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  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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  • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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  • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
  • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

• N-Phenpropylcvclopentyl-Substituted Glutaramide Derivatives as NEP Inhibitors for FSAD
• 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.
• NEP neutral endopeptidase enzyme
• 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).
• FSD female sexual dysfunction
• FSAD female sexual arousal disorder
• NEP inhibitors are disclosed in WO 91/07386 and WO 91/10644.
• NEP inhibitors for treating FSD is disclosed in EP1 097 719-A1.
• the invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof;
• R "1 is C-
• C-f _4alkoxycarbocyc!yloxy (preferably C-f _4alkoxyphenoxy), heterocyclyl, heterocyclyloxy, -NR 2 R 3 , -NR4COR5, -NR 4 SO R 5 , -CONR 2 R 3 , -S(O) p R6,
• R 1 is carbocyclyl (preferably C3_7cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more substituents from said list, which substituents may be the same or different, which list further includes C-
• R 2 and R 3 which may be the same or different, are carbocyclyl (preferably C3_7cycloalkyl or phenyl) or heterocyclyl (each of which may be substituted by C-j galkyl, hydroxy or C-
• R4 is hydrogen or C- ⁇ alkyl
• R 5 is C ⁇ _4alkyl, CF3, carbocyclyl (preferably phenyl), C-j_4alkylcarbocyclyl (preferably C-1.4 alkylphenyl), C ⁇ _4alkoxycarbocyclyl (preferably
• R6 is C-j_4alkyl, carbocyclyl (preferably phenyl), heterocyclyl or NR R 3 ;
• F is C-
• Y is phenyl or pyridyl, each of which may be substituted by one or more groups R 3 which may be the same or different, wherein R 3 is hydroxy; mercapto; halogen; cyano; acyl; amino; mono(C- ⁇ _4alkyl)amino; di(C-
• R 1 is hydrogen, C-j .galkyl, C-i .galkoxy, C-
• R ⁇ is hydrogen, C-
• R 1 is C ⁇ alkyl (preferably propyl) or C-j .galkoxyC-j galkyl (preferably methoxyC ⁇ _3alkyl, more preferably methoxyethyl).
• a preferred group of compounds are of formula la:
• n is 3 or 4, more preferably 3.
• q is 2 or 3, more preferably 2.
• X is -(CH2)rr wherein one or more hydrogen atoms in linkage X may be replaced by one or more of the groups defined for X in the first aspect.
• R 8 is C ⁇
• R 8 is carbocyclyl
• preferred groups are cyclopentyl, cyclopropyl, cyclohexyl or phenyl.
• preferred groups are pyridyl, oxadiazolyl, pyrazolyl or triazolyl.
• fused ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl.
• Preferred compounds of the invention are:
• a particularly preferred compound is (2S)-2- ⁇ [1-( ⁇ [3-(4-chlorophenyl)propyl]amino ⁇ carbonyl)cyclopentyl]methyl ⁇ -4-methoxybutanoic acid (Example 22).
• 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.
• any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic.
• Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl.
• Preferred unsaturated carbocyclyl groups contain up to 3 double bonds.
• a preferred aromatic carbocyclyl group is phenyl.
• the term carbocylic should be similarly construed.
• carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
• any heterocyclyl group contains 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.
• heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyraziny
• heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.
• heterocyclic should be similarly construed.
• Halo means fluoro, chloro, bromo or iodo.
• substituted means substituted by one or more defined groups.
• groups may be selected from a number of alternatives groups, the selected groups may be the same or different.
• 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, non-toxic 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 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 can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases.
• Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloine, megulamine and diethanolamine salts.
• suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.
• 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.
• HPLC high pressure liquid chromatography
• a preferred optically active base is pseudoephedrine (see Preparation 69).
• 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, ⁇ - pyridonyl.
• Preferred prodrugs for compounds of the invention include: esters, carbonate esters, hemi- esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo- compounds, phosphamides, glycosides, ethers, acetals and ketals.
• 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.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 8 0, 31 P,
• isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e. 3 H, and carbon- 14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e. 2 H, 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.
• ABP atrial natriuretic peptides
• bombesin bombesin
• bradykinin calcitonin gene-related peptide
• endothelins endothelins
• enkephalins neurotensin
• substance P and vasoactive intestinal peptide.
• the compounds of the invention by inhibiting the neutral endopeptidase EC.3.4.24.11 , can potentiate the biological effects of bioactive peptides.
• 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.
• the compounds because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma.
• 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).
• 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.
• 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)).
• FSD especially FSAD
• MED male erectile dysfunction
• 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.
• 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.
• 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.
• 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 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
• pain resulting from penetration may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
• 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.
• FSAD vasculogenic dysfunction
• Empirical drug therapy includes oestrogen administration (topically or as hormone replacement therapy), androgens or mood-altering drugs such as buspirone or trazodone.
• DSM Diagnostic and Statistical Manual
• FSAD Female Sexual Arousal Disorder
• 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.
• FSAD FSAD-induced sexual desire
• Drug candidates for treating FSAD 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 (PGEi) that are injected or administered transurethrally in men, and topically to the genitalia in women.
• oral or sublingual medications Apomorphine, Phentolamine, phosphodiesterase type 5 (PDE5) inhibitors e.g. Sildenafil
• PGEi prostaglandin
• 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.
• the compounds of the invention provide means to restore, or potentiate, the normal sexual arousal response.
• VIP vasoactive intestinal peptide
• 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.
• selective inhibitors of NEP EC 3.4.24.11 enhance pelvic nerve-stimulated and VIP-induced increases in vaginal and clitoral blood flow.
