KR20030092032A - N-phenpropylcyclopentyl-substituted glutaramide derivatives as nep inhibitors for fsad - Google Patents

Abstract

The present invention relates to compounds of formula (I) for example for treating sexual dysfunction:

Formula I

Where

R ¹ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, hydrogen, C ₁ -C ₆ alkoxy, -NR ₂ R ³ or -NR ⁴ SO ₂ R ⁵ ; X is-(CH ₂ ) _n -or-(CH ₂ ) _q -O-, wherein Y is bonded to oxygen, wherein at least one hydrogen atom in X is C ₁ -C ₄ alkoxy, hydroxy, hydroxy To be independently substituted with oxy (C ₁ -C ₃ alkyl), C ₃ -C ₇ cycloalkyl, carbocyclyl, heterocyclyl, or C ₁ -C ₄ alkyl optionally substituted with one or more fluoro or phenyl groups Can; n is 3, 4, 5, 6 or 7; q is 2, 3, 4, 5 or 6; Y is phenyl or pyridyl, which may each be substituted; Two R ⁸ groups on adjacent carbon atoms may form a substituted or unsubstituted 5- or 6-membered condensed carbocyclic or heterocyclic ring with the carbon atoms linked to each other.

Description

N-PHENPROPYLCYCLOPENTYL-SUBSTITUTED GLUTARAMIDE DERIVATIVES AS NEP INHIBITORS FOR FSAD} as NEP inhibitor against FSD

NEP inhibitors are described in International Patent Publication Nos. 91/07386 and 91/10644.

The use of NEP inhibitors to treat FSD is described in European Patent Publication No. 1 097 719 A1.

The present invention relates to inhibitors of neutral endopeptidase enzyme (NEP), uses thereof, methods for their preparation, intermediates used in their preparation and compositions comprising said inhibitors. Such inhibitors have utility in a variety of therapeutic fields, including the treatment of male and female sexual dysfunction, specifically female sexual dysfunction (FSD), especially female sexual arousal disorder (FSAD).

According to a first aspect, the invention is a compound of formula (I) and a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof:

Where

R ¹ is halo, hydroxy, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, carbocyclyl (preferably C ₃ -C ₇ cyclo Alkyl, C ₃ -C ₇ cycloalkenyl or phenyl), carbocyclyloxy (preferably phenoxy), C ₁ -C ₄ alkoxycarbocyclyloxy (preferably C ₁ -C ₄ alkoxyphenoxy), Heterocyclyl, heterocyclyloxy, -NR ² R ³ , -NR ⁴ COR ⁵ , -NR ⁴ SO ₂ R ⁵ , -CONR ² R ³ , -S (O) _p R ⁶ , -COR ⁷ and -CO ₂ (C ₁ -C ₄ alkyl) C ₁ -C ₆ alkyl, which is selected from the group may be substituted with one or more substituents which may be the same or different, or consisting of; R ¹ is each selected from the group further comprising C ₁ -C ₆ alkyl and may be substituted with one or more substituents which may be the same or different (preferably C ₃ -C ₇ cycloalkyl or phenyl ) Or heterocyclyl; Or R ¹ is hydrogen, C ₁ -C ₆ alkoxy, —NR ² R ³ or —NR ⁴ SO ₂ R ⁵ ;

R ² and R ³ are the same or different and are carbocyclyl (preferably C ₃ -C ₇ cycloalkyl or phenyl) or heterocyclyl, wherein each is C ₁ -C ₄ alkyl, hydroxy or C _1- C ₄ alkoxy); Hydrogen or C ₁ -C ₄ alkyl; Or R ² and R ³ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N- (C ₁ -C ₄ alkyl) piperazinyl group;

R ⁴ is hydrogen or C ₁ -C ₄ alkyl;

R ⁵ is C ₁ -C ₄ alkyl, CF ₃ , carbocyclyl (preferably phenyl), C ₁ -C ₄ alkylcarbocyclyl (preferably C ₁ -C ₄ alkylphenyl), C ₁ -C ₄ Alkoxycarbocyclyl (preferably C ₁ -C ₄ alkoxyphenyl), heterocyclyl, C ₁ -C ₄ alkoxy or —NR ² R ³ ;

R ⁶ is C ₁ -C ₄ alkyl, carbocyclyl (preferably phenyl), heterocyclyl or NR ² R ³ ;

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

p is 0, 1, 2 or 3;

X is-(CH ₂ ) _n -or-(CH ₂ ) _q -O-, wherein Y is bonded to oxygen, wherein at least one hydrogen atom in X is C ₁ -C ₄ alkoxy, hydroxy, hydroxy Can be independently substituted with hydroxy C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, carbocyclyl, heterocyclyl, or C ₁ -C ₄ alkyl, optionally substituted with one or more fluoro or phenyl groups, and ;

n is 3, 4, 5, 6 or 7;

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

Y is phenyl or pyridyl, which may each be substituted with one or more R ⁸ groups, which may be the same or different;

R ⁸ is hydroxy; Mercapto; halogen; Cyano; Acyl; Amino; Mono (C ₁ -C ₄ alkyl) amino; Di (C ₁ -C ₄ alkyl) amino; Carbocyclyl or heterocyclyl, one of which is C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or Substituted or unsubstituted with halogen); C ₁ -C ₆ alkoxy; Phenoxy; C ₁ -C ₆ alkylthio; Phenylthio; Or C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, halogen or phenylsubstituted alkyl; Or two R ⁸ groups on adjacent carbon atoms together with the carbon atoms linked to each other C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C It can form a 5- or 6-membered condensed carbocyclic or heterocyclic ring which is optionally substituted with ₆ alkylthio or halogen.

R ¹ is preferably hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C _1- C ₃ alkyl, or C ₁ -C ₆ alkyl substituted with phenyl.

R ¹ is more preferably hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl (preferably methoxy C ₁ -C ₃ alkyl) or C _1- C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl (preferably methoxyethoxymethyl).

R ¹ is even more preferably C ₁ -C ₄ alkyl (preferably propyl) or C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl (preferably methoxy C ₁ -C ₃ alkyl, more preferably Methoxyethyl).

One preferred group of compounds is of formula la:

n is preferably 3 or 4, more preferably 3.

q is preferably 2 or 3, more preferably 2.

X is preferably-(CH ₂ ) _n- , wherein one or more hydrogen atoms in X may be substituted with one or more groups defined for X in the first embodiment.

R ⁸ is preferably C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl; Or two R ⁸ groups on adjacent carbon atoms together with the carbon atoms linked to each other C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C It can form a 5- or 6-membered condensed carbocyclic or heterocyclic ring which is optionally substituted with ₆ alkylthio or halogen.

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

When R ⁸ is heterocyclyl, the preferred group is pyridyl, oxdiazolyl, pyrazolyl or triazolyl.

Y is phenyl and two R ⁸ groups on adjacent carbon atoms together with the carbon atoms linked to each other form a 5- or 6-membered condensed carbocyclic or heterocyclic ring, with preferred condensed ring systems being naphthyl, quinolinyl, iso Quinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl.

Preferred compounds of the present invention,

(2R) -2-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} pentanic acid (Example 16);

3-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] propanoic acid (Example 18);

3-{[1-({[3- (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] propanoic acid (Example 21);

2-{[1-({[3- (4-chlorophenyl) propyl] amino) carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 15);

2-{[1-({[3- (4-fluorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 4);

4-methoxy-2-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} butanoic acid (Example 1);

2-{[1-({[3- (2,3-Dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] -methyl} -4-methoxybutanoic acid (implemented Example 11);

(2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22); And

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

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

Unless otherwise indicated, the working groups may be straight or branched and have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms.

Unless otherwise indicated, carbocyclyl groups contain 3 to 8 ring atoms and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups include up to three double bonds. Preferred aromatic carbocyclyl groups are phenyl. The term "carbocyclic ring" should be interpreted analogously. The term "carbocyclyl" also includes condensation combinations of carbocyclyl groups such as naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise indicated, heterocyclyl groups contain 5 to 7 ring atoms, up to four of which may be heteroatoms such as nitrogen, oxygen, and sulfur, and which may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups include furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, Pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, ditianyl, thiomor Polyno, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanil, tetrazolyl, triazinyl, azepinyl, oxazinyl, thiazinyl, diazepinyl and thiazolinyl. The term "heterocyclyl" also refers to condensed heterocyclyl groups such as benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, quinolinyl, Quinazolinyl, quinoxazolinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepynyl, indolyl and isoindoleyl. The term "heterocycle" should be interpreted analogously.

Halo means fluoro, chloro, bromo or iodo.

For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted with one or more defined groups. If a group can be selected from a number of other groups, the selected groups can be the same or different.

For the avoidance of doubt, the term “independently” means that one or more substituents may be the same or different when selected from as many substituents as possible.

Pharmaceutically or veterinary acceptable salts of formula (I) comprising a basic center are, for example, non-toxic acids formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, carboxylic acids or organic-sulfonic acids Addition salts. Examples include HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharide, fumarate, malate, lactate, citrate, tartrate, gluconate , Calsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. The compounds of the present invention also provide pharmaceutically or veterinary acceptable metal salts with bases, in particular non-toxic alkali and alkaline earth metal salts. Examples include sodium, potassium, aluminum, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chlorine, megulamine and diethanolamine salts. Suitable pharmaceutical salts are described in Berge et al, J. Pharm, Sci., 66, 1-19, 1977; P Gould, International Journal of Pharmaceutics, 33, 201-217, 1986; And Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, Volume 13, 453-497, New York 1996.

The compounds, pharmaceutically acceptable salts thereof, solvates and polymorphs thereof (except for intermediate compounds in chemical preparation methods), as defined in the embodiments and preferred embodiments of the present invention, are designated as "compounds of the present invention". do.

Pharmaceutically acceptable solvent compounds of the compounds of the invention include their hydrates.

Compounds and intermediates of the present invention may exist in numerous stereoisomeric forms because they have one or more chiral centers. All stereoisomers and mixtures thereof are included within the scope of the present invention.

Each enantiomer is subjected to high pressure liquid chromatography (HPLC) of the corresponding racemate, or optionally to the corresponding racemate, using a variety of techniques known to those skilled in the art, for example, using suitable chiral carriers. It can be obtained by fractional crystallization of a diastereomeric salt formed by reacting with an optically active base. Preferred optically active bases are pseudoephedrine (see Preparation 69).

Separation of the diastereoisomers can be accomplished by conventional techniques such as fractional crystallization, chromatography or H.P.L.C.

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

Also claimed for example for 2-hydroxypyridinyl includes its tautomeric form, α-pyridonyl.

It is understood that certain protected derivatives of the compounds of the invention do not have pharmacological activity prior to the final deprotection step, but in certain cases can be metabolized in the body after oral or parenteral administration to form compounds of the invention having pharmacological activity. It is obvious to those skilled in the field. Thus, such derivatives are termed "prodrugs". In addition, certain compounds of the invention may also serve as prodrugs of other compounds of the invention.

All protected derivatives and prodrugs of the compounds of the present invention are included within the scope of the present invention. Examples of suitable prodrugs for the compounds of the present invention include Drugs of Today, Volume 19, 499-538, Number 9, 1983, Topics in Chemistry, Chapter 31, 306-316, and H. Bundgaard, Elsevier, "Design of Prodrugs", Chapter 1, 1985, the disclosure of which is incorporated herein by reference.

See also, for example, H. Certain residues known to those skilled in the art as “progen-residues” described in Bundgaard, “Design of Prodrugs”, the disclosures of which are incorporated herein by reference, depend upon suitable functional groups present in the compounds of the present invention. It will be apparent to those skilled in the art that they can be deployed.

Preferred prodrugs of the compounds of the present invention include esters, carbonate esters, hemiesters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals This includes.

Drug metabolism studies have shown that compounds of Formula I can form the following compounds that are inhibitors of NEP in vivo:

This metabolite is formed especially when R ¹ is methoxyethylated and -XY is 3- (4-chlorophenyl) propyl.

In addition, the present invention includes all suitable isotopic variations of the compounds of the present invention. Isotope variants are defined as compounds in which one or more atoms have the same atomic number but are generally substituted with atoms having an atomic mass different from the atomic mass found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine (eg, ² H, ³ H, ¹³ C, ¹⁴ C, respectively). , ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl). Certain isotopic variants of the invention, such as compounds incorporating radioisotopes such as ³ H and ¹⁴ C, are useful for drug and / or substrate tissue distribution studies. Isotopes of tritium ( ³ H) and carbon-14 ( ¹⁴ C) are particularly preferred because of their ease of preparation and detection sensitivity. In addition, in some situations, substitution with an isotope such as deuterium ( ² H) may result in certain therapeutic benefits as metabolic stability increases, such as, for example, an increase in half-life or a decrease in required dose in vivo. May be preferred. Isotope modifications of the compounds of the present invention may generally be prepared using conventional procedures, such as the methods or preparations described in the Examples and Preparations, and then using the appropriate isotopic modifications of the appropriate reagents.

The compounds of the present invention are inhibitors of zinc-dependent neutral endopeptidase EC.3.4.24.11, and the compounds of the present invention are proposed to treat the disease states set out below. Such enzymes involve breaking some bioactive oligopeptides and cleaving peptide bonds on the amino side of hydrophobic amino acid residues.

Metabolized peptides include atrial natriuretic peptide (ANP), bombesin, bradykinin, calcitonin gene related peptides, endothelin, enkephalins, neurotensin, P substances and vascular functional intestinal peptides. Some of these peptides have potent vasodilator and neurohormonal action, diuretic and natriuretic activity or indirect behavioral effects.

Thus, the compounds of the present invention can enhance the biological effects of bioactive peptides by inhibiting neutral endopeptidase EC.3.4.24.11. Thus, the compounds of the present invention in particular include hypertension, pulmonary hypertension, peripheral vascular disease, heart failure, angina pectoris, renal failure, acute renal failure, periodic edema, Menieres disease, hyperaldosteroneemia (primary and secondary) and hypercalciuria This is useful for treating a number of disorders. In addition, the compounds of the present invention are useful for treating glaucoma because they have the ability to enhance the effects of ANF. In addition, since the compounds of the present invention have the ability to further inhibit neutral endopeptidase EC3.4.24.11, for example, menstrual disorders, early analgesia, preeclampsia, endometriosis and genital diseases (particularly male and female infertility) , Polycystic ovary syndrome and implantation failure). In addition, the compounds of the present invention include asthma, inflammation, leukemia, pain, epilepsy, affective mental disorders, dementia and senile confusion, obesity and gastrointestinal disorders (particularly diarrhea and irritable bowel syndrome), wound healing (particularly diabetic and venous) Sex ulcers, and pressure sores), septic shock, gastric acid secretion control, hyperreninemia, cystic fibrosis, restenosis, diabetic complications and atherosclerosis. In a preferred embodiment, the compounds of the present invention are useful for treating male and female sexual dysfunction (FSD).

The compounds of the present invention are particularly advantageous for treating FSD (particularly FSAD) and male sexual dysfunction (particularly male erectile dysfunction (MED)).

In accordance with the present invention, FSD may be defined as a disorder or inability for a woman to gain satisfaction with sexual expression. FSD is a generic term for several different female sexual dysfunctions (Leiblum, SR, Definition and classification of female sexual disorders, Int. J. Impotence Res ., 10 , 104-106, 1998) and Berman, JR, Berman, L & Goldstein, I., Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options., Urology , 54 , 385-391, 1999). Women may suffer from a lack of desires, disorders of excitement or orgasm, pain following sexual intercourse, or a combination of these problems. Several types of diseases, medications, injuries or psychological problems can cause FSD. The therapies under development are aimed at the treatment of certain subtypes of FSD, mainly the needs and excitement disorders.

The category of FSD is best defined against the normal state of female sexual response of desire, excitement and orgasm (Leiblum, SR, Definition and classification of female sexual disorders, Int. J. Impotence Res ., 10 , 104- 106, 1998). Desire or sexual desire is the motivation for sexual expression. Signs often include sexual imagination when with a partner of interest or when exposed to other erotic stimuli. Excitement is a vascular response to sexual stimulation, an important factor of which is genital hyperemia, including increased vaginal lubricity, vaginal swelling and increased genital sensation / sensitivity. Orgasm is the relaxation of sexual tension accumulated during excitement.

Thus, FSD occurs when a woman has an insufficient or unsatisfactory response to any of the above conditions, typically desire, excitement or orgasm. FSD categories include disorders of libido, sexual arousal disorders, orgasm disorders, and sexual pain disorders. The compounds of the present invention improve genital response to sexual stimuli (as in female sexual arousal disorders) and at the same time improve related pain, grievances and discomfort due to sexual intercourse, and can also treat other female sexual dysfunctions.

If a woman has little or no sexual desire, and has little or no sexual imagination or fantasy, there is a disorder of decreased libido. This type of FSD can be caused by a decrease in testosterone levels due to natural menopause or surgical menopause. Other causes include illness, medication, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterized by inappropriate genital response to sexual stimulation. In the genitals, hyperemia does not occur, which characterizes normal sexual excitement. Insufficient lubrication of the vaginal wall causes painful intercourse. Orgasm may be inhibited. Excitatory disorders can be caused by vascular element related diseases such as diabetes and atherosclerosis, as well as due to a decrease in estrogen during menopause or postpartum and lactation. Another cause is the result of treatment with diuretics, antihistamines, antidepressants (eg SSRIs) or antihypertensives.

Sexual pain disorders (including sexual pain and vaginal spasms) are characterized by pain due to insertion and can be caused by lubrication reducing drugs, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary problems.

The prevalence of FSD is difficult to assess because the term FSD encompasses several types of problems (some of which are difficult to measure) and interest in FSD treatment in recent years. Many women's sex problems are directly related to the female aging process, or chronic diseases such as diabetes and hypertension.

There is no monotherapy because FSD consists of several subtypes that exhibit symptoms at separate times of the sexual response cycle. Currently, treatment of FSD is mainly focused on psychological or relational aspects. As clinical and basic scientific research has become more focused on the study of these medical problems, the treatment of FSD is increasingly developed. In particular, for individuals who may have elements of vascular disorders (eg, FSAD) that contribute to overall female sexual complaints, female sexual complaints are not all pathologically psychological. No drugs currently approved for the treatment of FSD. Empirical drug therapies include estrogen administration (locally or as a hormone replacement therapy), androgen or mood-modifying drugs such as buspyrone or trazodone. The choice of such therapies is often unsatisfactory due to low efficacy or unacceptable side effects.

Because of the relatively recent interest in pharmacological treatment of FSD, the therapy consists of study candidates, including drugs approved for psychiatric counseling, over-the-counter sexual lubricants, and other symptoms. These drugs consist of hormonal agents, testosterone or a combination of estrogen and testosterone, and more recently vascular drugs that have proven effective in male erectile dysfunction. None of these agents have proven very effective in treating FSD.

In the American Psychiatric Association's Diagnostic and Statistical Manual (DSM) IV, women's sexual arousal disorder (FSAD) refers to achieving or maintaining adequate lubrication-expansion of sexual arousal until completion of sexual activity. It is not sustainable or reproducible. These disorders should cause significant distress or interpersonal difficulties. "

The excitatory response consists of vascular redness, vaginal lubrication and swelling in the pelvis, and swelling of the external genitalia. The disorder causes significant anxiety and / or interpersonal difficulties.

