EA010133B1 - Formamide derivatives useful as adrenoceptor - Google Patents

Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

Description

This invention relates to 32 agonists of the General formula

in which K ¹ , B ² , η and θ 'have the following meanings, and to methods for producing such derivatives, compositions containing them and applications of such derivatives.

Adrenoreceptors are members of the large superfamily of C-protein-coupled receptors. The adrenoreceptor subfamily itself is divided into α- and β-subfamilies with a β-subfamily, which contains at least 3 receptor subtypes: β1, β2 and β3. These receptors exhibit different expression profiles in the tissues of various systems and organs of mammals. 32-adrenergic receptors (32) are mainly expressed in smooth muscle cells (e.g., vascular, bronchial, uterine or intestinal smooth muscles), while 33-adrenergic receptors are mainly expressed in adipose tissue (therefore, 33-agonists can be potentially suitable for the treatment of obesity and diabetes) and βΙ-adrenergic receptors are mainly expressed in cardiac tissues (therefore, βΐ-agonists are mainly used as pacemakers).

The pathophysiology and treatment of respiratory diseases is widely considered in the literature (for reference, see Batek, R. 1. Syek !, 1997, 111: 2, pp. 178-268 and Vguap, 8.A. et al., Ehrey Θρίηίοη οη ίηναΐίβαΐίοηαΐ bgidk, 2000, 9: 1, pp. 25-42), and therefore, only a brief summary will be included in this context to provide some necessary information.

Glucocorticosteroids, antileukotrienes, theophylline, cromons, anticholinergics, and 32 agonists make up the classes of drugs that are currently used to treat allergic and non-allergic respiratory diseases such as asthma and chronic obstructive pulmonary disease (SORE). Recommendations for the treatment of such diseases include both short-term and long-acting, 32-agonists administered by inhalation. Short-acting and fast acting 32-agonists are used for emergency bronchodilation, while long-acting forms provide long-term relief and are used as maintenance therapy.

Bronchodilation is mediated by the agonism of 32-adrenergic receptor expressed in the smooth muscle cells of the respiratory tract, which leads to relaxation and, consequently, bronchodilation. Thus, as functional antagonists, 32 agonists can prevent and nullify the actions of all bronchoconstrictors, including leukotriene Ό4 (ΕΤΏ4), acetylcholine, bradykinin, prostaglandins, histamine, and endothelin. Since 32 receptors are quite common in the airways, 32 agonists can also affect other types of cells that play a role in asthma. For example, it has been reported that 32 agonists can stabilize mast cells. Inhibition of the release of bronchoconstrictor substances can occur, since 32agonists block bronchostenosis caused by allergens, exercise, and cold air. In addition, 32 agonists inhibit cholinergic neurotransmission in the human respiratory tract, which can lead to reduced cholinergic-reflex bronchostenosis.

In addition to the airways, it has also been found that 32-adrenergic receptors are also expressed in other organs and tissues, and thus 32-agonists, such as those described in the present invention, can be used to treat other diseases, such as, but not limited only to those of the nervous system, premature birth, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where they contribute to a decrease gastric acidity, particularly in gastric and peptic ulcer.

However, numerous 32-agonists are limited in their use due to their low selectivity or adverse side effects, stimulated by high systemic availability and mainly mediated through action on 32-adrenoreceptors expressed outside the respiratory tract (muscle tremor, tachycardia, palpitations, anxiety) . Therefore, there is a need for improved agents of this class.

Accordingly, there is still a need for new 32 agonists that will have a suitable pharmacological profile, for example, in terms of efficacy, selectivity, pharmacokinetics or duration of action. According to this context, the present invention relates to new 32 agonists.

Various derivatives of formamide have already been described. For example, US Pat. No. 2004/0006112 describes compounds acting as a 32 agonist of the formula

- 1 010133

US Patent No. 2003/022 9058 describes selective (2-agonists of the formula

However, none of the above derivatives of formamide shows a pharmacological profile that allows it to be used as effective drugs for the treatment of (2-mediated diseases and / or conditions, such as allergic and non-allergic diseases of the respiratory tract; in particular, when administered by inhalation.

