RS75303A - N-phenpropylcyclopentyl-substituted glutaramide derivatives as nep inhibitors for fsad - Google Patents

Abstract

The invention relates to compounds of formula (I) for treating for example sexual dysfunction, wherein R1 is optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, hydrogen, C1-6alkoxy, -NR2 R3 or - NR4SO2R5; 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 C1-4alkoxy; hydroxy; hydroxy(C1-3alkyl); C3-7cycloalkyl; carbocyclyl; heterocyclyl; or by C1-4alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6, or 7; and q is 2, 3, 4, 5 or 6; and Y is phenyl or pyridyl, each of which may be substituted; or two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused optionally substituted 5- or 6-membered carbocyclic or heterocyclyic ring.

Description

Derivatives of N-phenylpropylcyclopenryl-substituted glutaramide as NEP inhibitors

FSAD

This invention relates to neutral endopeptidase (NEP) inhibitors, their use, methods of obtaining them, intermediates used in obtaining them and preparations containing these inhibitors. These inhibitors are used in a wide range of therapeutic areas, including the treatment of male and female sexual dysfunction, especially female sexual dysfunction (FSD), and especially when FSD is a disorder of sexual stimulation. (FSAD).

NEP inhibitors are described in WO 91/07386 and WO 91/10644.

The use of NEO inhibitors in the treatment of FSD is described in EP1 097-719-A1.

According to the first approach, the invention relates to compounds of formula (I), its pharmaceutically acceptable salts, solvates, polymorphs or prodrugs;

where:

R<1> is C1-6alkyl, which can be substituted by one or more substituents, which can be the same or different, selected from: halo, hydroxy, C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, carbocyclyl (preferably C 3-7 cycloalkyl, C 3-7 cycloalkenyl or phenyl), carbocyclyloxy (preferably phenoxy), C 1-4 alkoxycarbocyclyloxy (preferably C 1-4 alkoxyphenoxy), heterocyclyl, heterocyclyloxy, -NR<2>R<3>, -NR<4>COR<5>, -NR<4>SO2R<5>, -CONR<2>R<3>, -S(0)pR<6>, -COR<7> and CO2(C,-4 alkyl); or R1 is carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more of the aforementioned substituents, where the substituents may be the same or different, and includes C1-6alkyl; or R<1>is hydrogen, C1-6 alkoxy, -NR<2>R<3>or -

NR<4>S02R<5>;

R<2> and R<3>, which may be the same or different, are carbocyclyl (preferably C 3-7 cycloalkyl or phenyl) or heterocyclyl (where each may be substituted with C 1-4 alkyl, hydroxy or C 1-4 alkoxy);

or are hydrogen or C1-4alkyl; or R<2> and R<3>, together with the nitrogen to which they are attached form

a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1-4alkyl)piperazinyl group; R<4> is hydrogen or C1-4alkyl;

R<5>is C1-4alkyl, CF3, carbocyclyl (preferably phenyl), C1-4alkylcarbocyclyl

(preferably C1.4alkylphenyl), C1.4alkyloxycarbocyclyl (preferably C1.4alkylphenyl),

heterocyclyl, C 1-4 alkoxy or NR<2>R<3>;

R6 is C1-4alkyl, carbocyclyl (preferably phenyl), heterocyclyl or NR<2>R<3>;

and

R 7 is C 1-4 alkyl, carbocyclyl (preferably C 3-7 cycloalkyl or phenyl) or heterocyclyl;

p is 0, 1, 2 or 3;

X is a bond—(CH2)n- or -(CH2)q-0- (wherein Y is attached to oxygen); wherein one or more hydrogen atoms in X may be independently replaced by C1-4 alkoxy; hydroxy;

hydroxyC 1-3 alkyl, C 3-7 cycloalkyl, carbocyclyl, heterocyclyl or with C 1-4 alkyl, optionally substituted with one or more fluorine atoms or phenyl groups; her 3, 4, 5, 6 or 7; and q

is 2, 3, 4, 5 or 6; and

X is phenyl or pyridyl, each of which may be substituted by one or more R<8> groups which may be the same or different; wherein R g is hydroxy; mercapto, halogen, cyano, acyl, amino, mono(C1-4alkyl)amino; di(C 1-4 alkyl)amino; carbocyclyl or heterocyclyl (wherein either is optionally substituted with C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy;

C1-6 alkylthio or halogen); C1-6Alkoxy; phenoxy; C 1-6 alkylthio, phenylthio; or alkyl optionally substituted with C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylthio, halogen or phenyl;

or

two R Q groups on adjacent carbon atoms together with an internal bonding carbon atom can form a condensed 6- or 6-membered carbocyclic or

heterocyclic ring, optionally substituted with C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylthio or halogen.

Preferably, R<1> is hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C1-6 alkoxyC1-6 alkoxy C1-3 alkyl or C1-6 alkyl substituted with phenyl.

It is also preferred that R<1> is hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl (preferably methoxy C1-6 alkyl) or C1-6 methoxyC1-6 methoxy C1-6 alkyl (preferably methoxyethoxymethyl).

It is further preferred that R<1> is C1-4 alkyl (primarily propyl) or C1-6 alkoxy C1-4 alkyl (preferably methoxy C1-4 alkyl, i.e. methoxyethyl).

A preferred group of compounds are compounds of formula Ia:

Preferably it gives n, 3 or 4, more precisely 3.

Preferably q is 2 or 3, more precisely 2.

Preferably X gives -(CH 2 )n- where one or more hydrogen atoms attached to X may be replaced by one or more groups defined for X in the first aspect.

Preferably, R<8> gives C1-6alkyl, C1-6alkyl, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl or two R groups on adjacent carbon atoms together with the carbon atom that binds them together, can form a condensed 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted with C1-6alkyl, halo C1-6alkyl, C1-6alkyl, C1-6alkyl, halo C 1-6 alkyloxy, C 1-6 alkylthio or halogen.

When R<8> is carbocyclyl, preferred groups are cyclopentyl, cyclopropyl, cyclohexyl or phenyl.

When R 1 is heterocyclyl, preferred groups are pyridyl, oxadiazilyl, pyrazolyl or triazolyl.

When Y is phenyl and two R<8> groups on adjacent carbon atoms together with the carbon atom linking them together form a fused 5- or 6-membered carbocyclic or heterocyclic ring, preferred fused ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indalyl, benzisothiazolyl and benzothiazolyl.

Preferred compounds of this invention are:

( 2R )-2-{[ l-( {[3-( 4-methoxyphenyl )propyl]amino}carbonyl)cyclopentyl] methyl}-valeric acid (Example 16), 3-{[ l-( {[3-( 4-methoxyphenyl)propyl]amino }carbonyl)cyclopentyl]propionic acid (Example 18), 3-{[ l-( {[3-(2,3-dihydro-l-benzofuran-5-yl)propyl]amino }carbonyl)cyclopentyl]propionic acid (Example 21), 2-{[ l-( {[3-( 4-chlorophenyl )propyl]amine }carbonyl)cyclopentyl] methyl}-4-methoxybutyric acid (Example 15), 2-{[ l-( {[3-(4-fluorophenyl)propyl]amino jcarbonyl)cyclopentyl] methyl}-4-methoxybutyric acid (Example 4),

4-Methoxy-2-{[1-({[3-(4-Methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]-methyl}butyric acid (Example 1),

2-{[1-( {[3-(2, 3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]-methyl}-4-methoxybutyric acid (Example 11),

(2S)-2-{[ 1-( {[3-( 4-chlorophenyl)propyl]amino }carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22), and

(2S)-2-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]-methyl}-4-methoxybutyric acid (Example 25).

A particularly preferred compound is (2S)-2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22).

Unless otherwise noted, each alkyl group can be straight chain or branched and with 1 to 6 carbon atoms, preferably 1 to 4, and especially up to 3 carbon atoms.

Unless otherwise noted, each carbocyclic group contains 3 to 8 ring atoms and may be saturated, unsaturated or aromatic groups. Preferred saturated carbocyclic groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclic groups contain up to 3 double bonds. A preferred aromatic carbocyclic group is phenyl. The term carbocyclic should be interpreted similarly. Further, the term carbocyclic includes any fused combination of carbocyclic groups, for example naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise noted, each heterocyclic group contains 5 to 7 ring atoms of which up to 4 may be heteroatoms such as nitrogen, oxygen, and sulfur, and may be saturated, unsaturated, or aromatic. 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. Furthermore, the term heterocyclic includes fused heterocyclic groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepine, indolyl and isoindolyl. The term heterocyclic should be similarly characterized.

Halo means fluoro, chloro, bromo or iodo.

For the avoidance of doubt, unless otherwise noted, the term substituted refers to substituted with one or more defined groups. In the case where groups can be selected from a number of alternative groups, the selected groups may be the same or different.

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

Pharmaceutically or veterinary acceptable salts of compounds of formula I containing a basic center are, for example, non-toxic salts of addition acids, formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, with carboxylic acids or with organo-sulfo acids. Examples are 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. The compounds of the invention also describe pharmaceutically or veterinary acceptable metal salts, especially non-toxic alkali and alkaline earth metal salts, with bases. Examples are sodium, potassium, aluminum, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloin, megulamine and diethanolamine. For a review of suitable pharmaceutical salts, see Berge et al., J. Farm, ScL, 66, 1-19, 1977; P L Gould, International Journal of Pharmaceuticals, 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Ine, New York 1996, Volume 13, page 453-497.

Hereinafter, compounds of their pharmaceutically acceptable salts, solvates and polymorphs thereof, defined in each aspect of the invention or preferred approach (except intermediate compounds in chemical processes) are designated as "compounds of the invention".

Pharmaceutically acceptable solvates of the compounds of the invention are also their hydrates.

Compounds of the invention and intermediates may have one or more chiral centers and thus exist in numerous stereoisomeric forms. All stereoisomers and mixtures thereof are encompassed by the present invention.

Individual enantiomers can be obtained by various techniques known to a person skilled in the art, such as high pressure chromatography (HPLC) of the appropriate racemate with a suitable chiral base or fractional crystallization of diastereoisomeric salts obtained by reaction of the appropriate racemate with a suitable optically active base. The preferred optically active base is pseudoephedrine (see Preparation 69). Separation of diastereoisomers can be achieved by conventional techniques, eg, fractional crystallization, chromatography or H.P.L.C.

The compounds of the invention may exist in one or more tautomeric forms. All tautomers and their mixtures are included within the scope of this invention.

For example, 2-hydroxypyridinyl would include its tautomeric form α-pyridonyl.

One of ordinary skill in the art will appreciate the fact that certain protected derivatives of the compounds of the invention, obtainable prior to the final stage of deprotection, which may not have pharmacological activity as such, but may, in certain cases, be administered orally or parenterally and subsequently metabolized in the body to yield compounds of the invention that are pharmacologically active. These derivatives can be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs or other compounds of the invention.

All proprietary derivatives and prodrugs of the compounds of the invention are encompassed by this invention. Examples of suitable prodrugs of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983 pp. 499-538 and Topics in Chemistry, Chapter 31, pp. 306-316 and in "Design of Prodrugs", H Bundgaard, Elsevier, 1985, Chapter 1 (cited as a reference).

Furthermore, one of ordinary skill will recognize that certain groups, known as "pro-groups", as described for example by H. Bundgaard in "Design of Prodrugs" (incorporated herein by reference), can be placed on the corresponding functional groups, when these are present in the compounds of this invention.

Preferred prodrugs of the compounds of this invention are: esters, ester carbonates, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amidicarbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

Drug metabolism studies show that in vivo, compounds of formula I can form the following compounds, which compounds are also NEP inhibitors:

these metabolites are formed especially when R<1> is methoxyethyl and -XY is 3-(4-chlorophenyl)propyl.

The invention also relates to 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 with the same atomic number but an atomic mass that differs from the atomic mass axis commonly found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes such as<2>H,<3>H,13C,<14>C,<15>N,<17>0,<18>0,<31>P,32P,<3>5S,18F and 36C1. Certain isotopic variations of the present invention, for example, those in which an isotope such as<3>H or<14>C is incorporated, are useful in studies of drug and/or substrate redistribution in tissues. Tritium, e.g.<3>H and carbon 14, e.g.14C are<p>particularly preferred due to their ease of obtaining and detection. Furthermore, substitution with isotopes such as deuterium, e.g.<2>H, can show certain advantages in therapy, which arise as a result of greater metabolic stability, for example, an increase in vivo half-life or a reduced dosage regimen, and as such can be preferred in some cases. Isotopic variations of the compounds of the present invention can generally be obtained by conventional procedures such as the methods or preparations described in the Examples and Preparations below, using appropriate isotopic variations or suitable reagents.

these metabolites are formed especially when R<1> is methoxyethyl and -XY is 3-(4-chlorophenyl)propyl.

The invention also relates to 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 with the same atomic number but an atomic mass that differs from the atomic mass axis commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, azo, oxygen, phosphorus, sulfur, fluorine and Mor such as<2>H,<3>H,<1>3C,14C,15N,,<7>0,,<8>0,<3>,P,<32>P,<35>S,18Fi<36>C1. Certain isotopic variations of the present invention, for example, those in which an isotope such as<3>H or<14>C is incorporated, are useful in studies of drug and/or substrate redistribution in tissues. Tritium, e.g. <3>H and carbon 14, e.g. <14>C are particularly preferred due to their ease of acquisition and detection. Furthermore, substitution with isotopes such as deuterium, e.g.<2>H, may show certain advantages in therapy, which arise as a result of greater metabolic stability, for example, increased half-life or reduced dosage regimen, and as such may be preferred in some cases. Isotopic variations of the compounds of the present invention can generally be obtained by conventional procedures such as the methods or preparations described in the Examples and Preparations below, using appropriate isotopic variations or suitable reagents.

The compounds of the invention are inhibitors of the zinc-dependent, non-natural endopeptidase EC.3.4.24.11., and it is proposed that the compounds of the invention may treat the disease states listed below. This enzyme is involved in the degradation of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues. Metabolized peptides are atrial natriuretic peptides (ANP), bombesin, bradycardin, calcitonin gene-related peptide, endothelins, enkephalins, neurotensins, substance P and vasoactive intestinal peptides. Some of these peptides have strong vasodilatory and neurohormonal effects, diuretic and natriuretic activity or mediate behavioral effects.

Thus, the compounds of the present invention, by inhibiting the natural endopeptidase EC. 3.4.24.11 can potentiate the biological effect of bioactive peptides. Accordingly, the compounds of this invention in particular have applications in the treatment of numerous disorders, including hypertension, pulmonary hypertension, peripheral vascular disease, cardiac arrest, angina, renal failure, acute renal collapse, cyclic edema, Meniere's disease, hyperaldosteroneism (primary and secondary), and hypercalciuria. Furthermore, due to their ability to enhance the effects of ANF, the compounds are suitable for the treatment of glaucoma. As a further result of their ability to inhibit neutral endopeptidase E.C. 3.4.24.11 the compounds of the invention may also show activity in other therapeutic areas such as, for example, the treatment of menstrual disorders, premature birth, pre-eclampsia, endometriosis and reproductive diseases (especially male and female infertility, polycystic ovary syndrome, transplant failure). Also the compounds of the invention can treat asthma, inflammation, leukemia, pain, epilepsy, affective diseases, dementia and geriatric confusion, obesity and gastrointestinal diseases and venous ulcers and bedsores), septic shock, modulation of gastric secretion, treatment of hyperreninemia, cystic fibrosis, restenosis, complications of diabetes and atherosclerosis. In a preferred approach, the compounds of the invention are useful in the treatment of male and female sexual dysfunction.

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

According to the invention, FSD can be defined as a woman's difficulty or inability to find satisfaction in sexual expression. FSD is a collective term for several different sexual disorders in women (liblum, 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). A woman may experience reduced desire for sex, difficulty with stimulation or orgasm, pain during intercourse, or a combination of these problems. Several types of diseases, medications, injuries, and psychological problems can cause FSD. The investigated treatments are aimed at the treatment of certain subtypes of FSD, primarily disorders of desire and irritation.

These categories of FSD are best defined by comparison with the phases of normal sexual reaction in women: desire, arousal and orgasm (Leiblum, S.R (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, SI 04 - S106). Desire or libido is the drive for sexual expression. Their manifestations often include erotic (sexual) thoughts in the presence of an interested partner or when the subject is exposed to erotic stimuli. Stimulation is the vascular response to sexual stimulation, an important component of genital blood flow and includes increased vaginal lubrication, vaginal elongation, and increased genital arousal/sensitivity. Orgasm is the release of sexual tension that culminated during stimulation.

Thus, FSD occurs when a woman has an inadequate or unsatisfactory response in one of these phases, usually desire, stimulation or orgasm. FSD categories include disorders of hypoactive sexual desire, disorders of sexual arousal, disorders of achieving orgasm, and diseases caused by pain during sexual intercourse. Although the compounds of this invention improve the response of the genitals to sexual stimulation (as in sexual arousal disorders in women), they can also improve the accompanying phenomena that accompany intercourse such as pain that accompanies intercourse, exhaustion and discomfort, and thus treat other sexual disorders in women.

A disorder of hypoactive sexual desire is present if a woman shows no or little desire to be sexual and has no or only a few sexual fantasies or ideas. This type of FSD can be caused by low testosterone levels, or due to natural menopause or hydraulic menopause. Other causes can be illness, medication, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterized by inadequate genital response to sexual stimulation. There is no bleeding of the genitals, which characterizes normal sexual intercourse. Vaginal walls are poorly lubricated, so intercourse is painful. This can lead to prevention of orgasms. Irritability disorder can be caused by reduced estrogen levels in menopause or after childbirth or during lactation, as well as diseases with vascular characteristics such as diabetes and atherosclerosis - other causes can arise as a result of treatment with diuretics, antihistamines, antidepressants (eg SSIR) or antihypertensive agents.

Sexual pain disorder (eg, dyspareunia and vaginismus) is characterized by pain during penetration and can be caused by drugs that reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease, and urinary tract problems.

The impact of FSD is difficult to measure because the term covers several types of problems, some of which are difficult to measure and because interest in treating FSD has only recently emerged. Many sexual problems in women are related either directly to the aging process of women or to chronic diseases such as diabetes and hypertension.

Because FSD consists of several subtypes that show symptoms at different stages of the sexual cycle, there is no single therapy. Current treatment of FSD focuses primarily on the psychological issue and the issue of mutual relationships. The treatment of FSD is slowly evolving as more clinical and scientific research is devoted to examining the medical problem. Female sexual diseases are not only psychological and pathophysiological, especially for those patients who may also have a component of vascular dysfunction (eg FSAD) that contributes to overall sexual problems with desire. There are currently no drugs licensed for the treatment of FSD. Empiric drug therapy includes the administration of estrogen (topical or as hormone replacement therapy), androgens, or behavior (mood) altering drugs such as busiprone or trazodone. These treatments are often unsatisfactory due to low efficacy or unacceptable side effects.

Since the interest in treating FSD pharmacologically is relatively new, therapy consists of the following: -psychological counseling, readily available lubricants, and testing candidates, including taking medications for other conditions. These drugs consist of hormonal agents, either testosterone or a combination of estrogen and testosterone, and more recently vascular drugs, which have proven effectiveness in the treatment of erectile dysfunction in men. None of these agents have been shown to be very effective in the treatment of FSD.

The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines female sexual arousal disorder (FSAD) as: "persistent or recurrent inability to achieve or maintain an adequate lubrication-swelling response to sexual arousal until the end of sexual activity."

The irritation reaction consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. Distraction causes noticeable pain and/or interpersonal distress.

FSAD is a very dominant sexual disease that affects pre-, peri- and post-menopausal (± HRT) women. It is associated with co-morbidities such as depression, cardiovascular disease, diabetes and UG disorders.

The primary consequence of FSAD is non-bloodiness/swelling, non-lubrication and lack of satisfactory genital sensation. A secondary consequence of FSAD is reduced sexual desire, pain during intercourse and difficulty in reaching orgasm.

It has recently been hypothesized that there is a vascular basis for a proportion of patients with FSAD symptoms (Glodstein et al., Int. J. Impot. Res., 10, S84-S90, 1988) with data from animal experiments supporting this view (Park et al., Int.J. Impot. Res., 9, 27-37, 1997).

Medicines for the treatment of FSAD, the effectiveness of which is being tested, are primarily therapies for erectile dysfunction, which stimulate the circulation of the male genitalia. They consist of two types of formulations, an oral or sublingual drug (Apomorphine, Phentolamine, phosphodiesterase type 5 (PDE5) inhibitors, e.g. Sildenafil) and a prostaglandin (PGEi) that is injected or administered transurethally in men and topically on the genitals in women.

The compounds of the invention show the advantage of providing a way to restore the reaction of normal sexual stimulation - by increasing the blood supply to the genitals, which leads to vaginal, clitoral and labial swelling. This leads to increased vaginal lubrication via plasma secretion, increased vaginal flexibility and increased genital sensitivity.

Thus, the compounds of the invention provide a means of restoring or enhancing the normal sexual arousal response.

Without being bound by any theory, we believe that neuropeptides such as vasoactive intestinal peptide (VIP) are the main neurotransmitters in the control of the response to sexual stimulation in women, especially in the control of genital blood flow. VIP and other neuropeptides are degraded/metabolized by NEP EC3.4.24.11. thus, Nep inhibitors enhance vasorelaxant swelling as an effect of VlP release during stimulation. This leads to the treatment of FSAD, for example by increasing the blood flow through the genitals and thus the swelling of the genitals. We have shown that the selective NEP inhibitor EC 3.4.24.11 increases pelvic nerve stimulation and VlP-induced increases in vaginal and clitoral blood flow. Furthermore, selective NEP inhibitors increase VIP and relaxation of the isolated vaginal wall through nerve stimulation.

This invention further helps in finding a way to restore the reaction of normal sexual stimulation - by increasing the blood supply to the genitals which leads to vaginal, clitoral and labial swelling. this leads to increased vaginal lubrication via plasma secretion, increased vaginal flexibility and increased genital sensitivity. Thus, this invention provides a solution for restoring or enhancing the reaction of normal sexual stimulation.

Sexual dysfunction in men includes male erectile dysfunction, ejaculation disorder such as premature ejaculation (PE), anorgasmia (inability to achieve orgasm) and desire disorder, such as hypoactive sexual desire disorder (lack of interest in sex).

It should be noted that all the references listed here that refer to treatment include curative, palliative and prophylactic treatment.

