UA74630C2 - Derivatives of n-fenpropylcyclopentylsubstituted glutamide as nep inhibitors for treatment of sexual dysfunction - Google Patents

Abstract

The invention relates to compounds of formula (I) for treating for example sexual dysfunction, wherein R1 is optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, hydrogen, C1-6alkoxy, -NR2R3 or - NR4SO2R5; X is the linkage -(CH2)n- or -(CH2)q-O-(wherein Y is attached to the oxygen); wherein one or more hydrogen atoms in linkage X may be replaced independently by C1-6alkoxy; hydroxy; hydroxy(C1-3alkyl); C3-7cycloalkyl; carbocyclyl; heterocyclyl; or by C1-4alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6, or 7; and q is 2, 3, 4, 5 or 6; and Y is phenyl or pyridyl, each of which may be substituted; or two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused optionally substituted 5- or 6-membered carbocyclic or heterocyclyic ring.

Description

Description of the invention

The invention relates to neutral endopeptidase (NEP) enzyme inhibitors, their use, methods of their 2 preparation, intermediate compounds used in their preparation and compositions containing the mentioned inhibitors. These inhibitors have utility in a variety of therapeutic areas, including the treatment of male and female sexual dysfunctions, especially female sexual dysfunction (SHD), especially when the SHD is female sexual arousal disorder (FSD).

NELP inhibitors (described in UMO 91/07386 and UMO 91/106441. 70 Use of NEP inhibitors for the treatment of SJ (described in EP1 097 719-A11.

According to the first aspect, the invention provides a compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph or prodrug form; () 1

IN

M, N M sne nos 2 s (8) (I) "c) in which co

B is Su alkyl, which may be substituted with one or more substituents, which may be the same or different, and selected from the following list: halogen, hydroxy, C. alkyl, hydroxyC and alkyl, y-oi

Si valkoski Sivalkoski, carbocyclyl (mainly C3cycloalkyl, C3cycloalkenyl or phenyl), chZ carbocyclyloxy (mainly phenoxy), Si.lalkoskycarbocyclyloxy (mainly C. lalkoskyphenoxy), m heterocyclyl, heterocyclyloxy, -МВ2ВЗ, -МВ"СОВУ, -МА"8028?, « SOM, -8B(O)rV?, -SOV and -SOH(S. dalkil); or B! is carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more substituents from the aforementioned list, where the substituents may be the same or different, and the list of which includes C. alkyl; or VK! is hydrogen, C 1 -C 6 alkyl, -ME2EZ or -ME"50585; « where - c B? and BZ, which may be the same or different, are carbocyclyl (preferably C 3-7 cycloalkyl or a phenyl) or heterocyclyl (each of which may be substituted by C..alkyl, hydroxy, or C.alkyl); or is "hydrogen or C.alkyl; or is combined with the nitrogen atom to which they are attached to form pyrrolidinyl, piperidino, morpholino, piperazinyl, or M-(C.alkyl)piperazinyl;

B" is hydrogen or C. dalalkyl; and Vo is Cialkyl, C3, carbocyclyl (preferably phenyl), Silalkyl carbocyclyl (preferably "C, dalalkylphenyl), C 1 - dalcosylcarbocyclyl (preferably C 1 dalcosylphenyl), heterocyclyl, Su .4alkos o or - МВ2ВЗ; vo is Cu dalalkyl, carbocyclyl (preferably phenyl), heterocyclyl or Movu o B is Cu dalalkyl, carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl; o reb, 1, 2 or 3;

X is a bridge -""СНо)д- or -"(СН2)д-О- (where U is attached to oxygen); where one or more hydrogen atoms in the X bridge can be replaced, independently, by Sialkoski; hydroxy; hydroxyC3 and alkyl; C3.7cycloalkyl; carbocyclyl; heterocyclyl; or Si alkyl, optionally substituted with one or more fluorine atoms or phenyl groups; pe 3,4,5,b6babo7;ideg2,3,4,5abob;and o Y is phenyl or pyridyl, each of which can be substituted by one or more groups E.8, which where can be the same or different, where KZ is hydroxy; mercapto; halogen; cyano; acyl; amino; mono(C. dalalkyl)amino; di(Cu 4 alkyl)amino; carbocyclyl or heterocyclyl (any of which is, 60 optionally, substituted with C. valkyl, haloC. valkyl, C. valkoski, haloC. valkoski, C. valkylthio or halogen); Si-spindles; phenoxy; Su. valkiltio; phenylthio; or alkyl, optionally substituted C. valcoski, halogens 1.valkoski, C. valkylthio, halogen or phenyl; or two C groups on adjacent carbon atoms, together with the connecting carbon atoms, can form a condensed 5- or b-membered carbocyclic or heterocyclic ring, optionally, substituted with C alkyl, halogenC. valkilom, S. valkoski, halogensS. Valkoski, Si. valkylthio or halogen.

Mostly in! is hydrogen, Si valkyl, Si valkoski, Si valkoskiS and valkyl,

S. dalkoskiS. dalkoskiS. valkyl or C. valkyl substituted phenyl.

Mostly BC! is hydrogen, C.ivalkyl, Suvalkoski, SuvalkoskiS.i alkyl (predominantly methoxyS, alkyl) or C. valkoskiS valcoskiS alkyl (predominantly methoxyethoxymethyl).

Even more preferably, K' is C.sub.1 alkyl (preferably propyl) or C.sub.6 alkyl (preferably methoxyC) alkyl, more preferably methoxyethyl). The predominant group of compounds is the compound of formula Ia: (c) 70 c! ; M d y v

NOos at 7 Ta (a)

Preferably n is 3 or 4, more preferably 3. Preferably 4 is 2 or 3, more preferably 2.

X is preferably -(СНо)д-, where one or more hydrogen atoms in the X bond can be replaced by one or more groups specified for X in the first aspect. at

Preferably, KU is a alkyl, alkyl, hydroxy, mercapto, halogen, cyano, carbocyclyl or heterocyclyl; or two KZ groups on adjacent carbon atoms together with connecting carbon atoms can form a condensed 5- or b--membered carbocyclic or heterocyclic ring, optionally substituted "with

Si.valkylom, halogens). valkylom, Si valkoski, halogensS. valkoski, Si valkylthio or halogen.

When KZ is carbocyclyl, preferred groups are cyclopentyl, cyclopropyl, cyclohexyl or phenyl. at

When BZ is heterocyclyl, preferred groups are pyridyl, oxadiazolyl, pyrazolyl or triazolyl. (Se)

When U is phenyl and two KZ groups on adjacent carbon atoms, together with connecting carbon atoms "g" form a condensed 5- or b-membered carbocyclic or heterocyclic ring, preferably

Condensed systems include onaphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, etc. benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl. Preferred compounds of the invention are: (2kK)-2-C1-(113-(4-methoxyphenyl)propylamino)carbonyl)cyclopentyl|methyl)-pentanoic acid (Example 16), "3-11-(113-(4-methoxyphenyl) propyl|iamino)carbonyl)ucyclopentyl|ipropanoic acid (Example 18), 3-11-(113-(2,3-dihydro-1-benzofuran-5-yl)propylamino)carbonyl)ucyclopentyl|-propanoic acid (Example C c 21), "» 2-(C1-(I3-(4-chlorophenyl)propylIamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 15), " 2-4(1-(13-(4-fluorophenyl )propyl|Iamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 4), 4-methoxy-2-41-(1I3-(4-methoxyphenyl)propyl|Iamino)carbonyl)ucyclopentyl|-methylbutanoic acid (Example 1), s-2-(C1-(113-(2,3-dihydro-1-benzofuran-5-yl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 11), (25) -2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example

Me, 22), and 2) 20 (25)-2-C1-(113-(2,3-dihydro-1-benzofuran-5-yl)ipropylamino)carbonyl)cyclopentyl|-methyl)-4-methoxybutanoic acid ( Example 25). A particularly preferred compound is (25)-2-C1-(113-(4-chlorophenyl)propyl)amino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 22).

Unless otherwise indicated, any alkyl group may be branched or unbranched and contain from 1 22 to 6 carbon atoms, preferably from 1 to 4 and especially from 1 to 3 carbon atoms.

HF) Unless otherwise indicated, any carbocyclic group contains 3-8 ring atoms and may be saturated, unsaturated, or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, where cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclic groups contain up to 3 double bonds.

The preferred aromatic carbocyclyl group is phenyl. The term carbocyclic should be interpreted 60 similarly. In addition, the term carbocyclyl includes any condensed combination of carbocyclyl groups, for example, naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise indicated, any heterocyclyl group contains 5-7 ring atoms, up to 4 of which may be heteroatoms such as nitrogen, oxygen, and sulfur, and may be saturated, unsaturated, or aromatic.

Examples of heterocyclic groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,

isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazolinizepinyl, and thi. In addition, the term heterocyclyl includes fused heterocyclyl groups such as benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl iso. The term heterocyclyl should be interpreted similarly. Halogen means fluorine, chlorine, bromine or iodine.

To avoid repetition, unless otherwise indicated, the term substituted means substituted with one or more 7/0 number of specified groups. In the case where groups may be selected from a list of alternative groups, the groups selected may be the same or different.

To avoid repetition, the term independently means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

Pharmaceutically or veterinary acceptable salts of compounds of formula I which contain a basic center are, for example, non-toxic acid addition salts formed with inorganic acids, such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, with carboxylic acids or with organosulfonic acids. Examples are NOI, HBg, NO, sulfate or bisulfate, nitrate, phosphate or hydrophosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, cirate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.

The compounds of the invention can also provide pharmaceutically and veterinary acceptable metal salts, in particular, non-toxic alkaline alkaline earth metal salts, with bases. Examples are salts of sodium, potassium, aluminum, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, choline, megulamine and diethanolamine.

For an introduction to suitable pharmaceutical salts, see Vegde et al., U.RNagt, zZsi., 66, 1-19, 1977;

RG Botschid, Ipfegpayopa! Shotgpa! Ои РРаптасециисв, З3 (1986), 201-217; and Vidnieu ei aiYi.,, Epsusioredia oi sch dv RPagtaseciisa! Thesppoiodu, Mags! OekkKeg Ips, Mem/ Hogk 1996, Moishte 13, rade 453-497).

In the following, the compounds, their pharmaceutically acceptable salts, their solvates and polymorphs defined in any of i) aspects of the invention or preferred embodiments (except for intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Pharmaceutically acceptable solvates of the compounds of the invention are their hydrates. Compounds of the invention and intermediate compounds may have one or more chiral centers and therefore exist in a number of stereoisomeric forms. All stereoisomers and their mixture are included in the scope of the present invention. "at

Individual enantiomers can be obtained by various methods known to the chemist, such as high-performance liquid chromatography (HPLC) of the corresponding racemate using a suitable chiral support or by fractional crystallization of diastereoisomeric salts obtained by the reaction of the corresponding racemate with a suitable optically active base, in depending on the circumstances. The preferred optically active base is pseudoephedrine (see Preparation 69).

Separation of diastereomers can be carried out using well-known techniques, for example, using fractional crystallization, chromatography or HPLC. "

The compounds of the invention can exist in the form of one or more tautomeric forms. All tautomers and their mixtures are included in the scope of the present invention.

And for example, the claimed 2-hydroxypyridinyl will also convert to its tautomeric "" form, o-pyridonyl.

It should be understood by one skilled in the art that some protected derivatives of the compounds of the invention, which may be prepared prior to the final step of deprotection, may not have pharmacological activity per se, but may, in some cases, be administered orally or parenterally and thereafter metabolized in the body into compounds of the invention that are pharmacologically active. Such derivatives may therefore be described as "prodrugs". In addition, some compounds of the invention may act as prodrugs of other compounds of the invention.

Ge) All protected derivatives and prodrugs of the compounds of the invention are included within the scope of the invention. Examples of suitable prodrug forms of the compounds of the present invention (described in Ogidve oi Todau, Moishte 19, Mytbeg 9, 1983, pp. 499-538 and in

Mami Thorisv ip Spetivigu, Sparieg 31, pp. 306-316 and in "Oevidp oi Rgodgydv" ru N. Vypdaaga, EiIzemieg, 1985, Sparieg p. 1 (disclosures of which are included here as a reference)).

It should be clear to one skilled in the art that some substitutes known to those skilled in the art as "pRO substitutes" (for example, as described by N. Vipaddaaga ip "Oevidp oi Rgodgydv"| (disclosure of this document

Incorporated herein by reference) may be substituted with acceptable functional groups when the functional groups are present in the compounds of the invention. Preferred prodrugs of the compounds of the invention are: esters, carbonate esters, hemi-esters, phosphate esters, nitroesters, sulfatoesters, sulfoxides, amides, carbamates, azo compounds, phosphoramides, glycosides, ethers, acetals, and ketals. 60 Studies of the metabolism of the prodrug show that in addition to the compounds of formula I, the following compounds can be formed, which are also NEP inhibitors. b5

(MY) no i o I ai o i (M) (hyu v! son :

N o E Y o; and

N o a on M N o i; high school

Hn nn o ah) (av) zo e x so i y

M U. s « o - « s 40 (9 - z -I ih (e)) su 2 "2 (F) ko 60 65

1 00 k so,n:

N ge) o E Y u n er

Khya on N o to ya t y ah) 7 th: mu o s (their) o

These metabolites are formed, in particular, when VE is methoxyethyl and -XU is 3-(4-chlorophenyl)propyl.

The invention also relates to all suitable isotopic variations of the compounds of the invention. An isotopic variation is (a) a compound in which at least one atom is replaced by an atom that also has the same atomic number but an atomic mass that differs from the atomic mass normally found in nature. Examples of isotopes that can be included in the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as Ф as 2Н, ЗН, с, с, 195М, 17, 18, р, З2р, 355, 18 | Z6C, respectively. Some isotopic variations of the invention, for example, those that include radioactive isotopes such as ZN and C, are useful in drug studies and/or as substrates for tissue distribution studies. Tritiated, i.e., ЗН, и - carbon-14, i.e., "7C" isotopes are especially preferred, which is due to the ease of their acquisition and detection.

In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, may have some therapeutic advantages due to greater metabolic stability, e.g., increased half-life ip mimo " or decreased dose required, and therefore in some cases it may be more profitable. Isotopic variations of the compounds of the invention can be obtained using well-known methods, such as those described in

Examples and Preparations below, by replacing the non-isotope-labeled reagent with the isotope-labeled reagent. ;" The compounds of the invention are inhibitors of zinc-dependent neutral endopeptidase EC.3.4.24.11., and it is proposed that the compounds of the invention will treat the diseases listed below. This enzyme is included in the destruction of some bioactive oligopeptides, cleavage of peptide bonds at the amino end of hydrophobic amino acid residues. -I Peptides that are metabolized are atrial natriuretic peptides (PNP), bombesin, bradykinin, calcitonin, gene-dependent peptide, endothelins, enkephalins, neurotensin, substance P, and vasoactive and intestinal peptide. Some of these peptides have a significant vasodilatory and neurohormonal function,

He» diuretic and natriuretic activity or mediate behavior.

Thus, the compounds of the invention, inhibiting the neutral endopeptidase EC.3.4.24.11. can enhance the biological activity of bioactive peptides. Thus, in particular, the compounds are useful in the treatment of a number of disorders, including hypertension, pulmonary hypertension, peripheral vascular disease, heart failure, angina pectoris, renal failure, acute renal failure, periodic edema, disease

Menieres, hyperaldosteronemia (primary and secondary) and hypercalcinuria. In addition, since they are able to enhance the action of AME, the compounds are useful in the treatment of glaucoma. Due to their ability to inhibit the neutral endopeptidase E.C.3.4.24.11, the compounds of the invention may have activity in other therapeutic areas (F) including, for example, the treatment of menstrual disorders, premature births, preeclampsia, endometriosis and other disorders of the reproductive system (especially male and female infertility , polycystic ovary syndrome, transplant rejection). Also, the compounds of the invention will treat asthma, inflammation, leukemia, pain, epilepsy, affective disorders, dementia and geriatric disorders, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), improve wound healing (especially diabetic and venous ulcers and callous abscesses), septic shock, modulate gastric acid secretion, treat hyperreninemia, cystic fibrosis, restenosis, diabetic complications, and atherosclerosis. In a preferred embodiment, the compounds of the invention are useful in the treatment of women and female sexual dysfunction. 65 The compounds of the invention are particularly useful in the treatment of SJD (especially RSV) and male sexual dysfunction (especially male erectile dysfunction (EMD)).

In accordance with the invention, SJD can be defined as a woman's difficulty or inability to obtain pleasure in sexual expression. STD is a general term for several different sexual disorders in women (eibisht, 5.K. (1998). The definition and classification of sexual disorders in women is given in Ipi.

In Itroiepse Kev., 10, 5104-5106; Veptap, 9U.K., Veptap, Y. 5: Soidvieip, I. (1999). Rataiye zehtsa! auvipsiop:

Ipsidepse, raiyorpusioiodu, emaicayope and (geaitepi ooripe. Mgoiodu, 54, 385-391) A woman may have insufficient desire, difficulties with arousal or orgasm, pain during sexual contact, or a combination of these problems. Certain types of illnesses, treatments, injuries, or psychological problems can cause SJD. The goal of therapy is to treat subtypes of SJD, excessive desire, and arousal disorders. 70 Categories of SJ are best defined by comparing them with the phases of a woman's normal sexual response: desire, arousal and orgasm | Eirisht, 5.K. (1998). The definition and classification of sexual disorders in women is given in IP. u. Itroiepse Kevz., 10, 5104-5106). Desire or libido is a way of sexual expression. Its manifestations often include sexual thoughts or when in the company of an interesting partner, or when women are exposed to other erotic stimulants. Arousal is a vascular response to sexual/5 stimulation, an important component of which is genital blood flow and includes increased vaginal lubrication, vaginal distension, and increased genital perception/sensitivity. Orgasm is the release of sexual tension, which is the climax of arousal.

However, SJ occurs when a woman has an inadequate or unsatisfied response to any of these phases, usually desire, arousal, or orgasm. The categories of SJ are hypoactive sexual desire, 2nd sexual arousal disorder, orgasm disorders, and pain during sexual intercourse. While the compounds of the invention will improve genital response to sexual stimulation (as in female sexual arousal disorder), they may also reduce the associated pain, discomfort and discomfort associated with intercourse and thus treat other female sexual disorders.

Hypoactive sexual desire is present when a woman has no or little desire for sex, and no or very few sexual thoughts or fantasies. This type of SJ can be caused by low testosterone levels, due to natural menopause or surgical menopause. Other causes are illness, i) medications, fatigue, depression and anxiety.

Sexual arousal disorder in women (SAD) is characterized by an inadequate genital response to sexual arousal. The genitals do not experience the blood flow that characterizes normal sexual arousal. at

The walls of the lime are slightly lubricated so that sexual intercourse is painless. Orgasm is prevented. Arousal disorder can be caused by a decrease in the level of estrogen during menopause or after the birth of a child and during lactation, as well as as a result of a disease with vascular components, such as diabetes and atherosclerosis. Other causes that lead to this are treatment with diuretics, antihistamines, antidepressants (for example, ZK) or antihypertensive agents. "

Sexual pain (such as dyspareunia and vaginismus) is characterized by pain during intercourse and can be caused by medications that reduce lubrication, endometriosis, pelvic inflammatory disease, bowel inflammation, or urinary tract problems.

The prevalence of SCD is difficult to define because the term encompasses several types of problems, some of which are difficult to measure and define, and thus interest in treating SCD is relatively new. Many sexual problems of women are due either directly to the aging process of women or to chronic diseases, such as diabetes and hypertension. . Because STDs contain several subtypes that express symptoms at several phases of the sexual cycle? answers, there is more than one type of therapy. Existing treatment for SJD is primarily focused on psychological or relationship problems. Gradually, the treatment of SJ is developing in a more clinical direction, which is based on scientific studies of this medical problem. Not all sexual complaints of women are physiological -And from the point of view of pathophysiology, especially for those individuals who may have a component of vasculogenic dysfunction (for example, ROS), which fully covers all sexual complaints. To date, there are no drugs for the treatment of SJ. Empirical drug treatment is the administration of estrogen (locally or as

hormone replacement therapy), androgens or psychotropic drugs such as buspirone or trazodone. These 5 types of treatment are often unsatisfactory due to low effectiveness or unwanted side effects. o As interest in the pharmacological treatment of SJ has arisen, therapies include the following: psychological o recommendations, over-the-counter lubricants, and investigational candidates, including drugs used to treat other conditions. These drugs are hormonal agents, or testosterone, or combinations of estrogen and testosterone, and new vascular drugs that have improved efficacy in the treatment of erectile dysfunction in women. None of these agents has shown significant efficacy in the treatment of SJ.

Ф) Diagnostic and Statistical Manual (0О5М) IM of the American Psychiatric Association gives the following definition of sexual arousal disorder in women (SAD): "persistent or recurrent inability to achieve or maintain until the completion of sexual activity an adequate lubricating and swelling response to sexual arousal. Disorders must cause specified suffering or interpersonal difficulties.

The response to arousal is the narrowing of blood vessels in the pelvis, vaginal lubrication, and enlargement and swelling of the external genitalia. The causes of the disorder are determined by suffering or difficulties between partners.

PCOS is a highly prevalent sexual disorder affecting pre-, peri- and post-menopausal women (PC). This is associated with co-morbidities such as depression, cardiovascular disease, diabetes and HY 65 disorders.

The primary consequences of PCOS are insufficient blood flow/swelling, insufficient lubrication, and insufficient pleasurable genital sensitivity. A secondary consequence of PCOS is a decrease in sexual desire, or during intercourse and difficulty in achieving orgasm.

It has recently been suggested that this is a consequence of vascular problems in at least a proportion of patients

With symptoms of ROSZH (Soyazivip ei ai., pi. 9. Itroi. Kev., 10, 584-590.1998)| with data obtained on animals that confirm this assumption (Ragk ei ai., Ipi. 9U.Itroi. Kev., 9, 27-37, 1997).

Drugs used to treat erectile dysfunction in men that are under investigation for the treatment of RSV are those that promote circulation in the male genitalia. They are included in two types of formulations, oral or sublingual medications (Apomorphine, 7/0 Phentolamine, phosphodiesterase type 5 (PDE5) inhibitors, such as Sildenafil), and prostaglandin (POE) administered or administered transurethrally in men and topically in the genital area in women.

The compounds of the invention are useful by providing a means to restore normal sexual arousal, namely by increasing genital blood flow, resulting in vaginal, clitoral and labial blood flow. This leads to increased vaginal lubricity due to plasma transfer, increased vaginal pleasure and increased genital sensitivity. However, the compounds of the invention provide agents that restore or enhance the normal sexual response to arousal.

Without being bound by theory, we believe that neuropeptides such as vasoactive intestinal peptide (VIP) are a prime neurotransmitter candidate in the control of the response to sexual arousal in women, particularly in the control of genital blood flow. MIR and other neuropeptides are degraded/metabolized by NEP ES 2o 3.4.24.11. Thus, NEP inhibitors will be potential endogenous vasorelaxants acting on the release of MIR during excitation. This will lead to the treatment of STD, for example, due to an increase in genital blood flow and, accordingly, genital blood flow. We showed that selective inhibitors of NEP

ES 3.4.24.11 increase pelvic nerve-stimulated and MIR-induced increases in vaginal and clitoral blood flow. In addition, selective NEP inhibitors increase MIR and nerve-mediated relaxation of the isolated walls of lime.

Thus, the present invention is useful in that it helps provide a means to i) restore a normal response to sexual arousal, namely, increase genital blood flow, resulting in vaginal, clitoral, and labial blood flow. This will lead to an increase in vaginal lubricity due to plasma transduction, an increase in vaginal compliance and an increase in vaginal sensitivity. However, the present invention provides a means to restore or enhance the normal sexual response to arousal. and

Male sexual dysfunction includes male erectile dysfunction, ejaculation disorders such as premature ejaculation (PE), anorgasmia (inability to reach orgasm), and desire disorders such as hypoactive sexual desire (lack of interest in sex). "

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

The compounds of the invention are used in the following subpopulations of patients with SJ: young women, elderly women, premenopausal, menopausal, postmenopausal women with or without hormone replacement therapy. "

The compounds of the invention have been used in patients with SJD arising as a result of: c) Vasculogenetic etiology, for example, cardiovascular or atherosclerotic diseases. hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic and damage to the iliac-hypoabdominal vascular system of the external genitalia. Her) Neurogenic etiology, such as spinal cord injury or central nervous system disease, including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular injuries, peripheral-I neuropathy, trauma, or radical pelvic surgery. Her) Hormonal/endocrine etiology, such as hypothalamic/mucosal/gonadal axis dysfunction, or testicular dysfunction, pancreatic dysfunction, surgical or medical castration, androgen deficiency, high circulating prolactin levels, e.g. hyperprolactinemia, natural menopause, premature ovulation disorder , hyper and hypothyroidism. and them) Of psychogenic etiology, such as depression, obsessive-compulsive disorder, anxiety, postpartum depression/"Baby Blues", emotional and family problems, anxiety, family quarrels, dysfunctional relationships, sexual phobias, religious restrictions or traumatic previous experiences.

M) Sexual disorders caused by drugs as a result of therapy with a selective serotonin reuptake inhibitor (SRI) and other antidepressants (tricyclines and basic tranquilizers), antihypertensive therapies, sympatholytic drugs, chronic oral (F, contraceptive therapy. ka Patients with minor or moderate EHD should benefit from treatment with a compound of the invention and patients with severe EHD may also benefit.However, preliminary studies indicate that the response rate in patients with mild, moderate and severe EHD will be greater in combination with a PDE5 inhibitor. .

The compounds of the invention have found use in the following subpopulations of EHD patients: psychogenic, endogenous, neurogenic, arteriogenic, drug-induced sexual disorders (lactogenic) and sexual disorders 65 caused by cavernosal factors, especially venogenic cases. These groups of patients are described in more detail in (Siipisai Apagoisdu mo! 23, po.4, p.773-782, and chapter C of the book !. Eagaeu and K.bZeifia "EgesiShe

Buziipswop-Sygtepi Ipueziidayop apa Mapadetepi, published by Mozru-Umoige).

The compounds of the invention can be prepared in a known manner using various routes. In the following reaction schemes and thereafter, unless otherwise indicated, B, n, X and M are as defined in the first aspect. These methods constitute the following aspects of the invention.

In the entire description, the general formulas are marked with Roman numerals I, II, PS, IM, etc.

Subgroups of general formulas are marked as Ia, IB, Is, etc......YMa, IM, IMs, etc.

Compounds of the general formula | can be obtained by reacting a compound of formula II (in which R6 is a suitable protecting group) with an amine of formula II to give a compound of formula IM followed by deprotection (see Scheme 1). The preferred reaction conditions for the acid/amine condensation stage are the reaction of HER with

AI (or its amino salt) in the presence of an activating agent, optionally a catalyst, and an excess of an acid acceptor in a suitable solvent. Particularly preferred conditions for the reaction are the interaction of 1 (1-14.5 equivalents), PSh (or its salt 1-15 equivalents), in the presence of 1-"3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (MUZSOI) or M,M' -dicyclohexylcarbodiimide (OSS) 75. (1.1-1.3 equivalents), 1-hydroxybenzotriazole hydrate (NOVT) or dimethylaminopyridine (OMAR) (1.05-1.2 equivalents), M-methylmorpholine (MMM) or triethylamine ( 2.3-3 equivalents), in dimethylformamide or dichloromethane at room temperature to 902C for 16-18 hours.

The following particularly preferred reaction conditions are the interaction of 0 (1-1.5 equivalents) and 1,1-carbonyldiimidazole (1-1.5 equivalents) in a suitable solvent (such as tetrahydrofuran, isopropyl acetate or toluene) followed by the addition of ITS (or its amino salts , in which in the case of an organic base such as triethylamine or Hunig's base is present) at a reaction temperature from room temperature to 9026.

Scheme 1 with in! in! o) zh-x-MN() now is MY o on Ro -k

Re o so a) (M i « i - in! .

Removal of protection ------ but M. Y

X « - s ;» shko;

Alternatively, the acid/amine condensation step can be carried out over the acid chloride in the presence of an excess of acid acceptor in a suitable solvent. The chloride of the acid can be isolated or it can be - obtained from the solution. The preferred conditions for the reaction are the interaction of II acid chloride (1-1.1 equivalents), PI (or its 15" salt, 1-1.5 equivalents), triethylamine or M-methylmorpholine (1.4-10 equivalents) in dichloromethane at room temperature for 24 hours. Compounds of the formula II can be converted into the chloride of the acid ip vish

Me by treatment with oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide with 20 for 2 hours at room temperature.

Methods of deprotection from an acid group depend on the protecting group. For examples of methods of protection/removal of protection, see "Rgoigesiime dgoishrz ip Ogdapis zupipevziv", TMU OSgeepe apa ROM UUsche.

For example, when Rgoi is tert-butyl, the deprotection conditions are interaction of IM with trifluoroacetic acid/dichloromethane (1:1-2.5 v/v), at room temperature for 2-18 hours, optionally in 25 Presence of an absorber carbocation, such as anisole (10 equivalents). When X or Y contain a hydroxy group,

F! basic hydrolysis of the trifluoroacetic acid ester intermediate may be necessary. An alternative technique for deprotection when Rgoi is tert-butyl involves treating IM with hydrochloric acid in dichloromethane at room temperature for 3 hours. For the avoidance of doubt, Rgoi is tert-butyl is provided by way of example and is not intended to be limiting to tert-butyl. 60 The method according to Scheme 1 forms the next aspect of the invention.

Intermediate compounds of the general formula IM are new. According to the following aspect, the invention provides a compound of formula IM.

A number of compounds of formula II are known from the literature (see EP274234-81 and MUO9113054). Other compounds of formula II can be obtained in a similar way. because Compounds of the general formula | and Ii, in which KE! are not hydrogen, have a chiral center on the carbon attached to

B. Individual enantiomers can be obtained by various techniques known to those skilled in the art, such as obtaining the corresponding optically pure intermediates or by resolution. A preferred method of separation is the use of ()-pseudoephedrine salt (see UMO9113054), Example 10 here).

Alternatively, compounds of the formula Pa, that is, chiral compounds of the formula II, in which K ! is, optionally, substituted C. alkyl (where CO is a substituent on the C. alkyl group defined for B! in the first aspect), can be obtained by asymmetric hydrogenation of compounds of formula XI, XIII, or XII! according to reaction scheme 1a.

Scheme a o o | he vo o o c) (their) -K : a "U, he

Рг -- ж - он о о s

Rgoi (na) o) o o s o so (Se) o i on

Rgoi7 From the city of O

OK) "

Typical hydrogenation conditions are the treatment of compounds of formula XI, XI! or HEY! (or an organic or inorganic C salt thereof (e.g., sodium salt) with a suitable asymmetric hydrogenation catalyst under elevated pressure with hydrogen in a suitable solvent. Preferred catalysts contain one or more chiral ligands, preferably chiral phosphine ligands coordinated to a suitable transition metal (eg rhodium, ruthenium, iridium, palladium). The preferred catalysts are:

KRO-CH-2,2-bis(diphenylphosphino)-1,1-binaphthylchloro(para-cymene)ruthenium chloride (|9U.Ogu. Spet. 1994, 59, 3064-76); and I(5)-3,34,4,5,5'-hexamethyl(b,6'-diphenyl)-2,2'-diyl|Ibis(diphenylphosphino)ruthenium bis(trifluoroacetate) "" See MO 01/94359 );

КРО-С)-4,12-bis(isopropylphosphino)-(2,2|1-paracyclophano-(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate b M.At. Spec. Zos. 1997,119, 6207-6208) ; so 20 Ibis-(25,55)-2,5-dimethyl-1-phenylphospholano)(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (Teganeagop:

Avutt., 1991, 2, 569-921; and c KRO-(6,6-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphino)|ruthenium bis(trifluoroacetate) (ERZ981321.

Preferred reaction conditions are a hydrogen pressure of up to 150 psi and a reaction temperature of 0 to 1002 (preferably 50-6022). Preferred solvents are protic solvents such as methanol or ethanol.

In scheme and, the compound of formula (XIII) is the preferred starting material.

GF) The scheme method and constitutes the next aspect of the invention. 7 Alternative compounds of formula I! and IM can be obtained directly by asymmetric hydrogenation of unsaturated compounds corresponding to ХІ, ХІ and ХП. Compounds of formula Xa, that is, compounds of formula I in which X is -(CH 5 )3-, can be prepared according to reaction Scheme 2. First, compounds of formula M are subjected to the Heck reaction with acrylonitrile in the presence of a suitable catalytic system, such as palladium and an excess of a base such as triethylamine or 4-methylmorpholine to give compounds of formula MI. Typical reaction conditions are 1.0-1.5 equivalents of aryl halide, C equivalents of base, 0.1 equivalents of palladium catalyst (predominantly palladium(I) acetate), 0.2 equivalents of phosphine ligand (predominantly tri-o-tolylphosphine) in 1, 4-dioxane, acetonitrile or DMF (mainly acetonitrile) at boiling temperature. Compounds of formula MI are then subjected to catalytic hydrogenation to give compounds of formula Sha. Typical hydrogenation conditions are treatment of MI with Raney nickel in ethanol or methanol at a pressure of 15-150 psi and 25 and 800. Preferably in ethanol at 30 psi and 2596.

Scheme 2

I hydrogenation M acrylonitrile in m mo) (Ma)

Alternatively, compounds of the formula MI can be obtained according to reaction scheme C by means of the reaction of the compound MII with diethylcyanomethylphosphonate. Typical reaction conditions are reaction of diethyl cyanomethylphosphonate with a suitable base (eg sodium hydride, lithium chloride/Hunig's base or sodium ethoxide) in a suitable solvent at room temperature (eg dichloromethane, tetrahydrofuran or diethyl ether) followed by addition of a compound of formula MI. uh Scheme Z moti quo She s (8) (MI) (MI)

Alternatively, compounds of the formula Sha can be obtained according to Scheme 4. av!

Scheme 4 c and (Ce) 7) malonic acid, pyridine, EN y o No, Mi Reney, MebH Ya «

I nn nin nia and zv sn M oon v 2 (MY) "- s ;" 1) mMeOH, n. 804 VN I or h sh 45 21meon, MN. starting 5 ZMez dia pp ions of Ifni Y nia and soMN, nt M,

F and (Ша) (95) o Other compounds of formula (II), (M), (MI) and (MI) or easily obtained from commercial sources; known in this field; or can be obtained from compounds known from the prior art using methods known in the art or using the techniques described herein (see section Examples and Preparations).

All of the above reactions and methods of obtaining new starting compounds used in 59 previous methods are well known. Acceptable reagents and reaction conditions for their implementation or

GF) preparation, as well as methods of isolation of the desired products will be well known to a person skilled in the art with 7 references to the prior literature and Examples and Preparations provided herein.

A pharmaceutically acceptable salt of a compound of formula (I) can be readily prepared by mixing together solutions of a compound of formula (I) and the desired acid or base as required. The salt can be isolated from the solution and collected by filtration, or it can be obtained after evaporation of the solvent.