• selective NEP inhibitors enhance VIP and nerve-mediated relaxations of isolated vagina wall.
• the present invention is advantageous as it helps provide 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 vaginal sensitivity.
• the present invention provides a means to restore, or potentiate the normal sexual arousal response.
• Male 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).
• PE premature ejaculation
• anorgasmia inability to achieve orgasm
• desire disorders such as hypoactive sexual desire disorder (lack of interest in sex).
• 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.
• Vasculogenic etiologies eg cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vacular system.
• 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
• 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.
• the compounds of the invention find application in the following sub-populations of patients with MED: psycogenic, endocrinologic, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction related to cavernosal factors, particularly venogenic causes.
• psycogenic, endocrinologic, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction related to cavernosal factors, particularly venogenic causes 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 general formula I may be prepared by reacting a compound of formula II (where Prot is a suitable protecting group) with an amine of formula III to give compounds of formula IV followed by deprotection (see Scheme 1 ).
• Preferred reaction conditions for the acid/amine coupling step comprise reacting II with III (or its amine salt) in the presence of an activating agent, optionally a catalyst, and an excess of an acid acceptor, in a suitable solvent.
• Particularly preferred reaction conditions comprise reacting II (1-1.5 equivalents), III (or its salt 1-1.5 equivalents), in the presence of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI) or N,N'- dicyclohexylcarbodiimide (DCC) (1.1-1.3 equivalents), 1-hydroxybenzotrazole hydrate (HOBT) or dimethylaminopyridine (DMAP) (1.05-1.2 equivalents), ⁇ /-methyl morpholine (NMM) or triethyamine (2.3-3 equivalents), in dimethylformamide or dichloromethane at between room temperature and 90°C for 16-18 hours.
• WSCDI 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• DCC N,N'- dicyclohexylcarbodiimide
• HOBT 1-hydroxybenzotrazole hydrate
• DMAP dimethylaminopyridine
• reaction conditions comprise reacting II (1-1.5 equivalents) and 1 ,1'-carbonyldiimidazole (1-1.5 equivalents) in a suitable solvent (such as tetrahydrofuran, isopropylacetate or toluene) followed by addition of III (or its amine salt in which case an organic base such as triethylamine or Hunig's base is present) at a reaction temperature between room temperature and 90°C.
• a suitable solvent such as tetrahydrofuran, isopropylacetate or toluene
• the acid/amine coupling step may be performed via the acid chloride in the presence of an excess of acid acceptor, in a suitable solvent.
• the acid chloride may be isolated or it may be generated in situ.
• Preferred reaction conditions comprise reacting the acid chloride of II (1-1.1 equivalents), III (or its salt, 1 to 1.5 equivalents), triethyamine or ⁇ /-methyl morpholine (1.4-10 equivalents), in dichloromethane at room temperature for 24 hours.
• Compounds of formula II can be converted to the acid chloride in situ by treatment with oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide for 2 hours at room temperature.
• deprotection conditions comprise reacting IV with trifluoroacetic acid/dichloromethane (1 :1-2.5 by volume), at room temperature for 2-18 hours, optionally in the presence of a carbocation scavenger, e.g. anisole (10 equivalents).
• a carbocation scavenger e.g. anisole (10 equivalents).
• X or Y contains a hydroxy group
• base hydrolysis of the intermediate trifluoroacetic acid ester may be necessary.
• Alternative methodology for deprotection when Prot is te -butyl comprises treating IV with hydrochloric acid in dichloromethane at room temperature for 3 hours.
• Prot as tett-butyl is given by way of example and is not intended to be limited to terf-butyl.
• chiral compounds of formula II where R 1 is optionally substituted C 1-6 alkyl may be prepared by asymmetric hydrogenation of compounds of formula XI, XII, or XIII according to reaction scheme 1 a.
• Typical hydrogenating conditions comprise treating compounds of formula XI, XII or XIII [or an organic or inorganic salt (eg sodium salt) thereof] with a suitable asymmetric hydrogenation catalyst under elevated hydrogen pressure in a suitable solvent.
• Preferred catalysts contain one or more chiral ligands, preferably chiral phosphine ligands, coordinated to a suitable transition metal (for example rhodium, ruthenium, iridium, paladium).
• Preferred catalysts are: [(f?)-(+)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthylchloro(para-cymene)] ruthenium chloride (J. Org. Chem.
• reaction conditions comprise a hydrogen pressure of up to 150 psi and a reaction temperature between 0 and 100 °C (preferably 50 to 60 °C).
• Preferred solvents are protic, such as methanol or ethanol.
• Typical reaction conditions comprise 1.0-1.5 equivalents of the aryl halide, 3 equivalents of base, 0.1 equivalents of palladium catalyst (preferably palladium (II) acetate), 0.2 equivalents of phosphine ligand (preferably tri-o- tolylphosphine) in 1 ,4-dioxan, acetonitrile or DMF (preferably acetonitrile) at reflux.
• palladium catalyst preferably palladium (II) acetate
• phosphine ligand preferably tri-o- tolylphosphine
• Typical hydrogenation conditions comprise treating VI with Raney nickel in ethanol or methanol at a pressure of 15 to 150 psig and 25 and 80°C. Preferably in ethanol at 30psig and 25°C.
• compounds of formula VI may be prepared according to reaction scheme 3 by reacting compounds of formula VII with diethylcyanomethyl phosphonate.
• Typical reaction conditions comprise reacting diethylcyanomethyl phosphonate with a suitable base (for example sodium hydride, lithium chloride/Hunigs base or sodium ethoxide) in a suitable solvent at room temperature (for example dichloromethane, tetrahydrofuran or diethyl ether) followed by addition of compound of formula VII.