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

The compounds of the invention are first found in patients with FSD originating from:

i) vasculogenetic etiology, e.g. cardiovascular or atherosclerotic diseases,

hypercholesterolemia, smoking, diabetes, hypertension, radiation and perineal

trauma, traumatic injury of the iliohypogastric pufendal vascular system.

ii) Neurogenetic etiologies such as spinal column injuries and central nervous system diseases including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular injuries, peripheral neuropathies, trauma or radical pelvic surgery.

iii) Hormonal/endocrine etiologies such as hypothalamic/pituitary/gonadal axis dysfunction or ovarian dysfunction, pancreatic dysfunction, operative or medical castration, androgen deficiency, high prolactin levels in the blood eg hyperprolactinemia, natural menopause, premature ovarian failure, yips and hypothyroidism.

iv) Psychogenetic etiology such as depression, obsessive compulsive disorder, anxiety, postnatal depression / "Baby Blues", emotional problems and problems in mutual relationships, fear of performance during sexual intercourse, marital problems, dysfunctional attitude, sexual phobias, religious inhibitions or traumatic experience from the past.

v) Drug-induced sexual dysfunction, which occurred as a result of selective serotonin absorption inhibitor (SSRI) therapy and other anti-depressant therapies (tricyclic and more important sedatives), anti-hypertensive therapy, sympatholytic drugs, oral contraceptive 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 to therapy. However, early studies show that the response rate of patients with mild, moderate and severe MED is higher when combined with PDE5 inhibitors. Mild, emren, and severe MED are terms known to the average person skilled in the art, and 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: psychogenetic, endocrinological, neurogenetic, arteriogenic sexual dysfunctions, drug-induced sexual dysfunctions (lactogenetic) and sexual dysfunctions associated with cavernosal factors, especially venogenic causes. These patient groups are described in detail in Clinical Andrology vol. 23, no.4, p773-782 and the book chapter of I. Eardelv and K. Sethia "Erectile Dysfunction-Current Investigation and Management," published by Wosby-VWolfe.

The compounds of the invention can be prepared in a known manner and in various ways. In the following reaction schemes, unless otherwise noted, R<1>, n, X and Y are as defined in the first aspect. These processes are the basis for further aspects of the invention.

Compounds of general formula I can be obtained by reacting a compound of formula II (where Prot is a suitable protecting group) with an amine of formula III to give a compound of formula P, followed by deprotection (see Scheme 1). Preferred reaction conditions for the acid/amine coupling phase include the reaction of II with HI (or their amino salts) in the presence of an active agent, if necessary, a catalyst in an excess of acid acceptors, in a suitable solvent. Particularly preferred conditions include the reaction of II (1-1.5 equivalents), III (or its salts 1-1.5 equivalents), in the presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI) or N,N'-dicyclohexylcarbodiimide (DCC) (1.1-1.3 equivalents), 1-hydroxybenzorazole hydrate (HOBT) or dimethylaminopyridine (DMAP) (1.05- 1.2 equivalents), N-methyl morpholine (NMM) or triethylamine (2.3-3 equivalents) in dimethylformamide or dichloromethane at a temperature between room and 90°C, 16-18 hours.

Other, particularly preferred reaction conditions include the reaction of II (1-1.5 equiv) and 1,1'-carbonylimidazole (1-1.5 equiv) in a suitable solvent (such as tetrahydrofuran, isopropylacetate or toluene), followed by the addition of III (or Nmückeg amino salts in which case an organic base such as triethylamine or Hunig's base is present) at a reaction temperature between room and 90°C.

Scheme 1

Alternatively, the acid/amine coupling can be carried out with chloric anhydride in the presence of an excess of acid acceptor in a suitable solvent. Chloroanhydride can be isolated or obtained in situ. Preferred reaction conditions include chloroanhydride of compound II (1-1.1 equivalent), m (or its salt, 1 to 5 equivalents), triethylamine or N-methyl morpholine (1.4-10 equivalents) in dichloromethane at room temperature, 24 hours. Compounds of Formula II can be converted in chloranhydridine sieve by the addition of oxalyl chloride in the presence of a catalytic amount of dimethylformamide for 2 hours at room temperature.

Procedures for deprotection of an acid group will depend on the protecting group. For examples of protection/deprotection methodologies, see "Protective groups in Organic Synthesis", TW Green and PGM Wutz.

For example, when Prot is tert-butyl, the deprotection conditions include the reaction of IV with trifluoroacetic acid/dichloromethane (1:1-2.5 volume ratios), at room temperature for 2 to 18 hours, if necessary in the presence of an anti-soot additive, e.g. anisole (10 equivalents). When X or Y contains a hydroxy group, base hydrolysis of the trifluoroacetic acid ester intermediate may be necessary. An alternative deprotection methodology when the prot is tert-butyl involves the reaction of IV with hydrochloric acid in dichloromethane at room temperature for 3 hours. For the avoidance of doubt, Prot, as tert-butyl is given by way of example and is not limited to tert-butyl.

The procedure of Scheme 1 is the basis for further aspects of the present invention.

Intermediates of general formula IV us new. Thus, according to a further aspect, the invention relates to a compound of formula IV.

A number of compounds of formula II are known in the art (see ep274234-B1 and WO9113054). Other compounds of formula II can be obtained in an analogous way.

Compounds of formula I and II, where R<1> is not hydrogen, have a chiral center on the carbon attached to R<1>. individual enantiomers can be obtained by various methods known to a person skilled in the art, such as from a suitable optically pure intermediate or by resolution (separation). The preferred method of separation is via the (+)-pseudoephedrine salt (see Example 10 in WO9113054).

Alternatively compounds of formula Xa, e.g. chiral compounds of formula II, where R<1> is optionally substituted Ci_6alkyl (where Q is a substituent on the Ci_6alkyl group defined for R<1> in the first aspect), can be obtained by asymmetric hydrogenation of compounds of formula XI, XII or XIII according to reaction scheme 1 a.

Typical hydrogenation conditions include treating a compound of formula XI, XII or Xm [an organic or inorganic salt thereof (eg sodium salt)] with a suitable asymmetric hydrogenation catalyst, under elevated hydrogen pressure, in a suitable solvent. A preferred catalyst contains one or more chiral ligands, preferably chiral phosphine ligands, coordinated to a suitable transition metal (eg, rhodium, ruthenium, iridium, palladium). Preferred catalysts are: [(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthylchloro(para-cymene)] ruthenium chloride (J. Org Chem. 1994, 59, 3064-76);

[(S)-3,3',4,4',5,5'-hexamethyl(6,6'-diphenyl)-2,2'-diyl]bis(diphenylphosphmo}ruthenium bis(trifluoroacetate) (see WO 01/94359);

[(R)-( - )-4, 12-bis(diisopropylphosphino)-[2.2]-paracyclophane-(1,5-cyclooctadiene)] rhodium (I) tetrafluoroborate (J. Am. Chem. Soc. 1997, 119, 6207-6208);

[bis-((2S,5S)-2,5-dimethyl-1-phenylphospholano)(1,5-cyclooctadiene)] rhodium (I) tetrafluoroborate (Tetrahedron; Asimm., 1991, 2,569-92); and

[(R)-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphino)]ruthenium bis(trifluoroacetate) (EP398132).

Preferred reaction conditions are hydrogen pressure up to 150psi and reaction temperature between 0 and 100°C (preferably 50 to 60°C). Preferred solvents are protic solvents such as methanol or ethanol.

In scheme la, the only formula (XIII) is the preferred starting material.

The process in Scheme 1a forms the basis for other aspects of the invention.

Alternatively, compounds of formula I and IV can be obtained by direct asymmetric hydrogenation of unsaturated compounds corresponding to XI, XII and XIII.

Compounds of formula Xa, e.g. compounds of formula III where X , -(CH2)3-, can be obtained according to reaction Scheme 2. first, compounds of formula V are subjected to a Heck reaction with acrylonitrile in the presence of a suitable catalytic system such as palladium or an excess of base such as triethylamine or 4-methylmorpholine, to give compounds of formula VI. Typical reaction conditions include 1.0 - 1.5 equivalents of 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-dioxane, acetonitrile, or DMF (preferably acetonitrile) at reflux temperature. Compounds of formula VI are then subjected to catalytic hydrogenation to give compounds of formula Xa. Typical hydrogenation conditions involve reacting VI with Raney nickel in ethanol or methanol at 15 to 150 psig and 25 and 80°C. Preferably in ethanol at 30 psi and 25°C.

Alternatively, compounds of formula VI can be obtained according to reaction scheme 3, by reacting compounds of formula VII with diethylcyanomethyl phosphonate. Typical reaction conditions include reaction of diethylcyanomethyl phosphonate with a suitable base (for example sodium hydride, lithium chloride/Hunig's base or sodium ethoxide) in a suitable solvent at room temperature (for example dichloromethane, tetrahydrofuran or diethyl ether), followed by the addition of a compound of formula VII.

Other compounds of formula (III), (V), (VI) and (VII) are either commercially available, known in the art or can be obtained from compounds known in the art, using methods known in the art or according to the methods described herein (see the Examples and Preparations section).

All the above-mentioned reactions and preparations are new starting materials used in the mentioned methods are conventional. Appropriate agents and reaction conditions for their performance or preparation, as well as procedures for isolating the desired products, will be known to one of ordinary skill in the art, with reference to prior literature and the Examples and Preparations described below.

Pharmaceutically acceptable salts of compounds of formula (I) can be readily prepared by mixing solutions of compounds of formula (I) and the desired acid or base, as appropriate. The salt can be precipitated out of solution and collected by filtration or can be regenerated by evaporation of the solvent.

The compounds of the invention [especially (2S)-2-{[l-({[3-(4-chlorophenyl)propyl]amino}-carbonyl)-cyclopentyl]methyl}-4-methoxybutyric acid (Example 22)] can be combined with one or more active components selected from the following list: 1) one or more natural (can be found in nature) or synthetic prostaglandins or their esters. Suitable prostaglandins that can be used are compounds such as: alpostradil, prostaglandin Ei, prostaglandin E0, 13, 14-dihydro-prostaglandin Ei, prostaglandin E2, eprostinol, natural synthetic and semi-synthetic prostaglandins and their derivatives, including those described in WO-00033825 and/or US 6,037,346 issued on 14 March 2000, herein incorporated by reference, PGE0, PGEi, PGA1?PGB,, PGF, a, 19-hydroxy PGA,, 19-hydroxy- PGBU PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE301, carboprost tromethamine dinoprost, tromethanamine, dinoprostone, lipo prost, gameprost, methanoprost, sulprost, tiaprost and moxisylate. 2) One or more compounds of α-adrenergic receptor antagonists known as α-adrenergic receptors or α-receptors or α-blockers. Suitable compounds for use are: α-adrenergic receptor blockers as described in PCT application WO99/30697 published June 14, 1988, which relates to α-adrenergic receptors which are incorporated herein by reference and include selective α-adrenoreceptor or α2-adrenoreceptor blockers and non-selective α-adrenoreceptor blockers, suitable oii-adrenoreceptor blockers are: phentolamine, phentolamine mesylate, trazodone,. Alfuzosin, indoramine, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxane, yohimbine, rauwolfa alkaloids, Recordati 1/2739, SNA 1069, SNAP 5089, RS17053, SL 89.0591, doxazin, terazosin, abanochyl and prazosin; a2-blocker blockers from US 6,037,346 [March 14, 2000] dibenarnine, tolazoline, trimazosine and dibenarnine; α-adrenergic receptors described in US Patents: 4,188,390;

4,026,895; 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 incorporated herein by reference; <x2-Adrenoreceptor blockers are: clonidine, papaverine, papaverine hydrochloride, po

required in the presence of a karyotonic agent such as pirkamine.

3) One or more NO-donors (NO-agonists). Suitable compounds that can serve as NO donors are organic nitrates, such as mono-, di- or tri-nitrates or organic esters of nitrates including glyceryl binitrate (known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaeritol tetranitrate erythritol tetranitrate, sodium nitroprusside (SNP), 3-morpholinosidnonimine molsidomine, S-nitroso-N-acetyl penicillamine (SNAP). S-nitroso-N-glutathione (SNO-GLU), N-hydroxy - L-arginine, amyl nitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso - N-cysteine, diazenium diolates, (NONOates), 1, 5-pentandinitrate, L-arginine, ginseng, zizfi fructus, molsidomine, Re - 2047, derivatives of nitrosylated maxillitium such as NMI-678-11 and NMI-937 as is described in published PCT application WO

0012075. 4) One or more potassium channel openers or modulators. Suitable potassium channel openers/modulators that can be used are: nicorandil, cromokalim, leucromakalim, lemakalim, pinacidil, cliazoxide, minoxidil,

caribdotoxin, glyburide, 4-amino pyridine, BaCl2.

5) One or more dopaminergic agents, preferably apomorphine or a selective D2, D3 or D2/T>3 agonist such as pramipexole and ropirinol (as set forth in WO-0023056), PNU95666 (as set forth in WO-0040226). 6) One or more vasodilator agents. Suitable vasodilatory agents that can be used here are: 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 alkaloids. Suitable ergot alkaloids are described in US Patent 6,037,346 issued March 14, 2000, and are: acetergamine, brazergoline, bromerguride, cyanergoline, delorgotril, disulergin, ergonovine maleate, ergotamine tartrate, etisulergin, lergotril, lysergide, mezulergine, metergoline, metergotamine,

nicergoline, pergolide, propisergide, proterguride, terguride.

10) One or more compounds that modulate the action of natruretic factors, more precisely, atrial natruretic factor (known as atrial natruretic peptide), type B and type C

natural factors such as inhibitors or neutral endopeptidases.

11) One or more compounds that inhibit angiotensin-converting enzymes such as enapril, and combined angiotensin-converting enzyme inhibitors and

neutral endopeptidases, for example omapatrilat.

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

13) One or more substrates for NO synthases, 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 agents for lowering new cholesterol such as statins (eg atorvastatin/ Lipitor- brand) and fibrates. 17) One or more antiplatelet and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin inhibitors

activating factor.

18) One or more insulin-sensitizing agents such as rezulin and a hypoglycemic agent such as glipizide.

19) L-DOPA or carbidopa.

20) One or more acetylcholinesterase inhibitors such as donezipil.

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-tetrahydronaphthalen-2-ol and their pharmaceutically acceptable salts, the preparation of which is described in WO

96/21656.

23) One or more cannabinoid receptor modulators.

24) One or more NPI (neuropeptide I) inhibitors, i.e. NPY1 or NPY5 inhibitors, preferably an NPY1 inhibitor, further preferably provide NPY inhibitors (including NPY Yl and NPY Y5) with IC50 values of less than 100nM, i.e. less than 50nM. An assay for the identification of NPI inhibitors is given in WO-A-98/52890 (see page 96, lines 2 to 28). 25) One or more vasoactive intestinal proteins (VIP), mimic VIP, VIP analogue, i.e. through the mediation of one or more subtypes of VIP receptors: VPAC1, VPAC or PACAP (activating peptide of pituitary adenylate cyclase), One or more VIP receptor agonists or VIP analogues (e.g. Ro-125-1553) or VIP fragments, One or more a-adrenoceptor antagonists with VIP combination (e.g.

Invicorp, Aviptadil).

26) One or more melanocortin receptor agonists or melanocortin modulators or enhancers such as melanotan II, PT-14, PT-141 or compounds listed in WO-09964002, WO-00074679, WO-09955679, WO-00105401,

WO-00058361, WO-00114879, WO-00113112, WO-09954358. 27) One or more serotonin receptor agonists, antagonists or modulators, more specifically 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 androgens such as androsterone; dehydro-androsterone, testosterone, androstandione and synthetic androgen. 29) One or more estrogens such as estradiol, estrone, estriol and synthetic estrogen such as estrogen benzoate. 30) One or more transporter modulators for noradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659.

31) One or more purinergic receptor agonists and/or modulators.

32) One or more neurokinin (NK) receptor antagonists, including those described in

WO-09964008. 33) One or more opioid receptor agonists, antagonists or modulators, preferably agonists for the ORL-1 receptor. 34) One or more agonists or modulators for oxytocin/vasopressin receptors, preferably a selective oxytocin agonist or modulator. 35) One or more PDE inhibitors, more specifically a PDE 2, 3, 4, 5, 7 or 8 inhibitor, preferably a PDE2 or PDE5 inhibitor, preferably a PDE5 inhibitor (see further), wherein the given inhibitors have an IC50 of less than 100nM, relative to the corresponding enzyme. Suitable cGMP PDE5 inhibitors for use according to the present invention include the following: pyrazolo[4,3-d]pyrimidin-7-ones described in EP-A-0463756; pyrazolo [4,3-d]pyrimidin-7-ones described in EP-A-0526004; pyrazolo [4,3-d]pyrimidin-7-ones described in published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d]pyrimidin-4-ones described in published international patent application WO 93/07149; quinazolin-4-ones described in published international patent application WO 93/12095; pyrido [3,2-d]pyrimidin-4-ones described in published international patent application WO 94/05661; purin-6-ones described in published international patent application WO 94/00453; pyrazolo [4,3-d]pyrimidin-7-ones described in published international patent application WO 98/49166; pyrazolo [4,3-d]pyrimidin-7-ones described in published international patent application WO 99/54333; pyrazolo [4,3-d]pyrimidin-4-ones described in EP-A-0995751; pyrazolo [4,3-d]pyrimidin-7-ones described in published international patent application WO 00/24745; pyrazolo [4,3-d]pyrimidin-4-ones described in EP-A-0995750; compounds described in published international patent application WO95/19978; compounds described in published international patent application WO 99/24433 and compounds described in published international patent application WO 93/07124. Pyrazolo[4,3-d]pyrimidin-7-ones described in published international patent application WO 01/27112; pyrazolo [4,3-d]pyrimidin-7-ones

described in published international patent application WO 01/27113; compounds described in EP-A-1092718 and compounds described in EP-A-1092719.

Other suitable PDE5 inhibitors for use in the present invention are: 5-[2-ethoxy-5-( 4-methyl-l-piperazinylsulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil) known as l-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-l) H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-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-eul-5-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO98/49166); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-ylmethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO99/54333 ); (+)-3-ethyl-5-[5-(4-ethylpiperazin-l-ylsulfonyl)-2-(2-methoxy-l (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-l-ylsulfonyl]-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 WO 099/54333); 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-dpyrimidin-7-one, known as l-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-one] -oxo-2H-pyrazolo[4,3-d]-pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine (see WO 01/27113, Example 8); 5-[2-/iso-Butoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-(1 -methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113, Example 15); 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113; Example 66); 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-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-d]pyrimidin-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 (IC-351), e.g. compounds of Examples 78 and 95 of published International Patent Application WO95/19978, as well as the compounds of Examples 1, 3, 7 and 8; 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-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][1,2,4]-triazin-4-one) 1-f]-cao-triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethylpiperazine, e.g. compounds in Examples 20, 19, 337 and 336 of published International Patent Application WO99/24433; and compound Example 11 of published international patent application WO93/07124 (EISAI); and compounds 3 and 14 in Rotella D P,J. Med. Chem., 2000, 43, 1257.

Other suitable PDE5 inhibitors are: 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+ )-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-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- octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone; 1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kvovva Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plow); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bayer-38-3045 & 38-9456 (Bayer) and Sch-51866.

For the treatment of FSD, the compounds of the invention, [especially (2S)-2-{[l-({[3-(4-chlorophenyl)propyl]-amino}carbonyl)cyclopentylmethyl}-4-methoxybutyric acid (^Example 22)] may be combined as needed with one or more active ingredients from the following

list:

a) a PDE5 inhibitor, namely 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)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-351); 2-[2-ethoxy-5-(4-phenyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f[1,2,4]-triazin-4-one (vardenafil); 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)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-dpyrimidin-7-one and pharmaceutically acceptable salts thereof; b) an NPY Y1 inhibitor; c) a dopamine agonist such as apomorphine or a selective D2, D3 or D2/D3 agonist such as pramipexole and ropirinol; d) melanocortin receptor agonist or modulator or enhancer of melanocortin preferably melanotan II, PT-14, PT-141; e) agonist, antagonist or modulator for 5HT2C; f) estrogen receptor modulator, estrogen agonist and/or estrogen antagonist, preferably raloxifene, tibolone or lasofoxifene; d) androgen such as androsterone, dehydro-androsterone, testosterone androstanedione and synthetic androgen; and h) estrogen, such as estradiol, estrone, estriol, and synthetic estrogen, such as estrogen benzoate.

For the treatment of MED, the compounds of the invention [especially (2S)-2-{[l-({[3-(4-chlorophenyl)propyl]-amino}carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22)] can be combined with one or more active ingredients selected from: a) a PDE5 inhibitor, or 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)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-351); 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil); 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)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 their pharmaceutically acceptable salts; b) NPY Y1 inhibitor; c) a dopamine agonist (preferably apomorphine) or a selective D2, D3 or D2/D3 agonist such as pramipexole and ropirinol; d) receptor agonist melanocortin or modulator or enhancer of melanocortin preferably, melanotan II, PT-14, PT-141; and e) an agonist, antagonist or modulator for 5HT2C;

Particularly preferred combinations for the treatment of FSD are (2S)-2-{[l-({[3-(4-chlorophenyl)-propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22) and one or more active components selected from: 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)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-351);

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

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)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-1H-pyrazolo[4,3-d]pyrimidin-7-one;

apomorphine;

melanotan II;

PT-141;

lasofoxifene;

raloxifene;

tibolone;

androgen such as androsterone, dehydro-androsterone, testosterone, androstanedione and synthetic androgen; and

estrogen, such as estradiol, estrone, estriol, and synthetic estrogen, such as estrogen benzoate.

Particularly preferred combinations for the treatment of MED are (2S)-2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22) and one or more active components selected from: 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)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-351);

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

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)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-d]pyrimidin-7-one;

apomorphine;

melanotan II; and

PT-141.

If a combination of active agents is administered, then they can be administered simultaneously, separately or one after the other.

The compounds of the invention may be administered alone, but in human therapy, they will generally be administered admixed with a suitable pharmaceutical binder, diluent or carrier, selected according to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of the invention can be administered orally, buccally or sublingually and in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain a flavoring or coloring agent, for immediate-, delayed-, modified-, continuous-, dual-, controlled-, or pulse-release action. Pronal compounds can be administered via a fast-dispersing or fast-dissolving form.

Modified or pulsatile formulations may contain fillers such as those intended for sustained release along with additional binders acting as release rate modifiers, which may be on and/or internal to the formulation. Release rate modifiers include, but are not limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanhan gum, carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, kamauba wax, paraffin wax, cellulose phthalic acetate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer in mixtures thereof. Modified and pulsed release forms may contain one or a combination of release rate modifying agents. These agents can also be present in a dosage form, e.g. as part of the matrix and/or on the dosage form eg, on the surface or as a coating agent.

Fast Dispersing or Dissolving Dose Formulations (FDDF) 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, peppermint atom, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate. glycolate, sodium stearyl fumarate, sorbitol, xylitol. As used herein, the term dispersing or dissolution is used to describe FDDFs that are dependent on the solubility of the drug used, eg, when the drug is undissolved, a rapidly dispersing dosage form can be prepared and when the substance is a solution, a rapidly dissolving dosage form can be prepared.

The preparation of the present invention can be administered by direct injection. The preparation can be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, ocular, intraocular or transdermal administration. Depending on the need, the agent can be administered in a dose of 0.01 to 30 mg/kg body weight, such as 0.1 to 10 mg/kg, and preferably 0.1 to 1 mg/kg body weight.