The compounds of the invention (especially (25)-2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 22)) can be combined with one or more active ingredients selected from the following list: 1) One or more natural or synthetic prostaglandins or their esters. Suitable prostaglandins for use here are compounds such as alprostadil, prostaglandin E 4 prostaglandin Ed,

13, 14-dihydroprostaglandin E-, prostaglandin Eo eprostinol, natural, synthetic and semi-synthetic prostaglandins and their derivatives including those (described in UUO-00033825 and/or patent 05 6,037,346 published March 14, 2000) all of which are incorporated herein by reference, ROE 05, ROE:, ROA;, ROV., ROR.A, 19-hydroxy ROA; 19-hydroxy-ROV., ROE», ROV», 19-hydroxy-ROA», 19-hydroxy-ROV», ROEZA, carboprost, tromethamine, dinoprost, tromethamine, dinoprostone, lipoprost, hemeprost, metenoprost, sulprost, tiaprost and moxisylate . 2) One or more A-adrenergic receptor antagonists, also known as A-adrenergic receptors, or A-receptors, or A-blockers. Suitable compounds for use herein are: 7/0 A-adrenergic receptor blockers, (as described in PCT application UUO99/30697 published Jun. 14, 19981, which describes A-adrenergic receptors and the disclosure of which is incorporated herein by reference and includes selective blockers

A1-adrenoceptor or A2-adrenoceptor and non-selective adrenoceptor blockers, suitable A-adrenoceptor blockers are: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramine, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efferaxan, yohimbine, rauwolfia alkaloids,

Records 15/2739, MAR 1069, ZMAR 5089, K5 17053, 51. 89.0591, doxazosin, terazosin, abanoquil and prazosin;

Ao-blockers |from patent 5 6,037,346 March 14, 2000) dibenarnine, tolazoline, trimazozine and dibenarnine;

A-adrenergic receptors as described in patents 5: 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000| each of which is incorporated herein by reference; blockers of the A»o-adrenoceptor are: clonidine, paraverine, paraverine hydrochloride, optionally in the presence of a 2o Kkaryotonic agent such as pirksamine.

Q) One or more MO-donors (MO-agonists). Suitable MO donors useful herein include organic nitrates such as mono-, di-, or tri-nitrates or organic nitrate esters, including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythritol tetranitrate, nitroprusside sodium (BMR), 3-morpholinosydnonimine, molsidomine, sc dv 3-Nitroso-M-acetylpenicillamine, (ZMAP) 3-nitroso-M-glutathione (5MO-91O), M-hydroxy-I -arginine, amyl nitrate, linsidomine, linsidomine chlorhydrate, (51IM-1) З-nitroso-M-cysteine, diazenium diolates, (MOMO aty), (8) 1,5-pentane dinitrate, I -arginine, ginseng, zizfi, molsidomine, Ke-2047, derivatives of nitrosylated maxysilite, such as MMI-678-11 and MMI-937, (as described in published application RSTUUO 00120751. 4) One or more calcium channel openers or modulators. Suitable calcium channel openers/modulators for use here are nicorandil, cromocaline, leucromacaline, lemacaline, cliazoxide, minoxidil, charybdotoxin, gluburide, 4-aminepyridine, Vasi. and 5) One or more dopaminergic agents, preferably apomorphine or selective O", Oz or O02/O3z He agonists, such as pramipexole and ropirinol (as claimed in M/O-0023056, RMO95666 (as claimed in UUO-00402261. b ) One or more vasodilator agents. Suitable vasodilator agents for " zv Use herein are nimodepine, pinacidil, cyclandelate, isoxsuprine, chlorprumazine haloperidol, Kes 15/2739, itrazodone. 7) One or more thromboxane A2 agonists. 8) One or more agents active in relation to the central nervous system. 9) One or more horn alkaloids. Suitable ergot alkaloids are (described in U.S. Patent No. 8,037,346 issued March 14, 2000) and include acetergamine, brassergoline, bromerguride, cyanergoline, cs delogotril, disulergine, ergonovine maleate, ergotamine tartrate, etisullergine, lergotril, lysergide, mesulergine, methorgoline, metergotamine, nicergoline, pergolide, propysergide, proterguride, terguride. ;" 10) One or more compounds that modulate the action of natriuretic factors, in particular, atrial natriuretic factor (also known as atrial natriuretic peptide), type B and type C natriuretic factors, such as inhibitors or neutral endopeptidase. -And 11) One or more compounds that inhibit angiotensin-converting enzyme, such as enapril and combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase, such as omapatrilat.

Ge" 12) One or more angiotensin receptor antagonists, such as losartan. 13) One or more substrates of MO synthase, such as I -arginine. and 14) One or more calcium channel blockers such as amlodipine. o 15) One or more antagonists of endothelial receptors and inhibitors or endothelin-converting enzyme. 16) One or more cholesterol-lowering agents such as statins (eg atorvastatin/H Iriug - trade name) and fibrates. 17) One or more antiplatelet and antithrombotic agents, for example, IRA, CRA, warfarin,

F) hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors. ka 18) One or more insulin-sensitizing agents such as resulin and hypoglycemic agents such as glipizide. 19) Y-OORA or carbidopa. in 20) One or more acetylcholinesterase inhibitors, such as donezipil. 21) One or more steroidal or non-steroidal anti-inflammatory agents. 22) One or more estrogen receptor modulators, and/or estrogen agonists, and/or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene, (-)-cis-6-phenyl-5-(4-(2-pyrrolidine-1 -ylethoxy)phenyl|)-5,6,7 8-tetrahydronaphthalen-2-ol and its 65 pharmaceutically acceptable salts, the preparation of which is described in UMO 96/216561. 23) One or more cannabinoid receptor modulators.

24) One or more MRU (neuropeptide B) inhibitors, more particularly MRU1 or MRU5 inhibitor, preferably MRU1 inhibitor, preferably said MRU inhibitor (including MRU U1 and MRU U5) has an IC of less than 10OnM, more preferably less than 5OnM. Studies on the determination of MRU inhibitors (cited in

MUO-A-98/52890 (see page 96, lines 2-28)). 25) One or more Vasoactive Intestinal Protein (MIR), MIR mimetic, MIR analogs, more specifically, mediated by one or more MIR receptors of MPAS1, MPAS or RASAR (pituitary adenylate cyclase-activating peptide) subtypes, one or more agonists MIR receptor or MIR analogs (for example, Ko-125-1553) or MIR fragments, one or more antagonists 7/0. A-adrenoceptors with MIR (for example, Invicorp, Aviptadil). 26) One or more melanocortin receptor agonists or modulators or melanocortin-enhancing agents, such as melanotan II, RT-14, RT-141 or compounds, as claimed in UUMO-09964002,

UO-00074679, UUO-09955679, M/O-00105401, M/O-00058361, UUO-001 14879, UUO-001 13112, UUO-099543581. 27) One or more serotonin receptor agonists, antagonists or modulators, more particularly agonists, antagonists or modulators of 5BNTTA (including MMI 670), 5HT2A, 5HT2C, 5NT3 and/or 5HTb6 receptors, such as (described in UHO-09902159, including MUO-00002550 and/or M/O-000289931I. 28) One or more androgens such as androsterone, dehydroandrosterone, testosterone, androstenedione and synthetic androgens. 29) One or more estrogens, such as oestradiol, oestrone, oestriol and synthetic estrogen, 2o such as estrogen benzoate. 30) One or more modulators of norepinephrine, dopamine and/or serotonin transport, such as bupropion, SUU-320659. 31) One or more agonists and/or modulators of purinergic receptors. 32) One or more antagonists of the neurokinin (MC) receptor, including those described (|in sch g MO-09964008). 33) One or more agonists, antagonists or modulators of opioid receptors, preferably i) agonists of the OKI-1 receptor. 34) One or more oxytocin/vasopressin receptor agonists or modulators, preferably selective oxytocin agonists or modulators. o z o 35) One or more PDE inhibitors, more particularly PDE2, 3, 4, 5, 7 or 8 inhibitors, preferably PDE2 or PDE5 inhibitors and most preferably PDE5 inhibitors (see hereafter), said inhibitors preferably have an Iso to the corresponding enzyme is less than 100 nM. Suitable inhibitors of CGMP Ge

PDE5 for use according to the present invention are: pyrazolo|4,3-siIpyrimidin-7-ones (described in EP-A-0463756)|; Pyrazolo|4,3-4|Ipyrimidine-7-bases (described in "

ER-A-05260041; pyrazolo|4,3-4|Ipyrimidin-7-ones (described in the published international patent application No. 93/06104); isomeric pyrazolo!|3,4-si|Ipyrimidin-4-ones (described in the published international patent application UMO 93/071491; quinazolin-4-ones C|described in the published international patent application MUUO 93/12095); pyridoZ,2-4|Ipyrimidin-4-ones (described in the published international patent application MUO 94/05661); purine-6b-ones (described in the published international patent application MO 94/004531; pyrazolo|4,3-4|Ipyrimidin-7-ones (described in the published international patent application UUO 98/49166); pyrazolo (4, 3-4|Ipyrimidin-7-ones are described in the published international patent application MUUO 99/543331|; pyrazolo|4,3-4|Ipyrimidin-4-ones (described in . EP-A-09957511;. pyrazolo| 4,3-4|Ipyrimidin-7-ones (described in the published international patent application U/O y?" 00/247451; pyrazolo|4,3-4|Ipyrimidin-4-ones (described in EP-A-0995750 ); compounds described in published international application UUO 95/199781; compounds (described in published international application UUO 99/24433)| and compounds (described in published international application UUO 93/071241; pyrazolo|4,3-4|pyrimidine-7- sones (described in -I published international application UMO 01/271121; pyrazolo|4,3-4|Ipyrimidin-7-ones | described in published international application UMO 01/27113); compounds (described in EP-A-1092718) and compounds (described in EP-A-1092719). PDE5 inhibitors for use according to the present invention are:

He» 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo|4,3-4|pyrimides boro H-T-one (sildenafil) also known as o 1-((3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo|4,3-4|pyrimidine- 5-yl)-4-ethoxyphenyl|sulfonyl|-4-methyl o piperazine See EP-A-04637561; 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6- dihydro-7 H-pyrazolo|4,3-4|pyrimidin-7-one | see

ER-A-0526004); two 3-ethyl-5-(5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo|4 " 3-d|Ipyrimidin-7-one See MUO098/49166);

F) 3-ethyl-5-15-(4-ethylpiperazin-1-ylsulfonyl)-2-(2-methoxyethoxy)pyridin-3-yl|-2-(pyridin-2-yl)umethyl-2,6-dihydro ka -7H-pyrazoliI4,3-4|Ipyrimidin-7-one See UMUO99/54333); (-3-3-ethyl-5-15-(4-ethylpiperazin-1-ylsulfonyl)-2-(2-methoxy-1(K)-methylethoxy)pyridin-3-yl|-2-methyl-2,6 -dihydro in o-7H-pyrazolo|4,3-4|pyrimidin-7-one, also known as

3-ethyl-5-15-(4-ethylpiperazin-1-ylsulfonyl|-2-((1K)-2-methoxy-1-methylethyl|oxy)pyridin-3-yl)-2-methyl-2,6- digidro-7H-pyrazolo|4,3-4|Ipyrimidin-7-one See UMUO99/54333); 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazoloi|4,

C-4|pyrimidin-7-one, also known as 65 1-16-ethoxy-5-|13-ethyl-b,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo|4 ,3-4|Ipyrimidin-5-yl|-3-pyridylsulfoni l)|-4-ethylpiperazine See Me) 01/27113, Example 8;

5-(2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7

N-pyrazolo|4,3-4|pyrimidin-7-one See Me) 01/27113, Example 151; 5-(2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo|4,3-4|pyrimi dyn-7-one See IV) 01/27113, Example 661; 5-(5-Acetyl-2-propoxy-33-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3-si|pyrimidin -7-on See IV) 01/27112, Example 1241; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3-4|Ipyrimidine- 7-on

See IV) 01/27112, Example 1321; 70 (6К,12ак)-2,3,6,7,12,12а-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino-(2,1":6,1|pyridoyiZ,4- indole-1-4-dione (IS-351), that is, compounds of examples 78 and 95 of the published international application MUO95/19978), as well as compounds of examples 1, 3, 7 and 8; 2-(2-ethoxy- 5-(4-Ethylpiperazin-1-yl-1-sulfonyl)phenyl|-5-methyl-7-propyl-3H-imidazoi5,1-4(1,2,Atriazin-4-one (vardenafil), also known as 75. 1-II3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo|5,1-7-astriazin-2-yl)-4-ethoxyphenyl|sulfonyl)-4-ethylpiperazine, i.e., compounds of examples 20, 19, 337 and 336 |published international application U/O099/24433)|; and compounds of examples 11 (published international application M/O93/07124 (EIZAI)); and compounds C and 14 |from Koien O R , 9. Mea.

Spet., 2000, 43, 12571).

Other suitable PDE5 inhibitors are: 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy|-3(2H)pyridazinone; 1-14-K1,3-benzodioxol-5-ylmethyl)amino |-b-chloro-2-quinazolinyl|-4-piperidinecarboxylic acid, monosodium salt; (t)-cis-5,ba,7,9,9,9a-hexahydro-2-(4--trifluoromethyl)phenylmethyl-5-methyl-cyclopenty4,5imidazo|2,1-8|Hipurin-4(ZH) he furazlocillin; cis-2-hexyl-5-methyl-3,4,5,ba,7,8,9,Za-octahydrocyclopenti4,5imidazo|2,1-8|Hipurin-4-one; high school

C-acetyl-1-(2-chlorobenzyl)-2-propylindole-b-carboxylate;

C-acetyl-1-(2-chlorobenzyl)-2-propylindole-b-carboxylate; i) 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone; 1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-4)pyrimidin-7-one; 1-I4-K1,3-benzodioxol-5-ylmethyl)amino|-b-chloro-2-quinazolinyl|-4-piperidinecarboxylic acid, monosodium su

From pain; Rpagtargo)esiv Mo.4516 (Siaho UUeiYisote); Rpagtargo)esiv Mo.5051 (Vaueg); Rpagtargo)esiv Mo. 5064 (Kuozhma

Nakko; |see UMO 96/269401); Rpagtargoi|esiv Mo. 5069 (Zspegipd Riotsdy); CE-196960 (SiIaho U/ePsote); (E-8010 o and E-4010 (Eizai))i; Vau-38-3045 8. 38-9456 (Vaueg) and Zsp-51866. "at

For the treatment of SJ, compounds of the invention (especially (25)-2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 22))

335 can preferably be combined with one or more active ingredients selected from the following list: a) PDEB5 inhibitor, more preferably 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|-1- methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo|4,3-4|pyrimidine n-7-one (sildenafil); (bK, "12ac)-2,3,6,7,12 ... ); (vardenafil); 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)-2, 6-dihydro-7H-pyrazolo|4,

Z-cPpyrimidin-7-one; and -I 5-(5-acetyl-2-butoxy-33-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3- 4|pyrimidin-7-one and their pharmaceutically acceptable salts; and b) MRU inhibitor ХУ1; b c) a dopamine agonist, such as apomorphine or a selective agonist OO", Oz or 05/O53, such as pramipexole and ropirinol; o d) melanocortin receptor agonist or melanocortin modulator or enhancer, preferably melanotan I, o RT-14, RT-141; e) agonist, antagonist or modulator of 5HT2C; g) estrogen receptor modulator, estrogen agonists and/or estrogen antagonists, preferably raloxifene, Tibolon or lasofoxifene; f) androgen, such as androsterone, dehydroandrosterone, testosterone, androstandione and a synthetic androgen; and (F, g) estrogen such as oestradiol, oestrone, oestriol and synthetic estrogen such as estrogen benzoate. ka For the treatment of EDCH, the compounds of the invention (especially (25)-2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 22)) can preferably be combined with one or more active ingredients selected from the following list: a) PDEB5 inhibitor, more preferably 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo|4,3-4|pyrimidin-7-one (sildenafil); 65 (6К,12ак)-2,3,6,7,12,12а-hexahydro-2-methyl- 6-(3,4-methylenedioxyphenyl)-pyrazino|2,1":6,1|pyridoi|3,4-in|indole-1,4-dione (IS-351);

2-(2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl)phenyl|-5-methyl-7-propyl-ZN-imidazoi5,1-4(1,2,Atriazin-4-one (vardenafil); 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H- pyrazoles|4,

C-4|pyrimidin-7-one; and 5-(5-acetyl-2-butoxy-33-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3-4| pyrimidin-7-one and their pharmaceutically acceptable salts; b) MRU M1 inhibitor; c) a dopamine agonist, such as apomorphine or a selective agonist OO", Oz or 05/O53, such as pramipexole and 7/o ropirinol; d) melanocortin receptor agonist or melanocortin modulator or enhancer, preferably melanotan I,

RT-14, RT-141; e) agonist, antagonist or modulator of 5HT2C.

Particularly preferred combinations for the treatment of SAD are (25)-2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 22) and one or more active ingredients selected from the following list: 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|-1-methyl-3-p-propyl-1,6-dihydro-7H-pyrazolo|4,3-4|pyr midin-7-one (sildenafil); (6К,12ак)-2,3,6,7,12,12а-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino|2",1" :6,1|IpyridoiZ,4-c)indol-1,4-dione (IS-351); 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)phenyl|-5-methyl-7-propyl-ZN-imidazoi|5,1-4(1,2,Ctriazine -4-one (vardenafil); 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)|-2,6 -dihydro-7H-pyrazole 9|I4,3-4|Ipyrimidin-7-one; sc 5-(5-acetyl-2-butoxy-3-pyridine!)-3-ethyl-2-(1-ethyl-3 -azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3-4|Ipyrimidin-7-one; (8) apomorphine; melanotan II;

RT-141; o zo lasofoxifene; raloxifene; about tibolone; "o androgen such as androsterone, dehydroandrosterone, testosterone, androstenedione and synthetic androgens; and estrogen such as oestradiol, oestrone, oestriol and synthetic estrogen such as estrogen benzoate. -

Particularly preferred combinations for the treatment of EDH are η-(25)-2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 22) and one or more active ingredients selected from the following list: 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|-1-methyl-3-p-propyl-1,6-dihydro-7H-pyrazolo|4,3-4 |pyrimidin-7-one (sildenafil); "(bK,12ac)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazine(2", 1":6,1|Ipyrido3,4-indo z c l-1,4-dione (IS-351); 2-(2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl) )phenyl|-5-methyl-7-propyl-ZN-imidazoi5,1-41,2,Agriazin-4-;»one (vardenafil); 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl) )pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)|-2,6-dihydro-7H-pyrazole 9|I4,3-4|Ipyrimidin-7-one; -I 5-( 5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazoloi|4,3-4|pyrimidine- 7- he; apomorphine; melanotan 11; and RT-141. o If a combination of active agents is administered, then it can be administered alone directly, individually or sequentially. The compounds of the invention may be administered alone, but in human treatment they are usually administered in admixtures with pharmaceutically acceptable excipients, diluents, or carriers selected with reference to the desired route of administration and conventional pharmaceutical practice. o For example, the compounds of the invention may be administered orally, buccally, or sublingually in the form of tablets, capsules (including soft gelatin capsules), ovules, elixirs, solutions, or suspensions, which may contain flavors or dyes, for immediate, delayed, modified, detained,

B Combined, controlled or pulsatile release. The compounds of the invention can also be administered in the form of dosage forms that quickly disperse or dissolve.

F) Modified-release and pulsatile-release dosage forms may contain excipients such as those disclosed for immediate-release dosage forms along with additional excipients that act as release rate modifiers, i.e., a coating and/or body-incorporated space. . Release rate modifiers include, but are not limited to, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, polyethylene oxide, xylene gum, carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethylcellulose phtapaate, copolymer methacrylic acid and their mixtures. Dosage forms with modified and pulsatile release may contain one or a combination of excipients that modify the release rate. Excipients that modify the release rate can be present in the dosage form itself, that is, make up the matrix, and/or on the dosage form, that is, in the form of a surface or coating.

Rapidly Dispersible or Soluble Dosage Formulations (PRS) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl methylcellulose, magnesium stearate, mannitol, methyl methacrylate, peppermint flavor, polyethylene glycol, fumed silica, silica gel, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersible or soluble, as used herein, describes the DRSHDR is dependent on the solubility of the drug used, i.e. when the drug is insoluble, a rapidly dispersible dosage form can be obtained, and when the drug is soluble, a dosage form can be obtained that dissolves quickly. 70 The compositions of the invention can be administered by injection. The composition can be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, ocular, intraocular or transdermal administration. Depending on the need, the agent can be administered in a dose from 0.01 to ZOmg/kg of body weight, so from 0.1 to 1Omg/kg, more preferably from 0.1 to mg/kg of body weight.

The term "introduction" includes release by viral or non-viral techniques. Viral /5 Release mechanisms include, but are not limited to, adenoviral vectors, adeno-associated virus (AAM) vectors, herpes vectors, retroviral vectors, lentiviral vectors, and baculovirus vectors. Nonviral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (SEAZ), and combinations thereof. Routes for such delivery mechanisms include, but are not limited to, mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.

In addition or as an alternative, the compositions (or part of the components) of the present invention may be administered by direct injection. In addition or as an alternative, the compositions (or part of the components thereof) of the presented invention can be administered locally (preferably, in the genital area). In addition or as an alternative, the compositions (or part of the components thereof) of the present invention may be administered by inhalation. In addition or as an alternative, the compositions (or part of the components thereof) of the present invention may be administered by one or more routes: the mucosal route, for example, as a nasal spray or aerosol for inhalation or as a solution administered orally, or and ) parenterally, where the release is from an injectable form, such as, for example, rectal, ophthalmic (including vitreous or intracameral), nasal, topical (including buccal and sublingual), intrauterine, vaginal, or parenteral (including subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracranial, intratracheal, and epidermal) transdermal, intraperitoneal, intracranial, intracerebroventricular, intracerebral, intravaginal, intrauterine, or parenteral (eg, intravenous, intraspinal im, subcutaneous, transdermal or intramuscular) way. "

As an example, the pharmaceutical compositions of the invention can be administered according to a regimen of 1 to 10 times a day, for example, once or twice a day. The specific dosage level and frequency of administration for any individual patient may vary and will depend on a variety of factors, including the activity of the individual compound used, the metabolic stability and duration of action of the compound, age, body weight, general condition, sex, diet, route and the time of introduction, the rate of release, the combination of the drug, the complexity of the condition and the characteristics of the subject being treated. c c Therefore, the term "administration" includes, but is not limited to, delivery by the mucosal route, for example as

And a nasal spray or aerosol for inhalation or a solution administered through the mouth; parenterally, and? wherein the release is from an injectable form such as, for example, an intravenous, intramuscular or subcutaneous route.

Such tablets may contain such excipients as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium dihydrogen phosphate and glycine, disintegrants such as starch (mainly corn, potato or tapioca), sodium starch glycolate, croscarmellose sodium and some complex silicates, and also binding agents such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose

Ge" (HPC), sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of this type can also be used as fillers in gelatin capsules. Preferred excipients are lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavoring agents, colorants, emulsifiers and/or suspending agents, as well as diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The compounds of the invention may also be administered parenterally, e.g., intravenously, (F, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, ka intrasternally, intracranially, intramuscularly or subcutaneously, or may be administered by infusion. In addition, they may be administered by with the help of implants. For parenteral administration, it is better to use them in the form of sterile aqueous solutions, which may contain other substances, for example, a sufficient amount of salts or glucose, which makes the solution isotonic with blood. Aqueous solutions should be appropriately buffered (preferably to the pH level -9), if necessary. Preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques known to those skilled in the art. Parenteral formulations may be formulated for immediate, sustained, 65 modified, sustained, mixed, controlled release, and pulsatile release. .

The following dose levels and other dose levels are given for an average subject weighing from about 65 to

7 Okg. A person skilled in the art will readily determine the dose levels required for a subject whose weight falls outside this range, such as children and the elderly.

For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention or their salts or solvates is usually in the range of 10 to 50000 mg (in single or divided doses).

Thus, for example, tablets or capsules of the compounds of the invention, or their salts or solvates, may contain from 5 mg to 100 mg, for example, from 5 to 500 mg of the active compound for single administration, or twice, or more times, as appropriate. In any case, the doctor will determine the dose that will be most appropriate for each individual patient, which will vary depending on the age, weight and response of the individual patient.

The above doses are examples of an average case. There may be individual cases where higher or lower dose levels are more acceptable and are within the scope of the present invention. It should be understood by one skilled in the art that in the treatment of certain conditions (including SJ and EDH), the compounds of the invention may be used in a single dose on an "as needed" (ie, as needed or desired) basis.

The compounds of the invention may be administered intranasally or by inhalation and are conveniently administered from an inhaler containing a dry powder or an aerosol spray from a sealed container, pump, nebulizer or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane such as 1,1 . In the case of an aerosol that is under pressure, the dosage unit can be determined by providing it with a valve that releases a defined amount. Hermetic container, pump, nebulizer or atomizer may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as a solvent, which may additionally contain a lubricant, for example sorbitol trioleate. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insulphator may contain a powdered mixture of a compound according to the present invention and a suitable powdered base such as lactose or starch.

Aerosol or dry powder formulations are prepared so that each metered dose or "puff" contains from 1 to 500 mg of a compound of the invention for administration to a patient. The full daily dose of the aerosol will be in the range from 1 to 5Omg, and can be prescribed as a single dose, or, as a rule, divided into several doses during the day.

Alternatively, the compounds of the invention can be administered in the form of a suppository or pessary, or they can also be administered locally (preferably in the genital area) in the form of a gel, hydrogel, lotion, solution, cream, ointment or He powder. The compounds of the invention can be administered dermally or transdermally, for example, in the form of a patch on the skin. They can also be prescribed by ocular, pulmonary or rectal routes. -

For ophthalmic use, the compounds can be prepared in the form of finely ground suspensions in an isotonic, pH-specified, sterile saline solution, or, preferably, in isotonic, pH-specified, sterile saline solutions, optionally in combination with preservatives such as as benzylalkonium chloride. Alternatively, they can be made with an ointment such as petroleum jelly.

For local use on the skin, the compounds of the invention can be made in the form of an ointment that contains the active compound suspended or dissolved in, for example, a mixture of one or more of the following n) c substances: mineral oil, liquid petroleum jelly, medical petroleum jelly, propylene glycol, compounds of polyoxyethylene. polyoxypropylene, emulsified wax and water. Alternatively, they can be made in the form of a ? of a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following substances: mineral oil, sorbitol monoetherate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters of waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. -I Compounds of the invention can also be used in combination with cyclodextrin. Cyclodextrins are known to form inclusion complexes and non-inclusion complexes with drug molecules. The formation of a drug-dcyclodextrin complex can modify the solubility, dissolution rate, bioavailability and/or stability of the drug molecule. Drug-cyclodextrin complexes are

In general, suitable for almost all dosage forms and routes of administration. As an alternative to the formation of a complex with the drug, cyclodextrin can be used as an auxiliary admixture, for example, as a carrier, diluent or solvent. In most cases, alpha-, beta- and gamma-cyclodextrins are used, acceptable examples (described in UUO-A-91/11172, MMO-A-94/02518 and M/O-A-98/551481.

In a preferred embodiment, the compounds of the invention are released systemically (eg, orally, buccally and sublingually), more preferably orally. Mostly, such systemic (more preferably oral) administration is used to treat sexual dysfunction in women, mainly PCOS. (F, Thus, in a particularly preferred embodiment, it provides the use of the compounds of the invention in the manufacture of a medicament that is released systematically (preferably, oral release) for the treatment or prevention of SJD, more preferably ROSJ. 60 The preferred oral formulation used is tablets with immediate release, or rapid dispersing or dissolving dosage formulations (DRSHERD).

In the next preferred embodiment, the compounds of the invention are administered locally, preferably directly into the female genitalia, especially the vagina.

Since NEPs are present throughout the body, it is highly unexpected that the compounds of the invention can be administered systemically 65 and achieve a therapeutic response in the female genitalia without causing unacceptable (adverse) side effects. In EP 1 097 719-A1 and the animal models disclosed herein below, we showed that NEP inhibitors administered to rabbits (i.p.) systematically increased genital blood flow, sexual arousal (simulated by pelvic nerve stimulation) without adverse effects on cardiovascular parameters such as as the occurrence of significant hypotension or hypertension.

Preferably, the compounds of the invention are administered to treat SJ in a sexually stimulated patient (by sexual stimulation we include visual, auditory or tactile stimulation). Stimulation can be before, after or during said introduction.

Thus, the compounds of the invention augment the pathways/mechanisms underlying female genital-mediated sexual arousal and restore or enhance sexual arousal in response to 7/0 sexual stimulation.

Thus, a preferred embodiment provides the use of a compound of the invention for the preparation of a medicament for the treatment or prevention of SJ in stimulated patients.

For veterinary use, the compound of the invention is administered in the form of a suitable formulation in accordance with normal veterinary practice and the veterinarian will determine the dose interval and route of administration that will be /5 most acceptable for the individual animal.

The following recipe examples only reveal and do not limit the scope of the invention. The term "active ingredient" means a compound of the invention.

Recipe 1: The tablet is obtained using the following ingredients: the components were mixed and pressed into tablets.

Formulation 2: Formulations for intravenous administration can be obtained as follows:

Typical formulations useful for injecting the compound of the invention locally into the genitals are the following:

Recipe 3: Spray "E

Active ingredient (1.090) in isopropanol (3090) and water.

From Recipe 4: Foam and

Active ingredient, glacial acetic acid, benzoic acid, cetyl alcohol, methyl parahydroxybenzoate, phosphoric acid, polyvinyl alcohol, propylene glycol, sodium carboxymethyl cellulose, stearic acid, diethyl stearamide, van Duck Mo6301 flavor, purified water and isobutane. "

Recipe 5: Gel

Active ingredient, docusate sodium BP, isopropyl alcohol BP, propylene glycol, sodium hydroxide, o) c 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, Castor Oil, Potassium Hydroxide, Sorbic Acid and purified water. ш- Recipe 7: Pessary Their active ingredient, ketomacrogol 1000 BP, citric acid, PEG 1500 and 1000 and purified water.

The invention additionally includes:

Me, () A pharmaceutical composition containing a compound of the invention together with a pharmaceutically acceptable excipient, diluent or carrier. (iii) Compound of the invention for use as a medicament. me, (iii) Use of a compound of the invention as a medicament for the treatment or prevention of a condition for which a useful therapeutic benefit can be obtained by inhibiting a neutral endopeptidase. (m) Use of the compound of the invention as a medicament for the treatment or prevention of hypoactive sexual desire, sexual arousal disorder, orgasm disorder or pain during sexual intercourse,

F! preferably, disorder of sexual arousal, disorder of orgasm or pain during intercourse, more preferably, disorder of sexual arousal. where (M) A method of treating SJ or EDH in a mammal, which consists in treating said mammal with an effective amount of a compound of the invention. 6o (m) A pharmaceutical composition, for the treatment of SJ or EDH, containing a compound of the invention together with a pharmaceutically acceptable excipient, diluent or carrier. (my) A compound of the invention for use in the treatment of SJ or EDH. (my) Use of the compound of the invention in the production of a medicine for the treatment or prevention of SJ or

EDCH. b5 The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:

Agrase (is a filtering agent w wide

Vos tert-butoxycarbonyl

CO carbonyldiimidazole 5 chemical shift d doublet

And heating dew dicyclohexylcarbodiimide rsmM dichloromethane

OMA dimethylacetamide

DMFA M,M-dimethylformamide 75 DMSO / dimethylsulfoxide

ESU electrospray ionization with positive scanning

EC electrospray ionization with negative scanning

Pr Example g hours

NEW 1-Hydroxybenzotriazole

HPLC high performance liquid chromatography t/x mass spectrum peak min minutes

Mo mass spectrum with 29 NM nuclear magnetic resonance Ge)

Prec precursor

Prig Preparation

Kk quartet c singlet o t triplet c te trifluoromethanesulfonyl tFo trifluoroacetic acid i-o tgF tetrahydrofuran Y

TLC thin-layer chromatography i.e. thermospray ionization with positive scanning

MZS hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

The nuclear magnetic resonance (NMR) IR spectra corresponded to the proposed structures in all cases. "

Characteristic chemical shifts (5) were given in parts per million relative to tetramethylsilane using 22) c well-known abbreviations to indicate the main peaks: for example c, singlet; d, doublet; t, triplet; k, quartet; m, multiplet; w, wide The following abbreviations were used for common solvents: SOSI with, ;" deuterochloroform; DMSO, dimethyl sulfoxide. The abbreviation psi stands for pounds per square inch and NRMS stands for low-resolution mass spectroscopy. When thin layer chromatography (TLC) was used, it means that it was performed on silica gel TLC using silica gel plates 60 Rov/., Ku; is the distance traveled by the compound separating from the solvent front on the TLC plate. Melting points were determined using Regkip EITeg 0527 heating at a rate of 202C/minute). shk The powder radiograph (PRG) was taken using Zietepz ro powder

Gee! the X-ray diffractometer is equipped with an automatic sample changer, equipped with a theta-theta goniometer, slits that automatically change the beam divergence, a secondary monochromator and a scintillation counter. The sample was obtained for analysis by placing the powder on a silicone disk-shaped sample on the substrate. The sample was rotated until it was irradiated with copper K-alpha X-rays (wavelength -1.5046 Angstroms) with an X-ray tube operating at 40 kV/mA. The analysis was carried out with a goniometer passing in stepwise scanning with an interval of 5 minutes for 0.022 stage in the interval of two theta from 3 to 40s. In the results of the tables, "Angle 2-theta" depends on the interplanar arrangement of the crystal and the intensity expressed as a percentage of the largest peak (IL 4). o A skilled crystallographer will appreciate that the relative intensities of the peaks may vary due to a number of factors, such as the orientational effects of the crystals in the X-ray beam or the purity of the material being analyzed or the degree of crystallinity of the sample. The peaks may vary in height in the sample, but the location of the 60 peaks will remain essentially tabulated. In addition, measurement using different wavelengths can lead to differences in shifts according to the Bragg equation p X-2avipo. These variations caused by the use of alternative wavelengths are within the scope of the present invention.

Example 1 4-Methoxy-2-11-(113-(4-methoxyphenyl)propylamino)carbonyl)cyclopentyl|methyl)butanoic acid b5

Me. me 7 no AL : t Hydrogen chloride was bubbled through a solution of the tert-butyl ester of Preparation 1 (302mg, 0.72mmol) in dichloromethane (bml) at 09C for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was azeotroped with dichloromethane to give the title compound as a yellow oil, (23mg, 0.bmol, 8296); "H NMR (SOSIZ 400mhz) 8: 1.4-1.55 (m, 2H), 1.6-1.75 (m, 6H), 1.75-1.85 (m, 2H), 2, 4-2.5 (m, 1H), 2.6 (t, 2H), 3.2 (s, ЗН), 3.2-3.3 (m, 2H), 3.4 (t, 2H) . and VRMS p/» 392.2430 (C22NzzMOB is necessary 392.2432).

