Ｃ（＝Ｏ）Ｏ（Ｃ_１〜Ｃ_４アルキル）、−ＮＨＣ（＝Ｏ）（Ｃ_１〜Ｃ_４アルキル）、−Ｃ（＝Ｏ）ＮＨ_２、および−Ｃ（＝Ｏ）Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）から選択されるか、または−ＮＲ^１３Ｒ^１４のＲ^１３およびＲ^１４は、結合して４〜６員ヘテロシクロアルキルまたはヘテロアリール基を形成していてもよく、そのヘテロアリール基は、Ｎ、Ｓ、Ｏおよび−Ｃ（＝Ｏ）から選択される１〜３個の他のヘテロ部分を含んでいてもよく、
各Ｒ^１６およびＲ^１７は、独立して、Ｃ_６〜Ｃ_１４アリールおよび５〜１４員ヘテロアリールから選択され、前記ヘテロアリールは、Ｏ、Ｓ、−Ｃ（＝Ｏ）、およびＮから選択される１〜３個のヘテロ部分を含み、前記アリールおよびヘテロアリールは、１または２個の不飽和結合を含んでいてもよいＣ_１〜Ｃ_４アルキル、ハロゲン、−ＯＨ、−ＳＨ、−ＮＨ_２、−ＮＨ（Ｃ_１〜Ｃ_４アルキル）、−Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）、−Ｏ（Ｃ_１〜Ｃ_４アルキル）、−Ｓ（Ｃ_１〜Ｃ_４アルキル）、−ＣＮ、−ＮＯ_２、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_４アルキル）、−Ｃ（＝Ｏ）ＯＨ、−Ｃ（＝Ｏ）Ｏ（Ｃ_１〜Ｃ_４アルキル）、−ＮＨＣ（＝Ｏ）（Ｃ_１〜Ｃ_４アルキル）、−Ｃ（＝Ｏ）ＮＨ_２、および−Ｃ（＝Ｏ）Ｎ（Ｃ_１〜Ｃ_４アルキル）（Ｃ_１〜Ｃ_４アルキル）から選択される１〜３個の置換基で置換されていてもよく、
ｎは、０、１、２、３、４、および５から選択される整数である。

Where
X is H, halogen, —OH, —CN, —C ₁ -C ₄ alkyl substituted with 1 to 3 halogen atoms, or —O (C ₁ -C ₄ alkyl), —O ( _C 1 -C ₄ alkyl C ₁ -C ₄ alkyl) may be substituted with 1 to 3 halogen atoms,
Q is halogen, —OH, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ ). _{alkyl), - C (= O)} NH 2, -C (= O) NH (C 1 ~C 4 alkyl), - C (= O) N (C 1 ~C 4 _{alkyl) (C} 1 _{~C 4} alkyl _{), - NHS (= O)} 2 H or -NHS ₍₌ 0) or a ^{2 R 11,,}
Or Q forms a 5- or 6-membered cycloalkyl or heterocycloalkyl ring with either carbon atom adjacent to the carbon atom to which it is attached, thereby bicyclic to the phenyl to which it is attached. A fused ring system, wherein said heterocycloalkyl comprises 1 to 3 hetero moieties selected from O, S, -C (= O), and N, wherein said cycloalkyl or heterocycloalkyl May contain 1 or 2 double bonds,
R ¹ and R ² , together with the carbon to which they are attached, are bonded to C ₃ -C ₇ cycloalkyl or 1-3 hetero selected from O, S, —C (═O), and N Forms a 4-7 membered heterocycloalkyl containing moiety, said cycloalkyl or heterocycloalkyl may contain 1 or 2 double bonds, said cycloalkyl or heterocycloalkyl is C _6- C ₁₄ aryl or 5-14 membered heteroaryl group fused even if well,
Said C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl formed by R ¹ and R ² may each be substituted by 1 to 3 R ¹² groups, Each aryl or heteroaryl, which may be optionally substituted, may be independently substituted with 1 to 6 R ¹² groups, wherein the R ¹² group contains R ¹³ , R ¹⁶ , 1 or 2 unsaturated bonds. -C ₁ -C ₄ alkyl, _{^{halogen, -OR 13, -NO 2, -CN}} , -C 3 ~C 6 ^{cycloalkyl, -NR 13 R 14, -NR 13} C (= O) R 14, -C ( ^{= O) NR 13 R 14,} -OC (= O) R 13, -C (= O) OR 13, -C (= O) R 13, -NR 13 C (= O) OR 14, -NR 13 C (= O) NR ¹⁴ R ¹⁵ , -NR ¹³ S (= O ) ₂ R ¹⁴ , and —S (═O) ₂ R ¹³ ,
R ³ is C ₁ -C ₄ alkyl, and the C ₁ -C ₄ alkyl may contain 1 or 2 unsaturated bonds;
R ⁴ may contain one or two unsaturated bonds —C ₁ -C ₄ alkyl, —OH, —CN, —NO ₂ , —OR ¹⁶ , —NH ₂ , —NHR ¹⁶ , —NR ¹⁶ R ¹⁷ , or —NHC (═O) R ¹⁶ ,
R ⁵ and R ⁸ are each independently H or methyl;
R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are H;
R ¹¹ is C ₁ -C ₄ alkyl,-(C ₁ -C ₄ alkylene) -O- (C ₁ -C ₄ alkyl), 4- (1-methylimidazole),-(C ₁ -C ₄ alkylene). _{-NH 2, - (C 1 ~C} 4 alkylene) -NH _(C 1 ~C ₄ alkyl), - _(C 1 ~C ₄ alkylene) -N _(C 1 ~C _{4 alkyl) (C} 1 _{~C 4} alkyl )
Each R ¹³ , R ¹⁴ , and R ¹⁵ is independently H, R ¹⁶ , C ₁ -C ₄ alkyl, halogen, —OH, —SH, —NH ₂ , —NH (C ₁ -C ₄ alkyl). , -N _(C 1 _{~C 4 alkyl) (C} 1 _{~C 4 alkyl), - O (C 1 ~C} 4 _{alkyl), - S (C 1 ~C} 4 _{alkyl), - CN, -NO 2,} - _{C (= O) (C 1} ~C 4 alkyl), - C (= O) OH, -C (= O) O (C 1 ~C 4 _{alkyl), - NHC (= O)} (C 1 ~C 4 Alkyl), —C (═O) NH ₂ , and —C (═O) N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl) or R of —NR ¹³ R ^{14 13} and R ¹⁴ may be bonded to form a 4-6 membered heterocycloalkyl or heteroaryl group, its f Roariru group, N, S, O and -C (= O) may contain 1 to 3 other heteroatom moiety selected from,
Each R ¹⁶ and R ¹⁷ is independently selected from C ₆ -C ₁₄ aryl and 5-14 membered heteroaryl, wherein said heteroaryl is selected from O, S, —C (═O), and N 1 to 3 hetero moieties, wherein said aryl and heteroaryl may contain 1 or 2 unsaturated bonds, C ₁ -C ₄ alkyl, halogen, —OH, —SH, —NH ₂ , -NH _(C 1 _{~C 4 alkyl), - N (C 1 ~C} 4 _{alkyl) (C} 1 _{~C 4 alkyl), - O (C 1 ~C} 4 _{alkyl), - S (C 1 ~C} 4 _{alkyl), - CN, -NO 2,} -C (= O) (C 1 ~C 4 alkyl), - C (= O) OH, -C (= O) O (C 1 ~C 4 alkyl), - _{NHC (= O) (C 1} ~C 4 alkyl), - C (= O) NH 2, and - _{(= O) N (C 1} ~C 4 _alkyl) may be substituted with 1-3 substituents selected from _(C 1 -C ₄ alkyl),
n is an integer selected from 0, 1, 2, 3, 4, and 5.

  More preferred compounds are those of formula (II)

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｑ、ｎおよびＸは、上記に示した意味を有する。

In the formula, R ¹ , R ² , R ³ , R ⁴ , Q, n and X have the meanings indicated above.

Preferably R ³ is methyl, ethyl, isopropyl, or linear propyl.

Preferably, R ⁴ is —CN, —NO ₂ , —OH, —OCH ₃ , —CH ₂ OH, —NH ₂ , or —NHC (═O) CH ₃ .

Preferably, Q is F, —OH, —C (═O) NH ₂ , —NHS (═O) ₂ CH ₃ , —NHS (═O) ₂ CH ₂ CH ₃ , —NHS (═O) ₂ CH ₂ CH ₂ CH ₃ , —NHS (= 0) ₂ CH (CH ₃ ) (CH ₃ ), —NHS (═O) ₂ CH ₂ CH ₂ OCH ₃ , or —NHS (═O) ₂ (4- (1 -Methylimidazole)).

Preferably, X is, H, F, -OH, -C (= O) NH 2, or -CN.

Preferably, Q is halogen, —OH, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) (C ₁ -C _{4 alkyl), - C (= O)} NH 2, -C (= O) NH (C 1 ~C 4 alkyl), - C (= O) N (C 1 ~C 4 alkyl) _(C 1 ~ C ₄ alkyl), —NHS (═O) ₂ H, or —NHS (═O) ₂ R ¹¹ .

Preferably, R ¹ and R ² together with the carbon to which they are attached combine to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, each of which is substituted with 1 or 2 R ¹² groups May be.

Preferably, R ¹ and R ² together with the carbon to which they are attached form a cyclopentyl group or cyclohexyl group, the cyclopentyl group or cyclohexyl group being condensed with a benzene ring, The group or cyclohexyl group and / or the benzene ring may each be substituted with 1 or 2 R ¹² groups.

Preferably, R ¹ and R ² together with the carbon to which they are attached join to form a cyclobutyl group, which cyclobutyl group may be substituted with 1 or 2 R ¹² groups.

  Suitable methods for preparing such compounds are taught in WO 03/035622, the entire contents of which are hereby incorporated by reference.

Preferred compounds of the invention include
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl)- Methanesulfonamide;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl)- Methanesulfonamide citrate;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxymethyl-cyclopentyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl) -Methanesulfonamide;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro -Phenyl) -methanesulfonamide;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro -Phenyl) -methanesulfonamide besylate;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro-benzamide;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro-benzamide Tosylate;
Exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -methanesulfone An amide;
Exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -methanesulfone Amide mesylate;
Exo-2-methoxy-ethanesulfonic acid {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl]- Phenyl} -amide;
Exo-2-methoxy-ethanesulfonic acid (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0 hex-6-yl} -Phenyl) -amide;
Exo-3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide;
Exo-3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide citrate;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenol;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenol citrate;
Exo-2- [6-ethyl-6- (3-hydroxy-phenyl) -3-aza-bicyclo [3.1.0] hex-3-ylmethyl] -indan-2-ol;
Exo-3- {6-ethyl-3- [2- (2-hydroxy-indan-2-yl) -ethyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -benzamide;
(+/-)-exo-2-methoxy-ethanesulfonic acid {3- [6-ethyl-3- (2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -3-aza -Bicyclo [3.1.0] hex-6-yl] -phenyl} -amide;
(+)-Exo-N- {3- [6-ethyl-3- (2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -phenyl} -methanesulfonamide;
(−)-Exo-N- {3- [6-ethyl-3- (2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -phenyl} -methanesulfonamide;
Exo-3- [3- (2-hydroxy-indan-2-ylmethyl) -6-propyl-3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide;
Exo-3- {3- [3- (1- (1-hydroxy-cyclohexyl) -propyl] -6-propyl-3-aza-bicyclo [3.1.0] hex-6-yl} -benzamide;
Exo-N- (3- {3- [3- (1-cyano-cyclohexyl) -propyl] -6-ethyl-3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl)- Methanesulfonamide;
Exo-2-methoxy-ethanesulfonic acid {3- [3- (2-hydroxy-indan-2-ylmethyl) -6-propyl-3-aza-bicyclo [3.1.0] hex-6-yl]- Phenyl} -amide;
Exo-N- {3- [3- (2-hydroxy-indan-2-ylmethyl) -6-isopropyl-3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -methanesulfone An amide;
Exo-2-methoxy-ethanesulfonic acid (3- {3- [3- (1-hydroxy-cyclohexyl) -propyl] -6-isopropyl-3-aza-bicyclo [3.1.0] hex-6-yl } -Phenyl) -amide;
Exo-N- {3- [6-ethyl-3- (cis-1-hydroxy-3-phenyl-cyclobutylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl } -Methanesulfonamide;
Exo-3- [6-ethyl-3- (cis-1-hydroxy-3-phenyl-cyclobutylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide;
Exo-ethanesulfonic acid {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -amide And exo-ethanesulfonic acid (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl}- Phenyl) -amide;
And pharmaceutically acceptable salts thereof (if not specified).