• a suitable base for example sodium hydride, lithium chloride/Hunigs base or sodium ethoxide
• room temperature for example dichloromethane, tetrahydrofuran or diethyl ether
• a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate.
• the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
• the compounds of the invention [particularly (2S)-2- ⁇ [1-( ⁇ [3-(4- chlorophenyl)propyl]amino ⁇ carbonyl)cyclopentyl]methyl ⁇ -4-methoxybutanoic acid (Example 22)] may be combined with one or more further active ingredients selected from the list:
• prostaglandins for use herein include compounds such as alprostadil, prostaglandin E ⁇ prostaglandin E o , 13, 14 - dihydroprosta glandin E ⁇ prostaglandin E 2 ⁇ eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in WO-00033825 and/or US
• PGEo PGE L PGAL PGBL PGFT ⁇
• 19-hydroxy PGA- 19-hydroxy - PGB L PGE 2 , PGB 2 , 19-hydroxy-PGA 2 , 19-hydroxy-PGB 2 , PGE 3 ⁇
• ⁇ - adrenergic receptor antagonist compounds also known as ⁇ - adrenoceptors or ⁇ -receptors or ⁇ -blockers.
• Suitable compounds for use herein include: the ⁇ -adrenergic receptor blockerss as described in PCT application WO99/30697 published on 14th June 1998, the disclosures of which relating to ⁇ -adrenergic receptors are incorporated herein by reference and include, selective ⁇ i-adrenoceptor or ⁇ 2 -adrenoceptor blockers and non-selective adrenoceptor blockers, suitable ⁇ adrenoceptor blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohim
• Adrenoceptor blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine.
• NO-donor compounds 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 d
• potassium channel openers or modulators include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCI 2 .
• One or more dopaminergic agents preferably apomorphine or a selective D 2 , D 3 or D 2 /D 3 agonist such as, pramipexole and ropirinol (as claimed in WO-0023056), PNU95666 (as claimed in WO-0040226).
• One or more vasodilator agents include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, halo peridol, Rec 15/2739, trazodone.
• ergot alkoloids One or more CNS active agents.
• CNS active agents One or more CNS active agents.
• ergot alkoloids One or more ergot alkoloids. Suitable ergot alkaloids are described in US patent 6,037,346 issued on 14th March 2000 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 inhibitors or neutral endopeptidase.
• atrial naturetic factor also known as atrial
• One or more compounds which inhibit angiotensin-converting enzyme such as enapril, and combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat.
• One or more angiotensin receptor antagonists such as losartan.
• One or more substrates for NO-synthase such as L-arginine.
• One or more calcium channel blockers such as amlodipine.
• 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.
• One or more antiplatelet and antithrombotic agents e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors.
• One or more insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide.
• One or more acetylcholinesterase inhibitors such as donezipil.
• One or more steroidal or non-steroidal anti-inflammatory agents such as donezipil.
• 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.
• NPY neuropeptide Y
• NPY1 or NPY5 inhibitor preferably NPY1 inhibitor
• said NPY inhibitors having an IC50 of less than 100nM , more preferably less than 50nM.
• VIP vasoactive intestinal protein
• VIP mimetic VIP mimetic
• VIP analogue more particularly mediated by one or more of the VIP receptor subtypes VPAC1 NPAC or PACAP (pituitory 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 ⁇ -adrenoceptor antagonist with VIP combination (eg Invicorp, Aviptadil).
• 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-
• a serotonin receptor agonist, antagonist or modulator more particularly agonists, antagonists or modulators for 5HT1 A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO- 09902159, WO-00002550 and/or WO-00028993.
• an androgen such as androsterone, dehydro-androsterone, testosterone, androstanedione and a synthetic androgen.
• an oestrogen such as oestradiol, oestrone, oestriol and a synthetic estrogen, such as oestrogen benzoate.
• an oestrogen such as oestradiol, oestrone, oestriol and a synthetic estrogen, such as oestrogen benzoate.
• One or more of a purinergic receptor agonist and/or modulator One or more of a purinergic receptor agonist and/or modulator.
• NK neurokinin
• an opioid receptor agonist, antagonist or modulator preferably agonists for the ORL-1 receptor.
• One or more of an agonist or modulator for oxytocin/vasopressin receptors preferably a selective oxytocin agonist or modulator.
• 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
• Suitable cGMP PDE5 inhibitors for the use according to the present invention include:
• PDE5 inhibitors include:4-bromo-5-(pyridylmethylamino)-6-[3-
• 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 (IC
• 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 ⁇ '.l' ⁇ JpyridotS ⁇ -bJindole-l ,4-dione (IC-
• 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.
• an androgen such as androsterone, dehydro-androsterone, testosterone, androstanedione and a synthetic androgen
• an oestrogen such as oestradiol, oestrone, oestriol and a synthetic estrogen, such as oestrogen benzoate.
• Particularly preferred combinations for treating MED are (2S)-2- ⁇ [1-( ⁇ [3-(A- chlorophenyl)propyl]amino ⁇ carbonyl)cyclopentyl]methyl ⁇ -4-methoxybutanoic acid
• Example 22 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-
• 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.
• 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 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.
• 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.
• 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.
• 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.
• compositions (or component parts thereof) of the present invention may be administered by direct injection.
• compositions (or component parts thereof) of the present invention may be administered topically (preferably to the genitalia).
• compositions (or component parts thereof) of the present invention may be administered by inhalation.
• 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.
• a mucosal route for example, as a nasal spray or aerosol for inhalation or
• 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.
• 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.