The following compounds of formula I (see Table 1) can be obtained by methods similar to the method

Example 1 from the specified tert-butyl ester precursor. s (8) "c) so (Se) " i - " shi s z -I sh" (22) o 50 (42)

F) name) 60 b5 ran nose ' ()

TABLE 1 serial number (20270000

Prig2 / methoxyethyl OMe H"H NMR (SOSIv 400 MHz) 5: 1.1 (t, chih ZNU, 1.5 (m, 8H), 1.9 (m, 4H), 2.0

Me (m, 28), 2.5 (m, ЗН), 32 (s, ЗН), 3.3 (m, 2Н), 3.8 (t, 8Н), 4.0 (с, 1Н), 5.6 (d, 1H), 6.8 (d, 28), 7 (d, hn). NRMS: down 404 (M-NU).

From Prig3Z | methoxyethyl (y F "H NMR (SOSIB 400 MG in) 5: 1.4 (d, rt ЗН), 1.6 (m, 8Н), 2.0 (m, 4Н), 2.1

Me (dd, 1H), 2.5 (m, 18), 32 (d, ЗН), with 34 (m, 2H), 40 (k, 2H), 44 (she, o 1n), 62 (m, 1H), 6.9 (d, 2H), 72 o (t, 18), 7.4 (d, 1H). NRMS: tu/h o 410 (M-N"). VRMS pu 412.1885 M schi (Sa NaomMOBsi necessary - 412.1813)

Prig4a / methoxyethyl KE | NMR (SOS; 200 MHz) 8: 1.5 (m, « s 70 -ААХ 2Н), 1.6 (m, 4Н), 1.8 (t, 2НУ, 1.9 С g | (m, 2Н) , 20 (m, ?H), 2.4 (m, 19), 3.2 (s, AN), 3.3 (t, 2H), 6.0 (shs, 1H), 6.9 (t , 2), 7.1 (t, 2H), 10.4

In (she, 1H). NRMS: down 379 (M-N"). (e)) o 50 "2 (F. ko bo b5 sere t 1 62 20 22

Prig5 | methoxyethyl AALHY IN NMR (SOS; 400 MHz) 6: 1,4- ? 1.6 (m, 1OH), 1.8-2.0 (m, 4H), 2.4 (m, 1H), 2.6 (t, 2H), 3.2 (s, 4H),

Z, (t, 2H), 3.3 (t, 2H), 5.9 (she, then 1H), 7.1 (m, ЗM), 7.2 (t, 2H), 10.4 (she , 1H). NRMS: pug 374 (M-NU.

Prig 6 methoxyethyl F "H NMR (SOCIz 400MG) 6: 1,5-

I5 1.6 (m, 1OH), 1.8 (m, ЗН), 1.9 (m, 1Н), 2.0 (k, 1Н), 2.5 (m, 1Н), 2.6 ( t, 2), 3.2 (m, AN), 3.4 (k, 2H), 5.9 » (she, 1H), 7.1 (d, ЗН), 7.3 (m, 2H) .

NRMS: fluff 362 (MAN). 71 Prig7 | methoxyethyl "NMR (SOS 400 MHz) 5: 1.6 (m,

ОН И вн), 1.8 (m, 2Н), 2.0 (m, 2Н), 2.5 s , 2H), i) 3.4 (m, 2H), 5.7 (she, 1H), 6.7 (d, 2H), 7.0 (d, 2H). NRMS: po» 376 o (MAN. BRMS ot/ 378.2288 s (Blue MO» necessary 378.2275) He) methoxyethyl IN NMR (SOS 400MHz) 5: 1.5- sya zv AdDuk 2.1 (m, 14Н ), 2.5 (m, 1H), 2.7 (m, im 2H), 3.2 (s, 2H), 3.3 (m, 2H), 3.4 (m, 2H), 6, 8 (c, 1H), 7.25 (d, 2H), "ju 7.5 (d, 2H).- NRMS: pu" 428 (M- Z c NO. VRMS puh 430.2206;" (So NzoMO . ), 2.0

F (m, 2H), 2.5 (m, 1H), 2.6 (m, 4H), se 70 3.2 (s, ЗН), 3.3 (m, 2H), 3.4 (m , o | 2), 5.9 (shs, 1H), 7.0 (d, 4H).

And NRMS: fluff 388 (MAN). VRMS t/h2 390.2639 (SozNaMO.

F) necessary 390.2643) t bo b5 erery Gdyano 20202020300 | Prig10 | methoxyethyl Me Me PN NMR (SOS; 400 MHz) b: 1.5-9 "AD 1.85 (m, 11), 2.0-2.2 (m, ЗН), 2.3 (s, ЗН), 2.5 (m, 1), 2.6 (t, 28), 3.25 (s, 18), 3.3 (s, ZN), 3.35-3.5 10 (m, ZNU 3, 8 (s, ZN), 6.7-6.8 (m, 2H), 7.1 (d, 1H), 7.6 (s, 1H). Melting point 148-450 b NRMS: tu; 406 ( Man. VRMS t/x 406.2597 (Sez3NaieMO" necessary 406.2588).

Anal. calculated C, 67.71; N, 8.74; M, 3.41. Sonia MOBO15NO is necessary C, 67.67; N, 8.72; M, z, 43eo 11 | Prig11 | methoxyethyl -AZDYU "H NMR (SOS 400MGiu) 5: 0.9 (t, o 28), 1.3 (m, 2H), 1.6 (m, 8H), 1.8 (m, ЗН), 1 .9 (m, 1H), 2.0 (dd, 1H), zo 2.4 (m, 1H), 2.6 (t, 2H), 3.2 (t, 2H), her 3.3 ( m, 5H), 3.4 (m, 1H), 4.5 (t, o 2H), 5.9 (she, 1H), 6.7 (d, 1H), 6.9 « zv (d, 1H), 7.0 (shs, 1H). NRMS: t/; Kk 404 (MAN). VRMS ptu/ 404.2434 (SeeNiaMO" necessary 4042431) and 12 | Prigi2 | methoxyethyl "AHA 'n NMR (SOS 400MHz) 6: 1.5- Z s 1.6 (m, ЗН), 1.6-1.7 (m, ЕВ), 1.7- хз» OM | 1.85 (m, ЗН), 1.9 -2.05 (m, 4H), 2.5- 2.6 (m, 1H), 2.7 (t, ZNU, 3.1-3.2 (m, 1H), 32-3.3 (t, 1H), 33 (c, ЗН), their 3.4-3.5 (m, 2H), 6.6 (she, 1H), 6.7

F (d, 1H), 6.8 (t, 18), 7.0-7.1 (m, so 70 2H). NRMS; pug 376 (Mann). (42)

F) name) because b5

AG days

Y methoxyethyl -АХХ "H NMR (SOS 400MHz) 8: 1.5-

SI | 1.75 (m, 9H), 1.8-2.0 (m, BN), 2.1 (dd, 1H), 2.5-2.6 (m, 1H), 2.6 (t, 2H), 3.25 (s, ЗН), 3.25-3.3 (m, 2H), 7 3.35-3.4 (m, 2H), 5.9 (shs, 1H), 7 ( d, 1, 7.15-7.25 (m, ZN). NRMS: pukh 396 (MAN). VRMS pukh 396.1949 (Xia NaMO, SI necessary 396.1936) ) 5: 1.5-

Ф 1.75 (m, 9H), 1.75-2.0 (m, 5H), 2.1 (dd, 1H), 2.45-2.55 (m, 1H), 2.75 (t , 2H), 3.25 (s, ЗН), 3.20-3.3 (m, s 2H), 3.35-3.4 (m, 28), 6.1 (shs, o 1), 7.1-7.25 (m, 4H). NRMS: fluff 396 (MAN). VRMS tu/ 396,1946 zo (SynyMmO,s! she needs 396,1936) 15 | Prig15 | methoxyethyl I | H nNMR (SOCIs 400 MHz) 6; 1.5- her with 5 "AJ 1.75 (m, NU), 1.8-1.95 (m, 5H), shcha 2.05 (dd, 1H), 2.4-2.5 (m, 1H), 2.6 (t, 2H), 3.25 (s, ЗН), 3.20-3.3 (m, 2H), 3.35-3.4 (m, 2H), bi (she , h s 7 IN" ty (d, 2H), 7.2 (d, 2H). what is NRMS: down 396 (MN). VRMS t/y 3961943 (ShNyaMO, Si 47 necessary 396,1936) I h Prig 16 (B)-Re AH me | "N NMR (SOSI" 400 MHz) 5: 0.8 (t,

F ZN), 1.2-1.95 (m, 16H), 2.3 (m, su 1H), 2.55 (m, 2H), 3.25 (m, 2H), 3.7 o ( c, ZN), 5.7 (c, 1H), 5.8 (d, 2H), 71 " (d, 2H). HRMS: tu 374 (M-H).

VRMS ptu/h 376.2485 (SoeNzeMO,

F! necessary 376.2482) t bo b5 ettero 1701 17 | Prig17 (1)-Me OMe | "H NMR (SOS 400 MHz) 5: 1.18 and "AJ (d, ЗН), 1.45-1.96 (m, 11Н), 2.08 (m, 1Н), 2.41 (m, 1Н ), 2.59 (t, 2H), 3.3 (t, 2H), 3.8 (s, ЗН), 5.67 (m, ts 1H), 6.82 (d, 2H), 7, 08 (d, 2H).

NRMS: tu/h 348 (MAN). 18 | Prig18 ОМе | "H NMR (SOS; 400 MHz) 5: 1.47 "AMZHLH (m, 2NU, 1.73 (m, 4H), 1.77-2.00 (m, 6H), 2.31 (m, 2H) , 2.60 (t, 2H), 3.29 (m, 2H), 3.8 (s, ЗН), 5.57 (m, 1H), 6.82 (d, 2), 7.11 ( d, 2H).

NRMS: pu» 334 (MN). 19. | Prig 19 N AD "H NMR (SOS 400 MHz) 6: 1.47 in si OI (m, 2H), 1.73 (m, 4H), 1.77-2.00 (m, o 6H), 2, 31 (m, 2H), 2.80 (t, 2H), 3.29 (m, 2H), 3.8 (s, ЗН), 5.57 (m, 13, 6.82 (d, 2H) U, 7.11 (d, 2H). at 7 NRMS: pp/x 338 (MAN"). at 201 Prig20 N SG NO NMR (SOS 400MHZ) 5: 1.40- at "АЖ 1.98 (m, 12H), 2.37 (t, 2H), 2.58 Z z (t, 2H), 3.23 (k, 2H), 5.57 (m, 1H), and 7.07 (d, 2H ), 7.20 (d, 2H)3. NRMS: t/x 338 (MAN). "

Look at us NAM? (SOS; 400 MHz) 5 1.46 7 g (m, 2H), 1.66 (m, 4H), 1.73-1.98 (m, b), 2.29 (t, 2H), 2, 58 (t, 2H), 3.17 (t, 2H), 3.26 (k, 2H), 4.53 (t, and 2), 6.59 (m, 1H), 6.70 (d, 1H), and 6.90 (d, 1H), 7.01 (s, 1H). Tpl. s» 94.5-97.0 90 NRMS: alkali 346 o (MAN"). Anal. calculated C, and 68.50; NN, 7.78; M, 201. rya SgoNUMO.0.25Н20 necessary C, o 68.65: Н, 7.92; M, 4.0095 Кобо б5 ереертю Г я я 2 ЛО 22 | Приг22 | (5)-methoxy- ООН ЯМе (SOS 400МХС) 6: 1,5-th ethyl "АХ 1.7 (m, NU, 1.75-1.95 (m, 5H), 2.05 (dd, 1H), 2.4-2.5 (m, 1H), 2.6 (t, 2H ), 3.25 (s, ЗН), 3.20-3.3 (m, 10 2), 3.35-3.4 (m, 2Н), 6.1 (she, 1Н), 7.1 (d, 2H), 7.2 (d, 2H). Tll, 75-77 "0 NRMS: m/x 394 (M-H). 23 | Prig23 (5)-methoxy-"AL"I NMR (SOCIz 400 MHC) b: 1,4-ethyl 2.1 (m, 14H), 2.45 (m, 1H), 2.55 (m, 2H), 3.2 (c, ЗН), 3.25 (m , 2H), 3.35 (m, 2H), 5.9 (shs, 1H), 6.9 (m, 2H), 7 (m, 2H), 10.4 (shs, 1H). HRMS: tu /g 378 (M-NU). (0 to 20.4 (EN, s in 1). VRMS t/g 380.2232 o (SgoNzaMO" necessary 380.2225).

Anal. calculated C, 63.73; H, with 7.92; M, 4.11, SaNyuMmOzRO, 57HO o necessary C, 63.62; N, 8.04; M, o 3.829 F 24 | Prig24 | (5)-methoxy- Me | NMR (SOS 400 MHz) 8 1,-| M ethyl «AZ 1.70 (m, 8H), 1.80-2.05 (m, 6H), - 2.4-2.5 (m, TN), 2.6 (t, 2H), 32 (c, zn), 3.2-3.3 (m, 2H), 3.4 (t, 2H), « с 70 3.8 (c, ЗН), 5.8 (shs, 1H), 6 ,8 (d, a "with 2H), 74 (d, 2H). NRMS: fluff 390 (MAN). (from -0.01 (EN, c 1.87). 4 VRMS pt/x 392.2425 (SeeNaaMO5 m necessary 392.2432) o o 50 "2 (F. ko bo b5 ererytyu 167 dyan 25 | Prig25 | ( 5)-methoxy-"'H NMR (SOS: 400 MHz) 5: 1.41- and ethyl 2.06 (m, 14H), 2.43-2.60 (m, 2H), 2.57 (t, 2H), 3.18 (t, 2H), 3.33 (s,

ZH), 3.24-3.4 (m, 4H), 4.53 (t, 2H), then 5.80 (she, 1H), 6.66 (d, 1H), 6.88 (d, 1), 7.0 (s, 1H). NRMS: pu 402 (M-NU. (sdo 0.00 (EON, c 0.93). Anal. calculated b, 86.85; NN, 8.24; M, 3.35.

СоНаеМО5О,5Н»О is necessary С, уй 66,97; N, 8.31; M, 3.4095 26 | Prig26 "NYMR (SOSI", 400 MHz) 5: 1.13-2. 11.98 (m, TON), 2.16-2.28 (m, 4H), and "AZH 2.79-3.03 ( m, 4H), 5.60 (shs, 1H), o 8.88 (d. 1H), 7.40 (d, 18), 7.57 (d, 13, 8.08 (d, 1), 8.17 (d, 1H), 8.86 (d, 1H). NRMS: ES: pu? 353 o tho (M-H). so 27 | Prig27 | methoxyethyl mes "H YaMe (СосСИ5, 200MHz) 6: 1.20 i-th -AZHHS (m, 2H), 1.60 (m, 8), 180 (t, 2H). 00 1.90 (m, ЗН), 2.50 (m, 1H), 2 ,0 (t, - 2H), 3.20 (m, 5H), 3.20 (m, 2, 3.80 (s, ZN), 6.00 (she, 1), 6.90 « , 2Н), 7.10 (d, 2Н), 7.20 (d, 2Н). -

Sg"

F o 50 o (F) t bo b5 pe pek | And Y7711dan111 and 28 | Prig28 | methoxyethyl NMR (SOCI3, 400 MHz) 5: 1.30

Me | (m, 28), 1.40-1.70 (m, EN), 1.80 (m, -ADH 28), 1.90-2.10 (m, ZN), 2.30 (s,

ЗН), 2.42 (m, 2Н), 2.60 (t, 2Н), t 3.20 (с, ЗН), 3.30 (m, 2Н), 3.40 (m, 2Н), 5 .85 (she, 1H), 7.15 (she, 4H).

YARMO: ES" ot/» 376 (MN).

VRMS t/h2 376.2484. (SggNizichOH is necessary 376.2483).

Prig29 | methoxyethyl "NYAM (SOS, 400 MHz) 8: 1.60 "AD (m, 8H), 1.90 (m, 4H), 2.00 (m, 2H),

Ova | 2.50 (m, 1H), 2.60 (t, 2H), 3.20 (m,

BN), 3.30 (Kk, 2H), 5.00 (s, 2H), in 5.80 (she, 1H), 6.90 (m, ЗН), 7.20 o (t, 2H), 7.40 (m, 5H). NRMS: ES" 468 (ME),

From Prig 30 | methoxyethyl INyaYAME (SOS, 400 MGu) 8: 1,43- («c) 7 | -ADI 1.76 (m, 1OH), 1.80-2.15 (m, 4H), Fo

OMe | 2.50 (m, 1H), 2.60 (t, 2H), 3.25 (s, i-th

ZH), 3.30 (m, 2H), 3.35 (m, 2H), C 3.78 (d, 2H), 4.01. (t, 1H), 5.75- -

BOB (shm, 1H), 6.10-6.45 (shm, 1H), 6.70 (m, 1H), 6.90 (m, 1H), « 7.18 (m, 1). NRMS: ES" 392.2 2 s (Man). g" Prig 31 methoxyethyl NMR (SOS, 400MHz) 1.50- in du" 1.70 (m, 8H), 2.00 (m, ЗН), 2 ,10 - (dd, 1), 2.30 (m, 1H), 2.60 (t, e 2H), 3.20 (m, 2H), 3.30 (s, ЗН),

F 3.40 (k, 2H), 3.8 (d, 6H), 6.10 (she, o) 70 1n), 6.30 (shd, 2H), 7.00 (d, 1H). c Y NRMS: ES" 422.3 (MN). Anal. calculated С 65.16; НМ 8.46; M 52 3.1796. (С»zNaeMOv Necessary: С i) 65.53; Н 8.36; M 3.329) o bo b5 friction i 2 1 j 6 bottom 020207 32 | Prig 32 (5)- NMR (SOS, ZO0MHz) 1.50- and methoxyethyl of your 1.78 (m, 12Н), 1.91-2, 13 (m, 4H),

Ohme |1.48-1.62 (m, ZN), 3.20-3.47 (m, 7H), 3.80 (s, ZN), 5.82 (t, 18), then 6.83 (d, 2H), 7.10 (d, 2H). NRMS:

TS" pug 406 (MN). 33 Y Prig 33 n "NYMR (SOSI;, 400MHz) 5: 1.40 (m, 2H), 1.55 (m, AN), 1.80 (m, 4H), 8 1.90 (m, 2H), 2.2 (m, 2H), Z (t, 2H), 3.3 (Kk, 28), 5.60 (she, 1H), uh 7.25 (m , 1H), 7.35 (m, 1H), 7.45 (m, ?H), 7.70 (d, 1), 7.80 (d, 1H), 7.95 (d, 18). NRMS: EStu" 352 and (M-N), 705 (2M-N). p. 34 | Prig 34 'NMR (SOSIz, 400 MHz) 6: 1.40 (m, 2H), 1.50 (m, 4H), 1.70-1.90 (m, with 6H), 2.20 (m, 2H), 2.80 (t, 2H), o 3.30 (k, 2H), 5.60 (shs, 1H), 7.25 o (d, 1H), 7.40 (m, 2H), 7.55 (c, IN), i-o 7.70 (m, ZN). NRMS: ESpuh 352 t | (m-n), 705 (2M-H). i- 35 | Prig 35 (5)- "NMR (СО300, Z00MGy) 5: 1,45-methoxyethyl KE 1.88 (m, 8), 2.0-2.12 (m, ZN), « with AL, 2, 45 (s, 1H), 2.65 (t, 2H), 3.20 (t, - g 2), 325 (s, ЗН), 3.35 (t, 2H), 7.10-7.20 (m , 2H), 7.35 (d, 1).

NRMS: EStp/ 412 (М-Н). SNM: t 0.15 СН.

Sg"

F o 50 "2 (F. ko bo b5

Gran 71111111 (5)- "NMR (SOS, 400 MGu) 5: 1.45- and methoxyethyl ОЙ | 1.70 (m, 1OH), 1.75-1.83 (m, 1Н),

АЖ 1.85-1.96 (m, ЗН), 2.05-2.15 (m, 2Н), 2.43-2.52 (m, 1Н), 2.57 (t, then 2Н), 3.21 (c, ЗН), 3.35 (she, 2H), 5.80 (shs, 1H), 6.89 (d, 1H), 6.95 (d, 1H), 7.23-7 ,30 (m, 1H). NRMS:

ES" t/h 436 (MaMa). Found:

C, 59.36, 59.17; H, 7.30, 7.27; M, 2.68, 2.659. Required: C, 58.96;

N, 7.46; M, 3.03 (M 5 0.29 pentane 011 TFO -- 0.80 water) 37 | Prig 37 (53- ASU "NMR (CO2OB, 400 MHz) 5: 1.25 s methoxyethyl (m, 1H), 1.40-1.82 (m, 11H), 2.0 (m, o zn), 2 .38 (c, 1H), 2.60 (t, 2H), 3.08-3.18 (m, 7H), 5.46 (she, 1H),

OP VNE:

ES tukh 396 (M-N). SNM: 0.36 о снсиовно и з5 38 | Prig 38 "AZH "NYMR (SO5OB, 400MRts) 6: 1.23 k (d, 2H), 1.32-1.45 (m, 4H), 1.72 (t, 2), 1.81 (t , 2H), 1.93 (m, 2H), « and 2.16 (t, 2H), 2.60 (t, 2H), 345 (t, - s 2H), 6.77 (m, 2H) . , 2H), 1.51-1.65 (m, 4H), 1.75 (t,

F 2H), 1.80 (t, 28), 1.95 (m, 2H), 00 2.15 (t, 2H), 2.61 (t, 2H), 3.18 (t, o 2) , 6.85-7.95 (m, ZN). NRMS: ЭС " пух 338 (M.N). SNM: 0.068 NO (F. ko bo b5 per pek | Ya rdeni 1117

Prig 40 "NMR (СозО0, 400MHz) 6: 1.47 and OS, | (m, 2Н), 1.52-1.69 (m, 4Н), 1.75 (t, "АЖ 2Н), 1, 88 (t, 2H), 2.0 (m, 2H), 2.17 (t, 2H), 2.60 (t, 2H), 3.18 (t, 2H), then 7.1 (d, 2H), 7.23 (d, 2H), 7.68 (shs, 18). NRMS: EStukh 386 (M-H). sHnMm: om no : 41. | Prig 41 (5)- - Y "NYMR ( SOSI», ZO0Mhz) 6: 1,40-methoxyethyl" also 2.80 (m, 12H), 2.18-2.43 (m, 2H), 2.90-3.08 (m, 2H), 3 ,18-3.50 (m, 7), 6.18 (s, 1), 7.20-7.31 (m, 2H), 7.77 (t, 1H), 8.50 (d, 1 ). C 42 Prig42 "NYMR (SOS, 400 MHz) 8: 1.35- -ADU 1.43 (m, 2H), 1.55-1.85 (m, 4H), about 1.66-1.90 (m, 6H), 1.97-2.05 (m, 2), 2.20-2.29 (m, 2H), 2.58 (t, zo 2H), 2.80-2.90 ( m, 4H), 3.24-3.30 o (m, 2H), 5.49 (she, 1H), 6.90 (d, o 1H), 6.92 (s, 1H), 7.10 (d, 1H). her

NRMS: ES ot/; 342 (M-N). -

Found: C, 7371, 73.77; H, 908, 9.18; M, 3.36, 3.36.

Required: C, 73.81; N, 95.06; M, h 7 3.75 (M with 0.06 Es and 0.34 with pentane) 43 | Prig 43 (5)- "NIMR (SOS, Z00MGu) 5: 1.50- - 45 methoxyethyl АЖ 2.12 (m, 14Н), 2.48-2.62 (m, ЗН), гч о7 | 323- 347 (m, 7H), 425 (s, ЗН), o B.77 (t, 1H), 6.65-6.75 (m, 2H), s) 6.81 (d, 2H). NRMS: TS" down 420 o (Man). (F) ko bo b5 le pr! given 7

And 44 | Prig 44 (5)- "NMR (SOCI3, Z0OMGu) 5: 1.37- methoxyethyl CO 2.02 (m, 14H), 2.40-2.51 (m, 1H), 2.68-2.83 (k, 2H), 3.23-3.50 (m, 7H), 5.61 (s, 1), 7.22-7.38 (m, 7 ZN), 7.67-7.90 ( m, ZN), 8.72. (d, 45 | Prig 45 "NYMR (S500, 400MG) 5: 1.42- that is 1.51 (m, 2H), 1.55-1.68 (m, 4H), -ADE 1.72-1.79 (m, 2H), 1.83-1.90 (m, 2H), 1.98-2.05 (m, 2H), 2.17 (t, 2), 2.55 (t, 28), 3.17 (t, 2H), 7.06 (d, 2H), 7.35 (d, 2H). NRMS:

ES tu: 380 (M-N). Found: C, dv B7, B2, 57,59; H, 6.65, 6.66; M, at 3.37, 3.35. Required: C, 57.19;

H, 6.58; M, 3.58 (M -- 0.13 pentane) and Prig 46 "NMR (SOS, 400 MHz) 5: 1.41- o

Me | 1.55 (m, 2H), 1.57-1.73 (m, 4H), about pa; 1.82-2.00 (m, 6H), 2.33 (t, 2H), her 2.78 (t, 2H), 3.33 (k, 28), 4.07 (s, schi ZN) , 5.59 (t, 1H); 7.22-7.36 (m, M

NU, 7.51 (s, 18), 7.91 (s, 1H). 47 | Prigb7 "NMR (SOS, 400 MHz) 8: 1.45- h s 70 AD 1.52 (m, 2H), 1.58-1.65 (m, 4H), - g 1.75-1.90 ( m, 4H), 1.93-1.95 (m, 2H), 225-229 (m, 2H), 2.66 (t, 47 2H), 3.22-3.30 (m, 2H), 5.67 (shs, in INU 727 (d, 2H), 7.51 (d, 2H). ES" about t/h 327 (M-H). Found: C, syu BV, 78, 58.89; H, 8.96, 6.96; M, about 6.40, 6.41. Required: C, 58.57; and H, 6.58; M, 6.80 (M 4 1.17 water -- and 0.55 TFO). (F. ko bo b5 yar kt 1726611 two

And 48 | Prig47 "NYMR (SOS, 400 MHz) 6: 1.49

AD (m, 2), 1.65 (m, 4H), 1.90 (m, 6H), 2.30 (t, 2H), 2.77 (t, 2H), 3.35 (k, 2H ), 4.27 (s, 3H), 5.63 (she, 1H), then 7.23 (d, 2H), 7.45 (s, 1H), 7.70 (d, 2H), 7, 87 (p. 1H). NRMS: pug 358 (Maine), TS. '

Prig 48 N "NYMR (SOSI", 400 MHz) 8: 1.40- o. ), 2.56 (t, 2H), 2.77 (t, 2H), 3.27 (t, 2H), 4.14 (t, 2H),

B, B6 (shs, 1H), 6.71 (d, 1H), 6.82 (s, 1H), 6.88 (d, 1H). NRMS: ipu/x zv 358 (MAN) ES. - Anal. o calculated C, 69.81; H, 8.09; M, 3,895. C23NoMO.; it is necessary C, 70.17; H, 8.13; M, 3.9095. at 7 5O | Prig 49 TNYAMR (SOS, 400 MHz) 5: 1.37- so

AD 1.45 (m, 2H), 1.56-1.59 (m, 4H), ke; 1.73-1.90 (m, 6), 2.23 (t, 2H), t 2.40 (s, ЗН), 2.55 (t, 2H), 3.24 (dt, in 2H) , 5.60 (she, 1H), 7.05 (d, 2H), 7.14 (d, 2H).). NRMS: fluff 348 (M- "

H), EC. Anal. calculated C, w c 63.68; NN, 7.66; M, 3,675. :» SteНg/Моз5е0.09 TFO is necessary and S,va04;Н, 79: M, Y. - Prig 50 "NYMR (SOSIv, 400MHz) 5: 1.20 of them o | (d, ZN), 1.40 ( m, 2H), 1.50-1.90 (m, b 9, 1ОН), 2.20 (m, 2H), 2.60 (m, 1H), и ге AGE с и 1Н), 4.50 (t, 2H), 5.50 (shs, 1H), 6.70 (d, 1H), 6.90 (d, 18), 7.0 (s, 1). NRMS: fluff 358 (M-H ), ES. (F) t bo b5 eri i ro ornoi 02027022 52 | Prig 51 N "NYMR (SOS, 400 MHz) 6: 1.10 and O, | (d, ZN), 1.40 (m, 2H), 1.60 (m, EM), ky 1.90 (m, 4H), 2.30 (m, 2H), 2.50 (t,

Me 2H), 310 (t, 2H), 4.00 (m, 1H), then 4.50 (t, 2H), 5.40 (d, 1H), 6.65 (d, 1H), 6, 85 (d, 1H), 6.95 (c, 1H).

NRMS: down 358 (M-N), ES. i5 53 | Prig 52 (5)- "NMR (SOS, 400 MGy) 5: 1,45- methoxyethyl ZMe 1.64 (m, 8H), 1.78-1.94 (m, bH), "АЖ 2.41 (s , ZN), 2.45-2.50 (m, 1H), p 2.58 (t, 2H), 3.22-3.27 (m, 5H), 3.32-3.37 (m, 2). ,02; H, 8.54; M, 2.8795. CoNaziMO.50.26 EUAs required C, 64.64; H, 8.46; M, av) 7 3.169. so 54 | Prig 53 H "NMR ( SOS, 400 MHz) 5: 1.43- i-oi

IY 1.53 (m, ZN), 1.58-1.69 (m, 8H), t 35 1.70-1.82 (m, 1H), 1.83-2.01 (m, ge 4H ), 2.28 (t, 2), 3.33 (t, 2H), 3.42 (m, 1H), 4.23 (t, 1H), 4.60 (t, « 40 1H), 5 .70 (she, 1H), 6.78 (Dd, 1H), 2 in 6.88 (t, 1H), 7.11 (t, 19), 7.18 (dd, z» IN). NRMS: fluff 330 (M-H) ES" 332 МН" 354 ММа" ES". Anaya. and calculated C, 69.81; H, 8.09; M, ve 3.8895. C»iNaoMO is necessary C,

F 70.17; H, 8.13; M, 3,905. o 50 "2 (F. kobo b5 per pek | AG rdan111 ; BV | Prig 54 (5)- "NYMR (SOSI", 40OMGu) 6: 1,47- methoxyethyl 1,70 (m, 8H), 1, 73-1.79 (m, 2H),

KA, 1.94-2.06 (m, 5H), 2.45-2.51 (m, about 1H), 2.55 (t, 2H), 3.15-3.18 (m, then 4H3 . 6.89 (d, 1H), 7.02 (d, 1). NRMS: t/» 402 (M.N),

EC Anal. calculated C, 66.36; n, 8.20; M, 3,299,

SozNazichO5e0.147FO is necessary С, 66.66; H, 7.96; M, 3.3495. 56 | Prig 55 (5)- "NMR (SOS, 400 MHz) 5: 1.50- dv methoxyethyl Me about 1.70 (m, 6H), 1.80 (t, 2H), 1.90- about to 2.05 (m, 5H), 2.20 /s, ЗН), 2.50 (m, 2H), 2.55 (t, 2H), 3.15 (t, 2H), with 3.30 (m, 58 ), 340(m,2n)aBO(T, 2H), 5.80 (shs, IN), 670 (s, 6.85 (s, 1H). NRMS: pug 432 (MA! 0

H), EC. with and - 57 | Prig 56 (5)- "NMR (SOS, 400MHC) 6: 1,43- methoxyethoxy o (2.06 (m, 12H), 2.57 (t, 2H), 2.53 methyl "АЖ (shm, 1 ), 3.18 (t, 2H), 8.27 (Kk, h s 70 2H), 3.34 (s, ZN), 3.44-3.53 (m, - with ZN), 3.58 (t, 2H), 3.64 (pc, 1H), 4.53 (t, 2H), 5.90 (she, 18), 6.68 4? (d, 18), 6.89 (d, 1H), 7.00 (s, 1H). h NRMS: fluff 432 (M.N), ES. Anal.

F calculated C, 64.90; H, 8.16; M, syu 70 2.9995. SoaNaMOv»0.5NoO o necessary C, 65.14; H, 820; M, y 31695. (F) ko bo b5 breaks 00100000

BV | Prig57 (353- "NMR (SOS, 400 MHz) 8: 1.42 methoxyethoxy - ADM (c, 6H), 1.47-1.67 (m, 7), 1.76- methyl 1.86 (m, 4H ), 2.04 (dd, 1H), 2.55 (t, 2H), 2.59-2.65 (m, 1H), 2.94 (s, to 2), 3.23-3.28 (m, 2H), 3.32 (s,

ZN), 3.46-3.50 (m, ZN), 3.55-3.62 (m, ZN), 6.00 (shs, 1H), 6.60 (d, 75 1H), 6, 87 (d, 1H), 6.92 (s, others).

NRMS: PU 460 (M-N), EC Anal. calculated C, 56.62; N, 6.93; M,

M. 2.4195. SeNeMOve, 2 TFO is necessary C, 57.00: H, 6.77; M, 2.3495. Sh 59 | Prig58 | (A)-methyl NMR (SOS, 400MHz) 5: 1.08 schi AD (s, ЗН), 1.42-1.76 (m, 7Н), 1.80 (t, 6) ), 1.88-2.0 (m, 28), 210 (m, 1), 2.45 (m, 18), 2.60 (t, 2H), o 3.28 (m, 2H), 5.80 (shs, 1H), 6.82- s 692 (m, 2), 6.95 (dd, 1H). s

NRMS: down 396 (М-Н) EC 398 «

МН 420 ММа"- ES. Anal. cha . calculated С, 55.84; Н, 6.20; М, 30195. СоНобЕо МО» " ю е1н20г0.21СНоСи» necessary С, - с 56.03; Н, 6, 38; M, 3,295,

Iz» Prig 59 (5)- o 1 'NMR (SOCyz, ZO0MHz) 5: 1.20 methoxyethyl kA (d, ЗН), 1.40-1.85 (m, 12Н), 1.95 a Me (m , 2H), 2.45 (m, 1H), 2.65 (m, 1H), 3.05 (m, 1H), 3.15 (t, 2H), 3.25 (s,

F ZN), 3.30 (m, ZN), 4.50 (t, 2H), su 20 5.60 (she, 1H), 6.70 (d, 1H), 6.90 o I (d, 1), 7.00 (c, 1H). NRMS: down 416 (M-N), ES. (F)

Po) bo b5 -A1-

ertego i 122 56600 (yno 02020000 and Prig 60 (85)- "NMR (SOS, 300MGu) b: 1.50- methoxyethyl Me O011.70 (m, 8H), 1.75 (t, 2H), 1.90 -

AYU 2.10 (m, 4H), 2.21 (s, ЗН), 2.50 (m, 1), 2.60 (t, 2H), 3.25 (s, ЗН), 7 3.30 (m, 2H), 3.35 (m, 2H), 4.50 (m, 2H), 5.80 (she, 1H), 6.60 (s, IN), 6.95 (s, 1H) . NRMS: tu» 416 (M- to H), ES.