  A preferred compound is exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl. } Methanesulfonamide (also referred to herein as Compound A) and pharmaceutically acceptable salts thereof. This compound has the structure (III).

  A particularly preferred compound is exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl]- Phenyl} methanesulfonamide mesylate.

  This compound can be prepared according to the preparation methods taught in WO 03/035622, the entire contents of which are incorporated by reference.

  The term “alkyl” as used herein includes saturated monovalent hydrocarbon groups having a straight or branched moiety, unless otherwise indicated. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

  The term “cycloalkyl”, as used herein, unless otherwise indicated, includes non-aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

  The term “aryl” as used herein, unless otherwise indicated, includes organic groups derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. It is.

  The term “heteroaryl” as used herein refers to an aromatic group containing one or more heteroatoms (O, S, or N), preferably 1 to 4 heteroatoms. A polycyclic group containing one or more heteroatoms in which at least one ring of the group is aromatic is a “heteroaryl” group. The heteroaryl groups of the present invention also include ring systems that are substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzoimidazolyl, cindazolyl , Indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydro Isoquinolyl, tetrahydroisoquinolyl, benzene Zofuriru, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.

  Since the above groups are derived from the compounds listed above, they may be C or N bonded where possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The terms referring to these groups also include all possible tautomers.

  An alternative preferred μ selective opioid antagonist has the structure (IV).

  Compound (IV) was prepared according to Lett. Pept. Sci. It can be prepared according to the method of 1998, 5, 193.

  An alternative preferred mu selective opioid antagonist is cyprodim. Cyprodigm is the structure

を有する。

Have

Additional mu-selective opioid receptor antagonists useful in the present invention include crocinnamox, etonizenenyl isothiocyanate, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen- _{Thr-NH 2), CTP (} D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2), CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr- Pen-Thr-NH ₂ ), TCTOP (D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH ₂ ), SMS-201, 995 (D-Phe-Cys-Phe-D- Trp-Lys-Thr-ol), β-funaltrexamine, naloxonazine Alvimopan include LY-246 736 and cyprodime.

  Preferably, the patient is also receiving hormone replacement therapy (HRT), more preferably HRT and additional androgen therapy. Drugs used include estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie as a combination), or estrogen and methyltestosterone hormone replacement therapy (eg HRT, especially premarin, senestine, estrofeminal) (Oestrofeminal), Equin, Estrace, Estrofem, Eleste Solo, Estrad, Estraderm TTS, Estraderm Matrix, Dermestril, Dermestril, Prempre, P Premix, Estra Test, Estra Strike HS, tibolone) is included. Agents for androgen therapy include testosterone replacement agents (including dehydroandrostenedione), testosterone (Tostrele), dihydrotestosterone or testosterone implants.

  Reference to an antagonist, agonist or inhibitor is always in their free form (eg free and / or base form) and all pharmaceutically acceptable salts, polymorphs, hydrates, silicates It should be understood that all active forms of such agents are included, including stereoisomers (eg, diastereoisomers and enantiomers) and the like. Active metabolites of any compound in any form are included.

  Specific formulations of compounds for oral delivery or topical application (creams, gels) are included in the present invention and are described herein. Also included in the invention are intravaginal formulations comprising a compound or combination of compounds as defined herein, preferably a cream or gel.

  A method of enhancing female sexual function comprising administering a selective mu opioid receptor antagonist to a healthy female is another aspect of the present invention.

  Furthermore, another aspect of the present invention is a method for screening compounds useful for treating FSD, preferably FSAD and / or FOD, wherein the compounds are screened for selective mu opioid receptor antagonist activity, Ki is less than 50 nM in a binding assay (see Example 1), preferably Ki is less than 10 nM, more preferably Ki is less than 1 nM, or Ki in a functional assay (see Example 1), preferably less than 50 nM Is a method comprising selecting a compound with a Ki of less than 10 nM, more preferably a Ki of less than 5 nM.

  As used herein, the term “efficacy” is a measure of the concentration at which a compound is effective. The potency of a compound can be determined in a binding assay as described in the protocol, where potency in this context occupies 50% of the receptor in the absence of any compound Ki, ie, radioligand. Refers to the concentration of competing ligand in the likely competition assay. The potency of the compounds can also be determined in functional assays such as contraction assays for various tissues expressing various receptor subtypes as described in Example 1.

Co-active agents suitable for use in the combination of the present invention include:
1) Compounds that modulate the action of natriuretic factors, in particular atrial natriuretic factor (also known as atrial natriuretic peptide), B-type and C-type natriuretic factor, such as neutral endopeptidase inhibitors In particular, the compound described and claimed in WO 02/02513, WO 02/03995, WO 02/079143 and EP-A-1258474, in particular the compound (2S) -2 {[1- { 3-4 (-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid,
2) a compound that inhibits angiotensin converting enzyme such as enalapril, and a combined inhibitor of angiotensin converting enzyme and neutral endopeptidase such as omapatrilate,
3) substrate for NO synthase such as L-arginine,
4) cholesterol-lowering drugs such as statins (eg atorvastatin / Lipitor ™) and fibrates,
5) Estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or lasofoxifene, their preparation is detailed in WO 96/21656 (−)-cis-6 Phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and pharmaceutically acceptable salts thereof,
6) PDE inhibitors such as PDE2 (eg erythro-9- (2-hydroxyl-3-nonyl) -adenine) and EP 0771799, Example 100 incorporated herein by reference, in particular EP-A- Pyrazolo [4,3-d] pyrimidin-7-one disclosed in US Pat. No. 0463756, pyrazolo [4,3-d] pyrimidin-7-one disclosed in EP-A-0 526004, published international patent application WO 93 / Pyrazolo [4,3-d] pyrimidin-7-one disclosed in 06104, the isomeric pyrazolo [3,4-d] pyrimidin-4-one disclosed in published international patent application WO 93/07149, published Quinazolin-4-one disclosed in international patent application WO 93/12095, disclosed in published international patent application WO 94/05661 Pyrido [3,2-d] pyrimidin-4-one, purin-6-one disclosed in published international patent application WO 94/00453, pyrazolo [4 disclosed in published international patent application WO 98/49166 , 3-d] pyrimidin-7-one, pyrazolo [4,3-d] pyrimidin-7-one disclosed in published international patent application WO 99/54333, pyrazolo [4 disclosed in EP-A-0999511 , 3-d] pyrimidin-4-one, pyrazolo [4,3-d] pyrimidin-7-one disclosed in published international patent application WO 00/24745, pyrazolo [4 disclosed in EP-A-099750. , 3-d] pyrimidin-4-one, compounds disclosed in published international application WO 95/19978, published international application WO 99/24433. Disclosed compounds and compounds disclosed in published international application WO 93/07124, pyrazolo [4,3-d] pyrimidin-7-ones disclosed in published international application WO 01/27112, published international application WO 01/27113 PDE5 inhibitors such as pyrazolo [4,3-d] pyrimidin-7-one, compounds disclosed in EP-A-1092718 and compounds disclosed in EP-A-1092719
7) More specifically, vasoactive intestinal protein (VIP) mediated by one or more of VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), VIP mimetics A VIP analog, VIP receptor agonist or VIP analog (eg, Ro125 1553) or one or more of VIP fragments, a combination of one or more of adrenergic receptor antagonists and VIP (eg, Inbicorp (Avicorp, Aviptadil),
8) Serotonin receptor agonists, antagonists or modulators, more particularly 5HT1A (VML670 [WO02 / 074288], flibanserin, including those described in WO-09902159, WO-0000002550 and / or WO-00028993 [US2003 / 0104980] and OPC14523 [US2007 / 0142395]) agonists, antagonists or modulators for 5HT2A, 5HT2C, 5HT3 and / or 5HT6 receptors,
9) dehydroandrostenedione, testosterone (including Tostorel and Intrinsa), testosterone supplements including dihydrotestosterone or testosterone implant
10) Selective androgen receptor modulators such as LGD-2226,
11) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie as a combination), or estrogen and methyltestosterone hormone replacement therapy (eg HRT, especially premarin, senestine, estrofeminal, equine, estrace) , Estrofem, eleste solo, estring, estraderm TTS, estraderm matrix, dermestril, purine phase, prenepro, prenepac, premic, estratest, estratest HS, tibolone
12) Progesterone agonists or modulators such as progesterone, guestdin, ethinyl estradiol, ethinnodiol, etonogesterol implants, dihydrogesterone, progestogen, tetresecbens, norethinodrel or progesterone creams such as MuProgest, Natragest and Fem-Gest Agent or gel agent,
13) Modulators of transporters of noradrenaline, dopamine and / or serotonin such as bupropion, GW-320659,
14) an agonist or modulator for the oxytocin / vasopressin receptor, preferably a selective oxytocin agonist or modulator,
15) Melanocortin receptor agonists or modulators (including PT-141 [bremeranotide] and melanotan-II), preferably selective MCR3, MCR3 / 4 and / or MCR4 melanocortin agonists or modulators (MB-243, RO0282425) And the compounds described in WO 2005/77935 and PCT / IB07 / 000456),
16) Noradrenaline (norepinephrine) reuptake inhibitor (NRI), especially reboxetine (racemic (R, R / S, S), or optically pure (S, S) enantiomeric forms, especially (S, S) Selective NRI such as -reboxetine), dapoxetine, paroxetine, 3-[(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 28, WO0172687), 3-[(dimethyl Amino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 12, WO0218333), N-methyl-N-({3- [3-methyl-4- (methyl Sulfanyl) phenoxy] -4-pyridinyl} methyl) amine (Example 38, PCT Application No. PCT / B02 / 01032) selective serotonin reuptake inhibitor (SSRI) serotonin reuptake inhibitors including such as (SRI), or dopamine reuptake inhibitors (DRI) monoamine transport inhibitor, such as,
17) Pramipexole (Pharmacia Upjohn compound number PNU95666), ropinirole, apomorphine, surmanirole, quinerolane, PNU-142774, bromocriptine, carbergoline, lisuride, WO2004 / 115237, WO2005 / 116027, WO2005 / 111527 Dopamine agonists (especially selective D2, selective D3, selective D4 and selective D2-like agents),
18) one or more alpha adrenergic receptor antagonists (also known as alpha adrenergic receptor blockers, alpha receptor blockers or alpha blockers) (for suitable alpha ₁ adrenergic receptor antagonists, , Phentolamine, prazosin, phentolamine mesylate, trazodone, alfuzosin, indolamine, naphthopidyl, tamsulosin, phenoxybenzamine, laurophia alkaloid, record 15/2739, SNAP1069, SNAP5089, RS17053, SL89.0591, doxazosin, WO9830560 19, terazosin and Abanokiru contains, suitable alpha ₂ adrenergic receptor antagonist, Jibenarunin (dibenarnine), tolazoline, trimazosin, Efaroki , Yohimbine, idazoxan and clonidine, suitable non-selective alpha adrenergic receptor antagonists include dapiprazole, and other alpha adrenergic receptor antagonists, each of which is incorporated herein by reference. PCT application WO 99/30697 published on June 14, 1998 and U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836; No. 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 252,721 and 2,599,000),
19) anti-diabetic agents such as aldose reductase inhibitors such as zolpolrestat, glycogen phosphorylase or sorbitol dehydrogenase inhibitors, and 20) one or more NPY receptor modulators (agonists and / or antagonists) Drugs), for example, NPY-Y1, NPY-Y2, NPY-Y5 or modulators with complex pharmacology at these receptors.