The term "administration" includes application by viral or non-viral techniques. The mechanism of viral delivery includes, but is not limited to, adenoviral vectors, adeno-associated viral vectors (AAV), herpes viral vectors, retroviral vectors, lentiviral vectors, and baculoviral vectors. Non-viral mechanism includes transfection by means of lipids, liposomes, immunoliposomes, lifefectins, cationic facial amphiphiles (CFA) and combinations thereof. The method of application of these mechanisms includes, but is not limited to, mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual.

Additionally or alternatively, the preparations (or components thereof) of the present invention may be administered by direct injection. In addition or as an alternative, the preparations (or components thereof) of the present invention can be administered topically (preferably to the genitals). Additionally or alternatively, the preparations (or components thereof) of the present invention may be inhaled. Further, additionally or alternatively, the preparations (or components thereof) of the present invention may be administered in one or more of the following ways: mucosal, for example, as a drop spray or aerosol for inhalation or as a solution, for example, for oral administration or parenteral administration, where it is administered by injection, for example, rectally, ophthalmologically (including intravitreal or intracamerally), nasally, topically (including buccally and sublingually), intrauterineally, vaginally or parenterally. (including subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracarnial, intrathecal, and epidural), transdermal, intracranial, intracerebroventicular, intracerebral, intravaginal, intrauterine, or parenteral (eg, intravenous, intraspinal, subcutaneous, transdermal, or intramuscular).

As an example, a pharmaceutical preparation of the invention can be administered according to a regimen of 1 to 10 times per day, such as one to two times per day. The specific dosage level and frequency of the dosage form for each individual patient may vary depending on a number of factors and will depend on the type of factors involved in the activity of a particular compound, the metabolic stability and the length of the life of this compound, age, body weight, general condition, gender, diet, method and frequency of administration, rate of excretion, combination of drugs, severity of the condition and individual therapy.

Thus, the term "administered" refers to, but is not limited to, mucosal administration, for example, as a nasal spray or aerosol for inhalation or as a solution for swallowing; parenteral administration in the form of injectable forms such as shots, for example, intravenous, intramuscular or subcutaneous administration.

These tablets may contain fillers such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), starch sodium glycolate, croscarmellose sodium and certain complex silicates and granulating agents such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may also be added.

Solid preparations of a similar type can also be filled in gel capsules. For this purpose, preferred fillers are lactose, starch, 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 flavoring agents, colors, emulsifying and/or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

The compounds of the invention may be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intravertically, intrauterally, intrasternally, intracarnially, intramuscularly, or subcutaneously, or may be administered by infusion techniques. Furthermore, they can be administered in the form of implants. For such parenteral administration, it is best that they are in the form of sterile aqueous solutions containing other substances, for example, enough salt or glucose to obtain a solution that is isotonic with water. The aqueous solution should be buffered (preferably at a pH of 3 to 9), as needed. Obtaining suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques known to one of ordinary skill in the art. The parenteral formulation may be formulated for immediate-, delayed-, modified-, continuous-, dual-, controlled-release, or pulsatile release.

The following dosage levels and other dosage levels listed here are given for an average human weighing 65-70 kg. The average person skilled in the art will easily determine the dose level for a patient who does not fall into this group, such as a child or the elderly.

For oral and parenteral administration, the daily dose of this compound or salt or

of their solvates ranges from 10 to 1000 mg (in one or separate doses).

Thus, for example, tablets or capsules of the compounds of the present invention or salts or solvates thereof may contain from 5 to 1000 mg, such as 5 to 500 mg of the active compound for administration once or twice or more times a day, as needed. In any case, the doctor will determine the necessary dose that will best suit the patient and will vary depending on the patient's age, weight and reaction to the medicine. The above doses are examples for an average case. There will, of course, be cases when other dosage regimens must be applied, such as lower or higher doses, which are also covered by this invention. One of ordinary skill in the art will appreciate that for the treatment of certain conditions (including FSD and MED), the compounds of the present invention may be taken as a single dose or "as needed" (eg, as desired or needed).

The compounds of the invention can be administered intranasally or by inhalation or administered as a dry powder inhaler or as an aerosol spray contained in a pressurized container, with a pump, syringe or nebulizer with the use of a suitable fuel namely dichlorotetrauroethane, hydroxyfluoroalkane, such as 1,1,1,2-tetrafluoroethane (HFA 134 [trademark] or 1,1,1,2,3,3-heprafluoropropane (HFA 227EA [zig]), carbon dioxide and other suitable gas. In the case of pressurized aerosols, the delivery unit can be determined by placing a metered dose valve. The pressurized container, pump, spray or nebulizer can contain a solution or suspension of the active component, e.g., using a mixture of ethanol and fuel as a solvent, which can also contain a lubricant, e.g., sorbitan. trioleate Capsules and cartridges (made from, say, gelatin) for use in inhaler or insufflator can be formulated to contain a powder mixture of a compound of the invention and a suitable base in the suspension of the powder, such as lactose or starch.

Aerosol or dry powder formulations can be adjusted so that each metered dose or "puff" contains from 1 to 50 mg of a compound of the invention for administration to a patient. The total dose delivered by aerosol ranges from 1 to 50 mg which can be administered as a single dose or, more commonly, in multiple divided daily doses.

Alternatively, the compounds of the invention may be administered in the form of a suppository or pessary, or may be applied topically (preferably to the genitals) in the form of a gel, hydrogel, lotion, cream, salve or powder. The compounds of the invention can also be administered dermally. The compounds of the invention can also be administered transdermally, for example, using a patch. Furthermore, they can be administered ocularly, pulmonaryly, or rectally.

For ophthalmic use, the compounds may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline or, preferably, as a solution in isotonic, pH-adjusted sterile saline, optionally combined with a preservative such as benzalkonium chloride. Alternatively, they can be formulated in an ointment such as petroleum jelly.

For topical administration to the skin (preferably genitalia), the compounds of the invention can be formulated as an ointment containing the active compound suspended or dissolved in, for example, a mixture of one or more of: mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of: mineral oil, sobitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, wax cetyl ester, cetearyl alcohol, 2-octyldodecanol, besyl alcohol and water.

The compounds of the invention can be used in combination with cyclodextrin. Cyclodextrins are known to form inclusion or non-inclusion complexes with drug molecules. Drug-cyclodextrin complex formation can change the solubility, dissolution rate, bioavailability and/or stability of drug molecules. Drug-cyclodextrin complexes are generally used for many dosage forms and routes of administration. As an alternative to the direct complexation of the drug, cyclodextrin can be used as an additional additive, for example, a carrier, diluent or solvent. 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 approach, the compounds of the invention are administered systemically (say orally, buccally or sublingually), that is, orally. It is desirable to use this kind of systematic (preferably oral) administration for the treatment of sexual dysfunction in women, especially FSAD.

Further, a particularly preferred approach is where the use of the compound of the invention for the production of a drug for systemic administration (preferable oral example) is described, wherein the drug is for the treatment or prophylaxis of FSD, more precisely FSAD.

The preferred oral formulation involves immediate release tablets; fast dispersing or soluble dosage formulations (FDDF).

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

Since NEP is found throughout the body, it is highly unexpected that compounds of the invention can be administered systemically and achieve a therapeutic response in female genitalia without causing intolerable (adverse) side effects. In EP 1 097 719 -Al and the animal models given below, we have shown that NEP inhibitors administered in a rabbit model (in vivo) systematically increase blood flow through the genitals, after sexual stimulation (simulated by stimulation of the pelvic nerve) without adverse effects on cardiovascular parameters, such as causing significant hypertension or hypotension.

Preferably, the compounds of the invention are administered for the treatment of FSD in sexually stimulated patients (sexual stimulation includes visual, audio simulation or touch stimulation). Stimulation can be applied before, after or during administration.

Thus, the compounds of the invention improve the pathways/mechanisms underlying sexual stimulation of the female genitalia, thereby restoring or enhancing sexual arousal responses to sexual stimulation.

Thus, a preferred approach includes the use of a compound of the invention for the preparation of a medicament for the treatment or prophylaxis of FSD in immunocompromised patients.

For veterinary use, the compounds of the invention are administered as an acceptable formulation in accordance with common veterinary practice and the veterinarian will determine the dosage regimen and route of administration that will be most appropriate for a given animal.

The following formulations are only exemplary and do not in any way limit the scope of the invention. "Active component" refers to compounds of the invention.

The components are mixed and compressed into tablets.

Formulation 2: The intravenous formulation can be prepared as follows:

Typical formulations useful for administering the compounds of the invention topically to the genitals are:

Formulation 3: Spray

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

Formulation 4: Foam

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

Formulation 5: Gel

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

Formulation 6: Cream

Active component, benzoic acid, cetyl alcohol, lavender, compound 13091, methyleneparaaminobenzoic acid, propylparaaminobenzoic acid, propylene glycol, sodium carboxymethylcellulose, sodium lauryl sulfate, stearic acid, triethanolamine, glacial acetic acid, castor oil, potassium hydroxide, sorbic acid and purified water.

Formulation 7: Pessary

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

The invention further includes:

(i) a pharmaceutical preparation containing a compound of the invention together with a pharmaceutically acceptable excipient, diluent and carrier.

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

(iii) In need of a compound of the invention as a medicament for the treatment or prevention of a condition for which it is useful for a therapeutic response that can be produced by neutral endopeptidase inhibition. (iv) Use of the compound of the invention as a drug in the treatment or prevention of disorders of hypoactive desire for sex, disorders of sexual arousal, disorders with reaching orgasm or pain during intercourse, preferably disorders of sexual arousal, problems with achieving orgasm and pain during intercourse, that is, disorders of sexual arousal. (v) A method of treating FSD or MED in a mammal comprising treating the affected mammal with an effective amount of a compound of the present invention. (vi) A preparation for the treatment of FSD or MED, comprising the compounds of the invention together with a pharmaceutically acceptable excipient, diluent or carrier. (vii) A compound of the invention for use in the treatment of FSD or MED. (viii) Use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of FSD or MED.

The invention is illustrated by the following examples which do not limit the invention in any way, whereby the following abbreviations are used:

Arbacel® filter

no deadline

Boe tert-butoxycarbonyl

CDI carbonyldiimidazole

8 chemical shift

d doublet

And the warm-up

DCCl dicyclohexylcarbodiimide

DCM dichloromethane

DMA dimethylacetamide

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

ES<+>electrospray ionization scan in positive mode

ES" electrospray ionization scan in negative mode

Ex Example

h hours

HOBt 1-hydroxybenzotriazole

HPLC high pressure chromatography m/z maximum mass spectrum

min minutes

MS mass spectrum

NMR nuclear magnetic resonance

Prec precursor

Prep preparation

q quartet

with a singlet

t triplet

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TS<+>thermo spray ionizing scan

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

The 'H nuclear magnetic resonance (NMR) spectrum is in all cases consistent with the proposed structure. Characteristic chemical shifts (5) are given in parts per million relative to tetramethylsilane, using conventional abbreviations to indicate the main maxima: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; no, wide. The following abbreviations are used for solvents: CDCI3, deuterochloroform; DMSO, dimethylsulfoxide. The abbreviation psi stands for pounds per square inch and LRMS stands for low resolution mass spectroscopy. Thin layer chromatography (TLC) is used to label TLC on silica gel, using a silica gel 60 F254 plate, Rf is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. Melting points were determined on a Perkin Elmer DCS7 apparatus at a heating rate of 20°C/minute.

X-ray powder diffraction method (PXRD) was determined on a SIEMENS D5000 diffractometer equipped with an automatic sample holder, theta-goniometer, automatic beam gaps, secondary monochromator and scintillation counter. The sample was prepared for analysis by packing the powder on a silicone support. The sample was rotated while simultaneously irradiated with copper K-alpha1X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube set at 40kV/40mA. The analysis was done by shifting the angle of the goniometer for 5 seconds per 0.02° shift in the range of two theta angles from 3° to 40°. In the tables with the results, "2 theta angle" refers to the distance between the planes in the crystal, and the intensity is given as a percentage of the highest maximum (l/h).

An experienced crystallographer will recognize that the relative intensities of the peaks can vary due to a number of factors such as the effect of the orientation of the crystal with respect to the X-ray, the degree of purity of the material analyzed, or the degree of crystallinity of the sample. The position of the peak may vary in the sample, but the position of the peak will remain basically as given in the table. Furthermore, measurements at different wavelengths can give variations in displacement according to Bragg's equation = 2d sin 9. These variations obtained by applying alternative wavelengths are within the scope of the present invention.

Example 1

4- methoxy- 2- {\ 1 -( I r3-( 4- methoxyphenyl) propyl1amino | carbonyl) cyclopentyl" l- methyl} - buterna

acid

Hydrogen chloride gas was bubbled for 30 minutes through a solution of tert-butyl ester from preparation 1 (302 mg, 0.72 mmol) in dichloromethane (5 ml) at 0°C. The reaction mixture was concentrated in vacuo and the residue azeotroped with dichloromethanol to give the compound as a yellow oil (233 mg, 0.6 mmol, 82%); 1HNMR (CDC13, 400 MHz) 5 : 1.4-1.55 (m, 2H), 1.6-1.75(m, 6H), 1.75-1.85(m, 2H), 2.4-2.5 (m, IH), 2.6(t, 2H), 3.2 (s, 3H), 3.2-3.3 (m, 2H), 3.4 (t, 2H), 3.8 (s, 3H), 5.9 (t, 1H), 6.8 (d, 2H), 7.1 (d, 2H); LRMS: m/z 390 (M-H); and HRMS m/z 392.2430 (C 22 H 33 NO 5 implies 392.2432).

The following compounds of formula I (see Table 1) can be obtained by procedures analogous to those described in Example 1 from the labeled tert-butyl ester precursor.

Alternatively, Example 22 can be prepared as follows: ( 2S V2- U1 -( and 13 -( 4-Chlorophenylpiperilloamino}carbonyDcyclopentylmethyl 1}-4-Methoxybuterene

acid

To a solution of the product from Preparation 22 (9.6g, 21.2 mmol) in dichloromethane (52 ml) was added trifluoroacetic acid (16.3 ml, 212 mmol) and the resulting solution was stirred at room temperature for 3.75 hours in a stream of N2. Aqueous sodium carbonate solution (95ml of 10% v/v solution) was then added to the mixture with stirring until the pH of the aqueous solution was adjusted between 2 and 3. The layers were then separated and the organic layer was extracted with aqueous sodium carbonate solution (2 x 20 ml of 10% v/v solution). feed layers were combined and saturated salt solution (80ml) was added, followed by 2-butanone (40ml). The layers were separated and the aqueous layer was extracted once more with 2-butanone (2 x 50 ml). The combined organic layers were dried by esotropic distillation at atmospheric pressure to a volume of 70 ml, after which crystallization occurred and the mixture was diluted with 2-butanone (70 ml). The product was collected by filtration and dried at 50°C for 65 hours under vacuum to give the crude sodium salt of the title compound as a white solid (5.76g) which was purified by recrystallization. Ethyl acetate (87 ml) and ethanol (13 ml) were added to the crude product and the remaining undissolved material was removed by filtration. Ethanol was removed by azeotropic distillation at atmospheric pressure (to remove 110 ml of solvent) and replaced with ethyl acetate (145 ml), after which crystallization took place. The resulting crystallized product was then collected by vacuum filtration to give the pure sodium salt of the title compound as a white crystalline substance (4.51 g, 10.8 mmol, 51%); d.p. (ethyl acetate) 214-216°C; 1H NMR (CDCl3, 300MHz) δ : 1.26-1.58(m, 8H), 1.62-1.74(m, 3H), 1.74-1.86(m, 1H), 1.91-2.0(m, 3H), 2.57(t, 2H), 3.03(q, 2H), 3.10(s, 3H), 3.13-3.27(m, 2H), 7.22(d, 2H), 7.29 (d, 2H), 9.16(t, br, 1H); LRMS (ES negative); 789 [2M-H]" (<35>C1), 394 [M-H]" (<35>C1). For analytical purposes, this product (eg free acid) was obtained by dissolving the sodium salt in water, acidified with 5M hydrochloric acid and extracted with dichloromethane. Removal of the solvent by blowing nitrogen vapor over the sample gives the desired product; <!>H NMR (CDCl3, 300MHz) 5 : 1.22-1.80(m, 11H), 1.81-1.96 (m, 2H), 1.96-2.08(m, IH), 2.93-2.27 (m, IH), 2.53 (t, 2H), 3.03(q, 2H), 3.1 l(s, 3H), 3.16-3.25(m, 2H), 7.20(d, 2H), 7.30(d, 2H), 7.5 l(t, 1H); LRMS (ES negative); 789 [2M-H]"(<35>C1), 394 [M-H]" (<35>C1); HPLC (column: ChiralPAk AS (25 x 0.46 cm); mobile phase: hexane/IPA/acetic acid (95/5/0.5 z/'z/'z); flow rate: 1.0 ml/min; temperature: room; injected volume: 20ul; detection: UV'220 nm; concentration sample: 1.0 mg/ml prepared in the mobile phase) Retention Time: minor enantiomer 11.4 min (5.7%), major enantiomer 14.3 min (94.3%).

Sodium Salts from Example 22

a) Monohydrate

The sodium salt of Example 22 (200 mg) was added to a 1 ml solution of 3.9% water in

isopropanol. The resulting precipitate was stirred for 12 days, after which it was isolated by filtration. The resulting product has the following PXRD pattern:

Differential scanning calorimetry (DSC) was measured on a Perkin Elmer DSC-7 instrument equipped with an automatic sample changer. About 3 mg of the sample was accurately weighed into a 50 microliter aluminum container and sealed with a pre-perforated lid, then the edges were crimped. The sample was heated at 20°C/minute in the range from 40°C to 300°C in a stream of nitrogen. Dehydration takes place between 50 and 150°C, and melting between 212 and 225°C. One of ordinary skill in the art knows that the melting point can vary as a result of impurities present in the sample.

b) anhydrous salt

The sodium salt of Example 22 gives the following PXRD pattern:

Preparations

Preparation 1

Tert-butyl 4-methoxy-2-{ ri-({[ 3-( 4- methoxy:siphenyl)propynarryno}carbonincik:loperityl

methyl butanoate

The product of Preparation 68 (325mg, 1.08 mmol), the product of Preparation 73 (178 mg, 1.08 mmol), HOBt (146 mg, 1.08 mmol), WSCDI (207 mg, 1.08 mmol) and triethylamine (0.3 ml, 2.16 mmol) were mixed together in dichloromethane (5 ml) at room temperature for 14 h. The reaction mixture was diluted with dichloromethane (10 ml) and washed with water (2 x 20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography eluting with dichloromethane, then 99:1 dichloromethane:methanol, then 98:2 dichloromethane:methanol (Rf 0.2) to give a yellow oil (267 mg, 0.6 mmol); 1.8(m, 4H), 2.0(m, IH), 2.3(m, IH), 2.6(t, 2H), 3.2(s, 3H), 3.3(m, 2H), 3.7(s, 3H), 5.7(t, IH), 6.8(d, 2H), 7.0(d, IH); LRMS: m/z 448 (M-H<+>).

The following Examples of Formula (IVa), e.g. compounds of general formula IV where prot is tert-butyl were obtained by methods similar to those described in Preparation 1, from the indicated precursor (see Table 2).

Alternatively, Preparation 22 is obtained as follows:

To a solution of 1,1'-carbonyl diimidazole (73.9g, 0.45 mol) in azeotrope-dried isopropyl acetate (339 ml), isorpoyl acetate solution of the product from Preparation 69 was added with stirring at 60°C, in a stream of N2, over a period of 1.5 hours. The dishes were washed with dry isopropyl acetate (50 ml), the resulting solution was then stirred for another 4.5 hours at 60°C, and the reaction mixture was allowed to cool to room temperature and stirred for another 15 hours. Triethylamine (46. lg, 0.46 mol) was added to the obtained solution, then 3-(4-chlorophenyl)propylamine hydrochloride (J. Med. Chem., 1996, 39, 4942-51) (94.3 g, 0.46 mol). The resulting mixture was then heated for 7 hours at 60°C before cooling to room temperature. Deionized water (100 ml) was then added with stirring and then aqueous hydrochloric acid (190 ml of 5M solution) until the pH of the aqueous layer reached the order of 2 to 3. The aqueous layer was separated and the organic layer was washed with aqueous potassium carbonate solution (50 ml of 0.5M solution). The aqueous phase was separated and the organic layer was washed with saturated brine (100 mL). The aqueous layer was separated again, and the organic layer was concentrated by distillation under vacuum to obtain the desired compound as a yellow oil (200.3g, 443 mmol, 98% yield); 1h NMR (CDCl3, 300MHz) δ : 1.45 (s, 9H), 1.45-1.56(m, 1H), 1.56-1.74 (m, 6H), 1.74-2.11 (m, 7H), 2.32-2.43 (m, 1H), 2.64(t, 2H), 3.22-3.30(m, 2H), 3.27(s, 3H), 3.30-3.38 (m, 2H), 5.75-5.85 (m, br, 1H), 7.13(d, 2H), 7.26(d, 2H); LRMS (ES positive): m/z 452 [M+H]<+>(<35>C1).

Alternatively 3-(4-chlorophenyl)-propylamine was obtained as follows:

Boron dimethylsulfide complex (30 ml) was added to a solution of the starting material from phase b) below (11.3g, 62 mmol) in tetrahydrofuran (500 ml) and the mixture was refluxed for 12 hours. Methanol (100 mL) was added to the reaction mixture, concentrated in vacuo and refluxed for 4 hours in 3M HCl (200 mL). The aqueous layer was concentrated to 50 ml in vacuo, the precipitate was filtered and dried under reduced pressure, whereby the desired product was obtained in the form of a white powder (10.1g, 59.7 mmol, 96%); 7.2(d, 2H), 7.25(d, 2H).

Obtaining starting materials

a) methyl 3-(4-chlorophenyl) propionate

In a mixed solution of 3-(4-chlorophenyl)propionic acid (commercially available from

Mawbridge) (14.5 g, 77.1 mmol) in methanol (400 mL) was added acetyl chloride (50 mL) and the reaction mixture was refluxed for 20 h. After this, the reaction mixture was allowed to cool, before being concentrated under reduced pressure. The residue was then dissolved in DCM (200ml) and washed with 1M sodium hydroxide solution (100ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the desired product as a brown oil (15.7 g, 77 mmol 1, 100%); 1H NMR (400MHz, CDCl 3 ) δ : 2.55(t, 2H), 2.9 (t, 2H), 3.6 (s, 3H), 7.1 (d, 2H), 7.2 (d, 2H).

b) 3-(4-chlorophenyl)propionamide

The product from the previous step a) (15 g, 75.7 mmol) was dissolved in methanol (400 ml) before

rather it is cooled to 0°C. Ammonia gas was blown through the reaction mixture for 4 hours and the reaction mixture was left on the stirrer for 3 days. The solvent was removed under reduced pressure and the residue was treated with hot pentane. The remaining solid was dried in vacuo to give the desired product as a white powder (11.32g, 61.8mmol, 82%); 1H NMR (400MHz, CDCl3) δ : 2.45 (t, 2H), 2.9(t, 2H), 5.3(bs, IH), 5.5(bs, IH), 7.1 (d, 2H), 7.2 (d, 2H).