Prig 61 (8)- "NMR (SOS, ZOOMGhz) 6: 1.50 methoxyethoxy SI | (m, 2H), 1.60-2.00 (m, 108), 2.60 methyl -ADT (m, ЗН ), 3.20 (t, 2H), 3.30 (s, ЗН), 3.45 (m, ЗН), 3.55 (m, 2Н), 3.60 (m, 1Н), 6.0 (she, 1), 7.02 (d, 2H), sch 7.19 (d, 2H). NRMS: pu 424 (M- o

H), EC. 63 | Prigb2 (5)- about | NMR (SOS, 400 MGu) 5: 1.3 (s, ozo methoxyethyl kah vnuale (mi on, (tan!

Me 1.93 (m, 20), 2.42 (m, yin), ZY7(M| o 4H), 3.3 (s, ЗН), 3.38 (m, 2H), 4.55 - with (t, 2), 5.5 (she, 1H), 6.7 (d, 1H),. Kk 7 (d, 1n), 7,2 (p, 18). NRMS: M-

AI "

Y Prig 63 (83- "NMR (SOS, ZOOMHC) 5: 1.40- - s methoxyethyl CO | 2.23 (m, 15H), 2.43-2.63 (m, 1H), xz" in 2 ... 5.99 (w s, 1H), 7.19 (d, 2H), i" 7.30 (d, 2H). NRMS: MAN, 426.

F (te) su 70 Prig 64 (8)- I! G"NYMR (SOS, Z0OMHC) 5: 1.17-

He) methoxyethyl 2.17 (m, 17H), 2.40-2.58 (m, 1H),

Y o 2.98-3.57 (m, 7H), 3.81-3.77 (m, 2H), 5.93 (sh s, 1H), 7.20-7.43 (m, (F . AN). NRMS: MAN, 440. (TS) ko bo b5 -dD2-

er le r 00000000

Prig 65 (5)- "NMR (SOSiz, 300MHz) 6: 1,40-methoxyethyl АЖ 2.18 (m, 16Н), 2.43-2.68 (m, ЗН), со 18.30 (s, ЗН) . , 7.20 (c, 1H).

Anal. calculated C, 60.01; H, 7.60; M, 3,006.

SoNazosiMO5»0.75Н50 is necessary

C, 60.13; N, 7.68; M, 3, 1995. 67 ) Prig 66 (5)- "NMR (SOCIz, 400 MHz) b: 1.42 methoxyethyl AD" (d, ZN), 1.45-1.66 (BN), 1.74-1.80 (m, 2H), 1.82-1.95 (m, ЗН), 1.97-2.02 (1Н), 2.42-2.55 (m, ЗН), 2.75 (dd, 1Н), 3 ,20-3.27 (m, OH), 3.31" s 3.36 (m, 2H), 4.80-4.87 (m, 1), o 5.77 (she, 1H), 6 .61 (d, 1H), 6.85 (d, 1H), 6.93 (c, 1H). NRMS: M 5. o

Ma, 440. (ES. so (Se)

Alternatively, Example 22 can be obtained as follows: (25)-2-C1-(113-(4-Chlorophenyl)propyl|Iamino)carbonyl)ucyclopentyl|methyl)-methoxybutanoic acid C

Trifluoroacetic acid (16.3 mL, 212 mmol) was added to a solution of Preparation 22 (9.6 g, 21.2 mmol) in dichloromethane (52 mL), and the resulting solution was stirred at room temperature for 3.75 hours under a Mo atmosphere. Then, an aqueous solution of sodium carbonate (dbBml 1095 wt/vol of solution) was added to the reaction while stirring until the pH of the aqueous layer was between pH and 3. The layers were separated and the organic layer was extracted with an aqueous solution of sodium carbonate (2x20ml of 1095 wt/vol of solution). The aqueous layers were combined and then a saturated aqueous solution of sodium chloride (80ml) was added, followed by 2-butanone (40ml). The layers were separated and the aqueous layer was extracted again - with 2-butanone (2x5Oml). The combined organic solutions were then dried by azeotropic distillation at atmospheric pressure to a volume of 7 Oml, as a result of which crystallization occurred and the mixture was diluted with 2-butanone (7 Oml). The product was then collected by filtration and dried at 502 for 65 hours in a vacuum to obtain crude sodium salt of the title compound as a white solid (5.76 g), which was then purified by crystallization as shown below. Ethyl acetate (87ml) and ethanol (13ml) and insoluble material were added to the crude product and the residue was removed by filtration. Ethanol was then removed by azeotropic distillation at atmospheric pressure (removing 110ml of solvent) and replaced with ethyl acetate (145ml) resulting in crystallization.

The resulting crystalline product was collected by vacuum filtration to give the pure sodium salt of the title product as a white crystalline substance (4.51g, 10.8mmol, 5195); Tpl. (ethyl acetate) 214-2162C; "H NMR 2) 20 (DMSO-a5 ZOOMHz) 5: 1.26-1.58 (m, 8H), 1.62-1.74 (m, ZN), 1.74-1.86 (m, 1H), 1.91-2.07 (m, ЗН), 2.57 (t, о 2Н), 3.03 (k, 2Н), 3.10 (s, ЗН), 3.13-3, 27 (m, 2H), 7.22 (d, 2H), 7.29 (d, 2H), 9.16 (t, w, 1H); NRMSO (EC negative); 789 (2M-NI(29СИ) , 394. MANI (29CI). For analytical purposes, the title product (i.e., the free acid) was obtained by dissolving this sodium salt in water, acidifying with 5M hydrochloric acid, and extracting with dichloromethane. The solvent was removed by purging with nitrogen to obtain a sample of the title product ; "NN NMR (DMSO-av ZOOMHz) 5: 1.22-1.80 (m, 11), 1.81-1.96 (m, 2H), (F. 1.96-2.08 (m , 1H), 2.93-2.27 (m, 1H), 2.53 (t, 2H), 3.03 (k, 2H), 3.11 (s, ЗН), 3.16-3, 25 (m, 2H), 7.20 (d, ko 2H), 7.30 (d, 2H), 7.51 (t, 1); NRMS (ES negative); 78912М-НИ(25СИ), 394 | M-NI (Z9SI); TOP (column: SpigaIRak

AZ (2550.4 bsm); mobile phase: hexane/PA/acetic acid (95/5/0.506/o06/06); flow rate: 1.Oml/min.; because temperature: room temperature; injected volume: 20 μl; detection: UV 22Ohm; Sample concentration: 1.Omg/ml was obtained in the mobile phase) Retention time: minor enantiomer 11, 4 min. (5.790), the main enantiomer 14.3 min. (94,396).

Sodium salts of Example 22 a) Monohydrate 65 3.995 ml of water in isopropanol was added to the sodium salt of Example 22 (200 mg). The resulting suspension was stirred for 12 days, after which it was removed by filtration.

The product had the following peaks in PRG. we are 17800798 vm 023200zovv; that's why | 132 to2tz 005000 ovvmo 0002990 z3ya50m iv import | 69 it ma 000oveve00ot2 | zeoi115 lay |for 111

Differential scanning calorimetry (DSC) was performed using the device Regkip EIteg 0O50-7 equipped with an automatic sample changer. Approximately Zmg of the sample was carefully weighed in a 50 microliter c gr; aluminum cup and closed by clamping with a perforated lid. The samples were heated at a rate of 202C/minute in the range from 402 to 3009 in a stream of nitrogen. Dehydrogenation occurred in the range of 50 to 15090 and complete melting occurred in the range of 212 to 2252. One skilled in the art should appreciate that the melting point may fall outside this range due to sample impurities. b) Anhydrous salt (ав)

The sodium salt of Example 22 had the following peaks in PRG. co

Фий звтв 00вв60000лвви00овво0 ml" zezol m "zja siz" - Preparation of them Preparation of 1 tert-Butyl 4-methoxy-2-(1-(113-(4-methoxyphenyl)propylIamino)carbonyl)-cyclopentyl|methyl) butanoate (22)

Fo 2 Me. (42) and me

F) yu Me 0 . 60

Me o

Product of Preparation 68 (325mg, 1.08mmol), product of Preparation 73 (178mg, 1.08mmol), NEW (14bmg, 65 1.0v8mmol), MUZSOI (207mg, 1.08mmol) and triethylamine (0.3ml, 2.1bmmol) ) were stirred together in dichloromethane (bml) at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed with water (2 x 20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography using dichloromethane, eluting with 99:1 dichloromethanemethanol, then 98:22 dichloromethane:methanol (K; 0.2) to give the product as a yellow oil (267mg, 0.bmol);

TN NMR (SOCIz 400 MHz) 8: 1.4 (s, 9H), 1.6 (m, 5H), 1.8 (m, 4H), 2.0 (m, 1), 2.3 (m, 1H), 2.6 (t, 2H), 3.2 (s, 3H), 3.3 (m, 2H), 3.7 (s, 3H), 5.7 (t, 1H), 6, 8 (d, 2H), 7.0 (d, 2H); NRMS: t/z 448 (М-Н7).

The following Examples of formula (Ma), i.e., compounds of the general formula IM, where r is tert-butyl, were prepared by methods similar to Preparation 1, from the indicated precursors (see Table 2). in!

Me 0 o (Ma)

TABLE 2

Pryg Prek. Prec. amine -X-U Analytical Data - 2 Trigb8 | Bought in | methoxyethyl bme |"H NMR (SOS 400 MEN) 6: 1.4 (s, ZN), 1.520 (m,

ISM ki 16H), 2.3 (m, 1), 2.6 (t, 2H), 32 (d, ZN), 3.3 (t ZN),

Viotedisviv Me 3.7 (c, ЗН), 4.0 (m, 1Н), 5.5 (ns, 1Н), 6.8 (d, 2Н), 7

Ipe (d, 2H). NRMS: down 462 (M-N"). sch

From Prig 68 Prig 120 methoxyethyl and "H NMR (SOS 400 MhuC) 5: 1.4-1.45 (m, 108), 1.5-1.7 ro (m, bH), 1.7-1.8 (m, 2H), 1.9-2.1 (m, 4H), 2.3-2.4 (m, o

Me IN), Z (d, ZN), 3.1-3.35 (m, ZN), 3.9-4.0 (m, 2H), 4.3-4.4 (m, 1H), 6.1-6.2 (m, 1H), 6.8-6.9 (s, 2H), 7.2 (t, 1H), 7.8 id, 1). | "c) 4 Prig 68, Central Register Office 4533655, | methoxyethyl KOH NMR (SOS; 400 MHz) 8: 1.4 (s, ZNU, 1.5 (m, 2), 1.6 s! Example 7A -АХУ (t 4Н), 1.7 (dd, ЗН), 1.8 (m, 2H), 1.9 (m, ЗН), 2.3 (m, 1), 2.6 (t, 2Н), 31 (m, 1), 3.2 (s, ЗН ), 3.3 (t, 2H), 5.9 ise) (m, 1H), 6.9 (t, 2H), 71 (t, 2H). NRMS: ace 436 (MAN"). "g and -

Pryg Prek. Prec. amine -th Analytical Data 5 | Prigbv Purchased In | methoxyethyp a "I NMR (SOCIz 400 MHz) 8: 1.4 (s, 9H)U, 1.5-1.6 (m, "

Agagisn 10NU, 1.7 (m, 2H), 2.0 (m, 4H), 2.3 (m, 1H), 2.6 (t, 2H), | Spetis! 3.2 (c, BN), 3.3 (t, 2H), 5.9 (she, 1H), 7.1 (m, ЗN), 7.2 (t, Z s sho | M dlleveyutya "z in Prig 68 Purchased from | methoxyethyl - AL TN NMR (SOS 400 MHz) 5: 1.4 (s, 9H), 1.45 (m, 2H),

Aidhisn 1.6 (m, VN), 1.8 (m, 4H), 2.3 (m, 1H), 2.6 (t, 2H), 3.2 (e,

Spetisai ZNA), 3.3 (m, 4H), 3.8 (shs, 1H), 7.1 (d, ЗН), 7.2 (d, 2H). I Prig 68 Vioogd. May | methoxyethyl OH OT H NMR (SOS; 400MGu) 5: 1.4 (s, 1OH), 1.6 (m, 1OH), t» Spect., 19987, - AD 1.8 (m, 2H), 2, 9 (m, 1H), 2.6 (t, 2H), 3.2 (s, ЗН), 3.3 (m, o 5, 1675-83 AN), 5.7 (she, 1H), 6 .7 (d, 2H), 7.0 (d, 2H). NRMS: tug 50 I 434 (MAN). at 8 Pryg 68 Visogd. May, | methoxyethyl NMR (SOS 400MHz) 5: 1.5 (s, 9H), 1.5-2.4 (m, eOEZh goyu neveEyaeh 5, 1875-83 7.3 (m. 2H), 7.3 (m, 2H). NRMS: tu 486 (M-H"),

In Prig 68 Prig 74 methoxyethyl BO TN NMR (SOS 400MHz) 6: 1.2 (t, ЗН), 1.4 (s, 11Н), «АХ 1.6 (m. 9Н), 1.8 (m, ZA), 1.9 (m, 2H), 2.3 (k, 1H), 2.6 (k,

And AN), 3.2 (s, ЗН), 3.3 (m, 2Н), 3.35 (t, 2Н), 5.8 (she, 1Н), o I 7.1 (с, 4Н). NRMS: pu/2 446 (М-Н"). име) 60 b5 цлх чо5 (NN) 5023-45 ybaznu 5-5 (y NU BA (S 5NU 35(s ZNU Z'Be: 9 Tscm. 8 1eg redso|meviksnviMY i IN l (SOS chobuchil) 9: i cho (g zone 1-50

UB (y ZNU NYS: ilkh che5 (YZHNI ch015 (ybznu zya-zye (y NU vya (te anu mo (F 1Nu xZ- 1ave" za(zoU SI chnu vya (y ni B' there is (g BNU 35 (with ZNU 35-33 70 13 tsbm. ev t yva buesh" | yezoksnvimy I and o chib (SOS chOOyl) is: I (s ОН ge-5o (y chach (ino ez (ts nu ve ( r ZNU Uube (n ZNO n: shle vie-V'ya(y 5NU 35 (Ж 5Н)U 3'z (with ZNU zya-zyya (y NU

Heporyudsya still en gu-eve (m Yanu a-5'o (and ZNU 535 (and NU 15 15 Tsbm'bea fcbnchryaim Hu mezoksmvimy o IN shchi (SSR Foouyl) e: 14 (sb zone gezu (and (FaNnu uo (s z1n)U NMS: shlh cho (IN 5NI Z'5 (s ZNU z'Z(K5NUY I (5NU gy nu va 11 Tsbmov | He 3e mivzoKoneiny o; IN chiB (SOS! chobinl) 9: 10 (s en ge ( same zone 20 1 Well

ZNU 35 (with ZNU Z'zz (and Yanu Z'AV (with ZNU ee (with . Ge-5oz (and I5NU 55 (with ZNU 538 (and zn) 5'ed (g

Tstsom 68 tsobm le metoksmvimy diva in ON WE (SOS? OO) o: 1 (s oNuU che (zh 5NU kesioIM Ge moly Li |shzhne| what! oj | 0000 same 1000

Pryg Prek. Prec. amine -X-X Analytical Data 15 Prig 68 U, May. Sbet., | methoxyethyl AD "I NMR (SOS 40 MHz) 5: 1.4 (s, 108), 1.5-2.05 (m, 1996, 39, 13Н), 2.3-2.4 (m, 1Н), 2.6 (t, 2H), 3.25 (s, ZN), 3.20- o 4942-51 3.35 (m, 4H), 5.8 (she, 1H), 7.1 (d, 2H), 7.2 (d, 2H). so

NRMS: tu" 452 (MAN).

Prig 71 Prig 73 (8)-propyl meptn yaMe (SOSIz 400MGu) 5: 0.8 (t, ZNU, 1.2 (m, 6Н), 1.4 - "AZH (c, 9Н), 1.4 -1.9 (m, 10H), 2.2 (m, 1H), 2.5 (t, 2H), 32 i- (m, 2H), 3.7 (s, ЗН), 5.6 ( c, 1H), 6.8 (d, 2H), 7.1 (d, 2H),

NRMS: fluff 432 (М-Н)). 17 Prig 70 Prig 73 (B)-methyl OMe TTN NMR (SOC 400MHz) 5: 1.11 (t, ЗН), 1.38-2.10 (m, « s АЖ 21Н), 2.03 (m, 2), 2.33 (m, 1H), 2.62 (t, 2H), 3.28 (m, 2H), 3.80 (s, ЗН), 5.73 (m, 1H), 6, 83 (d, 2H), 712 (d, shi s 2n). khz" 18 | EP27423481, | Prig 73 n AD TN YAM (SOS: 400 MGu) 5: 1.43 (m, 9H), 1.48 (m, 2H),

Example 35 1.65 (m, 4H), 1.83 (m, 4H), 1.99 (m, 2H), 2.19 (m, 2H), 2.61 (t, 2H), 3.29 (k, 2H), 3.8 (s, ZNU), 5.59 (m, 1H), 6.84 (day), ti id, 2H). 19 of them ER274234VI, | U. Med. Spet., "I NMR (SOSIiz 400MG) b: 1.38-1.50 (m, 11), 1.62 t" Example 35 1896, З9(20), AZ (m, 4Н), 1.80 ( m, 4H), 1.94 (m, 2H), 2.13 (m, 2H), 2.59 b» 4017 (t, 28), 3.25 (k, 2H), 5.61 (m, 1H)), 7.03 (d, 18), 7.15 (m, i 50 zn). 62

F) why 65

Pryg Prek. Prec. amine - to Analytical Data

Che 20 | EP27423481, | IN). Honey. Spey, | N t |TN nMR (SOS 400 MHz) 5: 1.61-1.78 (m, 11Н), 1.66 s Example 35 | 1996, 39, "AD (m, 4H), 1.85 (m, 4H), 2.00 (m, 2H), 2.20 (m, 2H), 2.63

I 4942-51 (t, 2H), 3.29 (k, 2H), 5.64 (m, 1H), 7.13 (d, 2H), 7.26 (d, 2n). 81 1 EP274234B81, | Prig 76 H is OO Y NMR (SOSIz 400MHz) 0: 1.35-1.45 (m, 11H), 1.61

Prikpad 35 (m, 4H), 1.78 (m, 4H), 1.92 (m, 2H), 2.14 (t, 2H), 2.53 to (t, 2H), 3.14 (t , 2H), 3.24 (k, 2H), 4.50 (t, 2H), 5.53 (m, 1H), 6.66 (d, 1H), 6.84 (d, 1H), 6 .98 (c, 1H). 22 Prig 69 M. Med. Spet., | (5)-methoxyethyl I TTN NMR (SOS: 400 MHz) 5: 1.4 (s, 10), 1.5-2.05 (m, 1998, 39, "99591 13Н), 2.3-2.4 (m, 1H), 2.6 (t, 2H), 3.25 (s, ZN), 3.20- 4942-51 3.35 (m, YAN), 5.8 (shs, 18), 7 ,1 (d, 2H), 7.2 (d, 2H).

NRMS: t/; 452 (M-N). (du 00 (MeonN, s 0.35).

Anap. calculated C, 65.95; H, 8.66; M, 3.25.

SovNzvMO.Si»0.18H20O is necessary C, 65.95; H, 8.49; M,

ZOV

23 Prisb9 (05 4533655, ) (5)-methoxyetype TNMR (SOCIz 400 MEz) b: 1.4 (s, OH), 1.5-2.0 (m,

Example 7A - AD 14Н), 2.2 (m, 1Н), 2.5 (m, 2Н), 3.2 (in ЗН), 3.2-3.3 (m, and 4Н), 5.8 (shs, 1H), 6.9 (m, 2H), 7.1 (m, 24). NRMS: PU 436 (MAN). ! with: - and o

Pryg Prek. Prec. amine -X-U Analytical data of day 24 Prigb9 1 Prig 73 (8)-methoxyethyp me 1 NONMR (SOS 400 MHz) 5: 1.4 (s, H), 1.5-2.0 (m,

Y -АЖДХ 15Н), 2.3 (m, 1Н), 2.6 (t, 2Н), 3.2 (с, ЗН), 32-33 (m, (ав)

ZNU, 3.3 (t, 2H), 3.7 (s, ZH), 5.7 (shs, 1H), 6.8 (d, 2H), s 7.0 (d, 28). NRMS: fluff 448 (MAN). VRMS pu 448.3048 (Owl MO; necessary 448.3058) (se) 25 Prig 69 Prig 76 (5)-methoxybutyl AJ "I YAM (SOSIz 400MHz) 8: 1.40 (s, 9H), 1.50- 2.03 (m, "I 16H), 2.30-2.39 (m, 1H), 2.57 (t, 2H), 3.16 (t, 2H), 3.24 325 (s, ЗН ), 3.32 (t, 2H), 2.57 (t, 2H), 2H), 5.78 (she, 1H), - 6.68 (d, 1H), 6.90 (d, 18) . ,41 (c, 9H), 1.23-1.78 (m, -o

Example 35 zv BN), 1.80-2.03 (m, 4H), 2.07-2.28 (m, 4H), 2.83 (dt, s NI), 3.00 (shs, 2H) , 3.33 (k, 1H), 5.63 (she, 1H), 7.37 ; t (dd, 1H), 7.52-7.60 (m, 2H), 8.03 (dd, 2H), 8.84 (d, 1H).

NRMS: ES" pukh 411 (MAN). 27 Prig 68 Prig 82 methoxyethyl INYAMR (SOS 400 MHz) 5: 1.40 (s, 1OH), 1.80 (m, EN), -i. zhu 1.80 (m , 2H), 2.01 (m, 4H), 2.45 (m, 1H), 2.6 (t, 2H), 3.21 (m, 2H), 3.25 (s, ЗН), 3 ... 50 I and)

F) ko 60 b5

Pryg Prek. Prec. amine -X-U Analytical Data ey 28 Prig 68 Prig 83 methoxyethyl and "NMR (SOS A0OMH: 3) 6: 1.40 (c, 9H), 1.60 (m, 4H), -AMZDHI 1.80 (m , 4H), 2.10 (m, 44), 2.31 (s, ЗН), 2.42 (m, 1H),

And 2.60 (t, 2H), 3.21 (s, ЗН), 3.40 (m, 4H), 5.81 (shs, 1H), 7.10 (s, 4H). 29 Prig 68 Prig 84 methoxyethyl "AZ" NMR (SOSI 400 MHz) 5: 1.61 (m, TON), 1.90 (m, 48),

OVva | 2.01 (m, 2H), 2.53 (m, 1H), 2.60 (t, ЗН), 3.20 (m, 5H), then 3.30 (k, 2H), 5.01 ( s, 2H), 5.80 (she, 1H), 6.90 (m, ЗН), 7.21 (t, 1H), 7.40 (m, 5BN). NRMS: ES" tu/g 468 (MANNYA). 30 Prig 68 Prig 85 methoxyethyl Fu "NIMR (SOS 400 MHz) 5: 1.40 (m, 1OH), 1.60 (m, ЕН), 1.80 (m , 4H), 2.01 (m, 2H), 2.30 (m, 2H), 2.59 (t, 2H), 3.21 (s, ЗН), 3.30 (m, 2H), 3 .80 (d, ZN), 5.91 (shs, 1H), 6.21-6.39 (dd, 1H), 6.72 (dd, 18), 6.90 (d, 1H), 7, 11 (k,

TN). NRMO: ES" pu 448 (MAN). 31 Prig 68 Prig 86 methoxyethyl Meo. OMe /| "NMR (SOSI" 400 MHz) 6: 1.39 (s, 1OH), 1.55-1.61 (m, " AD 4H), 1.63-1.81 (m, 6H), 1.95 (m, 2H), 2.05 (dd, 2H), 2.55 (t, 2H), 3.20 (k, 2H), 3.22 (c, ЗН), 3.30 (t, 2H), 3.78 gd, 6H), 5.88 (int, 1H), 6.40 (m, 2H), 6.95 (d, 1H).

NRMS: ES" ti/g 478 (MH). z2 Prig 69 Prig i07 (5u-methoxyethyl tu "NYAM (SOS 300Mg tsu) 6: 1.39-2.08 (254, m), 2.34 ome | ( 1H, m), 2.57 (2H, t), 3.20-3.28 (5H, m), 3.33 (2H, t), s with 3.78 (ЗН, s), 5.74 (1H, m), 6.81 (2H, d), 7.07 (2H, d). Ge) "Prig. Prek. Prek. amine -x- Analytical Data a p PO 33 | ЕР27423481, | Preg 79 H " NMR (SOS 400MHz) 5: 1.20 (s, 9H), 1.60 (m, 4H), so

Example 35 1.75 (m, 2H), 1.80-2.00 (m, 6H), 2.10 (m, 2H), 3.05 (t,

And with 2H), 3.30 (m, 2H), 5.60 (s, 1), 7.25 (m, 1H), 7.35 (m, ke, 1H), 7.45 (m, 2H ), 7.65 (d, 1H), 7.80 (d, 1H), 7.95 (d, "E 1H). NRMO: ES" pug 410.2 (MNN).

From Z4 | EP274234B1, | Prig 78 n Fe "NYMR (SOSIv 400 MHz) 8: 1.40 (s, 9H), 4.42 (m, 2H), t

Example 35 1.60 m, 4H), 1.80 (m, 2H), 1.90 (m, 4H), 2.10 (m, 2H), 2.80 (t, 2H), 3.30, (k, 2H), 5.60 (shs, 1H), 7.30 (d, 1H), 7.40 (m, 2H), 7.60 (s, 11), 7.75 (m, ЗН) . NRMS: ЕС" " du | pukh 410.9 (MAN). - s 35 Prig 69 (5)-methoxyethyl Fe "NMR (SOS 400 MHz) 5: 1.4 (s, 9H), 1.55-1.81 (m, .si 1YAN), 1.8-2.0 (m, ЗН), 2.35 (m, 1Н), 2.55 (t, 2Н), 3.21 и" (с, ЗН) , 3.22 (t, 2H), 3.30 (t, 2H), 5.82 (she, 18), 7.0 (dd, 2H), 7.18 (d, 1). NRMS: ES" plow 471 (MAN). 6 Prig 69 Prig 94 (5)-methoxyethyl a "NMR (SOS 400 MHz) 8: 1.41 (s, 9H), 1.55-2.06 (m, iz ZN), 3.25-3.35 ( m, 4H), 5.81 (shs, 1H), 6.90 (d, 1H), 6.95 (d, 1H), 7.22-7.24 (m, 1H). NRMS: TSP" tu 470

Ge) - ' - (Manu. and at 50 and)

F) ko 60 b5

Pryg Prek. Prec. amine -th Analytical Data

Premium 37 Prig 69 Prig 77 (5)-Methoxyethyl E "NYMR (SOCIz 400 MHz) b: 1.4 (s, ZNU, 1.55-1.80 (m,

Y -ADHT 11), 1.85-2.05 (m, ЗН), 2.36 (m, 1Н), 2.69 (t, 2Н), 3.21 (с, ЗН), 3.25 ( t, 2H), 3.30 (t, 2H), 5.85 (she, 1H), 6.75 38 | EP27423481, | Prig 97 "NYMR (SOSIiv ZO0MHC) 8: 1.41 (s, 9ZH), 1.50 (m, 2H),

Example 35 AI 1.67 (m, 4H), 1.75-1.90 (m, 4H), 2.0 (m, 2H), 2.20 (t, 2H), 2.72 (t, 2H ), 3.28 (k, 2H), 5.80 (she, 1H), 6.85 (t,

W 2H), 7.16 (m, 18). NRMS: ES" down 396 (MAN). 89 | ER274234VI, | Prig 96 "NMR (SOSIz З00MHz) 8: 1.42 (s, 9H), 1.50 (m, 2H),

Example 35 ee 1.67 (m, 4H), 1.78-1.90 (m, 4H), 2.0 (m, 2H), 2.20 (t, 2H), 2.70 (t, 2H ), 3.30 (k, 2H), 5.85 (shs, 1H), 6.92-7.05 (m, ЗН). NRMS: ES" tu/g 396 (MAN). 540 | EP27423481, | Prig 98 OS | NMR (SOSIz 300 MHz) 8: 1.41 (s, 9H), 1.48 (m, 2H),

Example 35 - АЖДХХ 1.53 (m, AN), 1.75-1.90 (m, AN), 2.0 (m, 2Н), 2.18 (t, ?Н), 2.63 (t, 2Н ), 3.28 (k, 2H), 5.71 (she, 1H), 7.10 (dd, shcha 2H), 7.20 (dd, 2H). NRMS: ES" powder 444 (M.N). 41 Prig 69 Prig 108 (5)-methoxyethyl a Y NMR (SOCIz 300 MHz) 5: 1.38-2.10 (23Н, m), 2.38

I for (IN, m), 2.88 (2H, t), 3.27-3.38 (7H, m), 6.45 (1H, m),

PI SHY Sho en " p 29 Prig Prec. Prec. amine -K Analytical Data Ge)

MED lay PI POV KON 42 GER274234В1, | Prig 117 n AYU "NYAM (SOSI" 400 MGn) 8: 1.41 (s, ZN), 1.58 (shs, 4H),

Example 35; 1.72-1.82 (m, AN), 1.86-1.92 (m, 2H), 1.96-2.05 (m, 2H), o 2.10 (t, 2H), 2.54 (t, 2H), 2.83 (shs, 4H), 3.20-3.30 (m, 2), 5.52 (she, 18), 6.90 (d, 1), 7.00 ( c, 1H), 7.07 (d, and 1). NRMS: TS" pug 400 (Ma-H). Ge) 43 Prig 69 Prig 81 (5)-methoxyethyl o. "NIMR (SOSI; ZOOMHz) b: 1.39-2.08 (23Н, m), 2.38 « AHA (YAN, m), 2.58 (2H, t), 3.23-3.39 (7H, m), 4.23 (ZH, s), Z 5.78 (1H, m), 6, 63-6.72 (2H, m), 6.79 PN, d). - 44 Prig 69 Prig 80 (8)-Methoxystyp and Y TNYMR (SOSIH Z0OMGu) 8: 1.38-2.10 (23Н, m), 2.39

C (IN, m), 2.73 (2Н, t), 3.06-3.43 (7Н, m), 5.83 (1Н, m),

And 7.19-7.35 (ZH, m), 7.69-7.78 (2H, m), 7.94 (2H, d), 8.68 « ше - | EP27423481, | Prig 119 n -AZHD "NYMR (SOS; 200MHz) b: 1.40 (s, ZA), 1.42-1.44 (m, s) Example 35 2H), 1.58-1.83 (m, YAN ), 1.72-1.81 (m, AN), 1.95-1.98 m, :z» 2H), 2.15 (t, 2H), 2.55 (t, 2H), 3.20- 3.26 (m, 2H), 5.57 (shs, 1H), 7.02 (d, 2H), 7.35 (d, 2H). NRMS: ES" down 45 461 (MaeMa). -And 46 | ER274234VI, | Prig 113 Univ. Me | TNYMR (SOS 400 MHz) b; 1.39-1.52 (11Н, m), 1.63 4 3.32 (2Н, k), 4.06 (ЗН, с), 5.61 (МН, m), 7.23 (IN, d), (o) 7.33 (1H, d), 7.52 (1H, c), 7.90 (1H, c). at 50 (42)

F) name) 60 b5

Prig Porek, Prec. amine -X-U Anaphytical Data of women 47 ГЕР274234В1, | Prig 90 n1i25 AD» TNYMR (SOS 400 MHz) 5: 1.35-1.50 (m, 11), 1.62 (m, 9 Example 35 as 4H), 1.72-2.02 (m, 8H) , 2.18 (t, 2H), 2.72 (t, 2H), 3.31 (k, 2H), 4.21 (s, ZNU, 5.60 (m, 1H), 712 (d, 1H ), 7.41 (s, 48 | EP27423481, | Prig 88 n o "NMR (SOS 400 MHz) 5: 0.83 (t, 2H), 1.40 (s, 9H), /0 Example 35 "AD 1.18 -1.49 (m, 4H), 1.70-1.84 (m, 4H), 1.85-2.01 (m, 4H), 2.03-2.18 (m, 2H), 2 .50 (t, 28), 2.72 (t, 24), 3.22 (k, 2), 41 (t, 28), 5.60 (she, 1H), 6.65 (d, 1) , 6.80 (s, 1H), 6.84 (d, 18). NRMS: MAN, 416 (ES). 49 | ЕР274234В1, | Prig 100 n Me | NMR (SOS 400MHz) 6: 1.39 (s , 9H), 1.40-1.45 (m,

Example 35 AZ 2H), 1.58-1.63 (m, 4H), 1.76-1.80 (m, 4H), 1.89-1.95 (m, 2H), 2.05-2 ,12 (m, 2H), 2.44 (s, ЗН), 2.66 (t, 2H), 3.25 (dt, 2H), 5.56 (she, 1H), 7.07 (d, 2H), 7.15 (d, 2H).

NRMS: Mama, 428 (EC). 50 | EP274234B1, | Prig 133 N O.G NYM (SOS 400 MHz) 5: 1.20 (d, ZN), 1.40 (s, OH),

Example 35 kA 1.50-1.80 (m, 12H), 2.10 (m, 2H), 2.60 (m, 1H), 3.05 (m,

Me 1), ZY (t, 2H), 3.20 (m, 1H), 4.50 (t, 2H), 5.40 (shs, 1H), 6.65 (d, 1H), 6.90 (d, 1H), 7.0 (c, 18). NRMS:

I 9 MN, 415.8 (TS. p. o

Accepts Prek. Prec. amine -K-u Analytical Data be TET in | EP27423481, | Prig 141 n 00 | NMR (SOSIz 400 MHz) 5: 1.10 (d, ZN), 1.40 (s, 9H),

Example 35 o; 1.45 (m, 2H), 1.60 (m, 4H), 1.65 (m, 2H), 1.80 (m, 2H), o

Me 1.80 (m, 2H), 2.10 (m, 2H), 2.50 (t, 2H), 310 (t, 2H), so 4.00 (m, 1), 4.50 (t , 2H), 5.40 (d, 1H), 6.60 (d, 1H), 8.85 (d, 1H)), 6.95 (c, 18). NRMS: Man, 415.8 (TS). ke, general Prig 69 Prig 100 (5)-methoxyethyl a | "YAM? (SOSIz 400MGy) 8: 1.40 (s, 9H), 1.41-1.43 (m, chI -AdDU 2H), 1.56-2.00 (m, 12H), 2.26 -2.36 (m, 1H), 2.42 (p.