• 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, intraperitoneally, intrathecally, intraventricularly, intraurethrally intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
• they may be administered in the form of an implant.
• 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.
• parenteral formulations under sterile conditions are 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.
• 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.
• 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).
• 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.
• 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.
• a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,
• 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.
• 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.
• 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 transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
• 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.
• 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.
• ком ⁇ онентs 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.
• 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.
• the compounds of the invention are delivered systemically (such as orally, buccally and sublingually), more preferably orally.
• systemic (most preferably oral) administration is used to treat female sexual dysfunction, preferably FSAD.
• a preferred oral formulation uses immediate release tablets; or fast dispersing or dissolving dosage formulations (FDDFs).
• FDDFs fast dispersing or dissolving dosage formulations
• the compounds of the invention are administered topically, preferably directly to the female genitalia, especially the vagina.
• NEP 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.
• 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.
• the compounds of the invention enhance the pathways/mechanisms that underlie sexual arousal in the female gentialia restoring or improving the sexual arousal response to sexual stimulation.
• 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.
• 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.
• Active ingredient means a compound of the invention.
• Formulation 1 A tablet is prepared using the following ingredients: weight/mg
• Formulation 2 An intravenous formulation may be prepared as follows: Active ingredient 100mg
• Typical formulations useful for administering the compounds of the invention topically to the genitalia are as follows: Formualtion 3: A spray
• 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.
• 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.
• 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.
• 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.
• a method of treating FSD or MED in a mammal including treating said mammal with an effective amount of a compound of the invention.
• An FSD or MED treating pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable excipient, diluent or carrier.
• TLC thin layer chromatography
• 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 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.
• Example 22 may be prepared as follows: t ⁇ 2S)-2- ⁇ ri-(fr3-(4-Chlorophenyl)propynamino ⁇ carbonyl)cvclopentvnmethyl)-4- methoxybutanoic acid To a solution of the product from Preparation 22 (9.6 g, 21.2 mmol) in dichloromethane (52 ml) was added trifluoroacetic acid (16.3 ml, 212 mmol) and the resultant solution was stirred at room temperature for 3.75 hours under an atmosphere of N 2 .
• aqueous sodium carbonate solution 95 ml of a 10% w/v solution
• the layers were then separated and the organic layer was extracted with aqueous sodium carbonate solution (2 x 20 ml of a 10% w/v solution).
• the aqueous layers were combined and saturated brine (80 ml) was then added, followed by 2-butanone (40 ml). The layers were separated and the aqueous layer was extracted again with 2-butanone (2 x 50 ml).
• the ethanol was then removed by azeotropic distillation at atmospheric pressure (to remove 110 ml of solvent) and replaced with ethyl acetate (145 ml) whereupon crystallisation occurred.
• the resultant crystallised product was then collected by filtration under vacuum to give the pure sodium salt of the title product as a white crystalline solid (4.51 g, 10.8 mmol, 51 %); m.p.
• Example 22 To the sodium salt of Example 22 (200 mg) was added to 1 ml of a 3.9% water in isopropanol solution. The resulting slurry was stirred for 12 days whereupon it was isolated by filtration. The product gave the following PXRD pattern.
• DSC Differential scanning calorimetry
• aqueous layer was then separated, and the organic layer was washed with aqueous potassium carbonate (50 ml of a 0.5 M solution).
• aqueous potassium carbonate 50 ml of a 0.5 M solution.
• the aqueous phase was separated and organic phase was washed with saturated brine solution (100 ml).
• oven program initial temp. 100 °C, rate 10 °C/min, final temp. 230 °C, final time 10 min; column, BP-21 25 m x 0.25mm ID x 0.25um FT; detector FID) RT 16.1 min.
• the header tank was washed with 1 ,2-dimethoxyethane (2.5 L) and this was added to the reaction. The reaction mixture was then allowed to stir at -10 °C for 1.75 hours. To the resultant solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1 ,2-dimethoxyethane (10 L) over a period of 1.75 hours. The reaction was then stirred at this temperature for 4 hours before warming to 20 °C over a period of 4 hours. After stirring at this temperature for 8 hours the reaction was quenched by the addition of aqueous ammonium chloride (25 L of a 2.8 M solution), ethyl acetate (12.5 L) was then added.
• aqueous ammonium chloride 25 L of a 2.8 M solution
• Aqueous hydrochloric acid (10 L of 5 M solution) was then added with stirring to adjust the pH to between 2 and 3.
• the two phases were mixed and then separated.
• the organic phase was then extracted three times with aqueous potassium carbonate solution (0.3 M solution; 37.5 L, 12.5 L and then 6.25 L).
• aqueous potassium carbonate solution 0.3 M solution; 37.5 L, 12.5 L and then 6.25 L.
• n-heptane n-heptane
• aqueous hydrochloric acid (14.5 L of a 5 M solution
• a solution of the crude product from stage a) above in n-heptane (5.51 kg, 18.3 mol in a total solution weight of 41.4 kg) was concentrated by distillation at atmospheric pressure to remove 20 L of n-heptane
• cyclohexylamine (1.82 kg, 18.4 mol) as a solution in n-heptane (9.9 L) over a period of 0.5 hours.
• the transfer lines were then washed with n-heptane (1.1 L) and this was added to the reaction.
• the resultant slurry was then granulated with agitation at 22 °C for a period of 19.5 hours.
• the product was collected by filtration and washed with n-heptane (2 x 11.0 L) and the resultant solid was dried under vacuum at 50 °C for 20 hours.
• the resultant off-white solid (6.2 kg, 15.5 mol) was suspended in isopropyl acetate (37.2 L) and the resultant suspension was heated to 80 °C until a clear solution was obtained.
