EA006154B1 - N-phenpropylcyclopentyl-substituted glutaramide derivatives as nep inhibitors for fsad - Google Patents

Abstract

The invention relates to compounds of formula (I) for treating for example sexual dysfunction, wherein R<1> is optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, hydrogen, C1-6alkoxy, -NR2R<3> or -NR<4>SO2R<5>; X is the linkage -(CH2)n- or -(CH2)q-O- (wherein Y is attached to the oxygen); wherein one or more hydrogen atoms in linkage X may be replaced independently by C1-4alkoxy; hydroxy; hydroxy(C1-3alkyl); C3-7cycloalkyl; carbocyclyl; heterocyclyl; or by C1-4alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6, or 7; and q is 2, 3, 4, 5 or 6; and Y is phenyl or pyridyl, each of which may be substituted; or two R<8> groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring.

Description

This invention relates to inhibitors of the enzyme - neutral endopeptidase (ΝΕΡ), their use, methods for their preparation, intermediate compounds used in their preparation, and compositions containing these inhibitors. These inhibitors are used in a wide range of therapeutic areas, including the treatment of male and female sexual dysfunction, in particular female sexual dysfunction (Ρ8а, 1а §1 § § § § §узузузузузипБББBop), especially when ΡΡΌΌ is a sexual arousal disorder in women (P РАЭЭ 1 1еш § § § § § § §1111 а а1111111 )

ΝΕΡ inhibitors are disclosed in AO 91/07386 and AO 91/10644.

The use of ΝΕΡ inhibitors for the treatment of Ρ8Ό is disclosed in EP 1097719-A1.

According to a first aspect, the invention provides a compound of formula I, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof

where K ¹ represents C1-6 alkyl, which may be substituted by one or more substituents, which may be the same or different, selected from the following list: halogen, hydroxy, C1-6 alkoxy, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, carbocyclyl (preferably C3-7 cycloalkyl, C3-7cycloalkenyl or phenyl), carbocyclyloxy (preferably phenoxy), C1-4 alkoxycarbocyclyloxy (preferably C1-4 alkoxyphenoxy), heterocyclyl, heterocyclyloxy, -ΝΚ ² Κ ³ , -KHK ⁴ SOK ⁵ , -ΝΕ ⁴ 8Ο2Κ ⁵ , -COKK ² K ³ , -8 (O) RK ⁶ , -COK ⁷ and -CO2 (C _1-4 alkyl); or K ¹ is carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more substituents from the above list, the substituents being the same or different, the list additionally including C1-6 alkyl ; or K ¹ represents hydrogen, C1-6 alkoxy, -ΝΚ ² Κ ³ or -KK ⁴ 8O ₂ K ⁵ ;

where K ² and K ³ , which may be the same or different, are carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl (each of which may be substituted with C1-4 alkyl, hydroxy or C1-4 alkoxy); or are hydrogen or C1-4 alkyl; or K ² and K ³ together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or No. (C1-4 alkyl) piperazinyl group;

K ⁴ represents hydrogen or C _1-4 alkyl;

To ⁵ represents C _1-4 alkyl, SR _3, carbocyclyl (preferably phenyl), C _1-4 alkilkarbotsiklil (preferably _C1-4 alkylphenyl), alkoksikarbotsiklil C _1-4 (preferably C _1-4 alkoxyphenyl) heterocyclyl, C _1-4 alkoxy or -LK ² K ³ ;

K ⁶ is C _1-4 alkyl, carbocyclyl (preferably phenyl), heterocyclyl or —ΝΑΑ; and

K ⁷ is C _1-4 alkyl, carbocyclyl (preferably C _3-7 cycloalkyl or phenyl) or heterocyclyl;

p is 0, 1, 2 or 3;

X is a bond - (CH2) p- or - (CH2 \ -O- (where Υ is attached to oxygen); where one or more hydrogen atoms in the X bond can be independently replaced by C _1-4 alkoxy; hydroxy; hydroxyC _{1 -3} alkyl; C _3-7 cycloalkyl; carbocyclyl; heterocyclyl; or C _1-4 alkyl, possibly substituted with 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

Υ is phenyl or pyridyl, each of which may be substituted by one or more K ⁸ groups, which may be the same or different, where K ⁸ is hydroxy; mercapto; halogen; cyano; acyl; amino; mono (C _1-4 alkyl) amino; di (C _1-4 alkyl) amino; carbocyclyl or heterocyclyl (any of which is optionally substituted with C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC1-6 alkoxy, C ^ alkylthio or halogen); C ^ alkoxy; phenoxy; C ^ alkylthio; phenylthio; or alkyl, possibly substituted with C _1-6 alkoxy, haloC _1-6 alkoxy, C _1-6 alkylthio, halogen or phenyl; or two K ⁸ groups on adjacent carbon atoms together with the connecting carbon atoms can form a fused 5- or 6-membered carbocyclic or heterocyclic ring, possibly substituted with C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _{1 -6} alkoxy, C _1-6 alkylthio or halogen.

Preferably K ¹ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-3 alkyl, C _1-6 alkoxyC _1-6 alkoxyC _1-3 alkyl, or C _1-6 alkyl, substituted phenyl.

More preferably, K ¹ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-3 alkyl (preferably methoxyC _1-3 alkyl) or C _1-6 alkoxyC _1-6 alkoxyC _1-3 alkyl (preferably methoxyethoxyethyl).

Even more preferably, K ¹ is C _1-4 alkyl (preferably propyl) or C _1-6 alkoxyC _1-3 alkyl (preferably methoxyC _1-3 alkyl, more preferably methoxyethyl).

- 1 006154

A preferred group of compounds are compounds of formula 1a

O (1a)

Preferably, η is 3 or 4, more preferably 3.

Preferably c] is 2 or 3, more preferably 2.

Preferably X is - (CH ₂ ) _P -, where one or more than one hydrogen atom in the bond X can be replaced by one or more than one group defined for X in the first aspect of the invention.

Preferably, K ⁸ is C 1-6 alkyl, C 1-6 alkoxy, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl; or two K ⁸ groups on adjacent atoms together with the connecting carbon atoms can form a fused 5- or 6-membered carbocyclic or heterocyclic ring, possibly substituted by C 1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy , C _1-6 alkylthio or halogen.

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

When K ⁸ is heterocyclyl, preferred groups are pyridyl, oxadiazolyl, pyrazolyl or triazolyl.

When Υ is phenyl, and two K ⁸ groups on adjacent carbon atoms together with the connecting carbon atoms form a fused 5- or 6-membered carbocyclic or heterocyclic ring, the preferred fused ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl or benzothiazolyl.

Preferred compounds of the invention are (2K) -2 - {[1 - ({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} pentanoic acid (Example 16),

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

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

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

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

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

2 - {[1 - ({[3- (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] methyl} -4 methoxybutanoic acid (example 11), (28) -2- {[1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22) and (28) -2 - {[1 - ({[3- ( 2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] methyl} -4methoxybutanoic acid (Example 25).

A particularly preferred compound is (28) -2 - {[1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22).

Unless otherwise indicated, any alkyl group may be straight or branched and consists of 1-6 carbon atoms, preferably 1-4 and in particular 1-3 carbon atoms.

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

Unless otherwise indicated, any heterocyclyl group contains from 5 to 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 heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolynyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolyl, isaziazylazole dioxanyl, morpholino,

- 2 006154 dithianil, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepil or thiazolinyl. In addition, the term heterocyclyl includes fused heterocyclyl groups, for example, benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinodiolazinyl azolinyl, dihydroquinodiolazinyl azolinyl, The term heterocyclic should be interpreted in the same way.

Halo means fluoro, chloro, bromo or iodo.

For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more than one specific group. In the case where the groups can be selected from a number of alternative groups, the selected groups may be the same or different.

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

Pharmaceutically or veterinarily acceptable salts of compounds of formula I that contain a basic center are, for example, non-toxic acid addition salts formed by inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid; carboxylic acids or organosulfonic acids. Examples include salts of HC1, HBg, H1, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, sugar, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, para and pamoat. Pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, can also be prepared from the compounds of the invention with bases. Examples include salts of sodium, potassium, aluminum, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloin, megulamine and diethanolamine. For reviews of suitable pharmaceutical salts, see Vegde s1 e1., 1. Ryagt, 8c1., 66, 1-19, 1977; R. b. Soi16, 1p1egpayoia1 1oita1 οί Ryagtaseiysk, 33 (1986), 201-217; and B1dEeu c1 a1., Jesus1ore61a ίί Ryagtasei11sa1 Tesyio1odu, Magse1 Iekkeg 1ps., Iete Wogk, 1996, Woite 13, Rade 453-497.

Below in the description of the compound, their pharmaceutically acceptable salts, solvates and polymorphs thereof, as defined in any aspect of the invention or in a preferred embodiment (excluding intermediates in chemical methods) are referred to as compounds of the invention.

Pharmaceutically acceptable solvates of the compounds of the invention include hydrates thereof.

The compounds of the invention and intermediates may have one or more chiral centers and therefore exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention.

Individual enantiomers can be obtained using a number of methods known to those skilled in the art of chemistry, such as high pressure liquid chromatography (HPLC) of the corresponding racemate using a suitable chiral support or fractional crystallization of diastereoisomeric salts formed by reacting the corresponding racemate with a suitable optically active base, as appropriate. A preferred optically active base is pseudoephedrine (see Preparation 69).

Separation of diastereomers can be achieved by conventional methods, for example fractionated crystallization, chromatography or HPLC.

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

It will be apparent to those skilled in the art that certain protected derivatives of the compounds of the invention that can be prepared prior to the final deprotection step may not have pharmacological activity per se, but they can, in some cases, be administered orally or parenterally, after which they are metabolized in the body to form compounds of the invention that are pharmaceutically active. Such derivatives can therefore be described as prodrugs. In addition, some compounds of the invention may act as prodrugs of other compounds of this invention.

All protected derivatives and prodrugs of the compounds of the invention are included within the scope of this invention. Examples of suitable prodrugs for the compounds of the present invention are described in Igidk Tobau, Wojite 19, Tip 9, 1983, pp. 499-538, in Toryuk ίη Sететщщйуu, C11ar (eg 31, pp. 306316 and in Idi ί ί Rgobgidk N. Wiibdaagb, Ekéu1eg, 1985, Part 1) (descriptions of these documents are incorporated herein by reference).

In addition, it will be apparent to those skilled in the art that certain groups known to those skilled in the art as groupings, such as those described in N. Wiebdaagb Iemdi ί Rgobgidk (the description of which is incorporated into this description of the invention,

- 3 006154 coy) can be placed on the corresponding functional groups when such functional groups are present in the compounds of the invention.

Preferred prodrugs of the compounds of the invention include esters, carbonate esters, hemi esters, phosphate esters, nitroesters, sulfate esters, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

A study of drug metabolism showed that ίη νίνο compounds of formula I can form the following compounds, which are also inhibitors ΝΕΡ

These metabolites are formed, in particular, when I ¹ is methoxyethyl, and -ΧΥ is 3- (4-chlorophenyl) propyl.

The invention also includes all suitable isotopic varieties of the compounds of the invention. An isotopic species is defined as a species in which at least one atom is replaced by an atom having the same atomic number and an atomic mass different from the atomic mass commonly found in nature. Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² N, ³ N, ¹³ C, ¹⁴ C, ¹⁵ Ν, ¹⁷ O , ¹⁸ O, ³¹ P, ³² P, ³⁵ §, ¹⁸ E and ³⁶ C1, respectively. Some isotopic varieties of the invention, for example, those incorporating a radioactive isotope such as ³ H or ¹⁴ C, are useful for studies of the tissue distribution of drugs and / or substrates. Tritium, i.e. ³ N, and carbon-14, i.e. ¹⁴ C, isotopes are particularly preferred because of the ease of their preparation and detection. In addition, substitution with isotopes such as deuterium, i.e. ² N, may have certain therapeutic advantages due to greater metabolic stability, for example, increasing the half-life of ίη νίνο or lowering dosage requirements, and therefore may be preferred in some circumstances. Isotopic varieties of the compounds of the invention can generally be prepared by conventional methods, such as the methods or preparations described in the examples and preparations below in the application, using suitable isotopic varieties of the corresponding reagents.

The compounds of the invention are inhibitors of the zinc dependent neutral endopeptidase of EC.3.4.24.11. And it is intended that the compounds of the invention will treat the disease conditions listed below. This enzyme is involved in the cleavage of certain bioactive oligopeptides by cleaving peptide bonds at the amino terminus of hydrophobic amino acid residues. Metabolizable peptides include atrial natriuretic peptides (ΑΝΡ), bombesin, bradykinin, calcitonin, a genetically linked peptide, endothelin, enkephalin, neurotensin, substance P and a vasoactive intestinal peptide. Some of these peptides have strong vasodilating and neurohormonal functions, diuretic and natriuretic activity, or mediate behavioral effects.

Thus, the compounds of the invention by inhibiting the neutral endopeptidase of EC.3.4.24.11 can enhance the biological effects of bioactive peptides. Thus, in particular, these compounds are used in the treatment of a number of diseases, including hypertension, pulmonary hypertension, peripheral vascular disease, heart failure, angina pectoris, renal failure, acute renal failure, cyclic edema, Menieres disease (Meshetek), hyperaldosteronism (primary and secondary) and hypercalciuria. In addition, due to their ability to enhance the action of ΑΝΕ, these compounds are used in the treatment of glaucoma. As a further consequence of their ability to inhibit neutral endopeptidase E.C.3.4.24.11, the compounds of the invention may be active in other areas of therapy, including, for example, the treatment of menstrual irregularities, preterm labor, preeclampsia, endometriosis and reproductive disorders (especially male and female infertility, polycystic ovary syndrome, failure during implantation). Also, the compounds of the invention should treat asthma, inflammation,

- 4 006154 leukemia, pain, epilepsy, affective disorders, dementia and senile confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), promote wound healing (especially diabetic and venous ulcers and pressure sores), treat septic shock, change gastric acid secretion; treat hyperreninemia, cystic fibrosis, restenosis, complications of diabetes and atherosclerosis. In a preferred embodiment, the compounds of the invention are useful in the treatment of male and female sexual dysfunction.

The compounds of the invention are particularly useful for the treatment of E8E (especially Ρ8ΑΌ) and male sexual dysfunction (especially male erectile dysfunction (ΜΕΌ, tae eteiée yukGiisioi)).

According to the invention, Ρ8Ό can be defined as the difficulty or inability of women to find satisfaction in sexual expression. Ρ8Ό is a generic term for several different female sexual dysfunctions (Lewis, 8. V. (1998)). Oeyiyyuy ay ekak1yeeoi oG Getae kehia1 y1kogyegk. Ιηΐ. 1.18th Century., 10, 8104-8106 ;, Vegtai, EB., Vegtai, b. @ Oy1ksks, I. (1999). Retak kehia1 yukGiisyoi: 1is1ieeee, raShorkukyukdu, eu1iayoik aiy 1tea1tei1 oryoik. Igokdu, 54, 385-391). A woman may lack desire, have difficulty with excitement or orgasm, pain during sexual intercourse, or a combination of these problems. Ρ8Ό may be caused by certain types of diseases, medications, injuries, or physiological problems. The developed treatments are aimed at treating individual subtypes of Ρ8Ό, mainly impaired desire and arousal.

Categories Ρ8Ό are best defined by contrasting them with the phases of a normal female sexual reaction: desire, arousal, and orgasm (Lе1L1It, 8. V. (1998). OGGTsoyi eiakk1yeyoioi OG Getak kekhia1 Shkogyegk. 1i1. 1. 1trokie Vek., 10, 8104- 8106). Desire or libido is a stimulus of sexual expression. Its manifestations often include sexual thoughts either in the company of an interested partner, or when exposed to other erotic stimuli. Stimulation is a vascular response to sexual stimulation, an important component of which is a rush of blood to the genitals, it includes enhanced lubrication of the vagina, lengthening of the vagina and increased genital perception / sensitivity. An orgasm is the release of sexual tension that culminates in arousal.

Consequently, Ρ8Ό occurs when a woman shows an inadequate or unsatisfactory reaction in any of these phases, usually desire, arousal, or orgasm. Ρ8Ό categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, and sexual pain disorder. Although the compounds of the invention improve the genital response to sexual stimulation (as with a sexual arousal disorder in women), the associated pain, malaise and discomfort associated with sexual intercourse can also be reduced, and other female sexual disorders can be treated in this way.

A disorder in the form of a hypoactive sexual desire occurs if a woman has a weak desire to be sexual or does not have it and has few or no sexual thoughts or fantasies. This type of Ρ8Ό can be caused by low testosterone levels, either natural menopause or menopause caused by surgery. Other causes include illness, medication, fatigue, depression, and anxiety.

Female sexual arousal disorder (Ρ8ΆΌ) is characterized by an inadequate genital response to sexual stimulation. There is no rush of blood to the genitals characteristic of normal sexual arousal. The walls of the vagina are slightly lubricated, so that intercourse becomes painful. Achieving orgasm can be difficult. Excitation disorders can be caused by a decrease in estrogen levels during menopause, or after the birth of a baby, or during lactation, as well as diseases with vascular components such as diabetes or atherosclerosis. Other causes are treatment with diuretics, antihistamines, antidepressants (e.g. 88B1k (selective serotonin reuptake inhibitors)) or antihypertensive agents.

Sexual pain disorders (such as dyspareunia and vaginismus) are characterized by penetration pain and can be caused by medications that reduce blur, endometriosis, pelvic inflammation, inflammatory bowel disease, or urinary tract problems.

The prevalence of Ρ8Ό is difficult to assess, as this term covers several types of problems, some of which are difficult to assess, and also because the interest in treating Ρ8Ό is relatively recent. Many female sexual problems are associated either directly with the aging process of women, or with chronic diseases such as diabetes and hypertension.

Since Ρ8Ό consists of several subtypes, the symptoms of which manifest themselves in separate phases of the sexual response cycle, there is no single therapeutic treatment. Modern treatment Ρ8Ό focuses mainly on physiological problems or relationship problems. Ρ8Ό treatment is gradually developing, as more and more clinical and fundamental research is devoted to the study of this medical problem. Female sexual diseases by pato

- 5 006154 physiologies are not all physiological, especially for those individuals who may have a component of vasculogenous dysfunction (eg Ρ8ΑΌ) that contributes to all female sexual illness. There are currently no licensed medications for treating Ρ8Ό. Empirical drug therapy involves the administration of estrogens (topically or as hormone replacement therapy), androgens, or mood-enhancing drugs such as bisporin or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects.

Since interest in the pharmacological treatment of Ρ8Ό has appeared recently, therapy consists of the following: physiological counseling, over-the-counter lubricants for the genitals, and medications that are candidates for research, including medications approved for other conditions. These drugs consist of hormonal agents, either testosterone, or combinations of estrogen and testosterone, and completely new vascular drugs that have been shown to be effective in male erectile dysfunction. None of these agents have been shown to be very effective in treating Ρ8Ό.

Diagnostic and Statistics Manual (Ό8Μ, Egadposbos apb 81a11811sa1 Mapia1) of the Fourth American Psychiatric Association defines the sexual arousal disorder in women (Ρ8ΑΌ) as a constant or recurrent inability to achieve or maintain an adequate response in the form of smearing-swelling in response to sexual arousal before sexual activity . The disorder should cause noticeable discomfort or interpersonal difficulties.

The reaction in the form of excitement consists of hyperemia of the pelvic vessels, lubrication of the vagina and stretching and swelling of the external genitalia. The disorder causes noticeable discomfort or interpersonal difficulties.

Ρ8ΑΌ is a widespread sexual disorder affecting women before, near, and after menopause (± tubing). It is associated with concomitant disorders such as depression, cardiovascular disease, diabetes, and IP (urogenital) diseases.

The primary consequences of Ρ8ΑΌ are the lack of a rush of blood / swelling, the lack of lubrication and the absence of a pleasing genital sensation. The secondary consequences of Ρ8ΑΌ are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm.

Recently, it has been suggested that for at least some patients with Ρ8ΑΌ symptoms, the main thing is the vascular component (Co1b81esh c1 a1., Ιηΐ. I. Kez., 10, 884-890, 1998) and animal data have been obtained confirming this point of view (Ragk e1 a1., Ιηΐ. I. Ιιηροΐ. Thes., 9, 27-37, 1997).

Candidate drugs for the treatment of Ε8ΑΌ, which are at the stage of studying their effectiveness, are mainly therapeutic agents for erectile dysfunction, which activate blood circulation in the male genitalia. They consist of two types of drugs, oral or sublingual drugs (apomorphine, phentolamine, type 5 phosphodiesterase inhibitors (ΡΌΕ5), for example sildenafil), and prostaglandin (PCE ₁ ), which is injected or transurethrally men and locally in the genitals of women.

The compounds of the invention are useful because they are agents for restoring a normal response in the form of sexual arousal - namely, increased genital blood flow leading to a rush of blood to the vagina, clitoris and lips. This leads to increased lubrication of the vagina by transudation of the plasma, to increased compliance of the vagina and increased genital sensitivity.

Therefore, the compounds of the invention are agents for restoring or enhancing a normal response in the form of sexual arousal.

Without being bound by theory, the authors suggest that neuropeptides, such as the vasoactive intestinal peptide (νΙΡ), are major candidates for neurotransmitters in regulating the response to sexual arousal in women, especially in regulating genital blood flow. νΙΡ and other neuropetides are cleaved / metabolized by the enzyme ΝΕΡ EC3.4.24.11. Thus, ΝΕΡ inhibitors will enhance the endogenous vasodilating effect of νΙΡ released upon excitation. This leads to treatment of Ρ8ΑΌ, for example, by enhancing genital blood flow and, consequently, blood flow to the genitals. The authors showed that selective inhibitors of ΝΕΡ EC 3.4.24.11 increase the increase in vaginal and clitoral blood flow, stimulated by the pelvic nerves and induced by νΙΡ. In addition, selective ΝΕΡ inhibitors enhance νΙΡ and nerve-mediated relaxation of the isolated vaginal wall.

Thus, the present invention is useful because it helps to provide a means to restore a normal response to sexual arousal, namely increased genital blood flow leading to a rush of blood to the vagina, clitoris and lips. This leads to increased lubrication of the vagina by plasma extravasation, increased vaginal compliance and increased vaginal sensitivity. Therefore, the present invention provides means for restoring or enhancing a normal response to sexual arousal.

- 6 006154

Male sexual dysfunction includes male erectile dysfunction, ejaculation disorders, such as premature ejaculation (RE, rhesha Shge s) aeikShop). anorgasmia (inability to achieve orgasm) and desire disorders, such as a disorder in the form of hypoactive sexual desire (lack of interest in sex).

Obviously, all references in the description of the invention to treatment include therapeutic, palliative or prophylactic treatment.

The compounds of the invention are used in the following subpopulations of patients with Ε8Ό: young, elderly women, before menopause, near menopause, after menopause, with or without hormone replacement therapy.

The compounds of the invention find use in patients with Ε8Ό caused by

1) vasculogenic etiology, for example, cardiovascular or atherosclerotic diseases, hypercholesterolemia, smoking, diabetes, hypertension, radiation and trauma to the perineum, traumatic damage to the ileo-hypogastric vascular system of the external genital organs;

2) a neurogenic etiology, for example, spinal cord injuries or diseases of the central nervous system, including multiple sclerosis, diabetes, parkinsonism, strokes, peripheral neuropathies, trauma or radical surgery in the pelvic region;

3) hormonal / endocrine etiology, e.g. hypothalamic / pituitary / gonadal system dysfunction or ovarian dysfunction, pancreatic dysfunction, surgical or therapeutic castration, androgen deficiency, high levels of circulating prolactin, such as hyperlactinemia, natural menopause, premature ovarian failure, hyper- and ;

4) psychogenic etiology, such as depression, obsessive-compulsive disorder, anxiety disorder, postpartum depression BaBi B1ie8, emotional and relationship problems, marital disagreement, dysfunctional relationships, sexual phobias, religious repression or post-traumatic stress disorders;

5) drug-induced sexual dysfunction resulting from therapy with selective serotonin reuptake inhibitors (88K1§) and other antidepressant therapies (tricycles and major tranquilizers), antihypertensive therapies, sympatholytic drugs, ongoing oral contraceptive therapy.

Patients with mild to moderate должны should benefit from treatment with the compound of the invention, and patients with severe ΜΕΌ may also respond to it. However, early studies suggest that the degree of response of patients with mild, moderate, and severe ΜΕΌ will be greater in combination with a ΡΌΕ5 inhibitor. Weak, medium, and heavy ΜΕΌ are terms well-known to those skilled in the art, but guidance can be found in Thieu оит па о £ 1 1 оду,, νον. 151, 54-61 (1ap 1994).

The compounds of the invention are used in the following subpopulations of patients with ΜΕΌ: psychogenic, endocrinological, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction associated with cavernous factors, in particular with venogenic causes. These groups of patients are described in more detail in C11sh1a Lpbto1od νο1. 23, by. 4, p. 773-782, and part 3 of the book I. BagLeu apb K. 8e11pa 'Es Euse Hypsyop - Sittep! ^ yutdabop apb Μapadedetΐ published by Μο5Ь- \ Vο1ίс.

The compounds of the invention can be prepared in a known manner in a variety of ways. In the following reaction schemes and below, unless otherwise indicated, K ¹ , n, X and Υ are as defined in the first aspect. These methods form additional aspects of the invention.

Throughout the description, general formulas are indicated by Roman numerals I, II, III, IV, and so on. Subgroups of these general formulas are denoted by Ts, Σδ, Tv and so on, .... Sha, Shb, Shv and so on.

Compounds of general formula I can be prepared by reacting a compound of formula II (where Progo! Is a suitable protecting group) with an amine of formula III to give compounds of formula IV followed by deprotection (see Scheme 1). Preferred reaction conditions for the acid / amine coupling step include reacting II with III (or an amine salt thereof) in the presence of an activating agent, possibly a catalyst, and an excess of an acid acceptor in a suitable solvent. Particularly preferred reaction conditions include the interaction of II (1-1.5 equivalents), III (or its salt, 1-1.5 equivalents) in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (\ U8SE [) or Ν, Ν'-dicyclohexylcarbodiimide (ESA) (1.1-1.3 equivalents), 1-hydroxybenzotriazole hydrate (HOBT) or dimethylaminopyridine (ΌΜΆΡ) (1.05-1.2 equivalents), Ν methylmorpholine (ΝΜΜ) or triethylamine (2.3-3 equivalents) in dimethylformamide or dichloromethane at a temperature between room temperature and 90 ° C for 16-18 hours

In addition, particularly preferred reaction conditions include the reaction of II (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 addition III (or its amine salt, in this case an organic base is present, such as triethylamine or Hunig's (Nscheid'k) base) at a reaction temperature between room temperature and 90 ° C.

- 7 006154

Alternatively, the acid / amine coupling step can be carried out through the acid chloride in the presence of an excess of an acid acceptor in a suitable solvent. The acid chloride may be isolated or ίη δίίυ may be formed. Preferred reaction conditions include the interaction of acid chloride II (1-1.1 equivalents), III (or its salt, 1-1.5 equivalents), triethylamine or Ν methylmorpholine (1.4-10 equivalents) in dichloromethane at room temperature for 24 hours. Compounds of formula II can be converted into the acid chloride ίη L1 and treated with oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide for 2 hours at room temperature.

Methods for deprotecting an acid group depend on the protecting group. For examples of the methodology for establishing / removing protection, see Рgo! Uc! 1ue dgoirs ίη Ogdashs zupSheyz, TS Ogeepe apb ROM Shi1 /.

For example, when Rgo! is tert-butyl, deprotection conditions include the interaction of IV with a trifluoroacetic acid / dichloromethane mixture (1: 1-2.5 by volume) at room temperature for 2-18 hours, possibly in the presence of an acceptor of carbocations, for example, anisole ( 10 equivalents). When X or Υ contains a hydroxy group, alkaline hydrolysis of the trifluoroacetic acid ester intermediate may be necessary. An alternative methodology for removing protection in the case where the RGO! is tert-butyl, includes treatment with IV hydrochloric acid in dichloromethane at room temperature for 3 hours. To avoid uncertainty, Рго! in the form of tert-butyl is given as an example and is not limited to tert-butyl.

The method in accordance with scheme 1 forms another aspect of the present invention.

Intermediates of general formula IV are new. Therefore, according to another aspect, the invention provides a compound of formula IV.

A number of compounds of formula II are known from the prior art (see EP 274234-B1 and S0913054). Other compounds of formula II can be obtained in a similar manner.

Compounds of the general formula I and II, wherein B ^{1 is} not hydrogen, have a chiral center on carbon attached to K. ¹ . The individual enantiomers can be obtained by a number of methods known to those skilled in the art of chemistry, for example from the corresponding optically pure intermediate or by resolution. The preferred method is the separation by means of a salt with (+) pseudoephedrine (see SHO 9113054, example 10 in the description).

Alternatively, compounds of formula Pa, i.e., chiral compounds of formula II, wherein K ¹ is optionally substituted with C _1-6 alkyl (where O is a substituent on a C _1-6 alkyl group defined for K ¹ in the first aspect) can be obtained by asymmetric hydrogenation of compounds of formula XI, XII or XIII in accordance with reaction scheme 1A.

Typical hydrogenation conditions include treating compounds of formula XI, XII or XIII [or an organic or inorganic salt thereof (eg, sodium salt)] with a suitable asymmetric hydrogenation catalyst under elevated hydrogen pressure in a suitable solvent. Preferred catalysts contain one or more chiral ligands, preferably

- 8 006154 chiral phosphine ligands coordinated with a suitable transition metal (e.g. rhodium, ruthenium, iridium, palladium). Preferred catalysts are [(K) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthylchloro (paracymol)] ruthenium chloride (B. Ogd. Set. 1994, 59, 3064-76);

[(8) - (+) - 3.3 ', 4.4', 5.5'-hexamethyl (6.6'-diphenyl) -2,2'-diyl] bis (diphenylphosphino) ruthenium bis (trifluoroacetate) (see AO 01/94359);

[(K) - (-) - 4,12-bis (diisopropylphosphino) - [2.2] paracyclophano- (1,5-cyclooctadiene)] rhodium (1) tetrafluoroborate (former At. Syet. 8 pp. 1997, 119, 6207-6208);

[bis - ((28.58) -2,5-dimethyl-1-phenylphospholano) (1,5-cyclooctadiene)] rhodium (I) tetrafluoroborate (Te1gayebgop: Azutt., 1991, 2, 569-92); and [(K) - (6,6'-dimethoxybiphenyl-2,2'-diyl) bis (diphenylphosphino)] ruthenium bis (trifluoroacetate) (EP

398132).

Preferred reaction conditions include hydrogen pressures up to 150 psi. inch (1034.25 kPa) and a reaction temperature between 0 and 100 ° C (preferably 50-60 ° C). Preferred solvents are protic, such as methanol or ethanol.

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

The method in accordance with scheme 1 a forms another aspect of the present invention.

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

Compounds of formula Sha, that is, compounds of formula III where X is - (CH ₂ ) -, can be prepared according to Reaction Scheme 2. First, compounds of formula V are subjected to a Heck (Nesk) reaction with acrylonitrile in the presence of a suitable catalyst system such palladium, and an excess of a base such as triethylamine or 4-methylmorpholine, to give compounds of formula VI. Typical reaction conditions include 1.0-1.5 equivalents of aryl halide, 3 equivalents of base, 0.1 equivalents of palladium catalyst (preferably palladium (P) acetate), 0.2 equivalents of phosphine ligand (preferably triorthotolylphosphine) in 1,4- dioxane, acetonitrile or ΌΜΕ (dimethylformamide) (preferably acetonitrile) at the boil under reflux. The compounds of formula VI are then subjected to catalytic hydrogenation to give compounds of formula Sha. Typical hydrogenation conditions include treating VI with Raney Nickel (Kapeu) in ethanol or methanol at a pressure of 15 to 150 psi. inch (103.425-1034.25 kPa) and 25 and 80 ° C. Preferably in ethanol at 30 psi. inch (206.85 kPa) and 25 ° C.

Scheme 2

acrylonitrile

(V) (VI) (Sha)

Alternatively, compounds of formula VI can be prepared according to reaction scheme 3 by reacting compounds of formula VII with diethyl cyanomethylphosphonate. Typical reaction conditions include reacting diethyl cyanomethylphosphonate with a suitable base (e.g. sodium hydride, lithium chloride / Hunig base or sodium ethylate) in a suitable solvent at room temperature (e.g. dichloromethane, tetrahydrofuran or diethyl ether), followed by the addition of a compound of formula VII.