Preparation 67

Tert-butyryl-({ r3-(4-cyanophenyl) propynamino} carbonyl) cyclopentylacetate

The product of Preparation 45 (44 mg, 0.1 mmol) and Cu(I)CN (13.4 mg, 0.15 mmol) was dissolved in DMF (0.5 ml) under azo current and stirred at 130°C for 16 hours. After this, another 13 mg of Cu(I)CN was added and the temperature raised to 145°C, and the mixture was stirred for another 16 hours. After this, the last 26 mg of Cu(I)CN was added to the solution and the mixture was heated for 24 hours at 160°C. Water was then added to the reaction mixture and the organics extracted with EtOAc (50 ml), washed with brine and dried (MgSO4 and evaporated to a yellow oil. This oil was subjected to preparative TLC purification, using 7 : 3 pentane : EtOAc as eluent, to give the desired product, 6 mg (16 %); HNMR (400 MHz, CDCl 3 ) 8 : 1.40 (s, 9H); 1.62-1.64(m, 4H); 2.12-2.17(m, 2H); 6.65 (brs, IH); 7.23 (d, 2H); 7.54 (d, 2H); LRMS: m/z (ES<+>) 407 (M + Na).

Preparation 68

1-[2-(tert-butoxycarbonyl)-4-methoxybutylcyclopentanecarboxylic acid

A solution of tert-butyl 3-(1-carboxycyclopentyl)propionate (12g, 49.5 mmol) (see EP274234B1, Example 35) in dry tetrahydrofuran (100 ml) was added to a stirred solution of lithium diisopropylamide (130 ml) in a mixture of hexane (52 ml) and tetrahydrofuran (200 ml) at -78°C under a stream of nitrogen. After 1 hour, a solution of 2-bromoethyl methyl ether in tetrahydrofuran (100 ml) was added, maintaining the temperature at -78°C. The reaction mixture was allowed to warm to room temperature overnight. Water (100 ml) was added to the mixture and acidified to pH 1 by addition of 2M hydrochloric acid and extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the crude product, which was chromatographed on silica. Elution was carried out by increasing parts of methanol in dichloromethane (from pure dichloromethane to a ratio of 1:50), whereby an oil was obtained (7.7 g, 25.6 mmol, 52%); Rf 0.3 methanol, dichloromethane 1:20; HNMR (CDCl 3 , 400 MHz ) S: 1.4(s, 9H); 1.4-1.7 (m, 7H), 1.75-1.95 (m, 2H), 2.0-2.15 (m, 3H), 3.3 (s, 3H), 3.3-3.4 (m, 2H); LRMS: m/z 299 (M-H<+>).

Alternatively, the compounds of Preparation 68 were obtained as follows:

To a mixture of heptane (41.2L) and water (30.9L) was added the product from step b) from the following text (.15 kg, 12.9 mol). An aqueous solution of dilute hydrochloric acid was added

(2.6L of 5M solution), with stirring until the pH of the aqueous layer reached a value between 2 and 3. The layers were separated and the aqueous phase was then extracted with heptane (20.6L). The combined organic layers were washed with brine (15.5L) and then concentrated by distillation at atmospheric pressure to give the desired compound (3.90kg, 13.0mol, 100% yield) as a solution in heptane (total solution weight 44.0kg). An aliquot was taken and the solvent was evaporated under vacuum to give an analytical sample: HNMR ( CDCl 3,300 MHz) δ : 1.42 (s, 9H), 1.45-1.58 (m, 2H), 1.58-1.70 (m, 5H); 1.70-1.90 (m, 2H), 2.03-2.18 (m, 3H); 2.32-2.46 (m, 1H), 3.27 (s, 3H); 3.35 (t, 2H); LRMS (EI): m/z 244 [M-C4H8]<+>, 227 [M-C4H90]<+>, 199 [M-C4H9 02C]+, GC (injection program: start temp. 0°C, speed 150°C/min, end temp. 230°C; programmed chamber temperature: start Temp. 100°C, speed 10°C/min, final temp. 230°C, total time 10 min; column BP-25 0.25 mm ID x 0.25um FT) RT 16.1 min.

Preparation of starting materials

a) Raw 1- T2 - (tert-butoxycarbonyl)-4- methoxybutylcyclopentane carboxylic

acid

To a solution of purchased lithium diivopropylamide (9.63 kg, 2M, dissolved in tetrahydrofuran/n-heptane/ethylbenzene, 23.7 mol) in 1,2-dimethoxyethane (25 1) at -10°C in a stream of N2, a solution of l-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid (EP274234B1-see Example 35) was added. (2.5 kg 10.3 mol) in 1,2-dimethoxyethane (12.5 L) with stirring for a period of 4 hours while maintaining the reaction temperature at -10°C. The upper vessel was washed with 1,2-dimethoxyethane (2.5 L) and this was added to the reaction mixture. The reaction mixture was then allowed to stir at -10°C for 1.75 hours. To the resulting solution, a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (10 L) was added over 1.75 hours. The mixture was then stirred at this temperature for 4 hours before being warmed to 20°C over a period of 4 hours. After stirring for 8 hours at this temperature, an aqueous solution of ammonium chloride (25L 2.8M solution) was added to the mixture, followed by ethyl acetate (12.5L). Aqueous hydrochloric acid (10 L, 5M solution) was added with stirring to adjust the pH between 2 and 3. The two phases were mixed and separated. The organic phase was extracted three times with an aqueous solution of potassium carbonate (0.3M solution, 37.5 L, 12.5 L and finally 6.25 L). To the combined aqueous layer was then added n-heptane (15.6L) and aqueous hydrochloric acid (14.5L, 5M solution) with stirring until the pH of the aqueous layer was between 2 and 3. The layers were then separated and the aqueous layer was extracted with n-heptane (15.6L). The combined organic phases were then washed with brine (3.1L) and then concentrated in vacuo to afford the crude desired product (2.50 kg, 8.32 mol, 81% yield) as a solution in n-heptane (21.8 kg total solution weight).

b) cyclohexaminium 1-r2-(tert-butoxycarbonyl(-4-methoxybutylcyclopentane

carboxylate

A solution of the crude product from the previous step a) in n-heptane (5.5 lkg, 18.3 mol in a solvent with a total weight of 41.4kg) was concentrated by distillation at atmospheric pressure to remove 20L of n-heptane. Cyclohexylamine (1.82 kg, 18.4 mol) was added to the resulting solution as a solution in n-heptane (9.9 L) over a period of 0.5 hours. The vessels from which the solution was added were washed with n-heptane (1.1L) and ivo was added to the reaction mixture. The resulting muddy sediment was then granulated by mixing at 22°C for a period of 18.5 hours. The product was collected by filtration and washed with n-heptane (2 x 11.0L) and the resulting precipitate was dried in vacuo at 50°C for 20 hours. The resulting off-white solid (6.2 kg, 15.5 mol) was suspended in isopropyl acetate (37.2 L) and the resulting suspension was heated to 80°C until a clear solution was obtained. The resulting solution was then cooled to 50°C and a sample of the authentic crystallized compound (l.Og) was added to seed the crystallization. The crystallized sludge was then cooled to 20°C for 4 hours and then granulated at this temperature for 0.5 hours. The product was then collected by filtration and washed with n-heptane (2x6.2L) before drying under vacuum at 45°C for 11 hours. The resulting white solid (5.5 kg, 13.8 mol) was then suspended in isopropyl acetate (55.0 L) and heated to 80°C until the solution became clear. The resulting solution was then cooled to 50°C and a sample of the authentic crystalline compound (l.Og) was added to seed crystallization. The crystallized sludge was cooled to 20°C within 4 hours, and then granulated at this temperature for 22.5 hours.

The product was collected by filtration and washed with n-heptane (2 x 5.5L) before drying in vacuo at 45°C for 16.5 hours to give the desired product (5.15 kg, 12.9mol, 94% yield); mp (heptane) 12FC; 1HNMR (CDCl 3 , 300 MHz) δ: 1.06-1.37(m, 7H); 1.42(s, 9H); 1.50-1.67 (m, 5H); 1.67-1.86 (m, 5H); 1.86-2.18 )m, 5H); 2.30-2.58 (m, IH); 2.80-2.93 (m, IH); 3.29(s, 3H); 3.35(q, 2H); 7.29(s, no, 3H); Anal. Found C, 66.20; H, 10.26; N, 3.50; C22H41NO5 requires C, 66.13; H, 10.34; N, 3.51%.

Preparation 69

1-r(2S)-2-(tert-butoxycarbonyl)-4-methoxybutylcyclopentanecarboxylic acid

The product from Preparation 68 and (+)-pseudoephedrine were recrystallized nine times from hexane to give white solid crystals. Soy dissolved in ethyl acetate, washed with 0.5M hydrochloric acid, dried over magnesium sulfate and concentrated in vacuo, and the (S)-acid was obtained in 31%> yield as a bright yellow oil in > 90% ee NMR analysis of the maximum at 5 3.3 (+)-salt of pseudoephedrine; 1 HNMR (CDCl 3 , 400 MHz) δ: 1.4 (s, 9H); 1.4-1.7 (m, 7H), 1.75-1.9 (m, 2H); 2.0-2.15 (m, 3H); 2.35-2.45 (m, IH); 3.3(s, 3H); 3.3-3.4 (m, 2H); [α]D- 5.2 (EtOH, c 1.2).

Alternatively, Preparation 69 can be obtained as follows:

To a product solution of Preparation 68 (3.90 kg, 13.0 mol) in heptane (58.5 L, total solution weight 44.0 kg) was added (1S, 2S)-(+)-pseudoephedrine (2.13 kg, 12.9 mol) under a stream of nitrogen at 20°C. The suspension was heated to 70°C with stirring until a clear solution was obtained. The solution was then cooled to 40°C and a sample of an authentic crystal of the given compound (0.8g) was added to seed crystallization. The temperature of the mixture was maintained at 40°C for 2 hours, and the sludgy product was cooled to 20°C for 6 hours. The product was collected by filtration and washed with heptane (2x2.3L), then dried in vacuo for 22 hours at 50°C to give (1S,2S)-1-hydroxy-N-methyl-1-phenyl-2-propanaminium 1-[(2S)-2-(tert-butoxycarbonyl)-4-methoxybutyl]cyclopentane carboxylate (3.20 kg, 6.87 mol, 53% yield as 86:14 mixture of diastereoisomeric salts, mixed by HNMR). The product (3.20 kg, 6.87 mol) was then suspended in heptane (30 L) and heated to 70°C until a clear solution was obtained. The resulting solution was then cooled to 58°C and a sample of an authentic crystal of the given compound was added

(1 .Og) in order to seed crystallization. The solution was kept at 58°C for 1 hour and then cooled to 20°C for 6 hours. The slurry was then granulated at 20°C for 12 hours. The product was collected by filtration and washed with heptane (2x2L). It was dried in a vacuum oven at 50°C for 22.5 hours, yielding (1S, 2S)-1-hydroxy-N-methyl-1-phenyl-2-propanaminium 1-[(2S)-2-(tert-butoxycarbonyl)-4-methoxybutyl]cyclopentane carboxylate as a white crystalline substance (2.35 kg, 5.0 mol, 73% yield). T.t. (heptane); 95°C; 1 HNMR (CDCl 3 , 300 MHz) δ: 1.08 (d, 3H); 1.48(s, 10H), 1.56-1.74 (m, 4H), 1.74-1.90 (m, 2H), 1.90-2.03 (m, 2H), 2.03-2.27 (m, 2H), 2.4-2.53 (m, IH), 2.66(s, 3H), 3.08 (dq, 1H), 3.24 (s, 3H), 3.38 (q, 2H), 4.58 (d, 1H), 7.27-7.45 (m, 5H), 7.70 (s, br, 3H); Anal. Found C, 67.06; H, 9.35; N, 3.04; C26H43NO6 requires C, 67.07; H, 9.31; N, 3.01 %. The desired compound was obtained by destruction of the salt in the following manner. To a mixed suspension of (1S, 2S)-1-hydroxy-N-methyl-1-phenyl-2-propanaminium l-[(2S)-2-(tert-butoxycarbonyl)-4-methoxybutyl]cyclopentane carboxylate (210 g, 0.45 mol) in deionized water (1.26 L) and isopropyl acetate (1.47 L), was added an aqueous solution of hydrochloric acid (99.5 ml, 5M solution, 0.50 mol) until the pH of the aqueous solution reaches a value between pH 2 and 3. The layers are separated, the aqueous layer is extracted with isopropyl acetate (630 ml). The organic extracts were combined and washed with brine (420 ml). The organic phase was then concentrated by distillation at atmospheric pressure (to remove 1.4 L of isopropyl acetate) to give the desired compound as a solution in isopropyl acetate which was used directly in the next step. An aliquot was taken and the solvent removed to perform the analysis; ; 1 HNMR (CDCl 3 , 300 MHz) δ: 1.44 (s, 9H), 1.48-1.59 (m, 2H); 1.59-1.72 (M, 5H); 1.72-1.93 (m, 2H); 2.03-2.18 (m, 3H); 2.35-2.46 (m, IH); 3.31 (s, 3H); 3.38 (t, 2H); LRMS (EI) : m/z 244 [M-C4H8]<+>, 227 [M-C4H90]<+>, 199 [M-C4H902C]<+>, GC (injection program: start temp. 0°C, speed 150°C/min, end temp. 230°C; programmed chamber temperature: start Temp. 100°C, speed 10°C/min, final temp. 20 min; column BP-25 0.25 mm ID x 0.25um FT) RT 16.0 min; HPLC (column: ChiralPAk AD (25 x 0.46 cm); mobile phase: hexane/IPA/acetic acid (98/2/0.1 z/z/z); elution mobile phase: hexane/IPA DEA (80/20/0.5z/z/z); flow rate: 1.0 ml/min; temperature: room; injected volume: 20ul: ELSD detection) Analysis time : 20 minutes, followed by washing with hexane/IPA/acetic acid (98/2/0.2 z/z/z), followed by washing with hexane/IPA/acetic acid (98/2/0.2 z/z/z). Retention time: minor enantiomer 15.6 min (3.3%), major enantiomer 17.5 min (96.7%).

Alternatively, the product from Preparation 69 was obtained by asymmetric hydrogenation using numerous catalysts and under different conditions, as follows:

i) Hydrogenation 1

starting materials from phase c) below (62 mg, 0.21 mmol) and [(R)-(+)-2,2'-bis(diphenylphosphino)-1,r-binaphthylchloro(para-cymene)]ruthenium chloride (J. Org. Chem. 1994, 59, 3064-76) (2.0 mg, 0.0021 mmol) were placed in a pressure vessel. The vessel is blown with nitrogen, so it is exposed under a pressure of 10 bar, then releasing the valve. This blowing procedure was repeated 4 more times. Degassed methanol (2ml) was then added. The vessel was subjected to hydrogen pressure (10 bar), then the valve was unscrewed and again subjected to hydrogen pressure (10 bar). The mixture was mixed at 65°C (oil bath), for 18 hours. After cooling to room temperature, the pressure was released and the solvent was removed under reduced pressure to give the desired compound as an oil, HPLC (column: ChiralPak AD (25 x 0.46 cm); mobile phase: hexane/IPA/acetic acid (98/2/0.1 z/z/z); elution mobile phase: hexane/IPA/DEA (80/20/0.5 z/z/z); flow rate 1.0 ml/min; temperature: room; injected volume: 20ul: ELSD detection). Analysis time: 20 minutes, followed by 10 minutes of washing with hexane/IPA/acetic acid (98/2/0.2 z/z/z), followed by washing with hexane/IPA/acetic acid (98/2/0.2 z/z/z); retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min; 91% conversion, S-enantiomer, ee 97%.

ii) Hydrogenation 2

Starting material from step c) below (82 mg, 0.27 mmol), sodium tert-butoxide (25 mg, 0.26 mmol) and [(S)-3, 3', 4, 4, 5, 5'-hexamethyl (6,6'-diphenyl)-2,2'-diyl]bis(diphenylphosphino)ruthenium bis(trifluoroacetate) (see WO01/94359) (2.5 mg, 0.0027 mmol) were added to the pressure vessel. This blowing procedure was repeated 4 more times. Degassed methanol (2ml) was then added. The vessel was subjected to hydrogen pressure (10 bar), then the valve was unscrewed and again subjected to hydrogen pressure (10 bar). The mixture was stirred at 65°C for 18 hours. After cooling to room temperature, the pressure was released. Ethyl acetate/heptane (1:1, 10 ml) and hydrochloric acid (1M, 5ml) were then added to the reaction mixture. The organic phases were separated and dried over magnesium sulfate and the solvent was removed under reduced pressure to give the desired compound as an oil, HPLC (column: ChiralPak AD (25 x 0.46 cm); mobile phase: hexane/IPA/acetic acid (98/2/0.1z/z/z); mobile phase for elution: hexane/IPA/DEA (80/20/0.5 z/z/z); flow rate 1.0 ml/min; temperature: room; injected volume: 20ul: ELSD detection). Analysis time: 20 minutes, followed by 10 minutes of washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z), followed by washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z); Retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min; >98% conversion, R-enantiomer, ee 91%.

iii) Hydrogenation 3

Applying the same method as described for Hydrogenation in 2, using [(R)-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphino)]ruthenium bis(trifluoroacetate) (EP398132) as a pre-catalyst, the desired compound is obtained as an oil, HPLC (column: ChiralPak AD (25 x 0.46 cm); mobile phase: hexane /IPA/acetic acid (98/2/0.1 z/z); mobile phase: hexane/IPA/DEA; flow rate: room temperature: 20ul: ELSD detection. Analysis time: 20 minutes, followed by 10 minutes of washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z), followed by washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z); retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min; 57% conversion, S-enantiomer, ee >98%.

iv) Hydrogenation 4

Starting material from step i) (80 mg, 0.25 mmol) and [(R)-(-)-4,12-bis(diiso-propylphosphino)-[2.2]-paracyclophane-(1,5-cyclooctadiene)]rhodium (I) tetrafluoroborate (J. Am. Chem. Soc. 1997, 119, 6207-6208) (1.8 mg, 0.0025 mmol) were put in the court under pressure. The vessel was blown with nitrogen, by exposing it under a pressure of 10.5 bar, then releasing the valve. This blowing procedure was repeated 4 more times. Degassed methanol (2ml) was then added. The vessel was subjected to hydrogen pressure (10.5 bar), then the valve was unscrewed and again subjected to hydrogen pressure (10.5 bar). The mixture was stirred for 18 hours at room temperature, then the pressure was released. Tert-butyl methyl ether and 2M hydrochloric acid were added to the reaction mixture and the phases were mixed. The organic phase was separated, dried with magnesium sulfate and the solvent evaporated under reduced pressure to give the desired compound as an oil, HPLC (column: ChiralPak AD (25 x 0.46 cm); mobile phase: hexane/IPA/acetic acid (98/2/0.1 z/z/z); eluent mobile phase: hexane/IPA/DEA (80/20/0.5 z/z/z); flow rate 1.0 ml/min; temperature: room; injected volume: 20ul: ELSD detection). Analysis time: 20 minutes, followed by 10 minutes of washing with hexane/IPA/acetic acid (98/2/0.2 z/z/z), followed by washing with hexane/IPA/acetic acid (98/2/0.2 z/z/z); retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min; >98% conversion, R-enantiomer, ee 91%.

c) Hydrogenation 5

Starting material from step i) (80 mg, 0.25 mmol) and [(S)-3,3'4,4'5,5'-hexamethyl (6,6'-diphenyl)-2,2'-diil]bis)diphenylphosphino)n.!thenium bis(trifluoroacetate) see WO 01/94359 (2.3 mg, 0.0025 mmol) were added to the pressure vessel. The vessel is blown with nitrogen, so it is exposed under a pressure of 10.5 bar, then releasing the valve. This blowing procedure was repeated 4 more times. Degassed methanol (2ml) was then added. The vessel was subjected to hydrogen pressure (10.5 bar), then the valve was unscrewed and again subjected to hydrogen pressure (10.5 bar). The mixture was stirred at 45°C for 18 hours and then cooled to room temperature. The pressure was released and tert-butyl methyl ether and 2M hydrochloric acid were added to the reaction mixture and the phases were mixed. The organic layer was separated and dried over magnesium sulfate and the solvent was removed under reduced pressure to give the desired compound as an oil, HPLC (column: ChiralPak AD (25 x 0.46 cm); mobile phase: hexane/IPA/acetic acid (98/2/0.1 z/z/z); elution mobile phase: hexane/IPA/DEA (80/20/0.5 z/z/z); speed flow rate 1.0 ml/min; temperature: room; injected volume: 20ul: ELSD detection). Analysis time: 20 minutes, followed by 10 minutes of washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z), followed by washing with hexane/IPA/acetic acid (98/2/0.1z/z/z); retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min; >98% conversion, S-enantiomer, ee 97%.

vi) Hydrogenation 6

The product of step i) (80 mg, 0.25 mmol) and [(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium bis(trifluoroacetate)] (2.4 mg, 0.0025 mmol) or [(R)-(+)-2,2'-bis(diphenylphosphino)-1,rbinaphthylchloro(para-cymene)]ruthenium chloride (J. Org. Chem. 1994, 59, 3064 -76) (2.4 mg, 0.0025mmol) was added to the pressure vessel. Following the same procedure as that described in Preparation 6, the desired compound was obtained as an oil; HPLC (column : ChiralPak AD (25 x 0.46 cm); mobile phase : hexane/IPA/acetic acid (98/2/0.1 z/z/z); eluent mobile phase: hexane/IPA/DEA (80/20/0.5 z/z/z); flow rate 1.0 ml/min; temperature: room; injected volume : 20ul: ELSD detection). Analysis time: 20 minutes, followed by 10 minutes of rinsing with hexane/IPA/acetic acid (98/2/0.1 z/z/z), then rinsing with hexane/IPA/acetic acid (98/2/0.1 z/z/z); retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min; >98% conversion, S-enantiomer, ee >98%.

vi) Hydrogenation 7

The product from step i) (80 mg, 0.25 mmol) and [(R)-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphino)]ruthenium bis(trifluoroacetate) (EP398132) (2.3mg, 0.0025 mmol) were added to the pressure vessel. According to the same procedure described in the hydrogenation of 6, the desired compound was obtained as an oil; HPLC (column : ChiralPak AD (25 x 0.46 cm); mobile phase : hexane/IPA/acetic acid (98/2/0.1 z/z/z); eluent mobile phase: hexane/IPA/DEA (80/20/0.5 z/z/z); flow rate 1.0 ml/min; temperature: room; injected volume : 20ul: ELSD detection). Analysis time : 20 minutes, followed by 10 minutes of washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z) and then washing with hexane/IPA/acetic acid (98/2/0.1 z/z/z); retention time: R enantiomer 15.5 minutes; S enantiomer 17.5 min;> 98% conversion, S-enantiomer, ee 98%.