• the resultant solution was then cooled to 50 °C and a sample of authentic crystallised title compound (1.0 g) was added to seed the crystallisation.
• the crystallising slurry was then cooled to 20 °C over 4 hours and was then granulated at this temperature for 0.5 hours.
• the product was then collected by filtration and was washed with n-heptane (2 x 6.2 L) before being dried under vacuum at 45 °C for 11 hours.
• the resultant white solid (5.5 kg, 13.8 mol) was then suspended in isopropyl acetate (55.0 L) and was heated to 80 °C until a clear solution was obtained.
• the resultant solution was then cooled to 50 °C and a sample of authentic crystallised title compound (1.0 g) was added to seed the crystallisation.
• the crystallising slurry was then cooled to 20 °C over 4 hours and then granulated at this temperature for 22.5 hours.
• the resultant solution was then cooled to 58 °C and a sample of authentic crystallised title compound (1.0 g) was added to seed the crystallisation.
• the solution was then held at 58 °C for 1 hour and was then cooled to 20 °C over 6 hours.
• the slurry was then granulated at 20 °C for 12 hours.
• the product was then collected by filtration and was washed with heptane (2 x 2 L).
• the vessel was pressurised with hydrogen (10 bar), then vented and pressurised again with hydrogen (10 bar). The mixture was then stirred at 65°C for 18h. The vessel was then allowed to cool to room temperature and the pressure was then released. To the reaction mixture was then added ethyl acetate/heptane (1 :1 , 10 ml) and hydrochloric acid (1 M, 5 ml).
• the vessel was pressurised with hydrogen (10.5 bar), then vented and pressurised again with hydrogen (10.5 bar). The mixture was then stirred at room temperature for 18h and the pressure was then released. To the reaction mixture was added te/f-butyl methyl ether and 2M hydrochloric acid and the phases were mixed.
• the vessel was pressurised with hydrogen (10.5 bar), then vented and pressurised again with hydrogen (10.5 bar).
• the mixture was stirred at 45°C for 18h and then allowed to cool to room temperature. The pressure was then released and to the reaction mixture was added te/t-butyl methyl ether and 2M hydrochloric acid and the phases were mixed.
• CDCI 3 CDCI 3 ) ⁇ : 24.9, 25.2, 28.4, 34.7, 38.8, 41.7, 44.3, 53.5, 56.1 , 80.9, 101.9, 149.2, 174.5, 184.5.
• the reaction was then quenched by the addition of deionised water (100 ml) and the layers were then separated.
• the aqueous phase was then extracted with dichloromethane (100 ml) and the organic extracts were combined and washed with hydrochloric acid (50 ml of a 1 M solution).
• the organic layer was then washed with aqueous sodium thiosulfate (100 ml of a 5% w/v solution) and then with deionised water (100 ml).
• the organic layer was then dried over magnesium sulfate and the solvent was removed under reduced pressure to give the crude product as a dark oil (7.5 g, 22.0 mmol, 82% yield).
• CDCI 3 ⁇ ppm 1.45 (s, 9 H), 2.48 (s, 3 H), 3.14 (t, 2 H), 3.30 (s, 3 H), 3.51 (t, 2 H), 7.10 (s, 1 H), 7.35 (d, 2 H), 7.83 (d, 2 H).
• reaction mixture was then stirred for 10 minutes, and to the resultant solution was added a solution of the product from stage g) above (20.0 g, 58.7 mmol) in anhydrous THF (160 ml) over a period of 5 minutes).
• the reaction mixture was then stirred for 2 hours whilst maintaining the temperature between 0 to 5°C.
• the reaction was then allowed to warm to room temperature and stirred for 19 hours.
• the reaction was then quenched by the addition of isopropanol (120 ml) and the mixture was then stirred for 1 hour.
• the reaction mixture was filtered, and the solid by-products were then washed with THF (10 ml).
• Diethylcyanomethyl phosphonate (3.2ml, 18.9mmol) was taken up in dry THF (20ml) at 0°C under nitrogen, and stirred as a 60% oil dispersion of NaH (756mg, 18.9mmol) was added portionwise over ca. 10min. The resulting grey suspension was then stirred at 0°C for 1 h, before a solution of 4-chloro-3-f luoro benzaldehyde (Lancaster Synthesis) (3g, 18.9mmol) in 5ml THF was added dropwise. The whole reaction was then allowed to warm to room temperature over 60h. Water (5ml) was added, and the mixture extracted with EtOAc (3x50ml).
• the vinyl cyanide from Preparation 93 (500mg, 2.75mmol) was taken up in ethanol (36ml) and 0.88 NH 3 solution (18ml) and shaken with 150mg of 30%w/w RaNi under 15psi H 2 pressure overnight.
• 6-Methyl-quinoline (Aldrich Chemical Co.) (1 g, 7.0mmol) and selenium dioxide (2.32g, 21.Ommol) were combined in the absence of solvent and heated at 100°C under a nitrogen atmosphere for 16h. The reaction mixture was allowed to cool to room temperature, taken up in MeOH and presorbed onto silica gel.
• Di-terf-butyl dicarbonate (1.06g, 4.8mmol) was added in one portion to a stirred solution of the product from Preparation 104 (400mg, 2.4mmol) in a mixture of water (10ml) and dioxan (10ml) under nitrogen.
• the reaction was stirred for 72h, after which time potassium carbonate (2.0g, 14.4mmol) was added in one portion and the mixture stirred for a further 23h to completely hydrolyse any ester formed during the reaction.
• the mixture was transferred to a separating funnel, and the organic layer separated, dried over MgSO and evaporated to a yellow oil.