Scheme 3 γ — CHO НОСН2-Р (0) (EU) ₂ (VII)

Alternatively, compounds of formula Sha may be prepared according to Scheme 4. Scheme 4

1) malonic acid, pyridine, UNN γ fig " ^{2) Ng} " ^Ν ' ^Raney - MeOH * ^¥ ~ H- _C0 , n (Vii)

1) MeOH, Hg8O4 2) ΜβΟΗ, ΝΗ ₃ Υ— \ * A-soING IA1N ₄ OR, VN ₃ .8Mv2 Υ— ΝΗ, (Sha)

Other compounds of formula (III), (V) (VI) and (VII) are either commercially available; known from the prior art; or they can be obtained from compounds known from the prior art, using methods known from the prior art, or using the methods described in this description (see sections examples and preparatory examples).

- 9 006154

All of the above reactions and methods for producing new starting materials used in the previous methods are conventional. Suitable reagents and reaction conditions for their implementation or preparation, as well as methods for isolating the desired products are well known to specialists in this field of technology with reference to precedents from the literature and examples and preparatory examples in the description below.

A pharmaceutically acceptable salt of a compound of formula (I) can be easily prepared by mixing together solutions of a compound of formula (I) and the desired acid or base, as appropriate. Salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporation of the solvent.

The compounds of the invention [in particular (28) -2 - {[1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22)] can be combined with one or more than one additional active ingredient selected from the list.

1) One or more naturally occurring or synthetic prostaglandins or their esters. Suitable prostaglandins for use include compounds such as alprostadil, prostaglandin E ₁ , prostaglandin E ₀ , 13,14-dihydroprostaglandin E ₁ , prostaglandin E ₂ , eprostinol, natural synthetic and semisynthetic prostaglandins and their derivatives, including those described in AO-00033825 and / or I8 6037346, issued March 14, 2000, all of which are incorporated herein by reference, POE ₀ , POE ₁ , ΡΟΛι, PCB |. ROR! α, 19-hydroxy PCA |. 19-hydroxyROV1, POE ₂ , POB ₂ , 19-hydroxy-POA ₂ , 19-hydroxy-POB ₂ , PCE ₃ a, carboprost tromethamine, dinoprost, tromethamine, dinoprostone (bshorgoyope), lipoprost (Pro rgok!)), Hemeprost ( Desherga), methenoprost (Sche1eorgo81), Sulprostun (8i1rgo81ipe), Tiaprost (OargoL) and moxysilate (Shokh18u1a1e).

2) One or more of the antagonists of α-adrenergic receptors, also known as α-adrenergic receptors or α-receptors or a-blockers. Suitable compounds for use according to the invention include α-adrenergic receptor blockers, as described in PCT application XVO 99/30697, published June 14, 1998, the description of which relates to α-adrenergic receptors, is incorporated herein by reference and includes selective blockers αι-adrenoceptors or α ₂ -adrenoceptors and non-selective adrenoceptor blockers, suitable αι-adrenoceptor blockers include phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramine, naphthopidyl, tamsulo zine, dapiprazole, phenoxybenzamine, idazoxane, efaraxan, yohimbine, alkaloids of rauwolfia, Vesogbay 15/2739, 8ΝΑΡ 1069, 8ΝΑΡ 5089, B817053, 8B 89.0591, doxazosin, terazosin, abanokvil and prazosin; blockers of α ₂ blockers from I8 6037346 [March 14, 2000] dibenarnin, tolazoline, trimazosin and dibenamine; α-adrenergic receptors, such as those described in US patents: 4188390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2503059; 4,730,063; 3,381,809; 4,252,721 and 2,599,000, each of which is incorporated herein by reference; α ₂ -adrenoceptor blockers include clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a karyotonic agent such as pierxamine.

3) One or more than one compound is an ΝΟ-donor (ΝΟ-agonist). Suitable дон-donor compounds for use according to the invention include organic nitrates, such as mono-, diyl trinitrates or organic nitrate esters, including glyceryl brinitrate (also known as nitroglycerin), isosorbide-5-mononitrate, isosorbide dinitrate, pentaerythritol tetra nitrate, erythritol tetranitrate, sodium nitroprusside (8ΝΡ), 3-morpholinosidononymine molsidomine, 8nitroso-Y-acetyl-penicillamine (8ΝΑΡ), 8-nitroso-Y-glutathione (8ΝΟ-ΟΕΠ), Ν-hydroxy-E-arginine, amyl nitrate, linsidomine, linsidomine hydrochloride, (8ΙΝ-1) 8 -nitrozo-M-cysteine, diazenium diolates, (NΟNΟates), 1,5-pentandinitrate, y-arginene, ginseng, jujube fruits, molsidomine, Be-2047, nitrosylated maxysilite derivatives, such as ΝΜΙ-678-11 and ΝΜΙ-937 as described in PCT Application AO 0012075.

4) One or more than one means that modulates or opens potassium channels. Suitable potassium channel opening / modulating agents for use in the invention include nicorandil, chromocalym, levcromacaline, lemacalim, pinacidil, cliazoxide, minoxidil, charibdotoxin, glyburide, 4-aminopyridine, BaC12.

5) One or more dopaminergic agents, preferably apomorphine or a selective Ό ₂ , Ό ₃ or или ₂ / ϋ ₃ agonist, such as pramipexole and ropirinol (as stated in AO-0023056), ΡΝυ95666 (as stated in AO-0040226) .

6) One or more than one vasodilator. Suitable vasodilators for use according to the invention include nimodepine, pinacidil, cyclandelate, isoxssuprin, chlorpromazine, haloperiodol, Weight 15/2739, trazodone.

7) One or more than one thromboxane A2 agonist.

8) One or more than one agent active against ΟΝ8 (central nervous system).

9) One or more of the ergot alkaloids. Suitable ergot alkaloids are described in US Pat. No. 6,037,346, issued March 14, 2000, and include acetergamine, brazergoline, bromerguride, cyanergoline, delorgotril, disulergin, ergonovine maleate, ergotamine tartrate, ethisulergin, lehr

- 10 006154 Gotril, Lysergide, Mezulergin, Metergoline, Metergotamine, Nicergoline, Pergolide, Regergid, Protergurid, Tergurid.

10) One or more than one compound that modulates the action of natriuretic factors, in particular the atrial natriuretic factor (also known as the atrial natriuretic peptide), natriuretic factors B and C type, such as neutral peptidase inhibitors.

11) One or more than one compound that inhibits an angiotensin converting enzyme, such as enapril, and combined inhibitors of an angiotensin converting enzyme and neutral peptidase, such as omapatrilate.

12) One or more than one angiotensin receptor antagonist, such as losartan.

13) One or more than one substrate of β-synthase, such as β-arginine.

14) One or more than one calcium channel blocker, such as amlodipine.

15) One or more than one endothelin receptor antagonist and an endothelin converting enzyme inhibitor.

16) One or more cholesterol lowering agents, such as statins (for example, atorvastatin / Mriog is a trademark) and fibrates.

17) One or more than one antiplatelet or antithrombotic agent, for example, РА, IRA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin-activating factor inhibitors.

18) One or more than one insulin sensitizing agent, such as resulin, and hypoglycemic agents, such as glipizide.

19) b-ΌΟΡΑ or carbidopa.

20) One or more than one acetylcholinesterase inhibitor, such as donezipil.

21) One or more than one steroidal or non-steroidal anti-inflammatory agent.

22) One or more than one modulator of estrogen receptors and / or an estrogen agonist and / or estrogen antagonist, preferably raloxifene, tibolone or lazofoxifen, (-) - cis-6-phenyl-5- [4- (2pyrrolidin-1-yl- ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts, the preparation of which is described in detail in AO 96/21656.

23) One or more than one cannabinoid receptor modulator.

24) One or more than one inhibitor of ΝΡΥ (neuropeptide Υ), in the more particular case an inhibitor of ΝΡΥ1 or ΝΡΥ5, preferably ΝΡΥ1 inhibitor, preferably said ΝΡΥ inhibitors (including ΝΡΥ Υ1 and ΝΡΥ Υ5) having 1C50 less than 100 nM, more preferably less than 50 nM. An analysis for identifying ΝΡΥ inhibitors is presented in AO-A-98/52890 (see page 96, lines 228).

25) One or more than one vasoactive intestinal peptide (νΐΡ), νΐΡ-mimetic, νΐΡ-analogue, in a more particular case, mediated by one or more subtypes of νΐΡ receptors νΡΑί, Ί. VΡΑС or PACAP (a pituitary activating pituitary (ryyot) adenylate cyclase peptide), one or more than one νΐΡ receptor agonist or νΐΡ analog (e.g., Во-125-1553) or νΐΡ fragment, one or more than one α-adrenoceptor antagonist with νΐΡ combination ( e.g. invicorp (ΐηνίεοτρ), aviptadil (ΑνίρΙηάίΙ)).

26) One or more than one agonist of melanocortin receptors or a modulator or agent that enhances the action of melanocortin, such as melanotan ΐΐ, PT-14, PT-141 or the compounds claimed in AO-09964002, AO-00074679, AO-09955679, AO- 00105401, AO-00058361, AO-00114879, AO-00113112, AO-09954358.

27) One or more than one agonist, antagonist or modulator of serotonin receptors, in the more particular case, 5HT1A agonists, antagonists or modulators (including UMB 670), 5HT2A, 5HT2C, 5HTZ and / or 5HT6 receptors, including those described in AO-09902159, AO -00002550 and / or AO-00028993.

28) One or more than one androgen, such as androsterone, dehydroandrosterone, testosterone, androstandion, and synthetic androgen.

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

30) One or more than one modulator of carriers of norepinephrine, dopamine and / or serotonin, such as bupropion, OA-320659.

31) One or more than one agonist and / or modulator of purinergic receptors.

32) One or more than one antagonist of neurokininin (ΝΚ) receptors, including those described in AO-09964008.

33) One or more than one agonist, antagonist or modulator of opioid receptors, preferably OV1 receptor agonists.

34) One or more than one oxytocin / vasopressin receptor agonist or modulator, preferably a selective oxytocin agonist or modulator.

35) One or more than one ΡΌΕ inhibitor, more preferably an inhibitor of ΡΌΕ 2, 3, 4, 5, 7 or 8, preferably a ΡΌΕ2 or ΡΌΕ5 inhibitor, and most preferably a ΡΌΕ5 inhibitor (see the description below), said inhibitors preferably having 1C50 in relation to

- 11 006154 enzymes less than 100 nM. Suitable cMP (cycloguanosine monophosphate) # 5 inhibitors for use in accordance with the present invention include pyrazolo [4,3-6] pyrimidin7-ones disclosed in EP-A-0463756; pyrazolo [4,3-6] pyrimidin-7-ones disclosed in EP-A-0526004; pyrazolo [4,3-6] pyrimidin-7-ones disclosed in published international patent application XVO 93/06104; isomeric pyrazolo [3,4-6] pyrimidin-4-ones disclosed in published international patent application νθ 93/07149; quinazolin-4-ones disclosed in published international patent application νθ 93/12095; pyrido [3,2-6] pyrimidin-4-ones disclosed in published international patent application νθ 94/05661; purin-6-ones disclosed in published international patent application νθ 94/00453; pyrazolo [4,3-6] pyrimidin-7-ones disclosed in published international patent application νθ 98/49166; pyrazolo [4,3-6] pyrimidin-7-ones disclosed in published international patent application νθ 99/54333; pyrazolo [4,3-6] pyrimidin-4-ones disclosed in EP-A-0995751; pyrazolo [4,3-6] pyrimidin-7-ones disclosed in published international patent application νθ 00/24745; pyrazolo [4,3-6] pyrimidin-4-ones disclosed in EP-A-0995750; compounds disclosed in published international patent application νθ 95/19978; compounds disclosed in published international patent application νθ 99/24433 and compounds disclosed in published international patent application νθ 93/07124. Pyrazolo [4,3-6] pyrimidin-7-ones disclosed in published international patent application νθ 01/27112; pyrazolo [4,3-6] pyrimidin-7-ones disclosed in published international patent application νθ 01/27113; compounds disclosed in EP-A-1092718, and compounds disclosed in EP-A-1092719.

In addition, suitable ΡΌΕ5 inhibitors for use in accordance with the present invention include 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro -7H-pyrazolo [4,3-a] pyrimidin-7-one (sildenafil), also known as 1 - [[3- (6,7-dihydro-1methyl-7-oxo-3-propyl-1H-pyrazolo [ 4.3-6] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylppiperazine (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7-pyrazolo [4,3-c1] pyrimidin-7-one (see EP-A-0526004); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) 2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3- 6] pyrimidin-7-one (see νθ 98/49166); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin2-yl) methyl-2,6-dihydro-7H- pyrazolo [4.3-6] pyrimidin-7-one (see νθ 99/54333); (+) - 3-ethyl-5- [5- (4 ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (K) -methylethoxy) pyridin-3-yl] -2-methyl-2,6- dihydro-7Npyrazolo [4,3-6] pyrimidin-7-one, also known as 3-ethyl-5- {5- [4-ethylpiperazin-1-ylsulfonyl] -2 ([(1K) -2-methoxy-1 -methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin7-one (see νθ 99/54333); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-6 ] pyrimidin-7-one, also known as 1- {6-ethoxy-5- [3ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-6] pyrimidin-5-yl] -3-pyridylsulfonyl} 4-ethylpiperazine (see νθ 01/27113, example 8); 5- [2-isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1- (methylpiperidin-4-yl) -2,6-dihydro-7H- pyrazolo [4,3-6] pyrimidin-7-one (see νθ 01/27113, example 15); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3 ethyl 2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7-one (see νθ 01/27113, example 66); 5- (5-acetyl-2propoxy-3-pyridinyl ) -3-ethyl-2- (1 -isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7-one (see νθ 01/27112, example 124) ; 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-6] pyrimidin-7 -one (see νθ 01/27112, example 132); (6H, 12aH) 2,3,6,7,12,12a-hex agidro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ', 1': 6,1] pyrido [3,4-6] indole-1,4dione (1C-351), i.e. the compound of examples 78 and 95 from published international application νθ 95/19978, as well as the compound of Examples 1, 3, 7 and 8; 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1sulfonyl) phenyl] -5 methyl 7-propyl-3H-imidazo [5.1-1] [1,2,4] triazin-4-one (vardenafil), also known as 1 - [[3- (3,4-dihydro-5 -methyl-4-oxo-7-propylimidazo [5,1-1] -az-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperazine, i.e. the compound of Examples 20, 19, 337 and 336 published international application νθ 99/24433; and the compound of Example 11 of published international application νθ 93/07124 (E18A1); and compounds 3 and 14 from Hao1e11a Ό. Ρ, 1. Me6. Siet., 2000, 43, 1257.

Other suitable ΡΌΕ5 inhibitors include 4-bromo-5- (pyridylmethylamino) -6- [3- (4chlorophenyl) propoxy] -3 (2H) pyridazinone; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinosolinyl] -4-piperidinecarboxylic acid monosodium salt; (+) - cis-5,6a, 7,9,9,9a-hexahydro-2- [4 (trifluoromethyl) phenylmethyl-5-methylcyclopent-4,5] imidazo [2,1-b] purin-4 (3H )-it; furazlocilin, cis2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] -imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-c 1) pyrimidin-7-one; 1 - [4 [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid monosodium salt; Ρya ^ tar ^ ο ^ esΐ8 ΐο.4516 (C1aho Vе11состе); Ρya ^ tar ^ ο ^ esΐ8 Νο. 5051 (Woweg); Ρya ^ tar ^ ο ^ esΐ8 Νο. 5064 (Ι <ΛΌ \ ν; · ι Nakko; see νθ 96/26940); Ρya ^ tar ^ ο ^ esΐ8 Νο. 5069 (8 season Ρ1οιΐβ1ι); CE-196960 (ΟΗχο Vе11соте); Ε-8010 and E-4010 (E18a1); Wow-38-3045 & 38-9456 (Woweg) and 8sy-51866.

- 12 006154

For the treatment of Ε8Ό of the compound of the invention [in particular (28) -2- ([1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22)] you can preferably combined with one or more than one active ingredient selected from the list:

a) ΡΌΕ5 inhibitor, more preferably 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3-c1] pyrimidin-7-one (sildenafil), (6K, 12aK) -2.3, 6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ' 1 ': 6.1] pyrido [3,4-b] indole-1,4-dione (1C-351); 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1- [1,2,4] triazine- 4-one (vardenafil), 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H- pyrazolo [4,3-c 1] pyrimidin-7-one and 5- (5-acetyl-2-butoxy-3pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro -7H-pyrazolo [4,3-o] pyrimidin-7-one and their pharmaceutically acceptable salts;

b) ΝΡΥ Υ1 inhibitor;

c) a dopamine agonist such as apomorphine or a selective Ό ₂ , Ό ₃ or Ό ₂ / ϋ ₃ agonist such as pramipexole and ropirinol;

g) an agonist or modulator of melanocortin receptors or a modulator or enhancer of action of melanocortin, preferably melanotan II, PT-14, PT-141;

d) an agonist, antagonist or modulator of 5HT2C;

e) an estrogen receptor modulator, estrogen agonists and / or estrogen antagonists, preferably raloxifene, tibolone or lazofoxifen;

g) androgen, such as androsterone, dehydroandrosterone, testosterone, androstandion and synthetic androgen; and

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

For the treatment of the ΜΕΌ compound of the invention [in particular (28) -2- ([1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (example 22)] can preferably combined with one or more than one active ingredient selected from the list:

a) ΡΌΕ5 inhibitor, more preferably 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3- (1] pyrimidin-7-one (sildenafil), (6K, 12aK) -2.3, 6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ', 1': 6,1] pyrido [3,4-b] indole-1,4-dione (1 C-3 51); 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1- sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-1] [1,2,4] triazin-4-one (vardenafil), 5- [2-ethoxy-5- (4 -ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3ethyl-2- [2-methoxyethyl] -2, b-dihydro-7H-pyrazolo [4,3-c1] pyrimidin-7-one and 5- (5 -acetyl-2-butoxy-3pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl ) -2,6-dihydro-7H-pyrazolo [4,3-0] pyrimidin-7-one and their pharmaceutically acceptable salts;

b) ΝΡΥΥ1 inhibitor;

c) a dopamine agonist (preferably apomorphine) or a selective Ό2, Oz or Όζ / ϋδ agonist such as pramipexole and ropirinol;

g) an agonist or modulator of melanocortin receptors or an enhancer of action of melanocortin, preferably melanotan II, PT-14, PT-141; and

d) an agonist, antagonist or modulator of 5HT2C.

Particularly preferred combinations for treating Ε8Ό are (25) -2 - {[1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22) and one or more than one active ingredient selected from the list:

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

(6K, 12aK) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ', 1': 6,1] pyrido [3,4 B] indole-1,4-dione (1C-351);

2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-1] [1,2,4] triazin-4-one (vardenafil);

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

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

apomorphine;

melanotan II;

RT-141;

lazofoxifene;

raloxifene;

tibolone;

androgen, such as androsterone, dehydroandrosterone, testosterone, androstandion, and synthetic androgen; and

- 13 006154 estrogen, such as estradiol, estrone, estriol, and synthetic estrogen, such as estrogen benzoate.

Particularly preferred combinations for treating ΜΕΌ are (28) -2 - {[1 - ({[3- (4chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22) and one or more than one active ingredient selected from the list:

5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7-pyrazolo [4,3-c 1] pyrimidin-7- he (sildenafil);

(6K, 12aK) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ', 1': 6,1] pyrido [3,4 B] indole-1,4-dione (1C-351);

2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-1] [1,2 , 4] triazin-4-one (vardenafil);

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

5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3b | pyrimidin-7-one;

apomorphine;

melanotan II; and RT-141.

If a combination of active agents is administered, then they can be administered simultaneously, separately or sequentially.

The compounds of the invention can be administered on their own, but in the treatment of humans, they are generally administered in a mixture with a suitable pharmaceutical excipient, diluent or carrier selected based on the intended route of administration and traditional pharmaceutical practice.

For example, the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), vaginal suppositories, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate, delayed, modified, extended, repeated, controlled release, or for pulsatile delivery. The compounds of the invention can also be administered via rapidly disintegrating or rapidly dissolving dosage forms.

Modified release and pulsatile release dosage forms may contain excipients, such as those described in detail for immediate release dosage forms, together with additional excipients that act as release rate modifiers and are coated and / or incorporated into the core of the form. Release rate modifiers include, but are not limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammoniomethacrylate, castor oil, sodium hydrogen carbonate, castor oil, sodium phosphate acids and mixtures thereof. The modified release and pulsatile release dosage forms may contain one or a combination of excipients that modify the rate of release. Release rate modifying excipients may be present both within the dosage form, that is, inside the matrix, and / or on the dosage form, that is, on the surface or shell.

Rapidly disintegrating or dissolving dosage units (ΕΌΌΕκ, Hak! 618regktd og b188o1u1id in the Gogti1iopk box) may contain the following ingredients: aspartame, potassium acesulfame, citric acid, croscarmellose sodium, crospovidone, diacorbic acid, ethylcellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose nitrocellulose cellulose cellulose cellulose cellulose nitrocellulose cellulose gel , methyl methacrylate, peppermint flavoring, polyethylene glycol, highly dispersed silicon dioxide, silicon dioxide, sodium glycolate starch, sodium stearyl fumarate, sorbitol, xylitol. The terms disintegrating or dissolving are used here to describe that ΕΌΌΕκ depends on the solubility of the drug used, that is, when the drug is insoluble, a rapidly disintegrating dosage form can be prepared, and when the drug is soluble, a rapidly dissolving form can be prepared.

The compositions of the invention can be administered by direct injection. Compositions can be prepared in the form of a preparation for parenteral administration, administration through the mucous membranes, intramuscular, intravenous, subcutaneous, ophthalmic, intraocular and percutaneous administration. Depending on the need, the agent can be administered at a dose of from 0.01 to 30 mg / kg body weight, for example from 0.1 to 10 mg / kg, more preferably from 0.1 to 1 mg / kg body weight.

The term administered includes delivery using viral and non-viral techniques. Viral delivery mechanisms include, but are not limited to, adenoviral vectors, adeno-associated viral (AAU, abepoaaaa, U1a1) vectors, herpes virus-based vectors, retroviral vectors, lentiviral vectors and baculovirus vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic fascial amphiphiles (CEAc, sycopc Hac1a1 atrPyr), and combinations thereof. Ways of such

- 14 006154 delivery mechanisms include, but are not limited to, the mucous, nasal, oral, parenteral, gastrointestinal, local, or sublingual routes.

In addition or alternatively, the compositions (or their constituent parts) of the present invention can be administered by direct injection. In addition or alternatively, the compositions (or their constituent parts) of the present invention can be administered topically (preferably in the genitals). In addition or alternatively, the compositions (or their constituent parts) of the present invention can be administered by inhalation. In addition or alternatively, the compositions (or their constituent parts) of the present invention can also be administered in one or more than one of the following ways: through the mucous membrane, for example in the form of a nasal spray or aerosol for inhalation or in the form of a swallowed solution, for example by oral route, or parenteral route, where delivery is by injection, such as, for example, rectal, ophthalmic (including administration to the vitreous body or into the chamber), nasal, local (including buccal flax and sublingual), intrauterine, vaginal or parenteral (including subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracranial, intratracheal and epidural), percutaneous, intraperitoneal, intracranial, intramuscular, intramuscular, intracranial, intracerebral, subcutaneous, percutaneous or intramuscular) route.

As an example, the pharmaceutical compositions of the invention can be administered in accordance with a regimen comprising from 1 to 10 times a day, for example once or twice a day. The value of a specific dose and dosage frequency for an individual patient can be changed and they will depend on many factors, including the activity of the particular compound used, metabolic stability and duration of action of this compound, age, body weight, general health, gender, diet, method and time of administration , the rate of excretion, the combination of drugs, the severity of a particular condition and the individual therapy used.

Thus, the term is administered includes, but is not limited to, delivery through the mucous membranes, for example in the form of a nasal spray or aerosol for inhalation or a swallowed solution; parenteral route, when delivery is via an injectable form, such as, for example, intravenous, intramuscular or subcutaneous.

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

Solid compositions of a similar type can also be used as fillers in gelatin capsules. Preferred excipients in this case include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the compounds of the invention can be combined with various sweetening or flavoring agents, coloring agents or colorants, with emulating and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The compounds of the invention can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intratracheally, intraventricularly, intrauterine, intrathoracic, intracranial, intramuscular or subcutaneous, or they can be administered using an infusion technique. In addition, they can be administered in the form of an implant. For such parenteral administration, they are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. Aqueous solutions should be suitably buffered (preferably up to a pH of 3 to 9), if necessary. The preparation of suitable parenteral preparations under sterile conditions is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. Parenteral preparations can be formulated for immediate, delayed, modified, delayed, repeated, controlled release or pulsatile delivery.

The following dosage levels and other dosage levels in this description are for the average person having a weight in the range of from about 65 to 70 kg. One of skill in the art will easily determine the dosage levels required for a subject whose mass is outside these limits, such as children and the elderly.

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

Thus, for example, tablets or capsules of the compounds of the invention or their salts or solvates thereof may contain from 5 to 1000 mg, for example from 5 to 500 mg of the active compound for administration

- 15 006154 one or two or more times, as the case may be. In any case, the attending physician will determine the actual dose, which will be most suitable for each individual patient and will vary depending on the age, weight and reaction of a particular patient. The above dosages are examples of the average case. Of course, there may be individual cases where higher or lower doses are desired, and all this is within the scope of this invention. It will also be apparent to one skilled in the art that in the treatment of certain conditions (including E8I and ΜΕΌ), the compounds of the invention can be taken in a single dose based on how much is needed (i.e. how much is needed or desired).

The compounds of the invention can also be administered intranasally or by inhalation and are conventionally formulated as a dry powder inhaler or aerosol spray obtained from a pressurized container, pump, spray or nebulizer using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, such as hydrofluoroalkane 1,1,2-tetrafluoroethane (ΗΡΑ 134A [trademark]) or 1,1,1,2,3,3,3-heptafluoropropane (ΗΡΑ 227ΕΑ [trademark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, for example, by using a mixture of ethanol and a propellant as a solvent, which may further comprise a lubricant, for example sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator can be made containing a powder mixture of the compounds of the invention and a suitable powder base such as lactose or starch.

The aerosol or dry powder preparations are preferably formulated so that each metered dose or injection contains from 1 to 50 mg of a compound of the invention for delivery to a patient. The total daily dose with an aerosol will be in the range of 1 to 50 mg, which can be administered in a single dose or, usually, in divided doses throughout the day.

Alternatively, the compounds of the invention may be administered in the form of a suppository or pessary, or they may be applied topically (preferably on the genitals) in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder for dusting. The compounds of the invention can also be applied to the skin. The compounds of the invention can also be administered transdermally, for example using a skin patch. They can also be administered by ophthalmic, pulmonary or rectal routes.

For ophthalmic use, the compounds can be prepared in the form of micronized suspensions in isotonic, adjusted pH, sterile physiological saline, or, preferably, in the form of solutions in isotonic, adjusted pH, sterile physiological saline, possibly in combination with a preservative, such as benzalkonium chloride. Alternatively, they can be prepared in the form of an ointment, such as liquid paraffin.

For topical application on the skin (preferably on the genitals), the compounds of the invention can be prepared in the form of a suitable ointment containing the active compound, suspended or dissolved, for example, in a mixture with one or more than one of the following: mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifiable wax and water. Alternatively, they can be prepared in the form of a suitable lotion or cream, suspended or dissolved, for example, in a mixture of one or more than one of the following components: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, tseterilovy alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the invention can also be used in combination with cyclodextrin. It is known that cyclodextrins form inclusion complexes with and without inclusion with drug molecules. The formation of the drug-cyclodextrin complex can alter the solubility, dissolution rate, bioavailability and / or stability of the drug molecule. Drug-cyclodextrin complexes are typically used for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, for example, as a carrier, diluent or solubilizer. The most commonly used are alpha, beta, and gamma cyclodextrins, corresponding examples are described in νθ-Α-91/11172, \ νϋ-Α-94/02518 and \ νϋ-Α98 / 55148.

In a preferred embodiment, the compounds of the invention are delivered systemically (e.g., orally, buccally or sublingually), more preferably orally. Preferably, such systemic (more preferably oral) administration is used to treat female sexual dysfunction, preferably Ε8ΑΌ.

Thus, in a particularly preferred embodiment, the use of the compounds of the invention in the manufacture of a systemically delivered (preferably orally delivered) drug for the treatment or prevention of E8I, more preferably более8ΑΌ, is provided.

- 16 006154

Preferred oral formulations are immediate release tablets or rapidly disintegrating or dissolving unit dosage formulations (ΕΌΌΕκ, Hak! Fräggregg άίκκο1νίη§ in the case of Gotshkshopk).

In yet another preferred embodiment, the compounds of the invention are administered topically, preferably directly into the female genitalia, mainly into the vagina.

Since ΝΕΡ is present throughout the body, it is completely unexpected that the compounds of the invention can be administered systemically and achieve a therapeutic response in the female genitalia without causing unacceptable (harmful) side effects. In EP 1097719-A1 and the animal model in the description below, the authors showed that NΕΡ inhibitors introduced into the rabbit model (ίη νίνο) systemically increase blood flow in the genitals during sexual arousal (simulated stimulation of the pelvic nerve) without harmful effects on cardiovascular parameters such as the induction of significant hypotension or hypertension.

Preferably, the compounds of the invention are administered to treat a Ε8Ό sexually stimulated patient (sexual stimulation includes, as the authors suggest, visual, auditory or tactile stimulation). Stimulation may occur before, after, or during said administration.

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

Thus, in a preferred embodiment, there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of Ε8Ό in a stimulated patient.

For veterinary use, the compound of the invention is administered in the form of a suitable acceptable preparation in accordance with normal veterinary practice, and the surgeon-veterinarian determines the dosage regimen and route of administration that will be most suitable for a particular animal.

Examples of the following preparations are illustrative only and are not intended to limit the scope of the invention. Active ingredient means a compound of the invention.

Preparation 1. A tablet is made using the following ingredients:

mass / mg Active ingredient 250 Microcrystalline cellulose 400 Fine silica 10 Stearic acid 5 Total 665

The components are mixed and compressed to form tablets.

Drug 2. An intravenous drug can be obtained as follows:

Active ingredient 100 mg

Isotonic saline 1000 ml

Typical formulations suitable for administering the compounds of the invention locally on the genitals are as follows:

The drug 3. Spray.

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

Preparation 4. Foam.

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 Dyke perfume (να01, pure).

The drug 5. Gel.

Active ingredient, BP Docusate Sodium (British Pharmacopoeia), BP Isopropyl Alcohol, Propylene Glycol, Sodium Hydroxide, 934P Carbomer, Benzoic Acid and Purified Water.

Preparation 6. Cream.

Active ingredient, benzoic acid, cetyl alcohol, lavender, compound 13091, methyl paraben, propyl paraben, propylene glycol, sodium carboxymethyl cellulose, sodium lauryl sulfate, stearic acid, triethanolamine, glacial acetic acid, castor oil, potassium hydroxide, sorbic acid.

The drug 7. Pessary.

Active ingredient, ketomacrogol 1000 BP, citric acid, ΡΕΟ (polyethylene glycol) 1500 and 1000 and purified water.

This invention further includes:

1) a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable excipient, diluent or carrier;

2) a compound of the invention for use as a medicine;

- 17 006154

3) the use of a compound of the invention as a medicine for treating or preventing a condition in which a beneficial response to therapy can be obtained by inhibiting a neutral endopeptidase;

4) the use of a compound of the invention as a medicament for treating or preventing a disorder in the form of hypoactive sexual desire, a violation of sexual arousal, a violation of orgasm or a sexual pain disorder, preferably a violation of sexual arousal, an orgasm or a sexual pain disorder, more preferably a violation of sexual arousal;

5) a method of treating Ε8Ό or ΜΕΌ in mammals, comprising treating said mammal with an effective amount of a compound of the invention;

6) a Ε8Ό or ΜΕΌ treating pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable excipient, diluent or carrier;

7) a compound of the invention for use in the treatment of Ε8Ε or ΜΕΌ;

8) the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of Ε8Ό or ΜΕΌ.