Refutation of starting materials

a) 1-(2-tert-butoxycarbonyl-4-methoxy-3-oxo-butyl) cyclopentane carboxylic acid

A solution of diisopropylamine (835.0 ml, 250 mmol) in THF /70 ml) is under nitrogen

cooled to -15°C. (2.5M, 100 ml, 250 mmol) was added dropwise keeping the temperature below -10°C. To the resulting solution was added a solution of 1-(3-tert-butoxy-3-oxopropyl)-cyclopentane carboxylic acid (see EP274234B1, Example, 35) (27.52g, 113.6mmol) in THF (50ml) and the reaction mixture was stirred at -10 to -15°C for 1 h. A solution of methyl methoxyacetate (18.0 ml) in THF (20 ml) was then added to the reaction mixture and the resulting mixture was allowed to warm to room temperature and stirred for another 19 hours. tert-butyl methyl ether (300ml) and deionized water (300ml) were added to the mixture and the aqueous phase was then acidified with 2M hydrochloric acid to pH 3, with stirring. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (250ml). The combined organic phases were washed with water (250 ml), salt solution (250 ml), dried with magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with a mixture of ethyl acetate/heptane (1:2 to 1:1), whereby the desired product was obtained (17.35g, 55.2 mmol, 49% yield); 1 HNMR (400 MHz, CDCl 3 ) δ: 1.43 (s, 9H), 1.69-1.47 (m, 6H); 2.17-2.05 (m, 2H); 2.18 (dd, 1H), 2.32 (dd, 1H); 3.42 (s, 3H); 3.59 (t, IH); 4.17 (q, 2H); 13C NMR (100 MHz, CDCl 3 ) δ : 24.7, 27.8, 34.9, 35.8, 36.7, 53.2, 53.3, 59.2, 82.3, 168.3, 183.4, 203.2.

b) tert-butyl ester 8-methoxymethyl-6-oxo-7-oxa-spiror4. 51 decan-9- carboxylic

acids

A solution of product iy of phase i) (10.50g, 33.4 mmol) in methanol was cooled to 0 to -5°C under nitrogen. Sodium borohydride (2.02g, 53.4 mmol) was added to the resulting solution in portions, keeping the temperature below 0°C. The reaction mixture was stirred for 1 hour. ethyl acetate (150 ml) and sodium chloride (150 ml) were added and the aqueous phase was acidified by the addition of hydrochloric acid (50 ml of a 2M solution) with stirring. The phases were separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (50 ml) and then brine (50 ml). The combined aqueous washes were extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give a pale yellow oil (811.29 g), which was used in the next step without further purification. A portion of this oil (10.89g, 34.4 mmol) was dissolved in THF (100 ml) under a stream of nitrogen and dicyclohexylcarbodiimide (7.10g, 34.4 mmol) was added to the resulting solution. The mixture was stirred at room temperature for 19 hours. Methanol (5ml) and acetic acid (2ml) were added to the mixture and the mixture was stirred for another 30 minutes. The solvent was evaporated under reduced pressure. The crude product was then suspended in ethyl acetate (50 ml) and the reaction by-products were removed by filtration. The cake was washed with ethyl acetate (50 ml) and the filtrate was concentrated under reduced pressure. The crude compound was then purified by flash chromatography on silica gel, eluting with ethyl acetate/heptane (1:3 to 2:3), to give the desired product as a 2:1 mixture of diastereomers (8.19 g, 27.4 mmol, 80%); For analysis, the sample was purified by flash chromatography on silica gel, eluting with EtOAc/heptane (1:2); i) louse rf stain (one stereoisomer); 1HNMR (400 MHz, CDCl 3 ) δ: 1.47(s, 9H), 1.50-2.15 (m, 9H), 2.30 (m, 1H); 2.90 (td, 1H) 3.38 (s, 3H); 3.58 (d, 2H); 4.62 (dt, 1H); ii) lower rf spot (not fully resolved 3.5:1 mixture of diastereomers);

HNMR (400 MHz, CDCl 3 ) 8 : (major isomer) 1.47 (s, 9H); 1.49-2.10 (m, 8H); 2.18 (dd, IH); 2.43 (m, IH), 3.03 (m, IH); 3.35 (s, 3H); 3.60-3.67 (m, 2H); 4.72 (q, IH).

c) 1-(2-tert-butoxycarbonyl-4-methoxy-but-2E-enyl)-cyclopentane carboxylic acid

To a solution of the product from the previous step b) (6.1 lg, 20.49 mmol) in toluene (50 ml) was

,8-diazabicyclo[5.4.0]undec-7-ene (3.7 ml, 24.58 mmol) was added and the resulting solution was heated to reflux temperature under a stream of nitrogen for 5 hours. The solution was then cooled to room temperature and the solvent was removed under reduced pressure. To the obtained residue, deionized water (100 ml) was added and the mixture was extracted with tert-butyl methyl ether (30 ml). The phases were separated and the aqueous phase was acidified to p 2 by the addition of hydrochloric acid (15 ml, 2M solution) and then extracted with tert-butyl methyl ether (2 x 30 ml). The combined organic extracts were then washed with water (30 ml), then with salt solution (30 ml) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give the crude product (6.29g), which was then crystallized from heptane (15ml) at 0°C. the resulting solid residue was filtered, washed with ice-cold heptane (2 x 5ml) to give the desired compound as a white solid (1.79g, 6.0 mmol, 29%, E-

isomer assigned based on chemical shift); HNMR (400 MHz, CDCl 3 ) δ: 1.47 (s, 9H); 1.45-1.70 (m, 6H), 2.05-2.10 (m ,2H), 2.74 (s, 2H), 3.36 (s, 3H), 4.09 (d, 2H), 6.75(t, IH); <13>C NMR (100 MHz, CDCl3) 6 : 23.9, 28.0, 34.1, 35.0, 55.0, 58.6, 69.2, 80.8, 132.7, 139.1, 167.1, 183.3.

The filtrates were concentrated to give a yellow oil (4.02g). this mixture was purified by flash chromatography on a silica gel column, eluting with ethyl acetate/heptane (1:2 + 0.5% acetic acid): 'HNMR (400 MHz, CDCl 3 ) 5 : (major signals) 1.48 (s, 9H), 2.65 (s, 2H), 3.33 (s, 3H), 4.29 (d, 2H), 5.99 (t, IH).

A sample of the vinyl ether 1-[(3E)-2-(tert-butoxycarbonyl)-4-methoxycarbonyl)-4-methoxy-3-butenylcyclopentanecarboxylic acid was also isolated by flash chromatography (E geometry assigned from coupling constants): 'HNMR (400 MHz, CDCl 3 ) δ: 1.42 (s, 9H), 1.40-1.70 (m, 6H). 2.03 (d, 2H), 2.06 (m, IH), 2.17 (m, IH), 2.83 (s, IH), 3.49 (s, 3H), 4.66 (dd, IH), 6.35 (d, IH); <13>C NMR (100 MHz, CDCl3) 8 : 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.

d) 1- benzyl- 3- tert-butyl 2-( 2- rnetoxyethyl) malonate

Mashed suspension of sodium hydride (14.4 g, 60% dispersion in mineral oil) in

of THF (300 ml) was cooled to 0°C under a stream of nitrogen. A solution of benzyl tert-butyl malonate (90 g, 360 mmol) in THF (500 ml) was added to the slurry over a period of 45 minutes. The reaction mixture was allowed to warm to room temperature. then stir for another 1 hour. The reaction mixture was then cooled again to 0°C, and a solution of 2-bromoethyl methyl ether (50.0g, 360 mmol) in THF (100ml) was added over a period of 0.5 hours. The mixture was then allowed to warm to room temperature and stirred for an additional 19 hours. The mixture was then refluxed for 24 hours before cooling to room temperature. Deionized water (500 ml) was added to the reaction mixture and the product was extracted with ethyl acetate (3 x 500 ml). The organic fractions were combined, dried over magnesium sulfate and then concentrated by distillation under reduced pressure to give the product as a crude oil (lOOg). The product was then purified by silica gel column chromatography, eluting with 10% diethyl ether in heptane and then 20% diethyl ether in heptane to give the desired compound as an oil (37 lg, 120 mmol, 33% yield); TLC (diethylether/heptane 3:7, stained with Dragendorff's reagent) Rf 0.25; HNMR (300 MHz, CDCl 3 ) δ: 1.4 (s, 9H), 2.13(dt, 2H), 3.30 (s, 3H), 3.43 (t, 2H), 3.5l(t, 1H), 5.20 (d, 2H), 7.29-7.40 (m, 5H).

e) 2-(tert-butoxycarbonyl)-4-methoxybutyric acid

To a solution of the product from the previous step d) (37.1 g, 120 mmol) in dioxane (740 ml)

and water (111 ml) was added potassium hydroxide (6.73 g, 120 mmol) with stirring. The resulting solution was then stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure and the resulting concentrate was diluted with deionized water (300 ml), the aqueous solution was washed with diethyl ether (3 x 400 ml). To the aqueous phase was added 1M hydrochloric acid to pH 2. The acidified solution was then extracted with ethyl acetate (3 x 400 mL) and the combined organic layers were dried over magnesium sulfate.

The solvent was evaporated under reduced pressure to give the desired compound as an oil. (14.7g, 67.4 mmol, 56% yield); TLC diethyl ether / heptane 3:7, stained with Dragendorff's reagent) Rf 0.20; HNMR (300 MHz, CDCl 3 ) δ: 1.48 (s, 9H), 2.16 (dt, 2H), 3.16 (s, 3H), 3.27-3.51 8m, 3H).

f) tert-butyl 2-(2-methoxyethyl) acrylate

To a solution of the product from phase e) (20.8g, 95.3 mmol) in pyridine (170 ml), was added

piperidine (1.70 ml, 19.1 mmol), and then paraformaldehyde (3.89 g, 130 mmol). The resulting mixture was heated for 3.5 hours at 63°C. The mixture was then allowed to cool to room temperature and allowed to stir for an additional 19 hours. The solvent was evaporated by distillation under reduced pressure. Deionized water (250ml) was added to the concentrate, followed by hydrochloric acid (200ml, 2M solution). The aqueous phase was extracted with diethyl ether (1 x 350 ml, then 2 x 400 ml). The combined organic extracts were then washed with hydrochloric acid (400 ml, 2M solution) and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave the desired compound as an oil. HNMR (300 MHz, CDCl 3 ) δ: 1.50 (s, 9H), 2.56 (t, 2H), 3.35 (s, 3H), 3.46-3.53 (m, 2H), 5.54 (s, 1H), 6.13 (s, 1H); LRMS (EI): m/z 130 [M-C4H8]<+>, 113 [M-C4H90]<+.>

d) tert-butyl (2E)-2-(2-methylphenyl)-3-f(4-methylphenyl)sulforiyl-2-propenoate

In a mixed solution of para-toluenesulfonyl iodide (J. Chem. Soc. Perkin Trans. 1, 1988,

1029) (11.4g, 40.2 mmol) in dichloromethane (25.0 ml) was added to a solution of the product from phase f)

(5.0 g, 26.8 mmol) in dichloromethane (10 mL) at room temperature under a stream of nitrogen. The resulting solution was then stirred for 60 hours. The reaction mixture was cooled to 0°C and triethylamine (5.4g, 53.4 mmol) was added over a period of 15-20 minutes while maintaining the temperature at 0°C. The resulting mixture was stirred at 0°C for 0.5 hours before being warmed to room temperature and allowed to stir for another 5 hours. Deionized water (100 mL) was added to the reaction mixture and the layers were separated. The aqueous layer was extracted with dichloromethane (100 mL) and the organic extracts were combined and washed with hydrochloric acid (50 mL, IM solution). The organic layer was washed with aqueous sodium thiosulfate (100 ml, 5% v/v solution), and deionized water (100 ml) was added. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give the product as a dark oil (7.5g, 22.0 mmol, 82% yield). The reaction was repeated twice, under vacuum, and the combined crude products (74.6g) were purified by flash chromatography on silica gel, eluting with heptane/ethyl acetate (4:1), whereby the desired compound was obtained as a white crystalline substance (48.0g); d.p. (heptane/ethyl acetate) 84-86°C; TLC (ethyl acetate / heptane 1:4, illuminated UV @ 254 nm) Rf0.20: 1 HNMR (300 MHz, CDCl 3 ) δ: 1.45 (s, 9H), 2.48 (s, 3H), 3.14 (t, 2H), 3.30 (s, 3H), 3.51 (t, 2H); 7.10 (s, 1H), 7.35 (d, 2H), 7.83 (d, 2H).

h) 1 -["( 1 E)- 2- tert- butoxycarbonyl)- 4- methoxy- 1- butenyl - cyclopentane carboxylic

acid

To a stirred solution of lithium diisopropylamide (64.6 ml, 2M solution in THF/heptane/ethyl benzene) in anhydrous THF (200 ml) at 0°C was added a solution of cyclopentane carboxylic acid (7.0 ml, 58.7 mmol) in anhydrous THF (100 ml) over a period of 10 minutes under a stream of nitrogen. The mixture was then allowed to warm to room temperature with stirring for 2.5 hours. The resulting slurry was cooled to 0°C and zinc chloride (38.2 ml IM solution in diethyl ether) was added over 1 minute. The mixture was then stirred for 10 minutes and to the resulting solution was added a solution of the product from step g) (20.g, 58.7 mmol) in anhydrous THF (160 ml) over a period of 5 minutes). The reaction mixture was then stirred for 2 hours while maintaining the temperature between 0 and 5°C. The mixture was then allowed to warm to room temperature and stirred for an additional 19 hours. Isopropanol (120 ml) was then added to the mixture, and the mixture was stirred for another 1 hour. The mixture was then filtered and the solid byproducts were washed with THF (10 mL). To the filtrate was added deionized water (400 mL), aqueous sodium hydroxide solution (200 mL IM solution), and ethyl acetate (600 mL). More deionized water (600 ml) was added and the resulting solid was removed by filtration. The layers were separated and hydrochloric acid (1M solution) was added to the aqueous phase until pH 2. The aqueous layer was extracted with ethyl acetate (2 x 700 ml), the organic layers were combined, dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure to give the crude product as a yellow oil (16.7g). The product was then purified by flash chromatography on silica gel, eluting with dichloromethane/methanol (9:1) to give the desired compound as a yellow oil (15.2g, 50.9 mmol, 87% yield); TLC (dichloromethane/methanol 9:1, illuminated UV @ 254 nm) Rf 0.70: 'HNMR(300 MHz, CDCl3)5: 1.48 (s, 9H), 1.67-1.90 (m, 6H), 2.37-2.48 (m, 2H), 2.58(t, 2H), 3.32 (s, 3H), 3.48 (t, 2H); 6.83 (s, IH); LRMS (ES negative): m/z 253 [M-CO2H]-.

1) sodium 1 -[( 1 E)- 2-( tert- butoxycarbonylV4- methoxy- 1 - butenyl cyclopentane

carboxylate

To a mixed solution of the product from step h) (15.0g, 50.3 mmol) in isopropyl acetate (300 ml), sodium methoxide (3.0g, 55.6 mmol) was added. The resulting suspension was stirred for 19 hours at room temperature. The resulting solid was filtered under vacuum and washed with isopropyl acetate before drying in a vacuum oven at 50°C for 19 hours to give the title compound as a white solid (10.0 g, 31.2 mmol, 62% yield); d.p.

(isopropylacetate) 195-198°C.'HNMR (300 MHz, CDCl3)5: 1.48 (s, 9H), 1.51-1.72 (m, 6H), 2.21-2.37 (m, 2H), 2.61 (t, 2H), 3.34 (s, 3H), 3.51 (t, 2H), 6.86 (s, IH); LRMS (ES negative): m/z 253 [M-CC^Na]-.

Preparation 70

l- r( 2R)- 3- tert- butoxy- 2- methyl- 3- oxopropylcyclopentanecarboxylic acid

The title compound was obtained according to similar procedures described in Preparations 68 and 69, using methyl iodide instead of 2-bromoethylmethyl ether. Its (+) pseudoephedrine salt was recrystallized 3 times from hexane. The desired compound was obtained in 28% yield as a pale yellow oil in >95% ee, by NMR analysis of the peak at 8 1.4 of the (+) pseudoephedrine salt.; 1HNMR (CDCl 3 , 400 MHz,) δ: 1.13 (d, 3H), 1.40-1.60 (m, 11H), 1.60-1.78 (m, 5H), 2.14 (m, 3H), 2.38 (m, 1H); [α]D-24.2 (EtOH, c 1.2).

Preparation 71

l-f(2R)-2-(tert-butoxycarbonyl)-4-pentyl1cyclopentane carboxylic acid

A mixture of (R)-1-[2-(tert-butoxycarbonyl)-4-pentyl]-cyclopentane carboxylic acid (WO 9113054, Example 10) and 10% palladium on carbon (600 mg) in dry ethanol (25 ml) was hydrogenated for 18 hours at 1 atm. And room temperature. The reaction mixture was filtered through Arbocel ® and the filtrate evaporated under reduced pressure to give the desired compound as a yellow oil, 9.6g, 95%; HNMR (CDCl 3 ) δ: 0.86 (t, 3H), 1.22-1.58 )m, 15H), 1.6 (m, 4H), 1.78 (dd, 1H), 2.00-2.18 (m, 3H), 2.24 (m, 1H); [a]D= - 3.3°C (c = 0.09 ethanol).

Preparation 72

3-(4-methoxyphenyl)-2-propennitrile

A solution of 4-iodoanisole (1g, 4.2 mmol), acrylonitrile (0.3ml, 4.7 mmol), tr-o-tolylphosphine (243 mg, 0.4 mmol), palladium (II) acetate (90mg, 0.4 mmol) and triteylamine (1.78 ml, 12 mmol) in acetonitrile (20 ml) was refluxed under a stream of nitrogen for 14 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with 2M sodium bicarbonate (100 mL), the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and purified by column chromatography, eluting first with pentane, then 95:5 pentane:ethyl acetate, then 90:10 pentane:ethyl acetate, to give the desired compound (414 mg, 2.5 mmol) as a mixture of cis and trans isomers as yellow crystals, HNMR (CDCl3, 400 MHz) 5:3.8 (s, 3H), 5.7 (d, 1H), 6.9 (d, 1H), 7.2 (d, 1H), 7.4 (d, 2H); LRMS: m/z 176 (M+NH4<+>): Anal. Found C, 74.44; H, 5.66; N, 8.36. C10H39NO 0.1H2O requires C, 74.42; H, 5.65; N, 8.41%.

Preparation 73

3-(4-methoxyphenyl)-1-propanamine

A solution of the product from Preparation 72 (414 mg, 2.6 mmol) in ammonium hydroxide solution (810 ml) and ethanol (10 ml) was stirred under a stream of hydrogen at 40 p.s.i. with Ra-Ni (100 mg), 12 hours. The reaction mixture was filtered through Arbocel and washed with ethanol (20 mL), the filtrate concentrated in vacuo to give the title compound (183 mg, 1.1 mmol) as a yellow oil; HNMR (CDC13, 400 MHz) δ: 1.7 (bs, 2H), 2.0 (bs, 2H), 2.5 (t, 2H), 2.7

(bs, 2H), 3.7 (s, 3H), 6.7 (d, 2H), 7.0 (d, 2H); LRMS: m/z 376 (M+H<+>).

The following compounds of formula (Iia), e.g. compounds of the general formula II, where X is -

(CH2)3-, were obtained according to procedures similar to those described in Preparations 72 and 73 from the aforementioned precursor.

Preparation 93 3-(4-chloro-3-fluorophenyl)-2-propennitrile

Diethylcyanomethyl phosphonate (3.2ml, 18.9 mmol) was dissolved in dry THF (20ml) at 0°C under a stream of nitrogen and stirred while a 60% oil dispersion of NaH (756mg, 18.9 mmol) was added in portions over 10 minutes. The resulting gray suspension was then stirred at 0°C for 1 h before a solution of 4-chloro-3-fluoro benzaldehyde (Lancaster Synthesis) (3g, 18.9 mmol) in 5 ml of THF was added dropwise. The mixture was allowed to warm to room temperature over 60 hours. Water (5ml) was added and the mixture extracted with EtOAc (3 x 50ml), the combined organic extracts were dried (MgSC^) and evaporated to a yellow oil which was purified by column chromatography, eluting with 5% EtOAc in pentane, to give the desired product as a mixture of geometric isomers (2.4g, 70%); HNMR (400 MHz, CDCl 3 ) δ: 5.82 (d, 1H), 7.19(d, 1H), 7.23 (d, 1H), 7.30(d, 1H), 7.42 (approx. T, 1H); LRMS TS<+>199.1 (M+NH4<+>).

Preparation 94

3-(4-chloro-3-fluorophenyl)-1-propylamine

Vinyl cyanide from Preparation 93 (500mg, 2.75 mmol) was dissolved in ethanol (36ml) and 0.88 NH3 solution (18ml) and shaken with 150 mf of 30% w/v RaNi, under a pressure of H2 from 15

dogs, overnight. The catalyst was filtered through a layer of Arbocell and the filtrate evaporated in vacuo and then purified by column chromatography, eluting with 90:10:1 (DCM, MeOH, NH3) to give the desired product (320mg, 62%); HNMR (400 MHz, CDCl 3 ) δ: 1.65-1.78 (m, 2H), 2.53-2.70 (m, 4H), 6.85 (d, 1H), 6.90 (d, 1H), 7.22 (s, 1H); LRMS: m/z (TS<+>) 188 (M+H).

The following compounds of the formula (IIIa), for example, compounds of the general formula III where X, -

(CH_2)3-, were prepared by procedures similar to those described for Preparations 93 and 94 from the labeled precursor.

Preparation 102 Quinoline-6-carobosaldehyde

6-Methyl-quinoline (Aldrich Chemical Co) (1g, 7.0 mmol) and selenium dioxide (2.32g, 21.0 mmol) were combined without solvent and heated at 100°C under nitrogen stream for 16 h. The reaction mixture was allowed to cool to room temperature, dissolved in MeOH

and applied to silica gel. It was chromatographed eluting with 3:1 pentane:EtOAc to give the desired product (236mg, 21%), 'HNMR (CDCl 3 , 400 MHz) δ : (400 MHz, CDCl 3 ) δ : 7.46-7.52 (m, 2H), 7.98 (d, 1H), 8.33-8.37 (m, 2H), 9.03 (d, 1H), 10.18 (s, 1H), m/z (ES+) 315 (2MH+).