FSAD is a very predominant sexual disorder affecting women before, before, and after menopause (± HRT). It is associated with ancillary diseases such as depression, cardiovascular disease, diabetes and UG disorders.

The primary consequences of FSAD are lack of hyperemia / expansion, lack of lubrication and lack of genital pleasure. Secondary outcomes of FSAD are decreased sexual desire, pain during sexual intercourse, and difficulty reaching orgasms.

At least a portion of patients with FSAD symptoms are associated with vascular causes (see Goldstein et al., Int. J. Impot. Res. , 10 , 84-90, 1998), supporting this view. It has recently been assumed using animal data (see Park et al., Int. J. Impot. Res. , 9 , 27-37, 1997).

Efficacy is under study and candidate drugs for treating FSAD are primarily therapeutic agents for erectile dysfunction that promote circulation to the male genitalia. These are oral or sublingual drugs (apomorphine, phentolamine, phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil), and prostaglindines that are injected or transfused in men and topically in the genitals in women It consists of two types of preparations (PGE1).

The compounds of the present invention are advantageous in providing means for restoring normal sexual excitatory responses, ie vaginal, clitoris and labia congestion due to increased genital blood flow. As a result, vaginal lubrication is increased through plasma outflow, vaginal purity is increased, and vaginal sensation is increased. Thus, the compounds of the present invention provide a means for restoring or enhancing normal sexual arousal response.

Without wishing to be bound by theory, the inventors believe that neuropeptides, such as Vasoactive Intestinal Peptides (VIPs), are major neurotransmitter candidates in the regulation of female sexual arousal responses, particularly in the regulation of genital blood flow. VIPs and other neural peptides are degraded / metabolized by NEP EC3.4.24.11. Thus, NEP inhibitors enhance the endogenous vasorelaxant effect of VIP released during excitation. It treats FSAD through genital hyperemia due to increased genital blood flow. We have found that selective inhibitors of NEP EC3.4.24.11 improve an increase in vaginal and clitoris blood flow due to pelvic nerve-stimulation and VIP-induction. In addition, selective NEP inhibitors improve VIP and neuro-mediated relaxation of the isolated vaginal wall.

Thus, the present invention is advantageous because it helps to provide means for restoring normal sexual excitatory response, ie vaginal, clitoris and labia congestion due to increased genital blood flow. As a result, vaginal lubrication is increased through plasma outflow, vaginal purity is increased, and vaginal sensation is increased. Thus, the compounds of the present invention provide a means for restoring or enhancing normal sexual arousal response.

Male sexual dysfunction includes male erectile dysfunction, ejaculation disorders such as premature ejaculation (PE), sexual insensitivity (difficult to achieve orgasm) and desire disorders, such as impaired libido (lack of interest in sexual intercourse) .

It is apparent that the treatments cited herein by reference all include treatment, palliative and prophylactic treatments.

The compounds of the present invention are applied to secondary populations undergoing FSD with or without hormone replacement therapy, for example young, middle-aged, premenopausal, premenopausal and postmenopausal women.

Compounds of the invention are applied to patients suffering from FSD resulting from the following causes:

(i) Vascular etiology, such as cardiovascular disease or atherosclerosis, hypercholesterolemia, tobacco smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the subclavian vascular system.

(ii) neurological etiology, such as spinal cord injury, or central nervous system disease including multiple sclerosis, diabetes, Parkinson's disease, cerebrovascular accident, peripheral neuropathy, trauma or radical pelvic surgery.

(iii) hormonal / endocrine etiologies, such as hypothalamic / pituitary / gonadal dysfunction, ovarian disorders, pancreatic disorders, surgical or medical castration, androgen deficiency, high circulating levels of prolactin, for example hyperprolactinemia , Natural menopause, immature ovarian failure, hyperthyroidism and hypothyroidism.

(iv) psychogenic etiology, such as depression, obsessive-compulsive personality disorders, anxiety disorders, postpartum depression / "baby blue", emotional and relational problems, performance anxiety, marital discord, dysfunctional attitudes, sexual phobia, religious deterrence or Traumatic past experience.

(v) therapy with selective serotonin reuptake inhibitors (SSRIs) and other antidepressant therapies (tricyclic antidepressants and major opiates), antihypertensive therapy, sympathomimetic therapy, drug induced sexual dysfunction due to chronic oral contraceptive therapy.

Patients with mild to moderate MEDs are advantageous when treated with the compounds of the present invention, and patients with severe MEDs can also respond. However, early studies suggest that the response of patients with mild, moderate and severe MEDs is better when used in combination with PDE5 inhibitors. Mild, moderate and severe MEDs are terms known to those skilled in the art, but guidance can be found in The Journal of Urology, vol 151, 54-61, 1994.

The compounds of the present invention apply to subpopulations suffering from MED, for example psychogenic, endocrine, neurological, arterial, drug-induced sexual dysfunction (metastasis) and sexual dysfunction, especially venous factors associated with cavernous factors. Such patient populations are described in Clinical Andrology, vol 23 (4), 773-782 and in I. Eardley, and K. Sethia, chapter 3, "Erectile Dysfunction-Current Investigation and Management", Mosby-Wolfe.

The compounds of the present invention can be prepared by known methods in a variety of ways. In the following schemes and after, unless otherwise indicated, R ¹ , n and Y are as defined in the first embodiment. These methods form a further aspect of the invention.

Throughout the specification, chemical formulas are represented by Roman letters I, II, III, IV, and the like. Subsets of these formulas are defined as Ia, Ib, Ic and the like, ... IVa, IVb, IVc and the like.

Compounds of formula (I) can be prepared by reacting a compound of formula (II) wherein Prot is a suitable protecting group with an amine of formula (III) to afford a compound of formula (IV) and then deprotecting (see Scheme 1a). Preferred reaction conditions for the acid / amine coupling step include reacting the compound of formula II with the compound of formula III in a suitable solvent in the presence of an activator, an optional catalyst and an excess of acid acceptor. Particularly preferred reaction conditions are 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSCDI) or N, N'-dicyclohexylcarbodiimide (DCC) (1.1-1.3 equiv), 1- Dimethylformamide or dichloromethane in the presence of hydroxybenzotriazole hydrate (HOBT) or dimethylaminopyridine (DMAP) (1.05 to 1.2 equivalents), N-methyl morpholine (NMM) or triethylamine (2.3 to 3 equivalents) Reacting the compound of formula II (1 to 1.5 equivalents) with the compound of formula III (or a salt thereof, 1 to 1.5 equivalents) in a room temperature at 90 ° C. for 16-18 hours.

More particularly preferred reaction conditions comprise a compound of formula II (1 to 1.5 equivalents) and 1,1'-carbonyldiimidazole (1 to 1.5 equivalents) in a suitable solvent (e.g. tetrahydrofuran, isopropylacetate or toluene) After the reaction in a room temperature, to a reaction temperature of from room temperature to 90 ° C. (or a amine salt thereof which produces an organic base such as triethylamine or Hunig's base).

Alternatively, the acid / amine coupling step can be carried out via acid chloride in a suitable solvent in the presence of excess acid acceptor. Acid chlorides can be isolated or produced in situ. Preferred reaction conditions include the acid chlorides of formula II (1 to 1.5 equivalents) in a dichloromethane solvent in the presence of triethylamine or N-methyl morpholine (1.4 to 10 equivalents) for 24 hours at room temperature, Salt, 1 to 1.5 equivalents). The compound of formula II can be converted to acid chloride in situ by reacting with oxalyl chloride for 2 hours at room temperature in dichloromethane in the presence of a catalytic amount of dimethylformamide.

The deprotection method of acid groups depends on the protecting group. For example, protection / deprotection methods are described in TW Greene and PGM Wutz, "Protective groups in Organic synthesis".

For example, when Prot is t-butyl, the deprotection conditions may be achieved by treating the compound of formula IV with a trifluorine compound for 2-18 hours at room temperature, optionally in the presence of a carbo cationic trap, for example anisole (10 equivalents). React with roacetic acid / dichloromethane (1: 1 to 1.5 vol. Ratio). If X or Y comprises a hydroxy group, base hydrolysis of the intermediate trifluoroacetic acid ester may be required. Another method for deprotection when Prot is t-butyl involves reacting the compound of formula IV with hydrochloric acid for 3 hours at room temperature in dichloromethane. For the avoidance of doubt, Prot as t-butyl is presented by way of example, but is not limited to t-butyl.

The process according to Scheme 1a forms a further aspect of the invention.

Intermediates of formula IV are novel. Thus according to a further aspect the present invention provides a compound of formula IV.

Numerous compounds of formula II are known in the art (see European Patent Publication 274234-B1 and International Patent Publication No. 9113054). Other compounds of formula II can be prepared in a similar manner.

R compounds of formulas I and II ¹ is other than hydrogen have a chiral center at the carbon bonded to R ^1. Each enantiomer can be obtained by various methods known to the chemist in the art, for example from corresponding optically pure intermediates or through cleavage. A preferred method of cleavage is via the (+)-pseudoephedrine salt (see International Patent Publication No. 9113054 and Example 10 herein).

Alternatively, a compound of formula IIa, ie a chiral compound of formula II, wherein R ¹ is substituted or unsubstituted with C ₁ -C ₆ alkyl, wherein Q is C ₁ -C ₆ defined for R ¹ in the first embodiment Alkyl gas phase substituents) can be prepared by asymmetric hydrogenation of a compound of formula XI, XII or XIII according to Scheme 1b:

Typical hydrogenation conditions include treating a compound of formula (XI), XII or XIII (or an organic or inorganic salt thereof (eg sodium salt)) with a suitable asymmetric hydrogenation catalyst in a suitable solvent under hydrogen boost. Preferred catalysts include one or more chiral ligands, preferably chiral phosphine ligands, coordinated to suitable transition metals (eg rhodium, ruthenium, iridium and palladium). Preferred catalysts include

[(R)-(+)-2,2'-bis (diphenylphosphino) -1,1'-binafthylchloro (para-cymene)] ruthenium chloride ( J. Org. Chem ., 59 , 3064-3076, 1994);

[(S) -3,3 ', 4,4', 5,5'-hexamethyl (6,6'-diphenyl) -2,2'-diyl] bis (diphenylphosphino) ruthenium bis (tri Fluoroacetate) (International Publication No. 01/94359);

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

[Bis-((2S, 5S) -2,5-dimethyl-1-phenylphospholano) (1,5-cyclooctadiene)] rhodium (I) tetrafluoroborate ( Tetrahedron: Asymm. , 2 , 569-92, 1991); And

[(R)-(6,6'-dimethoxybiphenyl-2,2'-diyl) bis (diphenylphosphino)] ruthenium bis (trifluoroacetate) (European Patent No. 398132).

Preferred reaction conditions include a hydrogen pressure of 150 psi or less and a reaction temperature of 0-100 ° C. (preferably 50-60 ° C.). Preferred solvents are protic solvents such as methanol or ethanol.

In Scheme 1b, the compound of formula XIII is a preferred starting material.

The method of Scheme 1b forms a further aspect of the invention.

Alternatively, compounds of formulas (I) and (IV) can be prepared directly by asymmetric hydrogenation of unsaturated compounds corresponding to formulas (XI), (XII) and (XIII).

Compounds of formula IIIa, ie, compounds of formula III wherein X is-(CH ₂ ) _3- , can be prepared according to Scheme 2. First, the compound of formula V undergoes a Heck reaction with acrylonitrile in the presence of a suitable catalyst system such as palladium and an excess of base such as triethylamine or 4-methylmorpholine to produce the compound of formula VI. Typical reaction conditions include 1.0 to 1.5 equivalents of aryl halide, 3 equivalents of base, 0.1 equivalents of palladium catalyst (preferably palladium (II) acetate), and 1,4-dioxane, acetonitrile or DMF ( Preferably 0.2 equivalents of phosphine ligand (preferably tri-o-tolylphosphine) in acetonitrile. The compound of formula VI is then subjected to catalytic hydrogenation to produce the compound of formula IIIa. Typical hydrogenation conditions include reacting a compound of formula VI with Raney nickel in ethanol or methanol at a pressure of 15 to 150 psig and at a temperature of 25 to 80 ° C., preferably at 30 psig and 25 ° C.

Alternatively, the compound of formula VI can be prepared according to Scheme 3 by reacting the compound of formula VII with diethylcyanomethyl phosphonate. Typical reaction conditions include diethylcyanomethyl phosphonate in a suitable base (e.g., dichloromethane, tetrahydrofuran, or diethyl ether) at a suitable base (e.g., sodium hydride, lithium chloride / humige base). Or sodium ethoxide) and then adding the compound of formula VII.

Alternatively, the compound of formula IIIa can be prepared according to the following scheme 4:

Other compounds of Formulas III, V, VI, and VII are used from commercial sources known in the art, or using methods known in the art or using the methods described herein (see Examples and Preparations). It can be prepared from compounds known in the art.

All of the above reactions and the preparation of the novel starting materials used in the preceding methods are conventional. Suitable reagents and reaction conditions for their performance or preparation, and the procedures for isolating the desired compound, are well known to those of skill in the art in connection with the foregoing literature and the following examples and preparations.

Pharmaceutically acceptable salts of compounds of formula (I) can be readily prepared by mixing together with a solution of the compound of formula (I) and the desired acid or base, as the case may be. Salts can be recovered from the solution by precipitation and filtered or recovered by evaporation of the solvent.

Compounds of the Invention (especially (2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22)) may be mixed with one or more additional active ingredients selected from the group consisting of (1) to (35):

(1) one or more natural or synthetic prostaglandins or esters thereof:

Suitable prostaglandins as used herein include alprostadil, prostaglandin E ₁ , prostaglandin E ₀ , 13,14-dihydroprostaglandin E ₁ , prostaglandin E ₂ , eprostinol, natural, synthetic and semisynthetic prostaglandins and derivatives thereof (Including those described in International Patent Publication No. 00033825 and / or US Patent No. 6,037,346, issued March 14, 2000, which is incorporated herein by reference in its entirety), PGE ₀ , PGE ₁ , PGA ₁ , PGB ₁ , PGF ₁ α, 19- hydroxy-PGA _1, 19- hydroxy _{-PGB 1, PGE 2, PGB 2} , 19- hydroxy -PGA _2, 19- hydroxy -PGB _2, PGE ₃ α, carbonyl Frost Trojan meta Compounds such as min dinoprost, tromethamine, dinoprostone, lipofrost, gemeprost, methenoprost, sulfprostun, thiaprost and moxisylate.

(2) one or more α-adrenergic receptor antagonist compounds, also known as α-adrenergic receptors, α-receptors or α-blockers:

Suitable compounds for use herein include α-adrenergic receptor blockers as described in PCT Application International Patent Publication No. 99/30697, published June 14, 1998, the above publications relating to α-adrenergic receptors. The disclosure of which is incorporated herein by reference, includes optional α ₁ -adrenergic receptors or α ₂ -adrenergic receptor blockers and non-selective adrenergic receptor blockers, and suitable α ₁ -adrenergic receptor blockers include: Phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramine, naphthopydyl, tamsulosin, dapiprazole, phenoxybenzamine, idazoic acid, eparacic acid, yohimbine, laupula alkaloids, recortati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, tetrazosin, abanoquil and prazosin; Α ₂ -blocker blockers described in US Pat. No. 6,037,346 (March 14, 2000) include dibenanine, tolazoline, and trimazocin; α-adrenergic receptors are disclosed in U.S. Pat. 4,252,721 and 2,599,000; α ₂ -adrenergic receptor blockers include clonidine, papaverine and papaverine hydrochloride, optionally in the presence of a carriotonic agent such as pyroxamine.

(3) one or more NO-donor (NO-agent) compounds:

Suitable NO-donor compounds as used herein include organic nitrates such as mono-, di- or tri-nitrate or organic nitrate esters such as glyceryl brinitrate (also known as nitroglycerin), Isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erytrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosidoneimine molsididomine, S-nitroso-N-acetyl penicillamine (SNAP), S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amylnitrate, lincidomin, lincidomin chlorohydrate, (SIN-1) S-nitroso-N-cysteine, diazenium dioleate, (NONOate), 1,5-pentanedinitrate, L-arginine, ginseng, jujube, molecidomin, Re-2047 and nitrosylated Maximilite derivatives, for example PCT exodus The NMI-678-11 and NMI-937 as disclosed in International Patent Publication No. No. 0,012,075 are included.

(4) one or more potassium channel openers or modulators:

Suitable potassium channel openers / modulators as used herein include nicorandil, chromocalim, rebchromacalim, remakalim, finacyldyl, cliasides, minoxidil, caribdotoxin, glyburide, 4-amini Pyridine and BaCl ₂ .

(5) one or more dopamine agents, preferably apomorphine or optional D ₂ , D ₃ or D ₂ / D ₃ agonists such as pramipexole and lopynol (claimed in International Patent Publication No. 0023056) , PNU95666 (claimed in International Patent Publication No. 0040226).

(6) one or more vasodilators:

Suitable vasodilators as used herein include nimodepine, pinassidyl, cyclodelate, isoxsuphrine, chloroprazine, halo peridol, Rec 15/2739 and trazodone.

(7) one or more thromboxane A2 agonists.

(8) one or more CNS activators.

(9) one or more ergot alkaloids:

Suitable ergot alkaloids are described in US Pat. No. 6,037,346, issued March 14, 2000, which includes acetergamine, brasergoline, bromerguride, cynergolin, delorggotryl, disulgin, ergago Novin maleate, ergotamine tartrate, ethylsulgin, ergotryl, lyserguide, mesulingin, metergoline, metgotgotamine, nisergoline, pergolide, propireguide, proterguride And terguride.

(10) modulates the action of natriuretic factors, especially atrial natriuretic factors (also known as atrial natriuretic peptides), type B and C type diuretic factors such as inhibitors or neutral endopeptidase One or more compounds.

(11) one or more compounds that inhibit angiotensin converting enzymes, such as enapril, and inhibitors of combinations of angiotensin converting enzymes and neutral endopeptidase, such as omapatrilat.

(12) one or more angiotensin receptor antagonists such as losartan.

(13) Substrates for at least one NO-synthase, eg L-arginine.

(14) one or more calcium channel blockers, for example ammodipine.

(15) Antagonists of one or more endothelin receptors and inhibitors or endothelin converting enzymes.

(16) one or more cholesterol lowering agents, such as statins (eg, atorvastatin / lipitor-tradename) and fibrate.

(17) one or more antiplatelet and antithrombotic agents, for example tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors.

(18) one or more insulin sensitizers, such as lezulin, and hypoglycemic agents, such as glyphizide.

(19) L-DOPA or carbidopa.

(20) one or more acetylcholinesterase inhibitors, for example donegiefil.

(21) one or more steroidal or nonsteroidal anti-inflammatory agents.

(22) one or more estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxyphene or lasopoxifene, (-)-cis-6-phenyl-5- [4- (2-pyrroli) Din-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts (the preparation methods are described in detail in WO 96/21656). Described).

(23) Modulators of one or more cannabinoid receptors.

(24) at least one NPY (nerve peptide Y) inhibitor, more particularly NPY1 or NPY5 inhibitor, preferably NPY1 inhibitor, preferably said NPY inhibitor (NPY Y1 and having an IC ₅₀ of less than 100 nM, more preferably less than ₅₀ nM and NPY Y5 included):

Assays for the identification of NPY inhibitors are described in International Publication No. 98/52890 (see pages 2 to 28, line 96).