  Regarding cross-references herein to patents and compounds included in patent applications that can be used in accordance with the present invention, we refer to the claims (especially in claim 1) and specific examples (all of which are referenced) Refers to a therapeutically active compound as defined in US Pat.

  When administering a combination of active agents, they can be administered simultaneously, separately or sequentially.

Adjunct—PDE5 Inhibitor Particularly preferred herein as an adjunct activator is a PDE5 (or PDEV) inhibitor.

  The suitability of any particular cGMP PDE5 inhibitor is assessed using literature methods for its potency and selectivity, followed by its toxicity, absorption, metabolism, pharmacokinetics, etc. according to standard pharmaceutical practice. Can be easily determined.

IC ₅₀ values for cGMP-PDE5 inhibitors can be determined using the PDE5 assay (see herein below and WO 01/27113).

  The cGMP-PDE5 inhibitor used in the pharmaceutical combination according to the invention is preferably selective for the PDE5 enzyme. It is preferred that the inhibitor (when used orally) is more selective than for PDE3, more preferably than for PDE3 and PDE4. It is preferred (orally) that the cGMP-PDE5 inhibitors of the present invention have a selectivity ratio over PDE3, more preferably over PDE3 and PDE4, more preferably over 300.

The selectivity ratio can be easily determined by one skilled in the art. IC ₅₀ values for the PDE3 and PDE4 enzymes are described in the established literature methodology (S A Ballard et al., Journal of Urology, 1998, Vol. 159, pages 2164-2171, as detailed herein below. ) Can be used.

  Suitable cGMP PDE5 inhibitors for use in accordance with the present invention include pyrazolo [4,3-d] pyrimidin-7-one, disclosed in EP-A-0463756, EP-A-0526004. Pyrazolo [4,3-d] pyrimidin-7-one, disclosed in published international patent application WO 93/06104, pyrazolo [4,3-d] pyrimidin-7-one, disclosed in published international patent application WO 93/07149 Isomers of pyrazolo [3,4-d] pyrimidin-4-one, quinazolin-4-one disclosed in published international patent application WO 93/12095, disclosed in published international patent application WO 94/05661 Pyrido [3,2-d] pyrimidin-4-one, purine-6-disclosed in published international patent application WO 94/00453 Pyrazolo [4,3-d] pyrimidin-7-one disclosed in published international patent application WO 98/49166, Pyrazolo [4,3-d] pyrimidine- disclosed in published international patent application WO 99/54333 7-one, pyrazolo [4,3-d] pyrimidin-4-one disclosed in EP-A-0999511, pyrazolo [4,3-d] pyrimidine- disclosed in published international patent application WO 00/24745 7-one, pyrazolo [4,3-d] pyrimidin-4-one disclosed in EP-A-099750, hexahydropyrazino [2 ′, 1 ′ disclosed in published international application WO 95/19978: 6,1] pyrido [3,4-b] indole-1,4-dione, EP-A-1092719 and published international application WO99 / 24433 Embedded image imidazo [5,1-f] [1,2,4] triazin-ones, as well as bicyclic compounds disclosed in published international application WO 93/07124, all of which are incorporated herein by reference. Shall be incorporated into the document.

  Other examples of PDE5 inhibitors suitable for use herein include pyrazolo [4,3-d] pyrimidin-7-one, published international application WO01, disclosed in published international application WO01 / 27112. / 27113 disclosed pyrazolo [4,3-d] pyrimidin-7-one, compounds disclosed in EP-A-1092718 and compounds disclosed in EP-A-1092719, EP-A-1241170 A tricyclic compound disclosed in published international application WO 02/074744, an alkyl sulfone compound disclosed in published international application WO 02/072586, a compound disclosed in published international application WO 02/072586, a compound disclosed in published international application WO 02/079203 , Compounds described in WO01187882, described in WO0056719 Compound, for example, a compound described in BMS-341400, WO9966044, for example, a compound described in BMS-263504, EP-1057829 (Jordanian Pharmaceutical Manufacturing and Medical Equipment Company), a compound described in EP722936, WO93 The compounds described in 07124, the compounds described in WO 98/06722, the compounds described in EP 579496, in particular the compounds described in ONO 1505 (Ono), WO 97/03070, in particular OPC35564 (Otsuka), and WO 02 / 074312, all of which are incorporated herein by reference. Written is intended to be.

  Still other examples of PDE5 inhibitors suitable for use herein include the carboline derivatives described in WO03000691, WO02098875, WO02064591, WO02064590 and WO01068888, the pyrazino [1 ′, 2 ′: 1,6] pyrido [3,4-B] indole 1,4-dione derivatives, tetracyclic compounds described in WO02098428, compounds described in WO02088123 and WO0200656, described in WO0238563 and WO02000657 Condensed pyrazinedione derivatives, indole derivatives described in WO0236593, condensed pyrindoles (pyr described in WO0228865 and WO0228859) ndol) derivatives, hexahydropyrazino [1 ′, 2 ′: 1,6] -pyrido [3,4-B] indole-1,4-dione derivatives described in WO0228858 and WO0194345, described in WO0210166 Fused heterocyclic derivatives, cyclic GMP specific phosphodiesterase inhibitors described in WO0200658, tetracyclic diketopiperazine compounds described in WO0194347, compounds described in WO0298877 and applications described in WO0219213 All of which are incorporated herein by reference.

  Still other examples of PDE5 inhibitors suitable for use herein include the compounds described in WO0164192, DE10104800, WO0259126, DE10104095, WO0249651, DE10063224, DE10060338, DE10058662, and WO0200660. Are all incorporated herein by reference.

Still other PDE5 inhibitors useful in conjunction with the present invention include:
4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyridazinone,
1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinozolinyl] -4-piperidine-carboxylic acid, monosodium salt
(+)-Cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenylmethyl-5-methyl-cyclopenta-4,5] imidazo [2,1- b] Purin-4 (3H) -one, furazulocillin,
Cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopenta [4,5] -imidazo [2,1-b] purin-4-one,
3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate,
3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate,
4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3 (2H) pyridazinone,
1-methyl-5 (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-one,
1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium salt
Pharmaprojects No. 4516 (Glaxo Wellcome), Pharmaprojects No. 5051 (Bayer), Pharmaprojects No. 5064 (Kyowa Hakko; see WO96 / 26940), Pharmaprojects No. 5069 (Schering Plow), ER-118585, E-8010, E-4021 and E-4010 (Eisai), Bay-38-3045 and 38-9456 (Bayer), FR181074, FR229934 and FR226807 (Fujisawa), TA-1032 , T-0156 and TA-1790 (Tanabe Seiyaku), EMD82639 and EMR6203 (Merck), LAS34179 and LAS35917 (Almirall), Sch-51866, BMS-223131 (Bristol Myers Squibb), NCX724, NCX724, NCX724 ABT-670 (Abbott) is included.

Preferred PDE5 inhibitors for use in accordance with the present invention include
(I)
1-[[3- (6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl]- 5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-, also known as 4-methylpiperazine 7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) (see EP-A-0463756),
(Ii)
5- (2-Ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (EP-A- 052604)),
(Iii)
3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 98/49166),
(Iv)
3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6 -Dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO99 / 54333),
(V)
3-ethyl-5- {5- [4-ethylpiperazin-1-ylsulfonyl] -2-([(1R) -2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2-methyl (+)-3-ethyl-5- [5- (4-ethylpiperazin-1-yl), also known as -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one Sulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (See WO99 / 54333),
(Vi)
1- {6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl]- 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [also known as 3-pyridylsulfonyl} -4-ethylpiperazine 2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 8),
(Vii)
5- [2-Iso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl) -2,6- Dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15),
(Viii)
5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one (see WO 01/27113, Example 66),
(Ix)
5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-on (see WO01 / 27112, Example 124),
(X)
5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-one (see WO 01/27112, Example 132),
(Xi)
(6R, 12aR) -2,3,6,7,12,12a-Hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ′, 1 ′: 6,1] pyrido [3,4-b] indole-1,4-dione (tadalafil, IC-351, Cialis®), ie the compounds of Examples 78 and 95 of published international application WO 95/19978, and Examples 1, 3 , 7 and 8 compounds,
(Xii)
1-[[3- (3,4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl]- 2- [2-Ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo, also known as 4-ethylpiperazine [ 5,1-f] [1,2,4] triazin-4-one (Vardenafil), ie the compounds of Examples 20, 19, 337 and 336 of published international application WO 99/24433,
(Xiii) pyrazolo [4,3-d] pyrimidin-4-ones disclosed in WO 00/27848, in particular N-[[3- (4,7-dihydro-1-methyl-7-oxo-3-propyl -1H-pyrazolo [4,3-d] -pyrimidin-5-yl) -4-propoxyphenyl] sulfonyl] -1-methyl 2-pyrrolidinepropanamide [DA-8159 (Example 68 of WO 00/27848),
(Xiv) the compound of Example 11 of published international application WO 93/07124,
(Xv) 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazoline,
(Xvi) 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1H-imidazo [4,5-g] quinazoline,
(Xvii)
1- [3- [1-[(4-Fluorophenyl) methyl] -7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazolin-6-yl] -4-propoxyphenyl] Carboxamide,
(Xviii)
5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-on, and (xix)
1- {6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl]- 3-pyridylsulfonyl} -4-ethylpiperazine,
(Xx)
7- (3-Bromo-4-methoxyphenylmethyl) -1-ethyl-8-{[(1R, 2R) -2-hydroxycyclopropyl] amino} -3- (2-hydroxyethyl) -3,7- Dihydro-1H-purine-2,6-dione [dasantafil, SCH-446132], and pharmaceutically acceptable salts and solvates thereof are included.

  The suitability of any particular PDE5 inhibitor should be assessed using literature methods for its potency and selectivity, followed by its toxicity, absorption, metabolism, pharmacokinetics, etc. according to standard pharmaceutical practice. Can be easily determined.

It is preferred that the PDE5 inhibitor has an IC ₅₀ of less than 100 nanomolar, more preferably less than 50 nanomolar, more preferably even less than 10 nanomolar.

IC ₅₀ values for PDE5 inhibitors can be determined using the PDE5 assay described herein below.

The PDE5 inhibitor used in the pharmaceutical combination according to the invention is preferably selective for the PDE5 enzyme. They preferably have a selectivity of PDE5 over PDE3 of over 100, more preferably over 300. More preferably, the PDE5 inhibitor has a selectivity greater than both PDE3 and PDE4 greater than 100, more preferably greater than 300. The selectivity ratio can be easily determined by one skilled in the art. IC ₅₀ values for the PDE3 and PDE4 enzymes are described in the established literature methodology (S A Ballard et al., Journal of Urology, 1998, Vol. 159, pages 2164-2171, as detailed herein below. ) Can be used.

  Regarding cross-references herein to patents and compounds included in patent applications that can be used in accordance with the present invention, we refer to the claims (especially in claim 1) and specific examples (all of which are referenced) Refers to a therapeutically active compound as defined in US Pat.