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

Arbase1® - filtering agent;

Bg - wide;

Boc is tert-butoxycarbonyl;

СО1 - carbonyldiimidazole;

δ is the chemical shift;

- doublet;

Δ is the heat of the ESA dicyclohexylcarbodiimide;

OSM - dichloromethane;

ΌΜΑ - dimethylacetamide;

ΏΜΕ Ν, Ν - dimethylformamide;

ΌΜ8Θ - dimethyl sulfoxide;

E8 + - positive scan with electrospray ionization;

E8- - negative scanning with electrospray ionization;

Note - an example;

h - hours;

NEW! - 1-hydroxybenzotriazole;

HPLC - high pressure liquid chromatography;

t / ζ is the peak of the mass spectrum;

min - minutes;

Μ8 is the mass spectrum;

NMR - nuclear magnetic resonance;

Prev - predecessor;

Prep. an example is a preparatory example;

with. | - quartet;

k is a singlet;

ΐ - triplet;

Τί trifluoromethanesulfonyl;

TEM - trifluoroacetic acid;

TUE - tetrahydrofuran;

TLC - thin layer chromatography;

T8 + - positive scan with ionization by thermal spray;

\ ν? ΧΌΙ - 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

The ¹ H spectra ^of nuclear magnetic resonance (NMR) in all cases were consistent with the proposed structures. Typical chemical shifts (δ) are given in parts per million down the field from tetramethylsilane, using the corresponding abbreviations to indicate the main peaks, for example, k - singlet; 6 - doublet; ΐ - triplet; with. | - quartet; t - multiplet; Bg is wide.

For traditional solvents, the following abbreviations were used: СES1 ₃ - deuteriochloroform; ΌΜ80 - dimethyl sulfoxide. Abbreviation psi inch means pounds per square inch, and ΕΚΜ8 means low-resolution mass spectrometry (1 \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ 's When thin layer chromatography (TLC) was used, this refers to TLC on 60 E254 silica gel plates, and T2 is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. Melting points were determined using Regct E1teg E8C7 at a heating rate of 20 ° C / min.

- 18 006154

The powder X-ray diffraction pattern (ΡΧΚΏ, ^ бег Х га X-gau bijasop paPegp) was determined using 8ΙΕΜΕΝ8 1) 5000 x-ray powder diffractometer with automatic sample change, theta-goniometer, automatic beam divergence slits, secondary monochromator and scintillation counter. A sample was prepared for analysis by placing the powder on a sample holder from a silicon wafer. The sample was rotated by irradiating CuK-alpha1 with X-ray radiation (wavelength = 1.5406 A) with an X-ray tube operating at 40 kV / 40 mA. The analysis was carried out on a goniometer operating in a step-by-step scanning mode, set to a 5-second count at 0.02 ° step for an interval of two theta from 3 to 40 °. In the results tables, the 2-theta angle refers to the interplanar spacing in the crystal, and the intensity is given as a percentage of the largest peak (Ι / Ι1).

It is obvious to an experienced crystallographer that the relative intensities of the peaks can vary due to a number of factors, such as the effect of the orientation of the crystals in the x-ray beam or the purity of the substance being analyzed or the degree of crystallinity of the sample. The positions of the peaks may vary along the height of the sample, but the positions of the peaks remain essentially the same as shown in the table. In addition, measurements using different wavelengths can lead to shear changes in accordance with the Bragg equation −ηλ = 2b δϊηθ. Such variations obtained using other wavelengths are included in the scope of the present invention.

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

Hydrogen chloride gas was passed through a solution of tert-butyl ether from preparation Example 1 (302 mg, 0.72 mmol) in dichloromethane (5 ml) at 0 ° C 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 (233 mg, 0.6 mmol, 82%);

¹ H NMR (SPS13 400 MHz) δ: 1.4-1.55 (t, 2H), 1.6-1.75 (t, 6H), 1.75-1.85 (t, 2H), 2.4-2.5 (t, 1H), 2.6 (ΐ, 2H), 3.2 (h, 3H), 3.2-3.3 (t, 2H), 3.4 (ΐ, 2H), 3.8 (h, 3H), 5.9 (ΐ, 1H), 6.8 (b, 2H), 7.1 (b , 2H); LKM8 (low resolution mass spectrum): t / ζ 390 (M-H ⁺ ); and NKM8 (high resolution mass spectrum) t / ζ 392.2430 (for C2211 ₃₃ Ν (.) ₅ , 392, 2432 are required).

The following compounds of formula Ι (see table. 1) can be obtained by methods similar to the methods of example 1 from tert-butyl ether of the specified precursor

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Table 1

Note Prev P ¹ -Χ-Υ Data 2 Prep. Example 2 methoxyethyl me Ή NMR (СОС1 ₃ 400 MHz) δ: 1.1 (1, ЗН), 1.5 (t, 8Н), 1.9 (t, 4Н), 2.0 (t, 2Н), 2.5 (t, ЗН), 3.2 (з, ЗН) ), 3.3 (t, 2H), 3.8 (ί, 8H), 4.0 (5, 1H), 5.6 (ά, 1H), 6.8 (ά, 2H), 7.1 (ά, 2H). Ι-ΡΜ8: t / ζ 404 (Man. United 3 Prep. Example 3 methoxyethyl ^C1 X) Me Ή NMR (ССО13 400 MHz) δ \ 1.4 (s1, 3Н), 1.6 (t, 8Н), 2.0 (t, 4Н), 2.1 (άά, 1Н), 2.5 (t, 1Н), 3.2 (ά, ЗН) 3.4 (t, 2H), 4.0 (t, 2H), 4.4 (bt, 1H), 6.2 (t, 1H), 6.9 (t, 2H), 7.2 (1, 1H), 7.4 (t, 1H). Ι_ΡΜδ: t / ζ 410 (M-H ⁺ ). NRM8 t / ζ 412.1885 (for Ο ₂₁ Η ₃₀ ΝΟ ₅ ΟΙ 412.1813 is required) 4 Prep. example 4 methoxyethyl Ή NMR (СОС1 ₃ 400 MHz) δ: 1.5 (t, 2Н), 1.8 (1, 2Н), 1.9 (t, 2Н), 2.0 (t, 2Н), 2.4 (t, 1Н) ), 3.2 (8, 4H), 3.3 (1, 2H), 6.0 (b8, 1H), 6.9 (1, 2H), 7.1 (1, 2H), 10.4 (b3, 1H). LMP8: t / ζ 379 (MH ⁺ ). 5 Prep. example 5 methoxyethyl Ή NMR (СОС1 ₃ 400 MHz) δ: 1.41.6 (t, UN), 1.8-2.0 (t, 4Н), 2.4 (t, 1Н), 2.6 (1, 2Н), 3.2 (s, 4Н), 3.3 (ί, 2H), 3.3 (ί, 2H), 5.9 (b3, 1H), 7.1 (t, 3H), 7.2 (1, 2H), 10.4 (b3, 1H). 1 PM8: t / ζ 374 (M-H ⁺ ). 6 Prep. example 6 methoxyethyl ^ 0 Ή NMR (СОС1 ₃ 400 MHz) δ: 1.51.6 (t, UN), 1.8 (t, ЗН), 1.9 (t, 1Н), 2.0 (ς, 1Н), 2.5 (t, 1Н), 2.6 (ί , 2H), 3.2 (t, 4H), 3.4 (i, 2H), 5.9 (b3, 1H), 7.1 (6, 3H), 7.3 (t, 2H). LRMZ: t / ζ 362 (M + H ⁺ ). 7 Prep. example 7 methoxyethyl ^ σ ^0Η Ή NMR (СОС1 ₃ 400 MHz) δ: 1.6 (t, 2Н), 1.8 (t, 2Н), 2.0 (t, 2Н), 2.5 (t, 6Н), 3.2 (h, ЗН), 3.25 (t, 2Н) ), 3.4 (t, 2H), 5.7 (b3, 1H), 6.7 (s1, 2H), 7.0 (s1, 2H). LRMZ: t / ζ 376 (M-H ⁺ ). NRM8 t / ζ 378.2288 (for 0 ₂₁ Η ₃ ιΝ0 ₅ 378.2275 is required) 8 Prep. example 8 methoxyethyl Ή NMR (COC1 ₃ 400 MHz) δ: 1.52.1 (t, 14H), 2.5 (t, 1H), 2.7 (t, 2H), 3.2 (s, 2H), 3.3 (t, 2H), 3.4 (t , 2H), 6.8 (3, 1H), 7.25 (ά, 2H), 7.5 (ά, 2H). (_RM8: t / ζ 428 (MH ⁺ ). NRM8 t / ζ 430.2206 (430.2200 is required for CrgNeOiOdeEe)

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Note Prev K ¹ -Χ-Υ Data nine Prep. Example 9 methoxyethyl ¹ H NMR (COS13 400 MHz) <5: 1.2 (t, 3H), 1.6 (t, 8H), 1.9 (t, 4H), 2.0 (t, 2H), 2.5 (t, 1H), 2.6 (t, 4H), 3.2 (8, 3H), 3.3 (t, 2H), 3.4 (t, 2H), 5.9 (b3, 1H), 7.0 (t, 4H). Ι.ΚΜ8: t / ζ 388 (M-H ⁺ ). NRM8 t / ζ 390.2639 (390.2643 required for С23Нз ₅ МО ₄ ) 10 Prep. example 10 methoxyethyl Me ^ r-uOMe 'NMR (ССО1 ₃ 400 MHz) 6: 1.5-1.85 (t, 11Н), 2.0-2.2 (t, ЗН), 2.3 (5, ЗН), 2.5 (t, 1Н), 2.6 (ΐ, 2Н), 3.25 (5, 1H), 3.3 (δ, 3H), 3.35-3.5 (t, 3H), 3.8 (s, 3H), 6.7-6.8 (t, 2H), 7.1 (ά, 1H), 7.6 (s, 1H) ) Melting point 148-150 ° C. 1_KMZ: t / ζ 406 (M + H ⁺ ). HBM8 t / ζ 406.2597 (406.2588 is required for СГЭНзбИОб). Analit. Found: C, 67.71; H 8.74; N, 3.41. For CrzidIz. 0.15 H ₂ O requires C 67.67; H, 8.72; N 3.43%. eleven Prep. example 11 methoxyethyl ¹ H NMR (СОС1з 400 MHz) 6: 0.9 (t, 2H), 1.3 (t. 2H), 1.6 (t, 8H), 1.8 (t, 3H), 1.9 (t, 1H), 2.0 (άά, 1H) ), 2.4 (t, 1H), 2.6 (1, 2H), 3.2 (t, 2H), 3.3 (t, 5H), 3.4 (t, 1H), 4.5 (1, 2H), 5.9 (b3, 1H) 6.7 (ά, 1H), 6.9 (ά, 1H), 7.0 (b3, 1H). 1_NM8: t / ζ 404 (M + H ⁺ ). NYM8 t / ζ 404.2434 (for 0 ₂₃ Η ₃₄ Ν05 404.2431 is required). 12 Prep. example 12 methoxyethyl "And ¹ he ¹ H NMR (ΟϋΟΙ ₃₄₀₀ MHz) 6: 1.51.6 (m, SH), 1.6-1.7 (m, 6H), 1.71.85 (m, SH), 1.9-2.05 (m, 4H), 2.5-2.6 (t, 1H), 2.7 (1, 2H), 3.13.2 (t, 1H), 3.2-3.3 (1, 1H), 3.3 (8, 3H), 3.4-3.5 (t, 2H), 6.6 (b3 , 1H), 6.7 (ά, 1H), 6.8 (1, 1H), 7.0-7.1 (t, 2H). LAMZ: t / ζ 376 (M + H ⁺ ). thirteen Prep. example 13 methoxyethyl ¹ H NMR (COS13 400 MHz) 0: 1.51.75 (t, 9H), 1.8-2.0 (t, 5H), 2.1 (άά, 1H), 2.5-2.6 (t, 1H), 2.6 (1, 2H) 3.25 (h, 3H), 3.25-3.3 (t, 2H), 3.35-3.4 (t, 2H), 5.9 (b3, 1H), 7.1 (t, 1H), 7.15-7.25 (t, 3H). LKMZ: t / ζ 396 (M + H ⁺ ). NKMZ t / ζ 396.1949 (for Ο21Η ₃₁ ΝΟ ₄ ΟΙ 396.1936 is required).

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Note Prev K ¹ -Χ-Υ Data 14 Prep. example 14 methoxyethyl oe ¹ H NMR (COS13 400 MHz) δ: 1.51.75 (t, 9H), 1.75-2.0 (t, 5H), 2.1 (άά, 1H), 2.45-2.55 (t, 1H), 2.75 (ΐ, 2H) 3.25 (e, 3H), 3.20-3.3 (t, 2H), 3.35-3.4 (t, 2H), 6.1 (b3, 1H), 7.1-7.25 (t, 4H). Ι.ΚΜ8: t / ζ 396 (M + H ⁺ ). HPM8 t / ζ 396.1946 (for 02ιΗ ₃ ιΝ0 ₄ ΟΙ 396.1936 is required). fifteen Prep. example 15 methoxyethyl ¹ H NMR (COS13 400 MHz) δ: 1.51.75 (t, 9H), 1.8-1.95 (t, 5H), 2.05 (άά, 1H), 2.4-2.5 (t, 1H), 2.6 (ί, 2H) 3.25 (e, 3H), 3.20-3.3 (t, 2H), 3.35-3.4 (t, 2H), 6.1 (b3, 1H), 7.1 (t, 2H), 7.2 (t, 2H). LAMZ: t / ζ 396 (M + H ⁺ ). NMN8 t / ζ 396.1943 (396.1936 is required for С21Н ₃₁ НО ₄ С1). sixteen Prep. example 16 (K) -Rg χ_σ ^{0Μβ 1} H NMR (СОС1 ₃ 400 MHz) δ: 0.8 (1, ЗН), 1.2-1.95 (t, 16Н), 2.3 (t, 1Н), 2.55 (t, 2Н), 3.25 (t, 2Н), 3.7 ( 8, ZN), 5.7 (8, 1H), 6.8 (ά, 2H), 7.1 (ά, 2H). Lamb: t / ζ 374 (M-H). NKM8 t / ζ 376.2485 (for 0 ₂₂ Η ₃₅ ΝΟ ₄ , 376.2482 is required). 17 Prep. example 17 (K) -Me ¹ H NMR (СОС1 ₃ 400 MHz) δ: 1.18 (ά, ЗН), 1.45-1.96 (t, 11Н), 2.08 (t, 1Н), 2.41 (t, 1Н), 2.59 (1, 2Н), 3.3 ( ί, 2H), 3.8 (s, 3H), 5.67 (t, 1H), 6.82 (ά, 2H), 7.08 (ά, 2H). 1 PM8: t / ζ 348 (M + H ⁺ ). eighteen Prep. example 18 N ¹ H NMR (СОС1 ₃ 400 MHz) δ: 1.47 (t, 2Н), 1.73 (t, 4Н), 1.77-2.00 (t, 6Н), 2.31 (t, 2Н), 2.60 (1, 2Н), 3.29 ( t, 2H), 3.8 (s, 3H), 5.57 (t, 1H), 6.82 (ά, 2H), 7.11 (ά, 2H). Ι.ΚΜ8: t / ζ 334 (M + H ⁺ ). nineteen Prep. example 19 n H NMR (СОС1 ₃ 400 MHz) δ: 1.47 (t, 2Н), 1.73 (t, 4Н), 1.77-2.00 (t, 6Н), 2.31 (t, 2Н), 2.60 (1, 2Н), 3.29 (t , 2H), 3.8 (s, 3H), 5.57 (t, 1H), 6.82 (ά, 2H), 7.11 (ά, 2H). BRM8: t / ζ 338 (M + H ⁺ ). twenty Prep. example 20 n H NMR (СОС1 ₃ 400 MHz) δ: 1.401.98 (t, 12Н), 2.37 (ί, 2Н), 2.58 (ί, 2Н), 3.23 (i, 2Н), 5.57 (t, 1Н), 7.07 (ά , 2H), 7.20 (ά, 2H). Ι-ΚΜ8: t / ζ 338 (M + H ⁺ ).

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Note Prev K ¹ -Χ-Υ Data 21 Prep. example 21 N ¹ H NMR (СОС1з 400 MHz) δ: 1.46 (t, 2Н), 1.66 (t, 4Н), 1.73-1.98 (t, 6Н), 2.29 (ΐ, 2Н), 2.58 (ΐ, 2Н), 3.17 (4 , 2H), 3.26 (ς, 2H), 4.53 (4, 2H), 6.59 (t, 1H), 6.70 (ά, 1H), 6.90 (ά, 1H), 7.01 (5, 1H). Melting point 94.5-97.0 ° C. LMPb: t / ζ 346 (M + H ⁺ ). Analytic Found: C, 68.50; H 7.78; N, 4.01. For Ο ₂₀ Η ₂₇ ΝΟ ₄ 0.25 N ₂ O, C 68.65 is required; H 7.92; N 4.00%. 22 Prep. example 22 (8) methoxyethyl ¹ H NMR (СОС1 ₃ 400 MHz) δ: 1.51.7 (t, 9Н), 1.75-1.95 (t, 5Н), 2.05 (άά, 1Н), 2.4-2.5 (t, 1Н), 2.6 (4, 2Н) ), 3.25 (8, 3H), 3.20-3.3 (t, 2H), 3.35-3.4 (t, 2H), 6.1 (b3, 1H), 7.1 (t, 2H), 7.2 (t, 2H). Melting point 75-77 ° C. 1 NM8: t / ζ 394 (M-H). 23 Prep. example 23 (8) methoxyethyl ¹ H NMR (SOC13 400 MHz) δ: 1.42.1 (t, 14H), 2.45 (t, 1H), 2.55 (t, 2H), 3.2 (s, 3H), 3.25 (t, 2H), 3.35 (t , 2H), 5.9 (b3, 1H), 6.9 (t, 2H), 7.1 (t, 2H), 10.4 (b3, 1H). 1_RM8: t / ζ 378 (M-H ⁺ ). [σ] ο + 0.4 (E4OH, s1). NKM8 t / ζ 380.2232 (380.2225 is required for C ₂₂ H ₃₃ MO ₅ ). Analit. Found: C, 63.73; H 7.92; N, 4.11. For 0 ₂ ιΗ ₃₀ ΝΟ ₄ Ρ 0.67 H ₂ O, C 63.62 is required; H, 8.04; N 3.82%. 24 Prep. example 24 (8) methoxyethyl 'H NMR (СОС1 ₃ 400 MHz) δ: 1.41.70 (t, 8Н), 1.80-2.05 (t, 6Н), 2.4-2.5 (t, 1Н), 2.6 (4, 2Н), 3.2 (з, ЗН) ), 3.2-3.3 (t, 2H), 3.4 (4, 2H), 3.8 (8, 3H), 5.8 (b3, 1H), 6.8 (t, 2H), 7.1 (t, 2H). LRMZ: t / ζ 390 (M-H). [σ] _ο -0.01 (E4OH, s 1.87). NYM8 t / ζ 392.2425 (392.2432 required for 0 ₂₂ Η ₃₃ Ν0 ₅ ). 25 Prep. example 25 (8) methoxyethyl ¹ H NMR (СОС1 ₃ 400 MHz) δ '. 1.412.06 (t, 14H), 2.43-2.60 (t, 2H), 2.57 (4, 2H), 3.18 (4, 2H), 3.33 (s, 3H), 3.24-3.4 (t, 4H), 4.53 ( 4, 2H), 5.80 (b3, 1H), 6.66 (s, 1H), 6.88 (s, 1H), 7.0 (s, 1H). LAMZ: t / ζ 402 (M-H '). [σ] ₀ 0.00 (E4OH, s 0.93). Analit. Found: C, 66.85; H, 8.24; N, 3.35. For Ο ₂ 5Η ₃₅ ΝΟ ₅ 0.5 N ₂ O, C 66.97 is required; H, 8.31; N 3.40%.

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Note Prev K ¹ -Χ-Υ Data 26 Prep. example 26 N ¹ H NMR (COS1 ₃ 400 MHz) δ: 1.131.98 (t, UN), 2.16-2.28 (t, 4H), 2.70-3.03 (t, 4H), 5.60 (L3, 1H), 6.88 (O, 1H ), 7.40 (ά, 1H), 7.57 (ά, 1H), 8.08 (ά, 1H), 8.17 (6, 1H), 8.86 (ά, 1H). Ι_ΚΜδ: Εδ 't / ζ 353 (M-H). 27 Prep. example 27 methoxyethyl oe H NMR (СОС1 ₃ 400 MHz) δ: 1.20 (t, 2Н), 1.60 (t, 8Н), 1.80 (1, 2Н), 1.90 (t, ЗН), 2.50 (t, 1Н), 2.0 (ί, 2Н) ), 3.20 (t, 5H), 3.40 (t, 2H), 3.80 (δ, 3H), 6.00 (L3, 1H), 6.90 (t, 2H), 7.10 (6, 2H), 7.20 (D 2H). 1_ΚΜδ: Εδ + t / ζ 392 (M + H). ΗΚΜδ t / ζ 392.2431 (392.2422 is required for C _{2 2} NH3MO ₅ ). 28 Prep. example 28 methoxyethyl ¹ H NMR (СОС1 ₃ 400 MHz) δ: 1.30 (t, 2Н), 1.40-1.70 (t, 6Н), 1.80 (t, 2Н), 1.90-2.10 (t, ЗН), 2.30 (δ, ЗН), 2.42 (t, 2H), 2.60 (t, 2H), 3.20 (δ, 3H), 3.30 (t, 2H), 3.40 (t, 2H), 5.85 (b3, 1H), 7.15 (b3, 4H). Ι_ΡΜδ: Εδ + t / ζ 376 (M + H). ΗΡΜδ t / ζ 376.2484 (376.2483 is required for CrSiSiId). 29th Prep. example 29 methoxyethyl ⁽ H NMR (СОС1 ₃ 400 MHz) δ: 1.60 (t, 8Н), 1.90 (t, 4Н), 2.00 (t, 2Н), 2.50 (t, 1Н), 2.60 (1, 2Н), 3.20 (t, 5H), 3.30 (ς, 2H), 5.00 (δ, 2H), 5.80 (b3, 1H), 6.90 (t, 3H), 7.20 (ί, 2H), 7.40 (t, 5H). Ι ΚΜδ: Εδ + 468 (M + H). thirty Prep. example 30 methoxyethyl 'H NMR (СОС1 ₃ 400 MHz) δ: 1.431.76 (t, UN), 1.80-2.15 (t, 4Н), 2.50 (t, 1Н), 2.60 (ί, 2Н), 3.25 (h, ЗН), 3.30 (t, 2H), 3.35 (t, 2H), 3.78 (D 2H), 4.01 (1, 1H), 5.755.95 (Lmt, 1H), 6.10-6.45 (Lmt, 1H), 6.70 (t, 1H) ), 6.90 (t, 1H), 7.18 (t, 1H). 1_ΚΜδ: Εδ + 392.2 (M + H). 31 Prep. example 31 methoxyethyl MBO ^^ x-OMe Szi Ή NMR (СОС1 ₃ 400 MHz) δ: 1.501.70 (t, 8Н), 2.00 (t, ЗН), 2.10 (66, 1Н), 2.30 (t, 1Н), 2.60 (1, 2Н), 3.20 (t , 2H), 3.30 (s, 3H), 3.40 (6, 2H), 3.8 (6.6H), 6.10 (b3, 1H), 6.30 (bb, 2H), 7.00 (b, 1H). 1_ΚΜδ: Εδ + t / ζ 422.3 (M + H). Analit. Found: C, 65.16; H 8.46; N, 3.17%. For СГЭНзбИОб С 65.53 is required; H 8.36; N, 3.32%).

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Note Prev K ¹ -Χ-Υ Data 32 Prep. example 32 (5) methoxyethyl ¹ H NMR (СОС1 ₃ , 300 MHz) δ: 1.50-1.78 (t. 12Н), 1.91-2.13 (t, 4Н), 1.48-1.62 (t, ЗН), 3.20-3.47 (t, 7Н), 3.80 ( δ, 3Н), 5.82 (1, 1Н), 6.83 (ά, 2Н), 7.10 (ά, 2Н). LAMZ: T8 ⁺ t / ζ 406 (M + H). 33 Prep. example 33 N ¹ H NMR (СОС1 ₃₎ 400 MHz) δ: 1.40 (t, 2Н), 1.55 (t, 4Н), 1.80 (t, 4Н), 1.90 (t, 2Н), 2.2 (t, 2Н), 3.1 (ί , 2H), 3.3 (t, 2H), 5.60 (bf, 1H), 7.25 (t, 1H), 7.35 (t, 1H), 7.45 (t, 2H), 7.70 (b, 1H), 7.80 (t, 1H), 7.95 (ά, 1H). LYMZ: EZt / ζ 352 (M-H), 705 (2M-H). 34 Prep. example 34 N 'H NMR (СОС1 ₃ , 400 MHz) 6: 1.40 (t, 2Н), 1.50 (t, 4Н), 1.70-1.90 (t, 6Н), 2.20 (t, 2Н), 2.80 (1, 2Н), 3.30 (ς, 2H), 5.60 (L3, 1H), 7.25 (ά, 1H), 7.40 (t, 2H), 7.55 (δ, 1H), 7.70 (t, 3H). LKMZ: ЕЗт / ζ 352 (М-Н), 705 (2М-Н). 35 Prep. example 35 (8) methoxyethyl -__but: ¹ H NMR (00 ₃ 0ϋ, 300 MHz) δ: 1.45-1.88 (t, 8Н), 2.0-2.12 (t, ЗН), 2.45 (s, 1Н), 2.65 (1, 2Н), 3.20 (ί, 2Н) ), 3.25 (8, ЗН), 3.35 (1, 2Н), 7.10-7.20 (t, 2Н), 7.35 (ά, 1Н). CCM8: EZ 't / ζ 412 (M-H). CH1CH: 0.15CH ₂ C1 ₂ 36 Prep. example 36 (8) methoxyethyl ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.45-1.70 (t, UN), 1.75-1.83 (t, 1Н), 1.85-1.96 (t, ЗН), 2.05-2.15 (t, 2Н), 2.43- 2.52 (t, 1H), 2.57 (ί, 2H), 3.21 (s, 3H), 3.35 (b, 2H), 5.80 (b, 1H), 6.89 (ά, 1H), 6.95 (ά, 1H), 7.23 -7.30 (t, 1H). 1. YaMZ: E8 ⁺ t / ζ 436 (M + No.). Found: C, 59.36; 59.17; H, 7.30; 7.27; N 2.68, 2.69. Requires: C 58.96; H 7.46; N 3.03 (M + 0.29 pentane + 0.11 TPA + 0.80 water) 37 Prep. example 37 (8) methoxyethyl ¹ H NMR (NWCO, 400 MHz) δ: 1.25 (t, 1H), 1.40-1.82 (t, 11H), 2.0 (t, 3H), 2.38 (s, 1H), 2.60 (1, 2H), 3.08- 3.18 (t, 7H), 5.46 (b3, 1H), 6.80 (t, 2H), 7.25 (s, 1H). LKMZ: EZ 't / ζ 396 (M-H). ΟΗΝ: 0.36 CH ₂ C1 ₂ 0.6 N ₂ O

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Note Prev K ¹ -Χ-Υ Data 38 Prep. example 38 N ABOUT? ¹ H NMR (NWCO, 400 MHz) δ: 1.23 (ά, 2H), 1.32-1.45 (t, 4H), 1.72 (1, 2H), 1.81 (ΐ, 2H), 1.93 (t, 2H), 2.16 ( 1, 2H), 2.60 (1, 2H), 3.15 (1, 2H), 6.77 (t, 2H), 7.08 (1, 1H). LRMZ: E8 't / ζ 338 (M-H). ΟΗΝ: 0.51 CH ₂ C1 ₂ 39 Prep. example 39 N ¹ H NMR (CO ₃ OO, 400 MHz) δ: 1.45 (t, 2H), 1.51-1.65 (t, 4H), 1.75 (1, 2H), 1.80 (1, 2H), 1.95 (t, 2H), 2.15 (1, 2H), 2.61 (1, 2H), 3.18 (1, 2H), 6.85-7.95 (t, 3H). 1.RM8: E8 't / ζ 338 (M-H). ΟΗΝ: 0.08 N ₂ O 40 Prep. example 40 N ¹ H NMR (0ϋ 00 _3, 400 MHz) δ: 1.47 (t, 2H), 1.52-1.69 (m, 4H), 1.75 (1, 2H), 1.88 (ΐ, 2H), 2.0 (t, 2H), 2.17 (1, 2H), 2.60 (1, 2H), 3.18 (1, 2H), 7.1 (ά, 2H), 7.23 (ά, 2H), 7.68 (b3, 1H). LRMZ: E8 't / ζ 386 (M-H). ΟΗΝ: 0.1 N ₂ O 41 Prep. example 41 (8) methoxyethyl '-ABOUT ¹ H NMR (ΟϋΟΙ ₃ , 300 MHz) δ: 1.40-2.80 (t, 12H), 2.16-2.43 (t, 2H), 2.90-3.08 (t, 2H), 3.18-3.50 (t, 7H), 6.18 ( 8, 1H), 7.20-7.31 (t, 2H), 7.77 (1, 1H), 8.50 (ά, 1H). 42 Prep. example 42 N __00 H NMR (ΟϋΟΙ ₃ , 400 MHz) δ: 1.35-1.43 (t, 2H), 1.55-1.65 (t, 4H), 1.66-1.90 (t, 6H), 1.97-2.05 (t, 2H), 2.20-2.29 (t, 2H), 2.58 (1, 2H), 2.80-2.90 (t, 4H), 3.243.30 (t, 2H), 5.49 (Lb, 1H), 6.90 (ά, 1H), 6.92 (5, 1H) ), 7.10 (0, 1H). ί_ΡΜ8: E8 't / ζ 342 (M-H). Found: C, 73.71; 73.77; H, 9.08; 9.18; N, 3.36, 3.36. Requires: C 73.81; H 9.06; N 3.75 (M + 0.06 ESAc + 0.34 pentane) 43 Prep. example 43 (8) methoxyethyl __00 ¹ H NMR (СОС1 ₃ , 300 MHz) δ: 1.50-2.12 (hl, 14Н), 2.48-2.62 (t, ЗН), 3.23-3.47 (t, 7Н), 4.25 (8, ЗН), 5.77 (1, 1H), 6.65-6.75 (t, 2H), 6.81 (ά, 2H). LRMZ: T8 ⁺ t / ζ 420 (M + H). 44 Prep. example 44 (8) methoxyethyl ¹ H NMR (ΟϋΟΙ ₃ , 300 MHz) δ: 1.37-2.02 (t, 14H), 2.40-2.51 (t, 1H), 2.68-2.83 (ς, 2H), 3.23-3.50 (t, 7H), 5.61 ( 8, 1H), 7.22-7.38 (t, ZN), 7.67-7.90 (t, ZN), 8.72 (ά, 1H). 1.RM8: T8 ⁺ t / g439 (M + H).