(25) one or more vasoactive intestinal proteins (VIPs), VIP like agents and VIP analogs, more particularly mediated by one or more VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide) VIP receptor agonists or VIP analogs (eg Ro-125-1553) or VIP fragments, combinations of one or more α-adrenergic receptor antagonists with VIP (eg Invicorp, Aviptadil )).

(26) one or more melanocortin receptor agonists or modulators or melanocortin enhancers, for example melanotan II, PT-14, PT-141 or International Patent Publication Nos. 09964002, 00074679, 09955679, 00105401 Compounds as claimed in US Pat. Nos. 00058361, 00114879, 00113112 and 09954358.

(27) one or more serotonin receptor agonists, antagonists or modulators, more particularly agents, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and / or 5HT6 receptors (International Publication No. 09902159, 00002550) And / or as described in No. 00028993.

(28) one or more androgens such as androsterone, dehydro-androsterone, testosterone and synthetic androgens.

(29) one or more estrogens such as estradiol, estrone, estriol and synthetic estrogens such as estrogen benzoate.

(30) Modulators of transporters for one or more noradrenaline, dopamine and / or serotonin, for example bupropion and GW-320659.

(31) one or more purine 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 agents for the ORL-1 receptor.

(34) Agents or modulators for one or more oxytocin / vasopressin receptors, preferably selective oxytocin agonists or modulators.

(35) one or more PDE inhibitors, more particularly PDE 2, 3, 4, 5, 7 or 8 inhibitors, preferably PDE2 or PDE5 inhibitors, most preferably PDE5 inhibitors (see below):

The inhibitor preferably has an IC ₅₀ of less than 100 nM for each enzyme. Suitable cGMP PDE5 inhibitors for use in accordance with the present invention include pyrazolo [4,3-d] pyrimidin-7-ones disclosed in European Patent Publication No. 0463756; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in European Patent Publication No. 0526004; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 93/06104; Pyrazolo [3,4-d] pyrimidin-4-one isomers disclosed in WO 93/07149; Quinazolin-4-ones as disclosed in International Patent Publication No. 93/12095; Pyrido [3,2-d] pyrimidin-4-ones disclosed in WO 94/05661; Purin-6-ones disclosed in International Patent Publication No. 94/00453; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 98/49166; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 99/54333; Pyrazolo [4,3-d] pyrimidin-4-ones disclosed in European Patent Publication No. 0995751; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in WO 00/24745; Pyrazolo [4,3-d] pyrimidin-4-ones disclosed in European Patent Publication No. 0995750; The compounds disclosed in WO 95/19978; The compounds disclosed in WO 99/24433; The compounds disclosed in WO 93/07124; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in International Patent Publication No. 01/27112; Pyrazolo [4,3-d] pyrimidin-7-ones disclosed in International Patent Publication No. 01/27113; Compounds disclosed in European Patent Publication No. 1092718; And compounds disclosed in European Patent Publication No. 1092719.

Further suitable PDE5 inhibitors used in accordance with the present invention include 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) (also, 1-[[3- (6,7-dihydro-1-methyl-7-oxo Also with 3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine (see European Patent Publication No. 0463756). Known); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- On (see European Patent Publication No. 0526004); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one (see International Patent Publication No. 98/49166); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl- 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see International Publication No. 99/54333); (+)-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl]- 2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (also, 3-ethyl-5- {5- [4-ethylpiperazin-1-ylsulfur) Ponyl] -2-([(1R) -2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one (also known as International Publication No. 99/54333); 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 (also 1- {6-ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl ) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine (International Publication No. 01/27113, Example 8 Also known); 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 International Patent Publication No. 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 International Patent Publication No. 01/27113, Example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetinyl) -2,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one (see International Patent Publication No. 01/27112, Example 124); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetinyl) -2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one (see International Patent Publication No. 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), i.e. compounds of Examples 78 and 95 of WO 95/19978 and Examples 1, 3, 7 and 8 compound; 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, 1-[[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [ 5,1-f] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperazine), ie Example 20 of WO 99/24433 , 19, 337 and 336; The compound of Example 11 of International Patent Publication No. 93/07124 (EISAI); And in Rotella DP, J. Med. Chem ., 43 , 1257, 2000].

Other suitable PDE5 inhibitors include 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyridazinone; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinozolinyl] -4-piperidine-carboxylic acid, monosodium salt; (+)-Cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenylmethyl-5-methyl-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-pyrazole (4,3-d) pyrimidine-7 -On; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium salt; Pharmaproject 4516 (Glaxo Wellcome); Pharma Project 5051 (Bayer); Pharma Project 5064 (see Kyowa Hakko; International Patent Publication No. 96/26940); Pharma Project 5069 (Schering Plough); GF-196960 (Glaxo Welcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); And Sch-51866.

In order to treat FSD, compounds of the invention (particularly, (2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-meth Toxybutanoic acid (Example 22)) may be mixed with one or more active ingredients, preferably selected from the group consisting of (a) to (h):

(a) a PDE5 inhibitor, more preferably 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-azetinyl) -2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; And pharmaceutically acceptable salts thereof;

(b) NPY Y1 inhibitors;

(c) dopamine agonists such as apomorphine or optional D ₂ , D ₃ or D ₂ / D ₃ agonists such as pramipexole and ropylinol;

(d) melanocortin receptor agonists or modulators or melanocortin enhancers, preferably melanotan II, PT-14 and PT-141;

(e) agents, antagonists or modulators for 5HT2C;

(f) estrogen receptor modulators, estrogen agonists and / or estrogen antagonists, preferably raloxyphene, tibolone or lasopoxifen;

(g) androgens such as androsterone, dehydro-androsterone, testosterone and synthetic androgens; And

(h) Estrogens such as estradiol, estrone, estriol and synthetic estrogens such as estrogen benzoate.

In order to treat MED, the compound of the present invention ((2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxy moiety Carbonic acid (Example 22)) may be mixed with one or more active ingredients, preferably selected from the group consisting of (a) to (e):

(a) a PDE5 inhibitor, more preferably 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-azetinyl) -2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; And pharmaceutically acceptable salts thereof;

(b) NPY Y1 inhibitors;

(c) dopamine agonists (preferably apomorphine) or optional D ₂ , D ₃ or D ₂ / D ₃ agonists such as pramipexole and ropylinol;

(d) melanocortin receptor agonists or modulators, or melanocortin enhancers, preferably melanotan II, PT-14 and PT-141; And

(e) agents, antagonists or modulators for 5HT2C.

Particularly preferred mixtures for treating MSD include (2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22); And 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-azetinyl) -2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; Apomorphine; Melanotan II, PT-141; Lasopoxifen; Raloxyphene; Tibolone; Androgens such as androsterone, dehydro-androsterone, testosterone, androstandioone and synthetic androgens; And estrogens such as estradiol, estrone, estriol and synthetic estrogens such as estrogen benzoate.

Particularly preferred mixtures for treating MED include (2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22); And 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-azetinyl) -2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; Apomorphine; At least one active ingredient selected from the group consisting of melanotan II, and PT-141.

When administering a mixture of active agents, they may be administered simultaneously, separately or sequentially.

The compounds of the present invention may be administered alone, but in the case of human treatment it is generally administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected according to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of the present invention may be tablets, capsules (including soft gel capsules), which may include flavoring or coloring agents for immediate release, delayed, modified, sustained release, dual, controlled release or pulsatile delivery applications, It may be administered orally, buccally or sublingually in the form of obules, elixirs, solutions or suspensions. In addition, the compounds of the present invention may be administered in a rapid dispersion or rapid dissolution dosage form.

The modified release and pulsatile release dosage forms can include excipients as described above for immediate release dosage forms with additional excipients acting as release rate modifiers, which are coated on and / or within the body of the device. Included. Release rate modifiers include hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonio methacrylate copolymer, hardened beaver oil, carnauba Waxes, paraffin waxes, cellulose acetate phthalates, hydroxypropylmethyl cellulose phthalates, methacrylic acid copolymers and mixtures thereof, including but not limited to. Modified release and pulsatile release dosage forms can include one or a combination of release rate modified excipients. Release rate modifying excipients may be present in dosage forms, i.

Rapid disperse or dissolution dosage formulations (FDDF) include aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascovic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, Mannitol, methyl methacrylate, mint flavourant, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol and xylitol. The term "dispersion" or "dissolution" as used herein to describe FDDF depends on the solubility of the drug used. That is, a rapid disperse dosage form can be prepared if the drug is insoluble, and a quick dissolve dosage form can be prepared if the drug is soluble.

The composition of the present invention can be administered by direct infusion. The composition may be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, ocular, intraocular or transdermal administration. If desired, the formulation may be administered at a dosage of 0.01 to 30 mg, eg 0.1 to 10 mg, more preferably 0.1 to 1 mg per kg of body weight.

The term "administered" includes delivery by viral or nonviral technology. Viral delivery mechanisms include, but are not limited to, adenovirus vectors, adeno-associated virus (AAV) vectors, herpes virus vectors, retroviral vectors, lentiviral vectors, and baculovirus vectors. Nonviral delivery mechanisms include lipid mediated transfection, liposomes, immune liposomes, lipofectin, cationic facial amphoteric (CFA), and combinations thereof. Such mechanisms of delivery include, but are not limited to, mucosal, nasal, oral, parenteral, gastrointestinal, local or sublingual routes.

Additionally or alternatively, the compositions (or some components thereof) of the present invention may be administered by direct infusion. Additionally or alternatively, the compositions (or some components thereof) of the present invention may be administered topically (preferably to the genitals). Additionally or alternatively, the compositions (or some components thereof) of the present invention may be administered by inhalation. Additionally or alternatively, the compositions (or some components thereof) of the present invention may also be administered in mucosal routes administered as inhaled nasal sprays or aerosols, oral routes administered in digestible solutions, and parenteral routes delivered in injectable form. Eg, rectal, ocular (including intravitreal or anterior), nasal, topical (including buccal and sublingual), intrauterine, intravaginal or parenteral (subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracranial, Consisting of intratracheal and epidural), transdermal, intraperitoneal, intracranial, intraventricular, intracranial, intravaginal, intrauterine, and parenteral (eg intravenous, intrathecal, subcutaneous, transdermal or intramuscular) routes It can be administered by one or more routes selected from the group.

For example, the pharmaceutical composition of the present invention may be administered 1 to 10 times a day, for example once or twice a day, according to the regimen. The specific dosage and frequency of administration for any particular patient may vary, the activity of the specific compound applied, the metabolic stability and range of action of the compound, age, weight, overall health, sex, diet, mode and timing of administration, excretion It depends on a variety of factors, including rate, drug mixture, severity of certain symptoms, and the individual's ongoing therapy.

Thus, the term "administration" refers to a parenteral route, eg, intravenous, intramuscular or subcutaneous, delivered by mucosal route, or in injectable form, for example, by nasal spray or aerosol or digestible solution for inhalation. It may be conveyed by a route, but is not limited thereto.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate , Croscarmellose sodium and certain complex silicates, and granular binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia have. Lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may also be included.

In addition, solid compositions of a similar type can also be used as fillers in gelatin capsules. In this regard, preferred excipients include lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. In the case of aqueous suspensions and / or elixirs, the compounds of the present invention may be used in various sweeteners, flavors, colorants or dyes; Emulsifying and / or suspending agents; Diluents such as water, ethanol, propylene glycol and glycerin; And combinations thereof.

In addition, the compounds of the invention may be administered parenterally, eg intravenous, intraarterial, intraperitoneal, intradural, intraventricular, urethral, thymus, intracranial, intramuscular or subcutaneous, or infusion techniques It can be administered by. They can also be administered in the form of grafts. For parenteral administration, they may best be used in the form of sterile aqueous solutions which may contain other substances sufficient for the solution to be isotonic with the blood, for example salts or glucose. The aqueous solution should be appropriately buffered as desired (preferably pH 3-9). Preparation of suitable parenteral preparations under sterile conditions is readily carried out by standard pharmaceutical techniques well known to those skilled in the art. Parenteral preparations may be formulated for immediate release, delayed release, modified release, sustained release, dual release, controlled release or pulsatile delivery.

The following dosage levels and other dosage levels herein are for the average human individual having a weight range of about 65-70 kg. One skilled in the art can readily determine the dosage level required for an individual having a weight outside of this range, such as a child and an elderly person.

For oral and parenteral administration to human patients, the daily dosage level of a compound of the present invention or a salt or solvent compound thereof is typically 10 to 1000 mg (single or divided doses).

Thus, for example, tablets or capsules of the compounds of the invention or salts or solvent compounds thereof may optionally comprise from 5 to 1000 mg, for example from 5 to 500 mg of the active compound for single or two or more administrations. Can be. In any case, the practitioner will determine the actual dosage best suited for any individual patient, and the dosage will depend on the age, weight and response of the particular patient. The dosage is an example of an average case. Of course, there are also individual cases where more or less dosage ranges are appropriate, and are within the scope of the present invention. In addition, those skilled in the art will appreciate that in the treatment of certain symptoms (including FSD and MED), the compounds of the present invention may be applied in a single dose on an "as occasional" basis (ie, as needed or intended). .

In addition, the compounds of the present invention may be administered intranasally or by inhalation, and are conveniently suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes, for example For example 1,1,1,2-tetrafluoroethane (HFA 134A ™ or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA ™), carbon dioxide or other suitable Gas is delivered from a pressurized vessel, pump, nebulizer or nebulizer in the form of a dry powder inhalant or aerosol spray formulation In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The vessel, pump, nebulizer or nebulizer may comprise a solution or suspension of the active compound using a mixture of ethanol and propellant as the solvent, further comprising a lubricant, for example sorbent Non-elastic trioleate Capsules and cartridges (e.g., made from gelatin) used in an inhaler or insufflator comprise a powder mixture of a compound of the invention with a suitable powder base, e.g. lactose or starch. It can be formulated to.

Aerosol or dry powder formulations are preferably prepared to contain 1 to 50 mg of the compound of the invention, respectively, to which the metered dose or “puff” is delivered to the patient. For aerosols the total daily dose is 1-50 mg, which may be administered over a day in a single dose or more typically in divided doses.

Alternatively, the compounds of the present invention may be administered in the form of suppositories or pessaries, or may be applied topically (preferably to the genitals) in the form of gels, hydrogels, lotions, solutions, creams, ointments or dust powders. In addition, the compounds of the present invention can be administered to the skin. In addition, the compounds of the present invention can be administered transdermally, for example using skin patches. In addition, the compounds of the present invention can be administered by the ocular, pulmonary or rectal route.

When used in the eye, the compounds are formulated in finely divided suspensions in pH-adjusted isotonic sterile saline, or preferably in solution in pH-adjusted isotonic sterile saline, optionally mixed with a preservative such as benzylalkonium chloride. It can be formulated as. Alternatively, it may be formulated in an ointment such as petrolatum.

For topical application to the skin (preferably genitals), the compounds of the invention are selected from the group consisting of mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water, for example. It may be formulated into a suitable ointment comprising the active compound suspended or dissolved in a mixture with one or more. Alternatively, the compound of the present invention is a group consisting of mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water It may be formulated into a suitable lotion or cream suspended or dissolved in a mixture with one or more selected from.

In addition, the compounds of the present invention can be used in admixture with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of the drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and / or stability characteristics of the drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Alternatively to direct complexation with the drug, the cyclodextrin may be used as an adjuvant such as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, 94/02518 and 98/55148.

In a preferred embodiment, the compounds of the invention are delivered systemically (eg oral, buccal and sublingual), more preferably orally. Preferably systemic (most preferably oral) administration is used to treat female sexual dysfunction, preferably FSAD.

Thus, in a particularly preferred embodiment, there is provided the use of a compound of the invention for the preparation of a systemic delivery (preferably oral delivery) medicament for treating or preventing FSD, more preferably FSAD.

Preferred oral formulations use immediate release tablets, or rapid dispersion or dissolution dosage formulations (FDDF).

In a more preferred embodiment, the compounds of the invention are administered directly to the topical, preferably female genitals, especially the vagina.

Because NEPs are present throughout the body, it is very unexpected that the compounds of the present invention can be administered systemically and that a therapeutic response can be achieved in the female genitals without causing excessive (harmful) side effects. Thus, in European Patent Publication No. 1 097 719 A1 and in animal models, NEP inhibitors systemically administered to rabbit models (in vivo) do not have adverse effects on cardiovascular factors during sexual arousal (imitation by pelvic nerve stimulation). It has been found to increase genital blood flow, such as causing hypotension or hypertension.

Preferably, the compounds of the present invention are administered to treat FSD in sexually stimulated patients (meaning that sexual stimulation includes visual, auditory or tactile stimulation). The stimulation may be before, after or during administration.

Thus, the compounds of the present invention improve or restore the sexual arousal response to sexual stimulation by improving the pathways / mechanisms underlying sexual arousal in female genitals.

Accordingly, preferred embodiments provide the use of a compound of the invention for the manufacture of a medicament for treating or preventing FSD in a stimulated patient.

For veterinary use, the compounds of the present invention are administered as appropriate acceptable formulations in accordance with conventional veterinary practice, and the veterinarian determines the most appropriate dosage regimen and route of administration for a particular animal.

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

Formulation 1: Tablets were prepared using the following ingredients:

ingredient Weight / mg Active ingredient 250 Microcrystalline cellulose 400 Fumigation silicon dioxide 10 Stearic acid 5 Sum 665

The tablets were prepared by blending and compressing the components.

Formulation 2: Intravenous formulations may be prepared as follows:

ingredient amount Active ingredient 100mg Isotonic saline solution 1,000 ml

Typical agents useful for topical administration of a compound of the invention to the genitals are as follows:

Formulation 3: Spray

Isopropanol (30%) and active ingredient in water (1.0%).

Formulation 4: Foam

Active ingredient, glacial acetic acid, benzoic acid, cetyl alcohol, methyl parahydroxybenzoate, phosphoric acid, polyvinyl alcohol, propylene glycol, sodium carboxymethylcellulose, stearic acid, diethyl stearamide, van Dyke perfume 6301, Purified water and isobutane.

Formulation 5: Gel

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

Formulation 6: Cream

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

Formulation 7: Pessary

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

The present invention,

(i) a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutically acceptable excipient, diluent or carrier;

(ii) a compound of the present invention for use as a medicament;

(iii) the use of a compound of the invention for use as a medicament for treating or preventing a condition that can inhibit neutral endopeptidase to yield a beneficial therapeutic response;

(iv) for use as a medicament for treating or preventing sexual desire disorders, sexual arousal disorders, orgasm disorders and sexual pain disorders, preferably sexual arousal disorders, orgasm disorders and sexual pain disorders, more preferably sexual arousal disorders. The use of the compounds of the invention;

(v) a method of treating a mammalian FSD, comprising treating the mammal using an effective amount of a compound of the present invention;

(vi) a pharmaceutical composition for treating FSD or MED, comprising a compound of the invention in association with a pharmaceutically acceptable excipient, diluent or carrier;

(vii) further comprises a compound of the invention for treating FSD or MED.