  When administering a combination of active agents, they can be administered simultaneously, separately or sequentially.

Pharmaceutically acceptable salts Pharmaceutically acceptable salts are organic and inorganic acids such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, when the compound of the invention contains a basic moiety. Fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfone It can be formed from acids and similarly known acceptable acids. Salts can also be formed from organic and inorganic bases, preferably alkali metal salts such as sodium, lithium, or potassium, when the compounds of the invention contain an acidic moiety.

Asymmetry The compounds of the present invention may contain asymmetric carbon atoms, and some of the compounds of the invention contain one or more asymmetric centers, resulting in optical isomers and diastereomers. There is. Although shown without regard to stereochemistry, the present invention includes such optical isomers and diastereomers, as well as racemic and resolved enantiomerically pure R and S stereoisomers, and Other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof are included. It is recognized that one optical isomer, including diastereomers and enantiomers, or stereoisomers may have favorable properties over others. Thus, when disclosing and claiming the present invention, where one racemic mixture is disclosed, both optical isomers, including stereoisomers and enantiomers substantially free of others, or stereoisomerism It is expressly intended that the body be disclosed and claimed in the same way.

Pharmaceutical Compositions The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of an agent of the present invention and a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).

  The pharmaceutical composition may be for human or veterinary use in human medicine and veterinary medicine and usually comprises any one or more of pharmaceutically acceptable diluents, carriers or excipients. I will. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro, 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition may be any suitable one or more binders, one or more lubricants, one or more suspensions, as a carrier, excipient or diluent, or otherwise. Agent, one or more coating agents, and one or more solubilizers.

  Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

  There may be different composition / formulation requirements depending on the different delivery systems. By way of example, the pharmaceutical composition of the invention may be used with a minipump or by the mucosal route, for example as a nasal spray or aerosol or ingestible solution for inhalation, or the composition may be, for example, intravenous, muscle It can be formulated for parenteral delivery that is formulated in an injectable form for delivery by the internal or subcutaneous route. Alternatively, the formulation can be designed to be delivered by both routes.

  If the drug must be delivered by the mucosal route through the gastrointestinal mucosa, it must be able to remain stable while passing through the gastrointestinal tract, eg it is resistant to proteolysis and stable at acid pH. There must be resistance to the cleaning effect of bile.

  If desired, the pharmaceutical composition may be by inhalation, in the form of a suppository or vaginal suppository, topically in the form of a lotion, solution, cream, ointment or spray, by use of a skin patch, starch or lactose, etc. Orally in the form of tablets containing any of the excipients, or alone or in admixture with excipients in capsules or cavity suppositories, or elixirs, solutions or suspensions containing flavoring or coloring agents It can be administered in the form of an agent or the pharmaceutical composition can be injected parenterally, eg intravenously, intramuscularly or subcutaneously. For parenteral administration, the composition can optimally be used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, the compositions can be administered in the form of tablets or lozenges that can be formulated in conventional manner.

  In some embodiments, the agents of the present invention can also be used in combination with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may alter the solubility, dissolution rate, bioavailability and / or stability properties of the drug molecule. In general, drug-cyclodextrin complexes are useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, for example as a carrier, diluent or solubilizer. α-, β- and γ-cyclodextrins are most commonly used and suitable examples are disclosed in WO-A-91 / 11172, WO-A-94 / 02518 and WO-A-98 / 55148. Has been.

  In preferred embodiments, the agents of the invention are delivered systemically (orally, buccally, sublingually, etc.), more preferably orally.

  Accordingly, the drug is preferably in a form suitable for oral delivery.

Administration Compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products, or can exist in a series of solid states from fully amorphous to fully crystalline. . They can be obtained by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporative drying, for example as solid plugs, powders or films. Microwave or radio frequency drying can be used for this purpose.

  They may be administered alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or as any combination thereof). it can. Generally, they should be administered as a formulation with one or more pharmaceutically acceptable excipients. As used herein, the term “excipient” is used to describe any ingredient other than one or more compounds of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

  Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for preparing them will be readily apparent to those skilled in the art. Such compositions and methods for preparing them can be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

  The compounds of the present invention can be administered orally. Oral administration is one in which the compound is swallowed to enter the gastrointestinal tract, or buccal or sublingual administration where the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include, for example, tablets, capsules containing microparticles, liquids or powders, lozenges (including liquids), chews, multiparticulate and nanoparticulates, gels And solid preparations such as solid solutions, liposomes, films, vaginal suppositories, and sprays, as well as liquid preparations.

  Liquid preparations include, for example, suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and are usually carriers, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils, and one or more emulsifiers. And / or a suspending agent. Moreover, a liquid formulation can be prepared by reconstitution of solid, for example from a sachet.

  The compounds of the present invention can also be used in fast-dissolving, fast-disintegrating dosage forms such as the dosage forms described by Liang and Chen in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001).

  For tablet dosage forms, depending on dosage, the drug may make up from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In general, tablets contain a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch And sodium alginate. Generally, the disintegrant will comprise 1% to 25%, preferably 5% to 20% by weight of the dosage form.

  In general, binders are used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Also, tablets are diluted with lactose (monohydrate, spray dried monohydrate, anhydrous etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and dicalcium phosphate dihydrate etc. An agent can be contained.

  Tablets may also contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surfactant may comprise from 0.2% to 5% by weight of the tablet and the glidant may comprise from 0.2% to 1% by weight of the tablet.

  Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Generally, the lubricant comprises 0.25% to 10%, preferably 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

  Exemplary tablets include up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and lubricant From about 0.25% to about 10% by weight of the agent.

  Tablet blends can be compressed directly or by roller to make tablets. Alternatively, the tablet blend or portion of the blend can be wet, dry, or melt granulated, melt coagulated or extruded prior to tableting. The final formulation comprises one or more layers and may or may not be coated or encapsulated. Tablet formulation is described in H.C. Lieberman and L.L. Discussed in “Pharmaceutical Dosage Forms: Tablets” by Lachman, Volume 1 (Marcel Dekker, New York, 1980).

  Oral films that can be consumed for human or animal use are usually flexible, water-soluble or water-swellable thin film dosage forms that may be fast dissolving or mucoadhesive and are usually of formula (I ) Compounds, film-forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Some components of the formulation may perform more than one function.

  The compounds of the present invention may be water soluble or water insoluble. Usually, the water-soluble compound comprises 1% to 80% by weight of the solute, more typically 20% to 50%. Less soluble compounds can account for the majority of the composition, typically up to 88% by weight of the solute. Alternatively, the compound may be in the form of multiparticulate beads.

  The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is usually present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

  Other possible ingredients include antioxidants, colorants, flavors and seasonings, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, fillers, antifoams, interfaces Active agents and taste masking agents are included.

  Usually, the film according to the present invention is prepared by evaporating and drying a thin aqueous film coated on a peelable backing support or paper. This can be done in a drying oven or tunnel dryer, usually a composite coater dryer, or by freeze drying or vacuum suction.

  Solid formulations for oral administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  Suitable modified release formulations for the purposes of the invention are described in US Pat. No. 6,106,864. Details of other suitable release techniques such as high energy dispersion and osmotic pressure and coated particles can be found in “Pharmaceutical Technology On-line” by Verma et al., 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention can also be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion techniques. Typically, parenteral formulations are aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably a pH of 3-9), but for some applications, as sterile non-aqueous solutions Or more suitably formulated in dry form and used in conjunction with a suitable vehicle such as sterilized pyrogen-free water. Preparation of parenteral formulations under aseptic conditions, eg, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

  The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as the incorporation of solubility enhancers. Formulations for parenteral administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release. That is, the compounds of the present invention can be formulated as solids, semisolids, or thixotropic liquids for administration as implantable depots that provide controlled release of the active compound. Examples of such formulations include drug-coated stents and DL-lactic-glycolic acid copolymers (PGLA) microspheres.

  The compounds according to the invention can also be administered topically to the skin or mucosa, ie dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, implants, Sponges, fibers, bandages and microemulsions are included. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Permeation enhancers can be incorporated. See, for example, J Pharm Sci, 88 (10), 955-958 (October 1999) by Finnin and Morgan. Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject ™, Bioject ™, etc.) injection . Formulations for topical administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  Also, the compounds of the present invention are usually administered intranasally or by inhalation, usually from a dry powder inhaler to a dry powder (alone, for example, as a mixture in a dry blend with lactose, or mixed with a phospholipid such as phosphatidylcholine As mixed component particles) or with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane Regardless, it can be administered as a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to generate a fine mist), or an aerosol spray from a nebulizer. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or one or more jets as a suitable alternative agent, solvent for dispersion, solubilization, or extended release of the active substance Solutions or suspensions of one or more compounds of the invention comprising an agent and an optional surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be done by any suitable comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg, made of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or insufflators are suitable powder bases such as compounds of the invention, lactose or starch and l-leucine, mannitol, or stearin. It can be formulated to contain a powder mix of motion modifiers such as magnesium acid. Lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  A solution formulation suitable for use in an atomizer using electrohydrodynamics to generate a fine mist contains 1 μg to 20 mg of the compound of the invention per operation, and the operating volume varies from 1 μl to 100 μl. There is. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Appropriate flavors such as menthol and levomenthol, or sweeteners such as saccharin or saccharin sodium can be added to the formulations of the invention intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration can be formulated to be immediate release and / or modified release using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a certain amount. Usually the unit according to the invention is arranged to administer a certain amount or “puff” containing 2 to 30 mg of a compound of formula (I). Usually, the total daily dose is in the range of 50-100 mg which can be administered in a single dose or, more usually, as divided doses throughout the day.

  The compounds of the present invention can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as needed. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the present invention may also be administered directly to the eye or ear, usually in the form of a finely divided suspension or solution drop in isotonic pH adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses and niosomes. Or includes microparticles such as liposomes or vesicular systems. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum, together with preservatives such as benzalkonium chloride Can be incorporated. Such formulations can also be delivered by iontophoresis. Formulations for ocular / ear administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the present invention can be combined with soluble polymers such as cyclodextrins and appropriate derivatives thereof or polyethylene glycol-containing polymers and their solubility, dissolution rate, taste masking for use in any of the aforementioned administration methods. Bioavailability and / or stability can be improved. For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, ie carriers, diluents, or solubilizers. Α-, β- and γ-cyclodextrins are most commonly used for these purposes, examples of which are found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148. be able to.

  The compositions of the present invention can be administered by direct injection.

  For some applications, the drug is preferably administered orally.

  A particular advantage of the compounds of formulas (I), (II) and (III) above, in particular, is that they are orally active.

  For some applications, the drug is preferably administered locally.

Dosage level The exact dose that would normally be most appropriate for an individual subject will be determined by a physician. The specific dosage level and frequency of dose for any particular individual is the activity of the particular compound used, the metabolic stability and length of action of that compound, age, weight, overall health, gender, It will vary depending on a variety of factors including diet, method and time of administration, excretion rate, drug combination, severity of the particular condition, and the individual being treated. The agents and / or pharmaceutical compositions of the invention can be administered according to a dosage regimen of 1 to 10 times per day, such as once or twice per day.

  For oral and parenteral administration to humans, the daily dose level of the drug may be a single dose or a divided dose.

  Depending on the need, the drug can be administered at a dosage of 0.01-30 mg / kg body weight, such as 0.1-10 mg / kg, more preferably 0.1-1 mg / kg body weight. Of course, the doses mentioned herein are examples of an average case. It goes without saying that there may be individual cases where higher or lower dosage ranges are valuable.