Preparation 103

4-(4-methoxyphenyl)-butyramide

4-(4-Methoxyphenyl)-butyric acid (Aldrich Chemical Co.) (2g, 10.4 mmol) was dissolved in 50 ml of DCM, then thionyl chloride (1.85g, 15.5 mmol) was added dropwise with stirring. After the addition was complete, the mixture was refluxed for 4 hours. The solvent was removed in vacuo, solvent was added again, evaporated again and this addition/evaporation cycle was repeated until thionyl chloride was removed from the mixture. This mixture was dissolved in 20 ml of DCM and a solution of O.88NH3 at 0°C was added dropwise with stirring. AFTER the addition was complete, the mixture was stirred for 4 hours, the organic layer separated, dried (Na 2 SO 4 ) and evaporated to give the title compound as a solid amide (1.5 g), which was used further without purification. Preparation 104 4-(4-hydroxyphenyl)-butyramine

The product from Preparation 103 (38g, 0.20 mol) was added in portions to the mixed LiAlFL solution; (15g, 0.40 mol) in 1L of THF and the mixture was refluxed for 16h. Excess hydrate was removed by addition of EtOAc (400 mL) and most of the solvent was evaporated under reduced pressure. 30 ml of 2N NaOH solution was added (CAUTION!) which completed the decomposition of the hydride, so the resulting solution was acidified by adding IN HC1 and dissolved by extraction in water (2 x 200ml). Addition of 2N NaOH to the aqueous extracts increased the basicity, extracted with EtOAc, dried (MgSO4) and evaporated to give the crude amine as a yellow oil. This oil was refluxed in 160 ml of aqueous HBr for 4 hours, then 100 ml of water was added. Doadt is solid Na2C03 up to pH 9-10. The mixture was extracted with DCM (3 x 100 mL), dried (MgSO 4 ) and evaporated to a white solid which was recrystallized from benzene to give the desired product (6.4 g, 35%); d.p. 114-116°C.

Preparation 105

Tert-butyl-4-(4-hydroxyphenyl)butylcarbamate

Di-tert-butyl dicarbonate (1.06g, 4.8 mmol) was added all at once to a stirred solution of the product from Preparation 104 (400 mg, 2.4 mmol) in a mixture of water (10 ml) and dioxane (10 ml) under a stream of nitrogen. The mixture was stirred for 72 hours, after which potassium carbonate was suddenly added

(2.0g, 14.4 mmol) and the mixture was stirred for another 23 hours, until the esters formed during the reaction were completely hydrolyzed. The mixture was transferred to a separatory funnel and the organic layer was separated, dried with MgSO 4 and evaporated to a yellow oil. The oil was chromatographed, the mixture was used as an eluent

pentane : EtOAc, rpi to give the title compound (555 mg, 86%); 1H NMR (400 MHz, CDCl 3 ) δ : 1.41-1.62 (m, 13H), 2.53(t, 2H), 3.12 (m, 2H), 4.48 (1H, brs), 4.80 (s, 1H), 6.74 )d, 2H), 7.01 (d, 2H).

Preparation 106

Tert-butyl-(4-4-methoxyphenyl)butylcarbamate

A 60% dispersion of NaH in mineral oil (88 mg, 2.2 mmol) was added to a stirred solution of the product from Preparation 105 (555 mg, 2.1 mmol) in THF (7 mL) at room temperature under a stream of nitrogen. The mixture was stirred for 15 minutes, before adding Mel (0.14 ml, 2.2 mmol) all at once and stirring at room temperature for another 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with 3% NaHCO 3 (15 mL). The organic layer was dried over MgSO 4 and purified by chromatography, eluting with DCM to give the title compound (500 mg, 85%); *H NMR (400 MHz, CDCl 3 ) δ: 1.40-1.63 (m, 13H), 2.57 (t, 2H), 3.13 (m, 2H), 3.78 (s, 3H), 4.46 (1H, brs), 6.82 (d, 2H), 7.06 (d, 2H).

Preparatory 107

4-(4-methoxyphenyl)butylamine

The product from Preparation 106 (500 mg, 1.8 mmol) was dissolved in 3 ml of DCM and 3 ml of TFA and stirred under a stream of nitrogen for 16 h. To the mixture was then added 50ml of 10% aqueous Na 2 CO 3 and the organic layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried (MgSO 4 ) and evaporated to give the desired product (300 mg, 94%) which was used without further purification.

Preparation 108

3-(2-pyridinesD-1-propanamine).

2-Vinyl pyridine (105 g) and acetic anhydride (204 g) were combined at room temperature and a solution of KCN (130 g) in 250 ml of water was added dropwise with stirring. The addition rate was adjusted to maintain a gentle reflux. After the addition was complete, the mixture was refluxed for 22h and the pH of the solution was adjusted to 8 by adding Na2CC>3 solution. The mixture was extracted with DCM (600 mL), the extracts dried over MgSCU, then evaporated to a brown oil. The oil was vacuum distilled at a pressure of approximately 0.6 mmHg. The product was predistilled at 100-107°C as a clear oil in a yield of 56%. 2-(2-Cyanoethyl)-pyridine oil (200 mg, 1.5 mmol) was dissolved in 6 ml of EtOH and treated with 2 ml of a solution of 0.88 NH3 and 50 mg of RaNi. The mixture was hydrogenated for 16 h at 30 psi of hydrogen pressure and then evaporated to obtain the desired product (about 200 mg) which was used without further purification.

Preparation 109

2-acetyl-2H-indazole

Indazole (3.5g, 29.6 mmol) and acetic anhydride (35 ml) and heated to 60°C under nitrogen stream, 3h. The excess acetic anhydride was evaporated and the remaining oily residue was partitioned between 3% aqueous NaHCO 3 (20 mL) and EtOAc (30 mL). The organic layer was separated, dried (MgSO-Oi evaporated to give the desired product (4.5g, 96%);

1H NMR (400 MHz, CDCl 3 ) δ: 2.80(s, 3H), 7.37 (t, 1H), 7.58 (t, 1H), 7.75 (d, 1H), 8.46 (d, 1H).

Preparation 110

5-bromo-2H-indazole and 5-bromo-1H-indazole

The mixture of isomers from pPreparation 109 (450 mg, 2.8 mmol) was dissolved in acetic acid (0.5 ml) and stirred at room temperature under a stream of nitrogen. Bromine (0.5 ml) was added during 1 minute, and the mixture was stirred for another 16 h. Excess bromine was removed by blowing nitrogen through the solution for 30 minutes, forming a thick mixture. 5 ml of toluene was added and everything was evaporated in vacuo and the residue was treated with pentane (5 ml). The remaining solid was filtered off and dried in vacuo before 6ml each of 1M NaOH and EtOH were added. The mixture was heated for 1h at 50°C and then allowed to cool to room temperature. EtOH was evaporated and the residue extracted with DCM (2x10ml), which was then dried (MgSO4) and evaporated to give 400 mg of an inseparable 3:1 mixture of the desired 1-H:2-H isomers of indazole; <*>H NMR (400 MHz, CDCl3) δ: 7.41 (d, IH), 7.49 (d, IH), 7.92 (s, IH), 8.02 (s, IH).

Preparation 111

2- methyl- 5- bromo- 2H- indazole and 1- methyl- 5- bromo- 1H- indazole

A mixture of isomers from Preparation 110 (400 mg, 2.0 mmol) was dissolved in MeOH (8 mL) at room temperature under a stream of nitrogen and NaOMe (223 ng, 4.0 mmol) was added at once. Mel (0.32ml, 5mmol) was added dropwise and the mixture was heated under reflux for 4h. The mixture was allowed to cool to room temperature and then concentrated to a small volume (ca. 3ml) before the addition of EtOAc (20ml) and 3% NaHCOs solution. the organic layer was separated, dried (MgSO 4 ) and purified by chromatography, eluting with 99:1 DCM:MeOH to give the 1-Me isomer (100mg, 23%) and the 2Me isomer i (112mg, 26%); 1-Methyl isomer; *H NMR (400 MHz, CDCl 3 ) δ: 4.08 (s, 3H), 7.30-7.50 (m, 2H), 7.82 (s, 1H), 7.92 (s, 1H); 2-Methyl isomer; *H NMR (400 MHz, CDCl 3 ) δ: 4.13 (s, 3H), 7.35 (d, 1H), 7.59 (d, 1H), 7.81 (s, 1H), 7.85 (s, 1H).

Preparation 112

3-(2-methyl-1H-indazol-5-yl)-2-propennitrile

The 1-methyl isomer from Preparation 111 (100 mg, 0.47 mmol) was dissolved in dioxane (6 ml) and potassium carbonate (72 mg, 0.52 mmol), acetonitrile (0.035 ml, 0.052 mmol), Pd2(dba)3 (43 mg, 0.047 mmol) and PtercBu3 (0.038 ml, 0.16) were added in order. mmol). The mixture was then refluxed for 3 h under a stream of nitrogen before cooling to room temperature, filtering through a pad of Arbocei and evaporating the filtrate in vacuo. The residue was chromatographed, eluting with 99:1 DSM:MeOH to give the title compound (57mg, 66%) as a mixture of cis and trans geometric isomers; <*>H NMR (300 MHz, CDCl3) 6: 4.11 (s, 3H), 5.40 and 5.84 (d, IH), 7.37-8.18 (m, 5H).

Preparation 113

3-O-methyl-1H-indazol-5-yl)-1-propanamine

The product from Preparation 112 (55 mg, 0.29 mmol) was dissolved in ethanol (84 ml) and a solution of 0.88 NH3 (1 ml) and subjected to hydrogenation for 2 h at 30 psi and room temperature with the addition of 10 mg of 30% RaNi. The mixture was filtered through a pad of Arbocel and the filtrate evaporated to give the desired product which was used without further purification.

Preparation 114

2-(4-bromophenyl)-pyridine

"BuLi (1.6M in hexane, 34.4 ml, 55 mmol) was added dropwise to a stirred solution of 1,4-dibromobenzene (11.8 g, 50 mmol) in 100 ml of dry THF at -60°C. The mixture was stirred for 15 minutes at this temperature before a solution of ZnCl2 (0.5M in THF, 100 ml, 50 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 90 minutes, and then 2-bromopyridine (4.8 ml, 50 mmol) was added. The mixture was then evaporated to a volume of 10 ml with EtOAc (400 ml). water and salt solution (200 ml), dried (MgSO 4 ) and evaporated to a yellow/green solid residue. This residue was purified by chromatography eluting with 1:1 hexane : DCM to give the desired product (8.3g, 71%) m/z MH+ 234 (TS<+>); Found C 56.61%, H 3.37%, N 5.90%; calc. C 56.44%, H 3.44%; N 5.98%.

Preparation 115

3-(2,3-dihydro-1H-inden-5-yl)-propionic acid

3-(2,3-dihydro-1H-inden-5-yl)-acrylic acid (500 mg, 2.66 mmol) (obtained from Aldrich) was dissolved in ethanol (40 mL) and hydrogenated at 15 psi H 2 pressure with 40 mg 10% Pd/C, 4 hours. The mixture was filtered through a layer of Arbocel into the uaprene filtrate, obtaining the desired product (560 mg, approx. quantity), which was used without additional purification; 1H NMR (400 MHz, CDCl 3 ) δ: 1.98-2.07 (m, 2H), 2.75 (t, 2H), 2.80-2.90 (m, 6H), 6.95 (d, 1H), 7.03 (s, 1H), 7.08 (d, 1H); LRMS: m/z ES-189 (M-H).

Preparation 116

3-(2,3-dihydro-1H-inden-5-yl)-propanamide

The product from Preparation 115 (190 mg, 1 mmol) was dissolved in DCM (2 ml) at room temperature under a stream of nitrogen, then 132(4.1 (1.5 mmol) of oxalyl chloride was first added, then

then 1 drop of DMF. After foaming stopped, the mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was redissolved in 2 ml of THF and 0.6 ml of 0.88 NH3 solution was added and the mixture was stirred for 4 days. The mixture was added water and extracted with EtOAc (2x10 mL). The combined organic extracts were dried (MgSO 4 ) and evaporated to give the desired product (190mg, 99%>); 1H NMR (400 MHz, CDCl3) δ: 1.96-2.05 (m, 2H), 2.49 (t, 2H), 2.81-2.92 (m, 6H), 5.32 (brs, 2H), 6.93 (d, 1H), 7.05 (s, 1H), 7.08 (d, 1H); LRMS: m/z (ES-1) 189 (M-H).

Preparation 117

3-(2,3-dihydro-1H-inden-5-yl)-propylamine

The amide from Preparation 116 (170 mg, 0.9 mmol) was dissolved in dry THF (3 ml) at 0°C under a stream of nitrogen and stirred while a solution of LiAlH4 in THF (IM; 0.9 ml, 0.9 mmol) was added dropwise with vigorous gas evolution. The mixture was heated to 60°C and stirred at this temperature overnight. To the mixture was added water (1 ml), then 1N NaOH solution (1 ml), the solvent was extracted with EtOAc (2 x 50 ml), dried (MgSO 4 ), filtered and concentrated to a pale yellow oil. The oil was purified by chromatography, eluted 90:10 (DCM, MeOHmNH3), whereby the desired product was obtained (30 mg, 35%); 1H NMR (400 MHz, CDCl 3 ) δ: 1.72-1.77 (m, 2H), 1.96-2.03 (m, 4H), 2.57 (t, 2H), 2.70 (t, 2H), 2.80-2.85 (m, 4H), 6.90 (d, IH), 7.02 (s, IH), 7.09 (d, IH); LRMS: m/z (TS<+>) 176 (M+H).

Preparation 118

3-(4-bromophenyl)-2-propennitrile

A 60% suspension of NaH in mineral oil (2.16g, 54.1 mmol) was suspended in THF (50 ml) and cooled to 0°C. Diethyl cyanomethyl phosphonate (8.74 mL, 54.1 mmol) was added dropwise and the mixture was stirred at 0°C for 30 minutes. Then, 4-bromobenzaldehyde (10g, 54.1 mmol) was added dropwise as a solution in 20 ml of THF, which was then allowed to warm to room temperature overnight. Water was added to the mixture, extracted with EtOAc (3x50 mL), dried (MgSO 4 ) and then filtered and evaporated to a yellow oil. This oil was dissolved in 9:1 pentane:EtOAc from which the product was crystallized (5.8g, 52%); %);

1 H NMR (400 MHz, CDCl 3 ) δ: 5.82 (d, 1H), 7.21-7.28 (m, 3H), 7.50 (d, 2H).

Preparation 119

3-(4-bromophenyl)-1-propanamine

The desired compound was obtained by a modified procedure described by Iddon et al. (J.C.S. Perkin I, 1977, 2357). Solid LiAlH4 (1.2g, 31.6 mmol) was suspended in diethyl ether (35ml) and stirred under a stream of nitrogen while the suspension was heated to about 50°C. A solution of vinyl cyanide from Preparation 118 (2.06g, 9.88mmol) was added dropwise as a solution in ether (20ml) and the mixture was then heated for 90 minutes. After this, heating was stopped and the mixture was stirred at room temperature for 16 hours. Water was added, followed by 1N NaOH (30 mL) and EtOAc (60 mL) and the mixture was stirred vigorously for 30 min. The organic layer was separated, dried (MgSO4) and evaporated to a yellow oil which was purified by column chromatography, eluting with 90:10:1 (DCm:MeOH:NH3) to give the desired product (740 mg, 35%); %); 1 H NMR (400 MHz, CDCl 3 ) δ: 1.65-1.74 (m, 2H), 2.52 )t, 2H), 2.66 (t, 2H), 7.02 (d, 2H), 7.35 (d, 2H); LRMS: m/z (TS<+>) 214 (M+H).

Preparation 120

1-(2-chlorophenoxy)-2-propanamine

The product from Preparation 121 (1 lg, 55.2 mmol) in diethyl ether (41 ml) was added dropwise to a suspension of lithium aluminum hydride (4.1 g, 108 mmol) in diethyl ether (110 ml) under a stream of nitrogen. The reaction mixture was refluxed for 4 hours before ethyl acetate was added followed by water. The aqueous layer was acidified by the addition of 4N hydrochloric acid, shaken and then separated before its basicity was increased by the addition of 40% sodium hydroxide solution. The aqueous layer was extracted with diethyl ether (3 x 100ml) and the combined organic extracts were dried over magnesium sulfate. The diethyl ether extracts were acidified with hydrogen chloride and the resulting precipitate was filtered. The solid residue was recrystallized from ethanol/petroleum ether (m.p. 60-80°C) to give the desired product (2.5g, 20%); d.p. 126-127°C; %); 1H NMR (CDCl 3 , 400 MHz) δ: 1.55 (d, 3H), 3.80 (q, 1H), 4.20 (d, 2H), 6.90-700 (m, 2H), 7.15 (t, 1H), 7.30 (d, 1H), 8.60 (bs, 3H); Anal. Found C, 48.9%, II, 6.0; N, 6.5. C9H13NOCl2 requires C, 48.7; H, 5.9; N, 6.3%.

Preparatory 121

1 -( 2- chlorophenoxy)- 2- propanone oxime

1-(2-Chlorophenoxy)acetone (106.6 g, 0.58 mol) (J.Am.Soc. 75, 1953, 1134) was added to a solution of hydroxylamine hydrochloride (28.7g, 4mol) in 2N sodium hydroxide solution (420 ml) and enough ethanol to give a clear solution. The reaction mixture was stirred for 30 min, then concentrated in vacuo, the crude residue was extracted with diethyl ether (3 x 200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was distilled to give the desired product (134-136°C/1.35mmHg) (4.5g, 3.9%),; %,); 1 H NMR (CDCl 3 , 400 MHz) δ: 2.05 (s, 3H), 5.00 (s, 2H); 6.90-7.00 (m, 2H), 7.10 (t, IH), 7.30 (d, IH); 7.60 (s, IH); Anal. Found C, 54.95; H, 5.05 C9H10NO2CI requires C, 54.15; H, 5.05%.

Preparation 122

3-(4-methoxy-3-chlorophenyl)-1-propylamine

4-Methoxy-benzaldehyde (Aldrich) (42g, 0.31 mol) and pyridine (0.6ml, catalyst) were mixed together under a stream of nitrogen and sulfonyl chloride (51g, 0.37mol) was added over 30 minutes, maintaining the internal temperature of the reaction mixture between 25 and 30°C. A strong release of gas occurs. The mixture was stirred at room temperature for the next 30 minutes and then heated to 70°C for 4 hours. Excess agnas was removed by vacuum evaporation and

the residue was dissolved in 50 ml of di-isopropyl ether and added to 500 ml of hexane with vigorous stirring, whereupon the product precipitated. The solid residue was filtered and washed with hexane, then dried in vacuo to give the desired product (40.3g, 77%), m.p. 55-56°C; %); 1H NMR (400 MHz, CDCl 3 ) δ: 3.99 (s, 3H), 7.05 (dd, 1H), 7.91 (d, 1H), 9.86 (s, 1H); Anal. Found: C, 56.13; H, 4.14%. C8H7C102 requires C, 56.33; H, 4.47%.

Preparation 123

3-(4-methoxy-3-chlorophenyl)-1-propylamine

The product from Preparation 122 was converted into a diastereoisomeric mixture of the corresponding vinyl nitriles according to Preparation 93. The mixture (300mg, 1.55 mmol) was dissolved in DCM (6ml) at room temperature under a stream of nitrogen and tetra-nbutyl-ammonium borohydride (1.6g, 6.2mmol) was added in portions over 5 minutes. The mixture was refluxed for 4 hours and then evaporated to dryness. The residue was dissolved in about 6 ml of 10% HCl (aq.) and then refluxed for another 1 hour. The reaction mixture was cooled, extracted with EtOAc (3 x 30 mL), dried (MgSO 4 ) and evaporated to a yellow oil. This oil was passed through a column eluting with 95/5/0.5. then 95/5/1 DCM/MeoH/NH3 to give the desired product (75mg, 24%), %);<*>H NMR (400 MHz, CDCl3) δ: 1.60-1.74 (m, 2H), 2.56 (t, 2H), 2.67 (t, 2H), 3.82 (s, 3H), 6.79 (d, IH), 6.98 (d, IH), 7.15 (s, IH).

Preparation 124

Chrome

4-chromanol (Aldrich) (2.77g, 18.4 mmol9 was dissolved in acetic anhydride (3.5ml, 36.9 mmol) and acetic acid 30ml) and refluxed for 3h, then allowed to cool to room temperature for 16h. Then 10% w/w Pd/C was added to the solution and the mixture was hydrogenated at a hydrogen pressure of 40 p.s.i. for 16 hours. The catalyst was filtered through a layer of Arbocel and the filtrate was evaporated to a volume of 5 ml. The remaining liquid was dissolved in EtOAc (30 ml) and washed with water, then with NaHCO 3 solution (100 ml each). The organic layer was dried over MgSO 4 and evaporated to a light yellow oil. This oil was passed through a column eluting with 10% EtOAc/pentane to give the desired product (2.1g, 85%); %); 1 H NMR (400 MHz, CDCl 3 ) δ: 1.93-2.04 (m 2H), 2.79 (t, 2H), 4.18 (t, 2H), 6.78-6.83 (m, 2H), 7.00-7.10 (m, 2H).

Preparation 125

6-bromochroman

The product from preparation 124 (1g, 7.5 mmol) was dissolved in DCM (10 mL) and bromine (403 µl, 7.8 mmol) was added as a solution in DCM (3 mL) over several minutes. At the end of the addition, the brown color of the solution prevails. The mixture was stirred at room temperature for 3 hours, then washed with water (20 ml) and brine (20 ml) and the organic layer was separated, dried (MgSO 4 ) and evaporated to a thick yellow oil, which was purified by column chromatography, eluted with 5% EtOAc in pentane, to give the desired product (1.3 g, 82%); <]>H NMR (400 MHz, CDCl 3 ) 5: 1.90-1.98 (m, 2H), 2.73 8t, 2H), 4.14 (t, 2H), 6.61 (d, 1H), 7.08-7.15 (m, 2H).

Preparation 126

5- bromo- 2, 2- dimethyl- 2, 3- dihydrobenzo[ b1furan

2,2-dimethyl-2,3-dihydrobenzo[b]furan (prepared according to the method described by Baker Shulgin, J.Org. Chem., 28, 1963, 2468) (500mg, 3.38 mmol) was dissolved in dichloroethane (5.5 ml) and stirred at room temperature under a stream of nitrogen, bromosuccinimide (661mg, 3.72 mmol) was added at once. The mixture was then refluxed for 2 h, ether (10 ml) was added and the white precipitate of succinimide was filtered off. The filtrate was evaporated to dryness and then purified by column chromatography, eluting with 5% ether in pentane, to give the desired product (604mg, 79%); 1H NMR (400 MHz, CDCl 3 ) δ: 1.43 (s, 6H), 2.92 (s, 2H), 6.54 (d, 1H), 7.16 (d, 1H), 7.19 (s, 1H); LRMS: M+H, 227 (TS<+>).

Preparation 127

5-bromo-2-methyl-2,3-dihydro-1-benzolfuran

The desired product was prepared from _2-methyl-2,3-dihydro-1-benzo[b]furan (commercially available from TCI, Japan) according to the same procedure described for Preparation 126 (87%); HNMR(400 MHz, CDCl 3 ) δ: 1.43(d, 3H), 2.80 (dd, IH), 3.29 (dd, IH), 4.94 (m, IH), 6.61 (d, IH), 7.18 (d, IH), 7.22 (s, 2H).

