WO2006027680A1 - 3-(1-carbamoylcyclohexyl) propionic acid derivatives as inhibitors of neutral endopeptidase enzyme - Google Patents

Abstract

Compounds of the formula (I) and pharmaceutically acceptable salts, polymorphs, prodrugs and/or solvates thereof wherein R1, X and Y are as described herein, are useful as inhibitors of neutral endopeptidase (NEP).

Description

3-(1-Carbamoylcvclohexyπpropioπic acid derivatives as inhibitors of neutral endopeptidase enzyme.

The invention relates to inhibitors of neutral endopeptidase enzyme (NEP), uses thereof, processes for the preparation thereof, intermediates used in the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including the treatment of male and female sexual dysfunction, particularly female sexual dysfunction (FSD), especially wherein the FSD is female sexual arousal disorder (FSAD).

Various NEP inhibitors and their uses are disclosed in patent application publication numbers WO 91/07386, WO 91/10644, WO02/02513, WO02/079143, EP 1 258 474, EP 1 097 719 and International Patent Application PCT/IB2004/000822.

We have discovered that compounds of the formula (I) and pharmaceutically acceptable salts, polymorphs, prodrugs and/or solvates thereof

wherein

R¹ is hydrogen, C-^alkoxy, -NR² R³, -NR⁴SO₂R⁵, or

C-_| .galkyl (which may be substituted by one or more substituents, which may be the same or different, selected independently from the list¹: halo, hydroxy, C-|.galkoxy, hydroxyCi._βalkoxy, C-_|_ 6^a'koxyC-)_galkoxy, carbocyclyl, carbocyclyloxy, C-_|_4alkoxycarbocyclyloxy, heterocyclyl, heterocyclyloxy,

-NR²R³, -NR⁴COR⁵, -NR⁴SO₂R⁵, -CONR²R³, -S(O)_pR⁶, -COR⁷and -CO₂(Ci .₄alkyl)), or

R1 is carbocyclyl¹ or heterocyclyl¹ (each carbocyclyl¹ and heterocyclyl¹ may be independently substituted by one or more substituents from said list¹, which substituents may be the same or different, which list further includes Chalky!);

R² and R³, which may be the same or different, are: carbocyclyl or heterocyclyl (each of which may be substituted by a substituent independently selected from C-|_4alkyl, hydroxy and C-^alkoxy), or are hydrogen or C-^alkyl, or R² and R³ together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or /V-(C-] _4alkyl)piperazinyl group;

R⁴ is hydrogen or C-\ _4alkyl; R⁵ is C-^alkyl, CF3, carbocyclyl, C-^alkylcarbocyclyl, C-] ^alkoxycarbocyclyl, heterocyclyl, C-_| .4alkoxy or -NR²R³;

R6 is C-_| _4alkyl, carbocyclyl, heterocyclyl or NR²R³;

R⁷ is C-_j _4alkyl, carbocyclyl or heterocyclyl; p is 0, 1 , 2 or 3;

X is the linkage -(CH2 )_n- or -(CH2 )q-O- (wherein Y is attached to the oxygen), wherein one or more hydrogen atoms in linkage X may be replaced independently by a substituent selected independently from C-|_4alkoxy, hydroxy, hydroxyC-_j .βalkyl, C3_7cycloalkyl, carbocyclyl, heterocyclyl, and C-^alkyl

(said C-)_4alkyl being optionally substituted by one or more fluoro or phenyl groups); n is 3, 4, 5, 6 or 7; q is 2, 3, 4, 5 or 6; Y is phenyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridyl, each of which may be substituted by one or more groups R⁸ which may be the same or different; each R⁸ is independently selected from: hydroxy, mercapto, halogen, cyano, HC=O, CO2H, -CC^C-^alkyl), -CO(C-_|_4alkyl), NH2, mono(C-_|_

4alkyl)amino, di(C-_|_4alkyl)amino, C-] .galkoxy, phenoxy, C-j .galkylthio, phenylthio, carbocyclyl, heterocyclyl (each carbocyclyl and heterocyclyl being optionally substituted by one or more substituents selected independently from C-|_ρalkyl, haloC-_| -galkyl, C-_| .galkoxy, haloC^ .galkoxy,

C-] .galkylthio and halogen), and C-_j .galkyl (optionally substituted by C-_| .galkoxy, haloC-_| .galkoxy, C-| .galkylthio, halogen or phenyl), or two R⁸ groups on adjacent carbon atoms, together with the interconnecting carbon atoms, may form a fused 5- or 6-membered carbocyclyl or heterocyclyl² ring, or two R⁸ groups on adjacent carbon and nitrogen atoms, together with the interconnecting carbon and nitrogen atoms, may form a fused 5- or 6- membered heterocyclyl³ ring (each carbocyclyl, heterocyclyl² and heterocyclyl³ ring being optionally substituted by one or more substituents selected independently from C-] .galkyl, haloC-_| .galkyl,

Ci .galkoxy, haloC-_j. galkoxy, C-_j .galkylthio and halogen);

with the proviso that when R¹ is H or a (R)-CH^ group, and n is 3, Y and R⁸ do not form 2-methyl-1 ,3- benzothiazol-6-yl or 2-ethyl-1 ,3-benzothiazol-6-yl;

each "carbocyclyl" and "carbocyclyl¹", unless otherwise stated, independently mean a group including 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic, and also includes any fused combination of carbocyclic groups;

each "heterocyclyl" and "heterocyclyl¹", unless otherwise stated, independently mean a group including 5 to 7 ring-atoms, up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic; "heterocyclyl²" means a 5 or 6 membered saturated, partially unsaturated or unsaturated ring containing from 1 to 3 ring heteroatoms selected independently from N, O and S, and containing at least 2 adjacent carbon atoms;

"heterocyclyl³" means a 5 or 6 membered saturated, partially unsaturated or unsaturated ring containing from 1 to 3 ring heteroatoms selected independently from N, O and S, with the proviso that the ring contains at least 1 N atom;

"aryl" means phenyl or naphthyl, optionally substituted by one or more substituents selected from OH, CN, CF3, Ci -C4 alkyl, C1-C4 alkoxy, halo, -CONH2, aminosulphonyl, NH2, mono or di(C-_|-C4 alkyl)amino, and (C1-C4 alkanoyl)amino groups,

are useful agents for the inhibition of NEP and are thus potentially of use in the treatment of diseases or conditions mediated by NEP, such as those disclosed in patent application publication numbers WO 91/07386, WO 91/10644, WO02/02513, WO02/079143, EP 1 258 474 and also International Patent Application PCT/1B2004/000822.

Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.

Unless otherwise indicated, any "carbocyclyl" or "carbocyclyl¹" group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic. Preferred saturated groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated groups contain up to 3 double bonds. A preferred aromatic group is phenyl. The term "carbocylic" or "carbocylic¹" should be similarly construed. In addition, the term "carbocyclyl" or "carbocyclyl¹" includes any fused combinations such as naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise indicated, any "heterocyclyl", or "heterocyclyl¹" group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms selected independently from nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of "heterocyclyl", or "heterocyclyl¹" groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl.

In addition, the term "heterocyclyl" or "heterocyclyl¹" includes groups fused with a carbocyclyl group or with another "heterocyclyl" or "heterocyclyl¹" group, which is the same or different. Examples of said fused "heterocyclyl" or "heterocyclyl¹" groups include benzimidazolyl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, benzisothiazolyl, phthalimido, benzofuranyl, dihydrobenzofuranyl, benzodiazepinyl, indolyl, indazolyl, isoindolyl, imidazo[1 ,2-a]pyridinyl, pyrazolo[1 ,5-a]pyrimidinyl, imidazo[1 ,2-b]pyridazinyl, 2,1 ,3-benzoxadiazoIyl, 1 H-pyrrolo[2,3-b]pyridinyl, 1 H-pyrazolo[3,4-b]pyridinyl, and imidazo[1 ,2-c]pyrimidinyl. The term "heterocyclic" or "heterocyclic¹" should be similarly construed.

"heterocyclyl²" means a 5 or 6 membered saturated, partially unsaturated or unsaturated ring containing from 1 to 3 ring heteroatoms selected independently from N, O and S, and containing at least 2 adjacent carbon atoms, and includes, for example, furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,5- diazolyl, 1 ,2,3-triazolyl, 1-thia-2,3-diazolyl, pyranyl, pyridyl, piperidinyl, morpholino, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl and piperazinyl.

"heterocyclyl³" means a 5 or 6 membered saturated, partially unsaturated or unsaturated ring containing from 1 to 3 ring heteroatoms selected independently from N, O and S, with the proviso that the ring contains at least 1 N atom, and includes, for example, pyrrolyl, pyrrolidinyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1 -oxa-2,3-diazolyl, 1-oxa-2,5-diazolyl, 1 - oxa-2,4-diazolyl, 1 ,2,3-triazolyl, 1 ,3,4-triazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, pyridyl, piperidinyl, morpholino, pyridazinyl, pyrimidinyl, pyrazinyl and piperazinyl.

A preferred aspect of the compounds of formula (I) is wherein R^ is hydrogen, C-^galkyl, C-_j.galkoxy, C-_| _galkoxyCi_3alkyl, C-_|_6alkoxyCi_6alkoxyC-_|_3alkyl or C-^galkyl substituted by phenyl.

A preferred aspect of the compounds of formula (I) is wherein R^ is hydrogen, C-_|.galkyl, C-i.galkoxy, Ci .galkoxyCi ^aikyl or C-_| .galkoxyC-_j .galkoxyC-_j ^alkyl.

A preferred aspect of the compounds of formula (I) is wherein R¹ is H, C-^alkyl or C-| .βalkoxyCi _3alkyl.

A preferred aspect of the compounds of formula (I) is wherein R¹ is H, methyl, ethyl, or methoxyethyl.

A preferred aspect of the compounds of formula (I) is wherein the stereochemistry is as defined in formula (Ia):

A preferred aspect of the compounds of formula (I) is wherein X is -(CI-^)_n- and wherein one or more hydrogen atoms in linkage X may be replaced by a substituent independently selected from C-^alkoxy, hydroxy, hydroxyC-_j^alkyl, C3_7cycloalkyl, carbocyclyl, heterocyclyl, and C-^alkyl (said C-^alkyl being optionally substituted by one or more fluoro or phenyl groups);

A preferred aspect of the compounds of formula (I) is wherein, when X is -(CI-^)_n-, n is 3 or 4.