• 2-Vinyl pyridine (105g) and acetic anhydride (204g) were combined at room temperature, and a solution of KCN (130g) in 250ml of water was added dropwise to the stirring solution. The rate of addition was adjusted to maintain a gentle reflux. After the addition was complete, the mixture was refluxed for 22h, and the pH of the solution then adjusted to 8 with aqueous Na 2 CO 3 solution. The mixture was extracted with DCM (600ml), the extracts dried over MgSO and then evaporated to a brown oil. The oil was then vacuum distilled at approximately 0.6mmHg pressure. The product distilled over as a clear oil at 100-107°C in 56% yield.
• the 1 -methyl isomer from Preparation 111 (100mg, 0.47mmol) was taken up in dioxan (6ml), and potassium carbonate (72mg, 0.52mmol), acrylonitrile (0.035ml, 0.52mmol), Pd 2 (dba) 3 (43mg, 0.047mmol) and PtertBu 3 (0,038ml, 0.16mmol) were added in sequence.
• the reaction was then refluxed for 3h under a nitrogen atmosphere before cooling to room temperature, filtering through a short plug of arbocel and evaporation of the filtrate in vacuo.
• n BuLi (1.6M in hexanes, 34.4m!s, 55mmol) was added dropwise to a stirred solution of 1 ,4-dibromobenzene (11.8g, 50mmol) in 100ml of dry THF at -60°C.
• the mixture was stirred for 15min at this temperature before a solution of ZnCI 2 (0.5M in THF, 100ml, 50mmol) in THF was added dropwise.
• the mixture was allowed to warm to room temperature over 90min, and then Pd(PPh 3 ) 4 (200mg) was added, followed immediately by 2-bromopyridine (4.8ml, 50mmol).
• the product from preparation 115 (190mg, 1 mmol) was dissolved in DCM (2ml) at room temperature under nitrogen, and firstly 132 ⁇ l (1. ⁇ mmol) of oxalyl chloride, and then 1 drop of DMF were added. After the effervescence had subsided, the mixture was stirred at room temperature for 3h and then concentrated in vacuo. The residue was redissolved in 2m! of THF and 0.6ml of 0.88NH 3 solution added, and the whole stirred for 4 days. The reaction was quenched with water and extracted into EtOAc (2x10ml).
• the amide from Preparation 116 (170mg, 0.9mmol) was dissolved in dry THF (3ml) at 0°C under nitrogen and stirred as a solution of LiAIH 4 in THF (1 M, 0.9ml, 0.9mmol) was added dropwise with considerable effervescence. The reaction was warmed to 60°C and stirred at this temperature overnight. The mixture was quenched with water (1 ml), 1 N NaOH solution was added (1 ml) and the solution extracted with EtOAc (2x50ml), dried (MgSO ), filtered and concentrated to a pale yellow oil.
• the title compound was prepared by a modified procedure of that described by Iddon et al. (J.C.S. Perkin 1, 1977, 2367).
• Solid LiAIH 4 (1.2g, 31.6mmol) was suspended in diethyl ether (3 ⁇ ml) and stirred under nitrogen as the suspension was heated to ca. ⁇ O°C.
• a solution of the vinyl cyanide from Preparation 118 (2.06g, 9.88mmol) was added dropwise as a solution in ether (20ml) and the mixture then heated for 90min. After this time, the heating was stopped, and the reaction was stirred at room temperature for 16h. Water was added, followed by 1 N NaOH (30ml) and EtOAc (60ml) and the whole stirred vigorously for 30min.
• the product from preparation 121 (11g, 5 ⁇ .2mmol) in diethyl ether (41 ml) was added dropwise to a suspension of lithium aluminium hydride (4.1g, 108mmol) in diethyl ether (110ml) under nitrogen.
• the reaction mixture was refluxed for 4 hours before the addition of ethyl acetate then water.
• the aqueous layer was acidified with 4N hydrochloric acid shaken and then separated before been made alkaline with 40% sodium hydroxide solution.
• the aqueous layer was then extracted with diethyl ether (3x100ml) and the combined organic extracts were dried over magnesium sulphate.
• the diethyl ether extracts were acidified with hydrogen chloride and the resulting precipitate filtered.
• the product from Preparation 130 (200mg, 1.24mmol) was mixed with ethanol (20ml) and 20mg of 10wt% Pd/C and hydrogenated at 40p.s.i. hydrogen pressure for 48h. A further 20mg of catalyst was added, and the whole hydrogenated at 60p.s.i. and 40°C for a further 72h. The catalyst was filtered through a short plug of Arbocel, and the filtrate evaporated to dryness.
• the product from Preparation 132 was dissolved in ethanol (20ml) and ammonium hydroxide solution ( ⁇ ml), and the whole hydrogenated at 30p.s.i. hydrogen pressure over 200mg of 30wt% Ra-Ni for 16h. A further 10Omg of catalyst was then added and the hydrogenation continued for a further 16h. The reaction mixture was filtered through a short plug of Arbocel, and the filtrate evaporated in vacuo to low volume.
• lodoacetonitrile (5.03ml, 69.5mmol) was then added slowly, and the combined solution allowed to warm to room temperature over 72h. Saturated aq. NaHCO 3 solution (20 ml) was added, the mixture was concentrated to about 50ml under vacuum, and then treated with 1 N HCI (100ml).
• the product from Preparation 149 was alkylated according to an identical procedure to that described in Preparation 147, using methyl iodide as the alkylating agent.
• the title product was obtained in 95% yield after purification by column chromatography using 25% DCM in pentane as eluant; 1 HNMR (400MHz, CDCI 3 ) ⁇ : 1.39 (s, 9H), 1.41 (d, 3H), 3.59 (q, 1 H), 7.20 (d, 2H), 7.25 (d, 2H).