The invention is illustrated by, but not limited to, the following examples, the following abbreviations and definitions being used:

Arbacel®: filter agent;

br: wide;

Boc: t-butoxycarbonyl;

CDI: carbonyldiimidazole;

δ: chemical shift;

d: doublet;

Δ: heating;

DCCI: dicyclohexylcarbodiimide;

DCM: dichloromethane;

DMA: dimethylacetamide;

DMF: N, N-dimethylformamide;

DMSO: dimethyl sulfoxide;

ES ⁺ : electrospray ionization positive injection;

ES ⁻ : electrospray ionization negative injection;

Ex: Example;

h: hour;

HOBt: 1-hydroxybenzotriazole;

HPLC: high pressure liquid chromatography;

m / z: mass spectral peak;

min: min;

MS: mass spectrum;

NMR: nuclear magnetic resonance;

Prec: precursor;

Prep: manufacture;

q: quadruple;

s: singlet;

t: triplet;

Tf: trifluoromethanesulfonyl;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

TLC: thin layer chromatography;

TS ⁺ : thermal spray ionization positive injection; And

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

¹ H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structure in all cases. Characteristic chemical shifts (δ) are common abbreviations designated for major peaks, such as s (single line), d (dual line), t (double line), q (quadline), m (multiline), and The br (wide) is used to express downfield ppm from tetramethylsilane. In addition, the following abbreviations were used for common solvents: CDCl ₃ : deuterium chloroform; And DMSO: dimethyl sulfoxide. The abbreviation psi means lb / in ² and LRMS means low fractional mass spectrometry. When using thin layer chromatography (TLC), this means silica gel TLC using silica gel 60 F ₂₅₄ plates, where R _f is the distance traveled by the compound divided by the distance traveled by the solvent line on the TLC plate. Melting points were measured at a heating rate of 20 ° C./min using Perkin Elmer DSC7.

Powder X-ray diffraction (PXRD) patterns were measured using a Siemens D5000 powder X-ray diffractometer with a θ-θ goniometer, automatic beam divergence slit, second monochromator and scintillation counter. Samples were prepared for analysis by packing the powder onto a silicon wafer specimen substrate. The specimen was rotated while irradiating the specimen with copper K-α ₁ X-ray (wavelength = 1.5046 Hz) with an X-ray tube operated at 40 kV / 40 mA. The analysis was performed using a goniometer operating in a step-scan manner set up for a 5 second count per 0.02 ° step for two θ ranges of 3 ° to 40 °. In the results table, "angle 2-θ" relates to the mutual plane of crystals and the intensity is defined as the percentage of the largest peak (I / I ₁ ).

Crystalliteologists in the art will appreciate that the relative intensities of the peaks may vary depending on a number of factors, such as the effect of the orientation of the crystals in the X-ray beam, the purity of the material being analyzed, or the crystallinity of the sample. The peak position may vary depending on the sample height, but the sample position remains substantially planar. In addition, when measured using various wavelengths, it is possible to cause a shift in accordance with the Bragg equation of the following equation (1). Such changes generated using other wavelengths are within the scope of the present invention.

nλ = 2d sinθ

Example 1

4-methoxy-2-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} butanoic acid

Hydrogen chloride gas was passed through a solution of the t-butyl ester (302 mg, 0.72 mmol) obtained in Preparation Example 1 in dichloromethane (5 mL) at 0 ° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was azeotropic with dichloromethane to afford the title compound (233 mg, 0.6 mmol, 82%) as a yellow oil.

The compounds of formula (I) (see Table 1) can be prepared in a similar manner to Example 1 using the t-butyl ester precursor shown as starting material:

Formula I

Alternatively, Example 22 can be prepared as follows:

(2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid

To a solution of the product obtained in Preparation 22 (9.6 g, 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 under N 2 atmosphere for 3.75 h. Stirred. Then an aqueous sodium carbonate solution (95 mL of 10% weight / volume solution) was added to the reaction with stirring until the pH of the aqueous layer was pH 2-3. The layers were then separated and the organic layer was extracted twice with aqueous sodium carbonate solution (20 mL of 10% weight / volume solution). The aqueous layers were combined and then saturated brine (80 mL) was added followed by 2-butanone (40 mL). The layers were separated and the aqueous layer was extracted twice again with 2-butanone (50 mL). The combined organic layers were then azeotropically distilled under atmospheric pressure to dry to a volume of 70 ml, crystallization occurred and the mixture was diluted with 2-butanone (70 ml). The product was then recovered by filtration and dried in vacuo at 50 ° C. for 65 h to afford the crude sodium salt of the title compound as a white solid (5.76 g), which was then purified by recrystallization as follows. Ethyl acetate (87 mL) and ethanol (13 mL) were added to the crude product and the insoluble residual material was filtered off. Subsequently, azeotropic distillation under atmospheric pressure (to remove 100 ml of solvent) to remove ethanol and replacement with ethyl acetate (145 ml) resulted in recrystallization. The resulting crystallization product was then filtered and recovered in vacuo to yield the pure sodium salt of the title product as a white crystalline solid (4.51 g, 10.8 mmol, 51%); Melting point (ethyl acetate) 214 to 216 ° C;

For analytical purposes, the sodium salt was dissolved in water to give the title product (ie free acid), acidified with 5M hydrochloric acid and extracted with dichloromethane. Blowing a nitrogen stream to the sample to remove the solvent to afford the title product;

; HPLC (column: ChiralPak AS (25 × 0.46 cm); Mobile phase: Hexane / IPA / acetic acid (95/5 / 0.5 volume / volume / volume); Flow rate: 1.0 mL / min; Temperature: Ambient temperature; Injection volume : 20 μl; detection: UV at 220 nm; sample concentration: 1.0 mg / ml prepared in mobile phase; retention time: 11.4 min (5.7%) of minor enantiomers, 14.3 min (94.3%) of multiple enantiomers.

Sodium salt of Example 22:

(a) monohydrate

Example 22 (200 mg) of sodium salt was added to a solution of 3.9% water in isopropanol (1 mL). The resulting slurry was stirred for 12 hours and then isolated by filtration. The product showed the following RXRD pattern:

Differential scanning calorimetry (DSC) was performed using a Perkin Elmer DSC-7 instrument with an automatic sample changer. Approximately 3 mg of sample was accurately weighed and placed in 50 μl of aluminum pan and crimp sealed with a perforated lid. The sample was heated at 20 ° C./min in the range of 40-300 ° C. while purging with nitrogen gas. Dehydration occurred at 50-150 ° C. and mostly melted at 212-225 ° C. Those skilled in the art will appreciate that the melting point may vary outside the range depending on the results of the sample impurities.

(b) anhydrous salts

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

Production Example

Preparation Example 1

t-butyl 4-methoxy-2-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} butanoate

Product of Preparation 68 (325 mg, 1. 08 mmol), Product of Preparation 73 (178 mg, 1.08 mol), HOBt (146 mg, 1.08 mol), WSCDI (207 mg, 1.08 mmol) and triethylamine (0.3 mL, 2.16) mmol) were stirred together in dichloromethane (5 mL) for 14 h at room temperature. The reaction mixture was diluted with dichloromethane (10 mL) and washed twice with water (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography using dichloromethane, 99: 1 dichloromethane: methanol and 98: 2 dichloromethane: methanol (Rf 0.2) sequentially to afford the product (267 mg, 0.6 mmol) as a yellow oil. .

Examples of compounds of formula IVa, ie, compounds of formula IV wherein prot is t-butyl, were prepared in a similar manner to Preparation Example 1 using the precursors shown as starting materials (see Tables 2a to 2l below):

Alternatively, Preparation 22 was prepared as follows:

To a solution of 1,1′-carbonyldiimidazole (73.9 g, 0.45 mol) in azeotropic dried isopropyl acetate (339 mL), the product of Preparation 69 was stirred at 60 ° C. over 1.5 h under N ₂ atmosphere. Isopropyl acetate solution was added. The transfer line was then washed with anhydrous isopropyl acetate (50 mL). The resulting solution was then further stirred at 60 ° C. for 4.5 hours before the reaction mixture was cooled to room temperature and stirred for 15 hours. Triethylamine (46.1 g, 0.46 mol) was then added to the resulting solution followed by 3- (4-chlorophenyl) propylamine hydrochloride ( J. Med. Chem. , 39 , 4942-4951). , 1996) (94.3 g, 0.46 mol). The resulting mixture was then heated to 60 ° C. for 7 hours before cooling to room temperature. Deionized water (100 mL) was then added to the reaction mixture with stirring, and then 5M aqueous hydrochloric acid solution (190 mL) was added until the pH of the aqueous layer reached pH 2-3. The aqueous layer was then separated and the organic layer washed with 0.5 M aqueous potassium carbonate solution (50 mL). The aqueous phase was separated and the organic phase was washed with brine saturated solution (100 mL). The aqueous layer was then separated and the organic phase was concentrated by distillation under vacuum to afford the title compound (200.3 g, 443 mmol, 98% yield) as a yellow oil.

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

To a stirred solution of starting material (11.3 g, 62 mmol) in the following step (b) in tetrahydrofuran (500 mL) was added borane dimethylsulfide complex (30 mL) and the whole was refluxed for 12 h. The reaction mixture was quenched with methanol (100 mL), concentrated in vacuo and refluxed in 3M HCl (200 mL) for 4 h. The aqueous layer was concentrated to 500 ml under vacuum and the precipitate was filtered off and dried under reduced pressure to give the title compound (10.1 g, 59.7 mmol, 96%) as a white powder.

Preparation of Starting Material

(a) Methyl 3- (4-chlorophenyl) propanoate

To a stirred solution of 3- (4-chlorophenyl) propanoic acid (available from Maybridge) (14.5 g, 77.1 mmol) in methanol (400 mL) was added acetyl chloride (50 mL) and the reaction mixture was added to 20 Reflux for hours. Thereafter, the reaction mixture was cooled and then concentrated under reduced pressure. The residue was then dissolved in DCM (200 mL) and washed with 1M sodium hydroxide solution (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (15.7 g, 77 mmol, 100%) as a brown oil.

(b) 3- (4-chlorophenyl) propanamide

The product of step (a) (15 g, 75.7 mmol) was dissolved in methanol (400 mL) and then cooled to 0 ° C. Then, ammonia gas was aerated for 4 hours through the reaction mixture and the reaction was stirred for 3 days. The solvent was removed under reduced pressure and the residue was triturated with hot pentane. The residual solid was dried under vacuum to afford the title compound (11.32 g, 61.8 mmol, 82%) as a white powder.

Preparation Example 67

t-butyl- [1-({[3- (4-cyanophenyl) propyl] amino) carbonyl) cyclopentyl] acetate

The product of Preparation 45 (44 mg, 0.1 mmol) and Cu (I) CN (13.4 mg, 0.15 mmol) were dissolved in DMF (0.5 mL) under nitrogen and stirred at about 130 ° C. for 16 h. Then additional Cu (I) CN (13 mg) was added and the temperature was raised to 145 ° C. for 16 hours. The final Cu (I) CN (26 mg) was then added to the solution and the whole was heated at 160 ° C. for 24 hours. The reaction was quenched by the addition of water and the organics were extracted with EtOAc (50 mL), washed with brine, dried over MgSO ₄ and evaporated to give a yellow oil. The oil was purified by preparative TLC using 7: 3 pentane: EtOAc as eluent to afford the title compound (6 mg, 16%).

Preparation Example 68

1- [2- (t-butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylic acid

A solution of t-butyl 3- (1-carboxycyclopentyl) propanoate (12 g, 49.5 mmol) (European Patent Publication No. 274234 B1, Example 35) in anhydrous tetrahydrofuran (100 mL) was prepared by hexane ( 52 mL) and tetrahydrofuran (200 mL) were added to a stirred solution of lithium diisopropylamide (130 mL) at −78 ° C. under nitrogen. After 1 hour, a solution of 2-bromoethyl methyl ether in tetrahydrofuran (100 mL) was added while maintaining a temperature of -78 ° C. The reaction mixture was allowed to warm to rt overnight. The mixture was quenched with water (100 mL), acidified to pH 1 with 2M hydrochloric acid and extracted twice with ethyl acetate (150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the crude acid which was purified by silica gel chromatography. Eluting by increasing the ratio of methanol in dichloromethane (pure dichloromethane to 1:50) gave an oil (7.7 g, 25.6 mmol, 52%); Rf 0.3 methanol, dichloromethane 1: 20;

Alternatively, the compound of Preparation 68 was prepared as follows:

To the mixture of heptane (41.2 L) and water (30.9 L) was added the product of step (b) (5.15 kg, 12.9 mol). Then diluted 5M aqueous hydrochloric acid solution (2.6 L) was added with stirring until the pH of the aqueous layer was pH 2-3. The layers were separated and the aqueous phase extracted with heptane (20.6 L). The combined organic layers were then washed with saturated brine solution (15.5 L) and then concentrated by distillation under atmospheric pressure to give the title compound (3.90 kg, 13.0 mol, 100% yield) as a solution in heptane (44.0 kg total solution weight). It was. An aliquot was taken and the solvent removed under reduced pressure to obtain an assay sample.

GC (injector program: initial temperature 0 ° C., rate 150 ° C./min, final temperature 230 ° C .; oven program: initial temperature 100 ° C., rate 10 ° C./min, final temperature 230 ° C., final time 10 minutes; column, BP-21 25 m × 0.25 mm ID × 0.25 um FT; Detector FID) retention time 16.1 minutes.

Preparation of Starting Material

(a) Crude 1- [2- (t-butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylic acid

2M solution of commercially supplied lithium diisopropylamide (tetrahydrofuran / n-heptane / ethylbenzene in 1,2-dimethoxyethane (25 L) with a reaction temperature of -10 ° C and stirring over 4 hours, 9.63 kg, 23.7 mol), 1- (3-t-butoxy-3-oxopropyl) cyclopentane carboxylic acid (Europe) in 1,2-dimethoxyethane (12.5 L) at -10 ° C under N ₂ atmosphere A solution of (2.5 kg, 10.3 mol) was added (see patent publication 274234 B1, Example 35). The header tank was washed with 1,2-dimethoxyethane (2.5 L) and added to the reaction. The reaction mixture was then stirred at −10 ° C. for 1.75 h. To the resulting solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (10 L) over 1.75 hours. It was then stirred at this temperature for 4 hours and then warmed to 20 ° C. over 4 hours. After stirring for 8 hours at the same temperature, the reaction was quenched by the addition of 2.8 M aqueous ammonium chloride solution (25 L) followed by the addition of ethyl acetate (12.5 L). Subsequently, 5 M aqueous hydrochloric acid solution (10 L) was added with stirring to adjust the pH to 2-3. The two phases were mixed and then separated. The organic phase was then extracted three times with 0.3 M aqueous potassium carbonate solution (37.5 L, 12.5 L and 6.25 L). Then, n-heptane (15.6 L) and 5M hydrochloric acid aqueous solution (14.5 L) were added to the combined aqueous phases with stirring until the pH of the aqueous layer was 2-3. The layers were then separated and the aqueous phase extracted with n-heptane (15.6 L). The combined organic phases were then washed with saturated brine (3.1 L) and concentrated in vacuo to afford the crude title compound (2.50 kg, 8.32 mol, 81% yield) as a solution in n-heptane (21.8 kg, total solution weight). It was.

(b) cyclohexanealuminum 1- [2- (t-butoxycarbonyl) -4-methoxybutyl] cyclopentane carboxylate

The solution of the crude product of step (a) in n-heptane (5.51 kg, 18.3 mol, 41.4 kg total solution weight) was distilled off under atmospheric pressure to concentrate n-heptane (20 L). To the resulting solution was added cyclohexylamine (1.82 kg, 18.4 mol) over 0.5 h as a solution in n-heptane (9.9 L). The transfer line was then washed with n-heptane (1.1 L) and added to the reaction. The resulting slurry was then granulated with shaking at 22 ° C. for 19.5 hours. The product was collected by filtration, washed twice with n-heptane (11.0 L) and the resulting solid was dried at 50 ° C. for 20 h under vacuum. 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 added to crystallize a sample of true crystallization title compound (1.0 g). The crystalline slurry was then cooled to 20 ° C. over 4 hours and then granulated at this temperature for 0.5 hours. The product was then recovered by filtration, washed twice with n-heptane (6.2 L) and dried at 45 ° C. for 11 h under vacuum. 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 a clear solution was obtained. The resulting solution was then cooled to 50 ° C. and added to crystallize a sample of true crystallization title compound (1.0 g). The crystalline slurry was then cooled to 20 ° C. over 4 hours and then granulated at this temperature for 22.5 hours. The product was then recovered by filtration, washed twice with n-heptane (5.5 L) and dried under vacuum at 45 ° C. for 16.5 h to afford the title product (5.15 kg, 12.9 mol, 94% yield); Melting point (heptane) 121 ° C .;

Preparation Example 69

1-[(2S) -2- (t-butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylic acid

The product of Preparation 68 and (+)-pseudoephedrine were recrystallized 9 times from hexane to give a white crystalline solid. The salt was dissolved in ethyl acetate, washed with 0.5 M hydrochloric acid, dried over magnesium sulfate and concentrated in vacuo to yield the δ3.3 peak of the (+)-pseudoephedrine salt as (S) -acid as a pale yellow oil of more than 99% by NMR analysis. 31% yield).

Alternatively, Preparation 69 was prepared as follows:

To a solution of Preparation 68 (3.90 kg, 13.0 mol) in heptane (58.5 L, total solution weight 44.0 kg), (1S, 2S)-(+)-pseudoephedrine (2.13 kg, 12.9 mol) was added at 20 ° C. under nitrogen atmosphere. Was added. The suspension was then heated to 70 ° C. with stirring until a clear solution was obtained. The solution was then cooled to 40 ° C. and added to crystallize a sample of true crystallization title compound (0.8 g). The temperature of the mixture was maintained at 40 ° C. for 2 hours and then the slurry was cooled to 20 ° C. over 6 hours. The product was then recovered by filtration, washed twice with heptane (2.3 L) and then dried under vacuum at 50 ° C. for 22 h (1S, 2S) -1-hydroxy-N-methyl-1-phenyl-2- 86 of the diastereomeric salts as measured by propaneaminium 1-[(2S) -2- (t-butoxycarbonyl) -4-methoxybutyl] cyclopentane carboxylate (3.20 kg, 6.87 mol, ¹ H NMR: 53% yield as a 14 mixture) was obtained. 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 added to crystallize a sample of true crystallization title compound (1.0 g). The solution was then held at 58 ° C. for 1 hour and then cooled to 20 ° C. over 6 hours. The slurry was then granulated at 20 ° C. for 12 hours. The product was then recovered by filtration and washed twice with heptane (2 L). Dry in oven at 50 ° C. under vacuum for 22.5 hours to afford (1S, 2S) -1-hydroxy-N-methyl-1-phenyl-2-propaneaminium 1-[(2S) -2- (as white crystalline solid. t-butoxycarbonyl) -4-methoxybutyl] cyclopentane carboxylate (2.35 kg, 5.0 mol, 73% yield) was obtained. Melting point (heptane) 95 ° C.