  The daily oral dose is preferably 0.1 to 100 mg. The daily dose is more preferably 0.5 to 20 mg. Furthermore, the daily dose is more preferably 1 to 10 mg. Further, the daily dose is more preferably 2 to 5 mg. Most preferably, the daily dose is about 3 mg.

  Appropriate dosages will include dosages that allow a satisfactory therapeutic effect ratio between the treatment of female sexual dysfunction, particularly FSAD, and the induction of vomiting or other side effects.

Formulation The agent of the present invention is formulated into a pharmaceutical composition, such as by mixing with one or more of suitable carriers, diluents or excipients, using techniques known in the art. Can be

  The following are some non-limiting examples of formulations.

  Formulation 1: Tablets are prepared using the following ingredients:

成分を混合して圧縮し、各々の重量が６６５ｍｇである錠剤を形成する。

The ingredients are mixed and compressed to form tablets each weighing 665 mg.

  Formulation 2: An intravenous formulation can be prepared as follows.

Individual As used herein, the term “individual” refers to a member of a vertebrate, particularly a mammalian species. The term includes but is not limited to livestock, sport animals, primates and humans.

  The compounds of the invention apply to the following subpopulations of FSD patients: young women with or without hormone replacement therapy, older premenopausal, pre-menopausal and post-menopausal women.

  It should be understood that all references herein to treatment include curative, palliative and prophylactic treatment.

The compounds of the present invention
i) Angiogenic etiology such as cardiovascular or atherosclerotic disease, hypercholesterolemia, smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the subiliac abdominal genital vasculature,
ii) Central nervous system diseases including spinal cord injury or multiple sclerosis, diabetes, parkinsonism, cerebrovascular stroke, peripheral neuropathy, trauma or radical pelvic surgery, neurogenic etiology,
iii) Hypothalamic / pituitary / gonadal dysfunction, or ovarian dysfunction, pancreatic dysfunction, surgical or medical gonadectomy, androgen deficiency, high circulating levels of prolactin, eg hyperprolactinemia, natural Hormonal / endocrine pathogenesis such as menopause, premature menopause, hyperthyroidism and hypothyroidism,
iv) Depression, obsessive-compulsive disorder, anxiety disorder, postpartum depression / "baby blue", emotional and relational problems, performance anxiety, marital discord, non-functional attitude, sexual phobia, religious inhibition Or psychogenic etiology such as a traumatic past experience, and / or v) therapy with selective serotonin reuptake inhibitors (SSRI) and other antidepressant therapies (tricyclic antidepressants and major tranquilizers), Applies to FSD patients due to drug-induced dysfunction resulting from antihypertensive therapy, sympathetic blockade, long-term oral contraceptive pill therapy.

Bioavailability The compounds (and combinations) of the present invention are preferably orally bioavailable. Oral bioavailability refers to the proportion of orally administered drug that reaches the systemic circulation. Factors that determine the oral bioavailability of a drug are dissolution, membrane permeability and metabolic stability. Oral bioavailability is usually determined using an in vitro technique followed by a screening cascade of in vivo techniques.

  Dissolution, ie, solubilization of the drug by the aqueous content of the gastrointestinal tract (GIT), can be predicted from in vitro solubility experiments performed at an appropriate pH that mimics GIT. The compounds of the invention preferably have a minimum solubility of 50 mcg / ml. Solubility is measured in Adv. Drug Deliv. Rev. 23, 3-25, 1997 can be determined by standard procedures known in the art.

Membrane permeability refers to the passage of compounds through the cells of GIT. Lipophilicity is an important property that predicts membrane permeability and is defined by in vitro LogD _7.4 measurements using organic solvents and buffers. The compounds of the present invention preferably have a LogD _7.4 of -2 to +4, more preferably -1 to +2. logD is J. Pharm. Pharmacol. 1990, 42: 144 can be determined by standard procedures known in the art.

Cell monolayer assays such as caco2, the so-called caco-2 flux, substantially increase the prediction of favorable membrane permeability in the presence of efflux transporters such as p-glycoprotein. It is preferred that the compounds of the invention have a caco-2 flux greater than 2 × 10 ⁻⁶ cms ⁻¹ , more preferably greater than 5 × 10 ⁻⁶ cms ⁻¹ . The caco flux value is J. Pharm. Sci. 1990, 79, 595-600, and can be determined by standard procedures known in the art.

  Metabolic stability is directed to the ability of the GIT or liver to metabolize compounds during the absorption process, ie the first pass effect. Assay systems such as microsomes, hepatocytes, etc. predict metabolic instability. The compounds of the examples preferably exhibit metabolic stability in an assay system commensurate with a liver extraction of less than 0.5. Examples of assay systems and data manipulation are described in Curr. Opin. Drug Disc. Dev. 201, 4, 36-44, Drug Met. Disp. 2000, 28, 1518-1523.

  Due to the interaction of the above processes, further support that the drug is orally bioavailable in humans can be obtained by in vivo experiments in animals. In these studies, absolute bioavailability is determined by administering the compounds separately or as a mixture by the oral route. In the case of absolute determination (% absorption), the intravenous route is also used. An example of assessment of oral bioavailability in animals is given in Drug Met. Disp. 2001, 29, 82-87; Med Chem, 1997, 40, 827-829, Drug Met. Disp. 1999, 27, 221-226.

  Preferred features of each aspect of the invention are the same for each of the other aspects mutatis mutandis.

Protocol Protocol 1: Protocol for determining MOR antagonist activity μFLIPR protocol:
Transient cotransfection protocol (PER PLATE) cell line: Hek293T
HOPM complete medium: for 1 liter DMEM
100mL heat inactivated FBS
10mL L-glutamine 10mL Pen / Strep
10mL Geneticin G418

Inoculation The day before transfection, 7xe6 cells are seeded in T-175.

Cell Preparation Cells are collected with 2 mL of 0.25% trypsin from T-175 60% confluent.
Leave trypsin in the flask for about 5 minutes.
Close the flask once and resuspend the cells in 8 mL of complete medium.
Pipette the suspension up and down several times and transfer to a 50 mL polypropylene tube.
Spin down the cells for 5 minutes at 1,000 rpm.
Decant the supernatant and resuspend in 15 mL complete medium.
Counting cells gives a cell density of 4 × e5 cells per mL.
If necessary, dilute cells to a final volume of 15 mL of complete medium.

Transfection mix Set two polypropylene 14 mL tubes.
Add 1 mL DMEM serum-free medium and 70 mL Fugene 6 reagent to the first tube.
Add 1.84 mg HOPM DNA, 1.6 mg GqI5 and 10 mg pcDNA to the second tube.
Incubate for 5 minutes at room temperature.
Add DMEM / Fugene mix dropwise to DNA and mix gently.
The mixture is allowed to incubate for 20 minutes at room temperature.
Add the mixture dropwise to the cell suspension.
Mix gently by gently inverting the tube several times.
Add 130 mL per well to Black / Clear poly-d-lysine coated FLIPR plates.
Place in a 37 ° C. incubator for 48 hours.

Assay reagents:
Assay buffer 1 liter pH 7.4

プロベネシド（Ｐｒｏｂｅｎｉｃｉｄ）混合物

Probenicid mixture

細胞色素培地ＰＥＲ ＰＬＡＴＥ

Cell dye medium PER PLATE

Assay protocol:
One hour prior to assay, the cell plate is loaded with dye and incubated at 37 ° C. in a non-sterile incubator. Repel excess pigment. Wash plates with assay buffer in a Skatron plate washer.
Allow cells to equilibrate for 20-30 minutes.
Using FLIPR 384, drug is added at the first addition and monitored for 2 minutes at 2 second intervals.
Plates are preincubated with drug for 20 minutes.
The second addition is an agonist competitor (400 nM DAMGO), which is added and monitored for 2 minutes at 2 second intervals.
Data is analyzed using Excel and Graph Pad.

Interpretation Data are interpreted by characterizing the functional activity of a compound as an antagonist or agonist.

Protocol 2: Human δ opioid receptor competitive binding protocol (using ³ H-Nartrindole)
3H-Nartrindole Binding Assay Materials and Equipment:
Assay buffer—-50 mM Tris HCl pH 7.4, 5 mM MgCl ₂ , 100 ug / ml bacitracin, 1.08 μg / ml bestatin, and 0.3 μM thiorphan (at room temperature).
Polypropylene 96 well plate.
3H-Natrindole, NEN, NET-1065, 32 Ci / mmol, or Tocris Cookson, R740, 50 Ci / mmol, ˜0.5 nM.
CHO cells expressing the human opioid receptor (HOPD).
Membrane buffer 50 mM Tris HCl pH 7.4 and 1 mM EGTA.
Brinkmann PT3000 Polytron.
Wash buffer-50 mM Tris HCl, and 5 mM MgCl _2, (at 4 ° C.) pH 7.4.
Skatron harvester.
Whatman GF / C glass fiber filter polyethyleneimine (PEI).

Cell membrane preparation At 37 ° C, HOPD cells are removed from the bottom of the flask using D-PBS containing 5 mM EDTA. The detached cells are spun for 15 minutes at 18,000 rpm in an SS-34 rotor in a SORVALL centrifuge. Resuspend the pellet in 50 volumes of membrane buffer (50 mM Tris HCl pH 7.4, and 1 mM EGTA) using Polytron for 20 seconds at 15,000 rpm. Spin as above and resuspend pellet to a final concentration of 10 μg per well (0.4 mg / ml stock).

Binding assay Incubation mixture: 25 μl total, compound (at 10 ×), or blank 200 μl ³ H-NTI (˜0.5 nM final concentration) 25 μl cell membrane (-10 μg protein / well).

The reaction is initiated by adding cell membranes to each well of a polypropylene 96 well plate containing ³ H-NTI and an appropriate blank, competitor, or vehicle. Non-specific binding is estimated using 1 μM cold Narthindole. Incubate for 90 minutes at 37 ° C. The reaction is terminated by rapid filtration over Whatman GF / C filters (presoaked for at least 1 hour in 0.6% PEI) using a Skatron Green Machine harvester with program 555. The filter disc is allowed to air dry overnight, then placed in a sample bag and counted in a Betaplate counter.

Interpretation Data are expressed as Ki's (concentration occupying half of the receptor). If Ki is not obtained from the assay, report the inhibition at the highest dose tested. All data is analyzed using linear regression with the Quickbasic Beta software program.

Protocol 3: kappa opioid receptor binding protocol CHO-K1 cells expressing the human kappa opioid receptor are purchased as membrane preparations from Receptor Biology. Thaw a 400 microassay vial (volume 1 mL), add to 79 mL of assay buffer (50 mM Tris HCl, pH 7.4, 10 mM MgCl ₂ ) and homogenize with Polytron. Keep the tissue on ice. Compounds are solubilized in 100% DMSO and diluted in assay buffer. The blank is 10 μM naloxone and the ligand is 2 nM 3H diprenorphine (NEN # NET1121). Add 25 μL of compound, buffer or blank, followed by 25 μL of ³ H DPN and 200 μL of membrane to a 96 well polypropylene plate. Plates are incubated for 1 hour at room temperature on an orbital shaker. The assay is then collected on a Wallac print filter mat A presoaked in 0.5% PEI using a Skatron harvester and 50 mM Tris HCL pH 7.4 as wash buffer. Filters are dried overnight and counted the next day on a Betaplate counter for later analysis.

Interpretation Data is analyzed using Excel to determine IC ₅₀ and Ki values.

Protocol 4: GTPγS antagonist binding in flash plates for μ and δ and κ The specific activity of GTPγS is 1100-1200 Ci / mmole. http: // www. grafpad. The actual concentration of the stock is determined using a com radioactivity calculator. The final concentration of GTPγ ³⁵ S is 0.1 nM (stock 0.4 nM, 4 ×).