A preferred aspect of the compounds of formula (I) is wherein

R⁸ is C-₎.ρalkyl, C-_j._βalkoxy, hydroxy, mercapto, halogen, cyano, carbocyclyl or heterocyclyl; or two R⁸ groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused 5- or 6-membered carbocyclyl or heterocyclyl ring, (each carbocyclyl and heterocyclyl being optionally substituted by one or more substituents selected independently from C-_j.galkyl, haloCi.galkyl,

C-i .øalkoxy, haloC-_|_βalkoxy, C-|_galkylthio and halogen).

A preferred aspect of the compounds of formula (I) is wherein when R⁸ is carbocyclyl, R⁸ is cyclopentyl, cyclopropyl, cyclohexyl or phenyl.

A preferred aspect of the compounds of formula (I) is wherein when R⁸ is heterocyclyl, R⁸ is pyridyl, oxadiazolyl, pyrazolyl or triazolyl.

A preferred aspect of the compounds of formula (I) is wherein Y is phenyl, optionally substituted by one or more R⁸, wherein R⁸ is selected from halogen and OH.

A preferred aspect of the compounds of formula (I) is wherein Y and R⁸ together form a 4-chlorophenyl group.

A preferred aspect of the compounds of formula (I) is wherein when Y is phenyl, and two R⁸ groups on adjacent carbon atoms together with the interconnecting carbon atoms form a fused 5- or 6-membered carbocyclyl or heterocyclyl² ring, Y and R⁸ together form a group which is selected from naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl, (and are optionally substituted by one or more substituents selected independently from C^galkyl, haloCi^alkyl, C-i.galkoxy, haloC-i.galkoxy, and halogen).

A preferred aspect of the compounds of formula (I) is wherein Y and R⁸ together form a benzothiazolyl group (optionally substituted by one or more substituents selected independently from Ci.₆alkyl, haloCi.galkyl, C-|.galkoxy, haloC-i-galkoxy, and halogen). A preferred aspect of the compounds of formula (I) is wherein each of R¹, X and Y are as defined in relation to the Examples below.

A preferred aspect of the compounds of formula (I) is a compound selected from the Examples below.

Halo means fluoro, chloro, bromo or iodo.

For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternatives groups, the selected groups may be the same or different.

For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

The pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic centre are, for example, acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. Examples include the aspartate, bicarbonate, carbonate, edisylate, fumarate, gluceptate, glucuronate, hibenzate, isethionate, malonate, methylsulphate, 2-napsylate, nicotinate, orotate, stearate, HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. Compounds of the invention may also provide pharmaceutically or veterinarily acceptable base addition salts, in particular metal salts such as non-toxic alkali and alkaline earth metal salts. Examples include the ammonium, arginine, benzathine, diethylamine, glycine, lysine, tromethamine, sodium, potassium, aluminium, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, choline, meglumine and diethanolamine salts. For reviews on suitable pharmaceutical salts see Berge ef a/, J. Pharm, ScL, 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley ef a/, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.

Hereinafter, the compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention or preferred embodiment (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

The pharmaceutically acceptable solvates of the compounds of the invention include hydrates thereof.

The compounds of the invention and intermediates may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Individual enantiomers may be obtained by a variety of techniques known to the skilled chemist, such as by high pressure liquid chromatography (HPLC) of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active base, as appropriate. A preferred optically active base is pseudoephedrine.

Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C.

The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of the present invention. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, α-pyridonyl.

The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S,

¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e. ³H, and carbon-14, i.e. ¹⁴C isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the methods or preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.

The compounds of the invention are inhibitors of the zinc-dependent, neutral endopeptidase EC.3.4.24.11., and it is proposed that the compounds of the invention will treat the disease states listed below. This enzyme is involved in the breakdown of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues. The peptides metabolised include atrial natriuretic peptides (ANP), bombesin, bradykinin, calcitonin gene-related peptide, endothelins, enkephalins, neurotensin, substance P and vasoactive intestinal peptide. Some of these peptides have potent vasodilatory and neurohormone functions, diuretic and natriuretic activity or mediate behaviour effects.

Thus, the compounds of the invention, by inhibiting the neutral endopeptidase EC.3.4.24.11 , can potentiate the biological effects of bioactive peptides. Thus, in particular the compounds have utility in the treatment of a number of disorders, including hypertension, pulmonary hypertension, peripheral vascular disease, heart failure, angina, renal insufficiency, acute renal failure, cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure). Also the compounds of the invention should treat asthma, inflammation, leukemia, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, diabetic complications and athereosclerosis. In a preferred embodiment the compounds of the invention are useful in the treatment of male and female sexual dysfunction.

The compounds of the invention are particularly beneficial for the treatment of FSD (especially FSAD) and male sexual dysfunction (especially male erectile dysfunction (MED)).

In accordance with the invention, FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, S. R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106; , Berman, J. R., Berman, L. & Goldstein, I. (1999). Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options. Urology, 54, 385-391). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse or a combination of these problems. Several types of disease, medications, injuries or psychological problems can cause FSD. Treatments in development are targeted to treat specific subtypes of FSD, predominantly desire and arousal disorders.

The categories of FSD are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (Leiblum, S. R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106). Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli. Arousal is the vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity. Orgasm is the release of sexual tension that has culminated during arousal.

Hence, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm. FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders. Although the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), in doing so it may also improve the associated pain, distress and discomfort associated with intercourse and so treat other female sexual disorders. Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterised by inadequate genital response to sexual stimulation. The genitalia do not undergo the engorgement that characterises normal sexual arousal.

The vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded.

Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis. Other causes result from treatment with diuretics, antihistamines, antidepressants (e.g. SSRIs) or antihypertensive agents.

Sexual pain disorders (e.g. dyspareunia and vaginismus) is characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.

The prevalence of FSD is difficult to gauge because the term covers several types of problem, some of which are difficult to measure, and because the interest in treating FSD is relatively recent. Many women's sexual problems are associated either directly with the female ageing process or with chronic illnesses such as diabetes and hypertension.

Because FSD consists of several subtypes that express symptoms in separate phases of the sexual response cycle, there is not a single therapy. Current treatment of FSD focuses principally on psychological or relationship issues. Treatment of FSD is gradually evolving as more clinical and basic science studies are dedicated to the investigation of this medical problem. Female sexual complaints are not all psychological in pathophysiology, especially for those individuals who may have a component of vasculogenic dysfunction (eg FSAD) contributing to the overall female sexual complaint. There are at present no drugs licensed for the treatment of FSD. Empirical drug therapy includes oestrogen administration (topically or as hormone replacement therapy), androgens or mood-altering drugs such as buspirone or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects.

Since interest is relatively recent in treating FSD pharmacologically, therapy consists of the following:- psychological counselling, over-the-counter sexual lubricants, and investigational candidates, including drugs approved for other conditions. These medications consist of hormonal agents, either testosterone or combinations of oestrogen and testosterone and more recently vascular drugs, that have proved effective in male erectile dysfunction. None of these agents has been demonstrated to be very effective in treating FSD. The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines Female Sexual Arousal Disorder (FSAD) as being: "a persistent or recurrent inability to attain or to maintain until completion of the sexual activity adequate lubrication-swelling response of sexual excitement. The disturbance must cause marked distress or interpersonal difficulty."

The arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The disturbance causes marked distress and/or interpersonal difficulty.

FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post menopausal (±HRT) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and UG disorders.

The primary consequences of FSAD are lack of engorgement/swelling, lack of lubrication and lack of pleasurable genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm.

It has recently been hypothesised that there is a vascular basis for at least a proportion of patients with symptoms of FSAD (Goldstein ef a/., Int. J. Impot. Res., 10, S84-S90,1998) with animal data supporting this view (Park ef a/., Int. J. Impot. Res., 9, 27-37, 1997).

Drug candidates for treating FSAD, which have been under investigation for efficacy, are primarily erectile dysfunction therapies that promote circulation to the male genitalia. They consist of two types of formulation, oral or sublingual medications (Apomorphine, Phentolamine, phosphodiesterase type 5 (PDE5) inhibitors e.g. Sildenafil), and prostaglandin (PGE₁) that are injected or administered transurethral^ in men, and topically to the genitalia in women.

The compounds of the invention are advantageous by providing a means for restoring a normal sexual arousal response - namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity. Hence, the compounds of the invention provide means to restore, or potentiate, the normal sexual arousal response.

Without being bound by theory, we believe that neuropeptides such as vasoactive intestinal peptide (VIP) are major neurotransmitter candidates in the control of the female sexual arousal response, especially in the control of genital blood flow. VIP and other neuropeptides are degraded/ metabolised by NEP EC3.4.24.11. Thus, NEP inhibitors will potentiate the endogenous vasorelaxant effect of VIP released during arousal. This will lead to a treatment of FSAD, such as through enhanced genital blood flow and hence genital engorgement. We have shown that selective inhibitors of NEP EC 3.4.24.11 enhance pelvic nerve-stimulated and VIP-induced increases in vaginal and clitoral blood flow. In addition, selective NEP inhibitors enhance VIP and nerve-mediated relaxations of isolated vagina wall. MaIe sexual dysfunction includes male erectile dysfunction, ejaculatory disorders such as premature ejaculation (PE), anorgasmia (inability to achieve orgasm) and desire disorders such as hypoactive sexual desire disorder (lack of interest in sex).

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

The compounds of the invention find application in the following sub-populations of patients with FSD: the young, the elderly, pre-menopausal, peri-menopausal, post-menopausal women with or without hormone replacement therapy.

The compounds of the invention find application in patients with FSD arising from:- i) Vasculogenic etiologies eg cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vacular system. ii) Neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery. iii) Hormonal/endocrine etiologies such as dysfunction of the hypothalamic/pituitary/gonadal axis, or dysfunction of the ovaries, dysfunction of the pancreas, surgical or medical castration, androgen deficiency, high circulating levels of prolactin eg hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism. iv) Psychogenic etiologies such as depression, obsessive compulsive disorder, anxiety disorder, postnatal depression/"Baby Blues", emotional and relational issues, performance anxiety, marital discord, dysfunctional attitudes, sexual phobias, religious inhibition or a traumatic past experiences. v) Drug-induced sexual dysfunction resulting from therapy with selective serotonin reuptake inhibitors (SSRis) and other antidepressant therapies (tricyclics and major tranquillizers), anti- hypertensive therapies, sympatholytic drugs, chronic oral contraceptive pill therapy.