The salt was digested as follows to afford the title compound. (1S, 2S) -1-hydroxy-N-methyl-1-phenyl-2-propanealuminum 1-[(2S) -2- (t in deionized water (1.26 L) and isopropyl acetate (1.47 L) In a stirred solution of -butoxycarbonyl) -4-methoxybutyl] cyclopentane carboxylate (210 g, 0.45 mol), 5M aqueous hydrochloric acid solution (99.5 ml, 0.50 mol) until the pH of the aqueous layer is pH 2-3. ) Was added. The layers were then separated and the aqueous phase was extracted with isopropyl acetate (630 mL). The organic extracts were then combined and washed with brine saturated solution (420 mL). The organic phase was then distilled off under atmospheric pressure (to remove 1.4 L of isopropyl acetate) to give the title compound as a solution in isopropyl acetate which was used directly in the next step. An aliquot was taken and the solvent removed to give an analytical sample.

GC (injector program: initial temperature 0 ° C., rate 150 ° C./min, final temperature 230 ° C .; oven program: initial temperature 100 ° C., rate 10 ° C./min, final temperature 230 ° C., final time 20 minutes; column, BP-21 25 m × 0.25 mm ID × 0.25 um FT; detection FID) retention time 16.0 min; HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 mL / min; temperature: ambient temperature; injection volume: 20 μL; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: 15.5 minutes (3.3%) of minor enantiomers, 17.5 minutes (96.7%) of majority enantiomers.

Alternatively, the product of Preparation 69 was prepared by asymmetric hydrogenation using a number of catalysts and the following conditions:

(i) hydrogenation 1

Starting material (62 mg, 0.21 mmol) and ((R)-(+)-2,2'-bis (diphenylphosphino) -1,1'-binafthylchloro (para-between) Men)] ruthenium chloride (see J. Org. Chem ., 59 , 3064-3076) (2.0 mg, 0.0021 mmol) was charged to a pressure vessel. The vessel was pressurized to 10 bar and purged with nitrogen by leaking. This purging procedure was then repeated four more times. Degassing methanol (2 mL) was then added. The vessel was pressurized with hydrogen (10 bar), leaked and pressurized again with hydrogen (10 bar). The mixture was stirred at 65 ° C. (oil bath temperature) for 18 hours. After cooling to room temperature, the pressure was released and the solvent was removed under reduced pressure to afford the title compound as an oil. HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S enantiomer 17.5 min; 91% conversion, S-enantiomer, 97%.

(ii) hydrogenation 2

Starting material (82 mg, 0.27 mmol), nitrate t-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 WO 01/94359) (2.5 mg, 0.0027 mmol) Was charged to a pressure vessel. The vessel was pressurized to 10 bar and purged with nitrogen by leaking. This purging procedure was then repeated four more times. Degassing methanol (2 mL) was then added. The vessel was pressurized with hydrogen (10 bar), leaked and pressurized again with hydrogen (10 bar). The mixture was stirred at 65 ° C. for 18 h. The vessel was then cooled to room temperature and the pressure released. Then ethyl acetate / heptane (1: 1, 10 mL) and hydrochloric acid (1M, 5 mL) were added to the reaction mixture. The organic phase was separated, dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound as an oil. HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) Wash for 10 minutes then wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S enantiomer 17.5 min; Conversion greater than 98%, R-enantiomer, 91%.

(iii) hydrogenation 3

[(R)-(6,6'dimethoxybiphenyl-2,2'-diyl) bis (diphenylphosphino)] ruthenium bis (trifluoroacetate) as a pre-catalyst (European patent) The title compound was obtained as an oil using the same method as described for hydrogenation 2 above except for using publication 398132). HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S-enantiomer 17.5 min; 57% conversion, S-enantiomer, 98%.

(iv) hydrogenation 4

Starting material (80 mg, 0.25 mmol) and [(R)-(-)-4,12-bis (diisopropylphosphino)-[2.2] -paracyclophano- (1,5- Cyclooctadiene)] rhodium (I) tetrafluoroborate (see J. Am. Chem. Soc ., 119 , 6207-6208, 1997) (1.8 mg, 0.0025 mmol) was charged to a pressure vessel. The vessel was then pressurized to 10.5 bar and purged with nitrogen by leaking. This purging procedure was then repeated four more times. Degassing methanol (2 mL) was then added. The vessel was pressurized with hydrogen (10.5 bar) and then leaked and pressurized again with hydrogen (10.5 bar). The mixture was stirred at rt for 18 h before releasing the pressure. To the reaction mixture t-butyl methyl ether and 2M hydrochloric acid were added and the phases were mixed. The organic phase was separated, dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound as an oil. HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S enantiomer 17.5 min; Conversion greater than 98%, R-enantiomer, 91%.

(v) hydrogenation 5

Starting compound (80 mg, 0.25 mmol) of step (i) and [(S) -3,3 ', 4,4', 5,5'-hexamethyl (6,6'-diphenyl) -2,2 '-Diyl] bis (diphenylphosphino) ruthenium bis (trifluoroacetate) (see International Patent Publication 01/94359) (2.3 mg, 0.0025 mmol) was charged to a pressurized vessel. The vessel was then pressurized to 10.5 bar and purged with nitrogen by leaking. This purging procedure was then repeated four more times. Degassing methanol (2 mL) was then added. The vessel was pressurized with hydrogen (10.5 bar) and then leaked and pressurized again with hydrogen (10.5 bar). The mixture was stirred at 45 ° C. for 18 hours and then cooled to room temperature. The pressure was then released and t-butyl methyl ether and 2M hydrochloric acid were added to the reaction mixture and the phases were mixed. The organic phase was separated, dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound as an oil. HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S enantiomer 17.5 min; Conversion over 98%, R-enantiomer, 97%.

(vi) hydrogenation 6

Starting compound (80 mg, 0.25 mmol) and [(R)-(+)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] ruthenium bis (tri) of step (i) Fluoroacetate)] (2.4 mg, 0.0025 mmol) or [(R)-(+)-2,2'-bis (diphenylphosphino) -1,1'-binafthylchloro (para-cymene) ] Ruthenium chloride (see J. Org. Chem ., 59 , 3064-3076, 1994) (2.4 mg, 0.0025 mmol) was charged to a pressurized vessel. The same procedure as described in Preparation 6 was used to yield the title compound as an oil. HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S enantiomer 17.5 min; Conversion greater than 98%, S-enantiomer, greater than 98%.

(vii) hydrogenation 7

Starting material (80 mg, 0.25 mmol) and [(R)-(6,6'-dimethoxybiphenyl-2,2'-diyl) bis (diphenylphosphino)] ruthenium bis (tri) Fluoroacetate) (see European Patent Publication No. 398132) (2.3 mg, 0.0025 mmol) was charged to a pressure vessel. The same procedure as described for hydrogenation 6 was used to yield the title compound as an oil. HPLC (column: chiralpak AD (25 × 0.46 cm); mobile phase: hexanes / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); mobile phase for washing: hexane / IPA / DEA (80/20 / 0.5 volume) Volume / volume); flow rate: 1.0 ml / min; temperature: ambient temperature; injection volume: 20 μl; detection: ELSD) Run time: 20 with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume) 10 min wash followed by 10 min wash with hexane / IPA / acetic acid (98/2 / 0.1 volume / volume / volume); Retention time: R enantiomer 15.5 min, S enantiomer 17.5 min; Conversion greater than 98%, S-enantiomer, greater than 98%.

Preparation of Starting Material

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

A solution of diisopropylamine (35.0 mL, 250 mmol) in THF (70 mL) was cooled to -15 ° C under nitrogen. Then n-butyllithium (2.5M, 100 mL, 250 mmol) was added dropwise while keeping the temperature below -10 ° C. To the resulting solution, 1- (3-t-butoxy-3-oxopropyl) cyclopentane carboxylic acid (THE European Patent Publication No. 274234 B1, Example 35) in THF (50 mL) (27.52 g, 113.6 mmol) After addition of a solution of the reaction was stirred at -10 to -15 ° C for 1 hour. To the reaction mixture was then added a solution of methyl methoxyacetate (18.0 mL) in THF (20 mL), then the resulting mixture was allowed to warm to room temperature and then stirred for 19 h. To the reaction mixture was added t-butyl methyl ether (300 mL) and deionized water (300 mL) and the aqueous phase was acidified to pH 3 with stirring with 2M hydrochloric acid. The phases were separated and the aqueous phase was extracted with t-butyl methyl ether (250 mL). The combined organic phases were then washed with water (250 mL) then brine (250 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The crude title compound was then purified by silica gel flash chromatography using ethyl acetate / heptane (1: 2 to 1: 1) as eluent to afford the title compound (17.35 g, 55.2 mmol, 49% yield).

(b) 8-methoxymethyl-6-oxo-7-oxa-spiro [4.5] decane-9-carboxylic acid t-butyl ester

The solution of the product of step (a) in methanol (100 mL) was cooled to 0-5 [deg.] C. under nitrogen. Then, sodium borohydride (2.02 g, 53.4 mmol) was added in portions to the resulting solution while maintaining the temperature below 0 ° C. The reaction was then stirred for 1 hour. Ethyl acetate (150 mL) and water (150 mL) were then added, and 2M hydrochloric acid solution (50 mL) was added while stirring to acidify the aqueous phase. The phases were then separated and the aqueous phase extracted with ethyl acetate (100 mL). The combined organic phases were then washed with water (50 mL) followed by brine (50 mL). The combined aqueous washes were then extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were then dried over magnesium sulfate and the solvent was removed under reduced pressure to give a pale yellow oil (11.29 g) which was used in the next step without further purification. A portion of the oil (10.89 g, 34.4 mmol) was dissolved in THF (100 mL) under nitrogen and dicyclohexylcarbodiimide (7.10 g, 34.4 mmol) was added to the resulting solution. The mixture was then stirred at rt for 19 h. Subsequently, methanol (5 mL) and acetic acid (2 mL) were added to the reaction and the mixture was stirred for 30 minutes. Then the solvent was removed under reduced pressure. The crude product was then suspended in ethyl acetate (50 mL) and filtered to remove reaction byproducts. The filter foil was washed with ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure. The crude title compound was then purified by silica gel flash chromatography using ethyl acetate / heptane (1: 3 to 2: 3) as eluent to give a 2: 1 mixture of diastereomers (8.19 g, 27.4 mmol, 80%). The title compound was obtained. For analytical purposes, samples were purified by silica gel flash chromatography using EtOAc / heptanes (1: 2) as eluent: i) higher rf spots (single diastereomers);

; ii) lower rf spots (not completely isolated, 3.5: 1 mixture of diastereomers)

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

To a solution of the product of step (b) (6.11 g, 20.49 mmol) in toluene (50 mL) was added 1,8-diazabicyclo [5.4.0] undec-7-ene (3.7 mL, 24.58 mmol). After addition it was heated to reflux for 5 hours under nitrogen. The solution was then cooled to room temperature and the solvent removed under reduced pressure. Deionized water (100 mL) was then added to the resulting residue and the mixture was extracted with t-butyl methyl ether (30 mL). The phases were then separated and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid solution (15 mL) and then extracted twice with t-butyl methyl ether (30 mL). The combined organic extracts were then washed with water (30 mL) and then brine (30 mL) and dried over magnesium sulfate. The solvent was then removed under reduced pressure to afford the crude title compound (6.29 g) which was then crystallized from heptane (15 mL) at 0 ° C. The resulting solid was then collected by filtration and washed twice with ice cold heptane (5 mL) to yield the title compound (1.79 g, 6.0 mmol, 29%, E-isomer assigned on the basis of chemical shifts) as a white solid. .

The filtrate was concentrated to give a yellow oil (4.02 g). The mixture was purified by silica gel flash chromatography using ethyl acetate / heptane (1: 2 + 0.5% acetic acid) as eluent to further give the title compound and colorless oil (2.43 g, 1.1: 1 E / Z ratio). 1- (2-t-butoxycarbonyl-4-methoxy-but-2Z-enyl) -cyclopentane carboxylic acid was obtained.

In addition, samples of vinyl ether 1-[(3E) -2- (t-butoxycarbonyl) -4-methoxy-3-butenyl] cyclopentanecarboxylic acid were isolated by flash chromatography (based on coupling constants). Assigned geostructure).

(d) 1-benzyl 3-t-butyl 2- (2-methoxyethyl) malonate

A stirred solution of sodium hydroxide (14.4 g of 60% dispersion in mineral oil, 360 mmol) in THF (300 mL) was cooled to 0 ° C. under nitrogen. To the resulting slurry was added a solution of benzyl-t-butyl malonate (90.0 g, 360 mmol) in THF (500 mL) over 45 minutes. The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was then cooled back to 0 ° C. and then 2-bromoethyl methyl ether (50.0 g, 360 mmol) in THF (100 mL) was added over 0.5 h. The reaction was then warmed to rt and stirred for 19 h. The reaction was then refluxed for 24 hours and then cooled to room temperature. Deionized water (500 mL) was added to the reaction mixture, and the product was extracted three times with ethyl acetate (500 mL). The organic phases were combined, dried over magnesium sulphate and concentrated by evaporation under reduced pressure to afford the product (100 g) as a crude oil. The product was then purified by silica gel column chromatography using 10% diethyl ether in heptane followed by 20% diethyl ether in heptane to afford the title compound (37.1 g, 120 mmol, 33% yield) as an oil. . TLC (diethyl ether / heptane 3: 7, observed with Dragendorff's dip) R _f 0.25;

(e) 2- (t-butoxycarbonyl) -4-methoxybutanoic acid

To a solution of the product of 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 rt for 19 h. The solvent was then distilled off under reduced pressure and the resulting concentrate was diluted with deionized water (300 mL). The required solution was then washed three times with diethyl ether (400 mL). Then 1M hydrochloric acid was added to the aqueous phase until PH became 2. The acidic solution was then extracted three times with ethyl acetate (400 mL) and the combined organic layers were dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (14.7 g, 67.4 mmol, 56% yield) as an oil. TLC (diethyl ether / heptane 3: 7, observed with dragendorf slope) R _f 0.20;

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

To a mixture of the product of step (e) (20.8 g, 95.3 mmol) in pyridine (170 mL), piperidine (1.70 mL, 19.1 mmol) is added followed by paraformaldehyde (3.89 g, 130 mmol). It was. The resulting mixture was then heated at 63 ° C. for 3.5 hours. The reaction mixture was then cooled to rt and stirred for 19 h. The solvent was then distilled off under reduced pressure. Deionized water (250 mL) was then added to the concentrate followed by 2M hydrochloric acid solution (200 mL). The aqueous phase was then extracted with diethyl ether (350 mL once, then 400 mL twice). The combined organic extracts were then washed with 2M hydrochloric acid solution (400 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as an oil.

(g) t-butyl (2E) -2- (2-methoxyethyl) -3-[(4-methylphenyl) sulfonyl] -2-propenoate

To a stirred solution of para-toluenesulfonyl iodide (see J. Chem. Soc. Perkin Trans. , 1 , 1029, 1988) in dichloromethane (25.0 mL) (11.4 g, 40.2 mmol) under nitrogen A solution of the product of step (f) (5.0 g, 26.8 mmol) in dichloromethane (10 mL) at room temperature was added. The resulting solution was then stirred for 60 hours. The reaction mixture was then cooled to 0 ° C., then triethylamine (5.4 g, 53.4 mmol) was added over 15-20 minutes while maintaining the temperature at 0 ° C. The resulting mixture was then stirred at 0 ° C. for 0.5 h and then warmed to rt and further stirred for 5 h. Deionized water (100 mL) was then added to quench the reaction and the layers were separated. The aqueous phase was then extracted with dichloromethane (100 mL) and the organic extracts combined and washed with 1M hydrochloric acid solution (50 mL). The organic layer was then washed with sodium thiosulfate solution (100 mL, 5% weight / volume) followed by deionized water (100 mL). The organic layer was then dried over magnesium sulphate and the solvent was removed under reduced pressure to afford crude product (7.5 g, 22.0 mmol, 82% yield) as a thick oil. The reaction was repeated two more times using the same conditions, and then the crude product (74.6 g) was purified by silica gel flash chromatography using heptane / ethyl acetate (4: 1) as eluent to afford a white crystalline solid (48.0 g). To give the title compound; Melting point (heptane / ethyl acetate) 84-86 ° C .; TLC (ethylacetate / heptane 1: 4, observed with UV at 254 nm) R _f 0.20:

(h) 1-[(1E) -2- (t-butoxycarbonyl) -4-methoxy-1-butenyl] cyclopentane carboxylic acid

Cyclopentane carboxylic acid in dry THF (100 mL) over 10 hours under nitrogen at 0 ° C. in a stirred solution of lithium diisopropylamide (64.6 mL, 2M solution of THF / heptane / ethyl benzene) in dry THF (200 mL). (7.0 mL, 58.7 mmol) was added. The reaction was then warmed to room temperature with stirring for 2.5 hours. The resulting slurry was then cooled to 0 ° C. and then zinc chloride (1M solution in diethyl ether, 38.2 mL) was added over 1 hour. The reaction mixture was then stirred for 10 minutes and to the resulting solution was added a solution of the product of step (g) in dry THF (160 mL) over 15 minutes. The reaction mixture was then stirred for 2 hours while maintaining the temperature at 0-5 ° C. The reaction was then warmed to rt and stirred for 19 h. Isopropanol (120 mL) was then added to quench the reaction and the mixture was stirred for 1 h. The reaction mixture was filtered and then the solid byproduct was washed with THF (10 mL). Then, deionized water (400 mL), 1 M aqueous sodium hydroxide solution (200 mL) and ethyl acetate (600 mL) were added to the filtrate. Deionized water (600 mL) was further added and the resulting solid was removed by filtration. The layers were then separated and then 1M hydrochloric acid solution was added to the aqueous phase until the pH reached 2. The aqueous phase was then extracted twice with ethyl acetate (2700 mL), the organic layers combined and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude product (16.7 g) as a yellow oil. The product was then purified by silica gel flash chromatography using dichloromethane / methanol (9: 1) as eluent to afford the title compound (15.2 g, 50.9 mmol, 87% yield) as a yellow oil. TLC (dichloromethane / methanol 9: 1, observed with UV at 254 nm) R _f 0.70;

(i) sodium 1-[(1E) -2- (t-butoxycarbonyl) -4-methoxy-1-butenyl] cyclopentane carboxylate

To a stirred solution of the product of step (h) (15.0 g, 50.3 mmol) in isopropyl acetate (300 mL) was added sodium methoxide (3.0 g, 55.6 mmol). The resulting suspension was then stirred for 19 hours at room temperature. The solid was collected by filtration in vacuo, washed with isopropyl acetate and dried in a vacuum oven at 50 ° C. for 19 hours to afford the title compound (10.0 g, 31.2 mmol, 62% yield) as a white solid. Melting point (isopropyl acetate) 195-198 ° C .;

Preparation 70

1-[(2R) -3-t-butoxy-2-methyl-3-oxopropyl] cyclopentane carboxylic acid

The title compound was prepared in a similar manner to Preparations 68 and 69, except that methyl iodide was used instead of 2-bromoethylmethyl ether. NMR analysis of the δ 1.4 peak of the (+) pseudoephedrine salt gave the title compound (yield 28%) as more than 95% pale yellow oil.

Preparation Example 71

1-[(2R) -2- (t-butoxycarbonyl) -4-pentyl] -cyclopentane carboxylic acid

(R) -1- [2- (t-butoxycarbonyl) -4-pentenyl] -cyclopentane carboxylic acid in anhydrous ethanol (25 mL) (see International Patent Publication No. 9113054, Example 10) (10 g, 35.4 mmol) and 10% palladium on charcoal (600 mg) were hydrogenated at room temperature under 1 atm for 18 hours. The reaction mixture was filtered through Arbocel® and the filtrate was evaporated under reduced pressure to afford the title compound (9.6 g, 95% yield) as a yellow oil.