Preparation 128

2, 3- dihydrobenzolfuran- 7- carboxaldehyde

2,3-Dihydrobenzo[b]furan (Maybridge Chemicals) (25g, 0.21 mol) was dissolved in DCM (500 ml) and stirred under a stream of nitrogen at 0°C. SnClt (36.5 ml, 0.3 mol) was added at once, leaving a yellow solution. Dichloromethyl methyl ether (18.8 ml, 0.21 mol) was then added, and the solution was stirred for 30 minutes, after which the ice bath was removed and the mixture was poured into ice-cold water (1000 ml). The organic layer was separated, washed with water (2x100 ml), 2N HCl (100ml) and salt solution (50ml), and charcoal (30g) and Na2SO4 were added to the solution. filtration through Celite and evaporation gave a black oil, which was subjected to flash chromatography, eluted with 7-10% EtOAc in pentane, to give the desired product (190mg, 0.01%); *H NMR (400 MHz, CDCl 3 ) δ: 3.24 (t, 2H), 4.75 (t, 2H), 6.93 (t, 1H), 7.40 (d, 1H), 7.59 (d, 1H), 10.2 (s, 1H); LRMS: M+H, 227 TS<+>. Anal. Found: C, 72.98; H, 5.46%. C 9 H 8 O 2 requires C, 72.96; H, 5.44%.

Preparation 129

1 - benzophyran-3 - ylacetonitrile

Sodium hydride (268mg, 6.7 mmol) was dissolved in dry THF (10ml) at 0°C under a stream of nitrogen and diethyl cyanomethyl phosphonate (1.1ml, 6.7mmol) was added dropwise and the mixture was stirred for 45 minutes. 3-Coumaranone (Lancaster) (900 mg, 6.7 mmol) was added dropwise and the mixture was stirred at room temperature for 45 minutes. The mixture was diluted with EtOAc (15ml) and water (15ml) and the organic layer was then separated, dried (MgSC^) and evaporated and subjected to flash chromatography, eluting with 0-5% EtOAc in pentane, to give the title compound (940mg, 91%);<*>HNMR (400 MHz, CDCl3) 5: 3.77 (s, 2H), 7.25-7.40 (m, 2H), 7.52 (dd, IH), 7.58 (dd, IH), 7.67 (s, IH); LRMS: M+H, 175 (TS<+>).

Preparation 130

2-(1-benzofuran-3-yl)-ethylamine

The product from Preparation 129 (400 mg, 2.55 mmol) was combined with ammonium hydroxide solution (10 ml), ethanol (20 ml) and 30% wt.%> Ra -Ni (120mg, cat) and hydrogenated at a hydrogen pressure of 30 p.s.i., 16 hours. The catalyst was filtered through a pad of Arbocel and the yellow-brown filtrate was chromatographed eluting with 0-5%> MeOH in DCM to give the desired product (380mg, 93%); <!>H NMR (400 MHz, CDCl 3 ) δ: 1.20 (brs, 2H), 2.80 (t, 2H), 3.02 (t, 2H), 7.15-7.25 (m, 2H), 7.53 (dd, 2H), 7.55 (dd, 1H), LRMS: M+H, 162 (ES<+>).

Preparation 131

2-(2,3-dihydro-1-benzofuran-3-yl)-ethylamine

The product from Preparation 130 (200 mg, 1.24 mmol) was mixed with ethanol (20 ml) and 20 mg of 10% wt. Pd/C and hydrogenated at 40 p.s.i. of hydrogen for 48 hours. Another 20 mg of catalyst was added and the mixture was hydrogenated at 60 p.si. of hydrogen. and 40°C for another 72 hours. The catalyst was filtered through a pad of Arbocel and the filtrate evaporated to dryness. The residue was purified by column chromatography, eluting with 90/10/1 DCM/MeOH/NH3, to give the desired product (1 mg, 55%); 1H NMR (400 MHz, CDCl 3 ) δ: 1.8 l(m, IH), 1.98(m, lh), 2.75-2.83 (m, 2H), 3.50 (m, IH), 4.22 (t, IH), 4.60 (t, IH), 6.72 (d, IH), 6.85 (t, IH), 7.20 (d, IH); LRMS: M+H, 164. (ES<+>).

Preparation 132

(2E and 2Z)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-butenitrile

To a stirred suspension of sodium hydride (247mg, 6.16 mmol) in dry THF (6ml) at 0°C under a stream of nitrogen, a solution of diethylcyanomethyl phosphonate (0.98ml, 6.16 mmol) in 2ml THF was added and the mixture was stirred for 1 h at 0°C. 5-Acetyl-2,3-dihydro[b]benzofuran (Aldrich) (1g, 6.16 mmol) in THF (2ml) was added dropwise and the mixture was stirred for 16h at room temperature. Water (20ml) and EtOAc (20ml) were added, the organic layer was separated and the aqueous extracted with EtOAc (2x20ml). The combined organic extracts were dried over MgSO 4 , filtered and evaporated to give a brown oil which solidified on standing. The solid residue was purified by column chromatography, eluting with 20-30% EtOAc in pentane, to give the desired product (789mg, 69%); 1H NMR (400 MHz, CDCl 3 ) δ: 2.4 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 5.5 (s, 1H), 6.7 (d, 1H), 7.2 (d, 1H), 7.3 (s, 1H); LRMS : M+NH4203 (ES<+>).

Preparation 133

3-(2,3-dihydro-1-benzofuran-5-yl)-butylamine

The product from Preparation 132 was dissolved in ethanol (20 ml) and ammonium hydroxide solution (5 ml) and the mixture was hydrogenated for 16 h, at a hydrogen pressure of 30 p.s.i. with 200 mg 30% wt. Ra-Ni. Another 100 mg of catalyst was added and hydrogenation continued for another 16 hours. The reaction mixture was filtered through a pad of Arbocel and the filtrate evaporated in vacuo to a small volume. The residue was then co-evaporated from toluene (2x20ml) to remove traces of water to give the desired product (780mg, 96%>), which was used further without purification; 1H NMR (400 MHz, CDCl 3 ) δ: 1.2 (d, 3H), 1.7 (q, 2H), 2.5 (m, 2H), 2.65 (m, 1H), 3.1 (t, 2H), 4.45 8t, 2H), 6.6 (d, 1H), 7.0 (s, 1H); LRMS : M+H 192 (ES<+>).

Preparation 134

7- methyl- 2. 3- dihydro- l- benzofuran- 3- yl

To a stirred suspension of trimeryl sulfonium chloride (3.78g, 0.03 mol) in dry THF (60 mL), sodium hydride (1.16g, 0.03 mol) was added and the mixture was heated at reflux for 1 hour. 2-Hydroxy-3-methyl-benzaldehyde (Lancaster) (4g, 0.03 mol) in 30 ml of THF was added via syringe and the resulting orange suspension was stirred at reflux for 5 hours. Water (50 ml) was added and the organic portion was extracted with ether (3 x 50 ml). The combined organic extracts were dried (MgSO 4 ), filtered and evaporated in vacuo to an orange oil which was purified by column chromatography, eluting with 15-25%) EtOAc in pentane, to give the desired product (2g, 45%); 1H NMR (400 MHz, CDCl 3 ) δ: 2.2 (s, 3H), 4.45 (m, 2H), 5.3 (m, 1H), 6.8 (t, 1H), 7.1 (d, 1H), 7.2 (d, 1H); LRMS : M+H 151 (ES<+>).

Preparation 135

7- methyl- 2, 3- dihydro- l - benzofuran

Acetic anhydride (0.63 ml, 6.7 mmol) was added to a mixed solution of the product from Preparation 134 (500 mg, 3.3 mmol) in citric acid (5 ml) and the mixture was stirred under reflux in a stream of nitrogen for 2 h, and then left for more than 16 h to warm to room temperature. 10% by weight was added directly to the solution. Pd/C (30 mg) and hydrogenated at a hydrogen pressure of 40 p.s.i. for 16 h at room temperature. The catalyst was filtered through a pad of Arbocel and concentrated in vacuo to a pale yellow residue which was dissolved in EtOAc (20 ml), washed with water (3x20 ml), NaHCO 3 (20 ml), dried (MgSO 4 ) and evaporated to a pale yellow oil. The oil was purified by column chromatography, eluting with 3% EtOAc in pentane, to give the desired product (261 mg, 58%); 1 H NMR (400 MHz, CDCl 3 ) δ: 2.25 (s, 3H), 3.2 (t, 2H), 4.55 (t, 2H), 6.75 (t 1H), 6.9 (d, 1H), 7.05 (d, 1H).

Preparation 136

5- bromo- 7- methyl- 2, 3- dihydro- l - benzofuran

N-bromoscinimide (318mg, 1.79 mmol) was added to a mixed solution of the product from Preparation 135 (200mg, 1.49 mmol) in dichloroethane (2.5ml) and the mixture was stirred under reflux for 16 hours under a stream of nitrogen. The mixture was concentrated in vacuo to give a pale orange-brown solid, which was purified by column chromatography, eluting with 1% EtOAc in pentane, to give the desired product (112mg, 35%); HNMR (400 MHz, CDCl 3 ) δ: 2.1 (s, 3H), 3.15 (t, 2H), 4.5 (t, 2H), 7.0 (s, 1H), 7.1 (s, 1H).

Preparation 137

2- hydroxy- 4- methyl- benzaldehyde

SnCU (241 mg, 0.92 mmol) in tri-<n>butylamine (0.6 ml, 2.77 mmol) was added to a mixed solution of 3-methyl-phenol (1g, 9.2 mmol) in toluene (5 ml) at room temperature under a stream of nitrogen. After 20 minutes, paraformaldehyde (61 mg, 20.3 mmol) was added and the mixture was stirred at 100°C for 16 hours. The mixture was diluted with water (20ml), and acidified with 2N HCl to pH 2. The solution was extracted with ether (25ml), washed with brine (20ml), dried (MgSO4), filtered and evaporated to a brown oil. The oil was purified by column chromatography eluting with 5% EtOAc in pentane to give the desired product (319mg, 25%);<*>H NMR (400 MHz, CDCl3) δ: 2.3 (s, 3H), 6.75 (m, 2H), 7.35 (d, IH), 9.75 (s, IH), 11.00 (s, IH).

Preparation 138

5- bromo- 6- methyl- 2, 3- dihydrobenzofuran

The product from Preparation 137 was used to obtain the desired product in the same manner as described for Preparations 134-136; <*>H NMR (400 MHz, CDCl 3 ) δ: 2.3 (s, 3H), 3.55 (t, 2H), 4.5 (t, 2H), 6.7 (s, IH), 7.3 (s, IH); LRMS : M+H 214 (ES<+>).

Preparation 139

(3E)-4-(2,3-dihydro-1-benzofuran-5-yl)-3-buten-2-one

2,3-Dihydrobenzo[b]furan-5-carboxaldehyde (Aldrich Chemicals) (2g, 13.5 mmol), acetone (2.73 ml, 37.1 mmol), water (1.35 ml) and 10% NaOH (aq) (0.34 ml) were mixed and the mixture was stirred for 16 h at room temperature. The yellow solid was redissolved in ca. 15ml of DCM and 2N HCl was added to pH 2. Water (10ml) was added and the organic layer was extracted with DCM (2 x 20ml). The aqueous layer was separated and re-extracted with DCM (2 x 15ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to a yellow solid which was then purified by column chromatography, eluting with 15-30% EtOAc in pentane, to give the desired product (2.13g, 84%); 1H NMR (400 MHz, CDCl 3 ) δ: 2.3 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.45 (d, 1H); LRMS : M+H 189 (ES<+>).

Preparation 140

4-(2,3-dihydro-1-benzofuran-5-yl)-2-butanone

The product from preparation 139 (2.12 g, 11.3 mmol) was dissolved in ethanol (40 ml) and hydrogenated for 4 hours at 15 p.s.i. of hydrogen. and with 200 mg 10% wt. Pd/C. The mixture was filtered through a pad of Arbocel and the filtrate evaporated in vacuo to a colorless oil which was purified by column chromatography, eluting with 15-25% EtOAc in pentane, to give the desired product (1.53g, 71%); 1H NMR (400 MHz, CDCl 3 ) 5:2.1 (s, 3H), 2.7 (t, 2H), 2.8 (t, 2H), 3.1 (t, 2H), 4.5 (t, 2H), 6.65 (d, 1H), 6.9 (d, 1H), 7.0 (s, 1H); LRMS: M+NH42O8. (ES<+>).

Preparation 141

4-(2,3-dihydro-1-benzofuran-5-yl)-2-butanamine

Ammonium acetate (4.05g, 52.6 mmol) and sodium cyanoborohydride (661 mg, 10.5 mmol) were added to a mixed solution of the product from Preparation 140 (500mg, 2.6 mmol) in methanol (25ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (20ml) and water (20ml). the organic portion was extracted and washed with water (2 x 20ml), dried (MgSO4) and evaporated to a clear oil. This oil was purified by column chromatography eluting with 5% MeOH in DCM to give the title compound (187mg, 37%); 1H NMR (400 MHz, CDCl 3 ) δ: 1.3 (d, 3H), 1.8 (m, 2H), 2.6 (m, 2H), 3.1 (t, 2H), 3.2 (m, IH), 4.45 (t, 2H), 6.6 (d, IH), 6.9 (d, IH), 7.05 (s, IH); LRMS : M+H 192 (ES<+>).

Preparation 142

Methyl-(2E)-2-cyano-3-(2,3-dihydro-1-benzofuran-5-yl)-2-butenoate

To a mixed solution of 5-acetyl-2,3-dihydrobenzo[b]furan (Aldrich) (lg, 6.1 mmol) in toluene (60 ml) was added methyl cyanoacetate (0.6 ml, 6.78 mmol), benzylamine (0.0.7 ml, 0.61 mmol) and acetic acid (0.3 ml, 5.3 mmol) and the mixture was refluxed in a Dean-Stark apparatus 16 hours. The reaction mixture was cooled, washed with 2N HCl (30ml), NaHCO3 (30ml), brine (30ml), dried (MgSO4) and evaporated to a yellow residue. This residue was purified by column chromatography, eluting with 15-20% EtoAc in pentane, to give the desired product (902mg, 60%>); 1H NMR (400 MHz, CDCl 3 ) δ: 2.65 (s, 3H), 3.25 (t, 2H), 3.9 (s, 3H), 4.6 (t, 2H), 6.8 (d, 1H), 7.25 (d, 1H), 7.8 (s, 1H); LRMS : M+NH4261 (ES<+>).

Preparation 143

Methyl-2-cyano-3-(2,3-dihydro-1-benzofuran-5-yl)-3-methyl-butanoate

To a stirred mixture of MeLI (1.4 M in ether, 0.76ml, 1.07 mmol) in ether (2ml) at -25°C under a stream of nitrogen, was added copper(I) iodide (109mg, 0.57 mmol). After stirring for 10 minutes, a solution of the product from Preparation 142 (100 mg, 0.414 mmol) in ether (2 ml) was added dropwise over a period of up to 2 hours, and in the next 2 hours the solution was heated to 0°C. Brine (10ml) was added and the organic portion was extracted with EtOAc (10ml), dried (MgSO 4 ), filtered and evaporated. The residue was then purified by column chromatography, eluting with 20% EtOAc, to give the desired product (92mg, 86%); 1H NMR (400 MHz, CDCl 3 ) δ: 1.55 (d, 6H), 3.2 (m, 2H), 3.59 (s, 3H), 3.62 (s, 1H), 4.5 (t, 2H), 6.7 (d, 1H), 7.1 (d, 1H), 7.2 (s, 1H); LRMS : M+NH4277 (ES<+>).

Preparation 144

3-(2,3-Dihydro-14enzofuran-5-yl)-3-methylbutanenitrile

Solid KOH (87mg, 1.54 mmol) was added to a mixed solution of the product from Preparation 143 (400 mg, 1.54 mmol) in ethanol (1.5ml) and dioxane (1.5ml) and the mixture was stirred under reflux for 6h. The reaction mixture was concentrated in vacuo and dissolved in water (15ml). The aqueous layer was washed with toluene (15ml), then acidified to pH 1 with the addition of 2N HCl, from which the product was extracted with EtOAc (2 x 20ml). The organic fractions were combined, washed with brine (20ml), dried (MgSO 4 ), filtered and concentrated in vacuo to an orange oil, which was used without further purification; 1H NMR (400 MHz, CDCl 3 ) δ: 1.6 (d, 6H), 3.15 (t, 2H), 3.7 (s, 1H), 4.5 (t, 2H), 6.7(d, 1H), 7.1(d, 1H), 7.22 (s, 1H); LRMS: M+NH4<+>, 263 (ES<+>). This oil was dissolved in DMA (2ml) and heated for 2h at 150°C, then allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and then dissolved in EtOAc (10 ml). The organic layer was washed with brine (10 ml), dried with MgSO 4 , filtered and concentrated in vacuo to give an orange oil. This was purified by column chromatography eluting with 15% EtOAc in pentane to give the desired product (lOOmg, 32%);<L>H NMR (400 MHz, CDCl3) δ: 1.45 (s, 6H), 2.55 (s, 2H), 3.2(t, 2H), 4.5 (t, 2H), 6.7 (d, 1H), 7.1 (d, IH), 7.2 (s, IH); LRMS: M+NH4+, 219. (ES+).

Preparation 145

Tert-butyl-(3-(2.3-dihydro-1-benzofuran-5-yl)-3-methylbutylcarbamate

The product from Preparation 144 (250 mg, 1.24 mmol) was dissolved in methanol (12 ml) at 0°C in a stream of nitrogen and mixed with di-tert-butyl dicarbonate (542 mg, 2.48 mmol), then NiCl (161 mg, 1.24 mmol) and then NaBH4 (329 mg, 8.69 mmol) were added dropwise. the black solution was left overnight to warm to room temperature, then concentrated in vacuo. The residue was partitioned between EtOAc (20ml) and NaHCO3 solution (20ml), the mixture was filtered to remove solids, the filtrate was extracted with EtOAc (2x20ml), the combined organic extracts were dried over MgSO4, filtered and evaporated to give the desired product (366mg, 96%>) which was used without further purification; 1H NMR (400 MHz, CDCl3) δ: 1.25 (s, 6H), 1.35 (s, 9H), 1.7 (t, 2H), 2.9 (brs., 2H), 3.1 (t, 2H), 4.2 (brs., IH), 4.5 (t, 2H), 6.65 (d, IH), 7.0 (d, IH), 7.1 (s, IH; LRMS: M-BOC, 206. (ES<+>).

Preparation 146

f3-(2,3-dihydro-1-benzofuran-5-yl)-3-methylbutylamine

The product from Preparation 145 (366mg, 1.20 mmol) was dissolved in DCM (15ml) at 0°C and stirred while bubbling with hydrogen chloride for 15 minutes. The supply of HCl was stopped, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Ether (20ml) was added to the solution, causing precipitation. The precipitate was filtered, washed with ether and dried in vacuo to give the desired product (177mg, 61%); 1H NMR (400 MHz, MeOD) δ: 1.3 (s, 6H), 1.9 8m, 2H), 2.6 (m, 2H), 3.1 (m, 2H), 4.5 (m, 2H), 6.6 (s, IH), 7.01 (s, IH), 7.2 (s, IH); LRMS: M+H, 207 (ES<+>).

Preparation 147

Methyl-2-(4-chlorophenyl)-3-cyanopropanoate

To a mixed solution of diisopropylamine (8.65ml, 61.8 mmol) in dry THF (100ml) at -20°C under a stream of nitrogen, a 2.5M solution of BuLi in hexane (23.7ml, 25.9 mmol) was added dropwise. The solution was allowed to warm to 0°C over 20 minutes and then cooled to -70°C. A solution of methyl 2-(4-chlorophenyl)acetate (9.5g, 51.5mmol) in THF (5ml) was added and stirred for 30min up to about 50ml in vacuo, then treated with 1N HCl (100 mL). The mixture was extracted with EtOAc (120 mL), dried (MgSO 4 ) and evaporated to give a dark brown oil, which was purified by column chromatography, eluting with 2:1 DCM: pentane, to give the desired product (8.6 g, 75%);<*>H NMR (400 MHz, CDCl 3 ) 8: 2.88 (dd, lh), 3.00 (d, IH), 3.73 (s, 3H), 3.92 (dd, IH), 7.22 (d, 2H), 7.37 (d,

2H).

Preparation 148

4- amino- 2- 84- chlorophenyl) butanol

The product from Preparation 147 (235mg, 1.05 mmol) was dissolved in 1 ml of THF and added dropwise to a stirred solution of LiAlH4 (2.1ml, 1M solution in THF, 2.1 mmol) in THF at 0°C under a stream of nitrogen. The mixture was stirred at room temperature for 2 hours and cooled to 0°C. Water (0.08ml) was added, then 3N aqueous NaOH (0.08ml) was added to a mixture diluted with THF (2ml) and water (0.24ml). The suspension was stirred for 5 minutes, then filtered and the filtrate evaporated to a yellow gum. This was dissolved in EtAOc (5ml) and extracted with 0.5N HCl solution (0.3ml), which was later basified to pHlO by the addition of Na2CO3 solution and extracted with EtOAc (5x3ml), the combined organic extracts were dried (MgSO4) and evaporated to give the desired product (60mg, 29%); HNMR (400MHz, CDCl3) 5:1.62-1.95 (m, 2H), 2.58-3.00 (m, 3H), 3.58-3.80 (m, 2H), 7.02-7.39 (m, 4H).

Preparation 149

Tert-butyl-(4-chlorophenyl)acetate

To a suspension of N,N-dimethyl-formamide-di-tert-butal-acetal (25 ml, 104.4 mmol) in dry toluene (90 ml) was added p_-chlorophenyl acetic acid (5.94 g, 34.8 mmol) and the mixture was heated for 1 h at 80°C. The mixture was then diluted with EtOAc (50ml) and washed with water (50ml), 3% aqueous NaHCO 3 (50ml) and brine (20ml), then dried over MgSO 4 and evaporated to give an oil. This oil was purified by eluting first with 35% and then 50% DCM in pentane to give the desired product (2.4g, 30%);<!>H

NMR (400 MHz, CDCl 3 ) δ: 1.42 (s, 9H), 3.44 (s, 2H), 7.20 (d, 2H), 7.28 8d, 2H).

Preparation150

Tert-butyl-2-(4-chlorophenyl) propanoate

The product Preprate 149 was alkylated according to a procedure similar to that described in

Preparation 147, using methyl iodide as the alkylating agent. The desired product was obtained in 95% yield after purification by column chromatography eluting with 25% DCM in pentane; 1H NMR (400 MHz, CDCl 3 ) δ: 1.39 (s, 9H), 1.41 (d, 3H), 3.59 (q, 1H), 7.20 (d, 2H), 7.25 (d, 2H).

Preparation 151

The product of Preparation 150 was alkylated according to a procedure similar to that described in Preparation 137. The desired product was obtained in 82% yield after purification by column chromatography eluting first with 35%, then 70% DCM in pentane.<*>H NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 1.74 (s, 3H); 2.80 (D, IH); 2.95 (d, 1H), 7.24 (d, 2H); 7.35 (d, 2H).

Preparation 152

4-amino-2-(4-chlorophenyl)-2-methylbutanol

The product of Preparation 151 was reduced with L1ALH4 according to the procedure described in Preparation 148, yielding the desired product (35%). The product of this reduction is of sufficient degree of purity so that it does not require further purification; 1 H NMR (400 MHz, CDCl 3 ) 5:1.22 (s, 3H), 1.71 (ddd, 1H); 2.01 (ddd, IH), 2.60 (ddd, IH), 2.83 (ddd, IH), 3.60 (d, IH), 3.82 (d, IH), 7.27 (d, 2H), 7.38 (d, 2H).