Patients with mild to moderate MED should benefit from treatment with a compound of the invention and patients with severe MED may also respond. However, early investigations suggest that the responder rate of patients with mild, moderate and severe MED will be greater in combination with a PDE5 inhibitor. Mild, moderate and severe MED will be terms known to the man skilled in the art, but guidance can be found in The Journal of Urology, vol 151 , 54-61 (Jan 1994).

The compounds of the invention find application in the following sub-populations of patients with MED: psychogenic, endocrinologic, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction related to cavemosal factors, particularly venogenic causes. These patient groups are described in more detail in Clinical Andrology vol 23,no.4, p773-782, and chapter 3 of the book by I. Eardley and K. Sethia "Erectile Dysfunction - Current Investigation and Management, published by Mosby-Wolfe.

Compounds of formula (I) may be made by a variety of methods, such as those described below, wherein unless otherwise described, R¹, X and Y are as previously defined. For a key to abbreviations used, see later with regard to the Examples and Preparations. Any other abbreviations are standard in the art.

Compounds of formula (I) may be prepared according to the process described in scheme 1 wherein PG is a suitable acid protecting group, such as an alkyl ester, typically a CrC₄ alkyl or benzyl, and preferably fert-butyl or benzyl.

(H) (III) (IV)

Scheme 1

Step (a)-Acid/amine coupling.

The compound of formula (IV) may be prepared by reaction of the amine of formula (III) with the acid of formula (II).

The coupling may be undertaken by using either

(i) an acyl chloride of (II) (generated in-situ) + amine (III) with an excess of acid acceptor in a suitable solvent, or

(ii) the acid (II) with a conventional coupling agent + amine (III) optionally in the presence of a catalyst, with an excess of acid acceptor in a suitable solvent.

Typically the conditions are:

Acid (II), WSCDI /DCC and HOBT /HOAT, the amine (III), with an excess of NMM, Et₃N, or Hϋnig's base in THF, DCM, DMA or EtOAc, at rt. for 4 to 48 hrs; or, acid (II) PYBOP^®/PyBrOP^®/O-benzotriazol-1-yl-

N,N,N',N'-tetramethyluronium hexafluorophosphate an excess of amine (III), with an excess of NMM,

Et₃N, or Hϋnig's base in THF, DCM, DMA or EtOAc, at rt. for 4 to 24 hrs.

Preferred conditions are: Acid (II), amine (III) (1 -1.2eq), WSCDI (1-2eq), HOBT (1-1.2eq), Et₃N or NMM (3eq) in DCM at rt, or DMF at between rt and 90⁰C for up to 24 hours.

Step (b)-Deprotection

Deprotection of compound (IV) is undertaken using standard methodology, as described in "Protecting

Groups in Organic Synthesis" by T.W. Greene and P. Wutz.

When PG is ferf-butyl the preferred method is treatment with hydrogen chloride_(g) in a suitable solvent such as DCM at room temperature for up to 1 hour, or by treatment with a solution of trifluoroacetic acid in DCM (1 :1 by volume) for 4-18 hours.

When PG is benzyl, the preferred method is hydrogenation using a suitable palladium catalyst (e.g. 5-

10% Pd on charcoal), in ethanol at about 1 atm of H₂, for about 4 hours at rt.

Compounds of formula (II) may be prepared according to the process described in scheme 2.

(H)

Scheme 2

In the scheme above PG is as previously defined and HAL represents a halogen, preferably a Br or I.

Compounds of formula (V) and (Vl) are available from commercial sources.

Step (c)-Alkylation

The compound of formula (V) may be treated with a suitable strong base, such as an alkali metal base (eg NaHMDS, LDA) in a suitable solvent such as DME or THF, to provide an intermediate dianion. This may then by quenched in-situ by reaction with a suitable alkyl halide (Vl), to provide the compound of formula (VII). Preferred conditions are: Acid (V), LDA (2eq), THF at between -15⁰C and 0⁰C for 2.5 hrs, followed by halide (Vl) (1.05eq) at between 0°C and rt for up to 18 hrs.

Step (d)-Alkylation. Compounds of formula (VII) may be treated with a suitable strong base, such as an alkali metal base (eg NaHMDS, LDA) in a suitable solvent such as DME or THF, to provide an intermediate dianion. This may then by quenched in-situ by reaction with a suitable alkyl halide, R¹HAL to provide the compound of formula (II).

Preferred conditions are: Acid (VII), LDA (2eq), in DME at -10⁰C for 1 hr, followed by halide R¹HAL (1.2eq) at between 0⁰C and rt for up to 18 hrs.

Compounds of formula (VII) may alternatively be prepared according to the methods described in scheme 3.

Scheme 3

Compound of formula (VIlI) are either available commercially or may be prepared by analogy with the method of Cox et.al. J.C.S. Perkin 1, 1973, 174-8.

Step (e)-Hydrolysis/Esterification

Compounds of formula (VII) may be prepared by reaction of the anhydride of formula (VIII) with an alkoxide, PGO^" (generated in-situ by reaction of the alcohol, PGOH with a suitable base eg KOf-Bu) in a suitable solvent. Preferred conditions are:

Anhydride (VIII), PGOH (1 eq), KOf-Bu (1 eq), in THF at between O⁰C and rt for about 18 hrs.

When X represents -(CH₂)₃-, the compounds of formula (III) may be prepared according to the methods described in scheme 4. Y and HAL are as previously defined.

(IX) (X) (III)

Scheme 4 Step (f) Heck Reaction

Compounds of formula (IX) may undergo the Heck reaction with acrylonitrile in the presence of a suitable catalyst system such as palladium and excess base such as Et₃N or NMM to give compounds of formula (X).

Typical reaction conditions comprise 1.0-1.5 equivalents of Y-HAL, 3 eq of base, 0.1 eq of palladium catalyst (preferably palladium (II) acetate), 0.2 eq phosphine ligand (preferably tri-otolylphosphine) in 1 ,4 dioxan, acetonitrile or DMF, at reflux. Preferred conditions are: 1 eq Y-HAL, acrylonitrile (2eq), sodium acetate (1eq), palladium (II) acetate (2eq), tri-otolyl phosphine (0.15eq) in DMF at 130⁰C for about 18 hrs.

Step (g)-Reduction

Compounds of formula (X) may by subjected to catalytic hydrogenation (eg treatment with Raney® Nickel in ethanol under H₂), or may be treated with a suitable reducing agent (preferably NaBH₄ + NiCI₂) in the presence of di-ferf-butyl dicarbonate in a suitable solvent, typically methanol. Subsequent removal of the

Boc protecting group, using standard conditions (TFA:DCM or HCI in DCM, dioxan or ether), may provide the compound of formula (III).

Preferred conditions are: Nitrile (X), NaBH₄ (0.7eq), NiCI₂ (1eq), di-fert-butyl dicarbonate (2eq) in MeOH at rt for about 4 hrs, followed by treatment with excess 4MHCI in dioxan at rt for up to 18 hrs.

Other compounds of formula (IX), (X) and (111) are either available from commercial sources, known in the art, or can be prepared from compounds known in the art by using methods known in the prior art or by using methods descibed herein. The skilled person will appreciate that it is possible to make compounds of formula (I) via the methods described herein, routine modification thereof, or by other methods generally known in the art.

The biological activity of compounds of formula (I) may be tested using the methods described below

Assay of NEP peptidase activity

Production of native NEP enzyme:

NEP is isolated from kidneys following the method described by Kenny and Booth (Booth, A.G. & Kenny, AJ. (1974) Biochem. J. 142, 575-581 ).

The peptidase activity of NEP is measured by monitoring its ability to proteolyse the synthetic peptide substrate Rhodamine green-Gly-Gly-dPhe-Leu-Arg-Arg-Val-Cys(QSY7)-βAla-NH₂ :

Reagents for the assay are first prepared as follows: A substrate solution is made up by diluting a 2mM/100%DMSO Rhodamine green-Gly-Gly-dPhe-Leu- Arg-Arg-Val-Cys(QSY7)-βAla-NH₂ stock solution in 5OmM HEPES buffer pH7.4 (Sigma, UK) at a concentration of 2μM.

An aliquot of NEP enzyme described above is thawed then diluted in 5OmM HEPES, pH7.4 containing 1 EDTA free protease inhibitor cocktail tablet (Roche Diagnostics, UK) per 25ml. The dilution is by a predetermined factor specific to each enzyme batch, such that 15μl contains sufficient enzyme to convert approximately 30% of substrate to product during the assay.

A 4% DMSO solution comprised of 4ml DMSO plus 96ml 5OmM HEPES pH7.4 is prepared.

A product solution is prepared by adding 500μl of substrate solution to 250 μl enzyme solution plus 250μl of 4% DMSO solution, and incubating at 37⁰C for 16 hours.

Assays are set up as follows:

In a black 384 well microtitre plate, 15μl of enzyme solution is added to 15μl of 4% DMSO solution. A similar non-specific background blank is also set up in which the 15μl of 4% DMSO solution additionally contains 40μM phosphoramidon. 3OuI of substrate solution is then added to both the assay and blank, then the plate is incubated for 1 hour at 37⁰C. Following incubation a fluorescence measurement is taken (Ex485 / Em538). BMG galaxy fluorescence reader (BMG Lab technologies, Offenberg, Germany).

The proteolytic activity of the enzyme corresponds to the fluorescence of the sample minus the fluorescence of the non-specific background blank.

A fluorescence measurement taken from 60μl of product in a well on an identical microtitre plate may be taken. If required this value is used, together with the measured fluorescence units from the NEP assay to calculate the % of the substrate proteolysed during the 1 hour incubation period or to convert the measured fluorescence increase into other useful units such as ng substrate proteolysed/min/ml enzyme.

Using the assay to determine the lC50's of NEP inhibitors:

To determine the IC₅₀ of NEP inhibitors (for example phosphoramidon), multiple assays are performed as described above with a range of test concentrations of inhibitor included in the 15μl of DMSO solution. (Made by appropriate dilution of a 1OmM 100% DMSO stock of inhibitor with 4 % DMSO/50mM HEPES pH7.4.) Using a suitable standard graph fitting computer program, a sigmoidal dose response curve is fitted to a plot of log inhibitor concentration vs % inhibition or % activity. The IC₅₀ is calculated as the inhibitor concentration causing 50 % maximal inhibition. Typically for a given IC₅₀ determination, a dose range of at least 10 inhibitor concentrations used differing in half log unit increments is used. For inhibitors that give an IC₅₀ result less than approximately 2nM, the assay is repeated under modified assay conditions in which: The quantity of enzyme used is reduced to approx 1/10^th to 1/20^th; The substrate concentration is increased to 5DM; and the incubation time increased to 3 hours. This lowers the potency limit (tight binding limit) of the assay to a level where The IC₅₀ estimate of compounds whose Ki is in the range of ~0.2-2nM are not limited by the enzyme concentration.