ZH), 2.58 (t, 2H), 3.21-3.28 (m, 5H), 3.30 (t, 2H), 5.73 - (she, 1H), 7.07 (d, 2H), 7.15 (d, 2H). NRMS: Mnma, 486 (ES. 53 | ЕР274234В1, | Prig 131 N "NYMR (SOS 400 MHz) 6: 1.42 (s, 9H), 1.44-1.55 (m, "

She ee I s AN), 2.18 (i, 2H), 3.35 (m, 2H), 4.27 (t, 1H), 4.62 (t, y 1H), 5.72 (she, 1H), 6.79 (dd, 1H), 6.88 (t, 1H), 712 (t, "" 1NU, 7.18 (dd, 18). NRMS: MMa", 410 (ES"). 54 Prig 69 Prig 100 (5)-methoxyethyl "NMR (SOCI with 400 MHz) 5: 1.40 (s, 9H), 1.42-1.48 (m,

Y, 2H), 1.54-1.80 (m, 9H), 1.88-2.03 (m, 4H)), 2.29-2.35 (m, -i ! in! 1H), 2.57-2.80 (m, 2H), 3.15-3.21 (m, 4H), 3.23 (s, ЗН), 1» 3.30 (t, 2H), 4.53 ( t, 2H), 6.11 (shs, 1H), 6.75 (dd, 1H), , 6.80 (d, 1H), 7.01 (d, 1H). NRMS: M-Ma, 482 (ES"). (o) syu 50 62 (F) ko bo 65

Pryg Prek. Prec. amine -th Analytical Data

M PO POLO

55 Prig 69 Prig 9ba (8)-methoxyethyl M "NMR (SOCIv 400 MHz) 5: 1.40 (s, 9H), 1.50-2.00 (m, 2 s 14H), 2.10 (s, ЗН ), 2.30 (m, 1H), 2.50 (t, ?H), 310 (t,

I 28), 320 (s, ЗН), 3.30 (m, 4Н), 4.50 (t, 2Н), 5.70 (she, 1Н), 6.70 (s, 1Н), 6.80 (p. 18). NRMS: Man, 474.6 (to). 70 BV | EROZa2850, | Prig 76 (5) is in NMR (SOS! 400MHz) 6: 1.41 (s, 9H), 1.57-2.03 (m, see methoxyethoxy-16H), 2.58 (t, ЗН) , 3.32 (c, ЗН), 3.11-3.57 (m, ВН), 4.53 also Te! d, 1H), 6.90 (d, 1H), 7.01

Getsv., 1999, (p, 1H). NRMS: MA, 490 (ES. 40, 2187. 15 57 EROZ42850, | Prig 87 (5)-methoxy- -ADTE "NMR (SOS 400 MHz) 5: 1.36 (s, 9H), 1.40 (s, 6A), see ethoxymethyl Me | 1.58-1.52 (m, 4H), 1.67-1.79 (m, ЗН), 1.96-1.99 (m, ЗМ), also Thei. 2 .50-2.56 (m, ZN), 2.54 (s, 2H), 3.19-3.27 (m, 28), 3.30

Genv., 1999, (c, ZN), 3.38 (dd, 1H), 3.43-3.45 (m, 2H), 3.50-3.54 (m, 40, 2187. ZN), 5.82 (she, 1H), 6.59 (d, 1H), 6.85 (d, 2H), 6.81 (s, 20 1H). NRMS: MaMa, 540 (ES"). 58 Prig 70 Prig 89 (B)-metype - AD "NYAM (SOS ZOOMGhz) 5: 1.10 (d, ZN), 1.35-1.52 (m, o KOH), 158-163 (m, BN), 1.65-1.95 (m, ZN), 1.96-2.15 ' ! (m, 2H), 2.33 (m, 1H), 3.25 (m, 2H), 5.85 (shs, 1), 6.82-6.98 (m, ЗН). NRMO: МН (454) ММа" (476) ЕС". p. 25; at

Pryg Prek. Prec. amine -X-U Anaphytical Data

WEDNESDAY TO MON

Prig 69 Prig 133 (5)-methoxyethyl c o "NMR (SOS; 400MHz) 6: 1.20 (d, ЗН), 1.40 (c, 9Н), av) 1.50-1.90 (m, 14H), 2.30 (m, 1H), 2.65 (m, 1H), 3.05 (m, so 1H), 3.15 (t, 2H), 3.20 (m, 1H), 3 ... ) 1H), 7.0 (s, TN). NRMS: MAN, 474.3 (TS). "

Prig 69 Prig 91 (5)-methoxyethyl Me. ge) "NMR (SOS 400 MHz) 8: 1.40 (s, 9H), 1.50-2.00 (m,

Zo AYU 14Н), 2.20 (s, ЗН), 2.40 (m, 1), 2.55 (t, 2Н), 3.10 (m, v. 2Н), 3.30 (m, 7Н ), 4.50 (t, 2H), 5.80 (shs, 1H), 6.60 (s,

Y 1H), 6.90 (p. 13). NRMS: MAN, 474.4 (TS). 61 | EROZ42850, | 3. Med. Spet., | (5)- SOT NJMR (SOS; ZOOMG) 5: 1.40 (s, 9H), 1.52 (m, 2NU, " see 1996, 39, | methoxyethoxy- -АЖдЖХТ 1.60 (m, 4Н), 1.70 (m, 2H), 1.90 (m, 4H), 2.50 (m, 1H), - about 70 also Tag. | 4942-4951. | methyl 2.55 (t, 2H), 320 (m, 2H), 3.25 (s, ZN), 3.35 (m, s I aev., 1999, 1H), 3.40 (m, 2H), 3.50 (m, ZNU), 6 .05 (she, 1H), 7.05 (d,

Iz" 40, 2187. 2H), 7.17 (d, 2H), NRMS: MN, 483.8 (TS). 62 Prig 69 Prig 146 (5)-Methoxyethyl is o "NMR (SOC 200 MHz) 5: 1.35 (s, BN), 1.4 (s, 9H), -I Me Me 2H), 3.2 (t , 2H), 3.25 (c, ЗН), 3.35 (t, 2H), 4.53 (t, 2H), 5.45 (she, 1H), 6.7 id, 1), 7, 1 (d, 1H), 7.2 (s, 1H). ve 63 Prig 69 Prig 148 (5)-methoxyethyl c | mute (SOS 400 MHz) 8: 1.30-2.20 (m, 23H), 2 .38 (m, (o)-y 1H), 2.81 (m, 1H), 3.11-3.39 (m, 7H), 3.72 (m, 2H), 5.90 s 50 no (m, 1NU, 7.18 (d, 2H), 7.26 (d, 2H). 62

F) ko bo b5

"Pryg Prek. Prek. amine -X-U Analytical Data en 0 64 Preg 69 Preg152 (5)-methoxyethyl SOT NMR (SOCIz 400MHC) 6: 1.41 (s, 9H), 1.28-2.02 (m , , 17H), 2.26-2.38 (m, 1H), 3.00-3.11 (m, 14), 3.12-3.22

Me n (m, 1H), 3.26 (s, ЗН), 3.27-3.39 (m, 2H), 3.65-3.73 (m, 2H), 5.97 (ces, 1H ), 7.28-7.37 (m, 4H). 65 Prig 69 Prig 123 (5)-Methoxyethylpenome | NMR (SOSiz 400MHZ) 5: 1.20-2.00 (m, 23Н), 2.34 "АЖ, (sm, 1Н), 2.57 (t, 2Н), 3.22 (s, ЗН), 3.24-3.37 (m, 2H), 3.81 is, ZN), 4.10 (k, 2H), 5.80 (shs, 1H), 6.81 (d, 1H), 7, 02 (d, 1H), 748 (c, 1H).

Prig 69 Prig92 (5)-methoxyethyl NMR (SOS 400MHz) 5: 1.39-1.46 (m, 14H), 1.56- "AD" 2.02 (m, 12H), 2.30-2, 46 (m, 1H), 2.55 (dd, 2H), 2.76 75 (dd, 1H), 3.23-3.32 (m, VN), 4.83-4.93 (m, 1H ), 5.76 (shs, 1H), 8.63 (d, 1H), 6.90 (d, 1H), 6.97 (s, 1H).

NRMO: MeMa, 496 (EC").

Alternatively, the compound Preparation 22 was prepared as follows:

An isopropyl acetate solution of the product was added to a solution of 1,1-carbonyldiimidazole (73.9g, 045mol) in azeotropically dried isopropyl acetate (33O9ml) with stirring at 602C in an atmosphere of Mo for 1.5 hours

Preparation 69. The transport lines were washed with isopropyl acetate (5 Oml). The resulting solution was then stirred at 602C for another 4.5 hours and then the reaction mixture was allowed to cool to room temperature and stirred for 15 hours. Triethylamine (46.1g, 04bmol) was added to the resulting solution, followed by 3-(4-chlorophenyl)propylamine hydrochloride |U. Meia.Spet., 1996, 39, 4942-51) (94.3g, 0O.4bmol) . at

The resulting mixture was heated at 602C for 7 hours and then cooled to room temperature. Then, with stirring, deionized water (100 ml) was added to the reaction mixture, followed by aqueous hydrochloric acid (19 ml of a 5 M solution) until the pH of the aqueous layer was pH 2-3. The aqueous layer was separated and the organic layer was washed with aqueous potassium carbonate (5 Oml of 0.5 M solution). The aqueous phase was separated and the organic phase "2" was washed with a saturated aqueous solution of sodium chloride (100 ml). The aqueous layer was separated and the organic phase was concentrated by vacuum distillation to give the title compound as a yellow oil (200.3g, 443mmol, 9895 yield); "H NMR (SOSIz ZOOMHz) 5: 1.45 (s, 9H), 1.45-1.56 (m, 1H), 1.56-1.74 (m, 6H), 1.74-2, 11 (m, 7H), ke, 2.32-2.A3 (m, 1H), 2.64 (t, 2H), 3.22-3.30 (m, 2H), 3.27 (s, ZH), 3.30-3.38 (m, 2H), 5.75-5.85 (m, w, 71H), «i 7.13 (d, 2H), 7.26 (d, 2H) ; NRMS (E5 positive): t/2 452 MANI" (39C1).

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

To a stirred solution of the starting material of stage b) below (11.3g, b2mmol) in tetrahydrofuran (500ml) was added borane dimethylsulfide complex (30ml) and heated under reflux for 12h. The reaction mixture was quenched with methanol (100 ml), concentrated in vacuo and boiled for 4 h in ZM NOSI (200 ml). The aqueous layer was concentrated to 5Oml in vacuum, the precipitate was filtered off and dried under reduced pressure -o s 79 to obtain the product indicated in the title as a white powder (10.1g, 59.7mmol, 96965); "H NMR (400 MHz, MeOb) 5: 1.9 (quin, 2H), 2.65 (t, 2H), 2.9 (t, 2H), 7.2 (d, 2H), 7.25 ( d, 2H). :z» Preparation of starting materials a) Methyl 3-(4-chlorophenyl)propanoate

To a stirred solution of 3-(4-chlorophenyl)propanoic acid (purchased from Maubgiade) (14.5g, 77.1mmol)-1 in methanol (400ml) was added acetyl chloride (50ml) and the reaction mixture was heated under reflux for 20h . After that, the reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was then dissolved in OSM (200ml) and washed with 1M sodium hydroxide solution (100ml). Organic layer

F was dried over magnesium sulfate and concentrated in vacuo to give the title product as a brown oil (15.7g, 77mmol, 10095); TN NMR (400 MHz, SOSIz) 8: 2.55 (t, 2H), 2.9 (t, 2H), 3.6 (s, ЗН), 7.1 (d, o 2H), 72 (d, 2H). o b) 3-(4-chlorophenyl)propanamide

The product from step a) above (15g, 75.7mmol) was dissolved in methanol (400ml), cooled to 02C and bubbled through the ammonia reaction mixture for 4 hours and the reaction was allowed to stir for 3 days. The solvent was removed under reduced pressure and the residue triturated with hot pentane. The remaining solid was dried in vacuo to give the title product as a white powder (11.32g, 61.8mmol, 8295); "H NMR (400 MHz,

SOSI5) 6: 2.45 (t, 2H), 2.9 (t, 2H), 5.3 (shs, 1H), 5.5 (she, 1H), 7.1 (d, 2H), 7.2 (d, 2H). di Preparation 67 tert-Butyl (|1-(113-(4-cyanophenyl)propyl|iamino)carbonyl)ucyclopentyl|acetate 60 b5

SM

Me. 0 M mu and Me p o

The product from Preparation 45 (44mg, 0.1mmol) and Sshsh()CM (13.4mg, 0.15mmol) were introduced into DMF (0.5ml) under a nitrogen atmosphere and stirred at 1302C for 16h. After that, another 133 mg of SSH)CM was added and the temperature was raised from 75 to 1452 and kept for 16 hours. After that, another 2 mg of SSHCI)CM was added to the solution and heated at 16022 for 24 h. The reaction was quenched by adding water and the organic part was extracted with EtOAc (50 ml), washed with a saturated aqueous solution of sodium chloride and dried (Ma5O)) and evaporated to a yellow oil. This oil was purified by preparative TLC using 7:3 pentane"E(Ac) as eluent to give the title product, bmg (1690); "IN nMR (400MHz, SOCl3) 5:1.40 (s, 9H), 1.45 -1.49 (m, 2H), 1.62-1.64 (m, 4H), 41.79-1.83 (m, 4H), 1.94-2.00 (m, 2H), 2 ,12-2.17 (m, 2H), 2.65 (t, 2H), 3.22-3.35 (m, 2H), 5.65 (shs, 1H), 7.23 (d, 2H ), 7.54 (d, 2H); NRMOS: t/z2 (EC) 407 (M.-Ma).

Preparation 68 1-(2-(tert-Butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboxylic acid sc with Me. o «c) so

Me and he to her " and -

Me o

Solution of tert-butyl 3-(1-carboxycyclopentyl)propanoate (12g, 49.5mmol) See EP27423481, Example «

Z5| in dry tetrahydrofuran (100 ml) was added to the stirred solution of lithium diisopropylamide (13 Oml) in a p-eu s mixture of hexane (52 ml) and tetrahydrofuran (200 ml) at -782C in a nitrogen atmosphere. After 1 hour, a solution of 2-bromomethyl methyl ether in tetrahydrofuran (100 ml) was added, maintaining the temperature at -782C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water (100 mL) and acidified to pRNI using 2M hydrochloric acid and extracted with ethyl acetate (2x150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the crude acid, which -I was chromatographed on silica gel eluted by increasing a portion of methanol in dichloromethane (pure dichloromethane to 1:50) to give an oil (7.7g, 25.bmol, 52905); CC; 0.3 methanol, dichloromethane 1:20; HO (SOSIZ 400MG) 6: 1.4 (s, 9H), 1.4-1.7 (m, 7H), 1.75-1.95 (m, 2H), 2.0-2.15 (m , ZN), 2.3-24 (m, 1H), 3.3

Ф (с, ЗН), 3.3-3.4 (m, 2Н); NRMS: t/2 299 (M-H U. 9) 50 Alternatively, the compound Preparation 68 was obtained as follows:

The product of stage b) below (5.15 kg, 12.9 mol) was added to a mixture of heptane (41.2 L) and water (30.9 L). Diluted with aqueous hydrochloric acid (2.bl M solution) was added with stirring to the pH of the aqueous layer between pHNa2 and 3. The layers were separated and the aqueous phase was extracted with heptane (20.bl). The combined organic solutions were washed with saturated aqueous sodium chloride solution (15.5 L) and concentrated by distillation at atmospheric pressure to give 99 of the title compound (3.9Okg, 13.0 mol, 10095 yield) as a solution in heptane (total weight of the solution

GF) 44, Okg). An aliquot was taken and the solvent was removed under vacuum to obtain an analytical sample; "H NMR (SOSI»Z 7 ZOOMHC) 5: 1.42 (s, 9H), 1.45-1.58 (m, 2H), 1.58-1.70 (m, 5H), 1.70 -1.90 (m, 2H), 2.03-2.18 (m, ЗН), 2.32-2.А6 (m, 1Н), 3.27 (s, ЗН), 3.35 (t . ., final temperature 2302; oven program: initial temperature 10092С, speed 109С/min., final temperature 2302С, final time 10ОХmin.; column, ВР-21 25 mх0.25mm ИОх0О,25μm ET; detector РЙО) ЧУ 16.1 min.

Preparation of starting materials a) Crude 1-(2-(tert-butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboxylic acid 65 To a solution of commercially available lithium diisopropylamide (9.6 kg of a 2M solution in tetrahydrofuran/n-heptane/"ethylbenzene, 23.7 mol) in 1,2-dimethoxyethane (25 l) at -109C in a Mo atmosphere, a solution of 1-(3-tert-butoxy-3-oxopropyl)ucyclopentanecarboxylic acid (ЕР27423481 - see Example 35) (2.5 kg, 10.mol) in 1 ,2-dimethoxyethane (12.5 L) with stirring for 4 hours maintaining the reaction temperature at -109 C. The header was washed with 1,2-dimethoxyethane (2.5 L) and this solution was added to the reaction. The reaction mixture was left to stir at -109 C for 1, 75 hours. To the resulting solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (1Ol) for 1.75 hours. The reaction was stirred at this temperature for 4 hours and kept at 20 9C for 4 hours After stirring at this temperature for 8 hours, the reaction was quenched by adding aq ammonium chloride (25 L of 2.8 M solution), then ethyl acetate (12.5 L) was added. Then, with stirring, aqueous hydrochloric acid (70 ml of a 5M solution) was added, bringing the pH to 2-3. The two phases were mixed and separated. The organic phase was then extracted three times with an aqueous solution of potassium carbonate (0.3 M solution; 37.5 l, 12.5 l and then 6.25 l). N-heptane (15.bl) was added to the combined aqueous phases and the pH of the aqueous layer was adjusted to 2-3 with aqueous hydrochloric acid (14.5 l of a 5M solution). The layers were separated and the aqueous phase was extracted with n-heptane (15 ml). The combined organic phases were then washed with saturated aqueous sodium chloride solution (3.1 L) and then concentrated in vacuo to afford the crude title compound (2.50 kg, 8.32 mol, 8190 yield) as a solution in n-heptane (21, in kg total weight of the solution). b) Cyclohexanaminium 1-(2-(tert-butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboxylate

A solution of the crude product from stage a) above in n-heptane (5.51 kg, 18.3 mol, total weight of the solution 41.4 kg) was concentrated by distillation at atmospheric pressure to remove 20 l of n-heptane. Cyclohexylamine (1.82 kg, 18 .4 mol) as a solution in n-heptane (9.Ol) for 0.5 hours. The transport lines were flushed with n-heptane (1.1L) and added to this reaction. The resulting suspension was granulated by shaking at 222 for 19.5 hours. The product was collected by filtration and washed with n-heptane (2 x 11.0 L) and the resulting solid was dried under vacuum at 502C for 20 hours. The resulting off-white solid (6.2 kg, 15.5 mol) was suspended in isopropyl acetate (37.2 L) and the resulting suspension was heated at 809 to form a clear solution. The resulting solution was cooled to 502C and a sample of the authentically crystallized title compound (1.0 g) was added to seed crystallization. The crystallizing suspension was cooled to 20 C for 4 hours and granulated at this temperature for 0.5 hours. The product was collected by filtration and washed with n-heptane (2x6b, 2l) and then dried in a vacuum at 459C for 11 hours. The resulting white solid (5.5 kg, 13.8 mol) was suspended in isopropyl acetate (55.0 L) and heated at 802C until a clear solution was formed. The resulting solution was cooled to 502 and a sample of authentically crystallized indicated in was added. from the title of the compound (1.0 g) to seed crystallization. The crystallizing suspension was cooled to 20 °C over 4 hours and granulated at this temperature for 22.5 hours. Then the product was collected by filtration and washed with n-heptane (2 x 5.5 l) and dried in a vacuum at 459C for 16.5 hours, obtaining the product specified in the title (5.15 kg, 12.9 mol, 9495 yield); Tpl. (heptane) 12122; "H-NMR (SOCI3, ZOOMHz), 6: 1.06-1.37 (m, |ichsh 7Н), 1.42 (s, 9Н), 1.50-1.67 (m, 5Н), 1 .67-1.86 (m, 5H), 1.86-2.18 (m, 5H), 2.30-2.58 (m, 1H), 2.80-2.93 (m, 1H) . ; Co2Nla (MOB is necessary

C, 66.13; H, 10.34; M, 3,519. "

Preparation 69 1-K25)-2-(tert-Butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboxylic acid - c ;» Me. - and I with:

F Me. 1.0 on o 50 7 Me 0 o

The product from Preparation 68 and (α4)-pseudoephedrine was recrystallized nine times from hexane to give a white

HF) crystalline substance. The salt was dissolved in ethyl acetate, washed with 0.5 M hydrochloric acid, dried over 7 magnesium sulfate and concentrated in vacuo, the (5)-acid was obtained in 3195 yield as a pale yellow oil with »90965 ee, which NMR analysis showed with 5 3.3 peak of (7)-pseudoephedrine salt; "H NMR (SOCIz 400 MHz) 5: 1.4 (s, in 9H), 1.4-1.7 (m, 7H), 1.75-1.9 (m, 2H), 2.0-2 ,15 (m, ЗН), 2.35-2.45 (m, 1Н), 3.3 (с, ЗН), 3.3-3.4 (m, 2Н); I(А1о-5.2 (EUUN, p. 1,2).

Alternatively, Preparation 69 was obtained as follows:

(15.25)-(-)-pseudoephedrine (2.13kg, 12.9mol) was added to a solution of the product from Preparation 68 (3.9Okg, 13.0mol) in heptane (58.5L, total solution weight 44.Okg) ) in a nitrogen atmosphere at 2020. The suspension was then heated at 65°C to 702°C with stirring until a clear solution was obtained. The solution was cooled to 402C and a sample of authentically crystallized title compound (0.8g) was added to seed crystallization. The temperature of the mixture -B4-

maintained at 402 for 2 hours and then the suspension was cooled at 202C for b hours. The product was collected by filtration and washed with heptane (2 x 2.3 L), then dried under vacuum for 22 hours at 502 to give (15,25)-1-hydroxy-M-methyl-1-phenyl-2-propanammonium 8500 1-(25) -2-(tert-butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboxylate (3.20Okg, 6.87mol, 5395 yield as an 86:14 mixture of diastereomeric salts as measured by H NMR). Product (3.20kg, 6.87mol ) was suspended in heptane (Z0l) and heated at 702 until a clear solution was obtained. The resulting solution was then cooled to 58920 and a sample of the authentically crystallized title compound (1.0 g) was added to seed the crystallization. The solution was held at 582 for 1 hour and then cooled to 209 and kept for 6 70 hours. The suspension was granulated at 202C for 12 hours. The product was collected by filtration and washed with heptane (2x2L). Drying in a vacuum oven at 50 9C for 22.5 hours gave (15,25)-1-hydroxy-M -methyl-1-phenyl-2-propanammonium 1-(25)-2-(tert-butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboc silate as a white crystalline substance (2.35 kg, 5.Omol, 73905 yield). Tpl. (heptane); 9590; TN-NMR (SOSIz, ZOOMHC), 5: 1.08 (d, ЗН), 1.48 (s, 10Н), 1.56-1.74 y (m, 4Н), 1.74-1.90 (m, 2H), 1.90-2.03 (m, 2H), 2.03-2.27 (m, 2H), 2.4-2.53 (m, 71H), 2.66 (s . 5Н), 7.70 (s, w, ЗН); Anal. calculated C, 67.06; H, 9.35; M, 3.04; SobNazMO needs C, 67.07; H, 9.31; M, 3.0195. The title compound was obtained by extraction from the salt as follows. To a stirring suspension, (15,25)-1-hydroxy-N-methyl-1-phenyl-2-propanammonium 1-K25)-2-(tert-butoxycarbonyl)-4-methoxybutyl|cyclopentanecarboxylate (210g, 0, 45mol) in deionized water (1.26l) and isopropyl acetate (1.47l) was added aqueous hydrochloric acid (99.bml of 5M solution, 0.5Omol) to the pH of the aqueous layer pH2-3. The layers were separated and the aqueous phase was extracted with isopropyl acetate (60 mL). The organic extracts were combined and washed with a saturated aqueous solution of sodium chloride (420 ml). The organic phase was concentrated by distillation at atmospheric pressure (until 1.4 L of isopropyl acetate was removed) to obtain the title compound as a solution in isopropyl acetate, which was directly used in the next stage. (at)

An aliquot was taken and the solvent was removed to obtain an analytical sample; "H NMR (SOSIz ZOOMHz) 5: 1.44 (s,

OH), 1.48-1.59 (m, 2H), 1.59-1.72 (m, 5H), 1.72-1.93 (m, 2H), 2.03-2.18 ( m, ZN), 2.35-2.46 (m, 1H). 3.31 (c,

ZN), 3.38 (t, 2H); NRMO (EI): t/2 244 |M-S.NvI, 227 |M-S;АНеоОЙ", 199 |M-САНоО»СИ"; GC (injector program: "3 initial temperature 09С, speed 1509С/min, final temperature 2309С; furnace program: initial temperature 10092, speed 109С/min, final temperature 2309С, final time 20 Охв.; column, ВР-21 о 25мх0 ,25mm ЙОХО25μm ET; BI detection) Retention time 16b, Range; HPLC (column: SpPigaiRgak AO (se) (25x0.46 bsm); mobile phase: hexane/RA/acetic acid (98/2/0.106/o06/06); washing mobile phase: hexaneL/LRA/OEA «t (80/ 20/0.506/o6/06); flow rate: 1.00ml/min; temperature: room; injected volume: 20μl;

From detection: EІ5О) transmission time: 20 Ohv. after which 1 Ohv. washed with hexane/PA/acetic acid - (98/2/0.1o06/o6/06), after which 10 min. washed with hexane/RA/acetic acid (98/2/0.106/vol/06); Retention time: minor enantiomer 15.5 min. (3.395), the main enantiomer is 17.5 min. (96,790).

Alternatively, the product of Preparation 69 was obtained by asymmetric hydrogenation using the following catalysts and conditions. i) Hydrogenation of 1 c) c Starting material From stage c) below (b2 mg, 0О.21 mmol) and "» КРО--2,2-bis(diphenylphosphino)-1,1-binaphthylchloro(para-cymene)ruthenium chloride (9U .Ogu. Speth. 1994, 59, 3064-76) " (2.Omg, 0.0021 mmol) was loaded into the flask under pressure. The flask was flushed with nitrogen by pumping the pressure up to 10 bar and then venting. This procedure was repeated 4 more times. Then degassed methanol (2 ml) was added. The flask was filled with hydrogen (10 bar), then vented and filled again with hydrogen (10 bar). The mixture was stirred at 659C (oil bath temperature) for 18 hours. After cooling to room temperature, the pressure was released and the solvent was removed under reduced pressure to give the title compound as an oil, HPLC (column: SpPpigabac A (25 xO4bsm); mobile phase: hexane/RA/acetic acid b (98/2/0.106 /06/06); washing mobile phase: hexane/RA/OEA (80/20/0.5о6/о6/06); flow rate: 1.Oml/min; oz 20 temperature: room; volume that injected: 20 μl; detection: EI 50) Passage time: 20 min. after which 10 min. were washed with hexane/PA/acetic acid (98/2/0.1o06/o6/o06), after which 1 Ohv. washed with hexane/RA/acetic acid (98/2/0.106/o06/06); retention time: K enantiomer 15.5 min., C enantiomer 17.5 min.; 9195 conversion, z3-enantiomer, ee 97905. ii) Hydrogenation 2

Starting material from stage c) below (82mg, 0.27mmol), sodium tert-butoxide (25mg, 0.2bmmol) and

HF) I(3)-3,3,4,4,5,5'-hexamethyl(b,6'-diphenyl)-2,2'-diyl|Ibis(diphenylphosphino)ruthenium bis(trifluoroacetate) see UMO 01/ 94359) (2.5 mg, 0.0027 mmol) was loaded into the flask under pressure. The flask was flushed with nitrogen by pumping pressure up to 10 bar and subsequent ventilation. This washing procedure was repeated 4 more times. Then degassed methanol (2ml) was added. the flask was filled with hydrogen (10 bar), then ventilated and 60 again injected with hydrogen (10 bar). The mixture was stirred at 65923 for 18 h. The flask was allowed to cool to room temperature and the pressure was removed. Ethyl acetate/heptane (1:1, 10ml) and hydrochloric acid (1M, bml) were added to the reaction mixture. The organic phase was separated and dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound as an oil, HPLC (column: SpigaiRak AYU (25xX0.46 bsm); mobile phase: hexane/PA/acetic acid (98/2/0.106/ o6/06); Washing mobile phase: hexaneL/LPA/OEA bo (80/20/0.506/o6/06); flow rate: 1.Oml/min; temperature: room; injected volume: 20μl;

detection: EE! 5O)) Transmission time: 20 Ohv. after which 1 Ohv. were washed with hexane/PA/acetic acid (98/2/0.1o06/o6/o06), after which 1 Ohv. washed with hexane/RA/acetic acid (98/2/0.106/v/o06); Retention time: K enantiomer 15.5 min., 5 enantiomer 17.5 min.; 298905 transformation, K-enantiomer, ee 91905. ii) Hydrogenation With

The same method was used as described in Hydrogenation 2 above, but using

KRO-(6,6-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphino)|ruthenium bis(trifluoroacetate) (ERZO98132) as a catalyst to give the title compound as an oil, HPLC (column: SpigaIRak AS (25X0.46 bsm ); mobile phase: hexane/RA/acetic acid (98/2/0.106/o06/06); washing mobile phase: hexane/RA/OEA (80/20/0.5v/v/v); 7/0 speed flow rate: 1.00 ml/min.; temperature: room; injected volume: 20 μl; detection: EI 50) Passage time: 20 min. after which 1 Ohv. washed with hexane/PA/acetic acid (98/2/0.1o06/vol/o6), after which 10 min. washed with hexane/PA/acetic acid (98/2/0.106/o06/06); Retention time: K enantiomer 15.5 min., Z-enantiomer 17.5 min.; 5790 conversion, 5-enantiomer, ee 29890. im) Hydrogenation 4

Source material Kk! stage 3) below (vOmg, O.25mmol) and

KRO-C)-4,12-bis(isopropylphosphino)-(2,2I1-paracyclophano-(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate Yu.At.

Spent Zos. 1997, 119, 6207-6208) (1.6 mg, 0.0025 mmol) was loaded into the flask under pressure. The flask was flushed with nitrogen by pumping the pressure up to 10.5 bar and subsequent venting. This washing procedure was repeated 4 more times. Then degassed methanol (2 ml) was added. The flask was filled with hydrogen (10.5 bar), then vented and hydrogen was injected again (10.5 bar). The mixture was stirred at room temperature for 18 h and the pressure was removed. Tert-butyl methyl ether and 2M hydrochloric acid were added to the reaction mixture and the phases were mixed. The organic phase was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound as an oil, HPLC (column: Spiga!iRak AO (25x0.46 bsm); mobile phase: hexane/PA/acetic acid (98/2/ . input: 2 Ω, detection: ЕЕ! 5 О)) Transmission time: 20 Ohv. after which 1 Ohv. washed with hexane/PA/acetic acid and) (98/2/0.1o06/o6/o06), after which 1 Ohv. washed with hexane/RA/acetic acid (98/2/0.106/v/o06); Retention time: K enantiomer 15.5 min., 5 enantiomer 17.5 min.; 298905 transformation, K-enantiomer, ee 91905.

M) Hydrogenation 5 o

Source material Kk! stage 3) below (vOmg, O.25mmol) and

I(5)-3,34,4,5,5'-hexamethyl(b,6'-diphenyl)-2,2'-diyl|Ibis(diphenylphosphino)ruthenium bis(trifluoroacetate) o see UMO 01/94359) ( 2.3 mg, 0.0025 mmol) was loaded into the flask under pressure. The flask was flushed with nitrogen (He) by pumping the pressure up to 10.5 bar and subsequent venting. This washing procedure was repeated 4 more times. Then degassed methanol (2 ml) was added. The flask was filled with hydrogen (10.5 bar), then ventilated, and hydrogen (10.5 bar) was injected again from 3z5. The mixture was stirred at 452C for 18 h and then allowed to cool to room temperature. The pressure was removed and tert-butyl methyl ether and 2M hydrochloric acid were added to the reaction mixture and the phases were mixed. The organic phase was separated and dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound as an oil, HPLC (column: "

SpigaiRak AO (25x0.46 cm); mobile phase: hexane/LPA/acetic acid (98/2/0.106/o6/06); Washing mobile phase: 70 hexaneLRA/OEA (80/20/0.5о06/о6/о06); flow rate: 1.0 ml/min; temperature: room temperature; injected volume: - s 2Omkl; detection: EI ZO) Transmission time: 20 min. after which 100 min. washed with hexane/RA/acetic acid c (98/2/0.1006/06/006), after which 1 Ohv. washed with hexane/RA/acetic acid (98/2/0.106/v/o06); Retention time: K "» enantiomer 15.5 min., 5 enantiomer 17.5 min.; 298905 conversion, K-enantiomer, ee 97905. mi) Hydrogenation 6

Source material Kk! stage 3) below (vOmg, 0.25 mmol) and -i KRO-CH-2,2-bisidiphenylphosphino)-1,1-binaphthyliruthenium bis(trifluoroacetate)) (2..Amg, 0.0025 mmol) or from KRO-CH -2,2-bis(diphenylphosphino)-1,1-binaphthylchlor(para-cymene)Uruthenium chloride |U.Ogu. Spent 1994, 59, 3064-76) (2.4 mg, 0.0025 mmol) was loaded into the flask under pressure. Using the same procedure as (o) described in Preparation 6, the title compound was obtained as an oil; HPLC (column: SpigaiRak AO syu 50 (25x0.46 cm); mobile phase: hexane/RA/acetic acid (98/2/0.106/o6/o06); washing mobile phase: hexaneLRA/UEA (80/20/0.506/o6 /06); flow rate: 1.00ml/min; temperature: room; injected volume: 20µl; (ze) detection: EE!5O)) Passage time: 20Ohv. after which 1 Ohv. washed with hexane/PA/acetic acid (98/2/0.1o06/o6/o06), after which 10 min. washed with hexane/RA/acetic acid (98/2/0.106/o6b/06); Retention time: K enantiomer 15.5 min., 5 enantiomer 17.5 min.; 298905 conversion, 5-enantiomer, ee 29895. 22 mii) Hydrogenation 7

Gee! Source material Kk! stage 3) below (vOmg, O.25mmol) and

KRO-(6,6-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphino)|ruthenium bis(trifluoroacetate) (ERZO98132) (2.3mg, where 0.0025mmol) was loaded into a flask under pressure. Using the same technique as described in

In preparation 6, the title compound was obtained as an oil by HPLC (column: SpigaiRak AO (25 xO, 46 bsm); 60 mobile phase: hexane/PA/acetic acid (98/2/0.106/06/06); washing mobile phase: hexane /RA/OEA (80/20/0.506/o6/06); flow rate: 1.Oml/min; temperature: room; injected volume: 20µL; detection: EE!5O)) Passage time: 20Omin . after which 1 Ohv. were washed with hexane/PA/acetic acid (98/2/0.1o06/o6/o06), after which 1 Ohv. washed with hexane/RA/acetic acid (98/2/0.106/v/o06); Retention time: K enantiomer 15.5 min., 5 enantiomer 17.5 min.; 298905 conversion, 5-enantiomer, ee 29895. 65 Preparation of starting materials a) 1-(2-tert-Butoxycarbonyl-4-methoxy-3-oxobutyl)cyclopentanecarboxylic acid -58v-

A solution of diisopropylamine (35.00ml, 250mmol) in THF (70ml) was cooled to -1592C in a nitrogen atmosphere. Then n-butyllithium (2.5 g, 1000 ml, 250 mmol) was added dropwise, maintaining the temperature below -10 90. A solution of 1-(3-tert-butoxy-3-oxopropyl)ucyclopentanecarboxylic acid was added to the resulting solution.