Preparation Example 72

3- (4-methoxyphenyl) -2-propenenitrile

4-iodoanisole (1 g, 4.2 mmol), acrylonitrile (0. 3 mL, 4.7 mmol) in acetonitrile (20 mL), tri-o-tolylphosphine (243 mg, 0.4 mmol), palladium (II ) A solution of acetate (90 mg, 0.4 mmol) and triethylamine (1.78 mL, 12 mmol) was refluxed for 14 h under nitrogen. The reaction mixture was diluted with EtOAc (50 mL) and washed with 2M sodium hydrogen carbonate (100 mL) and the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and purified by column chromatography using pentane, followed by 95: 5 pentane: tilacetate, then 90:10 pentane: ethyl acetate to give the title compound as a mixture of cis and trans isomers of yellow crystals. 414 mg, 2.5 mmol) was obtained.

Preparation Example 73

3- (4-methoxyphenyl) -1-propanamine

A solution of the product of Preparation 72 (414 mg, 2.6 mmol) in ammonium hydroxide solution (10 mL) and ethanol (10 mL) was shaken with Ra-Ni (100 mg) for 12 h under 40 psi of hydrogen. The reaction mixture was filtered through avocel, washed with ethanol (20 mL) and the filtrate was evaporated in vacuo to yield the title compound (183 mg, 1.1 mmol) as a yellow oil.

The following compounds of formula IIIa, ie, compounds of formula III wherein X is — (CH ₂ ) ₃ —, were prepared in a similar manner to those described in Preparations 72 and 73 using the precursors indicated as starting materials:

Preparation Example 93

3- (4-chloro-3-fluorophenyl) -2-propenenitrile

Diethylcyanomethyl phosphonate (3.2 mL, 18.9 mmol) was dissolved in anhydrous THF (20 mL) at 0 ° C. under nitrogen and stirred and a 60% oil dispersion of NaH (756 mg, 18.9 mmol) was added in about 10 minutes. Add portion over. The resulting gray suspension was then stirred at 0 ° C. for 1 hour and then 4-chloro-3-fluoro benzaldehyde (lancaster synthesis) (3 g, 18.9 mmol) in THF (5 mL) was added dropwise. The whole was warmed to room temperature over 60 h Water (5 mL) was added and the mixture was extracted three times with EtOAc (50 mL) The combined organics were dried over MgSO ₄ and evaporated to give a yellow oil which was eluent. Purification by column chromatography using 5% EtOAc in pentane gave the title compound (2.4 g, 70%) as a mixture of geometric isomers.

Preparation Example 94

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

Vinyl cyanide (500 mg, 2. 75 mmol) of Preparation Example 93 was dissolved in ethanol (36 mL) and 0.88 NH ₃ solution (18 mL) and RaNi (150 mg, 30% weight / weight) under H ₂ pressure of 15 psi And shaken. The catalyst was filtered through a short plug of avocel and the filtrate was evaporated in vacuo and then purified by column chromatography using 90: 10: 1 DCM: MeOH: NH ₃ as eluent to give the title compound (320 mg, 62% yield). ) Was obtained.

The compounds of formula IIIa, ie, compounds wherein X is — (CH ₂ ) ₃ —, were prepared in a similar manner to those described in Preparations 93 and 94 using the precursors indicated as starting materials:

Formula IIIa

Preparation Example 102

Quinoline-6-carboxaldehyde

6-Methyl-quinoline (Aldrich Chemical Company) (1 g, 7.0 mmol) and selenium dioxide (2.32 g, 21.0 mmol) were combined in the presence of a solvent and heated at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, dissolved in MeOH and pre-adsorbed onto silica gel. Purification by chromatography using a 3: 1 mixture of pentane: EtOAc afforded the title compound (236 mg, 21% yield).

Preparation Example 103

4- (4-methoxyphenyl) -butyramide

4- (4-methoxyphenyl) -butyric acid (Aldrich Chemical Company) (2 g, 10.4 mmol) was dissolved in DCM (50 mL) and thionyl chloride (1.85 g, 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 and further added and then distilled off and the cycle of addition / evaporation continued until all thionyl chloride was removed from the crude mixture. This mixture was dissolved in DCM (20 mL) and added dropwise at 0 ° C. to a stirred solution of 0.88 NH ₃ . After the addition was complete, the whole was stirred for 4 hours, the organic layer was separated, dried over Na ₂ CO ₃ and evaporated to afford the title compound (1.5 g) as a white solid of amide, which was used without further purification.

Preparation Example 104

4- (4-hydroxyphenyl) -butyramine

The product of Preparation Example 103 (38 g, 0.20 mol) was added dropwise to a stirred solution of LiAlH ₄ (15 g, 0.40 mol) in THF (1 L), and then all were refluxed for 16 hours. EtOAc (400 mL) was added to break up the excess hydride and most of the solvent was removed under reduced pressure. After completion of the decomposition of the hydride by addition of 2N NaOH solution (attention!) (30 mL), the resulting solution was acidified with 1N HCl and extracted and dissolved twice in water (200 mL). The aqueous extract was basified with 2N NaOH, extracted with EtOAc, dried over MgSO ₄ and evaporated to give a yellow oil of the crude amine. This oil was refluxed in aqueous HBr (160 mL) for 4 hours and then poured into water (100 mL). Then solid Na ₂ CO ₃ was added until a pH of 9-10 was obtained. The mixture was extracted completely with DCM (100 mL), dried over MgSO ₄ and evaporated to afford a white solid which was recrystallized from benzene to give the title compound (6.4 g, 35% yield). Melting point 114-116 ° C.

Preparation Example 105

t-butyl-4- (4-hydroxyphenyl) butylcarbamate

Di-t-butyl dicarbonate (1.06 g, 4.8 mmol) was added in one portion to a stirred solution of the product of Preparation 104 (400 mg, 2.4 mmol) in a mixture of water (10 mL) and dioxane (10 mL). The reaction was stirred for 72 hours, then potassium carbonate (2.0 g, 14.4 mmol) was added in one portion and the mixture was further stirred for 23 hours to fully hydrolyze all esters formed during the reaction. The mixture was transferred to a separatory funnel and the organic layer was separated, dried over MgSO ₄ and evaporated to give a yellow oil. The oil was purified by chromatography using a 2: 1 mixture of pentane: EtOAc as eluent to afford the title compound (555 mg, 86% yield).

Preparation Example 106

t-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 of Preparation 105 (555 mg, 2.1 mmol) in THF (7 mL) at room temperature under nitrogen. The mixture was stirred for 15 minutes, then MeI (0.14 mL, 2,2 mmol) was added in one portion and further stirred at room temperature for 16 hours. The reaction was diluted with EtOAc (20 mL) and washed with 3% NaHCO ₃ solution (15 mL). The organic layer was dried over MgSO ₄ and purified by chromatography using DCM as eluent to afford the title compound (500 mg, 85% yield).

Preparation Example 107

4- (4-methoxyphenyl) butylamine

The product of Preparation 106 (500 mg, 1.8 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and stirred for 16 h under nitrogen. The mixture was then poured into 10% Na ₂ CO ₃ aqueous solution (50 mL) and the organics extracted twice with EtOAc (50 mL). The combined organic layers were dried over MgSO ₄ and evaporated to afford the title product (300 mg, 94% yield) and used without further purification.

Preparation Example 108

3- (2-pyridinyl) -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 water (250 mL) was added dropwise to the stirred solution. The rate of addition was adjusted to maintain gentle reflux. After the addition was complete, the mixture was refluxed for 22 hours and the pH of the solution was adjusted to 8 using Na ₂ CO ₃ aqueous solution. The mixture was extracted with DCM (600 mL), dried over MgSO ₄ and evaporated to give a brown oil. The oil was then vacuum distilled under a pressure of about 0.6 mm Hg. Distillation at 100-107 ° C. gave the product as a clear oil (56% yield). An oil of 2- (2-cyanoethyl) -pyridine (200 mg, 1.5 mmol) was dissolved in EtOH (6 mL) and reacted with 0.88 NH ₃ solution (2 mL) and RaNi (50 mg). The mixture was hydrogenated under H ₂ pressure of 30 psi for 16 hours, then filtered and evaporated to afford the title product (about 200 mg) and used without further purification.

Preparation Example 109

2-acetyl-2H-indazole

Indazole (3.5 g, 29.6 mmol) and acetic anhydride (35 mL) were heated at 60 ° C. for 3 hours under nitrogen. Excess acetic anhydride was evaporated and the remaining oily residue was partitioned in 3% aqueous NaHCO ₃ (20 mL) and EtOAc (30 mL). The organic layer was separated, dried over MgSO ₄ and evaporated to afford the title product (4.5 g, 96% yield).

Preparation 110

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

The product of Preparation 109 (450 mg, 2.8 mmol) was dissolved in acetic acid (0.5 mL) and stirred at room temperature under nitrogen. Bromine (0.5 mL) was added over about 1 minute and then the product was further stirred for 16 hours. Excess bromine was removed by aeration for 30 minutes with nitrogen through the solution, resulting in a thick solid in the flask. Toluene (5 mL) was added and the whole was evaporated in vacuo to triturate the residue with pentane (5 mL). The residual solid was filtered off and dried under vacuum and then reacted with 1M NaOH and EtOH (6 mL each). The mixture was heated to 50 ° C. for 1 hour and then cooled to room temperature. EtOH was evaporated and the residue was extracted twice with DCM (10 mL), then dried over MgSO ₄ and evaporated to afford a 3: 1 mixture (400 mg) of the title 1-H: 2-H indazoate isomer that could not be separated. It was.

Preparation Example 111

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

The isomeric mixture of Preparation 110 (400 mg, 2.0 mmol) was dissolved in MeOH (8 mL) at room temperature under nitrogen and NaOMe (223 mg, 4.0 mmol) was added in one portion. MeI (0.32 mL, 5 mmol) was added dropwise and the mixture was heated at reflux for 4 h. The reaction was cooled to room temperature and then concentrated to a small volume (about 3 mL), then partitioned into EtOAc (20 mL) and 3% NaHCO ₃ aqueous solution. The organic layer was separated and dried over MgSO ₄ and purified by chromatography using 99: 1 DCM: MeOH as eluent to afford 1-Me isomer (100 mg, 23%) and 2-Me isomer (112 mg, 26%). Was done; 1-methyl isomer;

Preparation Example 112

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

The 1-methyl isomer of Preparation 111 (100 mg, 0.47 mmol) was dissolved in dioxane (6 mL), potassium carbonate (72 mg, 0.52 mol), acrylonitrile (0.035 mL, 0.52 mol), Pd ₂ (dba) ₃ (43 mg, 0.047 mmol) and P t-Bu ₃ (0.038 mL, 0.16 mmol) were added in order. The reaction was then refluxed under nitrogen atmosphere for 3 hours, then cooled to room temperature, filtered through a short plug of avocel and the filtrate was evaporated in vacuo. The residue was then chromatographed using 99: 1 DCM: MeOH to afford the title product (57 mg, 66%) as a mixture of cis and trans geometric isomers.

Preparation Example 113

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

The product of Preparation 112 (55 mg, 0.29 mmol) was dissolved in ethanol (4 mL) and 0.88 NH ₃ solution (1 mL) and hydrogenated to 30 psi for 2 hours at room temperature under RaNi (10 mg, 30% weight / weight). . The mixture was filtered through a short plug of avocel and the filtrate was evaporated to give the title product which was used without further purification.

Preparation Example 114

2- (4-bromophenyl) -pyridine

ⁿ BuLi (1.6M in hexanes, 34.4 mL, 55 mmol) was added dropwise to a stirred solution of 1,4-dibromobenzene (11.8 g, 50 mmol) in dry THF (100 mL) at -60 ° C. The mixture was stirred at this temperature for 15 minutes and then a solution of ZnCl ₂ (0.5M in THF, 100 mL, 50 mmol) in THF was added dropwise. The mixture was allowed to warm to room temperature over 90 minutes before Pd (PPh ₃ ) ₄ (200 mg) was added, followed immediately by 2-bromopyridine (4.8 mL, 50 mol). The whole was stirred overnight at room temperature and then evaporated to a small volume (10 mL) and diluted with EtOAc (400 mL). The solution was washed with a solution of EDTA (32 g) in water (200 mL) and brine (200 mL). And dried over MgSO ₄ and evaporated to give a yellow / green solid. The solid was purified by column chromatography using 1: 1 hexanes: DCM as eluent to afford the title product (8.3 g, 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 Example 115

3- (2,3-Dihydro-1H-inden-5-yl) -propanoic acid

3- (2,3-Dihydro-1H-inden-5-yl) -propenoic acid (500 mg, 2.66 mmol) (commercially available from Aldrich) was dissolved in ethanol (40 mL) and 10% under 15 psi H ₂ pressure. Hydrogenated with Pd / C (40 mg) for 4 hours. The mixture was filtered through a short plug of avocel and the filtrate was evaporated to give the title product (560 mg, approximately quantitative) and used without further purification.

Preparation Example 116

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

The product of Preparation 115 (190 mg, 1 mmol) was dissolved in DCM (2 mL) at room temperature under nitrogen, oxalyl chloride (132 μl, 1.5 mmol) was added first followed by DMF (1 drop). After the foam had settled, the mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in THF (2 mL) and 0.88 NH ₃ solution (0.6 mL) was added and the whole was stirred for 4 days. The reaction was quenched with water and extracted twice in EtOAc (10 mL). The combined organics were dried over MgSO ₄ and evaporated to give the title product (190m, 99%).

Preparation Example 117

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

The amide of Preparation 116 (170 mg, 0.9 mmol) was dissolved in anhydrous THF (3 mL) at 0 ° C. under nitrogen and stirred with considerable foaming to add dropwise a solution of LiAlH ₄ in THF (1M, 0.9 mL, 0.9 mmol). It was. The reaction was warmed to 60 ° C. and stirred overnight at the same temperature. The mixture was quenched with water (1 mL) and 1N NaOH solution (1 mL) was added and the solution extracted with EtOAc (50 mL), dried over MgSO ₄ , filtered and concentrated to give a pale yellow oil. The oil was purified by column chromatography using DCM: MeOH: NH ₃ at 90: 10: 1 as eluent to afford the title product (30 mg, 35%).

Preparation Example 118

3- (4-bromophenyl) -2-propenenitrile

A 60% suspension (2.16 g, 54.1 mmol) of NaH in mineral oil was suspended in THF (50 mL) and cooled to 0 ° C. under nitrogen. Diethyl-cyanomethyl phosphonate (8.74 mL, 54.1 mmol) was added dropwise and the whole was stirred at 0 ° C. for 30 minutes. Then 4-bromobenzaldehyde (10 g, 54.1 mmol) was added dropwise into a solution in THF (20 mL) and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with water, extracted three times with EtOAc (50 mL), dried over MgSO ₄ , filtered and evaporated to give a yellow oil. This oil was dissolved in a 9: 1 mixture of pentane: EtOAc to crystallize the title product (5.8 g, 52%).

Preparation Example 119

3- (4-bromophenyl) -1-propanamine

The title compound was prepared by modifying the method described in Iddon et al., JCS Perkin I, 2357, 1977. The solid LiAlH ₄ (1.2 g, 31.6 mmol) was suspended in diethyl ether (35 mL) and the suspension was heated to about 50 ° C. with stirring under nitrogen. A solution of vinyl cyanide (2.06 g, 9.88 mmol) of Preparation 118 in ether (20 mL) was added dropwise and the mixture was heated for 90 minutes. Thereafter, heating was stopped and the reaction stirred at room temperature for 16 hours. After addition of water, 1N NaOH (30 mL) and EtOAc (60 mL) were added and the whole was stirred vigorously for 30 minutes. The organic layer was separated, dried over MgSO ₄ and evaporated to give a yellow oil which was purified by column chromatography using 90: 10: 1 DCM: MeOH: NH ₃ as eluent to afford the title product (740 mg, 35%). It was.

Preparation Example 120

1- (2-chlorophenoxy) -2-propanamine

A solution of the product of Preparation 121 (11 g, 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 nitrogen. The reaction mixture was refluxed for 4 hours, then ethyl acetate was added, followed by water. The aqueous layer was acidified with 4N hydrochloric acid, shaken and separated and then alkalined with 40% sodium hydroxide solution. The aqueous layer was then extracted three times with diethyl ether (100 mL) and the combined organic extracts were dried over magnesium sulfate. The diethyl ether extract was acidified with hydrogen chloride and the resulting precipitate was filtered off. The solid was recrystallized from ethanol / petroleum ether (boiling point 60-80 ° C.) to give the title product (2.5 g, 20%). Melting point 126 to 127 ° C;

Preparation Example 121

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

1- (2-chlorophenoxy) acetone (106.6 g, 0.58 mol) (see J. Am. Chem. Soc ., 75 , 1134, 1953) was dissolved in 2N sodium hydroxide solution (420 mL) and sufficient ethanol. To a solution of hydroxylamine hydrochloride (27.8 g, 4 mol) produced a clear solution. The reaction mixture was refluxed for 30 minutes and then concentrated in vacuo and the crude residue was extracted three times with diethyl ether (200 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was distilled off to give the title product (134-136 ° C./1.35 mmHg) (4.5 g, 3.9%).

Preparation Example 122

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

4-Methoxy-benzaldehyde (Aldrich) (42 g, 0.31 mol) and pyridine (0.6 mL, enzymatic) were stirred together in a steady state and sulfonyl chloride (51 g, 0.37 while maintaining the internal reaction temperature of 25-30 ° C) mol) was added over 30 minutes. There was a violent release of gas. The mixture was further stirred at rt for 30 min and then further warmed to 70 ° C. for 4 h. Excess reagent was removed by evaporation in vacuo and the residue was dissolved in diisopropyl ether (50 mL) and poured into hexane (500 mL) with vigorous stirring to precipitate the product. The solid was filtered off, washed with hexane and dried under vacuum to afford the title product (40.3 g, 77%). Melting point 55 to 56 ° C;

Preparation Example 123

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

The product of Preparation Example 122 was converted to the diastereomeric mixture of the corresponding vinyl nitrile according to Preparation Example 93. This mixture (300 mg, 1.55 mmol) was dissolved in DCM (6 mL) at room temperature under nitrogen and tetra- ⁿ butyl-ammonium borohydride (1.6 g, 6.2 mmol) was added in portions over 5 minutes. The mixture was then refluxed for 4 hours and then evaporated to dryness. The residue was dissolved in 10% aqueous HCl (about 6 mL) and then further refluxed for 1 hour. The reaction was cooled, extracted three times with EtOAc (30 mL), dried over MgSO ₄ and evaporated to a yellow oil. Purification by column with 95/5 / 0.5 followed by DCM / MeOH / NH ₃ at 95/5/1 gave the title product (75 mg, 24%).