The compounds of the Examples all exhibited IC₅₀ values less than 200OnM.

The utility of the compounds of the present invention to treat FSD and MED may be further determined using the techniques described in WO02/079143.

The advantageous pharmacokinetics of the compounds of the present invention may be demonstrated by using the CaCO-2 test. The CACO-2 assay is a widely accepted model for predicting the ability of a given molecule to cross the Gl tract. The test is conducted as described below:

Cell culture

Caco-2 cells are seeded in 24-well Falcon Multiwell® plates at 4.0 x 10⁴ cells/well. The cells are grown in culture media consisting of minimum essential medium (Gibco 21090-022) supplemented 20% Fetal Bovine serum, 1% non-essential ammino acids, 2mM L-glutamine and 2mM sodium pyruvate. The culture medium is replaced three times every week and the cells maintained at 37 ⁰C, with 5% CO₂ and at 90% relative humidity. Permeability studies are conducted when the monolayers were between 15 and 18 days old. Cells are used between passage 23 and 40.

Permeability Studies

Each test compound is prepared as a 10mM DMSO solution, 62.5 μl of this solution is then added to 25mL of transport buffer. Nadolol (25μM) is added to every well as a marker of membrane integrity. These solutions along with transport buffer are then warmed to 37 ⁰C. Transport buffer is HBSS (Hank's balanced salt solution) at pH 7.4 or pH 6.5. Before the commencing each study each monolayer is washed three times with HBSS. Transport Buffer with no compound added is placed in each acceptor well, 250 μl on the apical side and 1 ml_ into the basolateral well. The study is commenced by adding drug solution to each donor well, 250 μl to the apical wells and 1mL to the basolateral well. Following a two- hour incubation at 37 ⁰C for two hours samples are removed from all wells for LC-MS-MS analysis.

Human liver microsomes are a widely accepted model for predicting the metabolic stability of drug molecules towards metabolism in the liver. The test is conducted as follows:

Microsomal incubations AII incubations are carried out in a thermostatted shaking water-bath at 37 ⁰C. Each incubate contains 0.5μM CYP. Cofactors are added as NADPH regenerating system. It consists of 1.2 mM NADP, 5 mM MgCI₂ x 6H₂O, 5mM DL-isocitric acid and 1 unit/ml isocitric dehydrogenase, highly purified. All reagents are dissolved in phosphate buffer (50 mM; pH 7.4). The substrate concentration is 1 μM. Substrates are dissolved in acetonitrile with the final acetonitrile concentration in the incubation mixture lower than 0.1% (v/v). NADP is omitted from control incubations. In all experiments, samples are pre-incubated with microsomes, substrate and regenerating system in the absence of NADP for 5 min at 37 °C. The reaction is started by addition of NADP. Incubation time is 1 h. 100μl aliquots are removed after 0, 3, 5, 10, 15, 20, 30, 45 & 60 min. The aliquots are extracted with 400μl 1 M-acetic acid and 2.0ml of ethylacetate and analysed by LC-MS-MS.

The compounds of the invention may be combined with one or more further active ingredients selected from the list: 1) One or more naturally occurring or synthetic prostaglandins or esters thereof. Suitable prostaglandins for use herein include compounds such as alprostadil, prostaglandin E₁, prostaglandin E₀, 13, 14 - dihydroprosta glandin E₁, prostaglandin E₂, eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in WO- 00033825 and/or US 6,037,346 issued on 14th March 2000 all incorporated herein by reference, PGE₀, PGE₁, PGA₁, PGB₁, PGF₁ α, 19-hydroxy PGA₁, 19-hydroxy - PGB₁, PGE₂, PGB₂, 19- hydroxy-PGA₂, 19-hydroxy-PGB₂, PGE₃α, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprost and moxisylate.

2) One or more α - adrenergic receptor antagonist compounds also known as α - adrenoceptors or α-receptors or α-blockers. Suitable compounds for use herein include: the α-adrenergic receptor blockerss as described in PCT application WO99/30697 published on 14th June 1998, the disclosures of which relating to α-adrenergic receptors are incorporated herein by reference and include, selective α,-adrenoceptor or o^-adrenoceptor blockers and non-selective adrenoceptor blockers, suitable Ot₁ -adrenoceptor blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089,

RS17053, SL 89.0591 , doxazosin, terazosin, abanoquil and prazosin; α₂-blocker blockers from US 6,037,346 [14th March 2000] dibenamine, tolazoline, trimazosin and dibenarnine; α- adrenergic receptors as described in US patents: 4,188,390; 4,026,894; 3,511 ,836; 4,315,007; 3,527,761 ; 3,997,666; 2,503,059; 4,703,063; 3,381 ,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; α₂-Adrenoceptor blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine.

3) One or more NO-donor (NO-agonist) compounds. Suitable NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl brinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3- morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N- glutathione (SNO-GLU), N-hydroxy - L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso - N-cysteine, diazenium diolates, (NONOates), 1 ,5- pentanedinitrate, L-arginene, ginseng, zizphi fructus, molsidomine, Re - 2047, nitrosylated maxisylyte derivatives such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075. 4) One or more potassium channel openers or modulators. Suitable potassium channel openers/modulators for use herein include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCI₂. 5) One or more dopaminergic agents, preferably apomorphine or a selective D₂, D₃ or D₂/D₃agonist such as, pramipexole and ropirinol (as claimed in WO-0023056), PNU95666 (as claimed in WO-

0040226). 6) One or more vasodilator agents. Suitable vasodilator agents for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, halo peridol, Rec 15/2739, trazodone.

7) One or more thromboxane A2 agonists.

8) One or more CNS active agents.

9) One or more ergot alkoloids. Suitable ergot alkaloids are described in US patent 6,037,346, and include acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride, terguride.

10) One or more compounds which modulate the action of natruretic factors in particular atrial naturetic factor (also known as atrial naturetic peptide), B type and C type naturetic factors such as other inhibitors or neutral endopeptidase.

11) One or more compounds which inhibit angiotensin-converting enzyme such as enalapril, and combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat.

12) One or more angiotensin receptor antagonists such as losartan.

13) One or more substrates for NO-synthase, such as L-arginine.

14) One or more calcium channel blockers such as amlodipine.

15) One or more antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme.

16) One or more cholesterol lowering agents such as statins (e.g. atorvastatin/ Lipitor- trade mark) and fibrates.

17) One or more antiplatelet and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors.

18) One or more insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide.

19) L-DOPA or carbidopa.

20) One or more acetylcholinesterase inhibitors such as donepezil.

21) One or more steroidal or non-steroidal anti-inflammatory agents.

22) One or more estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1 -yl- ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof the preparation of which is detailed in WO 96/21656.

23) One or more modulators of cannabinoid receptors.

24) One or more NPY (neuropeptide Y) inhibitor, more particularly NPY1 or NPY5 inhibitor, preferably NPY1 inhibitor, preferably said NPY inhibitors (including NPY Y1 and NPY Y5) having an IC50 of less than 10OnM , more preferably less than 5OnM. An assay for identifying NPY inhibitors is presented in WO-A-98/52890 (see page 96, lines 2 to 28).

25) One or more of vasoactive intestinal protein (VIP), VlP mimetic, VIP analogue, more particularly mediated by one or more of the VIP receptor subtypes VPAC1 ,VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analogue

(eg Ro-125-1553) or a VIP fragment, one or more of a α-adrenoceptor antagonist with VIP combination (eg Invicorp, Aviptadil).

26) One or more of a melanocortin receptor agonist or modulator or melanocortin enhancer, such as melanotan II, PT-14, PT-141 or compounds claimed in WO-09964002, WO-00074679, WO- 09955679, WO-00105401 , WO-00058361 , WO-00114879, WO-00113112, WO-09954358.

27) One or more of a serotonin receptor agonist, antagonist or modulator, more particularly agonists, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993.

28) one or more of an androgen such as androsterone, dehydro-androsterone, testosterone, androstanedione and a synthetic androgen.

29) one or more of an oestrogen, such as oestradiol, oestrone, oestriol and a synthetic estrogen, such as oestrogen benzoate.

30) One or more of a modulator of transporters for noradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659. 31) One or more of a purinergic receptor agonist and/or modulator.

32) One or more of a neurokinin (NK) receptor antagonist, including those described in WO- 09964008.

33) One or more of an opioid receptor agonist, antagonist or modulator, preferably agonists for the ORL-1 receptor. 34) One or more of an agonist or modulator for oxytocin/vasopressin receptors, preferably a selective oxytocin agonist or modulator.

35) One or more of a PDE inhibitor, more particularly a PDE 2, 3, 4, 5, 7 or 8 inhibitor, preferably PDE2 or PDE5 inhibitor and most preferably a PDE5 inhibitor (see hereinafter), said inhibitors preferably having an IC50 against the respective enzyme of less than 10OnM. Suitable cGMP PDE5 inhibitors for the use according to the present invention include:

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7- ones disclosed in EP-A-0526004; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d]pyrimidin-4-ones disclosed in published international patent application WO 93/07149; the quinazolin-4-ones disclosed in published international patent application WO 93/12095; the pyrido [3,2-d]pyrimidin- 4-ones disclosed in published international patent application WO 94/05661 ; the purin-6-ones disclosed in published international patent application WO 94/00453; the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in published international patent application WO 98/49166; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 99/54333; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751 ; the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in published international patent application WO 00/24745; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; the compounds disclosed in published international application WO95/19978; the compounds disclosed in published international application WO 99/24433 and the compounds disclosed in published international application WO 93/07124. The pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/27112; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/27113; the compounds disclosed in EP-A-1092718 and the compounds disclose din EP-A-1092719.