• IC50 values of the compounds of the invention against NEP and ACE were determined using methods described in published patent application EP1097719-A1 , paragraphs [0368] to [0376].
• the IC50 values presented below were determined using NEP from canine kidney.
• the IC50 value of some compounds of the invention were determined using NEP from human kidney; these values were similar to the values determined using canine NEP.
• the compounds of the invention are potent inhibitors of NEP and are selective against ACE.
• the title compound of Example 3 showed an IC50 against NEP of 22 nM; the title compound of Example 4 showed an IC50 against NEP of 4 nM; the title compound of Example 21 showed an IC50 against NEP of 3 nM; the title compound of Example 33 showed an IC50 against NEP of 47 nM; the title compound of Example 43 showed an IC50 against NEP of 29 nM; and the title compound of Example 51 showed an IC50 against NEP of 9 nM.
• the title compounds of Examples 3, 4, 21 , 33, 43 and 51 were all greater than 300 fold selective against ACE.
• the title compound from Example 22 (herein after referred to as "the selected compound”) was administered according to the protocol described in EP1097719-A1 , paragraphs [0495] to [0499].
• the selected compound was made up in 5% saline.
• the selected compound and vehicle controls were infused using a Harvard 22 pump, infusing at 500 /l/min via a 3-way tap into the femoral vein. After the infusion, the catheter was flushed with heparinised saline (Hepsaline) so that none of the selected compound was left in the catheter.
• Hepsaline heparinised saline
• the selected compound tested at clinically relevant doses, significantly enhanced pelvic nerve stimulated increases in genital blood flow (See Figure 1).
• Figure 1 shows the effect of administering the selected compound on the genital blood flow in a rabbit.
• the selected compound enhanced pelvic nerve stimulated (PNS) increases in genital blood flow in the anaesthetised rabbit model of sexual arousal. Repetitive PNS at 15 minute intervals induced reproducible increases in genital blood flow (Hatched Bars).
• Administration of the elected compound enhanced the peak increase in clitoral and vaginal blood flow induced by submaximal stimulation frequencies (eg 4Hz) compared to increases observed during time matched control stimulations or vehicle controls (Hatched bar).
• mice Female New Zealand rabbits ( ⁇ 2.5kg) were pre-medicated with a combination of Medetomidine (Domitor®) 0.5ml/kg i.m., and Ketamine (Vetalar®) 0.25ml/kg i.m. whilst maintaining oxygen intake via a face mask.
• the rabbits were tracheotomised using a PortexTM uncuffed endotracheal tube 3 ID., connected to ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate tidal volume of 18-20 ml, and a maximum airway pressure of 10 cm H 2 O. Anaesthesia was then switched to Isoflurane and ventilation continued with O 2 at 2l/min.
• the right marginal ear vein was cannulated using a 23G or 24G catheter, and Lactated Ringer solution perfused at 0.5ml/min.
• the rabbit was maintained at 3% Isoflurane during invasive surgery, dropping to 2% for maintenance anaesthesia.
• the left groin area of the rabbit was shaved and a vertical incision was made approximately 5cm in length along the thigh.
• the femoral vein and artery were exposed, isolated and then cannulated with a PVC catheter (17G) for the infusion of drugs and compounds. Cannulation was repeated for the femoral artery, inserting the catheter to a depth of 10cm to ensure that the catheter reached the abdominal aorta.
• This arterial catheter was linked to a Gould system to record blood pressure. Samples for blood gas analysis were also taken via the arterial catheter. Systolic and diastolic pressures were measured, and the mean arterial pressure calculated using the formula (diastolic x2 + systolic) ⁇ 3.
• Heart rate was measured via the pulse oxymeter and Po-ne-mah data acquisition software system (Ponemah Physiology Platform, Gould Instrument Systems Inc).
• a ventral midline incision was made into the abdominal cavity.
• the incision was about 5cm in length just above the pubis.
• the fat and muscle was bluntly dissected away to reveal the hypogastric nerve which runs down the body cavity. It was essential to keep close to the side curve of the pubis wall in order to avoid damaging the femoral vein and artery which lie above the pubis.
• the sciatic and pelvic nerves lie deeper and were located after further dissection on the dorsal side of the rabbit. Once the sciatic nerve is identified, the pelvic nerve was easily located.
• pelvic nerve is loosely applied; anatomy books on the subject fail to identify the nerves in sufficient detail. However, stimulation of the nerve causes an increase in vaginal and clitoral blood flow, and innervation of the pelvic region.
• the pelvic nerve was freed away from surrounding tissue and a Harvard bipolar stimulating electrode was placed around the nerve. The nerve was slightly lifted to give some tension, then the electrode was secured in position. Approximately 1 ml of light paraffin oil was placed around the nerve and electrode. This acts as a protective lubricant to the nerve and prevents blood contamination of the electrode. The electrode was connected to a Grass S ⁇ Stimulator. The pelvic nerve was stimulated using the following parameters:- 0.5-5V, pulse width 0.5ms, duration of stimulus 10 seconds and a frequency range of 2 to 16Hz. Reproducible responses were obtained when the nerve was stimulated every 15-20 minutes.
• a frequency response curve was determined at the start of each experiment in order to determine the optimum frequency to use as a sub-maximal response, normally 4Hz.
• the compound(s) to be tested were infused, via the femoral vein, using a Harvard 22 infusion pump allowing a continuous 15 minute stimulation cycle.
• a ventral midline incision was made, at the caudal end of the pubis, to expose the pubic area.