Plate setup:
Add 2 μl of 100 × compound to the plate. The final concentration in the assay plate is 10 ⁻⁵ to 10 ⁻¹⁰ − Controls include 2 μl cold 1 mM GTPγS (non-specific), 2 μl DMSO buffer (total) and 2 μl DMSO (basic, no agonist) Must be included-Add 50 μl of 0.4 nM GTPγS to all wells-Add 128 μl (5 μg) of homogenized membrane in assay buffer to all wells (homogenize membrane in dounce)
-Shake briefly-Incubate for 10 minutes at 30 ° C-In every well except the basal (add 20 μl buffer), 10 μM b-endorphin for μ in assay buffer, or 10 nM BW373U86 for δ, Add 20 μl each of 100 nM dynorphin A to κ − Shake briefly − Incubate 60 minutes at 30 ° C. − Rotate 10 minutes at 1000 × G (2500 rpm) − Count 100 × protease inhibitor:
10 mg / ml bacitracin 10 mg / ml benzamidine 0.5 mg / ml aprotinin 0.5 mg / ml leupeptin Note:
-Keep assay buffer fresh-Keep assay buffer at room temperature during experiment-Make protease inhibitors at 100x concentration and store at -20 ° C

Binding Test: Selective Affinity of Compound A for μ Opioid Receptor The affinity and selectivity of Compound A binding to μ, δ, and κ opioid receptor subtypes were evaluated in a radioligand binding test. The affinity of Compound A for mu opioid receptors was determined using membrane preparations from Chinese hamster ovary (CHO) cells that stably express human mu opioid receptors. Compound A displaced the binding of [ ³ H] DAMGO to the human μ receptor with a K _i value of 0.88 ± 0.22 nM. Similar K _i values of 0.76 ± 0.19 nM were also obtained for rodent μ receptors (data not shown).

1, ^[3 H] DAMGO from binding to each human opioid receptors (mu ^{receptors), [3} H] naltrindole ([delta] receptor) and ^[3 H] compound of diprenorphine (kappa receptors) A substitution by A is shown.

Affinity for the δ receptor was determined using CHO cells expressing the human δ opioid receptor. Compound A displaced the [ ³ H] naltrindole bond with a K _i value of 2510 ± 578 nM.

Characterization of the binding of Compound A to the kappa receptor utilized HEK-T293 cells that stably express the human kappa receptor. In membrane binding studies, Compound A displaced [ ³ H] diprenorphine binding with a K _i value of 353 ± 140 nM.

In Vitro Test for Functional Activity of Compound A at the μ and κ Opioid Receptors Binding tests show the affinity of a compound for binding to a recognition site, but are not very helpful in understanding its functional effects. An additional in vitro test was performed on Compound A to assess its functional activity at the transiently expressed μ and κ receptors in CHO cells.

Three opioid receptors are all normally interact with heterotrimeric G proteins, particularly G _i and G _o. Because these proteins negatively couple opioid receptors to adenyl cyclase, opioid receptor activation leads to a decrease in cAMP concentration, which is often difficult to detect. However, the use of HEK cells that transiently express both the mu opioid receptor and the chimeric G protein results in the mobilization of intracellular Ca ⁺⁺ stores. Using a fluorescence imaging plate reader (FLIPR), changes in intracellular Ca ⁺⁺ concentration are imaged in real time using changes in Fluo-4 fluorescence.

DAMGO-induced increase in intracellular concentration of Ca ⁺⁺ was inhibited by Compound A in a dose-dependent manner with a K _i value of 2.9 ± 1.5 nM (N = 4). In contrast, Compound A, antagonize the increase induced by intracellular ^{Ca ++} by U-50,488 is a κ receptor selective agonist, _{K i} values are 72.8 ± 28nM (N = 4; Fig. 2).

FIG. 2 shows the inhibition by Compound A of the increase in intracellular Ca ⁺⁺ in CHO cells transiently transfected with μ receptor (square) and G _αQi5 G protein or κ receptor (circle) and G _αQi5 G protein. Shown, DAMGO (400 nM) is an agonist used to stimulate the μ receptor and U-50,488 (400 nM) activated the kappa receptor. Representative curve from 3 measurements.

  Table 1 summarizes the important pharmacological properties of Compound A.

Animal Care Rats were maintained in a light reverse cycle (09: 0 to 21:00 hours in the dark) for a minimum of 3 weeks prior to each test. During this period, animals received food and water ad libitum and were housed with one sex in groups of five. All behavioral tests were performed from 12:00 to 17:00 hours (during the dark period) under half-lux lighting conditions.

  The experiment was subject to local ethical review in accordance with UK law.

A-Receptivity model.
The test was performed in a separate circular Perspex arena with a diameter of about 50 cm. Test females were placed in an arena containing active male rats with sexual experience. Males were mounted 10 times with test females and the number of sexual behaviors was recorded.

Treatment of test females 48 hours before the test day, test females were administered 5 μg / rat estrogen subcutaneously. On the day of the test, progesterone (50 μg / rat subcutaneous) was administered to the test female and a preliminary test was performed 3-4 hours later to establish a pre-dose lordosis index and acceptability score. Test females were then given oral test compound (compound A), test compound vehicle (deionized water (5 mL / kg oral)), internal standard naloxone hydrochloride (2 mg / kg subcutaneous) or internal standard vehicle (saline 0.9%). w / v 1 mL / kg subcutaneously).

  Hormone replacement therapy (HRT) animals serve as positive controls and are primed to lead to a complete behavioral estrus exhibiting the highest receptive and active behavior. HRT animals received 5 μg / rat estrogen subcutaneously 48 hours prior to the test day and 1 mg / kg progesterone on the test day, but no preliminary test was performed.

  All females dosed with Compound A or deionized water were tested 60 and 120 minutes after dosing.

  Females receiving naloxone hydrochloride or saline were tested 30 minutes after administration.

Scoring method Receptivity was assessed using the Rhodosis index. The frequency of female lordosis (allowing / requiring dorsiflexion to occur) is recorded as a ratio of 10 mounts by sexually active male rats and expressed as a percentage. .

  Receptivity was also assessed using a receptivity score (RS) incorporating other behaviors in addition to rhodosis in response to male mounts.

A score criterion of 0 is assigned when a female stands and refuses on the hind legs, for example, in active avoidance behavior such as scolding and kicking in response to a mount,
1 is assigned if the male can be mounted with or without insertion, but the female does not show the lordosis position and remains stationary or leaves,
2 is assigned when a male mounts a female with or without insertion but forces the female to have a lordosis posture (the reaction of the lordosis is not complete)
3 is assigned when the male can be mounted with or without insertion and the female remains stationary during the interaction while showing a full lordosis posture,
Using the above criteria, behavioral outcomes in response to 10 mounts were recorded. The average receptivity score was calculated for each rat by summing the scores for each mount and then dividing by the number of mounts, ie 10.

Statistics and data analysis Receptivity score and Rhodosis index calculation Receptive behavior was recorded and scored on a score sheet using the criteria described above. Data from these sheets was transferred to an Excel spreadsheet. Using Excel, dividing the number of lordosis responses by 10 mounts and multiplying by 100, Compound A, deionized water (5 mL / kg), naloxone hydrochloride and saline (0.9% w / v) Rhodosis index per rat was calculated for each dose of 1 mL / kg).
Rhodosis index (LQ) = ((number of lordosis responses / 10) ^* 100.

Also, using Excel, one rat for each dose of Compound A, deionized water (5 mL / kg), naloxone hydrochloride and saline (0.9% w / v 1 mL / kg) using the following formula: The average acceptability score per hit was calculated.
Average acceptability score = Σ behavior score ^* (frequency of behavioral responses / 10)

  The calculated lordosis index and receptivity score were then averaged per treatment group, which was used to generate the mean receptivity score and lordosis index per treatment group and standard error of the mean (SEM). These data were used to generate graphs of mean lordosis index and acceptability score during the pre-test and 120 minutes post-dose treatment group.

  Statistical analysis was performed using the analysis of variance (ANOVA) package from Excel add-in LabStats (Tessella). The non-clinical statistics group recommended a number of different statistical methods for analyzing data including ANOVA, paired and unpaired t-tests.

Exclusion Criteria Animals that were deemed to be over or under acceptable in the preliminary test were excluded from the analysis. Under-receptive animals did not show the minimal receptive behavior expected from previous studies of combined estrogen-progesterone priming. Therefore, underaccepted animals were considered unlikely to be improvers and did not show any improvement by intervention with the test compound, as they did not respond well to hormonal priming . The minimum acceptable acceptability score for adoption in the study was 0.6 or higher. Over-receptive animals showed higher acceptable receptive behavior than expected for combined estrogen-progesterone priming based on previous studies. Over-receptive animals were also considered unlikely to be improvers because of the few treatment opportunities that showed some improvement with compound intervention. Over-receptive animals could result in false positives due to increased sensitivity to hormonal priming. The highest acceptable acceptability score and lordosis index for adoption in the study were 1.6 or less and 50% or less, respectively.
≧ 0.6 Acceptable range of acceptability score ≦ 1.6
Allowable range of Rhodosis index ≦ 50%

  Prior priming and proof-of-concept tests were used to observe the typical sexual and non-sexual behavior of females receiving combined estrogen-progesterone priming. Sexual (over-receptive and under-receptive animals—defined by the parameters above) and non-sexual (ie, stress or anxiety behaviors, eg, females that are sitting in a sitting position and rounded in one corner) Females who deviated from normal behavior in both were excluded from the study. They were obvious outliers. Because this test was not designed to pick up such behavior, this exclusion criterion was qualitative and not an observed phenomenon. (Approval from non-clinical statistics as a means of working from a limited population).

Analysis of acceptability scores ANOVA was used to analyze acceptability scores using preliminary test scores as covariates. Preliminary test values of acceptability scores (ie, prior to administration of Compound A, naloxone hydrochloride and their respective vehicles) showed a normal distribution that was the basis for using ANOVA. However, after administration of Compound A, naloxone hydrochloride or their respective vehicles, the treatment group dispersions were no longer comparable. ANOVA assumes a normal distribution and equal variance of values between treatment groups that do not apply to this study.

  In addition to ANOVA, a paired t-test was also used to compare the post-dose receptivity score of the treatment group at each test time point (VS) their own preliminary test receptivity score. An unpaired t-test comparing Compound A and naloxone hydrochloride acceptability scores versus their respective vehicles at each test time point was also applied. The statistical consequences from these t-tests were not different from ANOVA. However, since the t-test uses multiple comparisons, there was a greater risk of statistical error and therefore the results from ANOVA were felt to be more robust.

Analysis of lordosis index The lordosis index was analyzed using ANOVA and the preliminary test LQ as a covariate. Preliminary test lordosis index showed slope distribution and unequal variance between treatment groups. In addition, there was a high proportion of zero lordosis responses. ANOVA assumes normal distribution and equal variance and is not very robust for data containing a higher percentage of zeros. Scoring for the Rhodes index is categorical data or count data, but there is no consensus on the most appropriate method for analyzing the Rhodes index.

material:
Test substance Compound A (mesylate). MW 522.69
Naloxone hydrochloride (Sigma) lot number 064K0687, product number N7758. MW 399.87

Steroidal hormone β-estradiol 3-benzoate (Sigma) lot number 013K0586, product number E8515. MW 376.49
Progesterone (Organics) lot number A0222735. MW314.46

Test Compound Dosage Preparation Compound A was dissolved in deionized water and 20.3 mg / 5 mL (194 nM) (corresponding to a maximum dose of 16.7 mg / kg multiplied by a 1.22 correction factor due to salt). A stock solution was made. Subsequent dilutions were made using deionized water as the diluent.