Further suitable PDE5 inhibitors for the use according to the present invention include: 5-[2- ethoxy-5-(4-methyl-1 -piperazinylsulphonyl)phenyl]-1 -methyl-3-n-propyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (sildenafil) also known as 1-[[3-(6,7-dihydro-1 -methyl-7-oxo-3- propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine (see EP- A-0463756); 5-(2-ethoxy-5-morpholinoacetylphenyl)-1 -methyl-3-n-propyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (see EP-A-0526004); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-

2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO98/49166); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-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 ); (+)-3- ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl- 2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 3-ethyl-5-{5-[4-ethylpiperazin-1- ylsulphonyl]-2-([(1 R)-2-methoxy-1 -methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H- pyrazolo[4,3-d] pyrimidin-7-one (see WO99/54333); 5-[2-ethoxy-5-(4-ethylpiperazin-1- ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3- d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine (see WO 01/27113, Example 8); 5-[2-/so-

Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)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); 5-[2-Ethoxy-5-(4- ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (see WO 01/27113, Example 66); 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2- (1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-φyrimidin-7-one (see WO 01/27112,

Example 124); 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-φyrimidin-7-one (see WO 01/27112, Example 132); (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), i.e. the compound of examples 78 and 95 of published international application WO95/19978, as well as the compound of examples 1 , 3, 7 and 8; 2-[2-ethoxy-5-(4-ethyl- piperazin-1 -yl-1 -sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1 -f][1 ,2,4]triazin-4-one (vardenafil) also known as 1 -[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2- yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine, i.e. the compound of examples 20, 19, 337 and 336 of published international application WO99/24433; and the compound of example 11 of published international application WO93/07124 (EISAI); and compounds 3 and 14 from Rotella D P₁ J. Med. Chem., 2000, 43, 1257.

Still other suitable PDE5 inhibitors include:4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)- propoxy]-3(2H)pyridazinone; 1 -[4-[(1 ,3-benzodioxol-5- ylmethyl)amiono]-6-chloro-2-quinozolinyl]- 4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4- (trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a- octahydrocyclopentt4,5]-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; l-methyl-S^-morpholinoacetyl^-n-propoxyphenyO-S-n-propyl-i ^-dihydro- 7H- pyrazolo(4,3-d)pyrimidin-7-one; 1 -[4-[(1 ,3-benzodioxol-5-ylmethyl)arnino]-6-chloro-2- quinazolinyl]-4-piperidinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) and Sch-51866.

For treating FSD, the compounds of the invention may preferably be combined with one or more active ingredients selected from the list: a) a PDE5 inhibitor, more preferably 5-[2-ethoxy-5-(4-methyl-1 -piperazinylsulphonyl)phenyl]-1- methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil); (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); 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5- methyl-7-propyl-3H-imidazo[5,1 -f][1 ,2,4]triazin-4-one (vardenaf il); 5-[2-ethoxy-5-(4-ethylpiperazin- 1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one; and 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-cdpyrimidin-7-one and pharmaceutically acceptable salts thereof; b) an N PY Y1 inhibitor; c) a dopamine agonist such as apomorphine or a selective D₂, D₃ or D₂/D₃agonist such as, pramipexole and ropirinol; d) a melanocortin receptor agonist or modulator or melanocortin enhancer, preferably melanotan II, PT-14, PT-141 ; e) an agonist, antagonist or modulator for 5HT2C; f) an estrogen receptor modulator, estrogen agonists and/or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene; g) an androgen such as androsterone, dehydro-androsterone, testosterone, androstanedione and a synthetic androgen; and h) an oestrogen, such as oestradiol, oestrone, oestriol and a synthetic estrogen, such as oestrogen benzoate.

For treating MED, the compounds of the invention may preferably be combined with one or more active ingredients selected from the list: a) a PDE5 inhibitor, more preferably 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1 - methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil); (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); 2-[2-ethoxy-5-(4-ethyl-piperazin-1 -yl-1 -sulphonyl)-phenyl]-5- methyl-7-propyl-3H-imidazo[5,1 -f][1 ,2,4]triazin-4-one (vardenafil); 5-[2-ethoxy-5-(4-ethylpiperazin-

1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one; and 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one and pharmaceutically acceptable salts thereof; b) an NPY Y1 inhibitor; c) a dopamine agonist (preferably apomorphine) or a selective D₂, D₃ or D₂/D₃agonist such as, pramipexole and ropirinol; d) a melanocortin receptor agonist or modulator or melanocortin enhancer, preferably melanotan II, PT-14, PT-141 ; and e) an agonist, antagonist or modulator for 5HT2C;

Particularly preferred combinations for treating FSD are the compounds of the present invention and one or more active ingredients selected from the list:

5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (sildenafil); (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);

2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1 ,2,4]triazin-4-one (vardenafil);

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-αf]pyrimidin-

7-one; apomorphine; melanotan II; PT-141 ; lasofoxifene; raloxifene; tibolone; an androgen such as androsterone, dehydro-androsterone, testosterone, androstanedione and a synthetic androgen; and an oestrogen, such as oestradiol, oestrone, oestriol and a synthetic estrogen, such as oestrogen benzoate.

Particularly preferred combinations for treating MED are the compounds of the present invention and one or more active ingredients selected from the list:

5-[2-ethoxy-5-(4-methyl-1 -piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (sildenafil);

(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); 2-[2-ethoxy-5-(4-ethyl-piperazin-1 -yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1 ,2,4]triazin-4-one (vardenafil);

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsuIphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c/|pyrimidin- 7-one; apomorphine; melanotan II; and

PT-141.

For treating cardiovascular disorders, particular hypertension, the compounds of the invention may be combined with one or more active ingredient selected from the list: a) angiotensin receptor blockers (ARB), such as losartan, valsartan, telmisartan, candesartan, irbesartan, eprosartan and olmesartan; b) calcium channel blockers (CCB) such as amlodipine; c) statins, such as atorvastatin; d) PDE5 inhibitors, such as sildenafil, tadalafil, vardenafil, 5-[2-ethoxy-5-(4-ethylpiperazin-1- ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one; 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3- αf]pyrimidin-7-one and; the pyrazolo[4,3-d]pyrimidin-4-ones disclosed in WOOO/27848 particularly N-[[3-(4,7-dihydro-1 -methyl-7-oxo-3-propyl-1 H-pyrazolo[4,3-d]-pyrimidin-5-yl)-4- propxyphenyl]sulfonyl]-1 -methyl2-pyrrolidinepropanamide [DA-8159 (Example 68 of WOOO/27848)]; e) beta blockers, such as atenolol or carvedilol; f) ACE inhibitors, such as quinapril, enalapril and lisinopril; g) alpha-blockers such as doxazosin; h) selective aldosterone receptor antagonists (SARA), such as eplerenone or spironolactone; and i) imidazoline I₁ agonists, such as rilmenidine and moxonidine.

If a combination of active agents are administered, then they may be administered simultaneously, separately or sequentially. The compounds of the invention can be administered alone but, in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of the invention, can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications. The compounds of the invention may also be administered via fast dispersing or fast dissolving dosage forms.

Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.

Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used, i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.

The compositions of the invention may be administered by direct injection. The composition may be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, ocular, intraocular or transdermal administration. Depending upon the need, the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.

The term "administered" includes delivery by viral or non-viral techniques. Viral delivery mechanisms include but are not limited to adenoviral vectors, adeno-associated viral (AAV) vectos, herpes viral vectors, retroviral vectors, lentiviral vectors, and baculoviral vectors. Non-viral delivery mechanisms include lipid mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof. The routes for such delivery mechanisms include but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.

In addition or in the alternative the compositions (or component parts thereof) of the present invention may be administered by direct injection. In addition or in the alternative the compositions (or component parts thereof) of the present invention may be administered topically (preferably to the genitalia). In addition or in the alternative the compositions (or component parts thereof) of the present invention may be administered by inhalation. In addition or in the alternative the compositions (or component parts thereof) of the present invention may also be administered by one or more of: a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution such as by an oral route, or by a parenteral route where delivery is by an injectable form, such as, for example, by a rectal, ophthalmic (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), intrauterine, vaginal or parenteral (including subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracranial, intratracheal, and epidural) transdermal, intraperitoneal, intracranial, intracerebroventricular, intracerebral, intravaginal, intrauterine, or parenteral (e.g., intravenous, intraspinal, subcutaneous, transdermal or intramuscular) route.

By way of example, the pharmaceutical compositions of the invention may be administered in accordance with a regimen of 1 to 10 times per day, such as once or twice per day. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

Hence, the term "administered" includes but is not limited to delivery by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution; a parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The compounds of the invention can also be administered parenterally, for example, intravenously, intra- arterially, intraperitoneal^, intrathecally, intraventricular^, intraurethrally intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. In addition, they may be administered in the form of an implant. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Parenteral formulations may be formulated for immediate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery.

The following dosage levels and other dosage levels herein are for the average human subject having a weight range of about 65 to 70 kg. The skilled person will readily be able to determine the dosage levels required for a subject whose weight falls outside this range, such as children and the elderly.

For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 1000 mg (in single or divided doses).

Thus, for example, tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 to 1000 mg, such as 5 to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including FSD and MED), compounds of the invention may be taken as a single dose on an "as required" basis (i.e. as needed or desired).

The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134A [trade mark] or 1 ,1 ,1 , 2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff contains from 1 to 50 mg of a compound of the invention for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.

Alternatively, compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically (preferably to the genitalia) in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention may also be dermally administered. The compounds of the invention may also be transdermal^ administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.

For ophthalmic use, compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

For application topically to the skin (preferably to the genitalia), compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug- cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-

A-98/55148.

In a preferred embodiment, the compounds of the invention are delivered systemically (such as orally, buccally and sublingually), more preferably orally. Preferably such systemic (most preferably oral) administration is used to treat female sexual dysfunction, preferably FSAD. Th us in a particularly preferred embodiment, there is provided the use of the compounds of the invention in the manufacture of a systemically delivered (preferably orally delivered) medicament for the treatment or prophylaxis of FSD, more preferably FSAD.

A preferred oral formulation uses immediate release tablets; or fast dispersing or dissolving dosage formulations (FDDFs).

In a further preferred embodiment, the compounds of the invention are administered topically, preferably directly to the female genitalia, especially the vagina.

Since NEP is present throughout the body, it is very unexpected that the compounds of the invention can be administered systemically and achieve a therapeutic response in the female genitalia without provoking intolerable (adverse) side effects. In EP 1 097 719-A1 and the animal model hereinafter, we have shown that NEP inhibitors administered to a rabbit model {in vivo) systemically increased genital blood flow, upon sexual arousal (mimiced by pelvic nerve stimulation) without adversely affecting cardiovascular parameters, such as causing a significant hypotensive or hypertensive.

Preferably the compounds of the invention are administered for the treatment of FSD in the sexually stimulated patient (by sexual stimulation we mean to include visual, auditory or tactile stimulation). The stimulation can be before, after or during said administration.