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Note Prev K ¹ -Χ-Υ Data 45 Prep. example 45 N ^ ^{xg vg 1} H NMR (SOZOO, 400 MHz) δ: 1.42-1.51 (t, 2H), 1.55-1.68 (t, 4H), 1.72-1.79 (t, 2H), 1.83-1.90 (t, 2H), 1.98-2.05 (t, 2H), 2.17 (ί, 2H), 2.55 (1, 2H), 3.17 (1, 2H), 7.06 (ά, 2B), 7.35 (ά, 2H). 1.KM8: Εδ 't / ζ 380 (M-H). Found: C 57.52, 57.59; H, 6.65; 6.66; N, 3.37, 3.35. Requires: C 57.19; H 6.58; N 3.58 (M + 0.13 pentane) 46 Prep. example 46 N x ^ OO * ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.41-1.55 (П1, 2Н), 1.57-1.73 (t, 4Н), 1.82-2.00 (t, 6Н), 2.33 (1, 2Н), 2.78 (1, 2H), 3.33 (q, 2H), 4.07 (5, 3H), 5.59 (1, 1H), 7.227.36 (t, 2H), 7.51 (δ, 1H), 7.91 (5, 1H). 47 Prep. example 67 N .sy .__ σ ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.45-1.52 (t, 2Н), 1.58-1.65 (t, 4Н), 1.75-1.90 (t, 4Н), 1.93-1.95 (t, 2Н), 2.25- 2.29 (t, 2H), 2.66 (1, 2H), 3.22-3.30 (t, 2H), 5.67 (b3, 1H), 7.27 (t, 2H), 7.51 (b, 2H). E8 't / ζ 327 (M-H). Found: C 58.78, 58.89; H, 6.96; 6.96; N, 6.40, 6.41. Requires: C 58.57; H 6.58; N, 6.80 (M + 1.17 water + 0.55 TEM) 48 Prep. example 47 N GT ΝΜθ ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.49 (t, 2Н), 1.65 (t, 4Н), 1.90 (t, 6Н), 2.30 (ί, 2Н), 2.77 (1, 2Н), 3.35 (i , 2H), 4.27 (δ, 3H), 5.63 (L, 1H), 7.23 (b, 2H), 7.45 (8, 1H), 7.70 (ά, 2H), 7.87 (δ, 1H), LKMZ: t / ζ 358 (M + H) T8. 49 Prep. example 48 N - ^ 00 ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.40-1.53 (t, 2Н), 1.74-2.03 (t, 12Н), 2.28 (1, 2Н), 2.56 (1, 2Н), 2.77 (ί, 2Н) 3.27 (ί, 2H), 4.14 (1, 2H), 5.56 (bg, 1H), 6.71 (b, 1H), 6.82 (δ, 1H), 6.88 (b, 1H). Lamb: t / ζ 358 (M-H), E8 '. Analit. Found: C, 69.81; H, 8.09; N 3.88%. For Ο ₂₁ Η ₂₉ ΝΟ ₄ it is required: C 70.17; H, 8.13; N 3.90%

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Note Prev K ¹ -Χ-Υ Data fifty Prep. example 49 N ¹ H NMR (СОС1 ₃ , 400 MHz) 6: 1.37-1.45 (t, 2Н), 1.56-1.59 (t, 4Н), 1.73-1.90 (t, 6Н), 2.23 (ΐ, 2Н), 2.40 (5, ZN), 2.55 (ί, 2H), 3.24 (61, 2H), 5.60 (L3, 1H), 7.05 (ά, 2H), 7.14 (6, 2H). BRM8: t / ζ 348 (M-H), E8 '. Analit. Found: C, 63.68; H, 7.66; N 3.67%. For 0 ₁₉ Η ₂₇ Ν0 ₃ 8.0.09 TPA required: C 64.04; H 7.59; N 3.89% 51 Prep. example 50 N Me ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.20 (6, ЗН), 1.40 (t, 2Н), 1.50-1.90 (t, UN), 2.20 (t, 2Н), 2.60 (t, 1Н), 3.05 (t, 1H), 3.15 (1, 2H), 3.25 (t, 1H), 4.50 (ΐ, 2H), 5.50 (b3, 1H), 6.70 (ά, 1H), 6.90 (6, 1H), 7.0 ( 8, 1H). LRMZ: t / ζ 358 (M-H), EZ '. 52 Prep. example 51 N Me Ή NMR (СОС1 ₃ , 400 MHz) δ: 1.10 (6, ЗН), 1.40 (t, 2Н), 1.60 (t, 6Н), 1.90 (t, 4Н), 2.30 (t, 2Н), 2.50 (1, 2H), 3.10 (ί, 2H), 4.00 (t, 1H), 4.50 (1, 2H), 5.40 (6, 1H), 6.65 (6, 1H), 6.85 (6, 1H), 6.95 (s, 1H ) LRMZ: t / ζ 358 (M-H), EZ '. 53 Prep. example 52 (8) methoxyethyl ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.45-1.64 (t, 8Н), 1.78-1.94 (t, 6Н), 2.41 (h, ЗН), 2.45-2.50 (t, 1Н), 2.58 (1, 2H), 3.22-3.27 (t, 5H), 3.32-3.37 (t, 2H), 5.72 (L3, 1H), 7.07 (ά, 2H), 7.15 (6, 2H). 1.RMZ: t / ζ 406 (M-H), EZ '. Analit. Found: C, 65.02; H 8.54; N 2.87%. For С ₂₂ НззМО ₄ 3.0.26 ЕУАс is required; C 64.84; H 8.46; N 3.16% 54 Prep. example 53 N 0? ¹ H NMR (СОС13, 400 MHz) δ: 1.43-1.53 (t, ЗН), 1.58-1.69 (t, 8Н), 1.70-1.82 (t, 1Н), 1.83-2.01 (t, 4Н), 2.28 (1 , 2H), 3.33 (1, 2H), 3.42 (t, 1H), 4.23 (1, 1H), 4.60 (1, 1H), 5.70 (L3, 1H), 6.78 (66, 1H), 6.88 (1, 1H), 7.11 (ί, 1H), 7.18 (66, 1H). Ι.ΡΜ8: t / ζ 330 (M-H), E8 '332 MH ⁺ 354 MPa ⁺ E8 ⁺ . Found analyte: C, 69.81; H, 8.09; N 3.88%. For Ο21Η ₂₉ ΝΟ ₄ is required; C 70.17; H, 8.13; N 3.90%

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Note Prev K ¹ -Χ-Υ Data 55 C. 54 (8) methoxyethyl > _____ ¹ H NMR (СОС1з, 400 MHz) δ: 1.47-1.70 (t, 8Н), 1.73-1.79 (t, 2Н), 1.94-2.06 (t, 5Н), 2.45-2.51 (t, 1Н), 2.55 (1 , 2H), 3.15-3.18 (t, 4H), 3.23 (5, 3H), 3.33-3.36 (t, 2H), 4.53 (ΐ, 2H), 6.26 (b3, 1H), 6.75 (άά, 1H), 6.89 (ά, 1H); 7.02 (ά, 1H). 1.RM8: t / ζ 402 (ΜΗ), E8 '. Analit found: C, 66.36; H, 8.20; N 3.29%. For 0 ₂₃ Η ₃₃ Ν0 ₅ 0.14 TPA requires: C 66.66; H 7.96; N 3.34% 56 Prep. example 55 (8) methoxyethyl Me ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.50-1.70 (hl, 6Н), 1.80 (ί, 2Н), 1.90-2.05 (t, 5Н), 2.20 (5, ЗН), 2.50 (t, 2Н) , 2.55 (t, 2H), 3.15 (t, 2H), 3.30 (t, 5H), 3.40 (t, 2H), 4.50 (1, 2H), 5.80 (b3, 1H), 6.70 (5, 1H), 6.85 (8, 1H). LRMZ: t / ζ 432 (M-H), E8 '. 57 Prep. example 56 (8) methoxyethoxyethyl ¹ H NMR (COC1 ₃ , 400 MHz) δ: 1.43-2.06 (t, 12H), 2.57 (1, 2H), 2.63 (Lmr, 1H), 3.18 (1, 2H), 3.27 (H, 2H), 3.34 (h, 3H), 3.44-3.53 (t, 3H), 3.58 (ί, 2H), 3.64 (L, 1H), 4.53 (1, 2H), 5.90 (L3, 1H), 6.68 (ά, 1H), 6.89 (ά, 1H), 7.00 (s, 1H). LAMZ: t / ζ 432 (M-H), E8 '. Analit found: C, 64.90; H 8.16; N 2.99%. For Ο ₂₄ Η ₃₅ ΝΟ ₆ 0.5N ₂ O requires: C 65.14; H, 8.20; N 3.16% 58 Prep. example 57 (δ) methoxyethoxyethyl ¹ H NMR (COS1 ₃ , 400 MHz) δ: 1.42 (s, 6H), 1.47-1.67 (t, 7H), 1.761.86 (t, 4H), 2.04 (άά, 1H), 2.55 (1, 2H) , 2.59-2.65 (t, 1H), 2.94 (s, 2H), 3.23-3.28 (t, 2H), 3.32 (s, ZN), 3.46-3.50 (t, ZN), 3.55-3.62 (t, ZN) 6.00 (L3, 1H), 6.60 (ά, 1H), 6.87 (ά, 1H), 6.92 (s, 1H). 1_RM8: t / ζ 460 (M-H), E8 '. Analit found: C, 56.62; H 6.93; N 2.41%. For Ο ₂₆ Η ₃₉ ΝΟδ1,2 TPA, it is required: C 57.00; H 6.77; N 2.34%

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Note Prev K ¹ -Χ-Υ Data 59 Prep. example 58 (Yumethyl ¹ H NMR (COS13, 400 MHz) δ: 1.08 (5, 3H), 1.42-1.76 (hl, 7H), 1.80 (1, 2H), 1.88-2.0 (t, 2H), 2.10 (t, 1H), 2.45 (t, 1H), 2.60 (t, 2H), 3.28 (t, 2H), 5.80 (b, 1H), 6.826.92 (t, 2H), 6.95 (t, 1H). LRMZ: t / ζ 396 (M-H), E8'398 MH ⁺ 420 M№ ⁺ E8 ⁺ . Analit found: C, 55.84; H, 6.20; N 3.01%. For θ2οΗ25Ε2Νθ5ΐΗ ₂ ΟΌ, 21 СН ₂ С ( ₂ required: С 56.03; Н 6.38; N 3.23% 60 Prep. example 59 (6) methoxyethyl Me ¹ H NMR (СОС1 ₃ , 300 MHz) δ: 1.20 (ά, ЗН), 1.40-1.85 (t, 12Н), 1.95 (t, 2Н), 2.45 (t, 1Н), 2.65 (t, 1Н) , 3.05 (t, 1H), 3.15 (1, 2H), 3.25 (δ, 3H), 3.30 (t, 3H), 4.50 (1, 2H), 5.60 (LH, 1H), 6.70 (ά, 1H), 6.90 (ά, 1H), 7.00 (δ, 1 Η). Ι.ΚΜ8: t / ζ 416 (M-H), E8 ' 61 Prep. example 60 (8) methoxyethyl ¹ H NMR (СОС1 ₃ , 300 MHz) δ: 1.50-1.70 (t, 8Н), 1.75 (1, 2Н), 1.90-2.10 (t, 4Н), 2.21 (δ, ЗН), 2.50 (t, 1Н) 2.60 (1, 2H), 3.25 (δ, 3H), 3.30 (t, 2H), 3.35 (t, 2H), 4.50 (t, 2H), 5.80 (b, 1H), 6.60 (δ, 1H), 6.95 (δ, 1H). 1_NM8: t / ζ 416 (M-H), E8- 62 Prep. example 61 (δ) methoxyethoxymethyl ¹ H NMR (СОС1 ₃ , 300 MHz) δ: 1.50 (t, 2Н), 1.60-2.00 (t, UN), 2.60 (t, ЗН), 3.20 (ί, 2Н), 3.30 (δ, ЗН), 3.45 (t, 3H), 3.55 (t, 2H), 3.60 (t, 1H), 6.0 (Lgv, 1H), 7.02 (ά, 2H), 7.19 (ά, 2H). 1_NM8: t / ζ 424 (M-H), E3 ' 63 Prep. example 62 (3) methoxyethyl Me me H NMR (СОС1 ₃ , 400 MHz) <5: 1.3 (δ, 6Н), 1.4-1.79 (t, UN), 1.8 (1, 2Н), 1.93 (t, 2Н), 2.42 (t, 1Н), 3.17 (t, 4H), 3.3 (δ, 3H), 3.38 (t, 2H), 4.55 (1, 2H), 5.5 (Lga, 1H), 6.7 (ά, 1H), 7.1 (ά, 1H), 7.2 ( δ, 1H). LRMZ: M-N, 430, (E8 ') 64 Prep. example 63 (3) methoxyethyl - not 'H NMR (СОС1 ₃ , 300 MHz) δ: 1.40-2.23 (t, 15Н), 2.43-2.63 (t, 1Н), 2.80-2.95 (t, 1Н), 3.29 (δ, ЗН), 3.03-3.57 ( t, ZN), 3.60-3.83 (t, 2H), 5.99 (Lga, 1H), 7.19 (ά, 2H), 7.30 (ά, 2H). LRMZ: M + H, 426, (T8 ⁺ ) I

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Note Prev I am ¹ -Χ-Υ Data 65 Prep. example 64 (8) methoxyethyl Μβ ^Ζ 1 he ¹ H NMR (СОС1 ₃ , 300 MHz) δ: 1.17-2.17 (t, 17Н), 2.40-2.58 (t, 1Н), 2.98-3.57 (t, 7Н), 3.61-3.77 (t, 2Н), 5.93 ( Bz, 1H), 7.20-7.43 (t, 4H). Ι-ΚΜ8: M + H, 440. (T8 ⁺ ) 66 Prep. example 65 (8) methoxyethyl H NMR (СОС1 ₃ , 300 MHz) δ: 1.40-2.18 (t, 16Н), 2.43-2.68 (t, ЗН), 3.30 (s, ЗН), 3.26-3.48 (t, 2Н), 3.88 (5, ЗН) ), 5.83 (L3, 1H), 6.83 (ά, 1H), 7.04 (ά, 1H), 7.20 (s, 1H). Analit found: C, 60.01; H 7.60; N 3.00%. For θ2οΗ32θΙΝ0 ₅ Ό, 75Η ₂ 0 requires: C 60.13; H 7.68; N3.19% 67 Prep. example 66 (8) methoxyethyl ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.42 (b, ЗН), 1.45-1.66 (8Н), 1.74-1.80 (t, 2Н), 1.82-1.95 (t, ЗН), 1.972.02 (1Н) , 2.42-2.55 (t, 3H), 2.75 (bb, 1H), 3.20-3.27 (t, 6H), 3.313.36 (t, 2H), 4.80-4.87 (t, 1H), 5.77 (bg, 1H) 6.61 (ά, 1H); 6.85 (ά, 1H); 6.93 (s, 1H). LMP: M + Na, 440, (E8 ⁺ )

Alternatively, the compound of Example 22 can be prepared as follows.

(28) -2 - {[1 - ({[3- (4-Chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid.

Trifluoroacetic acid (16.3 ml, 212 mmol) was added to a solution of the product from 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 nitrogen. An aqueous solution of sodium bicarbonate (95 ml of a 10% (w / v) solution) was then added to the reaction mixture while stirring to a pH of the aqueous layer between 2 and 3. Then the layers were separated and the organic layer was extracted with an aqueous solution of sodium carbonate ( 2x20 ml of a 10% (w / v) solution). The aqueous layers were combined and then saturated brine (80 ml) was added, followed by 2-butanone (40 ml). The layers were separated and the aqueous layer was extracted again with 2-butanone (2x50 ml). The combined organic layers were then dried by azeotropic distillation at atmospheric pressure to a volume of 70 ml, crystallization occurred, and the mixture was diluted with 2-butanone (70 ml).

The product was then collected by filtration and dried at 50 ° C for 65 hours in vacuo to give the crude sodium salt of the title compound as a white solid (5.76 g), which was then purified by recrystallization as follows. Ethyl acetate (87 ml) and ethanol (13 ml) were added to the crude product, and the remaining insoluble matter was removed by filtration. Ethanol was then removed by azeotropic distillation at atmospheric pressure (to remove 110 ml of solvent) and replaced with ethyl acetate (145 ml), and crystallization occurred. The resulting crystallized product was then collected by suction filtration to obtain the pure sodium salt of the title product as a white crystalline solid (4.51 g, 10.8 mmol, 51%); melting point (ethyl acetate) 214-216 ° C;

¹ H NMR (ΏΜ8Ο-6 ₆ 300 MHz) δ: 1.26-1.58 (t, 8H), 1.62-1.74 (t, 3H), 1.74-1.86 (t, 1H), 1.91-2.07 (t, 3H), 2.57 (!, 2H), 3.03 (q, 2H), 3.10 ( ₈ , 3H), 3.13-3.27 (t, 2H), 7.22 (b, 2H), 7.29 (b, 2H), 9.16 (!, Bh, 1H ); ΓΚΜ8 (Ε8 negative): 789 [2М-Н] ^- ( ³⁵ С1), 394 [Μ-Н] ^- ( ³⁵ С1). For analytical purposes, the title product (i.e., free acid) was obtained by dissolving this sodium salt in water acidified with 5M hydrochloric acid, and extracted with dichloromethane. After removing the solvent by blowing a stream of nitrogen over the sample, the title product was obtained;

¹ H NMR (ΏΜ8Ο-6 ₆ 3 00 MHz) δ: 1.22-1.80 (t, 11H), 1.81-1.96 (t, 2H), 1.96-2.08 (t, 1H), 2.93-2.27 (t, 1H), 2.53 (!, 2H), 3.03 (q, 2H), 3.11 ( ₈ , 3H), 3.16-3.25 (t, 2H), 7.20 (b, 2H), 7.30 (b, 2H), 7.51 (1, 1H) ; ΓΚΜ8 (Ε8 negative): 789 [2М-Н] ^- ( ³⁵ С1), 394 [Μ-Н] ^- ( ³⁵ С1). HPLC (column: Syga1Rask A8 (25x0.46 cm); mobile phase: hexane / 1PA (isopropyl alcohol) / acetic acid (95/5 / 0.5 vol./about./vol.); Flow rate: 1.0 ml / min; temperature: ambient; injection volume: 20 μl; detection: UV (ultraviolet) at 220 nm; sample concentration: 1.0 mg / ml (prepared in the mobile phase); retention time: minor enantiomer 11.4 min (5.7%); main enantiomer 14.3 min (94.3%).

Sodium salts of the compounds of example 22.

a) Monohydrate.

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The sodium salt of the compound of Example 22 (200 mg) was added to 1 ml of 3.9% water in isopropanol solution. The resulting suspension was stirred for 12 days, after which it was isolated by filtration. The product had the following X-ray powder diffraction pattern (ΡΧΚΌ Rayet).

2-theta angle ° Intensity % 2-theta angle ° Intensity % 2-theta angle ° Intensity % 2-theta angle ° Intensity % 3,552 30.8 17,708 13.5 22,881 35 30,672 fifteen 7,154 8 17.93 29th 23,141 23,2 30,952 17.5 9,526 3,1 18,313 12 23,478 15.1 31,437 15.7 10,359 15.7 18,545 23.9 24,088 13.9 31,788 13.9 10,608 14.3 18,811 14 24,313 12.6 32,114 24.6 11.03 5 19.7 34.2 24,588 22.7 32,998 13.3 12,369 3,7 19,978 one hundred 25,013 25.8 33,375 18.8 12,939 13,2 20,273 90.6 25,514 29.9 33,815 14 13,233 12.3 20,627 51.9 25,987 25.5 34,266 14,4 13,835 14.2 20,829 29.4 27,107 18.2 35,705 15.7 14,345 37.9 20,926 28,4 27,395 30.6 35,989 14.1 14,887 sixteen 21,443 52.7 27,869 19,2 36,514 16.7 15.16 16.8 21,611 41.6 28,716 21 38,151 14.6 16,372 24.9 21,881 21,2 28,788 nineteen 38,925 17 16,813 6.9 22,174 24.3 28,989 27,2 39,091 nineteen 17,203 22.1 22,472 47.1 30,232 13,4 39,961 thirteen 17,408 32,7

Differential scanning calorimetry (E8C, b1 £ еп еп еп 11 11 ап ап ап ап оп оп оп оп оп)))))))))) was carried out using a Regx E1teg O8C-7 instrument equipped with a device for automatic sample change. Approximately 3 mg of the sample was carefully weighed into a 50 μl aluminum cuvette and tightly crimped with a perforated lid. Samples were heated at a rate of 20 ° C / min in the range from 40 to 300 ° C with a purge of gaseous nitrogen. Dehydration occurred between 50 and 150 ° C, and the main melting was between 212 and 225 ° C. It will be apparent to those skilled in the art that the melting point may go beyond these limits as a result of contamination of the sample.

b) Anhydrous salt.

The sodium salt of the compound of Example 22 had the following X-ray powder diffraction pattern (ΡΧΚΌ).

Angle 2-theta ° Intensity % 2-theta angle ° Intensity % 2-theta angle ° Intensity % 2-theta angle ° Intensity % 5,463 12,2 17,714 95.6 22,735 thirty 28,926 23.8 6,654 one hundred 18,083 31.7 23.36 56.5 29,802 23.5 7,546 66 18.64 28.8 24,126 31.9 30,454 30.7 9,336 31.3 18,902 82,4 24,388 45,2 30,885 29.2 10,953 9.7 19,696 40.1 24.72 25.8 31.48 21 11,571 55.9 20,406 33.9 25,298 26.7 32.66 16.8 12.56 10.9 20,502 31.8 25,579 20,4 34,027 23.1 13,287 22.9 20,683 45.4 26,718 17.6 34,494 17.6 15,125 33.6 20,942 31.5 27,151 24.2 36,011 nineteen 15,667 60.3 21,559 92.6 27.46 22.7 36,997 17.4 16,403 17,2 21,898 66,2 27,737 20,2 38,704 21,2 17,024 62,2 22,274 36.6 28.56 27.1 39,961 18.7

Preparatory Examples Preparatory Example 1. tert-Butyl-4-methoxy-2 - {[1 - ({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} butanoate

The product from preparatory example 68 (325 mg, 1.08 mmol), the product from preparatory example 73 (178 mg, 1.08 mmol), ΗΘΒΐ (146 mg, 1.08 mmol), \\ '8C1)! (207 mg, 1.08 mmol) and triethylamine (0.3 ml, 2.16 mmol) were stirred together in dichloromethane (5 ml) at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed with water ( 2x20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was cleaned

- 32 006154 column chromatography using dichloromethane, then with a mixture of 99: 1 dichloromethane: methanol, then with a mixture of 98: 2 dichloromethane: methanol (K _£ 0.2) to give the product as a yellow oil (267 mg, 0.6 mmol);

¹ H NMR (SECE 400 MHz) δ: 1.4 (t, 5H), 1.8 (t, 4H), 2.0 (t, 1H), 2.3 (t, 1H), 2.6 (ί, 2H) ), 3.2 (8, 3H), 3.3 (t, 2H), 3.7 (8, 3H), 5.7 (1, 1H), 6.8 (s, 2H), 7.0 (s, 2H); LKM8: t / ζ 448 (M-H ⁺ ).

The following examples of formula (IV; ·!). that is, compounds of general formula IV, where Rgo! represents tert-butyl, obtained by methods similar to preparative example 1, from these precursors (see table. 2).

<ινβ)

table 2

Prep. example Prev acid Prev amine K ¹ -Χ-Υ Analytic data 2 Prep. example 68 Available from ΙΟΝ Vyutebya15! Ps Methoxyethyl Md H NMR (СОС1 ₃ 400 MHz) <5: 1.4 (5, 9Н), 1.6-2.0 (t, 16Н), 2.3 (t, 1Н), 2.6 (1, 2Н), 3.2 (ά, ЗН), 3.3 ( t, 3H), 3.7 (5, 3H), 4.0 (t, 1H), 5.5 (b3, 1H), 6.8 (t, 2H), 7.1 (t, 2H). Ι ΜΚ8: t / ζ 462 (M-H *). 3 Prep. example 68 Prep. example 120 Methoxyethyl νΤΟ Me ______ - ^Ί Η NMR (SOS! Z 400 MHz) δ: 1.4-1.45 (t, UN), 1.51.7 (t, 6H), 1.7-1.8 (t, 2H), 1.9-2.1 (t, 4H), 2.3- 2.4 (t, 1H), 3.1 (ά, 3H), 3.1-3.35 (t, 3H), 3.9-4.0 (t, 2H), 4.3-4.4 (t, 1H), 6.1-6.2 (t, 1H), 6.8-6.9 (s, 2H), 7.2 (1, 1H), 7.3 (ά, 1H). 4 Prep. example 68 I5 4533655, Example 7A Methoxyethyl ¹ H NMR (СОС1 ₃ 400 MHz) <5: 1.4 (s, 9Н), 1.5 (t, 2Н), 1.6 (t, 4Н), 1.7 (άά, ЗН), 1.8 (t, 2Н), 1.9 (t , ЗН), 2.3 (t, 1Н), 2.6 (1, 2Н), 3.1 (t, 1Н), 3.2 (h, ЗН), 3.3 (1, 2Н), 5.9 (t, 1Н), 6.9 (1, 2H), 7.1 (ί, 2H). 1_ME8: t / ζ 436 (M-H *).

2H), 3.1 (I, 2H), 3.2 (5, 3H), 3.3 (η, 2H), 4.5 (1, 2H),

5.7 (t, 1H), 6.9 (ό, 1H), 7.0 (3, 1H). LMP3: t / ζ 460 (M-H).

Prep. example Prev acid Prev amine I am ¹ -Χ-Υ Analytic data 12 Prep. example 68 Available in selling from Heponews Methoxyethyl 'NNMR (СОС1 ₃ 400 MHz) δ: 1.4 (h, UN), 1.5-1.7 (t, 6Н), 1.7-1.85 (t, 4Н), 1.9-2.0 (t, ЗН), 2.3-2.4 (t, 1H), 2.6-2.7 (t, 2H), 3.2 (s, 2H), 3.3 (s, 3H), 3.3-3 4 (t, 2H), 6.3 (b3, 1H), 6.9 (1, 2H), 7.05 (bb, 2H). 1 MK8: t / ζ 434 (M + H *). thirteen Prep. example 68 1 Μβά. Sung., 1996, 39 (20), 4017 Methoxyethyl ¹ NNMR (СОС1 ₃ 400 MHz) δ: 1.4 (h, UN), 1.5-2.0 (t, 14Н), 2.3-2.4 (t, 1Н), 2.6 ((, 2Н), 3.2 (h, ЗН), 3.2 -3.3 (t, 3H), 3.4-3.5 (t, 2H), 5.8 (b3, 1H), 7.0 (t, 1H), 7.1-7.2 (t, 3H). 1 ME? 8: t / ζ 452 ( M + H *). 14 Prep. example 68 Those1. Ley., 1999, 40, 2033-4 Methoxyethyl ¹ H NMR (SOS! S 400 MHz) δ: 1.4-1.45 (t, UN), 1.52.0 (t, 13H), 2 3-2.4 (t, 1H), 2.7 (1, 2H), 3.2 (s , ZN), 3.25-3.35 (t, 4H), 5.8 (b3, 1H), 7.05-7.3 (t, 4H). 1 МРЗ: t / ζ 452 (М + Н *). fifteen Prep. example 68 1 meb. Sc., 1996, 39, 4942-51 Methoxyethyl νχΧτ ^α NMR (СОС1 ₃ 400 MHz) δ: 1.4 (s, UN), 1.5-2.05 (t, 13Н), 2.3-2 4 (t, 1Н), 2.6 (1, 2Н), 3.25 (s, ЗН), 3.20 -3.35 (t, 4H), 5.8 (b3, 1H), 7.1 (b, 2H), 7.2 (b, 2H). 1 MP8: t / ζ 452 (M + H *). sixteen Prep. example 71 Prep. example 73 (P) cut ¹ H NMR (СОС1 ₃ 400 MHz) δ: 0.8 (1, ЗН), 1.2 (t, 6Н), 1.4 (s, 9Н), 1.4-1.9 (t, UN), 2.2 (t, 1Н), 2.5 ( M, 2H), 3.2 (t, 2H), 3.7 (s, 3H), 5.6 (s, 1H), 6.8 (ά, 2H), 7.1 (b, 2H). LMP: t / ζ 432 (M-H ') 17 Prep. example 70 Prep. example 73 (K) -methyl , ^, ΟΜβ H NMR (SOC! ₃ 400 MHz) δ: 1.11 (I, 3H), 1.38-2.10 (t, 21H), 2.03 (t, 2H), 2.33 (t, 1H), 2.62 (ί, 2H), 3.28 ( t, 2H), 3.80 (s, 3H), 5.73 (t, 1H), 6.83 (ά, 2H), 7.12 (6, 2H). eighteen EP274234 B1 Example 35 Prep. example 73 N ¹ H NMR (CFCl ₁ 400 MHz) δ: 1.43 (t, 9H), 1.48 (t, 2H), 1.65 (t, 4H), 1.83 (t, 4H), 1.99 (t, 2H), 2.19 (t, 2H), 2.61 (ί, 2H), 3.29 (ς, 2H), 3.8 (s, 3H), 5.59 I (t, 1H), 6.84 (b, 2H), 7.11 (ά, 2H).

- 33 006154

Prev acid EP274234 B1.

Example 35

Example 35 example 68

Prep. example 83 example 68

Prep. example 68

Example 35

Prep. example 69 example 69 example 69

Prev acid

Prep. example 69

EP274234 B1 Example 35 Example 68

Example 7A

Prep. example 73

Prev amine

Prep. example 76

Prep. example 99

Methoxyethyl

Prep. example 85

Methoxyethyl

Methoxy 2H). Ι.ΚΜ8: gp / ζ 452 (M-H-). [σ] ₀ +0.0 (MeOH, s 0.35). Analytically found C, 65.95; H, 8.66; N

7.0 (b. 2H). 1_RM8: t / ζ 448 (M-H *). HPM8 t / ζ

448.3048 (M-H *) (for Ο ^ Η ^ ΝΟβ requires

448.3058)

Analytic data

- 34 006154

Prev amine

Prep. example 69

EP274234

IN 1,

Example 35

EP274234

IN 1,

Example 35

Prev Acid Prep. example 69

Prep. example 81

Prep. example 80

Prep. example 119

Prep. example 113

Prep. example 90

Example 35

Prep. example 88

B1 Example 35

- 35 006154

Prev amine

Prep. example 100

Prep. example 90a

Prep. example 69

Prev Acid Prep. example 69

EP0342850, see

methoxymethoxymethoxyethoxymeER0342850, see also Te). 1_e1) C., 1999, 2187 Prep. example 70

Prev Acid Prep. example 69

Prep. example 69

EP0342850, see also Te1 LeIz., 1999, 2187 Prep. example 69 example 69

Prep. example 69

Prep. example 89

Prev amine

Prep. example 133

Prep. example 152 methoxyethoxymethyl (5) methoxy-

Alternatively, the compound of Preparation 22 was prepared as follows.

To a solution of 1,1'-carbonyldiimidazole (73.9 g, 0.45 mol) in azeotropically dried isopropyl acetate (339 ml) was added an isopropyl acetate solution of the product from Preparation 69 with stirring at 60 ° C. under atmosphere Ν ₂ for a period of 1 , 5 h. The feed lines were then washed with dry isopropyl acetate (50 ml). The resulting solution was then stirred at 60 ° C. for another 4.5 hours, and then the reaction mixture was allowed to cool to room temperature and stirred for 15 hours. Triethylamine (46.1 g, 0.46 was added to the resulting solution) mol), then 3- (4-chlorophenyl) propylamine hydrochloride (I Cheb. Set, 1996, 39, 4942-51) (94.3 g, 0.46 mol). The resulting mixture was heated to 60 ° C. for 7 hours, then cooled to room temperature. Then, deionized water was added to the reaction mixture with stirring.

- 36 006154 (100 ml), then aqueous hydrochloric acid (190 ml of a 5 M solution) until the pH of the aqueous layer was between pH 2 and 3, the aqueous layer was then separated, and the organic layer was washed with aqueous potassium carbonate (50 ml 0.5 M solution). The aqueous phase was separated, and the organic phase was washed with saturated brine (100 ml). The aqueous layer was then separated, and the organic phase was concentrated by vacuum distillation to obtain the title compound as a yellow oil (200.3 g, 443 mmol, 98% yield);

¹ H NMR (SES1 ₃ 300 MHz) δ: 1.45 (s, 9H), 1.45-1.56 (t, 1 H), 1.56-1.74 (t, 6 N), 1.74-2.11 (t, 7 N), 2.32-2.43 (t, 1 N), 2.64 (ΐ, 2 N), 3.22-3.30 (t, 2 N), 3.27 (s, 3 N), 3.30-3.38 (t, 2 N), 5.75-5.85 ( t, Lt, 1 H), 7.13 (b, 2H), 7.26 (b, 2 H); Ι.ΚΜΙ) (E8 positive): 452 [M + H] ⁺ ( ³⁵ C1).

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

To a stirred solution of the starting material from step (b) below (11.3 g, 62 mmol) in tetrahydrofuran (500 ml) was added the borane-dimethyl sulfide complex (30 ml) and refluxed for 12 hours. The reaction mixture was quenched with methanol ( 100 ml), concentrated in vacuo and refluxed for 4 hours in 3M HCl (200 ml). The aqueous layer was concentrated to 50 ml in vacuo, the precipitate was filtered off and dried under reduced pressure to obtain the title product as a white powder (10.1 g, 59.7 mmol, 96%); ¹ H NMR (400 MHz, MeOE) δ: 1.9 (ςυίη, 2H), 2.65 (ΐ, 2H), 2.9 (ΐ, 2H), 7.2 (b, 2H), 7.25 (b, 2H).

Getting the starting materials.

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

To a stirred solution of 3- (4-chlorophenyl) propanoic acid (commercially available from Maubbde) (14.5 g, 77.1 mmol) in methanol (400 ml) was added acetyl chloride (50 ml) and the reaction mixture was refluxed for 20 hours. After this, the reaction mixture was allowed to cool, then concentrated under reduced pressure. The residue was then dissolved in 1) CM (200 ml) and washed with 1 M sodium hydroxide solution (100 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title product as a brown oil (15.7 g, 77 mmol, 100%); ¹ H NMR (400 MHz, COC1 ₃ ) δ: 2.55 (ΐ, 2H), 2.9 (ΐ, 2H), 3.6 (s, 3H), 7.1 (b, 2H), 7.2 (b, 2H).

b) 3- (4-Chlorophenyl) propanamide.