• Connective tissue was removed to expose the tunica of the clitoris, ensuring that the wall was free from small blood vessels.
• the external vaginal wall was also exposed by removing any connective tissue.
• One laser Doppler flow probe was inserted 3cm into the vagina, so that half the probe shaft was still visible.
• a second probe was positioned so that it lay just above the external clitoral wall. The position of these probes was then adjusted until a signal was obtained.
• a second probe was placed just above the surface of a blood vessel on the external vaginal wall. Both probes were clamped in position.
• Vaginal and clitoral blood flow was recorded either as numbers directly from the Flowmeter using Po-ne-mah data acquisition software (Ponemah Physiology Platform, Gould Instrument Systems Inc), or indirectly from Gould chart recorder trace. Calibration was set at the beginning of the experiment (0-125ml/min/100g tissue).
• Example 22 The title compound from Example 22 (“the selected compound") alone and in combination with the selective and potent PDE5 inhibitor 3-ethyl-5-[5-(4-ethylpiperazin-1- ylsulfonyl)-2-/7-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one were administered in accordance with the following protocol.
• the selected compound was made up in saline + 5% 1 M NaOH.
• the selected compound and vehicle controls were infused using a Harvard 22 pump, infusing at 500 l/min via a 3-way tap into the femoral vein.
• the catheter was flushed with heparinised saline (Hepsaline) so that none of the selected compound was left in the catheter.
• Hepsaline heparinised saline
• the PDE5 inhibitor was made up in saline + 5% 1 M HCI, the compounds and vehicle controls were infused at a rate of 0.1 ml/second and left for 15 minutes prior to pelvic nerve stimulation.
• ICP Intracavernosal pressure
• mice Male New Zealand rabbits ( ⁇ 2.5kg) were pre-medicated with a combination of Medetomidine (Domitor®) 0.5ml/kg i.m., and Ketamine (Vetalar®) 0.25ml/kg i.m. whilst maintaining oxygen intake via a face mask.
• the rabbits were tracheotomised using a PortexTM uncuffed endotracheal tube 3 ID., connected to ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate tidal volume of 1 ⁇ -20 ml, and a maximum airway pressure of 10 cm H 2 O. Anaesthesia was then switched to Isoflurane and ventilation continued with O 2 at 2l/min.
• the right marginal ear vein was cannulated using a 23G or 24G catheter, and Lactated Ringer solution perfused at
• the rabbit was maintained at 3% Isoflurane during invasive surgery, dropping to 2% for maintenance anaesthesia.
• the left jugular vein was exposed, isolated and then cannulated with a PVC catheter (17G) for the infusion of the selceted compound or combination thereof.
• the left groin area of the rabbit was shaved and a vertical incision was made approximately 5cm in length along the thigh.
• the femoral vein and artery were exposed, isolated and then cannulated with a PVC catheter (17G) for infusion of the selected compound or combination thereof. Cannulation was repeated for the femoral artery, inserting the catheter to a depth of 10cm to ensure that the catheter reached the abdominal aorta.
• This arterial catheter was linked to a Gould system to record blood pressure. Samples for blood gas analysis were also taken via the arterial catheter. Systolic and diastolic pressures were measured, and the mean arterial pressure calculated using the formula (diastolic x2 + systolic) ⁇ 3.
• Heart rate was measured via the pulse oxymeter and Po-ne-mah data acquisition software system (Ponemah Physiology Platform, Gould Instrument Systems Inc).
• a ventral midline incision was made into the abdominal cavity.
• the incision was about 5cm in length just above the pubis.
• the fat and muscle was bluntly dissected away to reveal the hypogastric nerve which runs down the body cavity. It was essential to keep close to the side curve of the pubis wall in order to avoid damaging the femoral vein and artery which lie above the pubis.
• the sciatic and pelvic nerves lie deeper and were located after further dissection on the dorsal side of the rabbit. Once the sciatic nerve is identified, the pelvic nerve was easily located.
• the term pelvic nerve is loosely applied; anatomy books on the subject fail to identify the nerves in sufficient detail.
• the pelvic nerve was freed away from surrounding tissue and a Harvard bipolar stimulating electrode was placed around the nerve. The nerve was slightly lifted to give some tension, then the electrode was secured in position. Approximately 1 ml of light paraffin oil was placed around the nerve and electrode. This acts as a protective lubricant to the nerve and prevents blood contamination of the electrode. The electrode was connected to a Grass S ⁇ Stimulator. The pelvic nerve was stimulated using the following parameters:- 0.5-5V, pulse width 0.5ms, duration of stimulus 20 seconds with a frequency of 2-16Hz.
• Reproducible responses were obtained when the nerve was stimulated every 15-20 minutes.
• Several stimulations using the above parameters were performed to establish a mean control response.
• the selected compound or combination thereof was infused, via the jugular vein, using a Harvard 22 infusion pump allowing a continuous 15 minute stimulation cycle.
• the skin and connective tissue around the penis was removed to expose the penis.
• a catheter set (Insyte-W, Becton-Dickinson 20 Gauge 1.1 x 4 ⁇ mm) was inserted through the tunica albica into the left corpus cavernosal space and the needle removed, , leaving a flexible catheter.
• This catheter was linked via a pressure transducer (Ohmeda 5299-04) to a Gould system to record intracavernosal pressure.
• Intracavernosal blood flow was recorded either as numbers directly from the Flowmeter using Po-ne-mah data acquisition software (Ponemah Physiology Platform, Gould Instrument Systems Inc), or indirectly from Gould chart recorder trace. Calibration was set at the beginning of the experiment (0-125ml/min/100g tissue).

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• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

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