Thus the compounds of the invention enhance the pathways/mechanisms that underlie sexual arousal in the female genitalia restoring or improving the sexual arousal response to sexual stimulation.

Thus a preferred embodiment provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophyaxis of FSD in the stimulated patient.

For veterinary use, a compound of the invention, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.

The following formulation examples are illustrative only and are not intended to limit the scope of the invention . "Active ingredient" means a compound of the invention.

Formulation 1 : A tablet is prepared using the following ingredients:

Weight / mg

Active ingredient 250

Cellulose, microcrystalline 400

Silicon dioxide, fumed 10 Stearic acid 5

Total 665 the components are blended and compressed to form tablets.

Formulation 2: An intravenous formulation may be prepared as follows:

Active ingredient 100mg

Isotonic saline 1 ,000ml

Typical formulations useful for administering the compounds of the invention topically to the genitalia are as follows:

Formualtion 3: A spray

Active ingredient (1.0%) in isopropanol (30%) and water.

Formulation 4: A foam

Active ingredient, acetic acid glacial, benzoic acid, cetyl alcohol, methyl parahydroxybenzoate, phosphoric acid, polyvinyl alcohol, propylene glycol, sodium carboxymethylcellulose, stearic acid, diethyl stearamide, van Dyke perfume No. 6301 , purified water and isobutane.

Formulation 5: A gel

Active ingredient, docusate sodium BP, isopropyl alcohol BP, propylene glycol, sodium hydroxide, carbomer 934P, benzoic acid and purified water.

Formulation 6: A Cream

Active ingredient, benzoic acid, cetyl alcohol, lavender, compound 13091 , methylparaben, propylparaben, propylene glycol, sodium carboxymethylcellulose, sodium lauryl sulfate, stearic acid, triethanolmine, acetic acid glacial, castor oil, potassium hydroxide, sorbic acid and purified water.

Formulation 7: A pessary

Active ingredient, cetomacrogol 1000 BP, citric acid, PEG 1500 and 1000 and purified water.

The invention additionally includes:

(i) A pharmaceutical composition including a compound of the invention, together with a pharmaceutically acceptable excipient, diluent or carrier,

(ii) A compound of the invention for use as a medicament.

(iii) The use of a compound of the invention as a medicament for treating or preventing a condition for which a beneficial therapeutic response can be obtained by the inhibition of neutral endopeptidase. (iv) The use of a compound of the invention as a medicament for treating or preventing hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder or sexual pain disorder, preferably sexual arousal disorder, orgasmic disorder or sexual pain disorder, more preferably sexual arousal disorder, (v) A method of treating FSD or MED in a mammal including treating said mammal with an effective amount of a compound of the invention, (vi) An FSD or MED treating pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable excipient, diluent or carrier, (vii) A compound of the invention for use in treating FSD or MED. (viii) The use of a compound of the invention in the manufacture of a medicament for treating or preventing FSD or MED.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

Arbocel® Filtration agent, from J. Rettenmaier & Sohne, Germany br broad

Boc terf-butoxycarbonyl

CDI carbonyldiimidazole δ chemical shift d doublet

DCCI dicyclohexylcarbodiimide

DCM dichloromethane

DMA dimethylacetamide

DMF Λ/,Λ/-dimethylformamide

DMSO dimethylsulfoxide

ES⁺ electrospray ionisation positive scan

ES- electrospray ionisation negative scan

Ex Example h hours

HOBt 1 -hydroxybenzotriazole

HPLC high pressure liquid chromatography m/z mass spectrum peak min minutes

MS mass spectrum

NMR nuclear magnetic resonance

Prec precursor

Prep preparation q quartet

S singlet t triplet

Tf trifluoromethanesulfonyl TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TS⁺ thermospray ionisation positive scan

WSCDI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures.

Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI₃, deuterochloroform; DMSO, dimethylsulphoxide. The abbreviation psi means pounds per square inch and

LRMS means low resolution mass spectrometry. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F₂₅₄ plates, R_f is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate. Melting points were determined using a Perkin Elmer DSC7 at a heating rate of 20°C/minute).

The powder X-ray diffraction (PXRD) pattern was determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. The sample was prepared for analysis by packing the powder on to a silicon wafer specimen mount. The specimen was rotated whilst being irradiated with copper K-alpha-i X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube operated at 40kV/40mA. The analysis was performed with the goniometer running in step-scan mode set for a 5 second count per 0.02° step over a two theta range of 3° to 40°. In the results tables "Angle 2- Theta" is related to the interplanar spacing of the crystal, and the intensity is given as a percentage of the greatest peak (l/h).

The skilled crystallographer will appreciate that the relative intensities of the peaks may vary due to a number of factors such as orientation effects of crystals in the X-ray beam or the purity of the material being analysed or the degree of crystallinity of the sample. The peak positions may vary in sample height but the peak positions will remain substantially as tabulated. In addition, measurements using a different wavelength may result variation in the shift according to the Bragg equation - nλ = 2d sin θ. These variations generated by use of alternative wavelengths are within the scope of the present invention.

Examples and Preparations

Preparation 3

1 -(3-fert-Butoxy-3-oxopropvl)cvclohexanecarboxvlic acid

A solution of cyclohexanexarboxylic acid (2.89g, 22.6mmol) in tetrahydrofuran (30ml) was added to a cooled (-15⁰C) solution of lithium diisopropylamide (2M in tetrahydrofuran/heptane/ethylbenzene, 24.3ml,

48.6mmol), so as to maintain the internal temperature below O⁰C. The reaction mixture was stirred at O⁰C for 2.5 hours, re-cooled to -15°C and a solution of tert-butyl 3-bromopropionate (5g, 23.9mmol) in tetrahydrofuran (150ml) was added dropwise so as to maintain the temperature below 0⁰C. The reaction was then allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the addition of 2M hydrochloric acid and the mixture extracted with ethyl acetate (2x200ml). The combined organic solutions were dried (MgSO₄) and concentrated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.5) as eluant to afford the title compound as an oil, 800mg.

¹H nmr (CDCI₃, 400MHz) δ: 1.41 (s, 9H), 1.16-1.45 (m, 8H), 1.86 (m, 2H), 2.00-2.07 (m, 2H), 2.22 (m, 2H).

LRMS : m/z ES^" 255 [M-H]^"

Preparation 4

3-(4-Fluorophenyl)propan-1 -amine

A mixture of 4-fluorocinnamonitrile (10g, 6.80mmol) and Raney® Nickel (2.2g) in ethanol (300ml) and 0.88 ammonia (100ml) was hydrogenated at 2 atmospheres (2 atm, 30 psi) of hydrogen and room temperature for 18 hours. The mixture was filtered through Arbocel® washing through with water and ethanol. The filtrate was concentrated under reduced pressure and the residue azeotroped with toluene, to give the title compound, 5.4g

¹H nmr (CD₃OD, 400MHz) δ: 1.75 (m, 2H), 2.58 (m, 4H), 6.94 (m, 2H), 7.18 (m, 2H).

Preparation 5 (+) and (-) 5-Bromo-2-methyl-2.3-dihvdro-1 -benzofuran

A mixture of 2,3-dihydro-2-methylbenzofuran (10g, 74.6mmol) and N-bromosuccinimide (13.26g, 74.6mmol) in dichloromethane (100ml) was stirred at room temperature for 18 hours. The reaction was washed with water (2x100ml), sodium meta-bisulphide solution (2x100ml), and then concentrated under reduced pressure. The residual oil was purified by column chromatography on silica gel using pentane:ethyl acetate (100:0 to 99:1) as eluant to provide an oil, 13.6g. This was further purified by HPLC using a Chiralcel OJ 250*20mm column and hexane:isopropanol (95:5) as eluant to afford the first enantiomer of the title compound, 5g. [α]_D = -27.77 (c= 0.10, methanol).

¹H nmr (CDCI₃, 400MHz) δ: 1.45 (d, 3H), 2.78 (dd, 1 H), 3.28 (dd, 1 H), 4.94 (m, 1 H), 6.62 (d, 1 H), 7.18 (d,

1 H)₁ 7.22 (s, 1 H).

Further elution provided the other enantiomer.

Preparation 6

3-(2-Methyl-2,3-dihvdro-1-benzofuran-5-vl)acrvlonitrile

A mixture of the second eluted enantiomer from preparation 5 (4.1 g, 19.2mmol), acrylonitrile (2.53ml, 38.2mmol), sodium acetate (1.16g, 19.2mmol), palladium (II) acetate (432mg, 1.9mmol) and tri-o-tolyl phosphine (1.17g, 2.8mmol) in N,N-dimethylformamide (60ml) was stirred at 130^cC for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in ether. The mixture was filtered through Arbocel®, the filtrate washed with water, dried (MgSO₄) and concentrated under reduced pressure. The crude product was pre-adsorbed onto silica gel, and then purified by column chromatography on silica gel using ethyl acetate:pentane (2:98 to 3:97) as eluant to afford the title compound, 2.5g. ¹H nmr (CDCI₃, 400MHz) δ: 1.49 (d, 3H), 2.82 (dd, 1 H), 3.36 (dd, 1 H), 5.00 (m, 1 H), 5.64 (d, 1 H), 6.78 (d, 1H), 7.21 (d, 1 H), 7.26 (m, 2H).

Preparation 7 terf-Butyl f3-(2-methyl-2.3-dihvdro-1-benzofuran-6-yl)propyπcarbamate

Sodium borohydride (3.58g, 9.4mmol) was added portionwise over 5 minutes to an ice-cooled solution of the compound from preparation 6 (2.5g, 13.4mmol), di-fert-butyl dicarbonate (5.9g, 26mmol) and nickel chloride (1.75g, 13.4mmol) in methanol (200ml), and the reaction was allowed to stir at room temperature for 4 hours. The reaction was concentrated under reduced pressure, the residue re-suspended in ethyl acetate and the mixture filtered through Arbocel®. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (3:97 to 8:92) to afford the title compound as a clear oil, 2.5g.

¹H nmr (CDCI₃, 400MHz) δ: 1.44 (m, 12H), 1.77 (m, 2H), 2.58 (t, 2H), 2.80 (dd, 1H), 3.17 (m, 2H), 3.29 (dd, 1 H), 4.50 (brs, 1 H), 4.92 (m, 1 H), 6.64 (d, 1 H), 6.88 (d, 1 H), 6.98 (s, 1 H).