The product from step (a) above (15 g, 75.7 mmol) was dissolved in methanol (400 ml), then cooled to 0 ° C. Then, gaseous ammonia was bubbled through the reaction mixture for 4 hours, and the reaction mixture was allowed to stir for 3 days. The solvent was removed under reduced pressure, and the residue was triturated with hot pentane. The remaining solid was dried in vacuo to give the title product as a white powder (11.32 g, 61.8 mmol, 82%); ¹ H NMR (400 MHz, COC1 ₃ ) δ: 2.45 (ΐ, 2H), 2.9 (ΐ, 2H), 5.3 (b3, 1H), 7.1 (b, 2H), 7.2 (b, 2H).

Preparatory Example 67. tert-Butyl- [1 - ({[[3- (4-cyanophenyl) propyl] amino} carbonyl) cyclopentyl] acetate.

The product from Preparation 45 (44 mg, 0.1 mmol) and SithCX (13.4 mg, 0.15 mmol) were transferred to ΌΜΡ (0.5 ml) under nitrogen and stirred at approximately 130 ° C for 16 hours After that, another 13 mg of SifSC was added, and the temperature rose to 145 ° C in 16 hours. After that, the last 26 mg of SifCX was added to the solution and the whole volume was heated at 160 ° C for 24 hours. The reaction was quenched by the addition of water, and the organics were extracted EJAc (50 ml), washed with brine, dried (MgSO ₄ ) and evaporated to a yellow oil. This oil was purified by preparative TEC. using a 7: 3 mixture of pentane: HUA Ac as an eluent to afford the title product, 6 mg (16%); ¹ H NMR (400 MHz, COC1 ₃ ) δ: 1.40 (s, 9H), 1.45-1.49 (t, 2H), 1.62-1.64 (t, 4H), 1.79-1.83 (t, 4H), 1.94-2.00 ( t, 2H), 2.12-2.17 (t, 2H), 2.65 (N, 2H), 3.22-3.35 (t, 2H), 3.22-3.35 (t, 2H), 5.65 (L3, 1H), 7.23 (b, 2H), 7.54 (b, 2H); LKMZ: t / ζ (Е3 ⁺ ) 407 (m + №).

Preparatory Example 68. 1- [2- (tert-Butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylic acid.

A solution of tert-butyl 3- (1-carboxycyclopentyl) propanoate (12 g, 49.5 mmol) (see EP274234B1, example 35) in dry tetrahydrofuran (100 ml) was added to a stirred solution of lithium diisopropylamide (130 ml) in a mixture of hexane (52 ml) and tetrahydrofuran (200 ml) at -78 ° C in a nitrogen atmosphere. After 1 h, a solution of 2-bromoethyl methyl ether in tetrahydrofuran (100 ml) was added, maintaining

- 37 006154 temperature at -78 ° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water (100 ml) and acidified to pH 1 with 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 a crude acid, which was chromatographed on silica. Elution with increasing proportions of methanol in dichloromethane (from pure dichloromethane to 1:50) gave an oil (7.7 g, 25.6 mmol, 52%); Βί 0.3 methanol, dichloromethane 1:20;

Ή NMR (ΟΌΟ1 ₃ , 400 MHz) δ: 1.4 (q, 9H), 1.4-1.7 (t, 7H), 1.75-1.95 (t, 2H), 2.0-2.15 (t, 3H), 2.3-2.4 (t , 1H), 3.3 (q, 3H), 3.3-3.4 (t, 2H); LBM8: t / ζ 299 (M-H ⁺ ).

Alternatively, the compound from Preparation 68 was prepared as follows.

To the mixture of heptane (41.2 L) and water (30.9 L) was added the product from step (b) below (5.15 kg, 12.9 mol). Then, diluted aqueous hydrochloric acid (2.6 L of a 5 M solution) was added with stirring until the pH of the aqueous layer was between pH 2 and 3. The layers were separated and the aqueous phase was then extracted with heptane (20.6 L). The combined organic layers were then washed with saturated brine (15.5 L) and then concentrated by distillation at atmospheric pressure to obtain the title compound (3.90 kg, 13.0 mol, 100% yield) as a solution in heptane ( total weight of the solution 44.0 kg). An aliquot can be taken and the solvent removed in vacuo to give a sample for analysis; ¹ H NMR (C1) C1 _; 300 MHz) δ: 1.42 (q, 9H), 1.45-1.58 (t, 2H), 1.58-1.70 (t, 5H), 1.70-1.90 (t, 2H), 2.03-2.18 (t, 3H), 2.32- 2.46 (t, 1H), 3.27 (q, 3H), 3.35 (!, 2H); LBM8 (ΕΙ): t / ζ 244 [M-C ₄ H ₈ ] +, 227 [M-C ₄ H ₉ O] +, 199 [MS ₄ H ₉ O ₂ C] +; OS (gas chromatography) (injector program: initial temperature 0 ° C, speed 150 ° C / min, final temperature 230 ° C; drying program: initial temperature 100 ° C, speed 10 ° C / min, final temperature 230 ° C, end time 10 min; column BP-21 25 mx 0.25 mm, inner diameter x 0.25 μm ET; HIS detector (flame ionization detector) retention time 16.1 min).

Getting the starting materials.

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

To a solution of a commercially available lithium diisopropylamide (9.63 kg of a 2M solution in a mixture of tetrahydrofuran / n-heptane / ethylbenzene, 23.7 mol) in 1,2-dimethoxyethane (25 L) at -10 ° C in an atmosphere of Ν _{2, a} solution was added 1- (3-tert-butoxy-3-oxopropyl) cyclopentanecarboxylic acid (EP274234B1 - see example 35) (2.5 kg, 10.3 mol) in 1,2-dimethoxyethane (12.5 L) with stirring for 4 h, maintaining the temperature of the reaction mixture -10 ° C. The pressure tank was washed with 1,2-dimethoxyethane (2.5 L) and the flush was added to the reaction mixture. The reaction mixture was then allowed to stir at -10 ° C for 1.75 hours. To the resulting solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (10 L) over a period of time 1.75 hours. The reaction mixture was then stirred at this temperature for 4 hours, then heated to 20 ° C. for 4 hours. After stirring at this temperature for 8 hours, the reaction was quenched by the addition of aqueous ammonium chloride (25 L, 2.8 M solution), then ethyl acetate (12.5 L) was added. Then, aqueous hydrochloric acid (10 L of a 5 M solution) was added with stirring to adjust the pH to between 2 and 3. The two phases were mixed and then separated. The organic phase was then extracted three times with an aqueous solution of potassium carbonate (0.3 M solution; 37.5 L, 12.5 L and then 6.25 L). To the combined aqueous phases were then added n-heptane (15.6 L) and aqueous hydrochloric acid (14.5 L of a 5 M solution) with stirring until the pH of the aqueous layer between 2 and 3. The layers were separated and the aqueous phase was extracted with n-heptane (15 , 6 l). The combined organic phases were then washed with saturated brine (3.1 L) and concentrated in vacuo to give the crude title compound (2.50 kg, 8.32 mol, 81% yield) as a solution in nheptane (21.8 kg total weight of the solution).

b) Cyclohexanamino-1- [2- (tert-butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylate.

A solution of the crude product from step (a) above in n-heptane (5.51 kg, 18.3 mol in a total solution weight of 41.4 kg) was concentrated by atmospheric distillation to remove 20 l of nheptane. To the resulting solution was added cyclohexylamine (1.82 kg, 18.4 mol) as a solution in n-heptane (9.9 L) over a period of 0.5 hours. The supply lines were then washed with n-heptane (1.1 k) and washout was added to the reaction mixture. The resulting suspension was then granulated with shaking at 22 ° C for a period of 9.5 hours. The product was collected by filtration and washed with nheptane (2 x 11.0 L) and the resulting solid was dried under vacuum at 50 ° C for 20 hours. the off-white solid (6.2 kg, 15.5 mmol) was suspended in isopropyl acetate (37.2 L) and the resulting suspension was heated to 80 ° C. until a clear solution was obtained. The resulting solution was then cooled to 50 ° C. and a sample of the true crystalline title compound (1.0 g) was added as a seed for crystallization. The crystallizing suspension was then cooled to 20 ° C in 4 hours and then granulated at this temperature for 0.5 hours. The product was then collected by filtration and washed with n-heptane (2 x 6.2 L), then dried under vacuum at 45 ° C. for 11 hours. The resulting white solid (5.5 kg, 13.8 mol) was then suspended in isopropyl acetate (55.0 L) and heated to 80 ° C. until a clear solution was obtained. The resulting solution was cooled to 50 ° C. and a sample of the true crystalline title compound (1.0 g) was added as

- 38,006154 seeds for crystallization. The crystallization suspension was then cooled to 20 ° C in 4 hours and then granulated at this temperature for 22.5 hours. The product was then collected by filtration and washed with n-heptane (2 x 5.5 L), then dried under vacuum at 45 ° C. within 16.5 hours to obtain the title product (5.15 kg, 12.9 mol, 94% yield); melting point (heptane) 121 ° C; ¹ H NMR (COC1 ₃ , 300 MHz) 5: 1.06-1.37 (t, 7H), 1.42 (q, 9H), 1.50-1.67 (t, 5H), 1.67-1.86 (t, 5H), 1.86-2.18 ( t, 5H), 2.30-2.58 (t, 1H), 2.80-2.93 (t, 1H), 3.29 (q, 3H), 3.35 (μ, 2H), 7.29 (k br, 3H). Analit. found C, 66.20; H 10.26; Ν 3.50; for C ₂₂ H ₄ ^ O ₅ C 66.13 is required; H 10.34; Ν 3.51%

Preparatory Example 69. 1 - [(28) -2- (tert-Butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylic acid.

The product from Preparation 68 and (+) - pseudoephedrine was recrystallized nine times from hexane to give a white crystalline solid. This salt was dissolved in ethyl acetate, washed with 0.5 M hydrochloric acid, dried over magnesium sulfate and concentrated in vacuo. (8) the acid was obtained in 31% yield as a light yellow oil with more than 90% enantiomeric excess according to NMR analysis of δ 3.3 peak (+) - pseudoephedrine salt; ¹ H NMR (СОС1 ₃ 400 MHz) δ: 1.4 (q, 9H), 1.4-1.7 (t, 7H), 1.75-1.9 (t, 2H), 2.0-2.15 (t, 3H), 2.35-2.45 (t , 1H); 3.3 (q, 3H); 3.3-3.4 (t, 2H); [α] _ο -5.2 (E1OH, p 1.2).

Alternatively, the compound from Preparation 69 was prepared as follows.

(18, 28) - (+) - pseudoephedrine (2.13) was added to a solution of the product from Preparation 68 (3.90 kg, 13.0 mol) in heptane (58.5 L, total weight of the solution 44.0 kg). kg, 12.9 mol) in a nitrogen atmosphere at 20 ° C. The suspension was then heated to 70 ° C. with stirring until a clear solution was obtained. The solution was then cooled to 40 ° C., and a sample of the true crystalline title compound (0.8 g) was added as a seed for crystallization. The temperature of the mixture was maintained at 40 ° C for 2 h, then the suspension was cooled to 20 ° C in 6 h. The product was then collected by filtration and washed with heptane (2 x 2.3 L), then dried under vacuum for 22 h at 50 ° C to obtain (18.28) 1-hydroxy-Y-methyl-1-phenyl-2-propanaminium-1 - [(28) -2- (tert-butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylate (3.20 kg, 6.87 mol, 53% yield as a 86:14 mixture of diastereoisomeric salts, as determined by ¹ H NMR). The product (3.20 kg, 6.87 mol) was then suspended in heptane (30 L) and heated to 70 ° C. until a clear solution was obtained. The resulting solution was then cooled to 58 ° C and a sample of the true crystalline title compound (1.0 g) was added as a seed for crystallization. The solution was then kept at 58 ° C for 1 h and then cooled to 20 ° C in 6 h. The suspension was then granulated at 20 ° C for 12 h. The product was then collected by filtration and washed with heptane (2x2 L). It was dried in a vacuum dryer at 50 ° C for 22.5 hours to obtain (18.28) -1-hydroxy-Y-methyl-1-phenyl-2-propanaminium-1 - [(28) -2- (tert- butoxycarbonyl) -4methoxybutyl] cyclopentanecarboxylate as a white crystalline solid (2.35 kg, 5.0 mol, 73% yield). Melting point (heptane) 95 ° C; ¹ H NMR (СОС1 ₃ 300 MHz), δ: 1.08 (6, 3Н), 1.48 (q, 10 N), 1.56-1.74 (t, 4Н), 1.74-1.90 (t, 2Н), 1.90-2.03 (t , 2H), 2.03-2.27 (t, 2H), 2.4-2.53 (t, 1H), 2.66 (q, 3H), 3.08 (6μ, 1H), 3.24 (q, 3H), 3.38 (μ, 2H), 4.58 (6, 1H), 7.27-7.45 (t, 5H), 7.70 (q, L, 3H); Found analyte: C 67.06; H, 9.35; Ν, 3.04; C ₂₆ H ₄ ^ O ₆ requires C 67.07; H, 9.31; Ν 3.01%. The title compound was prepared by disrupting the salt as follows. To a stirred suspension of (18.28) -1hydroxy-Y-methyl-1-phenyl-2-propanaminium-1 - [(28) -2- (tert-butoxycarbonyl) -4-methoxybutyl] cyclopentanecarboxylate (210 g, 0.45 mol) in deionized water (1.26 L) and isopropyl acetate (1.47 L) was added aqueous hydrochloric acid (99.5 ml of a 5 M solution, 0.50 mol) until the pH of the aqueous layer was in the range between 2 and 3. The layers were then separated, and the aqueous phase was extracted with isopropyl acetate (630 ml). The organic extracts were then combined and washed with saturated brine (420 ml). The organic phase was then concentrated by atmospheric distillation (to remove 1.4 L of isopropyl acetate) to obtain the title compound as a solution in isopropyl acetate, which was used directly in the next step. An aliquot can be taken and the solvent removed to obtain a sample for analysis;

Ή NMR (СОС1 ₃ 300 MHz) δ: 1.44 (q, 9H), 1.48-1.59 (t, 2H), 1.59-1.72 (t, 5H), 1.72-1.93 (t, 2H), 2.032.18 (t, 3H), 2.35-2.46 (t, 1H), 3.31 (q, 3H), 3.38 (ΐ, 2H); LAM8 (ΕΙ): t / ζ 244 [M-C ₄ H ₈ ] ⁺ , 227 [M-C4H9O] ⁺ , 199 [M-C4H ₉ O ₂ C] ⁺ ; SS (injector program: initial temperature 0 ° C, speed 150 ° C / min, final temperature 230 ° C; drying program: initial temperature 100 ° C, speed 10 ° C / min, final temperature 230 ° C, end time 20 min ; BP-21 column 25 mx 0.25 mm, inner diameter x 0.25 μm ET; HIS detector), retention time 16.0 min; ΕΡΕΟ (column: Sigatak AO (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.); Mobile phase to wash the sample: hexane / ΙΡΑ / ΟΕΑ (diethylaniline) (80/20 / 0.5 v / v / v); flow rate: 1.0 ml / min; temperature: okru

- 39 006154 living medium; injected volume: 20 μl; detection: EE8B (evaporative light scattering detector). Run time: 20 min, then 10 min washing with hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), Then 10 min washing with hexane / 1PA / acetic acid (98/2 (0.1 v / v / v). Retention time: minor enantiomer 15.5 min (3.3%), main enantiomer 17.5 min (96.7%). Alternatively, the product from Preparation 69 was obtained by asymmetric hydrogenation using a number of catalysts and the following conditions.

1) Hydrogenation 1.

Starting materials from step (c) below (62 mg, 0.21 mmol) and [(B) - (+) - 2,2'-bis (diphenylphosphino) 1,1'-binaphthylchloro (paracymol)] ruthenium chloride (1 Ogd. SN. 1994, 59, 3064-76) (2.0 mg, 0.0021 mmol) were loaded into a pressure vessel. The vessel was purged with nitrogen at an overpressure of 10 bar (1 MPa) and then vented. This purge procedure was then repeated 4 more times. Then, degassed methanol (2 ml) was added. An excess hydrogen pressure (10 bar (1 MPa)) was created in the vessel, then vented and an excess hydrogen pressure (10 bar (1 MPa)) was again created. The mixture was stirred at 65 ° C (oil bath temperature) for 18 hours. After cooling to room temperature, the pressure was removed and the solvent was removed under reduced pressure to obtain the title compound as an oil, HPBC (column: SYG1RACO AO (25x0.46 cm ); mobile phase: hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.); mobile phase for washing the sample: hexane / 1PA / EEA (80/20 / 0.5 vol. (v / v) with a mixture of hexane / 1PA / acetic acid (98/2 / 0.1 v / v / v), then 10 min washing with a mixture of hexane / 1PA / acetic acid (98/2 / 0.1 v / v / about.). Retention time: At enantiomer 15.5 min (3.3%), 8 enantiomer 17.5 min; 91% conversion. 8-enantiomer, enantiomeric excess of 97%.

2) Hydrogenation 2.

The starting material from step (c) is lower (82 mg, 0.27 mmol), sodium tert-butylate (25 mg, 0.26 mmol) and [(8) -3.3 ', 4.4', 5.5 '-hexamethyl (6,6'-diphenyl) -2,2'-diyl] bis (diphenylphosphino) ruthenium bis (trifluoroacetate) (see AO 01/94359) (2.5 mg, 0.0027 mmol) was loaded into a vessel under pressure. The vessel was purged with nitrogen at an overpressure of 10 bar (1 MPa) and then vented. This purge procedure was then repeated 4 more times. Then, degassed methanol (2 ml) was added. An excess hydrogen pressure (10 bar (1 MPa)) was created in the vessel, then vented and an excess hydrogen pressure (10 bar (1 MPa)) was again created. The mixture was then stirred at 65 ° C for 18 hours. The vessel was allowed to cool to room temperature and the pressure was removed. Ethyl acetate / heptane (1: 1, 10 ml) and hydrochloric acid (1 M, 5 ml) were then added to the reaction mixture. The organic phase was separated and dried over magnesium sulphate, the solvent was removed under reduced pressure to obtain the title compound as an oil, NRBS (column: Syga1Rac ΑΌ (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid (98 / 2 / 0.1 vol./about./vol.); Mobile phase for washing the sample: hexanLRA / BEA (80/20 / 0.5 vol./about./vol.); Flow rate: 1.0 ml / min; temperature: ambient; injected volume: 20 μl; detection: EE8B). Run time: 20 min, then 10 min washing with hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), Then 10 min washing with hexane / 1PA / acetic acid (98/2 (0.1 v / v / v). Retention time: B enantiomer 15.5 min (3.3%), 8 enantiomer 17.5 min; over 98% conversion, B-enantiomer, enantiomeric excess 91%.

3) Hydrogenation 3.

The same method is used as described for hydrogenation 2 above, but [(B) - (6,6'-dimethoxybiphenyl) -2,2'-diyl] bis (diphenylphosphino) ruthenium bis (trifluoroacetate) (EP398132) is used as catalyst to give the title compound as an oil, NRBS (column: Syga1Rak AB (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid (98/2 / 0.1 v / v / v .); mobile phase for washing the sample: hexane / 1PA / BEA (80/20 / 0.5 vol./about./vol.); flow rate: 1.0 ml / min; temperature: ambient; injected volume: 20 μl; detection: EB8B) Run time: 20 min, t m 10 min washing with a mixture of hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), then 10 min washing with a mixture of hexane / 1PA / acetic acid (98/2 / 0.1 vol. / rev./ob.). Retention time: B-enantiomer 15.5 min (3.3%). 8-enantiomer 17.5 min; 57% conversion, 8-enantiomer, enantiomeric excess over 98%.

4) Hydrogenation 4.

The starting material from step (1) is lower (80 mg, 0.25 mmol) and [(B) - (-) - 4,12-bis (diisopropylphosphino) - [2.2] -paracyclofano- (1,5-cyclooctadiene)] rhodium (1) tetrafluoroborate (Ат. At. SN. 8oc. 1997, 119, 6207-6208) (1.8 mg, 0.0025 mmol) was loaded into a pressure vessel. The vessel was purged with nitrogen at an overpressure of 10.5 bar (1.05 MPa) and then vented. This purge procedure was then repeated 4 more times. Then, degassed methanol (2 ml) was added. An excess hydrogen pressure (10.5 bar (1.05 MPa)) was created in the vessel, then vented and again placed under an excess hydrogen pressure (10.5 bar (1.05 MPa)). The mixture was then stirred at room temperature for 18 hours and the pressure removed. Tert-butyl methyl ether and 2 M hydrochloric acid were added to the reaction mixture, and the phases were mixed. The organic phase was separated, dried over magnesium sulfate, the solvent was removed under reduced pressure to obtain the title compound as an oil, NRBS

- 40 006154 (column: ΟιίΓαΙΡαΚΑΩ (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid (98/2 / 0.1 vol / vol / vol); mobile phase for washing the sample: hexane / ΙΡΑ / ΌΕΑ (80/20 / 0.5 vol./about./vol.); Flow rate: 1.0 ml / min; temperature: ambient; injected volume: 20 μl; detection: ΕΌ8Ό). Run time: 20 min, then 10 min washing with hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), Then 10 min washing with hexane / 1PA / acetic acid (98/2 (0.1 v / v / v). Retention time: Canantiomer 15.5 min (3.3%). 8-enantiomer 17.5 min; over 98% conversion, K-enantiomer, enantiomeric excess 91%.

5) Hydrogenation 5.

The starting material from step (1) is lower (80 mg, 0.25 mmol) and [(8) -3,3 ', 4,4', 5,5'-hexamethyl (6,6'-diphenyl) -2, 2'-diyl] bis (diphenylphosphino) ruthenium bis (trifluoroacetate) (see \ νϋ 01/94359) (2.3 mg, 0.0025 mmol) was loaded into a pressure vessel. The vessel was purged with nitrogen at an overpressure of 10.5 bar (1.05 MPa) and then vented. This purge procedure was then repeated 4 more times. Then, degassed methanol (2 ml) was added. An excess hydrogen pressure (10.5 bar (1.05 MPa)) was created in the vessel, then vented and again placed under an excess hydrogen pressure (10.5 bar (1.05 MPa)). The mixture was then stirred at 45 ° C for 18 hours and then allowed to cool to room temperature. The pressure was removed and tert-butyl methyl ether and 2 M 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 then removed under reduced pressure to obtain the title compound as an oil, HPBC (column: Syga1Pak ΑΌ (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid ( 98/2 / 0.1 vol./about./vol.); Mobile phase for washing the sample: hexane / ΙΡΑ / ΏΕΑ (80/20 / 0.5 vol./about./vol.); Flow rate: 1 , 0 ml / min; temperature: ambient; injected volume: 20 μl; detection: ΕΌ8Ό). Run time: 20 min, then 10 min washing with hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), Then 10 min washing with hexane / 1PA / acetic acid (98/2 (0.1 v / v / v). Retention time: K-enantiomer 15.5 min; 8-enantiomer 17.5 min; over 98% conversion, K-enantiomer, enantiomeric excess of 97%.

6) Hydrogenation 6.

The starting material from step (1) is lower (80 mg, 0.25 mmol) and [(K) - (+) - 2,2'-bis (diphenylphosphino) 1,1'-binaphthyl] ruthenium bis (trifluoroacetate)] ( 2.4 mg, 0.0025 mmol) or [(K) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthylchloro (paracymol)] ruthenium chloride (1. Ogd. SN. 1994 , 59, 3064-76) (2.4 mg, 0.0025 mmol) were loaded into a pressure vessel. Using the same procedures as described in Preparatory Example 6, the title compound was obtained in the form of an oil, HPBC (column: CHAl1Can ΑΌ (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid (98/2 / 0.1 vol / vol / vol); mobile phase for washing the sample: hexane / ΙΡΑ / / (80/20 / 0.5 vol / vol / vol); flow rate: 1.0 ml / min; temperature: ambient; injected volume: 20 μl; detection: ΕΌ8Ό). Run time: 20 min, then 10 min washing with hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), Then 10 min washing with hexane / 1PA / acetic acid (98/2 (0.1 v / v / v). Retention time: K-enantiomer 15.5 min; 8-enantiomer 17.5 min; over 98% conversion, 8-enantiomer, enantiomeric excess over 98%.

7) Hydrogenation 7.

The starting material from step (1) below (80 mg, 0.25 mmol) and [(K) - (6,6'-bis (dimethoxybiphenyl) -2,2'diyl) bis (diphenylphosphino)] ruthenium bis (trifluoroacetate) (EP398132) (2.3 mg, 0.0025 mmol) was loaded into a pressure vessel. Using the same procedures as described in hydrogenation 6, the title compound was obtained in the form of an oil, HPBC (column: CHAl1Can ΑΌ (25 x 0.46 cm); mobile phase: hexane / 1PA / acetic acid (98/2/0 , 1 v / v / v); mobile phase for washing the sample: hexane / IΡΑ / ^ ΕΑ (80/20 / 0.5 v / v / v); flow rate: 1.0 ml / min; temperature: ambient; injection volume: 20 μl; detection: ΕΌ8Ό). Run time: 20 min, then 10 min washing with hexane / 1PA / acetic acid (98/2 / 0.1 vol./about./vol.), Then 10 min washing with hexane / 1PA / acetic acid (98/2 (0.1 v / v / v). Retention time: K-enantiomer 15.5 min; 8-enantiomer 17.5 min; over 98% conversion, 8-enantiomer, enantiomeric excess over 98%.

Getting the starting materials.

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

A solution of diisopropylamine (35.0 ml, 250 mmol) in THP (70 ml) was cooled to −15 ° C. under a nitrogen atmosphere. Then n-butyllithium (2.5 M, 100 ml, 250 mmol) was added dropwise, keeping the temperature below -10 ° C. To the resulting solution was added a solution of 1- (3-tert-butoxy-3-oxopropyl) cyclopentanecarboxylic acid (see EP274234B1, Example 35) (27.52 g, 113.6 mmol) in THP (50 ml), and the reaction mixture was stirred at a temperature of from -10 to -15 ° C for 1 h. A solution of methyl methoxyacetate (18.0 ml) in THP (20 ml) was added to the reaction mixture, and the resulting mixture was allowed to warm to room temperature and then stirred for 19 h. Tert-butyl methyl ether (300 ml) and deionized water (300 ml) were added to the reaction mixture, and the aqueous phase was then acidified. 2M hydrochloric acid to pH 3 with stirring. The phases were separated and the aqueous phase was then extracted with tert-butyl methyl ether (250 ml). The combined organic phases were then washed with water (250 ml) and then with brine (250 ml), dried over magnesium sulfate and the solvent was then removed with pony

- 41 006154 female pressure. The crude title compound was then purified by flash chromatography on silica gel using ethyl acetate / heptane (1: 2 to 1: 1) as an eluent to obtain the title compound (17.35 g, 55.2 mmol, 49% yield) ); ¹ H NMR (400 MHz, SES1;) δ: 1.43 (8, 9H), 1.69-1.47 (t, 6H), 2.17-2.05 (t, 2H), 2.18 (άά, 1H), 2.32 (άά, 1H ), 3.42 (8, 3H), 3.59 (!, 1H), 4.17 (q, 2 H); ¹³ C NMR (100 MHz, SES1;) δ: 24.7, 27.8, 34.9, 35.8, 36.7, 53.2, 53.3, 59.2, 82.3, 168.3,

183.4, 203.2.

b) 8-Methoxymethyl-6-oxo-7-oxa-spiro [4,5] decane-9-carboxylic acid tert-butyl ether.

A solution of the product from step (a) above (10.50 g, 33.4 mmol) in methanol (100 ml) was cooled to a temperature of 0 to -5 ° C in a nitrogen atmosphere. Sodium borohydride (2.02 g, 53.4 mmol) was added in portions to the resulting solution, keeping the temperature below 0 ° C. The reaction mixture was then stirred for 1 hour. Ethyl acetate (150 ml) and water (150 ml) were then added, and the aqueous phase was acidified by the addition of hydrochloric acid (50 ml of a 2 M solution) with stirring. The phases were then separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were then washed with water (50 ml) and then brine (50 ml). The combined washings were then extracted with ethyl acetate (100 ml). The combined ethyl acetate extracts were then dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain a pale yellow oil (11.29 g), which was used in the next step without further purification. A portion of this oil (10.89 g, 34.4 mmol) was dissolved in THE (100 ml) under a nitrogen atmosphere, and dicyclohexylcarbodiimide (7.10 g, 34.4 mmol) was added to the resulting solution. The mixture was then stirred at room temperature for 19 hours. Methanol (5 ml) and acetic acid (2 ml) were then added to the reaction mixture, and the mixture was then stirred for 30 minutes. The solvent was then removed under reduced pressure. The crude product was then suspended in ethyl acetate (50 ml) and the reaction by-products were removed by filtration. The filter residue was washed with ethyl acetate (50 ml), and the filtrate was then concentrated under reduced pressure. The crude title compound was then purified by flash chromatography on silica gel using ethyl acetate / heptane (1: 3 to 2: 3) as an eluent to give the title compound as a 2: 1 mixture of diastereoisomers (8.19 g, 27 4 mmol, 80%). For analytical purposes, the sample was purified by flash chromatography on silica gel using a mixture of E! OAc / heptane ⁺ (1: 2) as an eluent; 1) a spot with a higher CT (separate diastereoisomer);

Ή NMR (400 MHz, ATP1 ₃ ). δ: 1.47 (8, 9H), 1.50-2.15 (t, 9H), 2.30 (t, 1H), 2.90 (! ά, 1H), 3.38 (8, 3H), 3.58 (ά, 2H), 4.62 (ά !, 1H); ¹³ C NMR (100 MHz, SES1 _; ) δ: ppm (parts per million) 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; 2) Spot with lower BT (not completely separated, 3.5: 1 mixture of diastereoisomers); 'H NMR (400 MHz, SES1 ₃ ) δ: (main isomer) 1.47 (8, 9H), 1.49-2.10 (t, 8H), 2.18 (άά, 1H), 2.43 (t, 1H), 3.03 (t, 1H), 3.35 (8, 3H), 3.60-3.67 (t, 2H), 4.72 (q, 1H).

c) 1- (2-tert-Butoxycarbonyl-4-methoxy-but-2E-enyl) -cyclopentanecarboxylic acid.

To a solution of the product from step (b) above (6.11 g, 20.49 mmol) in toluene (50 ml) was added 1.8 diazabicyclo [5.4.0] undec-7-ene (3.7 ml, 24.58 mmol) ), and the resulting solution was then refluxed under nitrogen for 5 hours. The solution was then cooled to room temperature and the solvent was removed under reduced pressure. To the resulting residue was then added deionized water (100 ml) and the mixture was then extracted with tert-butyl methyl ether (30 ml). The phases were then separated, and the aqueous phase was acidified to pH 2 with hydrochloric acid (15 ml of a 2 M solution) and then extracted with tert-butyl methyl ether (2 x 30 ml). The combined organic extracts were then washed with water (30 ml) and brine (30 ml) and dried over magnesium sulfate. The solvent was then removed under reduced pressure to obtain the crude title compound (6.29 g), which was then crystallized from heptane (15 ml) at 0 ° C. The resulting solid was collected by filtration, then washed with ice heptane (2 x 5 ml) to give the title compound as a white solid (1.79 g, 6.0 mmol, 29%, E-isomer, determined based on chemical shifts ); ^! H NMR (400 MHz, SES1;) δ: 1.47 (8, 9H), 1.45-1.70 (t, 6H), 2.05-2.10 (t, 2H), 2.74 (8, 2H), 3.36 (8, 3H), 4.09 (ά, 2H), 6.75 (!, 1H); ¹³ C NMR (100 MHz, SES1;) δ: 23.9, 28.0, 34.1, 35.0, 55.0, 58.6, 69.2, 80.8, 132.7, 139.1, 167.3, 183.3.

The filtered liquids were concentrated to give a yellow oil (4.02 g). This mixture was purified by flash chromatography on silica gel using ethyl acetate / heptane (1: 2 + 0.5% acetic acid) as an eluent to give an additional amount of the title compound and a colorless oil (2.43 g, 1.1: 1 E / Ζ ratio); 1- (2-tert-butoxycarbonyl-4-methoxy-but-22-enyl) cyclopentanecarboxylic acid; ¹ H NMR (400 MHz, SES1 ₃ ). δ: (key signals) 1.48 (8, 9Н), 2.65 (8, 2Н), 3.33 (8, 3Н), 4.29 (ά, 2Н), 5.99 (!, 1 Н).

A sample of vinyl ester 1 - [(3E) -2- (tert-butoxycarbonyl) -4-methoxy-3-butenyl] cyclopentanecarboxylic acid was also isolated by flash chromatography (E geometry was determined based on the binding constant) ^:! H NMR (400 MHz, SES1;) δ: 1.42 (8, 9H), 1.40-1.70 (t, 6H), 2.03 (ά, 2H), 2.06 (t, 1H), 2.17 (t, 1H), 2.83 ( 8, 1H), 3.49 (8, 3H), 4.66 (άά, 1H); 6.35 (ά, 1H); ¹³ C NMR (100 MHz, SES1;) δ: 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.