EP274234B1, example 35) (27.52 g, 113.bmol) in THF (5 Oml) and the reaction was stirred at -10 - -159C7 for h.

A solution of methyl methoxyacetate (18.00 mL) in THF (20 mL) was added to the reaction mixture, and the resulting mixture was allowed to warm to room temperature and then stirred for 19 hours. Tert-butyl methyl ether (300 ml) and deionized water (300 ml) were added to the reaction mixture, and the aqueous phase was acidified with 2 M hydrochloric acid to pH 3 with stirring. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether 70 (25 Oml). The combined organic phases were washed with water (250 Oml) and then with a saturated aqueous solution of sodium chloride (2500 ml), dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude title compound was purified by flash chromatography on silica gel using ethyl acetate/heptane (1:2-11) as eluent to give the title compound (17.35g, 55.2mmol, 4995 yield); "H NMR (400MHz,

SOCIz) 5: 1.43 (s, 9H), 1.69-1.47 (m, 6H), 2.17-2.05 (m, 2H), 2.18 (dd, 71H), 2, 32 (dd, 1H), 3.42 (s, ЗН), 72 3.59 (t, 1H), 4.17 (k, 2); C NMR (100 MHz, SOSIz) 5: 24.7, 27.8, 34.9, 35.8, 36.7, 53.2, 53.3, 59.2, 82.3, 168.3, 183.4 , 203.2. b) 8-Methoxymethyl-6b-oxo-7-oxaspiro|(4,5|decane-9-carboxylic acid tert-butyl ester

A solution of the product from stage a) above (10.50g, C33.4mmol) in methanol (100ml) was cooled to 0 - -590 in a nitrogen atmosphere. Sodium borohydride (2.02 g, 53.4 mmol) was added in portions to the resulting solution, maintaining the temperature below 02C. The reaction was stirred for 1 hour. Then ethyl acetate (150ml) and water (150ml) were added, and the aqueous phase was acidified by adding hydrochloric acid (50ml of a 2M solution) with stirring. The phases were separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with water (5Oml) and then with a saturated aqueous solution of sodium chloride (5Oml). The combined aqueous washing solutions were extracted with ethyl acetate (100 ml). The combined ethyl acetate extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to give a pale yellow oil (11.29g), which was used in subsequent stages without further purification. Part of this oil (10.89g, 34.4mmol) was dissolved in THF (100ml) under a nitrogen atmosphere and dicyclohexylcarbodiimide (7.10g, 34.4mmol) was added to the resulting solution. The mixture was stirred at room temperature for 19 hours. Methanol (b5ml) and acetic acid (2ml) were added to the reaction and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure. The crude product was suspended in ethyl acetate (50 mL) and the byproducts of the reaction were removed by filtration. The residue on the filter was washed with ethyl acetate (50 ml) and the filtrate was concentrated under reduced pressure. The crude title compound c was purified by flash chromatography on silica gel using ethyl acetate/heptane (1:3-2:3) as eluent to give the title compound as a 2:1 mixture of diastereomers (8.19g, 27.4mmol, 8095). For analytical purposes, the sample was purified by flash chromatography on silica gel using m

EudAc/heptane (1:2) as eluent; ii) Spot with higher P g (one diastereomer); "H NMR (400 MHz, SOSIv) 5: 1.47 (s,

OH), 1.50-2.15 (m, 9H), 2.30 (m, 1H), 2.90 (td, 1H), 3.38 (s, ЗН), 3.58 (d, 2H ), 4.62 (dt, 1H); ZSYMR (100 MHz,

SOSI5) 5 m.ch. 25.5, 25.8, 28.0, 36.9, 38.3, 39.6, 40.4, 47.8, 59.5, 73.1, 79.5, 81.8, 171.3, 176.5; her) Spot with a smaller K; " (not fully resolved, 3.5:1 mixture of diastereomers); "H NMR (400 MHz, SOSI»z) 5: (major isomer) 1.47 (s,

OH), 1.49-2.10 (m, 8H), 2.18 (dd, 1H), 2.43 (m, 1H), 3.03 (m, 1H), 3.35 (s, ЗН ), 3.60-3.67 (m, 2H), 4.72 (k, 1H). o) c c) 1 -(2-tert-Butoxycarbonyl-4-methoxybut-2E-enyl)ucyclopentanecarboxylic acid "» To the solution of the product from stage b) above (6.11 g, 204 μmol) in toluene (5 μmol) was added " 1, 8-diazabicycloi|5.4.Fundec-7-ene (3.7 ml, 24.58 mmol) and the resulting solution were heated under reflux in a nitrogen atmosphere for 5 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. Deionized water (100 ml) was added to the obtained residue and the mixture was extracted with tert-butyl methyl ether (30 ml). The phases were separated and the aqueous phase was acidified to pH2 with hydrochloric acid (15 ml of a 2M solution) and then extracted with tert-butyl methyl ether (2x3Oml). The combined organic extracts were washed with water (30 mL) and then with saturated aqueous sodium chloride solution (30 mL) and dried over

Me. magnesium sulfate. The solvent was removed under reduced pressure to give crude title 2) 20 compound (6.29g), which was then crystallized from heptane (15ml) at 029C. The resulting solid was collected by filtration, then washed with ice-cold heptane (2 x 5 mL) to give the title compound as a white solid (1.79 g, b, mol, 2996, E-isomer correlated based on chemical shifts); "H NMR (400MHz, SOCI3) 5: 1.47 (s, 9H), 1.45-1.70 (m, 6H), 2.05-2.10 (m, 2H), 2.74 (s . ,1, 35.0, 55.0, 58.6, 69.2, 80.8, 132.7, 13911, 167.1, 183.3.

F) Filter liquids were concentrated to obtain a yellow oil (4.02 g). This mixture was purified by flash chromatography on silica gel using ethyl acetate/heptane (1:2-0.5956 acetic acid) as eluent to give an additional amount of the title compound and a colorless oil (2.43g, 1.111 E/7 60 ratio ); 1-(2-tert-Butoxycarbonyl-4-methoxybut-22-enyl)ucyclopentanecarboxylic acid: TN nMR (400 MHz, SOCI3) 5: (main signals) 1.48 (s, 9H), 2.65 (s, 2H) 3.33 (c, ZN), 4.29 (d, 2H), 5.99 (t, 1H).

A sample of 1-CZE)-2-(tert-butoxycarbonyl)-4-methoxy-3-butenyl|cyclopentanecarboxylic acid vinyl ether was isolated using flash chromatography (E geometry was determined on the basis of splitting constants): "H NMR (400MHz, SOCI3) 5 : 1.42 (s, 9H), 1.40-1.70 (m, 6H) 2.03 (d, 2H), 2.06 (m, 1H), 2.17 (m, 7H), 2 .83 (s, 1H), bo 3.49 (s, ZN), 4.66 (dd, 1H), 6.35 (d, 1); C NMR (100 MHz, SOSI»v) 8: 24.9 , 25,2,28,4, 34,7, 38,8,41,7, 44,3,

53.5, 56.1, 80.9, 101.9, 149.2, 174.5, 184.5. d) 1-Benzyl 3-tert-butyl 2-(2-methoxyethyl)malonate

To a stirring suspension, sodium hydride (14.4 g of 6090 dispersion and mineral oil, ZbOmmol) in THF (30Oml) was cooled to 02C in a nitrogen atmosphere. A solution of benzyl tert-butyl malonate (90.0 g, ZbOmmol) in THF (500 ml) was added to the resulting suspension for 45 minutes. The reaction mixture was allowed to warm to room temperature and then stirred for 1 hour. The reaction mixture was again cooled to 09 and then a solution of 2-bromomethyl methyl ether (50.0 g, ZbOmol) in THF (10Oml) was added over 0.5 hours.

The reaction was allowed to warm to room temperature and allowed to stir for 19 hours. Reaction 70 was brought to a boil and boiled for 24 hours and then cooled to room temperature. Deionized water (5000 ml) was added to the reaction mixture and the product was extracted with ethyl acetate (3x500 ml).

The organic phases were combined, dried over magnesium sulfate and then concentrated by distillation under reduced pressure to give the product as a crude oil (100g). The product was purified by column chromatography on silica gel using 1095 diethyl ether in heptane, then 2095 diethyl ether in heptane as eluent to give the title compound as an oil (37.1 g, 120 mmol, 3395 yield); TLC (diethyl ether/heptane 3:7, vialyzed by immersion in Dragendorff) KB; 0.25; "H NMR (ZOOMHC, SOCIz) 5: 1.4 (s, 9H), 2.13 (dt, 2H), 3.30 (s, ЗН), 3.43 (t, 2H), 3.51 ( t, 1H), 5.20 (d, 2H), 7.29-7.40 (m, 5H). d) 2-(tert-Butoxycarbonyl)-4-methoxybutanoic acid

Potassium hydroxide (6.73g, 120mmol) was added to a solution of the product from step d) above (37.1g, 120mmol) in dioxane (/4O0ml) and water (111ml) with stirring. The resulting solution was stirred at room temperature for 19 hours. The solvent was removed by distillation under reduced pressure and the resulting concentrate was diluted with deionized water (300 ml). The aqueous solution was washed with diethyl ether (3x40 Oml). 1M hydrochloric acid was added to the aqueous phase to pH 2. The acidified solution was extracted with ethyl acetate (3x40 Oml) and the combined organic solutions were dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure to give the title compound as an oil (14.7g, 67.4mmol, 5690 yield); TLC (diethyl He) ether/heptane 3:7, vialyzed by immersion in Dragendorff) EC; 0.20; "H NMR (Z00MHZc, SOCI3) 5:1.48 (s, 9H), 2.16 (dt, 2H), 3.16 (s, ЗН), 3.27-3.51 (m, ЗН). e) tert-Butyl 2-(2-methoxyethyl)acrylate o z o To a solution of the product from step e) above (20.8 g, 95.3 mmol) in pyridine (17 Oml), piperidine (1.7 Oml, 19.0 mmol) was added, after to which paraformaldehyde (3.89 g, 130 mmol). The resulting mixture was heated at 632 for 3.5 Ge) hours. The reaction mixture was allowed to cool to room temperature and stirred for 19 hours. c

The solvent was removed by distillation under reduced pressure. Deionized water (250 ml) was added to the concentrate, followed by hydrochloric acid (200 ml of a 2M solution). The aqueous phase was extracted with diethyl ether (1xZBOml, Ж followed by 2x40Oml). The combined organic extracts were washed with hydrochloric acid (400 ml of 2M solution) and dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded the title compound as an oil. IN NMR (ZOOMHz, SOCI3) 5:1.50 (s, 9H), 2.56 (t, 2H), 3.35 (s, ЗН), 3.46-3.53 (m, 2H), 5 .54 (c, 1H), 6.13 (c, 18); NRMS (EI): m/2 130 M-C) Hvi", 113 (MAS, Neo". -2-propanoate

To a stirred solution of para-toluenesulfonyl iodide (U. Spet. Zos. Regkip Trans. 1, 1988, 1029) - c (11.4 g, 40.2 mmol) in dichloromethane (25.0 ml) was added a solution of the product from stage e) above (5.0 g, 26.8 mmol) in h dichloromethane (1 Oml) at room temperature under nitrogen atmosphere. The resulting solution was stirred for 60 hours. The reaction mixture was cooled to 09C and then triethylamine (5.4g, 53.4mmol) was added over 15-20 minutes while maintaining the temperature at 020. The resulting mixture was then stirred at 02C for 0.5 hours and then warmed to room temperature and stirred for another 5 hours The reaction was quenched by adding deionized water (1000 ml) and the layers were separated. The aqueous phase was extracted with dichloromethane (100 ml) and the organic extracts were combined and washed with hydrochloric acid (5 ml of 1 M solution). The organic layer was washed with aqueous sodium thiosulfate (100 ml of a 595 wt/vol solution) and then with deionized water (100 ml). Organic layer

Me, dried over magnesium sulfate and the solvent was removed under reduced pressure to give the crude product as a oo 20 dark oil (7.5g, 22.0mmol, 8295 yield). This reaction was repeated twice using the same conditions and the combined crude products (74.6 g) were purified by flash chromatography on silica gel using heptane/ethyl acetate (4:1) as eluent to afford the title compound as a white crystalline solid (48.0g); Tpl. (heptane/ethyl acetate) 84-86; TLC (ethyl acetate/heptane 1:4, visualized by UV 254 nm) K, 0.20: "H NMR (ZO0MHC, SOCl3) 5 m.p. 1.45 (s, 9H), 2.48 (s, ЗН), 3.14 (t, 2H), 3.30 (s, ЗН), 3.51 (t, 2H), 59 TLO (s, 1H), 7.35 (d, 2H), 7.83 (d, 2H).

HF) g) 1-1 E)-2-(tert-Butoxycarbonyl)-4-methoxy-1-butenyl|cyclopentanecarboxylic acid 7 To a stirred solution, lithium diisopropylamide (64.bml of a 2M solution in THF/heptane/ethylbenzene) in anhydrous THF (200 ml) at 09C, a solution of cyclopentanecarboxylic acid (7.0 ml, 58./7 mmol) in anhydrous THF (100 ml) was added for 10 minutes under a nitrogen atmosphere. The reaction was allowed to warm to room temperature with stirring for 2.5 hours. The obtained suspension was cooled to 02С and then for min. zinc chloride (38.2 ml of a 1M solution in diethyl ether) was added. The reaction mixture was stirred for 10 minutes, and to the resulting solution was added a solution of the product from step (e) above (20.0 g, 58.7 mmol) in anhydrous THF (160 mL) over 5 minutes). The reaction mixture was stirred for 2 hours while maintaining the temperature in the range of 65 0-50. The reaction was allowed to warm to room temperature and stirred for 19 hours. The reaction was quenched by adding isopropanol (120 ml) and the mixture was stirred for 1 hour. The reaction mixture was filtered and the biproduct solid was washed with THF (1 mL). Deionized water (400 ml), aqueous sodium hydroxide (200 ml of 1M solution) and ethyl acetate (bObOml) were added to the filtrate. Deionized water (b0Oml) was added and the resulting solid was removed by filtration. The layers were separated and hydrochloric acid (1M solution) was added to the aqueous phase to pH2. The aqueous phase was extracted with ethyl acetate (2x700ml), the organic layers were combined, dried over magnesium sulfate, and then the solvent was removed by distillation under reduced pressure to give the crude product as a yellow oil (16.7g). The product was purified by flash chromatography on silica gel using dichloromethane/methanol (9:1) as eluent to give the title compound as a yellow oil (15.2g, 50.9mmol, 8795 yield); TLC TLC (dichloromethane/methanol 9:1, visualized by UV 254nm) K, 0.20: TN yaYMMR 70 (ZO0OMHz, SOSIZ) 5 mch. 1.48 (s, 9H), 1.67-1.90 (m, 6H), 2.37-2.48 (m, 2H), 2.58 (t, 2H), 3.32 (s, ЗН), 3.48 (t, 2Н), 6.83 (s, 1Н); NRMO (EU negative): t/2 253 |IM-СО25НИ. h) Sodium 1-K1E)-2-(tert-butoxycarbonyl)-4-methoxy-1-butenyl|cyclopentane carboxylate

Sodium methoxide (3.0 g, 55.6 mmol) was added to a stirred solution of the product from step g) above (15.0 g, 50.6 mmol) in isopropyl acetate (300 mL). The resulting suspension was stirred for 19 hours at room temperature. The solid was collected by vacuum filtration and washed with isopropyl acetate and then dried in a vacuum oven at 502 for 19 hours to give the title compound as a white solid (10.0g, 31.2mmol, 6295 yield); Tpl. (isopropylacetag) 195-1982С; "H NMR (ЗО00МГЦц, SOСИз) 5 ppm 1.48 (s, OH), 1.51-1.72 (m, 6Н), 2.21-2.37 (m, 2Н), 2, 61 (t, 2H), 3.34 (s, ZN), 3.51 (t, 2H), 6.86 (s, 1H); NRMS (EC negative): t/2 253 IM-SO»Mai

Preparation of 70 1-C2P)-3-tert-Butoxy-2-methyl-3-oxopropyl|Icyclopentanecarboxylic acid c and Me o «c) c

Me oh "oh "

The title compound was prepared according to methods similar to Preparations 68 and 69, using methyl iodide instead of 2-bromomethyl methyl ether. Its (i-pseudoephedrine salt - was recrystallized three times from hexane. The title compound was obtained in 2895 yield as a pale yellow oil with 29595 ee determined by NMR analysis of the 5 1.4 peak of (-)-pseudoephedrine salt; "H . ), 2.38 (m, 1H) TA1r-24.2 (EUN, p 1.2).

Preparation 71 from p 70 1-K2P)-2-(tert-Butoxycarbonyl)-4-pentyl|cyclopentane carboxylic acid;» n - cha

They are not:

B

F. o co» No o no 59 Mixture of (K)-1-(2-(tert-butoxycarbonyl)-4-pentenyl|cyclopentanecarboxylic acid (МХО 9113054, Example 10)

HF) (og, 354 mmol) and 1095 palladium on carbon (bbOmg) in dry ethanol (25 ml) were hydrogenated at LTatm. and room temperature for 18 hours. The reaction mixture was filtered through AgrosecU and the filtrate was evaporated under reduced pressure to give the title compound as a yellow oil, 9.6g, 9595; "H NMR (SOSI", 0.86 (t,

ЗН), 1.22-1.58 (m, 15Н), 1.64 (m, 4Н), 1.78 (dd, 1Н), 2.00-2.18 (m, ЗН), 2.24 (m, 1H); IATr--3.39 (c-0.09, ethanol). 60 Preparation 72 3-(4-Methoxyphenyl)-2-propennitrile b5 metho Solution of 4-iodanizole (1 g, 4.2 mmol), acrylonitrile (0.3 ml, 4.7 mmol), tri-o-tolylphosphine (24 g,

0.4 mmol), palladium (I) acetate (dFOmg, 0.4 mmol) and triethylamine (1.78 ml, 12 mmol) in acetonitrile (20 ml) were boiled under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with EtOAc (50 ml) and washed with 2M sodium bicarbonate (1000 ml), the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and purified by column chromatography using pentane, then 95:5 t pentane:ethyl acetate, then 90:10 pentane"ethyl acetate to give the title compound (414 mg, 2.5 mmol) as a mixture of cis and trans isomers as yellow crystals , "H NMR (SOCIz 400 MHz) 8: 3.8 (s, ЗН), 5.7 (d, 1Н), 6.9 (d, 1Н), 7.2 (d, 1Н), 7.4 ( d, 2H); NRMS: t/: 176 (MAMN,)"); Anal. calculated C, 74.44; H, 5.66; M, 8.36. C10HzoMO.0.1850 required C, 74.42; H, 5, 65; M, 8.4195.

Preparation 73 3-(4-Methoxyphenyl)-1-propanamine

OoMe sch o "c) s, , , ,

A solution of the product from Preparation 72 (414mg, 2.bmmol) in a solution of ammonium hydroxide (10ml) and ethanol (10ml) was stirred under 40 psi hydrogen pressure with Ca-Mi (100mg) for 12 hours. The reaction mixture was filtered through so

Agros! and washed with ethanol (20ml), the filtrate was evaporated in vacuo to give the title compound (183mg, 1.immol) as a yellow oil; IN NMR (SOSIZ 400MHzC) 5: 1.7 (shs, 2H), 2.0 (shs, 2H), 2.5 (t, 2H), 2.7 " (she, 2H), 3.7 (s , ZN), 6.7 (d, 2H), 7.0 (d, 2H); NRMS: t/2 376 (MAN). -

The following compounds of formula (Pa), that is, compounds of the general formula I, where X is -(CH»)z-, were obtained by the methods described in Preparations 72 and 73 from the indicated starting compounds. shi s ;" -I sh" (22) at 50 (42)

F) name) 60 b5

NA it (na)

TABLE 74. H-bromo-4-ethylbenzene in "I NMR (ISOSO, 400 MHz) 5: 1.1 (Aiagisp Spetis! Co) (she, 3H), 1.7 (she, 2H), 2, 6 (shs, BN), 3.4 (shs, 1H), 7.1 (shs, AN). NRMS: then powder 164 (M i NU. 75 | 4-bromo-3-methyl-anisole - "H NMR (SOSIv, 400 MG) 5: 1.7 (m, (Sapsavieg) 2H), 2.25 (s, ЗН), 2.58 (m, 2H), 2.7 ke (m, 2H), 3, 72 (d, ZN), 6.65 (m, 2H), 7.01 (m, 1H). NRMS: fluff 180(M

WELL. ch 76 | B-iodo-2,3- F Z "H NMR (SOCI3, 400 MHz) 5: 1.8 (m, o dihydrobenzofuran 2H), 2.6 (t, 2H), 2.7 (t, 2H), 31 (m, (Maubgidde Spetisaiiv) 2H), 3.3 (t, 2H), 4.5 (t, 1H), 6.6 (d, with 1H), 6.9 (d, 1H), 7, 7 (c, 1H). o (ze) 77. | 2,4-difluoro-iodobenzene is "H NMR (SOCI, 400 MHz) 5: 1.64 (m, o (Aidpisp Spetis! So.) 2H), 2.6 (t, 2H), 2.7 (t, 2H), 6.7 (m, « with 2H), 7.1 (m, 1H). NRMS: fluff 172.1 k (M and N). 78 | 2-bromonaphthalene fi "H NMR (meO0, 400 MHz) 5: 2.0 (m, « (Aiaisp Spetis! So.) 2H), 2.9 (m, AN), 7.4 (m, ZNU, 7 .6 (m, - s 7 1H), 7.7 (m, ЗН). NRMS: t/g (ES") z" 186 (MaN). 79. 1 1-bromonaphthalene "H NMR (SOCI, 400 MHz ) b: 2.1 (m, 7 (Aiagisp Spetis! So.) 2n), Zm, 2H), Zm, 2H), 7.3(m, i» | phi 2H), 7.B(m, 2H ), 7.7(m, 1H), 7.v(m, b" 19). NRMS: down (ES) 186(M -- H). o 50 62 (F) ko bo b5

Prig 114 4 "H NMR (SOC, 400 MHz) 5: 1.78- " s 1.88(m, 2H), 2.68-2.83(m, 4H), 7.19- (A 7, Zb(m, Z), 7.70-7.77 (m, 2H), 7.92(d, 2H), 8.69(d, 1H). then 81 | Z.4-ethylenedioxy- - Crude amine used- bromobenzene (I apsavivg ro Z shafts without purification. Data for cis and

Zupipeziv) and trans mixtures of vinylinitriles: "H NMR (300 MHz, SOS") 5: 4.25-4.39 (m, 4H), 5.30 and 5.70 (d, 1H), 6.83-7 ... ), 2.6 (t, 2H), 2.8 (k, 2H), 3.8 (s,

ЗН), 6.8 (t, 7Н), 6.9 (d, 1Н), 71 (d,

IN), 7.2 (t, 1H). NRMS: pu (TS) at 166 (M and N). 83 | 4-bromotoluene (Aliisp te "H NMR (meSO, 400 MHz) 6: 1.9 (m, and Spetis! So.) not on), 2.2 (s, ЗН), 2.6 (t, 2Н) , 2.8 (t, o 2H), 7.0 (s, 4H). HRMS: puUg(TS) at 150 (M with H). 1.8 and benzene (Aiagisn ov (she, 2H), 2.6 (shm, 4H), 5.0 (shs, 2H), spetisai! So.) 6.9 (d, ЗН), 7.1 ( m, 2H), 7.3 (m, ЗН).

NRMS: pu (TS) 242(M -- H). h 47 Z-bromanizol fi TNMR (SOSI", 400 MHz) 5: 1.7 (m, Z z" (apsavieg Zupipeziv) 2H), 2.6 (t, 2H), 2.7 (t, 2H ), 3.8 (d,

ЗН), 8.3-6.4 (dd, 1H), 6.7 (dd, 1H), and 7 | и cones т. шим I ОИ яка б» benzene (Aagisn s) 0 Spetisai So.) o 87 | 5-Bromo-2,2-dimethyl- Me | N'YAME (400 MHz, ss» 6: 1.40 (s, 2.8- . j EN), 1.70 (tt, 2H), 2.54 (t, 2H), 2.70 dihydrobenzo(bifuran (t, 2H), 2.95 (s, 2H), 6.68 (d, IN),

He) (Preparation 126) 6.86 (d, 1H), 6.91 (s, 1H). NRMS: M o t N, 206. (TS. bo b5 tro 212 2 2 2 560202 1070 lelyuknian 88 | 6-Bromo- o "H YAM? (400 MHz, SOS") 8: 1,62- " tetrahydrobenzorugap LO 1 .78 (m, 2H), 1.84-2.03 (m, 2H), (Preparation 125) 2.44-2.58 (m, 2H), 2.61-2.78 (m, 4H) , 4.03-418 (m, 2H), 6.67 (d, 1), then 6.79-6.93 (m, 28). NRMS: t/" (M i

H) 182, ES. 5-bromo-2,2-difluoro- Ok "NYAMRI (IOO MHC, SOCsIiv) 8: 1.75 benzodioxolane pe; (quintet, 2H), 2.60 (t, 2n), 2.67 (t, (RInogospet ) 2H), 8.80-6.95 (m, ZA). NRMS: M

H, 216. (EC.

B-bromo-1-methyl-(1NI. shsh-x) Unpurified indazole was used without (Preparation n» purification or identification.

We found re 9ba (| 5-Bromo-7-methyl-2,3- F "H NMR (400 MHz, SOS") 5: 1.9 (m, o dihydrobenzo|(b|furan 2H), 2, 1 (s, ZN), 2.55 (t, 2H), 2.85 (Preparation 136) (t, 2 310 (t, 2H), 4.45 (t, 2H), z 6.70 (s, 1H), 6.80 (p, 1). NRMS: M ole i H, 192(EC). p

B-Bromo-b-methyl-2,3-du "H NMR (400 MHz, SOSI") 5: 1.8 (m, and with dihydrobenzo(b|furan 2H), 2.2 (m, ЗН), 2.6 (m, 2H), 2.9 (m, cha (Preparation 138) 2H), 31 (m, 2H), 4.4 (m, 2H), 6.5 (m, 192(EC). 40 With p 92 | 5-Bromo-2-methyl-2,3-?H NMR (400 MHz, SOS") 1.45 (d, xz" dihydro-1-ZN), 1.90-2.10 ( m, 2H), 2.50-2.63 (m, benzo(rifuran 2H), 2.88 (dd, 1H), 3.27 (dd, 1H),

And | Same price 1" 1H), 6.95 (s, 1H). NRMS: М - Н, bu 192.(ES), . at 20

Preparation 93 s 3-(4-Chloro-3-fluorophenyl)-2-propenenitrile

SI and AJ name)

SI ee: E

Diethylcyanomethyl phosphonate (3.2ml, 18.9mmol) was transferred to dry THF (20ml) at 02C in a nitrogen atmosphere and stirred, and the bObo dispersion in Mann oil (756bmg, 18.9mmol) was added in portions over 10 minutes. bo The resulting green suspension was then stirred at 09C for 1 h and then the solution was added dropwise

4-chloro-3-fluorobenzaldehyde (I apsazieg Zupipeziv) (Zg, 18.b0mmol) in 5 ml of THF. The reaction was allowed to warm to room temperature and stirred. Water (5ml) was added and the mixture was extracted with EUFAs (3x50ml). The combined organic solutions were dried (Ma5O)) and evaporated to a yellow oil, which was purified by column chromatography using 590 E(OAc in pentane as eluent to give the title product as a mixture of geometric isomers (2.4g, 70965); IN nMR (400 MHz, SOSIz) 8: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (approx. t , 1H); NRMS TS7199,1 (MAMN, 7).

Preparation 94 3-(4-Chloro-3-fluorophenyl)-1-propylamine

And "AJ

Vinyl cyanide from Preparation 93 (500 mg, 2.75 mmol) was taken up in ethanol (Zbml) and 0.88 MH solution (18 ml) and shaken with 150 mg of 3095 w/w CaMmi under 15 psi hydrogen pressure overnight. The catalyst was filtered through the fine path of Agrosea! and the filtrate was evaporated in vacuo and then purified by column chromatography using 90:10:11 (OSM, Meon, MH5) as eluent to give the title product (32Omg, 6296); "H NMR (400MHz, SOSIz) 1.65-1.78 (m, 2H), 2.53-2.70 (m, 4H), 6.85 (d, 1H), 6.90 (d, 1H ), 7.22 (c, 1H); HPMS: p/z (TS) 188 (MH). c 29 The following compounds of formula (Ча), that is, compounds of general formulas I, where X is -(СНо)з-, were obtained by (3 methods similar to those described in Preparations 93 and 94 from the specified precursors. h (av)

NAM tt o (Se) (Sha) " m. shi s ;" -I sh" (22) at 50 (42)

F) name) 60 b5

95 | 3-chloro-4-fluoro "NMR (400 MHz, SOS) 6: 1,62- and benzaldehyde Phi 1.77 (m, 2H), 2.55 (t, 2H), 2.64 (t, (Gapsazieg Zupineziv) 2H), 6.97-6.99 (m, 2H), 7.14 gd, 1H).

K- NRMS: t/2 TS 1881 (MN. to 2,3-difluoro "NMR (400 MHz, SOS") b: 1,66- benzaldehyde and 1,78 (m, 2H), 2,58-2, 75 (m, 4"H), (Hapsazieg Zupipeziv) 6.83-6.98 (m, ZN). NRMO: ptug TS" zaz (gMNU. 97 3 2,8-difluoro and "NYMR (400 MHz, SOSI ») 6: 1,68-benzaldehyde XA 1.83 (m, 2H), 2.57-2.83 (m, 4H), p (apsazieg Zupipeziv) and 6.70-6.92 (m, 2H) , 7.01-7.22 (m, 1H).

NRMS: pu/g TO 172.1 (MNU. 4-trifluoro-methoxy ha G'NMR (400 MHz, SOSIv) 8: 1,70- benzaldehyde (As and 1.82 (m, 2H), 2.60 ( t, 2H), 2.73 (t, Snetis! So.) 2), 7.07 (d, 2H), 7.18 (d, 2H). o

NRMS: t/2 ES" 220 (MNU.

Preparation of 102 M "NMR (400 MHz, SOS") 5: 1.66 (m, at 30 rev 2H), 1.89 (m, 2H), 2.42 (m, 2H), 7.36 so (m , 1H), 7.50-7.62 (m, 2H), 8.02 (m, (Ce) 2H), 8.93 (d, 1H). ! "I 35 100 | 4-(methylthio)- NMR (400 MHz, SOSIv) 8: 1.68- in benzaldehyde (Aagsn Ff 1.75 (m, 2H), 1.42 (s, ЗН), 2.59 (t,

Spaghtis! So.) 2H), 2.70 (t, 2H), 7.07 (d, 2n), 7.16 « (d, 2H). NRMS: M 5 H, 182. (TS). - p. 101 |2,3- | INYAMR (300 MHz, SOS) 5: 1.78 ;" dihydrobenzo|BIfuran-Z, (tt, 2H), 2.64 (t, 2H), 2.73 (t, 2H), 1 7-carboxaldehyde 3.22 (t, 2H), 4.55 (t, 2H), 8.78 (dd, - (Preparation 128) 1), 6.95 (d, 18), 7.05 (d, 18). i" NRMS: M "- N, 178. (TS). (o) syu 50 Preparation 102

Quinoline-6-carboxaldehyde c2 ono

M o i with M 60 b6-Methylquinoline (AliYidgispy Spetis! So.) (1g, 7.0mmol) and selenium dioxide (2.32g, 21.0mmol) were combined. in the absence of a solvent and heated at 1002 in a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature, transferred to Meon and sorbed on silica gel. Chromatographed using a 3:1 mixture of pentane-E(SA) to give the title product (23 mg, 2196); "H. NMR 65 (400 MHz, SOCI3) 5: 7.46-7.52 (m, 2H), 7, 98 (d, 1H), 8.33-8.37 (m, 2H), 9.03 (d, 1H), 10.18 (s, 1H); t/2 (EC)

Z15 (2МН).

Preparation of 103 4-(4-Methoxyphenyl)butyramide 7" mM and its 4-(4-Methoxyphenyl)butyric acid (Aliidgis Spetis! So.) (2g, 10.4mmol) were dissolved in 5Oml OSM and thionyl chloride (1) was added dropwise with stirring .85g, 15.5mmol). After the addition was complete, the mixture was boiled for 4h. The solvent was removed in vacuo, more was added and then evaporated and this addition/evaporation cycle was repeated until all thionyl chloride was removed from the crude mixture. This mixture was dissolved in 20 ml of SOSM and added dropwise to a stirred solution of 0.88 MH with at 09C After the addition was complete, stirring was continued for 4 h, the organic layer was separated, dried (Ma».CO3) and evaporated to give the title product as a white solid amide (1.5 g), which was used without further purification.

Preparation of 104 4-(4-Hydroxyphenyl)butyramine with pn o vy o and Mn, ii (Ce)

The product from Preparation 103 (38g, 0.20mol) was added in portions to a stirred solution of HIAIN in (15g, «

O.4Omol) in THF, and then boiled for 16 hours. them-

The excess of the hydride was destroyed by adding E(OAc (400 ml) and most of the solvents were removed under reduced pressure. The addition of 30 ml of 2 M Mahon solution (carefully!) completed the destruction of the hydride, and the resulting solution was acidified with 1 M HCl and extracted into water (2 x 200 ml). The aqueous extracts were basified with 2 M Mahogany, extracted

EtOAc, dried (M959,) and evaporated to give a yellow oil of the crude amine. This oil was boiled in 1 bOml "

AQUEOUS NWH for 4 hours, and then poured into 100 ml of water. Then solid Ma»2СО3 was added to obtain рНО-10. The mixture was completely extracted with OSM (3Xx100ml), dried (Ma95O)) and evaporated to a white solid, which was recrystallized from benzene to give the title product (6.4g, 3595); Tpl. 114-11626. "» Preparation 105

Tert-Butyl-4-(4-hydroxyphenyl)butylcarbamate - he and Me o

F Me at 50 o in N

Di-tert-butyldicarbonate (1.06g, 4.8mmol) was added in one portion to a stirred solution of product 29 from Preparation 104 (400mg, 2.4mmol) in a mixture of water (TOml) and dioxane (LOml) under nitrogen. The reaction

HF) was stirred for 72 g, after which potassium carbonate (2.0 g, 14.4 mmol) was added in one portion and the mixture was stirred for another 23 g until complete hydrolysis of any esters formed during the reaction. The mixture was transferred to a separatory funnel and the organic layer was separated, dried over Mo5O and evaporated to a yellow oil. The oil was chromatographed using a 2:11 mixture of pentane/OH/OAc as eluent to give the title product (555mg, 86905); IN nMR (400 MHz, SOSIz) 5: 1.41-1.62 (m, 1Z3H), 2.53 (t, 2H), 3.12 (m, 2H), 4.48 (IN, shs), 4 .80 (c, 1H), 6.74 (d, 2H), 7.01 (d, 2H).