Biological analyses

The IC50 values of the compounds of the invention against NEP and ACE were determined using the methods described in published patent application EP1097719-A1, paragraph [0368] to

[0376]. Values for IC50data below were determined using canine kidney NEP. Furthermore, the IC 50 values of some compounds of the present invention were determined using human kidney NEP; these values are similar to the values obtained for passion NEP.

The compounds of the invention are potent NEP inhibitors and selective for ACE.

The compounds of the Examples described herein have an IC 50 in relation to NEP of less than 400 nM:.

The compounds of Examples 1-25, 27-37, 39-41, 43-48, 50-53 and 55-67 have IC50 values against NEP less than or equal to 150 nM and are selective against ACE more than 300-fold.

Further, the compound from Example 3 has an IC 50 value of 22 nM relative to NEP; the compound from Example 4 has an IC50 value of 4 nM relative to NEP; the compound from Example 21 has an IC50 value of 3 nM relative to NEP; the compound from Example 33 has an IC 50 value of 47 nM relative to NEP; the compound of Example 43 has an IC 50 value of 29 nM relative to NEP and the compound of Example 51 has an IC 50 value of 9 nM relative to NEP. The compounds of Examples 3, 4, 21, 33, 43 and 51 are more than 300-fold selective for ACE.

Animal model of reaction to sexual stimulation in females

The compound of Example 22 (hereinafter referred to as "selected compound") was administered according to the protocol described in EP1097719-A1, paragraphs [0495] and

[0499]. The selected compound was made in 5% salt solution. The selected compound and control vehicle were infused with a Harvard 22 pump, infusing 5001/min through a 3-neck port into the femoral vein. After the infusion, the catheter was flushed with a heparin saline solution (Heparinsaline) so that there are no traces of the selected compound in the catheter. The selected compound, tested at clinically relevant doses, significantly increased stimulation of the pelvic nerve and increased blood flow to the genitals (see Figure 1). The selected compound increases the maximum increase in blood flow through the vagina by up to 56%

(n = 3) and clitoral blood flow by 50% (n = 3) compared to control.

Figure 1 shows the effect of administration of the selected compound on vaginal blood flow in rabbits. Increased stimulation of the pelvic nerve (PNS) by the effect of the selected compound also increases blood flow through the genitals in an anesthetized rabbit as a model for sexual stimulation. Repetitive PNS at 15-minute intervals induces a reproductive increase in blood flow through the vagina (hatched areas). Administration of the selected compound (grey area) increases peak blood flow through the clitoris and vagina with submaximal frequency stimulation (eg, 4Hz) compared to the increase observed during the follow-up period of control stimulation or control vehicle (hatched area). The following simultaneous increases were observed after approximately 0.5mg/kg iv bolus-, a 50% increase in blood flow in the clitoris and 56% in the vagina (n = 3). Data expressed as mean ± sem; all changes are monitored by laser Doppler technologies.

There are no major effects of NEP inhibition on either basal/unstimulated genital blood flow.

Female New Zealand rabbits (~ 2.5 kg) were previously treated with a combination of Medetomdin (Domitor®) 0.5 ml/kg i.m. and Ketamine (Vetalar®) 0.25/kg i.m. with oxygen intake through a mask. Rabbits were tracheotomized using a 3 ID Portex™ unattached endotracheal tube, connected to a ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate inflow volume of 18-20 ml and a maximum air pressure of 10 cm H2O. Anesthesia was then changed to

IsofTuran and 2L/min ventilation continued with O2. the right marginal jugular vein was cannulated using a 23G or 24G catheter and milk Ringer's solution was infused at a rate of 0.5 ml/min. The rabbit was maintained on 3% Isofurane during the invasive surgery, tapering to 2% to maintain anesthesia.

The left groin of the rabbit was shaved and a 5 cm long incision was made vertically along the thigh. The femoral vein and artery were exposed, isolated, and cannulated with a PVC catheter (17G) for infusion of drugs and compounds. Cannulation was repeated for the femoral artery, inserting the catheter to a depth of 10 cm to reach the abdominal aorta. This arterial catheter is connected to a Gould blood pressure recording system. Samples for blood gas analysis were also taken via the arterial catheter. Sytolic and diastolic pressures were measured and the mean arterial pressure was calculated using the formula (diatolic x 2 + systolic) /3. Heart rate (pulse) was measured using a pulse oximeter and a Ponemah data processing system (Ponemah Physiology Platform, Gould Instrument Systems Ine).

The abdominal cavity was cut ventrally in the middle. The length of the incision is about 5 cm, just above the pubis. Muscle and fat tissue were grossly removed to expose the hypogastric nerve leading to the body. The most important thing is to be as close as possible to the side of the pubic wall to avoid damage to the femoral vein and artery lying above the pubis. The sciatic and sciatic nerves lie deeper and are located on the dorsal side of the rabbit. Once the sciatic nerve is localized, then the pelvic nerve is easily identified. The vocal cord nerve is freely used; anatomy books do not describe nerves in detail. Furthermore, nerve stimulation causes an increase in blood flow in the vagina and clitoris and innervates the pelvic area. The spinal nerve was freed from the surrounding tissue and a Harvard bipolar stimulation electrode was placed around the nerve. The nerve is slightly raised to tighten it, then the fixed electrode is soldered. About lml of light paraffin oil is placed around the nerve and electrode. This serves as a protective agent on the nerve and prevents the electrode from being contaminated with blood. The electrodes are connected to the Grass S88 Stimulator. The cranial nerve was stimulated with the following parameters: -0.5-5V, pulse width 0.5ms, length of stimulation 10 seconds and frequency range from 2 to 16Hz. Reproductive responses were obtained when the nerve was stimulated every 15-20 minutes. A frequency response curve was determined at the beginning of each experiment to determine the optimal frequency for application as a sub-maximal response, normally 4Hz. Test compounds were infused through the femoral vein using a Harvard22 infusion pump, leaving a continuous 15-minute stimulation cycle.

A ventral incision was made at the caudal end of the pubis to expose the pubic area. Connective tissue is removed to isolate the clitoral membrane, so there are no small blood cells on the wall. The outer wall of the vagina is also exposed by removing the connective tissue. One laser Doppler electrode for flow measurement is inserted 3 cm into the vagina, so that half of the electrode is still visible. The second electrode is placed above the outer wall of the clitoris. The positions of these electrodes were then adjusted until a signal was obtained. The second probe is placed above the surface of a blood cell on the outer wall of the vagina. Both electrodes are attached with clamps. Blood flow through the vagina and clitoris was recorded either as a number directly from the Flowmeter using Ponemah Physiology Platform, Gould Instrument Systems Inc. or indirectly from Gould charts. Calibration was done at the beginning of the experiment (0-125ml/min/100g of tissue).

Animal model of erectile response in males

Anesthetized rabbit methodology

The compound of Example 22 ("selected compound") alone or in combination with the selective and potent PDE5 inhibitor 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-"-propoxyphenyl]-2-(pyridin-2-yl(methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) was administered according to the following protocol. The selected compounds were made in saline solution + 5% IM NaOH. The selected compound and control vehicle were infused at a rate of 500ul/min into the femoral vein. After infusion, the catheter was flushed with saline solution (Heparslin) so that no traces of the compound remained in the catheter. The compounds and control vehicle were infused at a rate of 0.1 ml/second. 15 minutes before stimulation pelvic nerve.

Two experiments were performed: the effect on intravernosal pressure (ICP) administered a) of the selected compound, alone and b) in combination with a PDE5 inhibitor. The effect of ICP is shown in Figure 2. Data were calculated as mean increase (%) + s.e. mean value. *P<0.01, Student's t-test compared to control increase.

Administration of the selected compound alone resulted in a 37±7% enhancement of submaximal stimulated intracavenotal pressure (see Figure 2, light gray column, n=4).

Administration of a combination of the selected compound with a selective PDE5 inhibitor (1 mg/kg iv, bolus) resulted in a 70± 4% increase in submaximal stimulated intracavernosal pressure (see Figure 2, gray column there; n= 3).

There are no major effects of NEP inhibition or concomitant NEP/PDE5 inhibition on basal-unstimulated intracavernosal pressure.

Male New Zealand rabbits (~ 2.5 kg) were previously treated with a combination of Medetomdin (Domitor®) 0.5 ml/kg i.m. and Ketamine (Vetalar®) 0.25/kg i.m. with oxygen intake through a mask. Rabbits were tracheotomized using a 3 ID Portex™ unattached endotracheal tube, connected to a ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate inflow volume of 18-20 ml and a maximum air pressure of 10 cm H2O. Anesthesia was then changed to Isoflurane and ventilation at 2L/min continued with O2. The right marginal jugular vein was cannulated using a 23G or 24G catheter and milk Ringer's solution was infused at a rate of 0.5 ml/min. The rabbit was maintained on 3% Isofurane during invasive surgery, tapering to 2% for maintenance of anesthesia. The left jugular vein was exposed, isolated and then cannulated with a PVC catheter (17G) for infusion of the selected compound or combination thereof.

The left groin of the rabbit was shaved and a 5 cm long incision was made vertically along the thigh. The femoral vein and artery were exposed, isolated, and cannulated with a PVC catheter (17G) for infusion of drugs and compounds. Cannulation was repeated for the femoral artery, inserting the catheter to a depth of 10 cm to reach the abdominal aorta. This arterial catheter is connected to a Gould blood pressure recording system. Samples for blood gas analysis were also taken via the arterial catheter. Sytolic and diastolic pressures were measured and the mean arterial pressure was calculated using the formula (diatolic x 2 + systolic)13. Heart rate (pulse) was measured using a pulse oximeter and a Ponemah data processing system (Ponemah Physiology Platform, Gould Instrument Systems Ine).

The abdominal cavity was cut ventrally in the middle. The length of the incision is about 5 cm, just above the pubis. Muscle and fat tissue were grossly removed to expose the hypogastric nerve leading to the body. The most important thing is to be as close as possible to the side of the pubic wall to avoid damage to the femoral vein and artery lying above the pubis. The sciatic and sciatic nerves lie deeper and are located on the dorsal side of the rabbit. Once the sciatic nerve is localized, then the pelvic nerve is easily identified. The vocal cord nerve is freely used; anatomy books do not describe nerves in detail. Furthermore, nerve stimulation causes an increase in intracavernosal pressure and intracavernosal blood flow and innervates areas of the pelvis. The spinal nerve was freed from the surrounding tissue and a Harvard bipolar stimulation electrode was placed around the nerve. The nerve is slightly raised to tighten it, then the fixed electrode is soldered. About lml of light paraffin oil is placed around the nerve and electrode. This serves as a protective agent on the nerve and prevents the electrode from being contaminated with blood. The electrodes are connected to a Grass S88 Stimulator. The spinal nerve was stimulated with the following parameters: -0.5-5V, pulse width 0.5ms, stimulation length 20 seconds and frequency range 2-16Hz. Reproductive responses were obtained when the nerve was stimulated every 15-20 minutes. Several simulations were performed with the above parameters to determine the mean control response. The test compound or its combination was infused through the jugular vein using a Harvard 22 infusion pump, leaving a continuous 15-minute stimulation cycle. The skin and connective tissue around the penis is removed to create a penis. A catheter (Insyte-W, Benston-Dickinson 20 gauge 1.1 x 4.8 mm) was inserted through the membrane into the left Sorpus carvenoral space and the needle was withdrawn, leaving behind a flexible catheter. This catheter was connected via a pressure regulator (Ohmeda 5299-04) to the Gould intracavernosal pressure recording system. Once intracavernosal pressure was established, the catheter was secured with Vetbond (tissue adhesive, 3M). Heart rate was measured with a pulse oximeter and a Pone-mah data processing system (Ponemah Physiology Platform, Gould Instrument System Inc.).

Intravenous blood flow was read either directly from the Flowmeter using the Ponemah Physiology Platform (Ponemah Physiology Platform, Gould Instrument System Inc.) or indirectly from the Gould chart. Calibration is complete

at the beginning of the experiment (0-125 ml/min/100g of tissue).

Claims (28)

1. A compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph or prodrug; where: R<1>is Ci-6 alkyl, which can be substituted by one or more substituents, which can be the same or different, selected from: halo, hydroxy, C1-6 alkoxy, hydroxy C1-6 alkoxy, C1-6 alkoxyC1-6 alkoxy, carbocyclyl (preferably C3-7cycloalkyl, C3.7 cycloalkenyl or phenyl), carbocyclyloxy (preferably phenoxy), C1-6 methoxycarbocyloxy (preferably C1-4 alkoxyphenoxy), heterocyclyl, heterocyclyloxy, -NR<2>R<3>, -NR<4>COR<5>, -NR<4>SO2R<5>, -CONR<2>R<3>, -S(0)pR<6>, -COR<7> and CO2(CM alkyl); or R 1 is carbocyclyl (preferably C 3-7 cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more of the aforementioned substituents, where the substituents may be the same or different, and includes C 1-6 alkyl; or R 1 is hydrogen, Q-6 alkoxy, -NR 2 R 3 or - Mt<4>SO2R<5>; R<2> and R<3>, which may be the same or different, are carbocyclyl (preferably C3.7cycloalkyl or phenyl) or heterocyclyl (wherein each may be substituted with C 1-6 alkyl, hydroxy or C 1-6 alkoxy); or are hydrogen or C1-4alkyl; or R<2> and R<3>, together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1 alkyl) piperazinyl group; R4 is hydrogen or C1-4 alkyl; R5 is C1-4 alkyl, CF3, carbocyclyl (preferably phenyl), C1-4 alkylcarbocyclyl (preferably C 1 -C 4 alkylphenyl), C 1 -C 4 methoxycarbocyclyl (preferably C 1 -C 4 alkoxyphenyl), heterocyclyl, C 1 -C 4 alkoxy or NR<2>R 3 ; R 6 is C 1-4 alkyl, carbocyclyl (preferably phenyl), heterocyclyl or NR 2 R 3 ; and R 7 is C 1 -C 1 alkyl, carbocyclyl (preferably C 3-7 cycloalkyl or phenyl) or heterocyclyl; p is 0, 1, 2 or 3; X is the bond -(CH.2)n- or -(CH2)q-0- (with Y attached to oxygen); where one or multiple hydrogen atoms in the X bond may be replaced independently by C1-4 alkoxy; hydroxy; hydroxyC 1-3 alkyl, C 3-7 cycloalkyl, carbocyclyl, heterocyclyl or with C 1-4 alkyl, optionally substituted with one or more fluorine atoms or phenyl groups; her 3, 4, 5, 6 or 7; and q is 2, 3, 4, 5 and 6; and X is phenyl or pyridyl, each of which may be substituted by one or more R o groups which may be the same or different; wherein R is hydroxy; mercapto, halogen, cyano, acyl, amino, mono(C1-4alkyl)amino; di(C 1-6 alkyl)amino; carbocyclyl or heterocyclyl (wherein either is optionally substituted with C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkylthio; C 1-6 alkylthio or halogen); C1-6Alkoxy; phenoxy; C 1-6 alkylthio, phenylthio; or alkyl optionally substituted with C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylthio, halogen or phenyl; or two R<8> groups on adjacent carbon atoms together with an internal bonding atom of carbon can form a fused 6- or 6-membered carbocyclic or heterocyclic ring, optionally substituted with C1-6alkyl, haloC1-6alkyl, C1-6Alkoxy, haloC1-6Alkoxy, C1-6alkylthio or halogen. 2. A compound according to claim 1, its pharmaceutically acceptable salt solvate, polymorph or prodrug, characterized in that R<1> is hydrogen, C1-6alkyl, C1-6 alkoxy, C1-6 alkoxy C1-3 alkyl, C1-6 alkoxyC1-6 alkoxy C1-3 alkyl or C1-6 alkyl substituted with phenyl. 3. A compound according to claim 2, its pharmaceutically acceptable salt solvate, polymorph or prodrug, characterized in that R<1> is hydrogen, C1-6alkyl, C1-6 alkoxy, C1-6 alkoxy C1-3 alkyl (preferably methoxy C1-6 alkyl) or C1-6 alkoxyC1-6 methoxy C1-6 alkyl. 4. A compound according to claim 3, its pharmaceutically acceptable salt solvate, polymorph or prodrug, characterized in that R<1> is C1.4alkyl or C1.6 alkoxy C1-6alkyl. 5. A compound according to one of the preceding claims or its pharmaceutically acceptable salt, solvate, polymorph or prodrug, formula Ia: 6. A compound according to one of the preceding claims or its pharmaceutically acceptable salt, solvate, polymorph or prodrug, characterized in that X , -(CH.2)n- and where one or more hydrogen atoms attached to X can be replaced by one or more groups defined in claim 1. 7. A compound according to one of the preceding claims or its pharmaceutically acceptable salt, solvate, polymorph or prodrug, indicated by the fact that in the case where n is present, it is 3 or 4. 8. A compound according to one of the preceding claims or its pharmaceutically acceptable salt, solvate, polymorph or prodrug, indicated by the fact that R, Q.6 alkyl, C1-6 alkoxy, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl or two R<8> groups on adjacent carbon atoms together with the carbon atom that binds them together can form a condensed 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted with C1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, haloC1-6alkalkoxy, C1-6alkylthio or halogen. 9. A compound according to one of the preceding claims or its pharmaceutically acceptable salt, solvate, polymorph or prodrug, characterized in that when R<8>, carbocyclyl, R<8> is cyclopentyl, cyclopropyl, cyclohexyl or phenyl. 10. A compound according to one of claims 1 to 8, its pharmaceutically acceptable salt, solvate, polymorph or prodrug, characterized in that when R Q is heterocyclyl, R Q is pyridyl, oxadiazolyl pyrazolyl or triazolyl. 11. The compound according to one of claims 1 to 8, its pharmaceutically acceptable salt, solvate, polymorph or prodrug, characterized in that when Y, phenyl and two R<8> groups on adjacent oleaginous atoms together with the carbon atoms through which they are attached form condensed 5- or 6-membered carbocyclic or heterocyclic rings, the condensed ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indalyl, benzisothiazolyl and benzothiazolyl. 12. The compound according to claim 1, its pharmaceutically acceptable salt, solvate, polymorph or prodrug, characterized in that the compound is: 2R)- 2-{[ l-( {[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyldopentyl] methyl}-valeric acid (Example 16), 3-{[ l-( {[3-(4-methoxyphenyl)propyl]amino }carbonyl)cyclopentyl]propionic acid (Example 18), 3-{[ l-( {[3-(2,3-dihydro-l-benzofuran-5-yl)propyl]amino }carbonyl)cyclopentyl]propionic acid (Example 21), 2-{[ l-( {[3-( 4-chlorophenyl )propyl]amine }carbonyl)cyclopentyl] methyl}-4-methoxybutymic acid (Example 15), 2-{[ l-( {[3-( 4-fluorophenyl)propyl]amino }carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 4), 4-methoxy-2-{[ l-( {[3-(4-methoxyphenyl)propyl]amino }carbonyl)cyclopentyl]-methylbutyric acid (Example 1), 2-{[l-( {[3-(2, 3-dihydro-l-benzofuran-5-yl)propyl]amino }carbonyl)cyclopentyl]-methyl}-4-methoxybutyric acid (Example 11), (2S)-2-{[ l-( {[3-(4-chlorophenyl)propyl]amino }carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22), and (2S )-2-{[ l-( {[3-(2,3-dihydro-l-benzofuran-5-yl)propyl]amino }carbonyl)-cyclopentyl]-methyl}-4-methoxybutyric acid (Example 25). 13. (2S)-2-{[1 -({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutyric acid (Example 22). 14. Use of a compound as defined in the preceding claims, its pharmaceutically acceptable salt, solvate, polymorph or prodrug, for the production of a drug for the treatment or prevention of conditions in which the beneficial reaction is caused by inhibition of natural endopeptidase. 15. Use of the compound according to claim 14, characterized in that the condition is female sexual dysfunction or male erectile dysfunction. 16. Application according to claim 15, characterized in that the condition is a disorder of sexual stimulation in women. 17. Use according to one of claims 14 to 16, characterized in that the compound is administered systemically. 18. Use according to claim 17, characterized in that the compound is administered orally. 19. Use according to one of claims 14 to 16, characterized in that the compounds are administered topically. 20. A compound defined according to one of claims 1 to 13, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for use as a drug. 21. A method of treating or preventing a condition beneficially affected by neutral endopeptidase inhibition in mammals, characterized in that it consists of treating said mammal with a therapeutically effective amount of a compound defined in one of claims 1 to 13, its pharmaceutically acceptable salt, solvate, polymorph or prodrug. 22. The method according to claim 21, characterized in that the condition is defined in the claims 23. Pharmaceutical preparation containing the compound defined in one of claims 1 to 13, its pharmaceutically acceptable salt, solvate, polymorph or prodrug, together with a pharmaceutically acceptable filler, diluent or carrier. 24 Combination of the compound defined in one of claims 1 to 13 and one or more active components selected from: a) PDE5 inhibitor, i.e. 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)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-351); 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f[1,2,4]-triazin-4-one (vardenafil); 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-dpyrimidin-7-one; and 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-dpyrimidin-7-one and their pharmaceutically acceptable salts; b) an NPY Y1 inhibitor; c) a dopamine agonist such as apomorphine or a selective D2, D3 or D2/D3 agonist such as pramipexole and ropirinol; d) melanocortin receptor agonist or modulator or enhancer of melanocortin preferably melanotan II, PT-14, PT-141; e) agonist, antagonist or modulator for 5HT2C; f) estrogen receptor modulator, estrogen agonist and/or estrogen antagonist, preferably raloxifene, tibolone or lasofoxifene; d) androgen such as androsterone, dehydro-androsterone, testosterone androstanedione and synthetic androgen; and h) estrogen, such as estradiol, estrone, estriol, and synthetic estrogen, such as estrogen benzoate. 25. Procedure for obtaining compounds of general formula I: where R<1>, X and Y are as defined in one of claims 1 to 13 or their salts, characterized by the fact that it consists of the following phases: a) reaction of a compound of formula II where Prot is a suitable protecting group, with a compound of formula III: whereby the compound of formula IV is obtained: then b) reaction of the compound of formula IV, under suitable deprotection conditions, whereby the compound of formula I is obtained; and c) if necessary, formation of salt. 26. The method according to claim 25, characterized in that it comprises the hydrogenation of one of the compounds of formula XI, XII or XIII where Q is a substituent on the C1-6 alkyl group defined for R<1> in claim 1, whereby the compound of formula Ha is obtained 27. The method, characterized in that it consists of asymmetric hydrogenation of one of the compounds of formula XI, XII or XIII where Q is a substituent on the C1-6 alkyl group defined for R<1> in claim 1, whereby the compound of formula Ha is obtained 28. Compound of formula IV characterized in that R<1>, X and Y are as defined in one of claims 1 to 13 and wherein Prot is a suitable protecting group.