- 42 006154

A stirred suspension of sodium hydride (14.4 g of a 60% dispersion in mineral oil, 360 mmol) in ΤΗΕ (300 ml) was cooled to 0 ° C in a nitrogen atmosphere. To the resulting suspension was added, over a period of 45 minutes, a solution of benzyl tert-butyl malonate (90.0 g, 360 mmol) in 45 (500 ml). The reaction mixture was allowed to warm to room temperature and then stirred for 1 h. The reaction mixture was then cooled again to 0 ° C, and then a solution of 2-bromoethyl methyl ether (50.0 g, 360 mmol) was added over a period of 0.5 h. ΤΗΕ (100 ml). The reaction mixture was then allowed to warm to room temperature and allowed to stir for 19 hours. The reaction mixture was then refluxed for 24 hours, then cooled to room temperature. Deionized water (500 ml) was added to the reaction mixture, and the product was then extracted with ethyl acetate (3 x 500 ml). The organic phases were combined, dried over magnesium sulfate and then concentrated by distillation under reduced pressure to obtain the product as a crude oil (100 g). The product was then purified by silica gel column chromatography using 10% diethyl ether in heptane, then 20% diethyl ether in heptane as an eluent, to give the title compound as an oil (37.1 g, 120 mmol, 33 % yield); TLC (diethyl ether / heptane 3: 7, manifestation by immersion in Dragendorf solution) K _£ 0.25; 'Η NMR (300 MHz, SES1 ₃ ) δ: 1.4 (δ, 9Η), 2.13 (άΐ, 2Η), 3.30 (δ, 3Η), 3.43 (ΐ, 2Η), 3.51 (ΐ, 1Η), 5.20 (ά , 2Η), 7.297.40 (t, 5Η).

d) 2- (tert-butoxycarbonyl) -4-methoxybutanoic acid.

To a solution of the product from step (g) above (37.1 g, 120 mmol) in dioxane (740 ml) and water (111 ml) was added potassium hydroxide (6.73 g, 120 mmol) with stirring. The resulting solution was then stirred at room temperature for 19 hours. The solvent was then removed by distillation under reduced pressure, and the resulting concentrate was diluted with deionized water (300 ml). The aqueous solution was then washed with diethyl ether (3 x 400 ml). To the aqueous phase was then added 1 M hydrochloric acid to pH 2. The acidified solution was then extracted with ethyl acetate (3 x 400 ml) and the combined organic layers were then dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain the title compound as an oil (14.7 g, 67.4 mmol, 56% yield); TLC (diethyl ether / heptane 3: 7, manifestation by immersion in Dragendorf solution) K _£ 0.20; '11 NMR (300 MHz, SES1 ₃ ) δ: 1.48 (δ, 9Н), 2.16 (άΐ, 2Н), 3.16 (δ, 3Η), 3.27-3.51 (t, 3Η).

e) tert-butyl-2- (2-methoxyethyl) acrylate.

To the solution of the product from step (e) above (20.8 g, 95.3 mmol) in pyridine (170 ml) was added piperidine (1.70 ml, 19.1 mmol), then paraformaldehyde (3.89 g, 130 mmol) ) The resulting mixture was heated at 63 ° C. for 3.5 hours. The reaction mixture was then allowed to cool to room temperature and stirred for 19 hours. The solvent was then removed by distillation under reduced pressure. Deionized water (250 ml) was then added to the concentrate, followed by hydrochloric acid (200 ml of a 2 M solution). The aqueous phase was then extracted with diethyl ether (1 x 350 ml, then 2 x 400 ml). The combined organic extracts were then washed with hydrochloric acid (400 ml of a 2 M solution) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the title compound as an oil, Η NMR (300 MHz, CES1 ₃ ) δ: 1.50 (δ, 9Η), 2.56 (ΐ, 2H), 3.35 (δ, 3Η), 3.463. 53 (t, 2Η), 5.54 (δ, 1Η), 6.13 (δ, 1Η); ШМ8 (ΕΣ (electron impact ionization)): t / ζ 130 | Μ-ί '. · | Η ₈ |'. 113 [M-C ₄ H ₉ O] ⁺ .

g) tert-Butyl- (2E) -2- (2-methoxyethyl) -3 - [(4-methylphenyl) sulfonyl] -2-propenoate.

To a stirred solution of paratoluenesulfanyl iodide (Σ. Sc. 8 ° C. Regksh Τπιηδ. 1, 1988, 1029) (11.4 g, 40.2 mmol) in dichloromethane (25.0 ml) was added a solution of the product from step (e) above (5 , 0 g, 26.8 mmol) in dichloromethane (10 ml) at room temperature under a nitrogen atmosphere. The resulting solution was then stirred for 60 hours. The reaction mixture was then cooled to 0 ° C and triethylamine (5.4 g, 53.4 mmol) was added over a period of 15-20 minutes, maintaining the temperature at 0 ° C. The resulting mixture was then stirred at 0 ° C for 0.5 h, then warmed to room temperature and stirred for another 5 h. The reaction was then quenched by the addition of deionized water (100 ml) and the layers were then separated. The aqueous phase was then extracted with dichloromethane (100 ml), the organic extracts were combined and washed with hydrochloric acid (50 ml of a 1 M solution). The organic layer was then washed with aqueous sodium thiosulfate (100 ml of a 5% (w / v) solution) and then with deionized water (100 ml). The organic layer was then dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain the crude product as a dark oil (7.5 g, 22.0 mmol, 82% yield). This reaction was repeated twice under the same conditions, and the combined crude products (74.6 g) were then purified by flash chromatography on silica gel using heptane / ethyl acetate (4: 1) as an eluent to give the title compound as white crystalline solid (48.0 g); melting point (heptane / ethyl acetate) 84-86 ° C; TLC (ethyl acetate / heptane 1: 4, manifestation in UV (ultraviolet radiation) at 254 nm) K _£ 0.20; 'Η NMR (300 MHz, SES1 ₃ ) δ ppm 1.45 (δ, 9Η), 2.48 (δ, 3Η), 3.14 (ΐ, 2Η), 3.30 (δ, 3Η), 3.51 (ΐ, 2Η), 7.10 (δ, 1Η), 7.35 (ά, 2Η), 7.83 (ά, 2Η).

h) 1 - [(1E) -2- (tert-butoxycarbonyl) -4-methoxy-1-butenyl] cyclopentanecarboxylic acid.

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To a stirred solution of lithium diisopropylamide (64.6 ml of a 2 M solution in a THP / heptane / ethylbenzene mixture) in anhydrous THR (200 ml) at 0 ° C was added a solution of cyclopentanecarboxylic acid (7.0 ml, 58.7 mmol) in anhydrous THR (100 ml) for a period of 10 minutes in a nitrogen atmosphere.

The reaction mixture was then allowed to warm to room temperature with stirring for 2.5 hours. The resulting suspension was then cooled to 0 ° C and then zinc chloride (38.2 ml of a 1 M solution in diethyl ether) was added over a period of 1 minute. The reaction mixture was then stirred for 10 minutes, and a solution of the product from step (g) above (20.0 g, 58.7 mmol) in anhydrous THP (160 ml) was added to the resulting solution over a period of 5 minutes. The reaction mixture was then stirred for 2 hours, maintaining the temperature between 0 and 5 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for 19 hours. The reaction was then quenched by the addition of isopropanol (120 ml) and the mixture was then stirred for 1 hour. The reaction mixture was filtered and the solid by-products were then washed with THP (10 ml). Deionized water (400 ml), aqueous sodium hydroxide (200 ml of a 1 M solution) and ethyl acetate (600 ml) were then added to the filtrate. More deionized water (600 ml) was added and the resulting solid was removed by filtration. The layers were then separated and hydrochloric acid (1 M solution) was added to the aqueous phase to pH 2. The aqueous phase was then extracted with ethyl acetate (2 x 700 ml), the organic layers were combined, dried over magnesium sulfate and then the solvent was removed by distillation under reduced pressure to obtain the crude product as a yellow oil (16.7 g). The product was then purified by flash chromatography on silica gel using a dichloromethane / methanol mixture (9: 1) as an eluent to give the title compound as a yellow oil (15.2 g, 50.9 mmol, 87% yield) ; T1.C (dichloro methane / methanol 9: 1, manifestation in UV at 254 nm); _G 0.70; ¹ H NMR (300 MHz, SES1 ₃ ) δ: ppm 1.48 (q, 9H), 1.67-1.90 (t, 6H), 2.37-2.48 (t, 2H), 2.58 (ΐ, 2H), 3.32 (q, 3H), 3.48 (ΐ, 2H), 6.83 (k, 1H); BVM8 (Ε8 negative): t / ζ 253 [M-CO ₂ H] ^- .

i) Sodium 1 - [(1 E) -2- (tert-butoxycarbonyl) -4-methoxy-1-butenyl] cyclopentanecarboxylate.

To a stirred solution of the product from step (h) above (15.0 g, 50.3 mmol) in isopropyl acetate (300 ml) was added sodium methylate (3.0 g, 55.6 mmol). The resulting suspension was stirred for 19 hours at room temperature. The solid was collected by suction filtration and washed with isopropyl acetate, then dried in vacuo at 50 ° C for 19 h to obtain the title compound as a white solid (10.0 g, 31.2 mmol, 62% yield) ); melting point (isopropyl acetate) 195-198 ° C; ¹ H NMR (300 MHz, SES1 ₃ ) δ: ppm 1.48 (q, 9H), 1.51-1.72 (t, 6H), 2.21-2.37 (t, 2H), 2.61 (ΐ, 2H), 3.34 (q, 3H), 3.51 (ΐ, 2H), 6.86 (k, 1H); BVM8 (E8 negative): t / ζ 253 [MCO ₂ \ a | ^- .

Preparatory Example 70. 1 - [(2B) -3-tert-Butoxy-2-methyl-3-oxopropyl] cyclopentanecarboxylic acid.

The title compound was prepared by methods similar to those of Preparations 68 and 69, using methyl iodide instead of 2-bromoethyl methyl ether. Its (+) - pseudoephedrine salt was recrystallized three times from hexane. The title compound was obtained in 28% yield as a pale yellow oil with more than 95% enantiometric excess according to NMR analysis of δ 1.4 peak (+) - pseudoephedrine salt; ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.13 (ά, 3Н), 1.40-1.60 (t, 11Н), 1.60-1.78 (t, 5Н), 2.14 (t, 3Н), 2.38 (t, 1Н) ; [α] π-24.2 (JUN, p 1.2).

Preparatory Example 71. 1 - [(2B) -2- (tert-Butoxycarbonyl) -4-pentyl] cyclopentanecarboxylic acid.

A mixture of (B) -1- [2- (tert-butoxycarbonyl) -4-pentenyl] -cyclopentanecarboxylic acid (\\ 'O 9113054, example 10) (10 g, 35.4 mmol) and 10% palladium on carbon (600 mg) in dry ethanol (25 ml) was hydrogenated at 1 atm (1.013.10 ⁵ Pa) and room temperature for 18 hours. The reaction mixture was filtered through AgYose1® and the filtrate was evaporated under reduced pressure to obtain the title compound as yellow oils, 9.6 g, 95%; ¹ H NMR (SES1 ₃ 0.86 (ΐ, 3H), 1.22-1.58 (t, 15H), 1.64 (t, 4H), 1.78 (άά, 1H), 2.00-2.18 (t, 3H), 2.24 (t, 1H) ); [α] ο = -3.3 ° (c = 0.09, ethanol).

Preparatory Example 72. 3- (4-Methoxyphenyl) -2-propenitrile.

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Solution of 4-iodoanisole (1 g, 4.2 mmol), acrylonitrile (0.3 ml, 4.7 mmol), tri-ortho-tolylphosphine (243 mg, 0.4 mmol), palladium (P) acetate (90 mg 0.4 mmol) and triethylamine (1.78 ml, 12 mmol) in acetonitrile (20 ml) were refluxed under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with EuAc (50 ml) and washed with 2 M sodium hydrogen carbonate solution. (100 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 a 95: 5 pentane: ethyl acetate mixture, then a 90:10 pentane: ethyl acetate mixture, to give the title compound (414 mg, 2.5 mmol) as a mixture of cis and trans isomers in the form of yellow crystals; ² H NMR (SES13, 400 MHz) δ: 3.8 (s, 3H), 5.7 (b, 1H), 6.9 (b, 1H), 7.2 (b, 1H), 7.4 (b, 2H); LKM8: t / ζ 176 (M + KH4 ⁺ ). Found analytic: C, 74.44; H 5.66; N, 8.36. For C11;. \ 0 · 0.ΙΙΙ; 0 requires C 74.42; H 5.65; Ν 8.41%.

Preparatory Example 73. 3- (4-Methoxyphenyl) -1-propanamine.

A solution of the product from Preparation 72 (414 mg, 2.6 mmol) in a solution of ammonium hydroxide (10 ml) and ethanol (10 ml) was shaken under a hydrogen atmosphere at 40 psi. inch (275.8 kPa) with Ka-Si (Raney nickel) (100 mg) for 12 hours. The reaction mixture was filtered through Α ^ οοё1® and washed with ethanol (20 ml), the filtrate was evaporated in vacuo to give the title compound (183 mg, 1.1 mmol) as a yellow oil; ² H NMR (SES1 ₃ , 400 MHz) δ: 1.7 (b3, 2H), 2.0 (b3, 2H), 2.5 (b, 2H), 2.7 (b3, 2H), 3.7 (s, 3 H), 6.7 ( b, 2H); 7.0 (b, 2H); LKM8: t / ζ 376 (M + H ⁺ ).

The following compounds of formula (Sha), that is, compounds of general formula ΙΙΙ, where X is - (CH2) 3-, were prepared by methods similar to those described in Preparatory Examples 72 and 73, from these precursors.

n, h U (P1a)

Table 3

Prep. example Prev Υ Analit. data 74 1-bromo-4-ethylbenzene (AIPSBET1CO1 Co.) hl ¹ H NMR (CO3, 400 MHz) δ: 1.1 (b3, 3H), 1.7 (b3, 2H), 2.6 (b3, 5H), 3.4 (b3, 1H), 7.1 (b3, 4H). LRMZ: t / ζ 164 (M + H ⁺ ). 75 4-bromo-Zmethylanisole (1_ apsaz1eg) Me ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.7 (h, 2H), 2.25 (s, 3H), 2.58 (t, 2H), 2.7 (t, 2H), 3.72 (ά, 3H), 6.65 (t , 2H); 7.01 (t, 1H). LRMZ: t / ζ 180 (M + H *). 76 5-iodine-2,3-dihydrobenzofuran (Maubps! De Syepisa15) ¹ H NMR (СОС1з, 400 MHz) δ: 1.8 (t, 2Н), 2.6 (ΐ, 2Н), 2.7 (ί, 2Н), 3.1 (t, 2 Н), 3.3 (1, 2Н), 4.5 (1 , 1H), 6.6 ά, 1H), 6.9 (ά, 1H), 7.1 (s, 1H). 77 2,4-difluoroiodo-benzene (ΑΙάποίΊ Spegp1sa1 Co.) XU ' Ή NMR (СОС1 ₃ , 400 MHz) δ: 1.64 (t, 2Н), 2.6 (ί, 2Н), 2.7 (1, 2Н), 6.7 (t, 2Н), 7.1 (t, 1Н). LAMZ: t / ζ 172.1 (M + H). 78 2 bromonaphthalene ¹ (ΑΙάποή Siet1sa1 So.) X; U ¹ H NMR (ΜβΟϋ, 400 MHz) δ: 2.0 (t, 2H), 2.9 (t, 4H), 7.4 (t, 3H), 7.6 (t, 1H), 7.7 (t, 3H). LRMZ: t / ζ (E3 ⁺ ) 186 (M + H). 79 1-bromonaphthalene (A1s1ps! 1 Syetua! Co.) H NMR (СОС1 ₃ , 400 MHz) δ: 2.1 (t, 2Н), 3.0 (t, 2Н), 3.1 (t, 2Н), 7.3 (t, 2Н), 7.5 (t, 2Н), 7.7 (t, 2H), 7.8 (t, 1H). ίΡΜ3: t / ζ (E3 ⁺ ) 186 (M + H). 80 Prep. example 114 ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.781.88 (t, 2Н), 2.68-2.83 (t, 4Н), 7.19-7.36 (t, ЗН), 7.70-7.77 (t, 2Н), 7.92 ( ά, 2H), 8.69 (ά, 1H).

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Prep. example Prev Υ Analit. data 81 3,4 ethylenedoxybromobenzene fapsaz1eg δγπίΐιβδίδ) / CO The crude amine was used without purification. Data for a mixture of cis- and trans-vinyl nitriles: ¹ H NMR (300 MHz, COC1 ₃ ) δ: 4.254.39 (t, 4H), 5.30 and 5.70 (ά, 1H), 6.83-7.00 (t, 3H), 7.21 -7.40 (t, 1H). 82 2-bromoanisole fapsase ^ ex 3γηΦβδίδ) with ¹ H NMR (МеСУ, 400 MHz) δ: 1.9 (t, 2Н), 2.6 (1, 2Н), 2.8 φ, 2Н), 3.8 (δ, ЗН), 6.8 (1, 1Н), 6.9 (ά, 1Н ), 7.1 (ά, 1H), 7.2 (1.1 N). LRMZ: t / ζ (T3 ⁺ ) 166 (M + H). 83 4-bromotoluene (ΑΙάποΙι Сет1са1 Со.) BUT ¹ H NMR (MeCIS, 400 MHz) δ: 1.9 (t, 2H), 2.2 (δ, 3H), 2.6 (1, 2H), 2.8 (1, 2H), 7.0 (δ, 4H). 1_YaMZ: t / ζ (Т3 ⁺ ) 150 (М + Н). 84 3 iodobenzyloxybenzene (ΛΙάποϊΊ CHet1ca1 Co.) one hundred ¹ H NMR (MeCIS, 400 MHz) δ: 1.8 φδ, 2H), 2.6 (Lt, 4H), 5.0 (Lb, 2H), 6.9 (0, H), 7.1 (t, 2H), 7.3 (t, H ) LNMZ: t / ζ (T3 ⁺ ) 242 (M + H). 85 3-bromoanisole (1-apsaz1eg Zup1eb51z) BUT ¹ H NMR (СОС1 ₃ , 400 MHz) δ: 1.7 (t, 2Н), 2.6 (1, 2Н), 2.7 (1, 2Н), 3.8 (ά, ЗН), 6.3-6.4 (άά, 1Н), 6.7 (άά, 1H), 6.9 (ά, 1H), 7.1 (t, 1H). 86 2,4-dimethoxybromobenzene (ΑΙάποΙι Сет1с1 Со.) LRMZ: t / ζ (T3 ⁺ ) 196 (M + H). 87 5-Bromo-2,2-dimethyl-2,3-dihydrobenzo [b] furan (Prep. Example 126) HCG: ¹ H NMR (400 MHz, СОС1 ₃ ) δ: 1.40 (δ, 6Н), 1.70 (,, 2Н), 2.54 φ 2Н), 2.70 φ 2Н), 2.95 (δ, 2Н), 6.68 (ά, 1Н), 6.86 (ά, 1H); 6.91 (δ, 1H). 1_YaMZ: M + H, 206. (T3 ⁺ ). 88 6-Bromotetrahydrobenzopyran (Prepared, Example 125) AO ¹ H NMR (400 MHz, COC1 ₃ ) δ: 1.621.78 (t, 2H), 1.84-2.03 (t, 2H), 2.44-2.58 (t, 2H), 2.61-2.78 (t, 4H), 4.03- 4.18 (t, 2H), 6.67 (ά, 1H), 6.79-6.93 (t, 2H). Ι-ΚΜ3: t / ζ (M + H) 192, E3 ⁺ . 89 5-bromo-2,2difluorobenzodioxolane (PiogosKet) XXX H NMR (400 MHz, COC1 ₃ ) δ: 1.75 (quintet, 2H), 2.60 (1, 2H), 2.67 f 2H), 6.80-6.95 (hl, 3H). 1.YaMZ: M + H, 216, (E3 ⁺ ). 90 5-bromo-1methyl- [1H] indole-zole (Sub. Example 111) —Me Used untreated without purification and identification

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Prep. example Prev Υ Analit. data 90a 5-Bromo-7methyl-2,3-dihydrobenzo [b] furan (Subt. Approx. 136) ςο Me ¹ H NMR (400 MHz, SODD δ: 1.9 (t, 2H), 2.1 (s, 3H), 2.55 (ί, 2H), 2.85 (ί, 2H), 3.10 (ί, 2H), 4.45 (ί, 2H) ), 6.70 (δ, 1H), 6.80 (δ, 1H). LKMZ: M + H, 192 (E8 ⁺ ). 91 5-Bromo-6methyl-2,3-dihydrobenzo [b] furan (Subtitle Example 138) at ¹ H NMR (400 MHz, COC1 ₃ ) δ: 1.8 (t, 2H), 2.2 (t, 3H), 2.6 (pl, 2H), 2.9 (t, 2H), 3.1 (t, 2H), 4.4 (t , 2H), 6.5 (t, 1H), 6.6 (t, 1H). LJMZ: M + H, 192 (E8 ⁺ ). 92 5-Bromo-2-methyl-2,3-dihydro-1-benzo [b] furan (Subp. Example 127) Ug ¹ H NMR (400 MHz, SIS) δ: 1.45 (b, 3H), 1.90-2.10 (t, 2H), 2.502.63 (t, 2H), 2.88 (bb, 1H), 3.27 (bb, 1H), 4.90 (t, 1H), 6.66 (b, 1H), 6.90 (b, 1H), 6.95 (δ, 1H). 1-PM8: M + H, 192. (E8 ⁺ ).

Preparatory Example 93. 3- (4-Chloro-3-fluorophenyl) -2-propenitrile

Diethyl cyanomethylphosphonate (3.2 ml, 18.9 mmol) was transferred to dry THE (20 ml) at 0 ° C under nitrogen and stirred until 60% Ka11 oil dispersion was added in portions over 10 minutes (756 mg, 18, 9 mmol). The resulting gray suspension was then stirred at 0 ° C for 1 h, then a solution of 4-chloro-3-fluoro-benzaldehyde (Epsa81e8UpFe818) (3 g, 18.9 mmol) in 5 ml of THE was added dropwise. The whole reaction mixture was then allowed to warm to room temperature over 60 hours. Water (5 ml) was added and the mixture was extracted with EJAc (3 x 50 ml). The combined organics were dried (Mg ₈ O ₄ ) and evaporated to a yellow oil, which was purified by column chromatography using 5% EuAc in pentane as an eluent to afford the title product as a mixture of geometric isomers (2.4 g, 70% ); ¹ H NMR (400 MHz, COC13) δ: 5.82 (b, 1H), 7.19 (b, 1H), 7.23 (b, 1H), 7.30 (b, 1H), 7.42 (arr. 1, 1H); EKM8 T8 ⁺ 199.1 (M + KH4 ⁺ ).

Preparatory Example 94. 3- (4-Chloro-3-fluorophenyl) -1-propylamine

The vinyl cyanide from Preparation 93 (500 mg, 2.75 mmol) was transferred to ethanol (36 ml) and a 0.88 × 11 ₃ solution (18 ml) and shaken with 150 mg of 30% (w / w) at an overpressure of 15 psi. inch (103.425 kPa) H ₂ during the night. The catalyst was filtered through a short plug of Lbose1, and the filtrate was evaporated in vacuo, then purified by column chromatography using 90: 10: 1 mixture (OSM, MeOH, Ν ^) as an eluent to obtain the title product (320 mg, 62%) ; ¹ H NMR (400 MHz, SPS1 ₃ ) δ: 1.65-1.78 (t, 1H), 2.53-2.70 (t, 4H), 6.85 (b, 1H), 6.90 (b, 1H), 7.22 (8, 1H) ; EKM8: t / ζ (T8 ⁺ ) 188 (M + H).

The following compounds of formula (Sha), that is, compounds of general formula III, where X is - (CH2) 3-, were prepared by methods similar to those described in Preparatory Examples 93 and 94 from these precursors.

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Prep. example Prev aldehyde Υ Analit. data 95 3-chloro-4-fluorobenzaldehyde (1-apsaz1eg 8up1nez1z) ¹ H NMR (400 MHz, COC1 ₃ ) δ: 1.62-1.77 (t, 2H), 2.55 (ί, 2H), 2.64 (1, 2H), 6.97-6.99 (t, 2H), 7.14 (ά, 1H) . 1.KM8: t / gT8 ⁺ 188.1 (MH ⁺ ). 96 2,3-difluorobenzaldehyde (1-apsaz1eg 8up111e81z) 'BUT ¹ H NMR (400 MHz, COC1 ₃ ) δ: 1.66-1.78 (t, 2H), 2.58-2.75 (t, 4H), 6.38-6.98 (t, 3H). Ι-ΚΜ8: t / ζ Т8 ⁺ 343.1 (2МН ⁺ ). 97 2,6-difluorobenzaldehyde (1-apsaz1e8n1b3e13) E ¹ H NMR (400 MHz, COC1 ₃ ) δ: 1.68-1.83 (t, 2H), 2.57-2.83 (t, 4H), 6.70-6.92 (t, 2H), 7.017.22 (t, 1H). ! _RMZ: t / ζΤδ * 172.1 (MH ⁺ ).

Preparatory Example 102. Quinoline-6-carboxaldehyde.

6-Methylquinoline (A1bpsy Syet1ca1 Co.) (1 g, 7.0 mmol) and selenium dioxide (2.32 g, 21.0 mmol) were combined in the absence of solvent and heated at 100 ° С under nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature, transferred to MeOH and pre-absorbed onto silica gel. Chromatography using a 3: 1 pentane: E1OAc mixture gave the title product (236 mg, 21%); '11 NMR (400 MHz, SBS1 ₃ ) δ: 7.46-7.52 (t, 2H), 7.98 (b, 1H), 8.33-8.37 (t, 2H), 9.03 (b, 1H), 10.18 (q, 1H) ; t / ζ (Ε8 ⁺ ) 315 (2Μ4 ⁺ ).

Preparatory Example 103. 4- (4-Methoxyphenyl) butyramide.

4- (4-Methoxyphenyl) butyric acid (A1pps Syethyl Co.) (2 g, 10.4 mmol) was dissolved in 50 ml Ι) 0'Μ and thionyl chloride (1.85 g, 15.5 mmol) was added dropwise at stirring. After the addition was complete, the mixture was refluxed for 4 hours. The solvent was removed in vacuo, added again and then evaporated, and this addition / evaporation cycle was continued until the thionyl chloride was completely removed from the crude mixture. This mixture was dissolved in 20 ml ΙΧΜ and was added dropwise to a stirred solution of 0.88 N ₃ at 0 ° C. After the addition was complete, everything was stirred for 4 hours, the organic layer was separated, dried (Na ₂ 8O ₃ ) and evaporated to give the title product as a white solid amide (1.5 g), which was used without further purification.

Preparatory Example 104. 4- (4-Hydroxyphenyl) butyramine.

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The product from Preparative Example 103 (38 g, 0.20 mol) was added portionwise to a stirred solution 1L1N ₄ (15 g, 0.40 mol) in 1 L of TNE, and then everything was heated under reflux for 16 h. The excess hydride was destroyed by adding ΕΐΟΑc (400 ml) and most of the solvents were then removed under reduced pressure. Adding 30 ml of 2n. of solution No. 1OH (CAUTION!) completed the decomposition of hydride, and the resulting solution was then acidified with 1N. HC1 and transferred by extraction into water (2x200 ml). Alkalization of aqueous extracts 2n. No. 1OH, extraction Εΐ0Α ^ drying (Μ§§0 ₄ ) and evaporation resulted in a yellow crude amine oil. This oil was refluxed in 160 ml of aqueous HBg for 4 hours and then poured into 100 ml of water. Then solid No. ₂ C.'Oz was added until a pH of 9-10 was obtained. The mixture was carefully extracted with ^ CΜ (3 x 100 ml), dried (Μ§§0 ₄ ) and evaporated to a white solid, which was recrystallized from benzene to give the title product (6.4 g, 35%); melting point 114-116 ° C.

Preparatory Example 105. Tert-butyl-4- (4-hydroxyphenyl) butyl carbamate.

Di-tert-butyl dicarbonate (1.06 g, 4.8 mmol) was added in one portion to a stirred solution of the product from Preparation 104 (400 mg, 2.4 mmol) in a mixture of water (10 ml) and dioxane (10 ml) in nitrogen atmosphere. The reaction mixture was stirred for 72 hours, after which potassium carbonate (2.0 g, 14.4 mmol) was added in one portion and the mixture was stirred for another 23 hours to completely hydrolyze any ester formed during the reaction. The mixture was transferred to a separatory funnel and the organic layer was separated, dried over Μ§§0 ₄ and evaporated to a yellow oil. The oil was chromatographed using a 2: 1 pentane: E! 0Ac mixture as the eluent to give the title product (555 mg, 86%); Ή NMR (400 MHz, COC1 ₃ ) δ: 1.41-1.62 (t, 13H), 2.53 (t, 2H), 3.12 (t, 2H), 4.48 (1H, bg8), 4.80 (8, 1H), 6.74 ( b, 2H); 7.01 (b, 2H).

Preparatory Example 106. Tert-Butyl- (4-4-methoxyphenyl) butylcarbamate.

A 60% dispersion of NaH in mineral oil (88 mg, 2.2 mmol) was added to a stirred solution of the product from Preparation 105 (555 mg, 2.1 mmol) in THE (7 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 minutes, then He1 (0.14 ml, 2.2 mmol) was added in one portion and stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with EuAc (20 ml) and washed with a 3% NaHCO solution ₃ (15 ml). The organic layer was dried over Μ§§0 ₄ and purified by chromatography using ^ CΜ as eluent to give the title compound (500 mg, 85%); 'H NMR (400 MHz, SIS1 ₃ ) δ: 1.40-1.63 (t, 13H), 2.57 (t, 2H), 3.13 (t, 2H), 3.78 (8.3H), 4.46 (1H, bg8), 6.82 (b, 2H); 7.06 (b, 2H).

Preparatory Example 107. 4- (4-Methoxyphenyl) butylamine.

The product from Preparation 106 (500 mg, 1.8 mmol) was transferred into 3 ml of ', Μ and 3 ml of TEM and stirred under nitrogen for 16 hours. The mixture was then poured into 50 ml of a 10% aqueous solution No. _{2 of} CO, the organics extracted EYuAs (2 x 50 mL). The combined organic layers were dried (Μ§§0 ₄₎ and evaporated to give the title product (300 mg, 94%) which was used without further purification.

Preparatory Example 108. 3- (2-Pyridinyl) -1-propanamine.

2-Vinylpyridine (105 g) and acetic anhydride (204 g) were combined at room temperature, and a solution of KCN (130 g) in 250 ml of water was added dropwise to the stirred solution. The rate of addition was set so as to maintain a slight boil under reflux. After completion of the addition, the mixture was refluxed for 22 hours, and the pH of the solution was then adjusted to 8 with an aqueous solution of NaCO ₃ . The mixture was extracted with Όί, Μ (600 ml), the extracts were dried over Mg§ ₄ and then evaporated to a brown oil. The oil was then distilled in vacuo at a pressure of approximately 0.6 mm Hg. Art. (79.98 Pa). After distillation, the product was obtained in the form of a clear oil at 100-107 ° C in 56% yield. An oil of 2- (2-cyanoethyl) -pyridine (200 mg, 1.5 mmol) was transferred to 6 ml of EUN and treated with 2 ml of 0.88 N4-, a solution and 50 mg of Ka№. The mixture was hydrogenated at an overpressure of H ₂ 30 psi. inch (206.85 kPa) for 16 hours, and then filtered and evaporated to give the title product (approximately 200 mg), which was used without further purification.

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Preparatory Example 109. 2-Acetyl-2H-indazole.

Indazole (3.5 g, 29.6 mmol) and acetic anhydride (35 ml) were heated at 60 ° C. under nitrogen for 3 hours. The excess acetic anhydride was evaporated and the remaining oil residue was partitioned between 3% aqueous No. 11CO ₃ (20 ml) and EJAc (30 ml). The organic layer was separated, dried (Μ§80 ₄ ) and evaporated to give the title product (4.5 g, 96%); ¹ H NMR (400 MHz, COC1 ₃ ) δ: 2.80 (q, 3H), 7.37 (ΐ, 1H), 7.58 (ΐ, 1H), 7.75 (6, 1H), 8.46 (6, 1H).

Preparatory Example 110. 5-Bromo-2H-indazole and 5-bromo-1H-indazole.