Preparation Example 124

Croman

4-Chromanol (Aldrich) (2.77 g, 18.4 mmol) was dissolved in acetic anhydride (3.5 mL, 36.9 mmol) and acetic acid (30 mL) and refluxed for 3 hours, then cooled to room temperature over 16 hours. Pd / C (10% weight / weight) was then added to the solution and the whole was hydrogenated for 16 hours under hydrogen pressure of 40 psi. The catalyst was filtered through an avocel pad and the filtrate was evaporated to a small volume (5 mL). The residual liquid was dissolved in EtOAc (30 mL) and washed with water (100 mL) followed by NaHCO ₃ solution (100 mL). The organic layer was dried over MgSO ₄ and evaporated to give a pale yellow oil. The oil was purified by column using 10% EtOAc / pentane to give the title product (2.1 g, 85%).

Preparation Example 125

6-bromochrome only

The product of Preparation 124 (1 g, 7.5 mmol) was dissolved in DCM (10 mL) and a solution of bromine (403 μL, 7.8 mmol) in DCM (3 mL) was added over a few minutes. After the addition was complete, the solution was brown. The mixture was stirred at rt for 3 h and then washed with water (20 mL) brine (20 mL) and the organic layer was separated, dried over MgSO ₄ and evaporated to give a dark yellow oil which was obtained using 5% EtOAc in pentane Purification by column chromatography gave the title product (1.3 g, 82%).

Preparation Example 126

5-bromo-2,2-dimethyl-2,3-dihydrobenzo [b] furan

2,2-dimethyl-2,3-dihydrobenzo [b] furan (prepared according to the method described in Baker and Shulgin, J. Org. Chem ., 28 , 2468, 1963) (500 mg, 3.38 mmol) ) Was dissolved in dichloroethane (5.5 mL), stirred at room temperature under nitrogen and N-bromosuccinimide (661 mg, 3.72 mmol) was added in one portion. The reaction was then refluxed for 2 hours, 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 using 5% ether in pentane as eluent to afford the title product (604 mg, 79%).

Preparation Example 127

5-bromo-2-methyl-2,3-dihydro-1-benzo [b] furan

Using the same procedure as Preparation Example 126, the title product (87%) was obtained from 2-methyl-2,3-dihydro-1-benzo [b] furan (commercially available from TCI, Japan).

Preparation Example 128

2,3-dihydrobenzo [b] furan-7-carboxaldehyde

2,3-dihydrobenzo [b] furan (Maveridge Chemicals) (25 g, 0.21 mol) was dissolved in DCM (500 mL) and stirred at 0 ° C. under nitrogen. SnCl ₄ (36.5 mL, 0.3 mol) was added in one portion to produce a pale yellow solution. Dichloromethyl methyl ether (18.8 mL, 0.21 mol) was then added and the solution stirred for 30 minutes before the cold bath was removed and the reaction poured into ice water (1000 mL). The organic layer was separated and washed twice with water (100 mL), 2N HCl (100 mL) and brine (50 mL), then charcoal (30 g) and Na ₂ SO ₄ were added to the solution. Filtration with celite and evaporation gave a black oil, which was purified by flash chromatography using 7-10% EtOAc in pentane to give the title product (190 mg, 0.01%).

Preparation 129

1-benzofuran-3-ylacetonitrile

Sodium hydride (268 mg, 6.7 mmol) was slurried in dry THF (10 mL) at 0 ° C. under nitrogen and diethyl cyanomethyl phosphonate (1.1 mL, 6.7 mmol) was added dropwise and the whole was stirred for 45 minutes. . Then 3-coumaranone (Coumaranone, Lancaster) (900 mg, 6.7 mmol) was added dropwise and the whole was stirred at room temperature for 45 minutes. The reaction was diluted with EtOAc (15 mL) and water (15 mL), then the organic layer was separated, dried over MgSO ₄ , evaporated, and the residue was purified by flash chromatography using 0-5% EtOAc in pentane. The title product (940 mg, 91%) was obtained.

Preparation Example 130

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

The product of Preparation 129 (400 mg, 2.55 mmol) was combined with ammonium hydroxide solution (10 mL), ethanol (20 mL) and 30 wt.% Ra-Ni (120 mg, catalyst) and 16 h at room temperature under 30 psi hydrogen pressure. Hydrogenated. The catalyst was filtered through plug abocel and the tan filtrate was purified by chromatography using 0-5% MeOH in DCM to afford the title product (380 mg, 93%).

Preparation Example 131

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

The product of Preparation 130 (200 mg, 1.24 mmol) was mixed with ethanol (20 mL) and Pd / C (20 mg, 10 wt.%) And hydrogenated for 48 hours under hydrogen pressure of 40 psi. Additional catalyst (20 mg) was added and the whole was further hydrogenated at 60 psi and 40 ° C. for 72 hours. The catalyst was filtered through a short plug of avocel and the filtrate was evaporated to dryness. The residue was purified by column chromatography using DCM / MeOH / NH ₃ at 90/10/1 as eluent to afford the title product (11 mg, 55%).

Preparation Example 132

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

To a stirred suspension of sodium hydroxide (247 mg, 6.16 mmol) in anhydrous THF (6 mL) was added a solution of diethylcyanomethyl phosphonate (0.98 mL, 6.16 mmol) in THF (2 mL) at 0 ° C. under nitrogen. The whole was stirred for 1 h at 0 ° C. A solution of 5-acetyl-2,3-dihydro [b] benzofuran (Aldrich) (1 g, 6.16 mmol) in THF (2 mL) was added dropwise and the whole was at room temperature. Stir for 16 h Water (20 mL) and EtOAc (20 mL) were added and the organic layer was separated and the aqueous layer was extracted twice with EtOAc (20 mL) The combined organics were dried over MgSO ₄ , filtered and evaporated. The solid was purified by column chromatography using EtOAc in 20-30% pentane as eluent to afford the title product (789 mg, 69%).

Preparation Example 133

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

The product of Preparation 132 was dissolved in ethanol (20 mL) and ammonium hydroxide solution (5 mL) and the whole was hydrogenated with Ra-Ni (200 mg, 30 wt.%) For 16 hours under hydrogen pressure of 30 psi. Then additional catalyst (100 mg) was added and hydrogenation continued for 16 h. The reaction mixture was filtered through a short plug of avocel and the filtrate was evaporated to a small volume under vacuum. The residue was then co-evaporated twice from toluene (20 mL) to remove traces of water to give the title product (780 mg, 96%) which was used without further purification.

Preparation Example 134

7-methyl-2,3-dihydro-1-benzofuran-3-ol

To a stirred suspension of trimethyl sulfoxium chloride (3.78 g, 0.03 mol) in anhydrous THF (60 mL), sodium hydroxide (1.16 g, 0.03 mol) was added and the whole was heated to reflux for 1 hour. A solution of 2-hydroxy-3-methyl-benzaldehyde (lancaster) (4 g, 0.03 mol) in THF (30 mL) was added by syringe and the resulting orange suspension was stirred at reflux for 5 hours. Water (50 mL) was added and the organics extracted three times with ether (50 mL). The combined organics were dried over MgSO ₄ , filtered and evaporated in vacuo to give an orange oil which was purified by column chromatography using EtOAc in 15-25% pentane to give the title product (2 g, 45%).

Preparation Example 135

7-methyl-2,3-dihydro-1-benzofuran

To a stirred solution of the product of Preparation 134 (500 mg, 3.3 mmol) in acetic acid (5 mL) was added acetic anhydride (0.63 mL, 6.7 mmol) and stirred under reflux for 2 hours under nitrogen, followed by room temperature over 16 hours. Warmed to. Pd / C (30 mg, 10 wt%) was added directly to the solution and hydrogenated for 16 hours at room temperature under hydrogen pressure of 40 psi. The catalyst was filtered through abocel of plugs and the filtrate was concentrated in vacuo to give a pale yellow residue which was dissolved in EtOAc (20 mL), washed three times with water (20 mL) and with NaHCO ₃ (20 mL) and with MgSO ₄ . Drying and evaporation gave a pale yellow oil. The oil was purified by column chromatography using 3% EtOAc in pentane as eluent to afford the title product (261 mg, 58%).

Preparation Example 136

5-bromo-7-methyl-2,3-dihydro-1-benzofuran

To a stirred solution of the product of Preparation 135 (200 mg, 1.49 mmol) in dichloroethane (2.5 mL) was added N-bromosuccinimide (318 mg, 1.79 mmol) and the whole was stirred under reflux for 16 hours under nitrogen. The mixture was concentrated in vacuo to yield a pale orange-brown solid and purified by column chromatography using 1% EtOAc in pentane as eluent to afford the title product (112 mg, 35%).

Preparation Example 137

2-hydroxy-4-methyl-benzaldehyde

To a stirred solution of the phenol (1g, 9.2 mmol), SnCl 4 (241mg, 0.92 mmol) at room temperature under nitrogen and tri-3-methyl-toluene (5㎖) was added ^n-butylamine (0.6㎖, 2.77 mmol) . After 20 minutes, paraformaldehyde (611 mg, 20.3 mmol) was added and the whole was stirred at 100 ° C. for 16 h. The reaction mixture was diluted with water (20 mL) and acidified to pH 2 with 2N HCl. The solution was extracted with ether (25 mL), washed with brine (20 mL), filtered over MgSO ₄ and evaporated to a brown oil. The oil was purified by column chromatography using 5% EtOAc in pentane as eluent to afford the title product (319 mg, 25%).

Preparation Example 138

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

The title compound was obtained from the product of Preparation Example 137 by the same three-step sequence as detailed above in Preparation Examples 134 to 136.

Preparation Example 139

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

2,3-dihydrobenzo [b] furan-5-carboxaldehyde (Aldrich Chemicals) (2 g, 13.5 mmol), acetone (2.73 mL, 37.1 mmol), water (1.35 mL) and 10% aqueous NaOH (0.34) Ml) were added together and the whole was stirred for 16 h at room temperature. The yellow solid was dissolved in DCM (about 15 mL) and 2N HCl was added to make a solution at pH 2. Water (10 mL) was added and the organic layer was extracted twice with DCM (20 mL). The combined organics were dried over MgSO ₄ and concentrated in vacuo to afford a yellow solid which was purified by column chromatography using 15-30% EtOAc in pentane as eluent to give the title product (2.13 g, 84%).

Preparation 140

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

The product of Preparation 139 (2.12 g, 11.3 mmol) was dissolved in ethanol (40 mL) and hydrogenated with Pd / C (200 mg, 10 wt.%) For 4 hours under 15 psi of hydrogen atmosphere. The mixture was filtered through a short plug of avocel and the filtrate was evaporated in vacuo to give a colorless oil and purified by column chromatography using 15-25% EtOAc in pentane to give the title product (1.53 g, 71%). It was.

Preparation Example 141

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

To a stirred solution of the product of Preparation 140 (500 mg, 2.6 mmol) in methanol (25 mL) was added ammonium acetate (4.05 g, 52.6 mmol) and sodium cyanoborohydride (661 mg, 10.5 mmol) and the whole was cooled to room temperature. Stir overnight at. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (20 mL) and water (20 mL). The organics were extracted, washed twice with water (20 mL), dried over MgSO ₄ and evaporated to afford a clear oil. The oil was purified by column chromatography using 5% MeOH in DCM as eluent to afford the title product (187 mg, 37%).

Preparation Example 142

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

To a stirred solution of 5-acetyl-2,3-dihydrobenzo [b] furan (Aldrich) (1 g, 6.17 mmol) in toluene (60 mL) methyl cyanoacetate (0.60 mL, 6.78 mmol), benzylamine (0.07 ML, 0.61 mmol) and acetic acid (0.3 mL, 5.3 mmol) were added and the whole was refluxed for 16 h with a Dean-Stark apparatus. The reaction mixture was cooled and washed with 2N HCl (30 mL), NaHCO ₃ (30 mL) and brine (30 mL), dried over MgSO ₄ and evaporated to give a yellow residue. The residue was purified by column chromatography using 15-20% EtOAc in pentane as eluent to afford the title product (902 mg, 60%).

Preparation Example 143

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

Copper (I) iodide (109 mg, 0.57 mmol) was added to a stirred mixture of MeLi (1.4 M in ether, 0.76 mL, 1.07 mmol) in ether (2 mL) at −25 ° C. under nitrogen. After stirring for 10 minutes, a solution of the product of Preparation 142 (100 mg, 0.41 mmol) in ether (2 mL) was added dropwise, and then the whole was stirred at -25 ° C. for 2 hours, further stirred for 2 hours, and 0 ° C. Warmed to. Saline (10 mL) was added and the organics were extracted with EtOAc (10 mL), dried over MgSO ₄ , filtered and evaporated. The residue in pentane was then purified by column chromatography using 20% EtOAc to afford the title product (92 mg, 86%).

Preparation Example 144

3- (2 3-dihydro-1-benzofuran-5-yl) -3-methylbutannitrile

To a stirred solution of the product of Preparation 143 (400 mg, 1.54 mmol) in ethanol (1.5 mL) and dioxane (1.5 mL), solid KOH (87 mg, 1.54 mmol) was added and the whole was stirred at reflux for 6 hours. The reaction mixture was concentrated in vacuo and dissolved in water (15 mL). The aqueous layer was washed with toluene (15 mL) and then acidified to pH 1 with 2N HCl and the product extracted twice with EtOAc (20 mL). The organic layers were combined, washed with brine (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo to yield an orange oil which was used without further purification.

The oil was dissolved in DMA (2 mL) and heated at 150 ° C. for 2 hours, then cooled to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and then dissolved in EtOAc (10 mL). The organics were washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo to give an orange oil. The oil was purified by column chromatography using 15% EtOAc in pentane as eluent to afford the title product (100 mg, 32%).

Preparation Example 145

t-butyl-3- (2,3-dihydro-1-benzofuran-5-yl) -3-methylbutylcarbamate

The product of Preparation 144 (250 mg, 1.24 mmol) was dissolved in methanol (12 mL) at 0 ° C. under nitrogen and di-t-butyl dicarbonate (542 mg, 2. 48 mmol), NiCl ₂ (161 mg, 1.24 mmol), NaBH ₄ (329 mg, 8.69 mmol was then added in portions. The black solution was warmed to rt overnight and then concentrated in vacuo. The residue was partitioned in EtOAc (20 mL) and NaHCO ₃ solution (20 mL) and the mixture was filtered All solids were removed and the filtrate was extracted twice with EtOAc (20 mL) The combined organics were dried over MgSO ₄ , filtered and evaporated to afford the title product (366 mg, 96%) and used without further purification.

Preparation Example 146

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

The product of Preparation 145 (366 mg, 1.20 mmol) was dissolved in DCM (15 mL) at 0 ° C. and hydrogen chloride gas was bubbled through the solution for 15 minutes with stirring. The flow of HCl was stopped and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was allowed to flow down into ether (20 mL) to form a white precipitate. This solid was filtered off, washed with ether and dried in vacuo to yield the title product (177 mg, 61%).

Preparation Example 147

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

To a stirred solution of diisopropylamine (8.65 mL, 61.8 mmol) in anhydrous THF (100 mL) was added dropwise a 2.5M solution (23.7 mL, 59.2 mmol) of ⁿ BuLi in hexanes at −20 ° C. under nitrogen. The solution was warmed to 0 ° C. over 20 minutes and then cooled to 70 ° C. A solution of methyl-2- (4-chlorophenyl) acetate (9.5 g, 51.5 mmol) in THF (5 mL) was added dropwise over 5 minutes and then the whole was stirred for 30 minutes. Iodoacetonitrile (5.03 mL, 69.5 mmol) was then added slowly and the combined solutions allowed to come to room temperature over 72 hours. A saturated aqueous NaHCO ₃ solution (20 mL) was added and the mixture was concentrated to about 50 mL in vacuo and then reacted with 1N HCl (100 mL). The mixture was extracted with EtOAc (120 mL), dried over MgSO ₄ and evaporated to afford a dark brown oil which was purified by column chromatography using 2: 1 DCM: pentane as eluent to give the title product (8.6 g, 75%). Obtained.

Preparation Example 148

4-amino-2- (4-chlorophenyl) butanol

The product of Preparation 147 (235 mg, 1.05 mmol) was dissolved in THF (1 mL) and added dropwise to a stirred solution of LiAlH ₄ (2.1 mL, 1M solution in THF, 2.1 mmol) in THF at 0 ° C. under nitrogen. The mixture was then stirred at rt for 2 h and cooled to 0 ° C. Water (0.08 mL) was added followed by 3N aqueous NaOH solution (0.08 mL), followed by dilution with THF (2 mL) and water (0.24 mL). The suspension was stirred for 5 minutes, then filtered and the filtrate was evaporated to yield a yellow gum. It was dissolved in EtOAc (5 mL) and extracted with 0.5N HCl solution (0.3 mL), basified to pH 10 with Na ₂ CO ₃ solution and extracted three times with EtOAc (3 mL). The combined organics were dried over MgSO ₄ and evaporated to give the title product (60 mg, 29%).

Preparation Example 149

t-butyl- (4-chlorophenyl) acetate

To a suspension of N, N-dimethyl-formamide-di-t-butyl acetal (25 mL, 104.4 mmol) in toluene (90 mL) was added p-chlorophenyl acetic acid (5.94 g, 34.8 mmol) and the whole was 80 Heated at < RTI ID = 0.0 > The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL), 3% aqueous NaHCO ₃ (50 mL) and brine (20 mL), dried over MgSO ₄ and concentrated to give an oil. The oil was purified using 50% DCM in pentane to give the title product (2.4 g, 30%).

Preparation 150

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

The product of Preparation 149 was alkylated using methyl iodide as alkylating agent following the same procedure as described in Preparation 147. Purification by column chromatography using 25% DCM in pentane as eluent gave the title product (95%).

Preparation Example 151

The product of Preparation 150 was alkylated following the same procedure as described in Preparation 137. Purification by column chromatography using 70% DCM in pentane as eluent gave the title product (82%).

Preparation Example 152

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

The product of Preparation 151 was reduced with LiAlH ₄ following the procedure of Preparation 148 to afford the title product (35%). This reduction product was pure enough without further purification.

Biological assay

IC ₅₀ values of the compounds of the present invention for NEP and ACE were determined using the methods described in EP 1097719 A1, paragraphs [0368] to [0376]. The IC ₅₀ values present below were measured using the NEP of dog kidneys. In addition, the IC ₅₀ values of some compounds of the invention were measured using the NEP of human kidneys, which were similar to the values measured using NEP in dogs.

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

The title compound of the examples herein showed an IC ₅₀ value for NEP of less than 400 nM.

The title compounds of Examples 1-25, 27-37, 39-41, 43-48, 50-53 and 55-67 exhibit IC ₅₀ values for NEPs up to ₁₅₀ nM and have more than 300 folds Selectivity was shown for ACE.

In particular, the title compound of Example 3 showed an IC ₅₀ value for NEP of 22 nM, the title compound of Example 4 showed an IC ₅₀ value for NEP of 4 nM, and the title compound of Example 21 gave a 3 nM NEP IC ₅₀ values for, the title compound of Example 33 showed an IC ₅₀ value for NEP of 47 nM, the title compound of Example 43 showed an IC ₅₀ value for NEP of 29 nM, and Example 51 The title compound showed an IC ₅₀ value for NEP of 9 nM. The title compounds of Examples 3, 4, 21, 33, 43 and 51 were all more than 300 folds selective for ACE.

Animal model of female sexual arousal reaction

The title compound of Example 22 (hereinafter referred to as "the selected compound") was administered according to the protocol described in EP 1097719 A1. The selected compound was dissolved in 5% physiological saline. Selected compounds and vehicle controls were injected at 500 [mu] l / min into the femoral vein through a three-way nipple using a Harvard pump. After injection, heparin physiological saline (Hepsaline) was flowed into the catheter so that selected compounds did not remain in the catheter.