  Naloxone hydrochloride was dissolved in saline (0.9% w / v 1 mL / kg) and made 30 minutes before use.

Steroidal Hormone Dosage Preparation 20 μg / β-estradiol 3-benzoate stock solution for rat prime was prepared as 100 μg / ml (0.266 nM) in corn oil. Corn oil was used as a diluent and subsequent dilutions were made.

  A 1000 μg / rat progesterone stock solution for priming was prepared as 5000 μg / ml (15.9 nM) in corn oil. Corn oil was used as a diluent and subsequent dilutions were made.

Dose level Compound A: 0.00167, 0.0167, 0.5, 1.67, 5 and 16.7 mg / kg (194 nM) Oral administration (PO).
Naloxone hydrochloride: 2 mg / kg (5 nM) administered subcutaneously (SC).
β-estradiol 3-benzoate: 5 μg / rat subcutaneous administration (SC).
Progesterone: 50 μg / rat and 1 mg / rat subcutaneously administered (SC).

Dosing volume Compound A: 5 mL / kg
Naloxone hydrochloride: 1 mL / kg
β-estradiol 3-benzoate: 0.2 ml / rat Progesterone: 0.2 ml / rat

Vehicle Compound A: Deionized water Naloxone hydrochloride: Saline (0.9% w / v)
β-estradiol 3-benzoate: corn oil Progesterone: corn oil

Results Compound A was administered at doses of 0.5 (p = 0.499), 1.67 (p = 0.021), 5 (p = 0.0002) and 10 (120 minutes after administration) compared to vehicle. p = 0.01) caused a statistically significant increase in acceptability score at mg / kg (FIG. 3).

  The summary figure (FIG. 3) shows the mean receptivity score at the pretest and 120 minutes after dosing calculated as an average value for each animal for each dose of Compound A or deionized water (Compound A vehicle). Show.

  Further, as shown in FIG. 4, Compound A is administered at doses of 0.0167 (p = 0.029), 0.5 (p = 0.041), 1.67 compared to vehicle 120 minutes after administration. It caused a statistically significant increase in lordosis index at (p = 0.065), 5 (p = 0.0003) and 16.7 (p = 0.0025) mg / kg (FIG. 4).

  Therefore, Compound A enhances the receptive behavior of female rats.

B-Active model The treatment of the test animals was the same as that of the acceptability model described above.

  Activeness was assessed by counting otorrhea. Otoirism is a rapid vibration of the ear that accompanies an increase in prosexual receptive behavior similar to sexual desire and interest.

  Ear tremors were counted 120 minutes after administration for Compound A (0.00167-16.7 mg / kg) oral. Using the otorhysmic score, the average otollytic score per treatment group and the standard error of the mean (SEM) were calculated. Using this data, a graph of the average ear tremor score per treatment at 120 minutes post-dose compared to vehicle was generated.

  The materials used, including the dosage preparation and dosage level, were the same as in the acceptability model described above.

Results Compound A caused a significant increase in mean ear tremor at doses of 0.0167, 0.5, 1.67, 5 and 16.7 mg / kg compared to vehicle at 120 minutes post-dose (FIG. 5). Therefore, Compound A enhances active behavior in female rats.

CONCLUSION In view of the effectiveness of Compound A to enhance active and receptive behavior in female rats, Compound A and other selective mu opioid receptor antagonists are used to treat and / or prevent female sexual dysfunction (FSD). It can be concluded that

  Suitable selective mu opioid receptor antagonists such as exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0 ] Hex-6-yl] -phenyl} methanesulfonamide (mesylate), a clinical trial using Compound A, was published in a published trial using sildenafil (Caruso, S. et al. (2001) BJOG 108, 623 628; Berman, JR et al. (2001) J Sex Marital Ther 27, 411-420).

  Briefly, women with FSAD are given an appropriate dose of compound or placebo. One skilled in the art should be able to determine the appropriate dosage for the compound to be used, and for the two compounds mentioned above, a dosage range of 0.1-50 mg can be used. This test can be performed over a suitable period of time, for example 6 weeks.

  Women are healthy premenopausal women aged 20 to 45 years who regularly use oral contraceptives. Women with other serious illnesses that cause female sexual dysfunction, women on regular use of drugs known to cause female sexual dysfunction, and those who gave birth during or 12 months prior to the study Exclude women who are planning to become pregnant.

  Evaluation of treatment effectiveness is based on physiological measurements in the clinic (eg, maximal systolic velocity and end diastole in the clitoris, labia (vestibular bulb), urethra, and vaginal arteries using dual Doppler ultrasonography. Measuring blood flow velocity, vaginal pH using a digital pH meter, maximum intravaginal pressure / volume change using a commercially available compliance balloon, vibration perception threshold recorded from the clitoris, and right and left using a standard biometric meter By evaluating and quantifying questionnaires, diary events such as subjective excitement, orgasm, fun, number of satisfied sexual experiences, frequency of intercourse, and number of sexual fantasies) It can be carried out.

  The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light of them should be suggested to those skilled in the art, and the spirit of the present application It should be understood that it should be included within the scope.

^[3 H] DAMGO from binding to each human opioid receptors (mu ^receptors), the substitution of Compound A ^[3 H] naltrindole ([delta] receptor) and ^[3 H] diprenorphine (kappa receptors) FIG. FIG. 5 shows inhibition by Compound A of an increase in intracellular Ca ⁺⁺ in CHO cells transiently transfected with μ receptor (square) and G _αQi5 G protein or κ receptor (circle) and G _αQi5 G protein. . DAMGO (400 nM) is an agonist used to stimulate the μ receptor and U-50,488 (400 nM) activates the kappa receptor. Representative curve from 3 measurements. FIG. 5 shows the effect of Compound A and naloxone hydrochloride on mean receptivity scores in OVX female rats treated with subthreshold hormone priming—5 μg estrogen and 50 μg progesterone. The acceptability score was calculated during the preliminary test (ie before administration of the test compound) and 120 minutes after administration of Compound A (0.000167-16.7 mg / kg oral) and deionized water (5 mL / kg oral). . Data are mean acceptability score ± SEM. Compound A vehicle (n = 7), 0.00167 mg / kg Compound A (n = 5), 0.0167 mg / kg Compound A (n = 8), 0.5 mg / kg Compound A (n = 8) 67 mg / kg Compound A (n = 8), 5 mg / kg Compound A (n = 4), 16.7 mg / kg Compound A (n = 5). Statistical significance was calculated using the analysis of variance (ANOVA) package from Excel add-in LabStats (Tessella), and acceptability scores for all treatment groups and time points were Compound A, deionized water (Compound A vehicle). The average value of each animal for each dose of was calculated. “Compound A veh” (or “veh”) = Compound A vehicle = Deionized water (vehicle for Compound A). The predicted free plasma level (nM) of Compound A is shown at the beginning of each dose response. FIG. 6 shows the effect of Compound A on mean lordosis index in OVX female rats treated with subthreshold hormone prime—5 μg estrogen and 50 μg progesterone. The lordosis index was calculated 120 minutes after administration of Compound A (0.000167 to 16.7 mg / kg oral). Data are mean values of Rhodesis index ± SEM. Compound A vehicle (n = 7), 0.00167 mg / kg Compound A (n = 5), 0.0167 mg / kg Compound A (n = 8), 0.5 mg / kg Compound A (n = 8) 67 mg / kg Compound A (n = 8), 5 mg / kg Compound A (n = 4) and 16.7 mg / kg Compound A (n = 5). Statistical significance for each dose group was calculated using the analysis of variance (ANOVA) package from Excel add-in LabStats (Tessella) for Compound A vehicle. The Rhodosis index for all dose groups was calculated as the average value of each animal for each dose of Compound A and Compound A vehicle (deionized water). “Compound A veh” (or “veh”) = Compound A vehicle (vehicle for Compound A) = deionized water. ( ^* = P <0.1, ^** = p <0.05, ^*** = p <0.001). FIG. 5 shows the effect of Compound A on mean ear frequency in OVX female rats treated with subthreshold hormone priming—5 μg estrogen and 50 μg progesterone. Ear tremor was calculated 120 minutes after administration of Compound A (0.00167 to 16.7 mg / kg oral). Data are mean + SEM. Compound A vehicle (n = 7), 0.00167 mg / kg Compound A (n = 5), 0.0167 mg / kg Compound A (n = 8), 0.5 mg / kg Compound A (n = 8) 67 mg / kg Compound A (n = 8), 5 mg / kg Compound A (n = 4) and 16.7 mg / kg Compound A (n = 5).

Claims (22)

  Use of a selective mu opioid receptor antagonist in the preparation of a medicament for treating and / or preventing female sexual dysfunction (FSD).   The use according to claim 1, wherein the selective mu opioid receptor antagonist is at least 10-fold selective for the mu opioid receptor over the kappa opioid receptor in a functional assay.   3. Use according to claim 1 or 2, wherein the selective mu opioid receptor antagonist is at least 50-fold selective for the mu opioid receptor over the kappa opioid receptor in a functional assay.   Use according to any of the preceding claims, wherein the selective mu opioid receptor antagonist is 10-fold selective for the mu opioid receptor over the delta opioid receptor in a functional assay.   Use according to any of the preceding claims, wherein the selective mu opioid receptor antagonist is at least 50-fold selective for the mu opioid receptor over the delta opioid receptor in a functional assay.   Use according to any of the preceding claims, wherein the selective mu opioid receptor antagonist is at least 50-fold selective for the mu opioid receptor over the kappa and delta opioid receptors in a functional assay.   Selective mu opioid receptor antagonists are functionally selective for mu opioid receptors compared to kappa opioid receptors, and that selectivity is achieved by naltrexone when using the same assay Use according to any of the preceding claims, which is at least three times the functional selectivity.   8. Use according to claim 7, wherein the selectivity is at least 5 times the functional selectivity achieved by naltrexone.   Selective mu opioid receptor antagonists are functionally selective for mu opioid receptors compared to delta opioid receptors, and that selectivity is achieved by naltrexone when using the same assay Use according to any of the preceding claims, which is at least three times the functional selectivity.   10. Use according to claim 9, wherein the selectivity is at least 5 times the functional selectivity achieved by naltrexone.   Use according to any preceding claim, wherein the female sexual dysfunction is female sexual arousal disorder (FSAD).   Use according to any one of claims 1 to 10, wherein the female sexual dysfunction is female orgasmic disorder (FOD) or anorgasmia.   The use according to any one of claims 1 to 10, wherein the female sexual dysfunction is hyposexual desire disorder (HSDD).   Use according to any of the preceding claims, wherein the selective mu opioid receptor antagonist compound is administered orally, buccally or sublingually. Use according to any of the preceding claims, wherein the compound is formula (I) or a pharmaceutically acceptable salt thereof.