The product from Preparation 109 (450 mg, 2.8 mmol) was transferred into acetic acid (0.5 ml) and stirred at room temperature under nitrogen. After about 1 minute, bromine (0.5 ml) was added and the reaction mixture was then stirred for another 16 hours. Excess bromine was removed by bubbling nitrogen gas through the solution for 30 minutes, after which a viscous substance formed in the vessel. 5 ml of toluene was added and everything was evaporated in vacuo, and the residue was triturated with pentane (5 ml). The remaining solid was filtered and dried under vacuum, then treated with 1M No. 011 and EUN 6 ml each. The mixture was heated to 50 ° C. for 1 h and then allowed to cool to room temperature. EUN was evaporated and the residue was extracted with ^ CΜ (2 x 10 ml), which was then dried (Μ§804) and evaporated to give 400 mg of a 3: 1 inseparable mixture of the title indazole 1-H: 2-H isomers; ¹ H NMR (400 MHz, SPS1 ₃ ) δ: 7.41 (6, 1H), 7.49 (6, 1H), 7.92 (q, 1H), 8.02 (q, 1H).

Preparatory Example 111. 2-Methyl-5-bromo-2H-indazole and 1-methyl-5-bromo-1 H-indazole.

A mixture of isomers from Preparation 110 (400 mg, 2.0 mmol) was transferred to MeOH (8 ml) at room temperature under nitrogen and was added in one portion NaOΜе (223 mg, 4.0 mmol). He1 (0.32 ml, 5 mol) was added dropwise and the mixture was refluxed for 4 hours. The reaction mixture was allowed to cool to room temperature and then concentrated to a small volume (approximately 3 ml), then partitioned between EluAc (20 ml ) and 3% aqueous solution No. HCO ₃ . The organic layer was separated, dried (Μ§80 ₄ ) and purified by chromatography using a 99: 1 ^ CΜ: ΜеОН mixture as eluent to give the 1-Me isomer (100 mg, 23%) and the 2-Me isomer (112 mg, 26%); 1-methyl isomer; ¹ H NMR (400 MHz, SPS13) δ: 4.08 (q, 3H), 7.30-7.50 (t, 2H), 7.82 (q, 1H), 7.92 (q, 1H); 2-methyl isomer; ¹ H NMR (400 MHz, SPS13) δ: 4.13 (q, 3H), 7.35 (6, 1H), 7.59 (6, 1H), 7.81 (q, 1H), 7.85 (q, 1H).

Preparation 112. 3- (1-Methyl-1H-indazol-5-yl) -2-propenitrile.

The 1-methyl isomer from Preparation 111 (100 mg, 0.47 mmol) was transferred to dioxane (6 ml) and potassium carbonate (72 mg, 0.52 mmol), acrylonitrile (0.035 ml, 0.52 mmol) were successively added. P6 ₂ (6ba) ₃ and PtretVi ₃ (0.038 ml, 0.16 mmol). The reaction mixture was then refluxed for 3 hours under nitrogen, then cooled to room temperature, filtered through a short plug of Arbose1 and the filtrate was evaporated in vacuo. The residue was then chromatographed using a 99: 1 ^ CΜ: ΜеОН mixture to give the title product (57 mg, 66%) as a mixture of cis and trans geometric isomers; ¹ H NMR (300 MHz, COC1 ₃ ) δ: 4.11 (q, 3H), 5.40 and 5.84 (6, 1H), 7.37-8.18 (t, 5H).

Preparatory Example 113. 3- (1-Methyl- ¹ H-indazol-5-yl) -1-propanamine.

The product from Preparation 112 (55 mg, 0.29 mmol) was transferred to ethanol (4 ml) and a 0.88 NH ₃ solution (1 ml) and hydrogenated at 30 psi. inch (206.85 kPa) and room temperature with 10 mg of 30% (w / w) ΙΕ1Ν1 for 2 hours. The mixture was filtered through a short plug of Arbose1 and the filtrate was evaporated to obtain the title product, which was used without further cleaning up.

- 50 006154

Preparatory Example 114. 2- (4-Bromophenyl) pyridine.

ΙιιΙ, ί (1.6 M in hexanes, 34.4 ml, 55 mmol) was added dropwise to a stirred solution of 1,4dibromobenzene (11.8 g, 50 mmol) in 100 ml of dry THE at -60 ° C. The mixture was then stirred for 15 minutes at this temperature, then a solution of Ζιι (Ί ₂ (0.5 M in THE, 100 ml, 50 mmol) in THE was added dropwise. The mixture was allowed to warm to room temperature for 90 minutes and then 1A1 was added (PP11 ₃ ). | (200 mg), immediately followed by 2-bromopyridine (4.8 ml, 50 mmol). All were stirred at room temperature overnight, then evaporated to a small (10 ml) volume and diluted with EyAc (400 mL). The solution was washed with a solution of 32 g ROTA (ethylenediaminetetraacetic acid) in 200 ml of water and brine (200 mL), dried (Md8O ₄₎ and evaporated to a yellow / . ELENITE solid This solid was purified by column chromatography using a 1: 1 mixture geksanYuSM as eluent to give the title product (8.3 g, 71%); m / ζ 234 MH ⁺ (T8 ⁺⁾ Found: C 56.61%, H 3.37%, N 5.90%; Calculated: C 56.44%, H 3.44%, N 5.98%.

Preparatory Example 115. 3- (2,3-Dihydro-1H-inden-5-yl) propanoic acid.

3- (2,3-Dihydro-1H-iden-5-yl) -propenoic acid (500 mg, 2.66 mmol) (commercially available from A1c! Ps11) was transferred to ethanol (40 ml) and hydrogenated at 15 lbs. ./sq. inch (103.425 kPa) H ₂ with 40 mg of 10% Pb / C for 4 hours. The mixture was then filtered through a short plug of Arboe1 and the filtrate was evaporated to give the title product (560 mg, approximately quantitatively), which was used without further purification ; * H NMR (400 MHz, SES1 ₃ ) δ: 1.98-2.07 (t, 2H), 2.75 (!, 2H), 2.80-2.90 (t, 6 H), 6.95 (b, 1H), 7.03 (q, 1H ), 7.08 (b, 1H); LBM8: t / ζ EH ^- 189 (M-H).

Preparatory Example 116. 3- (2,3-Dihydro-1H-iden-5-yl) propanamide.

The product from Preparation 115 (190 mg, 1 mmol) was dissolved in an ESM (2 ml) at room temperature under a nitrogen atmosphere and 132 μl (1.5 mmol) of oxalyl chloride was added first, followed by 1 drop of EME. When the foaming stopped, the mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was redissolved in 2 ml of TUE and 0.6 ml of 0.88 N11 ₃ solution was added and all was stirred for 4 days. The reaction was quenched with water and extracted into EJAc (2 x 10 ml). The combined organics were dried (Md8O ₄₎ and evaporated to give the title product (190 mg, 99%); Ή NMR (400 MHz, SPS1 ₃ ) δ: 1.96-2.05 (t, 2H), 2.49 (!, 2H), 2.81-2.92 (t, 6H), 5.32 (Lhc, 2H), 6.93 (b, 1H), 7.05 (q, 1H); 7.08 (b, 1H); LBM8: t / ζ (Ε8 ^- ) 189 (M-H).

Preparatory Primer 117. 3- (2,3-Dihydro-1H-iden-5-yl) propylamine.

The amide from Preparation 116 (170 mg, 0.9 mmol) was dissolved in dry THE (3 ml) at 0 ° C. under nitrogen and stirred as a solution of L1A1H ₄ in THE (1 M) was added dropwise with significant foaming. 0.9 ml, 0.9 mmol). The reaction mixture was heated to 60 ° C and stirred at this temperature overnight. The mixture was quenched with water (1 ml), 1N was added. ZhON solution (1 ml), and the solution was extracted with ЕУАс (2 x 50 ml), dried (Мd8О ₄ ), filtered and concentrated to a pale yellow oil. This oil was purified by column chromatography using a 90: 10: 1 mixture (ESM, MeOH, N11 ₃ ) as an eluent to give the title product (30 mg, 35%); ¹ H NMR (400 MHz, SPS1 ₃ ) δ: 1.72-1.77 (t, 2H), 1.96-2.03 (t, 4H), 2.57 (!, 2H), 2.70 (!, 2H), 2.80-2.85 (t, 4H), 6.90 (b, 1H), 7.02 (q, 1H), 7.09 (b, 1H); LBM8: t / ζ (T8 ⁺ ) 176 (M + H).

Preparatory Example 118. 3- (4-Bromophenyl) -2-propenitrile.

A 60% suspension of VF in mineral oil (2.16 g, 54.1 mmol) was suspended in THE (50 ml) and cooled to 0 ° C in a nitrogen atmosphere. Diethyl cyanomethylphosphonate (8.74 ml, 54.1 mmol) was added dropwise and the whole was stirred at 0 ° C for 30 minutes.

Then, 4-bromobenzaldehyde (10 g, 54.1 mmol) was added dropwise as a solution in 20 ml of THE, and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with water, extracted EYuAs (3 x 50 mL), dried (Md8O ₄₎ and then filtered and evaporated to a yellow oil. it

- 51 006154 oil was transferred to a 9: 1 mixture of pentane: ЕУАс from which the title product crystallized (5.8 g, 52%); '11 NMR (400 MHz, C1) C1 _; ) δ: 5.82 (b, 1H), 7.21-7.28 (t, 3H), 7.50 (b, 2H).

Preparatory Example 119. 3- (4-Bromophenyl) -2-propanamine.

The title compound was obtained using the modified method described by Ibop ea a1. (1.C.8. Retks I, 1977, 2357). Solid L1A1H ₄ (1.2 g, 31.6 mmol) was suspended in diethyl ether (35 ml) and stirred under nitrogen until the suspension was heated to about 50 ° C. The vinyl cyanide solution from Preparation 118 (2.06 g, 9.88 mmol) was added dropwise as a solution in ether (20 ml), and the mixture was then heated for 90 minutes. After this time, heating was stopped and the reaction mixture was stirred at room temperature for 16 hours. Water was added, then 1N. NaOH (30 ml) and EuAc (60 ml) and all were vigorously stirred for 30 minutes. The organic layer was separated, dried (MgSO ₄ ) and evaporated to a yellow oil, which was purified by column chromatography using a 90: 10: 1 mixture (ESM, MeOH, ΝΠ ₃ ) as an eluent to obtain the title product (740 mg, 35 %); ^! H NMR (400 MHz, SIS1 ₃ ) δ: 1.65-1.74 (t, 2H), 2.52 (ΐ, 2H), 2.66 (ΐ, 2H), 7.02 (b, 2H), 7.35 (b, 2H); LKMZ: t / ζ (TK ⁺ ) 214 (M + H).

Preparatory Example 120. 1- (2-Chlorophenoxy) -2-propanamine.

The product from Preparation 121 (11 g, 55.2 mmol) in diethyl ether (41 ml) was added dropwise to a suspension of lithium aluminum hydride (4.1 g, 108 mmol) in diethyl ether (100 ml) under nitrogen atmosphere. The reaction mixture was refluxed for 4 hours, then ethyl acetate and then water were added. The aqueous layer was acidified with 4n. hydrochloric acid, was shaken and then separated, previously alkalizing with a 40% sodium hydroxide solution. The aqueous layer was then extracted with diethyl ether (3x100 ml) and the combined organic extracts were dried over magnesium sulfate. The extracts in diethyl ether were acidified with hydrogen chloride and the resulting precipitate was filtered off. The solid was recrystallized from ethanol / petroleum ether (boiling point 60-80 ° C) to obtain the title product (2.5 g, 20%), melting point 126-127 ° C; ^! H NMR (SPS1 ₃ , 400 MHz) δ: 1.55 (b, 3H), 3.80 (f 1H), 4.20 (b, 2H), 6.90-7.00 (t, 2H), 7.15 (ΐ, 1H), 7.30 (b , 1H); 8.60 (b3, 3H); Found analytic. C 48.9; H 6.0; N 6.5. For СДН ^ OS ^ required: C 48.7; H, 5.9; N 6.3%.

Preparatory Example 121. 1- (2-Chlorophenoxy) -2-propanonoxime.

1- (2-Chlorophenoxy) acetone (106.6 g, 0.58 mol) (1. At. Siet. Zos. 75, 1953, 1134) was added to a solution of hydroxylamine hydrochloride (27.8 g, 4 mol) in 2n. a solution of sodium hydroxide (420 ml) and a sufficient amount of ethanol to obtain a clear solution. The reaction mixture was refluxed for 30 minutes, then concentrated in vacuo, the crude residue was extracted with diethyl ether (3 × 200 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was distilled to give the title product (134-136 ° C / 1.35 mm Hg (179.955 kPa)) (4.5 g, 3.9%); ^! H NMR (SIS1 ₃ , 400 MHz) δ: 2.05 (s, 3H), 5.00 (s, 2H), 6.90-7.00 (t, 2H), 7.10 (ΐ, 1H), 7.30 (b, 1H), 7.60 ( s, 1H); Found analytic. C 54.95; H, 5.05. For C ₉ H ₁₀ MO ₂ C1, it is required: C 54.15; H 5.05%.

Preparatory Example 122. 3- (4-Methoxy-3-chlorophenyl) -1-propylamine.

4-Methoxybenzaldehyde (A1bgtsy) (42 g, 0.31 mol) and pyridine (0.6 ml, catalytic) were stirred together under a nitrogen atmosphere and sulfuryl chloride (51 g, 0.37 mol) was added over 30 minutes, maintaining the internal temperature the reaction mixture is between 25 and 30 ° C. Intense gas evolution occurred. The mixture was stirred at room temperature for another 30 minutes and then heated to 70 ° C. for 4 hours. The excess reagents were removed by evaporation in vacuo and the residue was taken up in 50 ml of diisopropyl ether and poured onto 500 ml of hexane with vigorous stirring, whereby the product precipitated . The solid was filtered and washed with hexane and then dried in vacuo to give the title product (40.3 g, 77%), Melting point 55-56 ° C; ^! H NMR (400 MHz,

- 52 006154

SES13) δ: 3.99 (q, 3H), 7.05 (bb, 1H), 7.91 (b, 1H), 9.86 (k, 1H); Found analytical: C 56.13; H 4.14%. For C ₈ H ₂ C1O ₂ requires: C 56.33; H 4.14%.

Preparatory Example 123. 3- (4-Methoxy-3-chlorophenyl) -1-propylamine.

The product from Preparative Example 122 was converted to a diastereomeric mixture of the corresponding vinyl nitriles according to Preparation 93. The mixture (300 mg, 1.55 mmol) was transferred to 1) CM (6 ml) at room temperature under a nitrogen atmosphere and added portionwise tetra- ⁿ butylammonium borohydride (1.6 g, 6.2 mmol) in 5 minutes The mixture was then refluxed for 4 hours and then evaporated to dryness. The residue was taken up in approximately 6 ml of 10% HCl (aq.) And then refluxed for another 1 h. The reaction mixture was cooled, extracted with EuAc (3x30 ml), dried (MgO ₄ ) and evaporated to a yellow oil. This oil was separated on a column in 95/5 / 0.5, then 95/5/1 ESM / MeONZHN ₃ to give the title product (75 mg, 24%); ¹ H NMR (400 MHz, SES13) δ: 1.60-1.74 (t, 2H), 2.56 (ΐ, 2H), 2.67 (ΐ, 2H), 3.82 (q, 2H), 6.79 (b, 1H), 6.98 ( b, 1H); 7.15 (q, 1H).

Preparatory Example 124. Chroman.

4-Chranol (A1bpsN) (2.77 g, 18.4 mmol) was transferred to acetic anhydride (3.5 ml, 36.9 mmol) and acetic acid (30 ml) and refluxed for 3 hours, then allowed to cool to room temperature over 16 hours. Then 10% (w / w) Rb / C was added to the solution and hydrogenated at 40 psi hydrogen pressure. inch (275.8 kPa) for 16 hours. The catalyst was filtered through a pad of Arbose1 and the filtrate was evaporated to a small (5 ml) volume. The remaining liquid was dissolved in EJAc (30 ml) and washed with water, then with a solution of HCO ₃ (100 ml each). The organic layer was dried over MgSO ₄ and evaporated to a pale yellow oil. This oil was separated on a column in 10% ENAc / pentane to give the title product (2.1 g, 85%); ¹ H NMR (400 MHz, SES1 ₃ ) δ: 1.93-2.04 (t, 2H), 2.79 (ΐ, 2H), 4.18 (ΐ, 2H), 6.78-6.83 (t, 2H), 7.00-7.15 (t, 2H).

Preparatory Example 125. 6-Bromochroman.

The product from Preparation 124 (1 g, 7.5 mmol) was transferred to an ESM (10 ml) and bromine (403 μl, 7.8 mmol) was added as a solution in an ESM (3 ml) over several minutes. By the end of the addition, the solution retained a brown color. The mixture was stirred at room temperature for 3 hours and then washed with water (20 ml) and brine (20 ml), the organic layer was separated, dried (MgO ₄ ) and evaporated to a viscous yellow oil, which was purified by column chromatography using 5% EluAc in pentane to give the title product (1.3 g, 82%); ¹ H NMR (400 MHz, CECE) δ: 1.90-1.98 (t, 2H), 2.73 (ΐ, 2H), 4.14 (ΐ, 2H), 6.61 (b, 1H), 7.08-7.15 (t, 2H).

Preparatory Example 126. 5-Bromo-2,2-dimethyl-2,3-dihydrobenzo [b] furan.

2,3-Dimethyl-2,3-dihydrobenzo [b] furan (obtained according to the Wakeg method and 81ιιιιμίη, I. Ogd. SNet., 28, 1963, 2468) (500 mg, 3.38 mmol) was transferred to dichloroethane (5.5 ml) and stirred at room temperature under nitrogen and и-bromosuccinimide (661 mg, 3.72 mmol) was added in one portion. The reaction mixture was then refluxed for 2 hours, diethyl ether (10 ml) was added and a white succinimide precipitate was filtered off. The filtrate was evaporated to dryness and then purified by column chromatography using 5% diethyl ether in pentane as an eluent to give the title product (604 mg, 79%); ¹ H NMR (400 MHz, SES1 ₃ ) δ: 1.43 (q, 6H), 2.92 (q, 2H), 6.54 (b, 1H), 7.16 (b, 1H), 7.19 (q, 1H); BVM8: M + H, 227. (T8 ⁺ ).

Preparatory Example 127. 5-Bromo-2-methyl-2,3-dihydro-1-benzo [b] furan.

The title product was obtained from 2-methyl-2,3-dihydro-1-benzo [b] furan (commercially available from TC1, Japan) using procedures identical to those used in Preparation 126 (87%); ¹ H NMR (400 MHz, SECE) δ: 1.43 (b, 3H), 2.80 (bb, 1H), 3.29 (bb, 1H), 4.94 (t, 1H), 6.61 (b, 1H), 7.18 (b, 1H), 7.22 (q, 1H).

Preparatory example 128. 2.3-Dihydrobenzo [b] furan-7-carboxaldehyde.

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2,3-Dihydrobenzo [b] furan (Maubde CEeshyuak) (25 g, 0.21 mol) was transferred to an ESM (500 ml) and stirred under a nitrogen atmosphere at 0 ° C. 8pC1 ₄ (36.5 ml, 0.3 mol) was added in one portion to obtain a pale yellow solution. Then dichloromethyl methyl ether (18.8 ml, 0.21 mol) was added and the solution was stirred for 30 minutes, after which the cooling bath was removed and the reaction mixture was poured onto ice water (1000 ml). The organic layer was separated, washed with water (2x100 ml), 2N. HC1 (100 ml) and brine (50 ml) and then coal (30 g) and No. 2804 were added to the solution. After filtration through Ce11! E and evaporation, black oil was obtained which was flash chromatographed using 7-10% E! OAc in pentane to give the title product (190 mg, 0.01%); ¹ H NMR (400 MHz, SES13) δ: 3.24 (!, 2H), 4.75 (!, 2H), 6.93 (!, 1H), 7.40 (ά, 1H), 7.59 (ά, 1H), 10.2 (8, 1H); LBM8: (M + H) 149, T8 ⁺ . Found analytic: C, 72.98; H 5.46%. For С9Н ₈ О ₂ it is required: С 72.96; H 5.44%.

Preparatory Example 129. 1-Benzofuran-3-yl-acetonitrile.

Sodium hydride (268 mg, 6.7 mmol) was suspended in dry THE (10 ml) at 0 ° C under nitrogen atmosphere and diethyl cyanomethyl phosphonate (1.1 ml, 6.7 mmol) was added dropwise, the whole volume was stirred for 45 minutes . Then 3-couraranone (Lapsa8! Er) (900 mg, 6.7 mmol) was added dropwise and all was stirred at room temperature for 45 minutes. The reaction mixture was diluted with EJAc (15 ml) and water (15 ml), then the organic layer was separated, dried (Md ₈ O ₄ ) and evaporated, and the residue was flash chromatographed using 0-5% E! OAc in pentane to give the title product title (940 mg, 91%); ^! H NMR (400 MHz, COC1 _; ) δ: 3.77 (8, 2H), 7.25-7.40 (t, 2H), 7.52 (άά, 1H), 7.58 (άά, 1H), 7.67 (8, 1H); LBM8: M + NH ₄ ⁺ , 175. (T8 ⁺ ).

Preparatory Example 130. 2- (1-Benzofuran-3-yl) ethylamine.

The product from Preparation 129 (400 mg, 2.55 mmol) was combined with a solution of ammonium hydroxide (10 ml), ethanol (20 ml) and 30% by weight of Ba-Νί (120 mg, catalyst) and hydrogenated with hydrogen pressure 30 psi inch (206.85 kPa) at room temperature for 16 hours. The catalyst was filtered through a plug of Agbose1 and the tan filtrate was chromatographed using 0-5% MeOH in an ESM to give the title product (380 mg, 93%) ; ¹ H NMR (400 MHz, COC1 _; ) δ: 1.20 (L8, 2H), 2.80 (!, 2H), 3.02 (!, 2H), 7.15-7.25 (t, 2H), 7.43 (άά, 2H), 7.55 (άά, 1H); LBM8: M + H, 162. (E8 ⁺ ).

Preparatory Example 131. 2- (2,3-Dihydro-1-benzofuran-3-yl) ethylamine.

The product from Preparation 130 (200 mg, 1.24 mmol) was mixed with ethanol (20 ml) and 20 mg 10% (wt.) P6 / C and hydrogenated at 40 psi hydrogen pressure. inch (275.8 kPa) over 48 hours. An additional 20 mg of catalyst was added and all was hydrogenated at 60 psi. inch (413.7 kPa) and 40 ° C for another 72 hours. The catalyst was filtered through a short plug from Arbose1 and the filtrate was evaporated to dryness. The residue was purified by column chromatography using 90/10/1 OCM / MeOH ^ H ₃ as eluent to afford the title product (11 mg, 55%); ¹ H NMR (400 MHz, SES1 ₃ ) δ: 1.81 (t, 1H), 1.98 (t, 1H), 2.75-2.83 (t, 2H), 3.50 (t, 1H), 4.22 (!, 1H), 4.60 (!, 1Н), 6.72 (ά, 1Н), 6.85 (!, 1Н), 7.10 (!, 1Н), 7.20 (ά, 1Н); LBM8: M + H, 164. (E8 ⁺ ).

Preparatory Example 132. (2E and 2Ζ) -3- (2,3-Dihydro-1-benzofuran-5-yl) -2-butenonitrile.

To a stirred suspension of sodium hydride (247 mg, 6.16 mmol) in dry ТНЕ (6 ml) at 0 ° С in a nitrogen atmosphere was added a solution of diethyl cyanomethylphosphonate (0.98 ml, 6.16 mmol) in 2 ml ТНЕ and all were stirred at 0 ° C for 1 h. 5-Acetyl-2,3-dihydro [b] benzofuran (AIPSE) (1 g, 6.16 mmol) in THE (2 ml) was added dropwise and all was stirred at room temperature for 16 h. Water (20 ml) and E! OAc (20 ml) were added, the organic layer was separated and the aqueous layer was extracted with E! OAc (2 x 20 ml). The combined organics were dried over MD8O4, filtered and evaporated to give a pale

- 54 006154 brown oil, which hardened when standing. This solid was purified by column chromatography using 20-30% EJAc in pentane as an eluent to give the title product (789 mg, 69%); ¹ H NMR (400 MHz, SOSP) δ: 2.4 (k, 3H), 3.2 (ΐ, 2H), 4.6 (ΐ, 2H), 5.5 (k, 1H), 6.7 (ά, 1H), 7.2 (ά, 1H), 7.3 (q, 1H); LBM8: Μ + ΝΉ ₄ 203 (E8 ⁺ ).

Preparatory Example 133. 3- (2,3-Dihydro-1-benzofuran-5-yl) butylamine.

The product from Preparation 132 was dissolved in ethanol (20 ml) and a solution of ammonium hydroxide (5 ml) and all was hydrogenated at a hydrogen pressure of 30 psi. an inch (206.85 kPa) over 200 mg of 30% (wt.) Ba-Νί for 16 hours. Then another 100 mg of catalyst was added and hydrogenation was continued for another 16 hours. The reaction mixture was filtered through a short plug of AgYose1 and the filtrate was evaporated in vacuum to a small volume. The residue was then coevaporated with toluene (2 x 20 ml) to remove the last traces of water to give the title product (780 mg, 96%), which was used without further purification; ¹ H NMR (400 MHz, CEEC) δ: 1.2 (ά, 3H), 1.7 (s. |. 2H), 2.5 (t, 2H), 2.65 (t, 1H), 3.1 (ΐ, 1H), 4.45 ( ΐ, 2H), 6.6 (ά, 1H), 6.9 (ά, 1H), 7.0 (q, 1H); LBM8: M + H 192. (E8 ⁺ ).

Preparatory Example 134. 7-Methyl-2,3-dihydro-1-benzofuran-3-ol.

Sodium hydride (1.16 g, 0.03 mol) was added to a stirred suspension of trimethylsulfoxonium chloride (3.78 g, 0.03 mol) in dry THP (69 ml) and all was heated to reflux for 1 h. 2-Hydroxy-3-methyl-benzaldehyde (Yeisac1eg) (4 g, 0.03 mol) in 30 ml of THP was added via syringe and the resulting orange suspension was stirred at reflux for 5 hours. Water (50 ml) was added and the organics were extracted with ether (3 x 50 ml). The combined organics were dried (Md8O _4), filtered and evaporated in vacuo to an orange oil which was purified by column chromatography using 15-25% EYuAs in pentane to give the title product (2 g, 45%); Ή NMR (400 MHz, ATP1 _; ) δ: 2.2 (k, 3H), 4.45 (t, 2H), 5.3 (t, 1H), 6.8 (ΐ, 1H), 7.1 (ά, 1H), 7.2 (ά, 2H); LBM8: M + H, 151. (E8 ⁺ ).

Preparatory Example 135. 7-Methyl-2,3-dihydro-1-benzofuran.

To a stirred solution of the product from Preparation 134 (500 mg, 3.3 mmol) in acetic acid (5 ml) was added acetic anhydride (0.63 ml, 6.7 mmol) and the whole was stirred at reflux under nitrogen in for 2 hours, then left to warm to room temperature for 16 hours. 10% (wt.) Ρά / С (30 mg) was added directly to the solution and hydrogenated at a pressure of 40 psi hydrogen. inch (275.8 kPa) for 16 hours at room temperature. The catalyst was filtered through a stopper from ArHose1 and the filtrate was concentrated in vacuo to a pale yellow residue, which was dissolved in EJAc (200 ml), washed with water (3 x 20 ml), NaHCO ₃ (20 ml), dried (MD8O ₄ ) and evaporated to pale yellow oil. This oil was purified by column chromatography using 3% EJAc in pentane as an eluent to give the title product (261 mg, 58%); Ή NMR (400 MHz, SPS1 _; ) δ: 2.2 (k, 3H), 3.2 (ΐ, 2H), 4.55 (ΐ, 2H), 6.75 (ΐ, 1H), 6.9 (ά, 1H), 7.05 (ά, 1H).

Preparatory Example 136. 5-Bromo-7-methyl-2,3-dihydro-1-benzofuran.

To a stirred solution of the product from Preparation 135 (200 mg, 1.49 mmol) in dichloroethane (2.5 ml) was added Ν-bromosuccinimide (318 mg, 1.79 mmol) and all was stirred at reflux for 16 hours in an atmosphere of nitrogen. The mixture was concentrated in vacuo to give a pale orange-brown solid, which was purified by column chromatography using 1% EuAc in pentane as an eluent to give the title product (112 mg, 35%); Ή NMR (400 MHz, SOSP) δ: 2.1 (q, 3H), 3.15 (ΐ, 2H), 4.5 (ΐ, 2H), 7.0 (k, 1H), 7.1 (8, 1H).

Preparatory Example 137. 2-Hydroxy-4-methylbenzaldehyde.

- 55 006154

Μθ

To a stirred solution of 3-methylphenol (1 g, 9.2 mmol) in toluene (5 ml) at room temperature under an atmosphere of nitrogen was added 8pS1 ₄ (241 mg, 0.92 mmol) and ^{tri-n-butylamine} (0.6 mL, 2.77 mmol).

After 20 minutes, paraformaldehyde (611 mg, 20.3 mmol) was added and all was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (20 ml) and acidified with 2N. 11С1 to pH 2. The solution of the extract is

riveted to brown oil. This oil was purified by column chromatography using 5% EJAc in pentane as the eluent to give the title product (319 mg, 25%); ¹ Η NMR (400 MHz, SBS) δ: 2.3 (δ, 3Η), 6.75 (t, 2Η), 7.35 (ά, 1Η), 9.75 (δ, 1Η), 11.00 (δ, 1Η).

Preparatory Example 138. 5-Bromo-6-methyl-2.3-dihydrobenzofuran.

,about

The product from Preparation 137 was converted to the title compound by a 3-step sequence identical to that described in detail in Preparations 134-136; ¹ Η NMR (400 MHz, SHS1 ₃ ) δ: 2.3 (δ, 3Η), 3.55 (ί, 2Η), 4.5 (ί, 2Η), 6.7 (δ, 1Η), 7.3 (δ, 1Η): BKM8: Μ + Η, 214. (Ε8 ⁺ ).

Preparatory Example 139. (3E) -4- (2,3-Dihydro-1-benzofuran-5-yl) -3-buten-2-one.

2,3-dihydrobenzo [b] furan-5-carboxaldehyde (AMpsy Syet1caE) (2 g, 13.5 mmol), acetone (2.73 ml, 37.1 mmol), water (1.35 ml) and 10% -NO11 (aq) (0.34 ml) was added together and all was stirred at room temperature for 16 hours. The yellow solid was redissolved in approximately 15 ml of ESM and 2N was added. 11Cl to reach a solution of pH 2. Water (10 ml) was added and the organic layers were extracted with BSM (2 x 20 ml). The aqueous layers were separated and again extracted with BSM (2x15 ml). The combined organics were dried (MdO ₄ ) and concentrated in vacuo to a yellow solid, which was purified by column chromatography using 15-30% EluAc in pentane as an eluent to afford the title product (2.13 g, 84%); ¹ Η NMR (400 MHz, SBS1 ₃₎ δ: 2.3 (δ, 3Η ), 3.2 ( 1

2Η), 4.6 (1, 2Η), 6.5 (ά, 1Η), 6.75 (ά, 1Η), 7.3 (ά, 1Η), 7.4 (ά, 1Η), 7.45 (ά, 1Η); BKM8: Μ + Η, 189. (Ε8 ⁺ ).

Preparatory Example 140. 4- (2,3-Dihydro-1-benzofuran-5-yl) -2-butanone.

Me '

The product from Preparation 139 (2.12 g, 11.3 mmol) was transferred to ethanol (40 ml) and hydrogenated with a hydrogen pressure of 15 psi. inch (103.425 kPa) over 200 mg of 10% (wt.) Ρά / C for 4 hours. The mixture was filtered through a short plug of Arbose1 and the filtrate was evaporated in vacuo to a colorless oil, which was purified by column chromatography using 15-25% EuAc in pentane to give the title product (1.53 g, 71%); ¹ Η NMR (400 MHz, SBS1 ₃ ) δ: 2.1 (δ, 3Η), 2.7 (1, 2Η), 2.8 (1, 2H), 3.1 (1, 2Η), 4.5 (1, 2Η), 6.65 (ά , 1Η), 6.9 (ά, 1Η), 7.0 (δ, 1Η); BKM8: Μ + ΝΗ ₄ , 208. (Ε8 ⁺ ).

Preparatory Example 141. 4- (2,3-Dihydro-1-benzofuran-5-yl) -2-butanamine.