Preparation 8 3-(2-Methyl-2.3-dihvdro-1 -benzofuran-6-yl)propan-1 -amine hydrochloride

A solution of the compound from preparation 7 (1g, 3.43mmol) in 4M hydrochloric acid in dioxan (10ml) was stirred at room temperature for 18 hours at room temperature. The solution was evaporated under reduced pressure to afford the title compound as a white solid.

¹H nmr (CD₃OD, 400MHz) δ: 1.39 (d, 3H), 1.90 (m, 2H), 2.62 (t, 2H), 2.78 (dd, 1 H), 2.90 (t, 2H), 3.30 (m, 2H), 6.60 (d, 1H), 6.92 (d, 1H), 7.03 (s, 1H).

Preparation 11 fetf-Butyl 3-f1 -((r3-(4-fluorophenyl)propyllamino)carbonyl)cvclohexyllpropanoate

A mixture of the acid from preparation 3 (140mg, 0.55mmol), the amine from preparation 4 (110mg, 0.7mmol), 1 -hydroxybenzotriazole hydrate (89mg, 0.66mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (126mg, 0.66mmol) and N-methylmorpholine (181μl, 1.65mmol) in N₁N- dimethylformamide (10ml) was stirred at 90°C for 18 hours under nitrogen. The reaction was diluted with water and the mixture extracted with ethyl acetate (2x). The combined organic solutions were dried (MgSO₄) and concentrated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using pentane:ethyl acetate (100:0 to 50:50) to afford the title compound as a yellow oil, 184mg.

¹H nmr (CDCI₃, 400MHz) δ: 1.18-1.42 (m, 13H), 1.54 (m, 4H), 1.67 (m, 2H), 1.75-1.88 (m, 4H), 2.14 (m, 2H), 2.59 (m, 2H), 3.24 (m, 2H), 5.62-5.76 (m, 1 H), 6.92 (m, 2H), 7.08 (m, 2H). LRMS : m/z TSP⁺ 358 [MNa]⁺

Preparation 12 tert-Butyl 3-ri -((r3-(2.3-dihvdro-1-benzofuran-5-ylbropynamino)carbonyl)cvclohexynpropanoate

The title compound was prepared as an oil in 77% yield, from the acid from preparation 3 and 3-(2,3- dihydro-benzofuran-5-yl)-propylamine (WO 2002 079413), following the procedure described in preparation 11. Preparation 13 fert-Butyl 3-π-((r3-(2-methyl-2.3-dihvdro-1-benzofuran-5-yl)propyllamino)carbonyl)cvclohexyπpropanoate

A mixture of the acid from preparation 3 (150mg, 0.58mmol), the amine hydrochloride from preparation 8 (132mg, 0.58mmol), 1 -hydroxybenzotriazole hydrate (89mg, 0.58mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (246mg, 1.28mmol) and triethylamine (325μl, 2.23mmol) in N₁N- dimethylformamide (5ml) was stirred at 6O⁰C for 24 hours under nitrogen. The reaction was diluted with 10% potassium carbonate solution (25ml) and the mixture extracted with ether (2x50ml). The combined organic solutions were dried (MgSO₄) and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using pentane:ethyl acetate (85:15) as eluant to afford the title compound as a white crystalline solid, 180mg.

¹H nmr (CDCI₃, 400MHz) δ: 1.22-1.61 (m, 20H), 1.72 (m, 2H), 1.81 (m, 4H), 2.16 (t, 2H), 2.59 (t, 2H), 2.79 (dd, 1 H), 3.30 (m, 3H), 4.92 (m, 1 H), 5.61 (m, 1 H), 6.66 (d, 1 H), 6.92 (d, 1 H), 7.00 (s, 1 H). LRMS : m/z ES⁺ 452 [MNa]⁺

Preparation 14

Benzyl 4-methoxy-2-{H -((r3-(2-methyl-2.3-dihvdro-1 -benzofuran-5- vDpropynaminolcarbonvDcvclohexyllmethvDbutanoate

The title compound was obtained as an oil in 55% yield from 1 -{2-[(benzyloxy)carbonyl]-4- methoxybutyl}cyclohexanecarboxylic acid (EP 274234 ex 31) and the amine from preparation 8, following a similar procedure to that described in preparation 13.

¹H nmr (CDCI₃, 400MHz) δ: 1.15-1.68 (m, 19H), 1.72-1.85 (m, 4H), 1.99 (m, 2H), 2.58 (m, 2H), 2.78 (m,

1 H), 3.23 (m, 3H), 4.86 (m, 1 H), 5.05 (m, 2H), 5.61 (m, 1 H), 6.64 (dd, 1 H), 6.90 (d, 1 H), 6.98 (s, 1 H), 7.18

(m, 2H), 7.38 (m, 3H).

LRMS : m/z ES⁺ 544 [MNa]⁺

Preparation 15

Benzyl 2-(H -((r3-(2.3-dihvdro-1 -benzofuran-δ-ylΪpropyπaminolcarbonvDcvclohexylimethylM- methoxvbutanoate

A mixture of 1-{2-[(benzyloxy)carbonyl]-4-methoxybutyl}cyclohexanecarboxylic acid (EP 274234 ex 31) (393mg, 1.13mmol), 3-(4-methoxyphenyl)-propylamine (WO 2002 079413) (200mg, 1.13mmol), 1- hydroxybenzotriazole hydrate (152mg, 1.13mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (216mg, 1.13mmol) and triethylamine (470μl, 3.39mmol) in N,N-dimethylformamide (10ml) was stirred at room temperature for 48 hours. The reaction was concentrated under reduced pressure and the residue dissolved in dichloromethane and the mixture washed with water (1x50ml) and brine (20ml). The organic solution was dried (MgSO₄) and evaporated under reduced pressure. The residual oil was purified by chromatography on silica gel using dichloromethane:methanol (98:2 to 96.5:3.5) to afford the title compound as a yellow oil, 230mg.

¹H nmr (CDCI₃, 400MHz) δ: 1.37-1.84 (m, 15H), 1.98-2.10 (m, 4H), 2.35 (m, 1 H), 3.24 (s, 3H), 3.27-3.38 (m, 3H), 3.51 (m, 1 H), 4.08 (m, 2H), 5.04 (m, 2H), 5.30 (m, 1 H), 7.11 (d, 1H), 7.21 (s, 1 H), 7.25 (s, 1 H), 7.31 (m, 1 H), 7.40 (m, 2H), 7.58 (d, 2H). LRMS : m/z APCI⁺ 508 [MH]⁺

Example 1

3-H-((r3-(4-Fluorophenyl)propyllaminolcarbonyl)cvclohexyllpropanoic acid

A solution of the compound from preparation 11 (183mg, 0.47mmol) in dichloromethane (4ml) and trifluoroacetic acid (4ml) was stirred at room temperature for 4 hours. The solution was then evaporated under reduced pressure and the residue azeotroped with toluene. The residual green oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 98:2) to afford the title compound as an oil, 51 mg. ¹H nmr (CDCI₃, 400MHz) δ: 1.20-1.38 (m, 5H), 1.44-1.60 (m, 3H), 1.74-1.86 (m, 6H), 2.24 (t, 2H), 2.58 (t, 2H), 3.25 (t, 2H), 5.68 (m, 1 H), 6.95 (m, 2H), 7.09 (m, 2H). LRMS : m/z ES⁺ 358 [MNa]⁺

Example 2

3-F1 -((r3-(2.3-dihvdro-1 -benzofuran-δ-vDpropyllaminolcarbonvDcvclohexyllpropanoic acid

The title compound was obtained as an oil in 56% yield from the compound from preparation 12, following the procedure described in example 1.

¹H nmr (CDCI₃, 400MHz) δ: 1.22-1.40 (m, 5H), 1.57 (m, 3H), 1.74-1.84 (m, 6H), 2.24 (t, 2H), 2.58 (t, 2H),

3.18 (t, 2H), 3.30 (t, 2H), 4.56 (t, 2H), 5.66 (m, 1H), 6.69 (d, 1H), 6.90 (d, 1H), 7.00 (s, 1H).

LRMS : m/z ES⁺ 382 [MNa]⁺

Example 3

(+)-3-[1-(([3-(2-Methyl-2.3-dihvdro-1 -benzofuran-5-yl)propyllamino>carbonyl)cvclohexylipropanoic acid

A solution of the compound from preparation 13 (180mg, 0.42mmol) in dichloromethane (2ml) and trifluoroacetic acid (2ml) was stirred at room temperature for 18 hours. The pH of the solution was adjusted to 3 using 10% aqueous potassium carbonate solution and the mixture extracted with dichloromethane (2x1 OmI). The combined organic solutions were dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant. The resulting foam was further purified by HPLC using a Phenomenex Luna C18 column and acetonitrile:water:trifluoroacetic acid (5:95:0.1 ):acetonitrile (95:5 to 5:95) to afford the title compound, 68mg.

¹H nmr (CD₃OD, 400MHz) δ: 1.20-1.41 (m, 8H), 1.53-1.62 (m, 3H), 1.78 (m, 4H), 2.02 (m, 2H), 2.19 (t, 2H), 2.56 (t, 2H), 2.76 (m, 1 H), 3.19-3.28 (m, 3H), 6.58 (d, 1 H), 6.88 (d, 1 H), 7.00 (s, 1 H). LRMS : m/z ES⁺ 374.45 [MH]⁺ [α]_D = +16.91 (c = 0.17 in methanol)

Example 4

2-(f1-((r3-(2.3-Dihvdro-1-benzofuran-5-yl)propyllaminolcarbonyl)cvclohexyllmethyl)-4-methoxybutanoic acid

A mixture of the compound from preparation 15 (230mg, 0.45mmol) and 5% palladium on charcoal (30mg) in ethanol (25ml) was hydrogenated at 1 atm hydrogen and room temperature for 4 hours. The mixture was filtered through Arbocel®, washing through with additional ethanol. The filtrate was concentrated under reduced pressure and the residue was pre-adsorbed onto silica gel. This was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate:methanol (50:50:0 to 0:100:0 to 0:95:5) to afford the title compound, 40mg.