Preparation 106

tert-Butyl-(4-4-methoxyphenyl)butylcarbamate b5 re AADHT n: c: bObo dispersion of Mann in mineral oil (88mg, 2.2mmol) was added to a stirred solution of the product from Preparation 105 (555mg, 2.1mmol) in THF (7 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 min., and then Mei (0.14 mL, 2.2 mmol) was added in one portion and stirred at room temperature for another 16 h. The reaction was diluted with EtOAc (20 mL) and washed with 395 Manceau solution (15 mL). The organic layer was dried over Mo950O and purified by chromatography using OCM as eluent to give the title compound (500 mg, 8596); "H NMR ( 400MHz, SOSI»z) 5: 1.40-1.63 (m, 13H), 2.57 (t, 2H), 3.13 (m, 2H), 3.78 (s, ЗН), 4, 46 (1H, she), 6.82 (d, 2H), 7.06 (d, 2H).

Preparation 107 4-(4-Methoxyphenyl)butylamine

OoMe s o nm o so

The product from Preparation 106 (500 mg, 1.9 mmol) was transferred to 3 ml of YUOSM and 3 ml of TFO and stirred under a nitrogen atmosphere for 1 h. The mixture was poured into 5 Oml of 1095 aqueous solution of Ma 2CO3 and the organic part was extracted with EtOAc (2x5 Oml). The combined organic solutions were dried (Mo5O)) and evaporated to give the title product (Z0Omg, 94905), which was used without further purification. 3o Preparation of 108 - 3-(2-pyridinyl)-1-propanamine 2 M eh Z is with M Shi -i 2-Vinylpyridine (105g) and acetic anhydride (204g) were combined at room temperature and dropwise to the solution , which is mixed, a solution of KSM (130 g) in 250 ml of water was added. The rate of addition was such that the mixture would gently boil. After completion of the addition, the mixture was heated under reflux for 22 h (o) and the pH of the solution was adjusted to 8 with an aqueous solution of Mo2.CO3. The mixture was extracted with OSM (bOOml), the extracts were dried over 50 Massot, and then evaporated to a brown oil. The oil was then distilled at approximately 0.bmm Na. The distilled product was a clear oil with Tkip. 100-107 with 5695 output. 2-(2-Cyanoethyl)pyridine oil (20Omg, with 1.5mmol) was transferred to bml of EN and treated with 2ml of 0.88MN from the solution and 5Omg of Kami. The mixture was hydrogenated at 30 psi NO for 16 h and then filtered and evaporated to give the title product (200 mg), which was used without further purification.

Preparation 109 o 2-Acetyl-2H-indazole her M o 60 - "K ions Y in b5

Indazole (3.5g, 29.bmmol) and acetic anhydride (Zbml) were heated at 6b02C in a nitrogen atmosphere for 3 h.

The excess acetic anhydride was evaporated and the remaining oil was partitioned between 3906 aqueous Manceau with (20 mL) and

EUOAc (ZOml). The organic layer was separated, dried (Ma50O)) and evaporated to obtain the title product (4.5 g, 96965); "H NMR (400MHz, SOS") 8: 2.80 (s, ЗН), 7.37 (t, 1Н), 7.58 (t, 1Н), 7.75 (d, 1Н), 8.46 (d. 1H).

Preparation of 110 5-Bromo-2H-indazole and 5-bromo-1H-indazole from above

The product from Preparation 109 (4500 mg, 2.8 mmol) was taken up in acetic acid (0.bml) and stirred at room temperature under a nitrogen atmosphere. Bromine (0.5 mL) was added over about 1 minute and the reaction was then stirred for another 16 h. Excess bromine was removed by bubbling nitrogen through the solution

Heat until a finely dispersed precipitate forms in the flask. 5 ml of toluene was added and everything was evaporated in vacuo and the 70% residue was triturated with pentane (5 ml). The remaining solid was filtered off and dried in vacuo and then treated with bml 1M Mason and EOH. The mixture was heated at 502 for 1 h and then allowed to cool to room temperature. EUN was evaporated and the residue was extracted with OSM (2x1Oml), which was then dried (Ma95O4) and evaporated to give 40Omg of a 3:1 inseparable mixture of the title 1-H:2-H isomers of indazole; /H s NMR (400 MHz, SOSI") 6: 7.41 (6, 1H), 7.49 (d, 1H), 7.92 (s, 1H), 8.02 (s, 1H).

Preparation of 111 o 2-Methyl-5-bromo-2H-indazole and 1-Methyl-5-bromo-1H-indazole re o and so shM-Me M with ssh and ich- in Vg

A mixture of isomers from Preparation 110 (40Omg, 2.0mmol) was transferred to Meon (8ml) at room temperature under a nitrogen atmosphere and MaOMe (22Zmg, 4.00mmol) was added in one portion. Mey (0.32 mL, 3 mmol) was added dropwise and the mixture was heated under reflux for 4 h. The reaction was allowed to cool to room temperature and then concentrated to a smaller volume (3ml) and then partitioned between EtOAc (20ml) and 395% aqueous MnHsCO3. The organic layer was separated, dried (M950;5) and purified by chromatography using 99:11 OSM:Meon as eluent to give the 1-Me isomer (10mg, 2390) and the 2-Me isomer and 15 (112mg, 2696); 1-Methyl isomer; "H NMR (400MHz, SOSIz) 8: 4.08 (s, ЗН), 7.30-7.50 (m, 2Н), 7.82 (s, 1Н), 7.92 -1 (s, 1Н ); 2-Methyl isomer; "H NMR (400 MHz, SOS") 8: 4.13 (s, 3H), 7.35 (d, 1H), 7.59 (d.1H), 7.81 (s , 1H), 7.85 (c, 1H).

Preparation 112 pi 3-(1-Methyl-1H-indazol-5-yl)-2-propennitrile (22) in 50 g) 1-methyl isomer from Preparation 111 (100 mg, 0.47 mmol) was transferred to dioxane (bml), and potassium carbonate (72mg, 0.52mmol), acrylonitrile (0.035ml, 0.52mmol), Raz(dba)z (4mg, 0.047mmol) and RtretVis (0.038ml, 0.1bmmol) were added sequentially. . The reaction was then refluxed for 3 h under a nitrogen atmosphere and then cooled to room temperature, filtered through a thin layer of Agrose! and the filtrate was evaporated in vacuo. The residue was chromatographed using 99:1 OSM:Meon to give the title product (B7mg, 6696) as a mixture of cis and trans geometric isomers; "H NMR (Z00MHZ, SOSIz) 6: 4.11 (s, ЗН), 5.40 and 5.84 65 (d, 1Н), 7.37-8.18 (m, 5Н).

Preparation 113

3-(1-Methyl-1H-indazol-5-yl)-1-propanamine and

The product from Preparation 112 (55mg, 0.29mmol) was transferred to ethanol (4ml) and 0.88MH solution (ml) and 75 was hydrogenated at 30 psi and room temperature over 1Omg 3095 va/wg Kami for 2h. The mixture was filtered through a thin layer of Agrose! and the filtrate was evaporated to give the title product, which was used without further purification.

Preparation 114 2-(4-Bromophenyl)pyridine 20

Ve c 25 (8) o 30 M dya s (Ce) "Vi and (1.6M in hexanes, 344ml, 5bmmol) was added dropwise to a stirred solution of "Her 1,4-dibromobenzene (11.8g, Hommol ) in 100 ml of dry THF at -602 C. The mixture was stirred for 15 min and at

From this temperature, a solution of 7pSiO (0.5M THF, 100 ml, 5 mmol) in THF was added dropwise to the solution. The mixture was allowed to warm to room temperature over 10 h, and then Pa(PPRI 3z) 4 (200 mgHg) was added, after which 2-bromopyridine (4.8 mL, 500 mmol) was immediately added. The mixture was stirred at room temperature overnight, then evaporated to a smaller (10ml) volume and diluted with EtOAc (400ml). The solution was washed with a solution of 32 g of EOTA in 200 ml of water and a saturated aqueous solution of sodium chloride (200 ml), dried (MosO)) and evaporated to a yellow/green solid. This solid was purified by column chromatography using 1:1 hexane:OSM as eluent to give the title product (8.3g, 7190); :z" t/2 MH234 (TS); Found C 56.61905, H 3.3795, M 5.9095; Calculated C 56.4495, H 3.44905, M 5.9895.

Preparation 115 3-(2,3-Dihydro-1H-inden-5-yl)propanoic acid -1. (42) 3-(2,3-Dihydro-1H-inden-5-yl)propenoic acid (500 mg, 2.6 mmol) (obtained from Aiagisp) was transferred to (F) ethanol (4 Oml) and hydrogenated at a pressure of H215 psi with 40 mg of 1095 Ra/C for 4 h. The mixture was filtered through a thin layer

Hey Agros! and the filtrate was evaporated to give the title product (560 mg, approximately quantitative), which was used without further purification; IN nMR (400MHz, SOSIz) 6: 1.98-2.07 (m, 2H), 2.75 (t, 2H), 6o 2.80-2.90 (m, EN), 6.95 (d , 1H), 7.03 (s, 1H), 7.08 (d, 1H); NRMS: t/2 (EU) 189 (M-N).

Preparation 116 3-(2,3-Dihydro-1H-inden-5-yl)/propanamide b5 g)

The product from Preparation 115 (190 mg, thymol) was dissolved in OSM (2 ml) at room temperature under a nitrogen atmosphere, and first 132 μl (1.5 mmol) of oxalyl chloride and then 1 drop of DMF were added. After boiling, the mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved 715 in 2 ml of THF and 0.bml of 0.88 MNU solution was added, and the mixture was stirred for 4 days. The reaction was quenched with water and extracted with EtOAc (2x10ml). The combined organic solutions were dried (Mo5O)) and evaporated to give the title product (190mg, 99905); IN nMR (400 MHz, SOCI3) 5: 1.96-2.05 (m, 2H), 2.49 (t, 2H), 2.81-2.92 (m, 6H), 5.32 (she, 2H), 6.93 (d, 1H), 7.05 (s, 1H), 7.08 (d, 1H); NRMS: t/2 (EU) 189 (M-N).

Preparation 117 3-(2,3-Dihydro-1H-inden-5-yl)propylamine c o z o Amide from Preparation 116 (17Omg, 0.Ummol) was dissolved in dry THF (3ml) at 0 C under a nitrogen atmosphere and stirred and to this solution was added dropwise, a solution of GiAIN; in THF (m, O,Uml, O,Ummol) during which significant foaming was observed. The reaction was heated at 602C and stirred at this temperature overnight. "at

The mixture was quenched with water (ml), 1M Mahon solution (ml) was added and the solution was extracted with EtOAc (2x5Oml), dried (Ma950)), filtered and concentrated to a pale yellow oil. This oil was purified using column M

35 chromatography using 90:10:11 (OSM, Meon, MH") as eluent, obtaining the title product (ZOmg, 3595); "H NMR (400 MHz, SOSIz) 8: 1.72-1.77 (m, 2H), 1.96-2.03 (m, 4H), 2.57 (t, 2H), 2.70 (t , 2H), 2.80-2.85 (m, 4H), 6.90 (d, 1H), 7.02 (s, 1H), 7.09 (d, 1H); NRMS: t/2 ( TS) 176 (M.N).

Preparation of 118 "3-(4-Bromophenyl)-2-propennitrile - s Be z i ee: sh" (o) 6090 Mann suspension in mineral oil (2.16 g, 54 1 mmol) was suspended in THF (5 Oml) and cooled with 50 until 09Sb in a nitrogen atmosphere. Diethylcyanomethylphosphonate (8.74 mL, 54.1 mmol) was added dropwise and the mixture was stirred at 09C for 30 h, then 4-bromobenzaldehyde (10 g, 54.1 mmol) was added dropwise as a solution in 20 mL of THF, and the mixture was allowed to warm to room temperature. temperature during the night. The reaction was quenched with water, extracted with EtOAc (3x50ml), dried (Ma95O)) and then filtered and evaporated to a yellow oil. This oil was transferred to a 9:1 mixture of pentane:EdAc, from which the title product was crystallized (5.8g, 5295); / H 22 NMR (400MGu, SOSI") 5: 5.82 (d, 1H), 7.21-7.28 (m, ЗН), 7.50 (d, 2H).

GF) Preparation 119 3-(4-Bromophenyl)-1-propanamine ime) 60 b5

AJU

The compound indicated in the title was obtained according to the modified method described (adop eii a!., 9.0.5. Regkip

I, 1977, 23571. Solid HYAIN (1.2g, 31.bmol) was suspended in diethyl ether (Zbml) and stirred in a nitrogen atmosphere as the suspension was heated at 5020. A solution of vinyl cyanide from Preparation 118 75 (2.06g, 9 ,8 in 8 mmol) in ether (20 ml) and the mixture was then heated with a train of 9 Ohv. After that, heating was stopped and the reaction was stirred at room temperature for 16 h. Water was added, after which 1M Maon (Zoml) and

EtOAc (bOml) and the mixture were intensively stirred for 30 minutes. The organic layer was separated, dried (M950) and evaporated to a yellow oil, which was purified by column chromatography using 90:10:11 (OSM, Meon, MN) as eluent to give the title product (740mg, 3595); "H NMR (400MHz,

SOS) 5: 1.65-1.74 (m, 2H), 2.52 (t, 2H), 2.66 (t, 2H), 7.02 (d, 2H), 7.35 (d, 2H); NRMS: t/z: (TS) 214 (Min).

Preparation 120 1--2-Chlorophenoxy)-2-propanamine

MN, sia "Zh o

Me oh so si her "! ! - uh-

The product from Preparation 121 (11g, 55.2mmol) in diethyl ether (41ml) was added dropwise to a suspension of lithium aluminum hydride (4.1g, 108mmol) in diethyl ether (110ml) under a nitrogen atmosphere. The reaction mixture was heated under reflux for 4 hours and then ethyl acetate was added followed by water. The aqueous layer was acidified with 4M hydrochloric acid, shaken and separated and then made basic using 4095 sodium hydroxide solution. The aqueous layer was extracted with diethyl ether (3x1000 ml) and the combined organic extracts were dried over magnesium sulfate. Ether extracts were acidified with hydrogen chloride and the obtained precipitate was filtered. The solid was recrystallized from ethanol/petroleum ether (B.P. 60-80). "" obtaining the product indicated in the title (2.5 g, 2095), Mpl. 126-1272С; "H NMR (SOSIS 400 MHz) 5: 1.55 (d, ЗН), 3.80 (k, 1Н), 4, 20 (d, 2H), 6.90-7.00 (m, 2H), 7.15 (t, 1H), 7.30 (d, 1H), 8.60 (shs, ZN); Anal. calculated С,48,9; H, 6.0; M, 6.5. SoNiZzMOsSI" is necessary C, 48.7; H, 5.9; M, 6,390. -I Preparation of 121st" 1--2-Chlorophenoxy)-2-propanone oxime

The background is 50 HER

F) in SI 60 1--2-Chlorophenoxy)acetone (106.6 bg, 0.58 mol) (U.At. Spect. bos, 75, 1953, 1134) was added to a solution of hydroxylamine hydrochloride (27.8 g, mol) in 2M solution of sodium hydroxide (420 Oml) and a sufficient amount of ethanol, obtaining a clear solution. The reaction mixture was heated under reflux for 30 minutes, then concentrated in vacuo, the crude residue was extracted with diethyl ether (3x200Oml). c The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. The residue was distilled to give the title product (134-1362C, 1.35mm Na) (4.5g, 3.996); "H NMR (SOSIz 400 MHz) 5: 2.05

(c, ЗН), 5.00 (c, 2H), 6.90-7.00 (m, 2H), 7.10 (t, 1), 7.30 (d, 1H), 7.60 ( c, 1H); Anal. calculated C, 54.95; N, 5.05. SoNioMO»SsI is necessary C, 54.15; H, 5.05905.

Preparation 122 3-(4-Methoxy-3-chlorophenyl)-1-propylamine 70 s

OoMa 4-Methoxybenzaldehyde (AlHiagisp) (42g, 0.3mol) and pyridine (0O0.bml, catalytic amount) were stirred together under a nitrogen atmosphere and for 30 minutes. Sulfuryl chloride (51 g, 0.37 mol) was added, maintaining the internal 2° reaction temperature within 25-30. Intense gas release was observed. The mixture was stirred at room temperature for another 30 minutes. and then heated at 702C for 4 hours. Excess reagents were removed by evaporation in a vacuum, and the residue was transferred to 50 ml of diisopropyl ether and poured into 50 ml of hexane with intensive stirring, from which the product precipitated. The solid was filtered off and washed with hexane and then dried under vacuum to give the title product (40.3g, 7796), M.p. 55-562C; IN NMR (400 MHz, CM 25 SOS") 6: 3.99 (s, ЗН), 7.05 (dd, 1Н), 7.91 (d, 1Н), 9.86 (s, 1Н); Anal. calculated: C, 56.13; H, 4.1495. SeH7SiO" (5) requires C, 56.33; H, 4.1495.

Preparation 123 3-(4-Methoxy-3-chlorophenyl)-1-propylamine «c) 30 so (Ce) « 35 N.M and -

The product from Preparation 122 was converted into a diastereomeric mixture with the appropriate vinyl nitriles

Preparation 93. This mixture (ZOOmg, 1.55mmol) was transferred to OSM (bml) at room temperature in an atmosphere of -0 with nitrogen and in portions for 5 min. tetrabutylammonium borohydride (1.6g, 6.2mmol) was added. The mixture was then boiled for 4h and then evaporated to dryness. The residue was taken up in about 1095 bml NOSI (aq.) and then boiled for for another 1 g. The reaction was cooled, extracted with EtOAc (3 x 30 mL), dried (Mo 5 O)), and evaporated to a yellow oil. This oil was passed through a column of 95/5/0.5, then 95/5/71 OSM/Meon/MmN » with obtaining the title product (75mg, 2495); "H NMR (400MHz, SOCI8) 8: 1.60-1.74 (m, 2H), 2.56 (t, 2H), 2.67 (t , 2H), and 3.82 (s, 3H), 6.79 (d, 1H), 6.98 (d, 1H), 7.15 (s/1H).

Preparation 124 t Chroman (22) with Chroman (42)

Ф) from (8) 60 4-Chromanol (Ayagisi) (2.77g, 18.4mmol) was transferred to acetic anhydride (3.5ml, 36b.9mmol) and acetic acid (30ml) and refluxed for 3h and then left to cool to room temperature for 16h, then 1095 va/wg Ra/s was added to the solution and the mixture was hydrogenated at a hydrogen pressure of 40 psi for 16bg. The catalyst was filtered through a layer of Agrose! and the filtrate was evaporated to a smaller (ml) volume. 65 The remaining liquid was dissolved in E(OAc (30 mL) and washed with water, then Manceau solution with (100 mL each). The organic layer was dried over Mo95O and evaporated to a pale yellow oil. This oil was passed through a column of 1095 E( OAc/pentane to give the title product (2.1g, 8595); "H NMR (400MHz, SOC") 6: 1.93-2.04 (m, 2H), 2.79 (t, 2H), 4 .18 (t, 2H), 6.78-6.83 (m, 2H), 7.00-7.10 (m, 2H).

Preparation 125 6b-Bromchromane

Be

The product from Preparation 124 (1g, 7.5mmol) was transferred to OSM (10ml) and 75 bromine (40µl, 7.9mmol) was added over several minutes as a solution in OSM (3ml). After the addition, the solution turned brown. The mixture was stirred at room temperature for 3h and then washed with water (20ml) and saturated aqueous sodium chloride solution (200ml) and the organic layer was separated, dried (Mo5O54) and evaporated to a clear yellow oil which was purified by column chromatography using 595 EOAc in pentane obtaining the title product (1.3g, 8295); "H NMR (400 MHz, SOSIz) 8: 1.90-1.98 (m, 2H), 2.73 (t, 2H), 4.14 (t, 2H), 6.61 (d. 1H), 7.08-7.15 (m, 2H).

Preparation 126 5-Bromo-2,2-dimethyl-2,3-dihydrobenzo|p|furan ve to o o | "c) so 2,2-Dimethyl-2,3-dihydrobenzo|p|Ifuran (obtained according to the method of VaKeg apa ppzidip, U. Ogo. Spet., 28, 1963, 24681 (500 mg, 3.3 mmol) was transferred into dichloroethane (5.5 ml) and stirred at room temperature under a nitrogen atmosphere, and M-bromosuccinimide (6.1 mg, 3.72 mmol) was added in one portion. The reaction was boiled for 2 h, ether (1 ml) was added, and the white precipitate of succinimide was filtered off. The filtrate was evaporated to dry and afterwards

Zo was purified by column chromatography using 590 ether in pentane as eluent to give the title product (b04mg, 79965); IN nMR (400MHz, SOCI5) 5: 1.43 (s, 6H), 2.92 (s, 2H), 6.54 (d, 1H), 7.16 (d, 1H), 7.19 (s , 1H); NRMS: INN, 227. (TO).

Preparation of 127 "5-Bromo-2-methyl-2,3-dihydro-1-benzo|r an du r dihydro IBIfur with c and Vg i?

V. o sh" b" The product indicated in the title was obtained from 2-methyl-2,3-dihydro-1-benzo|(p|-furan (Purchased from TSI, Darap) 5r Using the identical method used in Preparation 126 (8796); "H NMR (400 MHz, about SOS") 8: 1.43 (d, ЗН), 2.80 (dd, 1Н), 3.29 (dd, 1Н), 4.94 (m, 1Н ), 6.61 (d, 1H), 7.18 (d, 1H), 7.22 (s, 1H). o Preparation 128 2,3-Dihydrobenzo|p|furan-7-carboxaldehyde

Ф) e o 60 2,3-Dihydrobenzo|p|Ifuran (Maubgidde SPetisaiv) (25g, 0.21mol) was transferred to OSM (500ml) and with stirring in a nitrogen atmosphere at 09C, ZpSi was added in one portion; (36b, 5ml, 0.Zmol) obtaining a pale yellow solution. Then dichloromethyl methyl ether (18.vml, 0.21mol) was added and the solution was stirred for 30 minutes, after which the cooling bath was removed and the reaction was poured into ice-water (1000ml). The organic layer was separated, washed with water (2x10O0ml), 2M HCl (100ml) and a saturated aqueous solution of chloride

Sodium (5Oml), and then charcoal (30g) was added to the solution. Filtration through Seille and evaporation gave a black oil which was subjected to flash chromatography using 7-10956 EtOAc in pectane to give the title product (190mg, 0.0195); IN NMR (400 MHz, SOS) 5: 3.24 (t, 2H), 4.75 (t, 2H), 6.93 (t, 1H), 7.40 (d, 1H), 7.59 (d , 1H), 10.2 (s, 1H); NRMS: (MAN) 149, (TS). Anal. calculated: C, 72.98; H, 5.4696.

SeN'O" must be C, 72.96; H, 5.4495.

Preparation 129 1-Benzofuran-33-ylacetonitrile

Sodium hydride (268mg, b,/mmol) was suspended in dry THF (1Oml) at 02C in a nitrogen atmosphere, diethylcyanomethylphosphonate (1, ml, 6b, 7mmol) was added dropwise and the mixture was stirred for 45 minutes. Then, 3-coumaranon (I apsavzieg) (90mg, 6.7mmol) was added dropwise and the mixture was stirred at room temperature for 45min. The reaction was diluted with EtOAc (15ml) and water (15ml) and the organic layer was separated, dried (Mo5O)) and evaporated and the residue subjected to flash chromatography using 0-5906 E(OAc in pentane to give the title product (940mg, 9195); IN NMR (400 MHz, SOSI5) 5: 3.77 (s, 2H), 7.25-7.40 (m, 2H), 7.52 o (dd, 1H), 7.58 (dd, 1H), 7 ,67 (p. 18); NRMS: MAMN, 7, 175. (TS). p.

Preparation of 130 2-(1-Benzofuran-3-yl)ethylamine

The product from Preparation 129 (400mg, 2.55mmol) was combined with a solution of ammonium hydroxide (1Oml), ethanol-I (2O0ml) and ZOwag.bo Ca-Mi (12Omg, cat.) and hydrogenated under a hydrogen pressure of 30 psi at room temperature temperature for 16 h. The catalyst was filtered through a pad of Agrosea and the yellow-brown filtrate was chromatographed using 0-5956 MeOH OSM to give the title product (38Omg, 9395); "H NMR (4SOMHC, SOSI5) 5: 1.20 (she, (22) 2H), 2.80 (t, 2H), 3.02 (t, 2H), 7.15-7.25 (m, 2H), 7.43 (dd, 2H), 7.55 (dd, 1H); NRMS: INN, 162. (EC). syu 50 Preparation 131 2-(2,3-Dihydro-1-benzofuran-3- yl)ethylamine (42)

F) name) 60

The product from Preparation 130 (20Omg, 1.24mmol) was mixed with ethanol (2Oml) and 20mg of 1Owag.9o Ra/s and hydrogenated at a hydrogen pressure of 40 psi for 48h. Another 2Omg of the catalyst was added and the mixture was hydrogenated at 60 psi and 402 for another 72 h. The catalyst was filtered through a thin layer of Agrosea! and the filtrate was evaporated to dryness. The residue was purified by column chromatography using 90/10/1 OSM/Meon/MmN" as an eluent to obtain the title product (11mg, 5596); IN NMR (400MHz, SOSIz) 8: 1.81 (cu, 1H), 1.98 (m, 1H), 2.75-2.83 (m, 2H), 3.50

(m, 1H), 4.22 (t, 1H), 4.60 (t, 1H), 6.72 (d, 1H), 6.85 (t, 1H), 7.10 (t, 1H) , 7.20 (d, 1H); NRMS: MN, 164. (EU).

Preparation of 132 (2E ii 22)-3-(2,3-Dihydro-1-benzofuran-5-yl)-2-butenenitrile 70 oi

To a stirred suspension of sodium hydride (247mg, 6.1bmmol) in dry THF (bml) at 02C under a nitrogen atmosphere was added a solution of diethylcyanomethylphosphonate (0.98ml, 6b.1bmmol) in 2ml THF and the mixture was stirred at 02 for 1h. 5-Acetyl-2,3-dihydro(b|benzofuran (Alagisn)) (1g, 6.1bmmol) in THF (2ml) was added dropwise and the mixture was stirred at room temperature for 16h. Water (20ml) and EtOAc (20ml) were added. , the organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic solutions were dried over

Ma5O, was filtered and evaporated to give a pale brown oil which solidified on standing. This solid was purified by column chromatography using 20-3095 Es in pentane as eluent to give the title product (789mg, 6995); "H NMR (400 MHz, SOSI3) 6: 2.4 (p, ЗН), 3.2 (t, 2Н), 4.6 (t, 2Н), 5.5 (с, 1Н), 6.7 ( d, 1H), 7.2 (d, 1H), 7.3 (s, 1H); NRMO: MAMN, 203 (ES. s

Preparation of 133 o 3-(2,3-Dihydro-1-benzofuran-5-yl)butylamine "c) with

N.M te « o i -

The product from Preparation 132 was dissolved in ethanol (2Oml) and ammonium hydroxide solution (5ml) and the mixture was hydrogenated under a hydrogen pressure of ZO psi over 200 mg of ZOwag.bo Ca-Mi for 16bg. Then another 10 mg of catalyst was added and the hydrogenation was continued for another 16 h. The reaction mixture was filtered through a thin layer of Agbrosea and the filtrate was evaporated in vacuo to a smaller volume. The residue was then evaporated from toluene (2x20ml) to remove the last traces of water from C to give the title product (78Omg, 9690), which was used without further purification; IN nMR (400MHz, SOCI3) 5: 1.2 (5, ЗН), 1.7 (k, 2Н), 2.5 (m, 2Н), 2.65 (m, 1Н), 3.1 (t , 2H), 4.45 (t, 2H), 6.6 (d, 1H), 6.9 (d, 1H), 7.0 (s, IN; NRMS: MAN 192. (EC).

Preparation 134 -I 7-Methyl-2,3-dihydro-1-benzofuran-3-ol sh» o ' o 50 (42) o Me ime)

To a stirred suspension of trimethylsulfoxonium chloride (3.78g, 0.0Zmol) in dry THF (bOml) 60 was added sodium hydride (1.16g, 0.0Zmol) and the mixture was heated under reflux for 1h. 2-Hydroxy-3-methyl-benzaldehyde (I apsazieg) (4 g, 0.0003 mol) was added through a syringe to 3 ml of THF, and the resulting orange suspension was stirred at reflux for 5 h. Water (50ml) was added and the organic part was extracted with ether (3x50ml). The combined organic solutions were dried (M9505), filtered and evaporated in vacuo to an orange oil, which was purified by column chromatography using 15-25965 EOAc in pentane to give the title product (2g, 4595); "H NMR (400 MHz,

SOSI") 8: 2.2 (p, ЗН), 4.45 (m, 2Н), 5.3 (m, 1Н), 6.8 (t, 1Н), 7.1 (d, 1Н), 7.2 (d, 1H); NRMS: MN, 151. (EU).

Preparation 135 7-Methyl-2,3-dihydro-1-benzofuran 70 v and 19 To a stirred solution of the product from Preparation 134 (500 mg, 3.3 mmol) in acetic acid (ml) was added acetic anhydride (0.6 ml, 6.7 mmol) and the mixture was stirred at boiling in a nitrogen atmosphere for 2 h, then allowed to warm to room temperature for 16 h. Directly to the solution was added 1Owag.o Ra/C (ZOmg) and hydrogenated at a hydrogen pressure of 40 psi for 16bg at room temperature. The catalyst was filtered through a layer of Agrosea! and the filtrate was concentrated in vacuo to a pale yellow residue, which was dissolved in

Juds (20ml), washed with water (3x20ml), MansSoO»z (20ml), dried (M9505) and evaporated to a pale yellow oil. This oil was purified by column chromatography using 396 EAs in pentane as eluent to give the title product (261mg, 5896); "H NMR (400MHz, SOSI»z) 8: 2.2 (p, ЗН), 3.2 (t, 2Н), 4.55 (t, 2Н), 6.75 (t, 1Н), 6, 9 (d, 1H), 7.05 (d, 1H). p

Preparation 136 5-Bromo-7-methyl-2,3-dihydro-1-benzofuran (o) «c) so o (Se) « 5 Me t

To a stirred solution of the product from Preparation 135 (200 mg, 1.49 mmol) in dichloroethane (2.5 mL) was added M-bromosuccinimide (318 mg, 1.79 mmol) and the mixture was stirred at reflux for 16 h under atmosphere nitrogen The mixture was concentrated in vacuo to give a pale orange-brown solid, which was purified by column chromatography using 195 EtOAc in pentane as eluent to give the title product (112 mg, 3596); "H NMR (400 MHz, SOSIv) 8: 21 (p, ЗН), 3.15 (t, 2H), " 4.5 (t, 2H), 7.0 (s, 1H), 7.1 (s , 1H).

Preparation 137 2-Hydroxy-4-methylbenzaldehyde - 50 (42)

F) t Me 60 Zpsiu (241mg, 0.92mmol) and trimethylamine (0.bml, 2, 77 mmol). In 20 minutes. paraformaldehyde (611 mg, 20.mmol) was added and the mixture was stirred at 1002 for 16 h. The reaction mixture was diluted with water (2 Oml) and acidified with 2M HCl to pH2. The solution was extracted with ether (25 ml), washed with a saturated aqueous solution of sodium chloride (20 ml), dried (M95054), filtered and evaporated to a brown oil. This oil was purified by column chromatography using 595 EtOAc in pentane as eluent to give the title product (319mg, 2595); "H NMR (400MHz, SOSI3) 6: 2.3 (p, ЗН), 6.75 (m, 2Н), 7.35 (d, 1Н), 9.75 (s, 1Н), 11.00 ( with, 1H).

Preparation 138 5-Bromo-b6-methyl-2,3-dihydrobenzofuran

From the product of Preparation 137, the title compound was obtained using an identical technique

With the stages given in Preparations 134-136; IN NMR (400MHz, SOSI»z) 6: 2.3 (p, ЗН), 3.55 (t, 2Н), 4.5 (t, 2Н), 6.7 (с, 1Н), 7.3 (c, 1); NRMS: INN, 214. (EC).

Preparation of 139 s (ZE)-4-(2,3-Dihydro-1-benzofuran-5-yl)-3-buten-2-one o "c)

Me and o (Ce) o « m. 2,3-Dihydrobenzo|p|Ifuran-5-carboxaldehyde (AIDgisp o SPpetisaiv) (2g, 13.B5mmol), acetone (2.7Zml, 37.mmol), water (1 .35ml) and 1095 Mahon (aq.) (0.34ml) were added together and the mixture was stirred at room temperature for 16h. The yellow solid was dissolved in approx. 15 ml of OSM and added 2M HCl, bringing the pH of the solution to 2. Water (10 ml) was added and the organic layer was extracted with OSM (2x20 ml). The aqueous layers were separated and re-extracted with OSM (2 x 15 ml). The combined organic solutions were dried (Ma5O)) and concentrated in vacuo to a yellow solid, which was purified by column chromatography using 15-30956 E(OAc in . "" pentane as eluent to give the title product (2.13g , 8495); "H NMR (400 MHz, SOCI3) 6: 2.3 (p,

ЗН), 3.2 (t, 2H), 4.6 (t, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 7.3 (d, 1H), 7, 4 (c, 1H), 7.45 (d, 1H); NRMO: MN, 189. (EU).

Preparation of 140 - and 4-(2,3-Dihydro-1-benzofuran-5-yl)-2-butanone (22) o 50 o Me o

F) ka The product from Preparation 139 (2.12g, 11.3mmol) was transferred to ethanol (4Oml) and hydrogenated at a hydrogen pressure of 15 psi over 200mg of 1Owag.9o Ra/C for 4h. The mixture was filtered through a thin layer of Agrosea and the filtrate was evaporated in vacuo to a colorless oil, which was purified by column chromatography using 15-2590

Es in pentane to give the title product (1.53g, 7195); "H NMR (400 MHz, SOSI") 5: 271 (p, ZN), 2.7 (t, 2H), 2.8 (t, 2H), 3.1 (t, 2H), 4.5 (t , 2H), 6.65 (d, 1H), 6.9 (d, 1H), 7.0 (s, 1H); NRMS: MAMN,, 208. (EC).