[Where:
X is H, halogen, —OH, —CN, —C ₁ -C ₄ alkyl substituted with 1 to 3 halogen atoms, or —O (C ₁ -C ₄ alkyl), —O ( _C 1 -C ₄ alkyl C ₁ -C ₄ alkyl) may be substituted with 1 to 3 halogen atoms,
Q is halogen, —OH, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ ). _{alkyl), - C (= O)} NH 2, -C (= O) NH (C 1 ~C 4 alkyl), - C (= O) N (C 1 ~C 4 _{alkyl) (C} 1 _{~C 4} alkyl _{), - NHS (= O)} 2 H or -NHS ₍₌ 0) or a ^{2 R 11,,}
Or Q forms a 5- or 6-membered cycloalkyl or heterocycloalkyl ring with either carbon atom adjacent to the carbon atom to which it is attached, thereby bicyclic to the phenyl to which it is attached. A fused ring system, wherein said heterocycloalkyl comprises 1 to 3 hetero moieties selected from O, S, -C (= O), and N, wherein said cycloalkyl or heterocycloalkyl May contain 1 or 2 double bonds,
R ¹ and R ² , together with the carbon to which they are attached, are bonded to C ₃ -C ₇ cycloalkyl or 1-3 hetero selected from O, S, —C (═O), and N Forms a 4-7 membered heterocycloalkyl containing moiety, said cycloalkyl or heterocycloalkyl may contain 1 or 2 double bonds, said cycloalkyl or heterocycloalkyl is C _6- C ₁₄ aryl or 5-14 membered heteroaryl group fused even if well,
Said C ₃ -C ₇ cycloalkyl or 4-7 membered heterocycloalkyl formed by R ¹ and R ² may each be substituted by 1 to 3 R ¹² groups, Each aryl or heteroaryl, which may be optionally substituted, may be independently substituted with 1 to 6 R ¹² groups, wherein the R ¹² group contains R ¹³ , R ¹⁶ , 1 or 2 unsaturated bonds. -C ₁ -C ₄ alkyl, _{^{halogen, -OR 13, -NO 2, -CN}} , -C 3 ~C 6 ^{cycloalkyl, -NR 13 R 14, -NR 13} C (= O) R 14, -C ( ^{= O) NR 13 R 14,} -OC (= O) R 13, -C (= O) OR 13, -C (= O) R 13, -NR 13 C (= O) OR 14, -NR 13 C (= O) NR ¹⁴ R ¹⁵ , -NR ¹³ S (= O ) ₂ R ¹⁴ , and —S (═O) ₂ R ¹³ ,
R ³ is C ₁ -C ₄ alkyl, and the C ₁ -C ₄ alkyl may contain 1 or 2 unsaturated bonds;
R ⁴ may contain one or two unsaturated bonds —C ₁ -C ₄ alkyl, —OH, —CN, —NO ₂ , —OR ¹⁶ , —NH ₂ , —NHR ¹⁶ , —NR ¹⁶ R ¹⁷ , or —NHC (═O) R ¹⁶ ,
R ⁵ and R ⁸ are each independently H or methyl;
R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are H;
R ¹¹ is C ₁ -C ₄ alkyl,-(C ₁ -C ₄ alkylene) -O- (C ₁ -C ₄ alkyl), 4- (1-methylimidazole),-(C ₁ -C ₄ alkylene). _{-NH 2, - (C 1 ~C} 4 alkylene) -NH _(C 1 ~C ₄ alkyl), - _(C 1 ~C ₄ alkylene) -N _(C 1 ~C _{4 alkyl) (C} 1 _{~C 4} alkyl )
Each R ¹³ , R ¹⁴ , and R ¹⁵ is independently H, R ¹⁶ , C ₁ -C ₄ alkyl, halogen, —OH, —SH, —NH ₂ , —NH (C ₁ -C ₄ alkyl). , -N _(C 1 _{~C 4 alkyl) (C} 1 _{~C 4 alkyl), - O (C 1 ~C} 4 _{alkyl), - S (C 1 ~C} 4 _{alkyl), - CN, -NO 2,} - _{C (= O) (C 1} ~C 4 alkyl), - C (= O) OH, -C (= O) O (C 1 ~C 4 _{alkyl), - NHC (= O)} (C 1 ~C 4 Alkyl), —C (═O) NH ₂ , and —C (═O) N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl) or R of —NR ¹³ R ^{14 13} and R ¹⁴ may be bonded to form a 4-6 membered heterocycloalkyl or heteroaryl group, its f Roariru group, N, S, O and -C (= O) may contain 1 to 3 other heteroatom moiety selected from,
Each R ¹⁶ and R ¹⁷ is independently selected from C ₆ -C ₁₄ aryl and 5-14 membered heteroaryl, wherein said heteroaryl is selected from O, S, —C (═O), and N 1 to 3 hetero moieties, wherein said aryl and heteroaryl may contain 1 or 2 unsaturated bonds, C ₁ -C ₄ alkyl, halogen, —OH, —SH, —NH ₂ , -NH _(C 1 _{~C 4 alkyl), - N (C 1 ~C} 4 _{alkyl) (C} 1 _{~C 4 alkyl), - O (C 1 ~C} 4 _{alkyl), - S (C 1 ~C} 4 _{alkyl), - CN, -NO 2,} -C (= O) (C 1 ~C 4 alkyl), - C (= O) OH, -C (= O) O (C 1 ~C 4 alkyl), - _{NHC (= O) (C 1} ~C 4 alkyl), - C (= O) NH 2, and - _{(= O) N (C 1} ~C 4 _alkyl) may be substituted with 1-3 substituents selected from _(C 1 -C ₄ alkyl),
n is an integer selected from 0, 1, 2, 3, 4, and 5.] Compound is
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl)- Methanesulfonamide;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl)- Methanesulfonamide citrate;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxymethyl-cyclopentyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl) -Methanesulfonamide;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro -Phenyl) -methanesulfonamide;
Exo-N- (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro -Phenyl) -methanesulfonamide besylate;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro-benzamide;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -5-fluoro-benzamide Tosylate;
Exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -methanesulfone An amide;
Exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -methanesulfone Amide mesylate;
Exo-2-methoxy-ethanesulfonic acid {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl]- Phenyl} -amide;
Exo-2-methoxy-ethanesulfonic acid (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0 hex-6-yl} -Phenyl) -amide;
Exo-3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide;
Exo-3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide citrate;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenol;
Exo-3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -phenol citrate;
Exo-2- [6-ethyl-6- (3-hydroxy-phenyl) -3-aza-bicyclo [3.1.0] hex-3-ylmethyl] -indan-2-ol;
Exo-3- {6-ethyl-3- [2- (2-hydroxy-indan-2-yl) -ethyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -benzamide;
(+/-)-exo-2-methoxy-ethanesulfonic acid {3- [6-ethyl-3- (2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -3-aza -Bicyclo [3.1.0] hex-6-yl] -phenyl} -amide;
(+)-Exo-N- {3- [6-ethyl-3- (2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -phenyl} -methanesulfonamide;
(−)-Exo-N- {3- [6-ethyl-3- (2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -phenyl} -methanesulfonamide;
Exo-3- [3- (2-hydroxy-indan-2-ylmethyl) -6-propyl-3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide;
Exo-3- {3- [3- (1- (1-hydroxy-cyclohexyl) -propyl] -6-propyl-3-aza-bicyclo [3.1.0] hex-6-yl} -benzamide;
Exo-N- (3- {3- [3- (1-cyano-cyclohexyl) -propyl] -6-ethyl-3-aza-bicyclo [3.1.0] hex-6-yl} -phenyl)- Methanesulfonamide;
Exo-2-methoxy-ethanesulfonic acid {3- [3- (2-hydroxy-indan-2-ylmethyl) -6-propyl-3-aza-bicyclo [3.1.0] hex-6-yl]- Phenyl} -amide;
Exo-N- {3- [3- (2-hydroxy-indan-2-ylmethyl) -6-isopropyl-3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -methanesulfone An amide;
Exo-2-methoxy-ethanesulfonic acid (3- {3- [3- (1-hydroxy-cyclohexyl) -propyl] -6-isopropyl-3-aza-bicyclo [3.1.0] hex-6-yl } -Phenyl) -amide;
Exo-N- {3- [6-ethyl-3- (cis-1-hydroxy-3-phenyl-cyclobutylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl } -Methanesulfonamide;
Exo-3- [6-ethyl-3- (cis-1-hydroxy-3-phenyl-cyclobutylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -benzamide;
Exo-ethanesulfonic acid {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} -amide And exo-ethanesulfonic acid (3- {6-ethyl-3- [3- (1-hydroxy-cyclohexyl) -propyl] -3-aza-bicyclo [3.1.0] hex-6-yl}- Phenyl) -amide;
16. The use according to claim 15, wherein said compound is selected from said non-salt form, pharmaceutically acceptable salts thereof.   The compound is exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} The use according to claim 16, which is methanesulfonamide or a pharmaceutically acceptable salt thereof.   The compound is exo-N- {3- [6-ethyl-3- (2-hydroxy-indan-2-ylmethyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -phenyl} The use according to claim 17, which is methanesulfonamide mesylate. A selective mu opioid receptor antagonist in the preparation of a medicament for treating and / or preventing female sexual dysfunction;
i) a compound that modulates the action of natriuretic factor, in particular atrial natriuretic factor,
ii) a compound that inhibits angiotensin converting enzyme,
iii) a substrate for NO synthase,
iv) cholesterol-lowering drugs,
v) estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists,
vi) phosphodiesterase (PDE) inhibitors,
vii) vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, VIP receptor agonists or VIP fragments, or a combination of an adrenergic receptor antagonist and VIP,
viii) serotonin receptor agonists, antagonists or modulators,
ix) testosterone supplements or testosterone implants,
x) selective androgen receptor modulators,
xi) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie in combination), or estrogen and methyltestosterone hormone replacement therapy,
xii) agonists or modulators of progesterone such as progesterone, guestdin, ethinyl estradiol, ethinnodiol, etonogesterol implant, dihydrogesterone, progestogen, tetresecbens, norethinodrel or progesterone creams such as MuProgest, Natragest and Fem-Gest Agent or gel agent,
xiii) modulators of noradrenaline, dopamine and / or serotonin transporters,
xiv) agonists or modulators of oxytocin / vasopressin receptors,
xv) a melanocortin receptor agonist or modulator,
xvi) monoamine transport inhibitors,
xvii) dopamine agonists (especially selective D2, selective D3, selective D4 and selective D2-like agents),
xviii) α-adrenergic receptor antagonists (also known as α-adrenergic receptor blockers, α-receptor blockers or α-blockers),
xix) Use in combination with an adjuvant selected from one or more of antidiabetic agents, and xx) NPY receptor modulators (agonists and / or antagonists). A selective mu opioid receptor antagonist and i) a compound that modulates the action of natriuretic factor, in particular atrial natriuretic factor,
ii) a compound that inhibits angiotensin converting enzyme,
iii) a substrate for NO synthase,
iv) cholesterol-lowering drugs,
v) estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists,
vi) phosphodiesterase (PDE) inhibitors,
vii) vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, VIP receptor agonists or VIP fragments, or a combination of an adrenergic receptor antagonist and VIP,
viii) serotonin receptor agonists, antagonists or modulators,
ix) testosterone supplements or testosterone implants,
x) selective androgen receptor modulators,
xi) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie in combination), or estrogen and methyltestosterone hormone replacement therapy,
xii) agonists or modulators of progesterone such as progesterone, guestdin, ethinyl estradiol, ethinnodiol, etonogesterol implant, dihydrogesterone, progestogen, tetresecbens, norethinodrel or progesterone creams such as MuProgest, Natragest and Fem-Gest Agent or gel agent,
xiii) modulators of noradrenaline, dopamine and / or serotonin transporters,
xiv) agonists or modulators of oxytocin / vasopressin receptors,
xv) a melanocortin receptor agonist or modulator,
xvi) monoamine transport inhibitors,
xvii) dopamine agonists (especially selective D2, selective D3, selective D4 and selective D2-like agents),
xviii) α-adrenergic receptor antagonists (also known as α-adrenergic receptor blockers, α-receptor blockers or α-blockers),
xix) A pharmaceutical composition comprising one or more adjuvants selected from antidiabetic agents, and xx) NPY receptor modulators (agonists and / or antagonists).   A selective mu opioid receptor antagonist for use in the treatment and / or prevention of female sexual dysfunction (FSD).   A method for treating and / or preventing female sexual dysfunction (FSD) comprising administering to a subject in need thereof a therapeutic amount of a selective mu opioid receptor antagonist.

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