Selected compounds tested at clinically relevant doses significantly stimulated the pelvic nerves to increase genital blood flow (see FIG. 1). Selected compounds with high peaks increased vaginal blood flow up to 56% (n = 3) and clitoris blood flow up to 50% (n = 3) compared to the control increase over time.

1 shows the effect of administration of selected compounds on genital blood flow in rabbits. The selected compound improved pelvic nerve stimulated (PNS) increase in genital blood flow in a sexually excited anesthesia rabbit model. Repeatable PNS at 15 minute intervals induced a reproducible increase in genital blood flow (hatched bars). Administration of the selected compound (grey bar) shows peaks in the clitoris and vaginal blood flow induced by submaximal stimulation frequency (eg, 4 Hz) compared to the control stimulation over time or the increase observed in the vehicle control (dashed bar). The increase was improved. Improving stimulation of the clitoris blood flow 50% and vaginal blood flow 56% (n = 3) after about 0.5 mg / kg intravenous bolus injection. All changes in data expressed as mean ± sem were monitored using laser Doppler technology.

There was no major effect on NEP inhibition or basal / unstimulated genital blood flow.

Female New Zealand rabbits (approximately 2.5 kg) to 0.5 ml / kg (muscle) of medetomidine (Domitor®) and 0.25 ml / kg (muscle of ketamine (Vetalar®)) ) Mixture was pre-dosed and oxygen uptake was maintained through the face mask. The rabbit was tracheotomized using a Portex (trademark) with an uncuffed endotracheal tube ID, connected to the respiratory tract, a breathing rate of 30-40 breaths per minute, a breathing volume of about 18-20 ml, and It was maintained under the maximum airway pressure of 10 cm H ₂ O. The anesthetic was then replaced with isoflurane and O ₂ continued to breathe at ₂ L / min. The right ear marginal vein was cannulated using 23 or 24G urinary catheter and injected with lactate ringer solution at 0.5 ml / min. During invasive surgery the rabbits were kept at 3% isoflurane and dropped to 2% to maintain anesthesia.

The left inguinal part of the rabbit was depilated and made a vertical incision approximately 5 cm long along the thighs. Femoral veins and arteries were exposed, isolated and cannulated with PVC catheter (17G) for infusion of drugs and compounds. Cannulation was repeated for the femoral artery and the catheter was inserted 10 cm deep to allow the catheter to reach the abdominal aorta. The arterial catheter was connected to a Gould system to measure blood pressure. In addition, samples for blood gas analysis were also taken through arterial catheterization. Systolic and diastolic blood pressures were measured and average arterial blood pressure was calculated using the formula [(dilator × 2 + systolic) ÷ 3]. Heart rate was measured using a pulse oximeter and Po-ne-mah data acquisition software system (Ponemah Physiology Platform, Gould Instrument Systems Inc).

An abdominal cavity was incised to create an abdominal cavity. An incision was made approximately 5 cm long just above the pubic bone. The fat and muscles were dissected smoothly to expose the lower abdominal nerves flowing down the body cavity. It is important to keep close to the side curves of the pubic wall to avoid damaging the femoral veins and arteries above the pubic bone. The sciatic and pelvic nerves are at the core and their backs are further dissected to confirm their location. Once the sciatic nerve was identified, the pelvic nerve location was easily identified. The term "pelvic nerve" is a generic term and therefore cannot be identified in greater detail in the anatomical books associated with it. However, the stimulation of the nerve increases the vaginal and clitoris blood flow, and the nerve response of the pelvic region. The pelvic nerve was removed from the surrounding tissue, and a Harvard bipolar stimulating electrode was placed around the nerve. The nerve was slightly lifted up and slightly tensioned, and the electrode was fixed at that position. Approximately 1 ml of light paraffin wax was applied around the nerve and electrode. It acts as a protective lubricant for nerves and prevents blood contamination of the electrodes. The electrode was connected to a Grass S88 stimulator. Pelvic nerves were stimulated using variables of −0.5 to 5V, pulse width 0.5 ms, duration of stimulation 10 seconds and frequency range 2-16 Hz. When the nerve was stimulated every 15-20 minutes, a reproducible response was obtained. A frequency response curve was determined at the beginning of each experiment to determine the optimum frequency (usually 4 Hz) used as the submaximal response. The Harvard 22 infusion pub was used to inject the compound (s) to be tested through the femoral vein under a continuous 15 minute stimulation cycle.

The abdominal center was dissected at the tail end of the pubic bone to expose the pubic area. Any connective tissue was removed, the film of the clitoris was exposed, and its walls were free of small vessels. Any connective tissue was removed to expose the outer wall. The first laser Doppler flow probe was inserted 3 cm into the vagina so that half of the probe was visible. The second probe was placed just above the clitoris wall. The positions of these probes were then adjusted until a signal appeared. The second probe was placed just above the vessel surface on the outer wall. These two probes were fixed in that position. Vaginal and clitoris blood flows were recorded numerically directly from the flowmeter using Four-Ne-Ma data acquisition software, or indirectly by Gould chart recorder tracking. Calibration was made at the start of the experiment (0-125 ml / min / 100g tissue).

Animal models of male erection reaction

Anesthetized rabbit way

The title compound of Example 22 ("Selected Compound") alone and in an optional and potent PDE5 inhibitor 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl]- A mixture with 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 compound was dissolved in physiological saline + 5% 1M NaOH. The Harvard 22 pump was used to inject selected compounds and vehicle controls at 500 μl / min through the 3-way nipple into the femoral vein. After injection, the catheter was run with heparinized saline solution (hepatalline) so that the selected compound did not remain in the catheter. PDE5 inhibitors were dissolved in physiological saline + 5% 1M HCl and compound and vehicle controls were injected at a rate of 0.1 ml / sec and maintained for 15 minutes before stimulating the pelvic nerves.

Two experiments were performed: (a) effect on penile cavernous intracranial pressure (ICP) following administration of selected compounds alone and (b) mixtures with PDE 5 inhibitors. The effect on ICP is shown in FIG. 2. Data are expressed as mean percentage increase ± sem. ^* P <0.01, married Student's t-test increased compared to control.

When administered alone, a 37 ± 7% increase in submaximal stimulated penile cavernous internal pressure was observed (see FIG. 2, light gray column, n = 4).

Administration of a mixture of selected compounds with a selective PDE5 inhibitor (1 mg / kg intravenous bolus) resulted in a 70 ± 4% increase in submaximal stimulated penile cavernosal pressure (see FIG. 2, dark gray column, n =). 3).

There was no major effect of concomitant NEP / PDE5 inhibition on NEP inhibition or basal / unstimulated penile cavernous intracranial pressure.

Male New Zealand rabbits (approximately 2.5 kg) were pre-mixed with a mixture of 0.5 ml / kg (intramuscular) of medetomidine (domer®) and 0.25 ml / kg (in muscle) of ketamine (betatal®) Dosing and oxygen inhalation were maintained through the face mask. The rabbit is tracheotomized using a Fortex® with uncurved endotracheal tube ID, connected to the respiratory tract, and has a breathing rate of 30-40 breaths per minute, a breathing volume of about 18-20 ml and a maximum of 10 cm H ₂ O. Kept under airway pressure. The anesthetic was then replaced with isoflurane and O ₂ continued to breathe at ₂ L / min. The right ear marginal vein was cannulated using 23 or 24G urinary catheter and injected with lactate ringer solution at 0.5 ml / min. Rabbits were maintained in 3% isoflurane and dropped to 2% to maintain anesthesia during open surgery. After exposing and isolating the left jugular vein, a PVC catheter (17G) was intubated to inject the selected compound or mixture thereof.

The hair of the rabbit's left inguinal region was removed and a vertical incision of about 5 cm along the thigh was performed. After exposing and isolating the femoral vein and artery, the PVC catheter (17G) was intubated to inject the selected compound or mixture thereof. Intubation was repeated in the femoral artery, with the catheter inserted 10 cm deep to ensure that the catheter reached the abdominal aorta. The arterial catheter was connected to a Gould system to record blood pressure. In addition, a sample for blood gas analysis was taken through an arterial catheter. The systolic and diastolic blood pressures were measured and the average arterial blood pressure was calculated using the equation, diastolic blood pressure x 2 + systolic blood pressure) ÷ 3. Pulse oxymeter and Po-ne-mah data acquisition software systems (Ponemah Physiology Platform, Gould Instrument Systems Inc.) Heart rate was measured.

An abdominal central incision was made into the abdominal cavity. The incision was about 5 cm long just above the pubic bone. The fat and muscles were bluntly dissected to reveal the lower abdominal nerves in the lower body cavity. It was essential to keep close to the lateral curves of the pubic wall to avoid damage to the femoral veins and arteries placed on the pubic bone. The sciatic and pelvic nerves were deeper and additional post-incision locations were found on the back of the earthenware. The sciatic nerve was identified, and then the pelvic nerve was easily found. The term pelvic nerve is loosely applied, and anatomy books on it do not sufficiently confirm this nerve. However, the stimulation of this nerve causes intracavernosal pressure and increased corpus cavernosum blood flow, and innervation of the pelvic region. Pelvic nerves were liberated from surrounding tissue and placed Harvard bipolar stimulation electrodes around the nerves. After the nerves were slightly lifted up and slightly tense, the position of the electrodes was fixed. Approximately 1 ml of light paraffin oil was provided around the nerves and electrodes. It acts as a protective lubricant for nerves and prevents blood contamination of the electrodes. The electrode was connected to a Grass S88 stimulator. Pelvic nerves were stimulated using the following parameters: 20 seconds of stimulation duration at 0.5-5 V, pulse interval 0.5 ms, and frequency 2-16 Hz. A reproducible response was obtained when nerves were stimulated every 15-20 minutes. Several stimuli using these parameters were performed to establish an average regulatory response. Selected compounds or mixtures thereof were injected via the cervical vein using a Harvard 22 infusion pump that allows a continuous 15 minute stimulation cycle. The skin and connective tissue around the penis were removed to expose the penis. A catheter set (Insyte-W, Becton-Dickinson 20 gauge 1.1x48 mm) was inserted through the tunica albica into the left cavernous cavernous space, the needle was removed, and the flexible catheter was left. The catheter was connected to the Gould system via a transformer (Ohmeda 5299-04) to record intracavernosal pressure. Once the intracavernosal pressure was established, the catheter was sealed in place using Vetbond (tissue adhesive, 3M). The heart rate was measured using a pulse oximeter and a Ponema Data Acquisition software system (Ponema Physiologic Platform, Wolfe Instruments Systems, Inc.).

Numbers obtained directly from the flowmeter using a Foreman Data Acquisition Software System (Ponema Physology Platform, Gould Instrument Systems, Inc.), or indirectly from the trace of the Gould chart recorder. The blood flow in the corpus cavernosum was recorded as the number obtained. The scale was calibrated at the start of the experiment (0-125 ml / min / tissue 100 g).

Claims (28)

A compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof: Formula I Where R ¹ is halo, hydroxy, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, carbocyclyl, carbocyclyloxy, C ₁ -C ₄ alkoxycarbocyclyloxy, heterocyclyl, heterocyclyloxy, -NR ² R ³ , -NR ⁴ COR ⁵ , -NR ⁴ SO ₂ R ⁵ , -CONR ² R ³ , -S (O) _p R ⁶ , -COR ^7, and -CO ₂ (C ₁ -C ₄ alkyl) C ₁ -C ₆ alkyl, which is selected from the group may be substituted with one or more substituents which may be the same or different, or consisting of; R ¹ is carbocyclyl or heterocyclyl, each of which is further selected from the group further comprising C ₁ -C ₆ alkyl and may be substituted with one or more substituents which may be the same or different; Or R ¹ is hydrogen, C ₁ -C ₆ alkoxy, —NR ² R ³ or —NR ⁴ SO ₂ R ⁵ ; R ² and R ³ are the same or different and are carbocyclyl or heterocyclyl, each of which may be substituted with C ₁ -C ₄ alkyl, hydroxy or C ₁ -C ₄ alkoxy; Hydrogen or C ₁ -C ₄ alkyl; Or R ² and R ³ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N- (C ₁ -C ₄ alkyl) piperazinyl group; R ⁴ is hydrogen or C ₁ -C ₄ alkyl; R ⁵ is C ₁ -C ₄ alkyl, CF ₃ , carbocyclyl, C ₁ -C ₄ alkylcarbocyclyl, C ₁ -C ₄ alkoxycarbocyclyl, heterocyclyl, C ₁ -C ₄ alkoxy or -NR ² R ³ ; R ⁶ is C ₁ -C ₄ alkyl, carbocyclyl, heterocyclyl or NR ² R ³ ; R ⁷ is C ₁ -C ₄ alkyl, carbocyclyl or heterocyclyl; p is 0, 1, 2 or 3; X is-(CH ₂ ) _n -or-(CH ₂ ) _q -O-, wherein Y is bonded to oxygen, wherein at least one hydrogen atom in X is C ₁ -C ₄ alkoxy, hydroxy, hydroxy Independently substituted with hydroxy C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, carbocyclyl, heterocyclyl, or one or more fluoro or phenyl groups substituted or unsubstituted C ₁ -C ₄ alkyl ; n is 3, 4, 5, 6 or 7; q is 2, 3, 4, 5 or 6; Y is phenyl or pyridyl, which may each be substituted with one or more R ⁸ groups, which may be the same or different; R ⁸ is hydroxy; Mercapto; halogen; Cyano; Acyl; Amino; Mono (C ₁ -C ₄ alkyl) amino; Di (C ₁ -C ₄ alkyl) amino; Carbocyclyl or heterocyclyl, one of which is C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or Substituted or unsubstituted with halogen); C ₁ -C ₆ alkoxy; Phenoxy; C ₁ -C ₆ alkylthio; Phenylthio; Or alkyl substituted with C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, halogen or phenyl; Or two R ⁸ groups on adjacent carbon atoms together with the carbon atoms linked to each other C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C It can form a 5- or 6-membered condensed carbocyclic or heterocyclic ring which is optionally substituted with ₆ alkylthio or halogen. The method of claim 1, R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl Or a C ₁ -C ₆ alkyl substituted with phenyl, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The method of claim 2, R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl Phosphorus compounds, or pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof. The method of claim 3, wherein R ¹ is C ₁ -C ₄ alkyl or C ₁ -C ₆ alkoxy C ₁ -C ₃ alkyl, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The method according to any one of claims 1 to 4, A compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof: Formula Ia The method according to any one of claims 1 to 5, A compound wherein X is-(CH ₂ ) _n -and at least one hydrogen atom in X may be substituted with one or more groups as defined in claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The method according to any one of claims 1 to 6, When present, n is 3 or 4, or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof. The method according to any one of claims 1 to 7, R ⁸ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl; Or two R ⁸ groups on adjacent carbon atoms, together with the carbon atoms linked to each other, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C A compound capable of forming a 5- or 6-membered condensed carbocyclic ring or heterocyclic ring which is optionally substituted with ₆ alkylthio or halogen, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The method according to any one of claims 1 to 8, R ⁸ is carbocyclyl selected from cyclopentyl, cyclopropyl, cyclohexyl and phenyl, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The method according to any one of claims 1 to 8, R ⁸ is a heterocyclyl selected from pyridyl, oxadiazolyl, pyrazolyl and triazolyl, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The method according to any one of claims 1 to 8, Y is phenyl, and two R ⁸ groups on adjacent carbon atoms together with the carbon atoms linked to each other are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzo A compound which forms a 5- or 6-membered condensed carbocyclic or heterocyclic ring selected from furanyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl, or a pharmaceutically acceptable salt, solvent compound thereof Shape or prodrug. The method of claim 1, (2R) -2-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} pentanic acid (Example 16); 3-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] propanoic acid (Example 18); 3-{[1-({[3- (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] propanoic acid (Example 21); 2-{[1-({[3- (4-chlorophenyl) propyl] amino) carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 15); 2-{[1-({[3- (4-fluorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 4); 4-methoxy-2-{[1-({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} butanoic acid (Example 1); 2-{[1-({[3- (2,3-Dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] -methyl} -4-methoxybutanoic acid (implemented Example 11); (2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22); And (2S) -2-{[1-({[3- (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxy moiety A compound selected from the group consisting of carbonic acid (Example 25), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. (2S) -2-{[1-({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22). 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable thereof, for use in the manufacture of a medicament for treating or preventing a condition that can inhibit a neutral endopeptidase resulting in a beneficial response. Use of possible salts, solvates, polymorphs or prodrugs. The method of claim 14, Use if symptoms are female sexual dysfunction or male erectile dysfunction. The method of claim 15, Symptomatic female sexual excitement for disabled use. The method according to any one of claims 14 to 16, Use for systemic administration of a compound. The method of claim 17, Use for oral administration of the compound. The method according to any one of claims 14 to 16, Use for topical administration of a compound. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for use as a medicament. A method of treating a mammal, comprising treating the mammal using a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvent compound, polymorph or prodrug thereof. A method of treating or preventing a condition that can inhibit neutral endopeptidase to yield a beneficial response. The method of claim 21, The method in which symptoms are defined in claim 15 or 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, together with a pharmaceutically acceptable excipient, diluent or carrier. A mixture of a compound according to any one of claims 1 to 13 and at least one active ingredient selected from the group consisting of (a) to (h): (a) a PDE5 inhibitor, more preferably 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-azetinyl) -2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; And pharmaceutically acceptable salts thereof; (b) NPY Y1 inhibitors; (c) dopamine agonists such as apomorphine or optional D ₂ , D ₃ or D ₂ / D ₃ agonists such as pramipexole and ropylinol; (d) melanocortin receptor agonists or modulators, or melanocortin enhancers, preferably melanotan II, PT-14 and PT-141; (e) agents, antagonists or modulators for 5HT2C; (f) estrogen receptor modulators, estrogen agonists and / or estrogen antagonists, preferably raloxyphene, tibolone or lasopoxifen; (g) androgens such as androsterone, dehydro-androsterone, testosterone, androstandioone and synthetic androgens; And (h) Estrogens such as estradiol, estrone, estriol and synthetic estrogens such as estrogen benzoate. (a) reacting a compound of formula I with a compound of formula III to yield a compound of formula IV; (b) reacting the compound of formula IV under suitable deprotection conditions to yield the compound of formula I; And optionally (c) forming a salt A process for preparing a compound of formula (I) or a salt thereof, comprising: Formula I In the above formulas, R ¹ , X and Y are as defined in any one of claims 1-13; Prot is a suitable saver. The method of claim 25, Further comprising asymmetrically hydrogenating one of the compounds of formulas XI, XII, and XIII to yield a compound of formula IIa: In the above formulas, Q is a substituent of a C ₁ -C ₆ alkyl gas phase as defined for R ¹ in claim ¹ . Asymmetrically hydrogenating one of the compounds of formulas (XI), (XII) and (XIII) to yield a compound of formula (IIa): Formula IIa Formula XI Formula XII Formula XIII In the above formulas, Q is a substituent of a C ₁ -C ₆ alkyl gas phase as defined for R ¹ in claim ¹ ; Prot is a suitable saver. A compound of formula IV: Formula IV Where R ¹ , X and Y are as defined in any one of claims 1-13; Prot is a suitable saver.