Me '

To a stirred solution of the product from Preparation 140 (500 mg, 2.6 mmol) in methanol (25 ml) was added ammonium acetate (4.05 g, 52.6 mmol) and sodium cyanoborohydride (661 mg, 10 mmol) at room temperature overnight. The reaction mixture was concentrated in vacuo and then partitioned between SJAc (20 ml) and water (20 ml). The organics were extracted and washed with water (2 x 20 ml), dried (Μ ^ 8Ο ₄ ) and evaporated to a clear oil. This oil was purified by column chromatography using 5% MeOH in OS Μ as the eluent to give the title product (187 mg, 37%); ² H NMR (400 MHz, SES1 ₃ ) δ: 1.3 (6, 3H), 1.8 (t, 2H), 2.6 (t, 2H), 3.1 (1, 2H), 3.2 (t, 1H), 4.45 (1 , 1H), 6.6 (6, 1H), 7.05 (q, 1H); BEM8: M + H, 192. (Ε8 ⁺ ).

Preparatory Example 142. Methyl- (2Ε) -2-cyano-3- (2,3-dihydro-1-benzofuran-5-yl) -2-butenoate.

To a stirred solution of 5-acetyl-2,3-dihydrobenzo [b] furan (Α16ηΛ) (1 g, 6.17 mmol) in toluene (60 ml) was added methylcyanoacetate (0.60 ml, 6.78 mmol), benzylamine ( 0.07 ml, 0.61 mmol) and acetic acid (0.3 ml, 5.3 mmol) and all were boiled under reflux in a DeanStark apparatus for 16 hours. The reaction mixture was cooled, washed with 2N. HCl (30 ml), No. 11CO ₃ (30 ml), brine (30 ml), dried (Md ₈ O ₄ ) and evaporated to a yellow residue. This residue was purified by column chromatography using 15-20% ΕΐOΑc in pentane as an eluent to give the title product (902 mg, 60%); ² H NMR (400 MHz, SES1 ₃ ) δ: 2.65 (q, 3H), 3.25 (1, 2H), 3.9 (q, 3H), 4.6 (1, 2H),

6.8 (b, 1H), 7.25 (b, 1H), 7.8 (q, 1H); BKM8: M + KH ₄ ⁺ , 261. (Ε8 ⁺ ).

Preparatory Example 143. Methyl-2-cyano-3- (2,3-dihydro-1-benzofuran-5-yl) -3-methylbutanoate.

Copper iodide (1) (109 mg, 0.57 mmol) was added to a stirred MeB1 mixture (1.4 M in diethyl ether, 0.76 ml, 1.07 mmol) in diethyl ether (2 ml) at -25 ° C. in an atmosphere of nitrogen. After stirring for 10 minutes, a solution of the product from Preparation 142 (100 mg, 0.41 mmol) in diethyl ether (2 ml) was added dropwise and then all was stirred at -25 ° C for 2 hours, and for another 2 h during heating to 0 ° C. Brine (10 ml) was added and the organics were extracted with E1OAc (10 ml), dried (Md ₈ O ₄ ), filtered and evaporated. The residue was then purified by column chromatography using 20% E1OAc in pentane as an eluent to give the title product (92 mg, 86%); Ή NMR (400 MHz, SPS1 ₃ ) δ: 1.55 (6, 6H), 3.2 (t, 2H), 3.59 (q, 3H), 3.62 (q, 1H), 4.5 (1, 2H), 6.7 (6, 1H), 7.1 (6, 1H), 7.2 (q, 1H); BKM8: M + KH ₄ ⁺ , 277. (Ε8 ⁺ ).

Preparatory Example 144. 3- (2,3-Dihydro-1-benzofuran-5-yl) -3-methylbutannitrile.

N0 '

To a stirred solution of the product from Preparation 143 (400 mg, 1.54 mmol) in

refluxing for 6 hours. The reaction mixture was concentrated in vacuo and dissolved in water (15 ml). The aqueous layer was washed with toluene (15 ml) and then acidified to pH 1 with 2N. HC1, and the product E1OAc (2 x 20 ml) was extracted from it. The organic layers were combined, washed with brine (20 ml), dried (Md ₈ O ₄ ), filtered and concentrated in vacuo to give an orange oil, which was used without further purification; ² H NMR (400 MHz, COC13) δ: 1.6 (6, 6H), 3.15 (1, 2H), 3.7 (q, 1H), 4.5 (1, 2H), 6.7 (6, 1H), 7.1 ( 6, 1H); 7.22 (q, 1H); BKM8: M + KN4 ⁺ , 263. (Ε8 ⁺ ). This oil was transferred to OM / X (2 ml) and heated at 150 ° C. for 2 hours and then allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and then dissolved in E1OAc (10 ml). The organics were washed with brine (10 ml), dried over MgSO 4, filtered and concentrated in vacuo to give an orange oil. It was purified by column chromatography using 15% E1OAc in pentane as an eluent to give the title product (100 mg, 32%); ² H NMR (400 MHz, COC1 ₃ ) δ: 1.45 (q, 6H), 2.55 (q, 2H), 3.2 (1, 2H), 4.5 (1,

2H), 6.7 (6, 2H), 7.1 (6, 1H), 7.2 (q, 1H); BKM8: M + KN4 ⁺ , 219. (Ε8 ⁺ ).

Preparatory Example 145. Tert-Butyl-3- (2,3-dihydro-1-benzofuran-5-yl) -3-methylbutylcarbamate.

The product from Preparation 144 (250 mg, 1.24 mmol) was transferred to methanol (12 ml) at 0 ° C under nitrogen and stirred with di-tert-butyl dicarbonate (542 mg, 2.48 mmol), ΝίΟ _: (161 mg, 1.24 mmol) and then No. B11 ₄ (329 mg, 8.69 mmol) 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 E1OAc (20 ml) and a solution of 11CO ₃ (20 ml), the mixture was filtered to remove all solid particles, the filtrate was extracted with E1OAc (2 x 20 ml). The combined organics were dried over MD8O ₄ , filtered

- 57 006154 were evaporated and evaporated to give the title product (366 mg, 96%) which was used without further purification; Ή NMR (400 MHz, SES1Z) δ: 1.25 (8, 6Н), 1.35 (8, 9Н), 1.7 (ΐ, 2Н), 2.9 (L8., 2H), 3.1 (ΐ, 2H), 4.2 (L8. , 1H), 4.5 (ΐ, 2H), 6.65 (b, 1H), 7.0 (b, 1H), 7.1 (8, 1H); ΕΚΜ8: Μ-Β0% 206. (Ε8 ⁺ ).

Preparatory Example 146. 3- (2,3-Dihydro-1-benzofuran-5-yl) -3-methylbutylamine.

The product from Preparation 145 (366 mg, 1.20 mmol) was transferred to 1) 01 (15 ml) at 0 ° C and stirred while gaseous hydrogen chloride was bubbled through the solution for 15 minutes. The HC1 stream was stopped and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was poured with diethyl ether (20 ml), which caused the formation of a white precipitate. This solid was filtered off, washed with diethyl ether and dried in vacuo to give the title product (177 mg, 61%); 'ΐ I NMR (400 MHz, SES1 ₃ ) δ: 1.3 (t, 2H), 1.9 (t, 2H), 2.6 (t, 2H), 3.1 (t, 2H), 4.5 (t, 2H), 6.6 ( 8, 1H), 7.01 (8, 1H), 7.2 (8, 1H); ΕΚΜ8: Μ + H, 207. (Ε8 ⁺ ).

Preparatory Example 147. Methyl 2- (4-chlorophenyl) -3-cyanopropanoate.

To a stirred solution of diisopropylamine (8.65 ml, 61.8 mmol) in dry THE (100 ml) at -20 ° C in a nitrogen atmosphere was added dropwise a 2.5 M solution of ΒιιΙ l in hexanes (23.7 ml, 59, 2 mmol). The solution was allowed to warm to 0 ° C for 20 minutes and then cooled to -70 ° C. A solution of methyl 2- (4chlorophenyl) acetate (9.5 g, 51.5 mmol) in THE (5 ml) was added dropwise over 5 minutes and then all was stirred for 30 minutes. Then iodoacetonitrile (5.03 ml, 69.5 mmol) was slowly added and the combined solution was allowed to warm to room temperature for 72 hours. A saturated aqueous solution of HCO ₃ (20 ml) was added, the mixture was concentrated to approximately 50 ml under vacuum and then treated with 1n. HC1 (100 ml). The mixture was extracted with E! 0Ac (120 ml), which was dried (Md80 ₄ ) and evaporated to give a dark brown oil, which was purified by column chromatography using a 2: 1 mixture of ESM: pentane as an eluent to obtain the title product (8 6 g, 75%); Ή NMR (400 MHz, SES1Z) δ: 2.80 (bb, 1H), 3.00 (b, 1H), 3.73 (8, 3H), 3.92 (bb, 1H), 7.22 (b, 2H), 7.37 (b, 2H) )

Preparatory Example 148. 4-amino-2- (4-chlorophenyl) butanol.

The product from Preparatory Example 147 (235 mg, 1.05 mmol) was transferred into 1 ml of THE and added dropwise to a stirred solution of L1A1H ₄ (2.1 ml, 1 M solution in THE, 2.1 mmol) in THE at 0 ° C in an atmosphere of nitrogen. The mixture was then stirred at room temperature for 2 hours and cooled to 0 ° C. Water (0.08 ml) was added, followed by a 3 N aqueous solution No. 0H (0.08 ml), and then all was diluted with THE (2 ml) and water (0.24 ml). The suspension was stirred for 5 minutes and then filtered and the filtrate was evaporated to a yellow gum. It was transferred to E! 0Ac (5 ml) and extracted with 0.5 N HC1 solution (0.3 ml), which was then basified with a solution of ΝΟΌ ₃ to pH 10 and extracted with E! 0Ac (5 × 3 ml). The combined organics were dried (Μ§80 ₄ ) and evaporated to give the title product (60 mg, 29%); '11 NMR (400 MHz, SES1Z) δ: 1.62-1.95 (t, 2H), 2.58-3.00 (t, 3H), 3.58-3.80 (t, 2H), 7.02-7.39 (t, 4H).

Preparatory Example 149. Tert-Butyl- (4-chlorophenyl) acetate.

To a suspension of Ν, Ν-dimethyl-formamide-di-tert-butyl acetal (25 ml, 104.4 mmol) in dry toluene (90 ml) was added para-chlorophenylacetic acid (5.94 g, 34.8 mmol) and all were heated at 80 ° C for 1 h. The mixture was diluted with E! 0Ac (50 ml) and washed with water (50 ml), 3% aqueous solution No. HCO ₃ (50 ml) and brine (20 ml) and then dried over M §80 ₄ , and evaporated to give an oil. This oil was purified using 35%, then 50% 1) 01 in pentane to give the title product (2.4 g, 30%); Ή NMR (400 MHz, SPS1 ₃ ) δ: 1.42 (8, 9Н), 3.44 (8, 2Н), 7.20 (b, 2Н), 7.28 (b, 2Н).

Preparatory Example 150. Tert-Butyl-2- (4-chlorophenyl) propanoate.

- 58 006154

Μθ

The product from Preparation 149 was alkylated in accordance with procedures identical to those described in Preparation 147 using methyl iodide as the alkylating agent. The title product was obtained in 95% yield after column chromatography using 25% ESM in pentane as an eluent; ¹ H NMR (400 MHz, CECE) δ: 1.39 (δ, 9H), 1.41 (4, 3H), 3.59 (q, 1H), 7.20 (ά, 2H), 7.25 (ά, 2H).

Preparatory Example 151.

The product from Preparation 150 was alkylated according to a procedure identical to that described in Preparation 137. The title product was obtained in 82% yield after purification by column chromatography using 35%, then 70% ESM in pentane as eluent; Ή NMR (400 MHz, СОС1 _; ) δ: 1.40 (δ, 9Н), 1.74 (δ, 3Н), 2.80 (ά, 1Н), 2.95 (ά, 1Н), 7.24 (ά, 2Н), 7.35 (ά, 2H).

Preparatory Example 152. 4-Amino-2- (4-chlorophenyl) -2-methylbutanol.

The product from Preparation 151 was recovered using ^^ Α1Η ₄ in accordance with the procedures of Preparation 148 to give the title product (35%). The product of this reduction was sufficiently pure and did not require further purification; ¹ H NMR (400 MHz, COC1 _; ) δ: 1.22 (δ, 3H), 1.71 (άάά, 1H), 2.01 (άάά, 1H), 2.60 (άάά, 1H), 2.83 (άάά, 1H), 3.60 (ά , 1H), 3.82 (ά, 1H), 7.27 (ά, 2H), 7.83 (ά, 2H).

Biological tests

The 1C50 values (concentration causing 50% inhibition) of the compounds of the invention with respect to NΕΡ and ACE were determined using the methods described in published patent application EP1097719-A1, paragraphs [0368] - [0376]. The 1C50 values given below were determined using ΝΈΓ from the dogs kidney. In addition, the 1C50 of some compounds of the invention was determined using NΕΡ from a human kidney; these values were similar to those determined using canine No.P.

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

The title compounds of the compounds exemplified 1C50 for a CAR 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 showed 1C50 values for NΕΡ less than or equal to 150 nM, and more than 300-fold selectivity regarding ACE.

In particular, the title compound of Example 3 showed 1C50 at отношении of 22 nm; the title compound of Example 4 showed 1C50 with respect to ΝΈΤ of 4 nM; the title compound of Example 21 showed 1C50 with respect to NΕΡ of 3 nM; the title compound of Example 33 showed 1C50 at NΕΡ of 47 nM; the title compound of Example 43 showed 1C50 at NΕΡ of 29 nM; and the title compound of Example 51 showed 1C50 at NΕΡ of 9 nM. The title compounds of Examples 3, 4, 21, 33, 43, and 51 were all more than 300 times more selective for ACE.

Animal model of female reaction in the form of sexual arousal

The title compound of Example 22 (hereinafter referred to as the selected compound) was introduced according to the protocol described in EP1097719-A1, paragraphs [0495-0499]. The selected compound was prepared in 5% saline. The selected compound and controls with the vehicle were infused using a Nagui 22 pump at an infusion rate of 500 μl / min through a 3-way drainage into the femoral vein. After infusion, the catheter was rinsed with heparinized saline solution (Kerδa1 ^ ηе) so that no trace of the selected compound remained in the catheter.

The selected compound, tested in clinically relevant doses, significantly enhanced pelvic nerve stimulated genital blood flow (see FIG. 1). The selected compound enhanced

- 59 006154 peak increase in vaginal blood flow by up to 56% (n = 3), and clitoral blood flow - by 50% (n = 3) compared to time-controlled control increases.

In FIG. 1 shows the effect of administering a selected compound on genital blood flow in a rabbit. The selected compound enhanced the increase in genital blood flow stimulated by the pelvic nerve (ΓΝ8) in a rabbit sexual arousal model under anesthesia. Repeated ΓΝ8 at 15-minute intervals induced reproducible increases in genital blood flow (shaded columns). The administration of the selected compound (gray column) increased the peak increase in clitoral and vaginal blood flow induced by submaximal stimulating frequencies (e.g. 4 Hz), compared with the increases observed during time-coordinated control stimulations or control vehicle administrations (shaded column). The following concurrent increases were observed after a bolus of approximately 0.5 mg / kg iv. - 50% increase in clitoral blood flow and 56% increase in vaginal blood flow (n = 3). Data are expressed as mean ± standard deviation; all changes were monitored using laser Doppler techniques.

No apparent effects of NΕP inhibition on baseline / unstimulated genital blood flow were observed.

Female New Zealand rabbits (approx. 2.5 kg) were previously given a combination of medetomidine (Ethyog®) 0.5 ml / kg m. and ketamine (Ye! a1ag®) 0.25 ml / kg m., while maintaining oxygen consumption with a mask. The rabbits were tracheotomized using Royeh ™ 3 без cuffless endotracheal tube connected to the breathing apparatus and maintained at a respiratory rate of 30-40 breaths per minute, with an approximate respiratory volume of 18-20 ml and a maximum air pressure of 10 cm H ₂ O (980 7 Pa). Isoflurane anesthesia was then turned on and external respiration was continued at 0 ₂ 2 l / min. The right marginal ear vein was cannulated using a 23C or 24C catheter, and Ringer's lactate solution was perfused at 0.5 ml / min. The rabbit was maintained at 3% isoflurane during invasive surgery, reducing to 2% to maintain anesthesia.

The rabbit's left inguinal region was shaved and a vertical incision was made approximately 5 cm long along the thigh. The femoral vein and artery were opened, isolated and then cannulated with a RUS (polyvinyl chloride) catheter (17C) for infusion of drugs and compounds. The cannulation was repeated for the femoral artery by 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 (Soi16) to record blood pressure. Samples for analysis of blood gases were also taken through an arterial catheter. Systolic and diastolic pressures were measured and mean arterial pressure was calculated using the formula (diastolic x 2 + systolic) / 3. Heart rate was measured using a pulse oximeter and a Ro-pe-tai data collection software system (Ropetai Ryukyuodu P1a1Gogt, Soi16 1pkyyetp 8uk1etk 1ps).

An incision was made along the abdominal midline into the abdominal cavity. The incision was approximately 5 cm long, directly above the pubis. Fat and muscle were exfoliated to open the hypogastric nerve, which goes down into the body cavity. It was important to stay close to the lateral curve of the pubic wall in order to avoid damage to the femoral vein and artery that lie above the pubis. The sciatic and pelvic nerves lie deeper and their location was determined after additional dissection of the dorsal area of the rabbit. Once the sciatic nerve is determined, the location of the pelvic nerve is easily determined. The term pelvic (reMC) nerve is used quite freely; in books on anatomy these nerves are not identified in sufficient detail. However, stimulation of this nerve causes an increase in vaginal and clitoral blood flow and innervation of the pelvic region. The pelvic nerve was released from the surrounding tissue and a Harvard bipolar stimulating electrode (Naguag6) was placed around the nerve. The nerve was slightly raised until some tension was obtained, then an electrode was fixed in this position. Approximately 1 ml of light paraffin oil was placed around the nerve and electrode. It acts as a protective lubricant for the nerve and prevents blood contamination of the electrode. The electrode was connected to the Sgacc 888 stimulator. The pelvic nerve was stimulated using the following parameters: - 0.5-5 V, pulse duration 0.5 ms, stimulation duration 10 s, frequency range from 2 to 16 Hz. Reproducible responses were obtained when the nerve was stimulated every 15-20 minutes. A frequency response curve was determined at the beginning of each experiment to determine the optimal frequency to use as a submaximal response, typically 4 Hz. The compounds that were tested were infused through the femoral vein using a Naguag6 22 infusion pump, providing continuous 15-minute stimulation cycles.

An incision was made along the abdominal midline at the caudal end of the pubis to open the pubic region. Connective tissue was removed to open the clitoris membrane in order to ensure that the wall is free of small blood vessels. The external wall of the vagina was also opened, removing all the connective tissue. One laser Doppler probe for flow was inserted 3 cm into the vagina so that half of the probe body remained visible. The second probe was placed so that it was located directly above the outer wall of the clitoris. The position of these probes was then adjusted until a signal was received. The second probe was placed directly above the surface.

- 60 006154 sti blood vessel on the outer wall of the vagina. Both probes were fastened in this position. Vaginal and clitoral blood flow was recorded either as numbers directly from E1o1, using the Po-pei data collection software (Ropetai Ryukyuodu P1a (Gogt, Soi1b Ipk! At the beginning of the experiment, calibration was performed (0-125 ml / min / 100 g of tissue).

Animal model of male erectile reaction

Methodology with anesthetized rabbit.

The title compound of Example 22 (selected compound), alone and in combination with a selective and potent REY5 inhibitor of 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2n-propoxyphenyl] -2- ( pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-b] pyrimidin-7-one was introduced in accordance with the following protocol. The selected compound was dissolved in physiological saline + 5% 1M No. OH. The selected compound and control media were infused using a Natuatb 22 pump, infusing at 500 μl / min through a 3-way drainage into the femoral vein. After infusion, the catheter was washed with heparinized saline (Nerkayye) so that no catheter remained from the selected compound. REY5 inhibitor was dissolved in physiological saline + 5% 1M HC1, compounds and control excipients were infused at a rate of 0.1 ml / s and left for 15 min before stimulation of the pelvic nerve.

Two experiments were carried out: the effect on the intracavernous pressure (1СР) of the administration of a) a selected compound per se and b) in combination with a REY5 inhibitor. The effect on 1CP is shown in FIG. 2. Data are expressed as mean percentage (%) increase ± standard error. * P <0.01, unpaired Student's 1-test in comparison with control increases.

The introduction of the selected compound alone resulted in a (37 ± 7%) increase in sub-maximally stimulated intracavernous pressure (see Fig. 2, light gray column; n = 4).

The introduction of a combination of the selected compound with a selective REY5 inhibitor (1 mg / kg iv bolus) resulted in a (70 ± 4%) increase in submaximal stimulated intracavernous pressure (see Fig. 2, dark gray column; n = 3) .

No apparent effects of ΝΕΓ inhibition or concomitant NΕP / P ^ Ε5 inhibition on baseline / unstimulated intracavernous pressure were observed.

Male New Zealand rabbits (approx. 2.5 kg) were previously given a combination of medetomidine (Iotyot®) 0.5 ml / kg and ketamine (Ue! A1ag®) 0.25 ml / kg intramuscularly, while maintaining oxygen consumption with masks. The rabbits were tracheotomized using a Royeh ™ cuffless endotracheal tube 3 GO connected to the breathing apparatus and maintained at a respiratory rate of 30-40 breaths per minute with an approximate respiratory volume of 18-20 ml and a maximum air pressure of 10 cm H ₂ O (980, 7 Pa). Isoflurane anesthesia was then connected and artificial respiration was continued at Ο ₂ 2 l / min. The right marginal ear vein was cannulated using a 23C or 24C catheter, and Ringer's lactate solution was perfused at 0.5 ml / min. The rabbit was maintained at 3% isoflurane during invasive surgery, reducing to 2% to maintain anesthesia. The left jugular vein was opened, isolated and then cannulated with a RUS catheter (17C) to infuse the selected compound or its combination.

The rabbit's left inguinal region was shaved and a vertical incision was made approximately 5 cm long along the thigh. The femoral vein and artery were opened, isolated and then cannulated with a RUS catheter (17C) to infuse the selected compound or its combination. The cannulation was repeated for the femoral artery, introducing the catheter to a depth of 10 cm in order to ensure that the catheter reached the abdominal aorta. This arterial catheter was connected to the Gould system to record blood pressure. Samples for analysis of blood gases were also taken through an arterial catheter. Systolic and diastolic pressures were measured and mean arterial pressure was calculated using the formula (diastolic x 2 + systolic) / 3. Heart rate was measured using a pulse oximeter and a Ro-pe-tai data collection software system (Ropetay Ryukyuodu P1a (Gogt, Soi1b 1pk1gitep1 8uk! Etc 1ps).

An incision was made along the abdominal midline into the abdominal cavity. The incision was approximately 5 cm long, directly above the pubis. Fat and muscle were exfoliated to open the hypogastric nerve, which goes down into the body cavity. It is essential to stay close to the lateral curve of the pubic wall to avoid damage to the femoral vein and artery that lie above the pubis. The sciatic and pelvic nerves lie deeper and their location was determined after additional dissection from the back of the rabbit. Once the sciatic nerve is determined, the location of the pelvic nerve is easily determined. The term sciatic (reMc) nerve is used quite freely; in books on anatomy these nerves are not identified in sufficient detail. However, stimulation of this nerve causes an increase in intracavernous pressure and cavernous blood flow, as well as an innervation of the pelvic region. The pelvic nerve was released from the surrounding tissue and a Harvard bipolar stimulating electrode was placed around the nerve. The nerve was slightly raised until some tension was obtained, then an electrode was fixed in this position. Approximately 1 ml of light paraffin oil was placed around the nerve and electrode. It acts as a protective lubricant for the nerve and prevents contamination of elec

- 61 006154 troda blood. The electrode was connected to Ogazz 888 8it1aFg. The pelvic nerve was stimulated using the following parameters: - 0.5-5 V, pulse duration 0.5 ms, duration of stimulating effect 20 s with a frequency of 2 to 16 Hz. Reproducible responses were obtained when the nerve was stimulated every 15-20 minutes. Several stimulations were performed with the above parameters to establish the average control response. The selected compound or combination thereof was administered via the femoral vein using a Naguagb 22 infusion pump, providing continuous 15 minute stimulation cycles. The skin and connective tissue around the penis were removed to open the penis. A set of catheters (Inzu-A, VesFp-Bhsktzop 20 Oaide 1.1 x 48 mm) was inserted through the white membrane (Shhssa a1Ysa) into the space of the cavernous body and the needle was removed, leaving a flexible catheter. This catheter was connected through a pressure transducer (Oiteba 5299-04) to the Gould system for recording intracavernous pressure. As soon as intracavernous pressure was established, the catheter was hermetically closed in place using UeFopb (tissue adhesive, 3M). Heart rate was measured using a pulse oximeter and a Ro-pe-tai data collection software system (Ropetai Ryuzyuodu P1a11ogt, Ooi1b FzGitep 8uzetz Ys).

Intracavernous blood flow was recorded either as numbers directly from 1 ^; 1o \ tte1eg, using the Ro-pe-tai data collection software (Ropetai Ryuzyuodu Р1а11огт, Оо1б РтзПитеп! 8УЗетз Ыс), or indirectly with the curve of the chart recorder Oo1b. At the beginning of the experiment, calibration was performed (0-125 ml / min / 100 g of tissue).

Claims (23)

1. The compound of formula I, its pharmaceutically acceptable salt, MES or polymorph where K ¹ represents hydrogen; C 1-6 alkyl which may be substituted by one or more substituents which may be the same or different, selected from C1-6 alkoxy and C1-6 alkoxy C1 _-6 alkoxy; or _C1-6 alkoxy; X is a bond - (CH _{2) n} - or - (CH _{2) q} -O- (where Υ is attached to the oxygen) wherein one or more than one of the hydrogen atoms in the connection X may be replaced independently C1 _-4 alkoxy, gidroksiS1 _-3 alkyl or C1 _-4 alkyl; n is 3 or 4 and ς is 2; and Υ represents phenyl or pyridyl, each of which may be substituted by one or more K ⁸ groups, which may be the same or different, where K ⁸ represents hydroxy, halogen, cyano, pyridyl, C1-6 alkoxy, phenoxy, C1-6 alkylthio phenylthio; or C 1-6 alkyl optionally substituted with halogen or phenyl, or two K ⁸ groups on adjacent carbon atoms together with the connecting carbon atoms can form a fused 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted with C 1-6 alkyl or halogen. 2. A compound according to claim 1, a pharmaceutically acceptable salt, solvate, or polymorph, where R ¹ is hydrogen, C1 _-6 alkyl, C1 _-6 alkoxy, C1 _-6 alkoksiS1 _{-3 -6} alkyl or C1 _-6 alkoksiS1 alkoksiS1 _-3 alkyl. 3. A compound according to claim 2, a pharmaceutically acceptable salt, solvate or polymorph, where R ¹ represents a C1 _-4 alkyl or C1 _-6 alkyl alkoksiS1 _-3. 4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, MES or polymorph of the formula! (1a) 5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, MES or polymorph, where X represents - (CH2) p - and where one or more than one hydrogen atom in the bond X can be replaced by one or more one group defined in claim 1. 6. The compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein K ⁸ is C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo, cyano or pyridyl, or two K ⁸ groups on adjacent atoms carbon together with the connecting carbon atoms can form a fused 5- or 6-membered carbocyclic or heterocyclic ring, possibly substituted with C 1-6 alkyl or halogen. - 62 006154 7. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, solvate or polymorph, where when Υ is phenyl, and two B ⁸ groups on adjacent carbon atoms together with the connecting carbon atoms form a condensed 5- or A 6-membered carbocyclic or heterocyclic ring, the fused ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothi. 8. The compound according to claim 1, a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein the compound is (2B) -2 - {[1 - ({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} pentanoic acid (Example 16); 3 - {[1 - ({[3 - (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] propanoic acid (Example 18); 3- {[1 - ({[3 - (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] propanoic acid (Example 21); 2 - {[1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 15); 2 - {[1 - ({[3- (4-fluorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 4); 4-methoxy-2 - {[1 - ({[3- (4-methoxyphenyl) propyl] amino} carbonyl) cyclopentyl] methyl} butanoic acid (Example 1); 2 - {[1 - ({[3 - (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] methyl} -4 methoxybutanoic acid (Example 11); (28) -2 - {[1 - ({[3- (4-chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22) and (28) -2- {[1- ({[3- (2,3-dihydro-1-benzofuran-5-yl) propyl] amino} carbonyl) cyclopentyl] methyl} -4methoxybutanoic acid (Example 25). 9. (28) -2 - {[1 - ({[3- (4-Chlorophenyl) propyl] amino} carbonyl) cyclopentyl] methyl} -4-methoxybutanoic acid (Example 22). 10. The use of a compound as defined in any one of claims 1 to 9, its pharmaceutically acceptable salt, solvate or polymorph in the manufacture of a medicament for the treatment or prevention of a condition in which a beneficial result is achieved by inhibiting neutral endopeptidase. 11. The use of claim 10, where the condition is a female sexual dysfunction or male erectile dysfunction. 12. The use of claim 11, wherein the condition is a sexual arousal disorder in women. 13. The use according to any one of claims 10-12, wherein the compound is administered systemically. 14. The application of item 13, where the compound is administered orally. 15. The use according to any one of paragraphs.10-12, where the compounds are administered topically. 16. A method of treating or preventing a condition in which a beneficial result is achieved by inhibiting a neutral endopeptidase in a mammal, wherein said mammal is treated with a therapeutically effective amount of a compound as defined in any one of claims 1 to 9, a pharmaceutically acceptable salt, solvate or polymorph thereof. 17. The method according to clause 16, where the condition is defined in clause 11 or 12. 18. A pharmaceutical composition comprising a compound as defined in any one of claims 19, a pharmaceutically acceptable salt, solvate or polymorph thereof, together with a pharmaceutically acceptable excipient, diluent or carrier. 19. The combination of a compound as defined in any one of claims 1 to 9 and one or more than one active ingredient selected from the following list: a) REE5 inhibitor, more preferably 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3 ^] pyrimidin-7-one (sildenafil), (6B, 12aB) -2,3,6, 7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ', 1 ': 6.1] pyrido [3,4-H] indole-1,4-dione (1C-351); 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-G] [1,2,4] triazin-4-one (vardenafil), 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl2- [2-methoxyethyl] -2,6-dihydro 7H-pyrazolo [4,3 ^] pyrimidin-7-one and 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2.6 -dihydro-7H-pyrazolo [4,3 ^] pyrimidin-7-one and their pharmaceutically acceptable salts; b) ΝΡΥ Υ1 inhibitor; c) a dopamine agonist, such as apomorphine, or a selective Ό ₂ , Ό _3, or Ό ₂ / Ό ₃ agonist, such as pramipexole and ropirinol; d) an agonist of melanocortin receptors or a modulator or enhancer of melanocortin, preferably melanotan II, PT-14, PT-141; d) an agonist, antagonist or modulator of 5HT2C; - 63 006154 e) an estrogen receptor modulator, estrogen agonists and / or estrogen antagonists, preferably raloxifene, tibolone or lazofoxifen; g) androgen, such as androsterone, dehydroandrosterone, testosterone, androstandion and synthetic androgen and h) estrogen, such as estradiol, estrone, estriol, and synthetic estrogen, such as estrogen benzoate. 20. The method of obtaining the compounds of General formula I (O where K ¹ , X and Υ are such as defined in any one of claims 1 to 9, or its salts, which includes stages in which a) carry out the interaction of the compounds of formula II o about (II) where Rgo! is a suitable protecting group, with a compound of formula III b) carry out the interaction of the compounds of formula IV under suitable deprotection conditions to obtain a compound of formula I; then c) possibly form a salt. 21. The method according to claim 20, further comprising asymmetric hydrogenation of any of the compounds of formulas XI, XII or XIII where 9 is a substituent on a C _1-6 alkyl group defined for K ¹ in claim 1, to obtain a compound of formula On 22. The method in which the asymmetric hydrogenation of any of the compounds of formulas XI, XII or XIII - 64 006154 where is a substituent on the C1 _-6 alkyl group defined for B ¹ in claim 1, and Rgo! is a suitable protecting group to give a compound of formula Pa 23. The compound of formula IV where In ¹ , X and Υ are as defined in any one of claims 1 to 9, and where Rgo! is a suitable protecting group. Increased genital blood flow ΝΕΡ inhibitors Vaginal blood flow Clitoral blood flow FIG. one Increased intracavernous pressure (1CP) ΝΕΡ inhibitors