Preparation 141 4-(2,3-Dihydro-1-benzofuran-5-yl)-2-butanamine b5 o

Ammonium acetate (4.05g, 52.mmol) and sodium cyanoborohydride (6.1mg, 10.5mmol) were added to a stirred solution of the product from Preparation 140 (50mg, 2.mmol) in methanol (25ml) and the mixture was stirred at 75°C. temperature during the night. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (200 mL) and water (20 mL). The organic part was extracted and washed with water (2 x 20 ml), dried (MA53O)) and evaporated to a clear oil. This oil was purified by column chromatography using 595 MeonN in OSM as eluent to give the title product (187mg, 3795); "H NMR (400 MGu,

SOSI5) 6: 1.93 (d, ЗН), 1.8 (m, 2Н), 2.6 (m, 2Н), 31 (t, 2Н), 3.2 (m, 1Н), 4.45 (t, 2H), 6.6 (d, 1n), 6.9 that (d, 1H), 7.05 (s, 1H); NRMS: MAN, 192. (ES.

Preparation 142

Methyl (2E)-2-cyano-3-(2,3-dihydro-1-benzofuran-5-yl)-2-butenoate c (8)

MeO, S and o so

OM o Te) « 3o To a stirred solution of 5-acetyl-2,3-dihydrobenzo|rB|Ifuran (Aidgist) (1g, 6.17mmol) in toluene - (bOml) was added methyl cyanoacetate (0.b0ml, 6 .78mmol), benzylamine (0.07ml, 0.bimmol) and acetic acid (0.3ml, 5.zmmol) and the mixture was refluxed with a Dean-Stark nozzle for 16h. The reaction mixture was cooled, washed with 2M HCl (30 ml), ManxSO3 (30 ml), saturated aqueous sodium chloride solution (30 ml), dried (Ma95O)) and evaporated to a yellow residue. This residue was purified by column chromatography using 15-2095 EOAc in pentane as eluent to give the title product in c (902mg, 6095); "H NMR (400 MHz, SOCIz) 5: 2.65 (s, 3H), 3.25 (t, 2H), 3.9 (s, 3H), 4.6 (t, 2H), 6.8 ( d, 1H), :z" 7.25 (d, 1H), 7.8 (s, 18); NRMS: MAMN, 7, 261. (ES.

Preparation 143 415 Methyl 2-cyano-3-(2,3-dihydro-1-benzofuran-5-yl)-3-methylbutanoate -I im Me Me

F MeO, o o 50 and cm -

Copper modide (I) (109mg, 0.57mmol) was added to a mixture of Meill (1.4M in ether, 0./bml, 1.07mmol) that (F) was stirred in ether (2ml) at -2592C under a nitrogen atmosphere . After stirring for 1 min. a solution of the product from Preparation 142 (100 mg, O0.41 mmol) in ether (2 ml) was added dropwise, and the mixture was then stirred at -259C7 for 2 h, and heated to 0 °C for another 2 h. A saturated aqueous solution of sodium chloride was added, and the organic part was extracted with EtOAc (10 ml), dried (M950;), filtered and evaporated. The residue was purified by column chromatography using 2095 EIAs in pentane to give the title product (92 mg, 86965 ); IN nMR (400MHz, SOSI3) 6:1.55 (d, 6H), 3.2 (m, 2H), 3.59 (s, ЗН), 3.62 (s, 1H), 4.5 (t, 2H), 6.7 (d, 1H), 7.1 (d, 1H), 7.2 (c, 1); NRMOS: MAMN, 7, 277. (EC).

Preparation 144 65 3-(2,3-Dihydro-1-benzofuran-5-yl)-3-methylbutanenitrile

And AJ is Me Me

To a stirred solution of the product from Preparation 143 (400 mg, 1.54 mmol) in ethanol (1.5 mL) and dioxane (1.5 mL) was added solid KOH (87 mg, 1.54 mmol) and the mixture was stirred at reflux refrigerator during The reaction mixture was concentrated in vacuo and dissolved in water (15 ml). The aqueous layer 7/5 was washed with toluene (15 mL) and then acidified to pH 1 using 2M HCl, from which the product was extracted

EUAs (2x20ml). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride (2 Oml), dried (M950)), filtered and concentrated in vacuo to give an orange oil, which was used without further purification; "H NMR (400 MHz, SOSI53) 6: 1.6 (d, 6H), 3.15 (t, 2H), 3.7 (s, 1H), 4.5 (t, 2H), 6.7 ( d, 1H), 7.1 (d, 1H), 7.22 (s, 18); NRMS: MAMN, z, 263. (ES"). This oil was transferred to OMA (2ml) and heated at 1502 for 2h and then allowed to cool to room temperature and stirred overnight.

The reaction mixture was concentrated in vacuo and then dissolved in E(Ac (1Oml). The organic part was washed with a saturated aqueous solution of sodium chloride (1Oml), dried over M950);, filtered and concentrated in vacuum to obtain an orange oil. It was purified by column chromatography using 1595 EOAc in pentane as eluent to give the title product (100 mg, 3295); "H NMR (400MGu, s 29 SOSI.) 6: 1.45 (s, 6H), 2.55 (s, 2H), 3.2 (t, 2H), 4.5 (t, 2H), 6 ,7 (d, 1H), 7,1 (d, 1H), 7,2 (s, 13); NRMS: MAMNA", 219. Go) (EC).

Preparation of 145 tert-Butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-3-methylbutylcarbamate o o so (Se)

Me o M h

Mr. and Mrs.

The product from Preparation 144 (250mg, 1.24mmol) was transferred to methanol (12ml) at 02С under a nitrogen atmosphere and was stirred with di-tert-butyldicarbonate (542mg, 2.48mmol), MiCl (161mg, 1.24mmol) and then Mavn,y (329mg, 8.69mmol) was added in portions. The black solution was allowed to warm to room temperature overnight and then concentrated in vacuo. The residue was partitioned between E(OAc (20ml) and Manceau solution (20ml), the mixture was filtered to remove all solids and the filtrate was extracted with E(OAc (2 x 20ml). The combined organic solutions were dried over Ma5O5, filtered and evaporated to give the indicated in title product (Zbbmg, 9690), which was used without further purification; IN NMR (400MHz, SOS) 8: 1.25 (s, 6H), 1.35 (s, 9H), 1.7 ih (t, 2H), 2.9 (shs, 2H), 3.1 (t, 2H), 4.2 (shs, 1H), 4.5 (t, 2H), 6.65 (d, 1H), 7, 0 (d, 1H), 7.1 (s, 1H); NRMO:

M-VOS, 206. (EC). me) Preparation of 146 so 20 3-(2,3-Dihydro-1-benzofuran-5-yl)-3-methylbutylamine and o o N.M imme) in Me Me

The product from Preparation 145 (Zbbmg, 1.20mmol) was transferred to ХОСМ (15ml) at 09С and stirred by passing hydrogen chloride through the solution for 15min. Passage of NS was terminated and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solution was poured with ether (20 Oml), which caused the formation of a white precipitate. This solid was filtered, washed with ether and dried in vacuo to give the title product (177mg, 6195); "H NMR (400 MHz, MeOb) 5: 1.3 (s, 6H), 1.9

(m, 2H), 2.6 (m, 2H), 3.1 (m, 2H), 4.5 (m, 2H), 6.6 (s, 1H), 7.01 (s, 1H) , 7.2 (c, 1); NRMS: MN, 207. (EU).

Preparation 147

Methyl 2-(4-chlorophenyl)-3-cyanopropanoate / АЖ 19 A 2.5 M solution was added dropwise to a stirred solution of diisopropylamine (8.65 mL, 61.9 mmol) in dry THF (100 mL) at -209С under a nitrogen atmosphere "You in hexanes (23.7ml, 59.2mmol). The solution was allowed to warm to 02 for 2h and then cooled to -702C. A solution of methyl 2-(4-chlorophenyl)acetate (9, 5g, 51.5mmol) in THF (bml) and the mixture was then stirred for 3h, then iodoacetonitrile (5.0gml, 69.5mmol) was added slowly and the combined solutions were allowed to warm to room temperature over 72h. A saturated aq. MannSO" (20 mL), the mixture was concentrated to about 50 mL in vacuo and then treated with 1M HCl (100 mL). The mixture was extracted with EtOAc (120 mL), which was dried (Mo 5 O 3 ) and evaporated to give a dark brown oil which was purified by column chromatography using 2:1 OSM:pentane as eluent to give the title product (8.6g, 7596); "H NMR s (400MHz, SOSI") 5:2.8 0 (dd, 1H), 3.00 (d, 1H), 3.73 (s, ЗН), 3.92 (dd, 1H), 7.22 (d, 2H), 7.37 (d, 2H ).

Preparation 148 o 4-Amino-2-(4-chlorophenyl)butanol c o c o (Ce) « i -

The product from Preparation 147 (235 mg, 1.05 mmol) was transferred to 1 ml of THF and added dropwise to a solution that was stirred with HIAIN 4 (2.1 ml, IM solution in THF, 2.1 mmol) in THF at 09С in an atmosphere nitrogen The mixture was stirred at room temperature for 2 h and cooled to 02C. Water (0.08 ml) was added, after which 3M aqueous Mahon solution (0.08 ml) was added and the mixture was diluted with THF (2 ml) and water (0.24 ml). The suspension was stirred for 5 min., filtered and the filtrate was evaporated to a yellow gum. This residue was transferred to EtOAc (5 mL) and extracted with a 0.5 M NOCI solution (0.3 mL), which was then basified with NaClCO3 solution to pH 10 and extracted with EtOAc (5 x mL). The combined organic solutions were dried (Ma5O)) and evaporated to obtain their product indicated in the title (bOmg, 2995); "H NMR (400 MHz, SOCI3) 5: 1.62-1.95 (m, 2H), 2.58-3.00 (m, ЗН), 3 .58-3.80 (m, 2H), 7.02-7.39 (m, 4H).

Me. Preparation 149 o 70 tert-Butyl (4-chlorophenyl)acetate (42)

F) Me di Me o 60 p-Chlorophenylacetic acid (5.94 g, 34.8 mmol) was added to a suspension of M,M-dimethyl-formamide-di-tert-butyl acetal (25 ml, 104.4 mmol) in dry toluene (9 Oml) and the mixture was heated at 809 for 1 h. The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL), 396 aqueous solution of MnSO 3 p (50 mL) and saturated aqueous sodium chloride solution (2 O mL) and then dried over Mo2O and evaporated to give an oil. This oil was purified using 3595, then 5095 OSM in pentane to give the title product (2.4g, 3096); "N. NMR bo (400 MHz, SOSI") 8: 1.42 (s, 9H), 3.44 (s, 2H), 7.20 (d, 2H), 7.28 (d, 2H).

Preparation 150 tert-Butyl 2-(4-chlorophenyl)propanoate 5. i u Me o t The product of Preparation 149 was alkylated according to a procedure identical to that described in Preparation 147, using methyl iodide as the alkylating agent. The title product was obtained in 9595 yield after purification by column chromatography using 2595 OSM in pentane as eluent; "H NMR (400 MHz, SOS") 5: 1.39 (s, 9H), 1.41 (d, ЗН), 3.59 (k, 1H), 7.20 (d, 2H), 7.25 (d, 2H).

Preparation 151 s in Me o

Me o so

PM her

The product from Preparation 150 was alkylated according to a procedure identical to that described in Preparation 137.

The title product was obtained in 8295 yield after purification by column chromatography using 3596, then 7095 OSM in pentane as eluent; "H NMR (400 MHz, SOCI3) 8: 1.40 (s, 9H), 1.74 (s, ЗН), 2.80 (d, 1H), 2.95 (d, 1H), 7.24 ( d.2H), 7.35 (d.2H).

Preparation 152 "4-Amino-2-(4-chlorophenyl)-2-methylbutanol sh si Z c 2" n. After 50 s, the product from Preparation 151 was regenerated by the method of Preparation 148 to obtain the title product (3595). The product of this reduction was pure enough not to be subjected to further purification; "H NMR (400MHz, SOSIZ) 8: 1.22 (s, ЗН), 1.71 (ddd, 1H), 2.01 (ddd, 1H), 2.60 (ddd, 1H), 2.83 52 (ddd, 1H), 3.60 (d, 1H), 3.82 (d, 1H), 7.27 (d, 2H), 7.38 (d, 2H). o Biological research

The IC value of the compounds of the invention against NEP and ACE was determined using the methods described in the application of Ina patent EP1097719-A1Y|, paragraphs (0368) to (0376). The IC 59 values given below were determined using

NEP from dog kidneys. In addition, the IC values of some compounds of the invention were determined using NEP from the kidneys of 60 people; these values were similar to those determined using canine NEP.

The compounds of the invention are strong NEP inhibitors and are selective ACE agonists.

The compounds indicated in the titles of the Examples had ICs against NEP of less than 400 nm.

The compounds indicated in the headings of Examples 1-25, 27-37, 39-41, 43-48, 50-53 and 55-67 had ICs against NEP less than or equivalent to 15OHM and selectivity to ACE more than 300 times. 65 In particular, the compound indicated in the title of Example C had an IC of 22 nM against NEP; the compound indicated in the title of Example 4 had an ISvo against NEP of 4nM; indicated in the title of Example 21, the compound had an ICso against NEP ZNM;

the compound indicated in the title of Example 33 had an ISvo against NEP of 47nM; the compound indicated in the title of Example 43 had an ICso against NEP of 29 nM; and the compound indicated in the title of Example 51 had IC50 against NEP U9nNM. The title compounds of Examples 3, 4, 21, 33, 43 and 51 all had greater than 300-fold selectivity for ACE.

An animal model of the response to sexual arousal in a woman

The compound indicated in the title of Example 22 (hereinafter referred to as "selected compound") was administered according to the protocol (described in EP1097719-A1), paragraphs (10495) to (0499). The selected compound was obtained in 5965 saline.

The selected compound and control solvents were injected using a Nagmaga 22 pump, injected at 50 Ωcl/min. by

C-channel tap into the femoral vein. After the infusion, the catheter was flushed with heparinized saline (Nerzaiipe), so 7/0 that not even traces of the selected compound remained in the catheter.

The selected compound, studied in clinically relevant doses, significantly increases the pelvic nerve, which stimulates an increase in blood flow in the genital organs (see Fig.1). The selected compound increases the peak increase in vaginal blood flow by 5695 (n-33) and trough flow in the clitoris by 5095 (n-3) compared to the time-matched control increase.

Fig. 1 shows the effect of administration of a selected compound on genital blood flow in rabbits. The selected compound increases pelvic nerve stimulation (PMS) increases in genital blood flow in anesthetized rabbits, models of sexual arousal. Repeating PMZ every 15 minutes causes a reproducible increase in genital blood flow (shaded bars). Administration of the selected compound (gray bar) increases the peak increase in clitoral and vaginal blood flow inducing submaximal stimulation frequencies (eg, 4 Hz) compared to the increase observed during time-matched control stimulation or control solvents (shaded bar). The following simultaneous increases were observed after approximately 0.5 mg/kg per pellet - 5095 increase in clitoral and 5695 increase in vaginal blood flow (p-3). The data were expressed as -scp value (mean square error of measurement); all changes were monitored using a Doppler laser. with

These were not main effects of NEP inhibition or basal/unstimulated genital blood flow.

Female New Zealand rabbits (-2.5 kg) were injected with a combination of Medetomidine (JuOtiigme) 0.5 mg/kg intravenously. and about

Ketamine (Meiaiag?) 0.25ml/kg IV, giving oxygen through a mask at this time. Rabbits were tracheotomized using a Rogiechtm endotracheal tube without a cuff with IO., connected to a ventilator and maintaining a ventilation rate of 30-40 breaths per minute, with an approximate tidal volume of 18-20Oml, and a maximum air pressure of TOcm H 20. Then anesthesia was started. with isoflurane and ventilation was continued OO" 2 l/min. The right extreme ear vein was cannulated using a 230 or 245 catheter and perfused with lactonized Ringer's solution at a rate of 0.5 ml/min. Rabbits were maintained at 395 isofuran during invasive surgery, with drips up to 295 to maintain anesthesia.

The left side of the groin of the rabbit was shaved and a vertical incision about 5 cm long was made along the thigh. The femoral vein and artery were removed, isolated, and then cannulated with a PVC catheter (170) for infusion of drugs and compounds. Cannulation was repeated for the femoral artery, inserting the catheter to a depth of 10 cm to ensure that the catheter reached the abdominal aorta. This arterial catheter was connected to the Gould system to relieve blood pressure. Samples for gas analysis were also taken through the arterial catheter. Systolic and diastolic pressures were measured and blood pressure values were calculated using the formula (diastolic x 2 and systolic)/3. The heart rhythm was measured by measuring the pulse with an oximeter and - with using the Ro-pe-type data acquisition software system (Ropetai Rpuzioiodu Riayogt, Socia Ipvigitepi a Zuzietv Ips). "" An incision was made in the middle of the abdomen in the abdominal cavity. The incision was approximately 5 cm in length above the pubis.

Fat and muscles were bluntly cut, revealing the hypogastric nerve, which was lowered into the hollow of the body. In fact, it was kept closed to the curved wall of the pubis to avoid damage to the femoral vein and artery, which lies above the pubis. The sciatic and pelvic nerves are located deeper and are located behind the incision on the dorsal side of the rabbit. As only the sciatic nerve was found, the pelvic nerve was easily positioned. The term pelvic nerve is used loosely; anatomy books make it easy to identify nerves with sufficient detail. However, (o) stimulation of the nerve causes an increase in vaginal and clitoral blood flow and innervation of the pelvic area by 50. The pelvic nerve was isolated from the surrounding tissue and a Harvard bipolar stimulating electrode was placed around the nerve. The nerve was slightly raised, receiving some stretching, then the electrode was fixed in this 62 position. Approximately 1 ml of light paraffin oil was placed around the nerve and electrode. This is used as a protective lubricating agent for the nerve and prevents contamination of the electrode with blood. The electrode was connected to the stimulator OSgazz 588 Zi(ytshishaig). The pelvic nerve was stimulated using the following parameters: 0.5-58, pulse length 0.5ms, stimulation time 10 seconds and frequency intervals 2-16Hz. Reproducible responses were obtained when the nerve was stimulated during 15-20 minutes The frequency response was determined at the beginning of each experiment to determine the optimal frequency to use as a submaximal response, normally 4Hz. Compound(s) were tested by femoral vein injection using a Nagmag 22 infusion pump allowing a 15 minute stimulation cycle. Because they made an incision in the middle of the abdomen, through the entire pubis to the tail, revealing the pubic part. Connective tissues were removed to reveal the clitoris shell, to free the wall from small blood vessels.

The outer wall of the vagina was also opened by removing any connective tissue. One of the laser flux probes

The Doppler was inserted into the vagina at a depth of 3 cm, so that the end of the probe was still visible.

The second probe was placed so that it lay above the outer wall of the clitoris. The position of these 65 probes was adjusted until a signal was received. The second probe was placed above the surface of the blood vessel on the outer surface of the vagina. Both probes healed in positions. Values of vaginal and clitoral blood flow were recorded or as values from a flowmeter using data collection software Ro-pe-tap (Ropetai

RPpuzioiodu Riayogt, socia Ipzigitepi Zuzietwe Ips), or not directly from the projection of the curve diagram of Gould of the scribe. At the beginning of the experiment, calibration was performed (0-125ml/min/100g of tissue).

An animal model of the male erectile response

Methodology of anesthetizing a rabbit

The title compound from Example 22 ("selected compound") alone and in combination with a selective and potent PDE5 inhibitor 3-ethyl-5-(5-(4-ethyl piperazin-1-ylsulfonyl)-2-n-propoxyphenyl|- 2-(pyridin-2-yl)umethyl-2,6-dihydro-7H-pyrazolo|4,3-4|Ipyrimidin-7-one 7/0 U was administered according to the following protocol. The selected compound was dissolved in saline 45956 1M Mahon Selected compound and control solvents were infused using a Nagmaga 22 pump at a rate of 5O0Omcl/min

C-channel valve in the femoral vein. After infusion, the catheter was flushed with heparinized saline (Nerzaiipe) so that no selected compound remained in the catheter. The PDE5 inhibitor was dissolved in saline 4595 1M CARRIER, compounds and control solvents were infused at a rate of 0.Iml/second and left for 15 minutes before stimulation of the pelvic nerve.

Two experiments were conducted: the effect on intracavernous pressure (ICP) of administration of a) only the selected compound, and b) in combination with the PDE5 inhibitor. The effect on ISR is shown in Fig.2. Data were expressed as a percentage increase in value (90)ns.a. value. "P" 0.01, Student's t-test is unpaired with comparisons with a control increase.

Administration of the selected compound resulted in 37 -795 potential submaximal stimulation of intracavernosal pressure (see Fig. 2, left gray column; n-4).

Administration of a combination of the selected compound with a selective inhibitor of PDE5 (mg/kg i.m. swarms) resulted in 70-490 potential submaximal stimulation of intracavernosal pressure (see Fig. 2, dark gray column; n--3). Ha

These were not major manifestations of NEP inhibition or concomitant NEP/PDE5 inhibition of basal/unstimulated intracavernosal pressure. at

Male New Zealand rabbits (-2.5 kg) were administered a combination of Medetomidine (Uotiomke) 0.5 mg/kg intravenously. and

Ketamine (Meiaiag?) 0.25ml/kg IV, giving oxygen through a mask at this time. Rabbits were tracheotomized using a Rogiechtm endotracheal tube without a C IO cuff, connected to a ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate tidal volume of 18-20 ml, and a maximum air pressure of 1Osm H 20. Then anesthesia was started. isoflurane and ventilation was continued O5 2l/min. The right extreme ear vein was cannulated using a 230 or 240 catheter and perfused with lactonized Ringer's solution at a rate of 0.5 ml/min. Rabbits were maintained at 395 isofuran during invasive surgery with drips up to 295 to maintain anesthesia. The right jugular vein was opened, C was isolated and then cannulated with a PVC catheter (170) for infusion of the selected compound or combination thereof. uh-

The left side of the groin of the rabbit was shaved and a vertical incision about 5 cm long was made along the thigh.

The femoral vein and artery were removed, isolated and then cannulated with a PVC catheter (170) for infusion of the selected compound or combinations thereof. Cannulation was repeated for the femoral artery, inserting the catheter to a depth of 10 cm to ensure that the catheter would reach the abdominal aorta. This arterial catheter was connected to the Gould system to relieve blood pressure. Samples for gas analysis were also taken through the arterial catheter. - c Cystolytic and diastolic pressures were measured and blood pressure values were calculated using a formula (diastolytic x2 "cystolytic)/3. The heart rhythm was measured by measuring the pulse with an oximeter and is" using the Ro-pe-type data acquisition software system (Ropetai Rpuzioiodu Riayogt, Socia Ipvigitepi

Zuzietv Ips).

An incision was made in the middle of the abdomen in the abdominal cavity. The incision was approximately 5 cm in length above the pubis. - Fat and muscles were bluntly cut, opening the hypogastric nerve, which was lowered into the hollow of the body. In fact, they were kept closed on the curved wall of the pubis to avoid damage to the femoral vein and artery, which lies above the pubis. The sciatic and pelvic nerves are located deeper and are located behind the incision on the dorsal side of the rabbit. As (22) only the sciatic nerve was found, the pelvic nerve was easily positioned. The term pelvic nerve is freely used; anatomy books make it easy to identify nerves with sufficient detail. However, nerve stimulation causes an increase in intracavernosal and cavernosal blood flow and 62 innervation of the pelvic region. The pelvic nerve was isolated from the surrounding tissue and a Harvard bipolar stimulating electrode was placed around the nerve. The nerve was raised a little, receiving some stretching, then the electrode was fixed in this position. Approximately iml of light paraffin oil was placed around the nerve and the electrode. This is used as a protective lubricating agent for the nerve and prevents contamination of the electrode with blood. The electrode was connected to the stimulator Sgazz 588 BZiitshtsaug. The pelvic nerve was stimulated using the following parameters: 0.5-58, pulse length 0.5ms, stimulation time 20 seconds with a frequency of 2-16Hz. Reproducible responses were obtained when the nerve was stimulated for 15-20 minutes. Several stimulations with the parameters mentioned above were used to obtain a stable value of the control response. The selected compound or combination thereof was administered by infusion through the femoral vein using a Nagmag 22 infusion pump allowing a 15 minute stimulation cycle. The skin and connective tissues around the penis were removed, revealing the penis. A catheter (Ipzuie-MU, Vesiop-Oiskipwop 20 (1.1x48 mm) was inserted through the white corpuscle into the left part of the cavernosal plane, the needle was removed, leaving a flexible catheter. This catheter was connected through a pressure indicator (OPpteda 5299-04) to the Gould system of removal of intracavernosal pressure. Once b5 intracavernosal pressure was established, the catheter was closed in place using Vetbond (adhesive pressure, ZM). Heart rate was measured through a pulse oximeter and using the Ropetai software data acquisition system (Ropetai Rnuzioiodu Rianogt, Socia Ipzigitepi Zuzietv Ips ).

Intracavernosal blood pressure was taken as a value directly from a potichometer using the software system for obtaining data Ro-pe-tai (Ropetai РНузиоиоду Райцогт, Соция Ипзиготепи Зузиетв Ипс), or not directly from the projection of the curve of the recorder's Gould diagram. At the beginning of the experiment, calibration was performed (0-125ml/min/100g of tissue).

Claims (26)

The formula of the invention -. and , , , 1. The compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph or prodrug form Х их М. р -6- 2 сч 2 НО о о ; at 30 in which B! is C 1 -alkyl, which may be substituted by one or more substituents, which may be the same or different, selected from the list: halogen, hydroxy, C.valkoxy, hydroxyC 1 valkoxy, C 1 valkoxyC y valkoxy, carbocyclyl, carbocyclyloxy, C daloxycarbocyclyloxy, heterocyclyl , o heterocyclyloxy, -MK2BZ, -"MA"SOnB, -mA"80o85, -"SOMAgVU, -B(O)re?, -СОвB' and -СО5(Sidalkyl); or K! is "Ke carbocyclyl or heterocyclyl, each of which may be substituted with one or more substituents from the 35 mentioned list, where the substituents may be the same or different, where the mentioned list includes C. alkyl; - or B is hydrogen, C 6 , 50285; where B 2 and 23, which may be the same or different, are carbocyclyl or heterocyclyl (each of which may be substituted by C. . . or C./Alkoxy); - c or is hydrogen or C; alkyl; or 2 and c, together with the nitrogen atom to which they are attached, also form pyrrolidinyl, piperidino, morpholino, piperazinyl or M-(C.lalkyl)piperazinyl; "» B is hydrogen or S. dalkil; Vo is Ci dalalkyl, CE', carbocyclyl, Ci dalalkylcarbocyclyl, Ci daloxycarbocyclyl, heterocyclyl, Ci 4 alkoxy or -ME 2 EZ; Is 25 C. dalkyl, carbocyclyl, heterocyclyl, or ME? and r»B is alkyl, carbocyclyl or heterocyclyl; reeo,1,2 or 3; F X is a bridge -""СНо)д- or -"СН2)д-О-(where U is attached to oxygen); where one or more hydrogen atoms (9) 20 in bridge X can be replaced, independently, by C..lalkoxy; hydroxy; hydroxyS. Zalkali; C3.7cycloalkyl; carbocyclyl; heterocyclyl; or C. dalalkyl, optionally substituted by one or more fluorine atoms or phenyl groups; 3,4,5,b6babo7;ideg2,3,4,5abob;and U is phenyl or pyridyl, each of which may be substituted by one or more B 9 groups, which may be the same or different, where BU is hydroxy ; mercapto; halogen; cyano; acyl; amino; mono(C, dalalkyl)amino; di(Si-alkyl)amino; carbocyclyl or heterocyclyl (any of which is, and F) optionally, substituted with C/alkyl, halogenC alkyl, C. valkoxy, halogenC. valkoxy, Si valkylthio or cohalogen); Si-valcox; phenoxy; Su. valkiltio; phenylthio; or alkyl, optionally, substituted C. valkoxy, halogens 4 valkoxy, Si. valkylthio, halogen or phenyl; or because two BZ groups on adjacent carbon atoms, together with the connecting carbon atoms, can form a condensed 5- or b-membered carbocyclic or heterocyclic ring, optionally substituted with C alkyl, halogenC. valkylom, S. valkoxy, halogensS. valkoxy, Si valkylthio or halogen. 2. The compound according to point 1, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, in which B! is hydrogen, Si alkyl, Si valkoxy, Si valkoxyS. zalkylom, Si-valukoxy Si valkoxy. Si alkyl 65 or S. alkyl substituted phenyl. 3. The compound according to point 2, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, in which V! is hydrogen, Su valkyl, Si. valkoxy, Si valkoxyS in alkyl or Su. valkoxyS 1 valkoxyS and zalkylom. 4. The compound according to point 3, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, in which B! is Si dalkilom or S. valkoxysS zalkilom. 5. The compound according to any of the previous clauses, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, formula Ia: 70 ini ch sh ia M - ra u o (Iv). 6. The compound according to any of the previous clauses, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, in which X is -(CH2)p- and where one or more hydrogen atoms in the X bridge can be replaced by one or more groups defined in point 1. 7. A compound according to any of the preceding clauses, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, in which, when present, n is C or 4. 8. A compound according to any of the preceding clauses, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, in which K 8 is C 1 alkyl, C 1 alkyl, hydroxy, mercapto, halogen, cyano, azo carbocyclyl or heterocyclyl; or two C groups on adjacent carbon atoms together with connecting carbon atoms can form a condensed 5- or b-membered carbocyclic or heterocyclic ring, optionally substituted with C 3 alkyl, halogenC. valkylom, C. valkoxy, halogenC.-valkoxy, C. valkylthio or "0 halogen. 9. A compound according to any of the preceding clauses, a pharmaceutically acceptable salt, solvate, polymorph C or prodrug thereof, wherein C is a carbocyclyl, namely cyclopentyl, cyclopropyl, cyclohexyl, or phenyl. 10. A compound according to any one of items 1-8, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, in which, B C is heterocyclyl, namely pyridyl, oxadiazolyl, pyrazolyl or triazolyl. 11. The compound according to any of the items 1-8, its pharmaceutically acceptable salt, solvate, polymorph or c) c prodrug form in which, when U is phenyl and two C groups on adjacent carbon atoms together with connecting Ys » carbon atoms form a condensed 5- or b--membered carbocyclic or heterocyclic ring, and condensed cyclic systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl, and benzothiazolyl. 12. The compound according to point 1, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, where the compound is: "" (2kK)-2-C1-(113-(4-methoxyphenyl)propylamino)carbonyl)ucyclopentyl|methyl )pentanoic acid (Example 16); 3-11-(113-(4-methoxyphenyl)propyl|iamino)carbonyl)ucyclopentyl|Ipropanoic acid (Example 18); b 3-11-(113-(2,3-dihydro-1-benzofuran-5-yl)propylamino)carbonyl)ucyclopentyl|Ipropanoic acid (Example 21); so 20 2-(C1-(I3-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 15); 2-4(1-(13-(4-fluorophenyl)propyl|Iamino)carbonyl)ucyclopentyl|methyl)-4-methoxybutanoic acid (Example 4); c 4-methoxy-2-41-(113-(4-methoxyphenyl)propyl|Iamino)carbonyl)ucyclopentyl|methyl)butanoic acid (Example 1); 2-(C1-(113-(2,3-dihydro-1-benzofuran-5-yl)propyl|Iamino)carbonyl)ucyclopentyl)methyl)-4-methoxybutanoic acid (Example 11); 29 (25)-2-C1-(113-(4-chlorophenyl)propylamino)carbonyl)cyclopentyl|methyl)-4-methoxybutanoic acid (Example HF) 22)1 yuyu (25)-2-C1-(113-( 2,3-dihydro-1-benzofuran-5-yl)propylamino)carbonyl)cyclopentyl|methyl)-4-methoxybutanoic acid (Example 25). 13. The compound according to point 1, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, which is (25)-2-41-(1N3-(4-chlorophenyl)propylamino)carbonyl)ucyclopentyl|methyl)-4- methoxybutanoic acid (Example 22). 14. A compound according to any one of items 1-13, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for use as a medicament. 15. Use of a compound according to any of the preceding clauses, its pharmaceutically acceptable salt, or solvate, polymorph or prodrug form, in the manufacture of a medicament for the treatment or prevention of a condition for which neutral endopeptidase inhibition is beneficial. 16. Use according to claim 15, wherein the condition is female sexual dysfunction or male erectile dysfunction. 17. The use according to claim 16, wherein the condition is female sexual arousal disorder. 18. Use according to any one of items 15-17, wherein the compound is administered systemically. 19. Use according to claim 18, wherein the compound is administered orally. 20. Use according to any one of claims 15-17, wherein the compounds are administered topically. 21. A method of treating or preventing a condition, the therapeutic effect of which is achieved due to the inhibition of 7/0 neutral endopeptidase in a mammal, in which a therapeutically effective amount of the compound defined in any of items 1-13, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form. 22. The method according to clause 21, where the condition is defined in clause 16 or 17. 23. A pharmaceutical composition containing a compound defined in any of items 1-13, its pharmaceutically acceptable salt, solvate, polymorph or prodrug form together with a pharmaceutically acceptable excipient, diluent or carrier. 24. The combination of the compound defined in any of items 1-13 and one or more active ingredients selected from the following list: a) FDEB5 inhibitor, more preferably 3-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl) )phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo|4,3-a|pyrimido n-7-one (sildenafil); (6К,12ак)-2,3,6,7,12,12а-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino|2,1":6,1|pyridoyiZ,4-b |indole-1"A4-dione (IS-351); 2-(2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl)phenyl|-5-methyl-7-propyl-ZN-imidazoi5 ,1-14-1,2,)griazin-4-one (vardenafil); 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl 2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazoloyl|4, i) 3-4|pyrimidin-7-one; and 5-(5-acetyl-2-butoxy-33-pyridinyl)- 3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4, Za|Ipyrimidin-7-one and their pharmaceutically acceptable salts; o zo b) inhibitor of MRU M1; c ) a dopamine agonist, such as apomorphine or a selective 02, ХО3 or О02/O3 agonist, such as pramipexole and o ropirinol; He d) a melanocortin receptor agonist or a modulator or enhancer of melanocortin, preferably melanotan I, RT-14, RT-141; - e) agonist, antagonist or modulator of 5HT2C; e) e) estrogen receptor modulator, estrogen agonists and/or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene; e) androgen , such as androsterone, dehydroandrosterone, testosterone, androstenedione and synthetic androgen; " and g) estrogen, such as oestradiol, oestrone, oestriol and synthetic estrogen, such as estrogen benzoate. in the village 25. The method of obtaining a compound of the general formula;" -I 2 1 her U oz 7 ra y sНnaASN H ai o H 2 ime) ХО) 60 in which B", X and U are as defined in any of clauses 1-13 or its salts, in which they carry out: a) the interaction of the compound of the formula II b5 with Rgoi » o o ; (1) in which Rgoi is a suitable protecting group, with the compound of the formula III U-X-MH", (1) c 29 to obtain the compound of the formula IM; Ge) "in ) vi y yo u F ke r "I z o sNnsno H m Rgoi Z " y o 7 s ;" " ; (M) b) deprotection of the compound of the formula IM to obtain the compound of the formula |; c) optionally, obtaining a salt. -I 26. The method according to point 25, which, in addition, carries out asymmetric hydrogenation of any of the compounds of formula XI, XIII or KhPI i» form. (22) at 50 (42) F) name) 60 b5