¹H nmr (CDCI₃, 400MHz) δ: 1.22-1.41 (m, 6H), 1.42-1.60 (m, 5H), 1.64 (m, 1 H), 1.67-1.96 (m, 5H), 2.00 (m, 1 H), 2.54 (m, 1 H), 2.58 (t, 2H), 3.18 (t, 2H), 3.30 (m, 3H), 3.39 (m, 2H), 4.55 (t, 2H), 5.80 (m, 1 H), 6.70 (d, 1H), 6.90 (d, 1H), 7.02 (s, 1H). LRMS : m/z APCl⁺ 418 [MH]⁺

Example 5

Potassium 4-methoxy-2-(π -(([3-(2-methyl-2.3-dihvdro-1 -benzof uran-5- vDpropyllaminoJcarbonvDcvclohexvnmethvllbutanoate

A mixture of the compound from preparation 14 (270mg, 0.52mmol) and 10% palladium on charcoal (30mg) in ethanol (10ml) was hydrogenated at 1atm of hydrogen at room temperature for 4 hours. The mixture was fltered through Arbocel®, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 95:5). The product was dissolved in dichloromethane, the solution treated with potassium carbonate (300mg), and the mixture stirred at room temperature for 18 hours. The mixture was filtered, and the filtrate evaporated under reduced pressure to afford the title salt as an off- white foam, 60mg. ¹H nmr (CD₃OD, 400MHz) δ: 1.22-1.34 (m, 4H), 1.39 (m, 5H), 1.44-1.61 (m, 5H), 1.70-1.83 (m, 3H), 1.95- 2.04 (m, 3H), 2.25 (m, 1 H), 2.58 (t, 2H), 2.74-2.79 (m, 1 H), 3.18-3.38 (m, 7H), 4.83 (m, 1 H), 6.38 (d, 1 H), 6.90 (d, 1 H), 7.01 (s, 1H). LRMS : m/z ES^" 430 [M-H]^"

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof;

wherein:

R¹ is hydrogen, C-_| .galkoxy, -NR² R³, -NR⁴SO₂R⁵, or

Ci_galkyl (which may be substituted by one or more substituents, which may be the same or different, selected independently from the list¹: halo, hydroxy, C-_|.galkoxy, hydroxyC-_j .galkoxy, C-) _ galkoxyC-_j .galkoxy, carbocyclyl, carbocyclyloxy, C-_| ^alkoxycarbocyclyloxy, heterocyclyl, heterocyclyloxy,

-NR²R³, -NR⁴COR⁵, -NR⁴SO₂R⁵, -CONR²R³, -S(O)_pR⁶, -COR⁷and -CO₂(Ci _₄alkyl)), ^or

R¹ is carbocyclyl¹ or heterocyclyl¹ (each carbocyclyl¹ and heterocyclyl¹ may be independently substituted by one or more substituents from said list¹, which substituents may be the same or different, which list further includes C-_| .galkyl);

R² and R³, which may be the same or different, are: carbocyclyl or heterocyclyl (each of which may be substituted by a substituent independently selected from C-_| _4alkyl, hydroxy and C-_| galkoxy), or are hydrogen or C-_| ^alkyl, or R² and R³ together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or Λ/-(C-_| _4alkyl)piperazinyl group;

R⁴ is hydrogen or C-^alkyl;

R⁵ is Chalky!, CF3, carbocyclyl, C-] ^alkylcarbocyclyl, C-] ^alkoxycarbocyclyl, heterocyclyl, C-\ galkoxy or -NR²R³;

R⁶ is C-_j^alkyl, carbocyclyl, heterocyclyl or NR²R³;

R⁷ is C-_|_4alkyl, carbocyclyl or heterocyclyl; p is 0, 1 , 2 or 3;

X is the linkage -(CH₂ )_n- or -(CH₂ )q-O- (wherein Y is attached to the oxygen), wherein one or more hydrogen atoms in linkage X may be replaced independently by a substituent selected independently from C-_|_4alkoxy, hydroxy, hydroxyC-_| ^alkyl, C3_7cycloalkyl, carbocyclyi, heterocyclyl, and C-^alkyl (said C-_| _4alkyl being optionally substituted by one or more fluoro or phenyl groups); n is 3, 4, 5, 6 or 7; q is 2, 3, 4, 5 or 6; Y is phenyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridyl, each of which may be substituted by one or more groups R⁸ which may be the same or different; each R⁸ is independently selected from: hydroxy, mercapto, halogen, cyano, HC=O, CO2H, -CO2(C-|.4alkyl), -CO(Ci _4alkyl), ^NH2_> rnono(C-| _

4alkyl)amino, di(C-_| _4alkyl)amino, C-_j.galkoxy, phenoxy, C-₍.galkylthio, phenylthio, carbocyclyi, heterocyclyl (each carbocyclyi and heterocyclyl being optionally substituted by one or more substituents selected independently from C-|.galkyl, haloC-_j.galkyl, C-^galkoxy, haloCi_galkoxy,

C-] .galkylthio and halogen), and

C-| _galkyl (optionally substituted by C-_|.galkoxy, haloC-_j .galkoxy, C-_| .galkylthio, halogen or phenyl), or two R⁸ groups on adjacent carbon atoms, together with the interconnecting carbon atoms, may form a fused 5- or 6-membered carbocyclyi or heterocyclyl² ring, or two R⁸ groups on adjacent carbon and nitrogen atoms, together with the interconnecting carbon and nitrogen atoms, may form a fused 5- or 6- membered heterocyclyl³ ring

(each carbocyclyi, heterocyclyl² and heterocyclyl³ ring being optionally substituted by one or more substituents selected independently from C-j.galkyl, haloC-_j .galkyl, C-_j.galkoxy, haloC-_|.galkoxy, C-_j. galkylthio and halogen);

with the proviso that when R^ is H or a (R)-CH^ group, and n is 3, Y and R⁸ is not 2-methyl-1 ,3- benzothiazoI-6-yl or 2-ethyl-1 ,3-benzothiazol-6-yl;

each "carbocyclyi" and "carbocyclyi¹", unless otherwise stated, independently mean a group including 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic, and also includes any fused combination of carbocyclic groups;

each "heterocyclyl" and "heterocyclyl¹", unless otherwise stated, independently mean a group including 5 to 7 ring-atoms, up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic;

"heterocyclyl²" means a 5 or 6 membered saturated, partially unsaturated or unsaturated ring containing from 1 to 3 ring heteroatoms selected independently from N, O and S, and containing at least 2 adjacent carbon atoms; "heterocyclyl³" means a 5 or 6 membered saturated, partially unsaturated or unsaturated ring containing from 1 to 3 ring heteroatoms selected independently from N, O and S, with the proviso that the ring contains at least 1 N atom;

"aryl" means phenyl or naphthyl, optionally substituted by one or more substituents selected from OH, CN, CF3, C-1-C4 alkyl, C1 -C4 alkoxy, halo, -CONhtø, aminosulphonyl, NH2, mono or di(C-₍-C4 alkyl)amino, and (C1-C4 alkanoyl)amino groups.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt and/or solvate thereof, wherein R^ is hydrogen, C-_| .galkyl, C-i .galkoxy, C-_|_6alkoxyCi_3alkyl, Ci_5alkoxyCi_6alkoxyC-_| _3alkyl or

C-_|.galkyl substituted by phenyl.

3. A compound according to claim 2, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R¹ is hydrogen, C-_|_galkyl, C-_j.galkoxy, C-_|_QalkoxyCi_3alkyl or C-j.galkoxyC-i.galkoxyCi.salkyl.

4. A compound according to claim 3, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R¹ is H, C-^alkyl or C-_|_6alkoxyC-_| _3alkyl.

5. A compound according to claim 4, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R^ is H, methyl, ethyl, or methoxyethyl.

6. A compound according to any preceding claim, or a pharmaceutically acceptable salt and/or solvate thereof, of formula (Ia):

7. A compound according to any preceding claim, or a pharmaceutically acceptable salt and/or solvate thereof, wherein X is -(CH2)_n- and wherein one or more hydrogen atoms in linkage X may be replaced by a substituent independently selected from C-^alkoxy, hydroxy, hydroxyC-^alkyl, C3_7cycloalkyl, carbocyclyl, heterocyclyl, and C-^alkyi (said C-^alkyl being optionally substituted by one or more fluoro or phenyl groups);

8. A compound according to any preceding claim, or a pharmaceutically acceptable salt and/or solvate thereof, wherein, when X is -(CH2)_n-_> n is 3 or 4.

9. A compound according to any preceding claim, or a pharmaceutically acceptable salt and/or solvate thereof, wherein

R⁸ is present and is C-_| .galkyl, C-_| .galkoxy, hydroxy, mercapto, halogen, cyano, carbocyclyl or heterocyclyl; or two R⁸ groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused 5- or 6-membered carbocyclyl or heterocyclyl ring, (each carbocyclyl and heterocyclyl being optionally substituted by one or more substituents selected independently from C-j.ealkyl, haloC-_|_galkyl,

C-| _6alkoxy, haloC-| .galkoxy, C-μgalkylthio and halogen).

10. A compound according to claim 9, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R⁸ is cyclopentyl, cyclopropyl, cyclohexyl or phenyl.

11. A compound according to claim 9, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R⁸ is pyridyl, oxadiazolyl, pyrazolyl or triazolyl.

12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt and/or solvate thereof, wherein Y is phenyl, optionally substituted by one or more substituents independently selected from halogen and OH.

13. A compound according to claim 12, or a pharmaceutically acceptable salt and/or solvate thereof, wherein Y and R⁸ together form a 4-chlorophenyl group.

14. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt and/or solvate thereof, wherein, when Y is phenyl, and two R⁸ groups on adjacent carbon atoms together with the interconnecting carbon atoms form a fused 5- or 6-membered carbocyclyl or heterocyclyl² ring, Y and

R⁸ together form a group which is selected from naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl, ( each of which is optionally substituted by one or more substituents selected independently from C-j.galkyl, haloC-_|.galkyl, C-_|. galkoxy, haloC-] .galkoxy, and halogen).

15. A compound according to claim 14, or a pharmaceutically acceptable salt and/or solvate thereof, wherein Y and R⁸ together form a benzothiazolyl group optionally substituted by one or more substituents selected independently from C-j_galkyl, haloC-|.galkyl, C-| .galkoxy, haloC-] .galkoxy, and halogen.

16. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 15, or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier.

17. A compound of formula (I) as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament.

18. A method of treatment of a disorder or condition where inhibition of NEP is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

19. Use of a compound of formula (I) as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition where inhibition of NEP is known, or can be shown, to produce a beneficial effect.

20. A compound according to claim 17, a method according to claim 18 or a use according to claim 19, wherein the disorder or condition is selected from female sexual dysfunction (FSD), female sexual arousal disorder (FSAD), male sexual dysfunction (MSD), and male erectile dysfunction (MED).