This invention relates to compounds of the general formula (1)

where (CH ₂ ) _m —C (= O) O ¹ group is in the meta or para position, B ¹ and B ^{2 are} independently selected from H and C ₁ -C ₄ alkyl;

n is 0, 1 or 2;

where p means 1 or 2 and s. | means 1 or 2, and the above group is optionally connected to

and * -XB ⁸ -p ² -A groups, where O ² is C 1 -C 4 alkylene, B ⁸ is H or C 1 -C 4 alkyl and A is pyridyl, C ₃ -C ₁ -cycloalkyl, wherein the above cycloalkyl is optionally connected bridging at 1 or more, preferably 1, 2, 3 or 4, carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, or a group

B ³ , B ⁴ , B ⁵ , B ⁶ and B ⁷ are the same or different and are selected from H, C1-C4 alkyl, OB ⁹ , 8B ⁹ , 8OB ⁹ , 8O2B ⁹ , halogen, CH, CO ² B ⁹ , CP ³ , OCP ₃ , 8О ₂ ХВ ⁹ В ¹⁰ , СОВВВ ', НВ ⁹ В ¹⁰ , КНСОВ and phenyl optionally substituted by 1-3 groups selected from OB ⁹ , halogen and С ₁ -С ₄ -alkyl;

B ⁹ and B ¹⁰ are the same or different and are selected from H or C 1 -C ₄ alkyl and * represents the point of attachment of a carbonyl group;

or, respectively, to their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations.

The compounds of formula (1) are agonists of (2-receptors, which are particularly suitable for the treatment of (^ -mediated diseases and / or conditions, due to the manifestation of excellent efficacy, in particular when administered by inhalation.

- 2 010133

In the above general formula (1) _C1-C4 alkyl and _C1-C4 alkylene denote a linear or branched group containing 1, 2, 3 or 4 carbon atoms. This also applies if they contain substituents or occur as substituents of other radicals, for example, in O (C ₁ -C ₄ ) alkyl radicals, 8- (C ₁ -C ₄ ) alkyl radicals, etc. Examples of suitable (C ₁ -C ₄ ) alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Examples of suitable O- (C ₁ -C ₄ ) alkyl radicals are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.

C ₃ -C ₁ o-cycloalkyl, where 2 or more carbon atoms are optionally bridged at 1 or more carbon atoms, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, adamantyl, bicyclo [3,1,1] heptane, bicyclo [2,2,1] heptane, bicyclo [2,2,2] octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl.

In conclusion, halogen means a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular a fluorine or chlorine atom.

In the following, a free bond of a phenyl group, such as in the structure below

means that phenyl can be substituted in the meta or para position. The compounds of formula (1)

can be obtained using standard techniques, such as the following illustrated methods, in which p ¹ , p ² . K ¹ , B ² , A and η are indicated above for compounds of formula (1), unless otherwise specified.

Amide derivatives of formula (1) can be prepared by coupling an acid of formula (2)

with an amine of the formula ΝΗΒ ^Χ -Ο ² -Λ (3)

Binding is usually carried out with an excess of the above amine, as an acid receptor, using a standard binding agent (such as 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride, Ν, Ν'-dicyclohexylcarbodiimide or O- (1H-benzotriazol-1-yl ) -C ^ No., Tetramethyluronium hexafluorophosphate), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole) and optionally in the presence of a tertiary amine as a base (e.g. Ν-methylmorpholine, triethylamine or di opropiletilamin). The reaction can take place in a suitable solvent, such as pyridine, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate, and at a temperature of 1-4 ° C (room temperature) for 1-24 hours.

The above amine (3), (3 '), (3) or (3' '') is either commercially available or can be obtained using standard techniques well known to those skilled in the art (e.g., reduction, oxidation, alkylation , transition metal mediated binding, protection, deprotection, etc.) from a commercially available substance.

An acid of formula (2) can be obtained from the corresponding ester of formula (4)

- 3 010133 where H denotes a suitable acid-protecting group, preferably a benzyl group or a (C _£ -C ₄ ) alkyl group, which includes, but is not limited to, methyl and ethyl, in accordance with any technique well known to those skilled in the art the art to produce acid from an ester, without modifying the rest of the molecule. For example, an ester can be hydrolyzed by treatment with aqueous acid or a base (e.g., hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or solvent mixture (e.g., water, 1,4-dioxane, tetrahydrofuran / water) at a temperature of 20-100 ° C for 1-40 hours. Alternatively, if the ester contains a benzyl group, the ester can be hydrogenated in the presence of a suitable catalyst (for example, palladium-carbon or palladium-on-carbon hydroxide ), in odhodyaschem solvent such as methanol, ethanol, 2M ammonia solution in methanol, at a temperature of 20-50 ° C for 1-48 hours, at a hydrogen pressure of 1-4 atm.

An ester of formula (4) can be prepared by reacting an amine of formula (5)

About where Na and η have the above meanings, with a bromide of the formula (6)

In a typical procedure, an amine of formula (5) is reacted with a bromide of formula (6), optionally in the presence of a solvent or mixture of solvents (e.g. dimethyl sulfoxide, toluene, Ν, dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine , potassium carbonate), at a temperature of 80-120 ° C, for 12-48 hours

The bromide of the formula (6) can be obtained in accordance with the procedure described in Otdash Przeksk Nekeatsy apy Peuöorschep1, 1998, 2, 96-99.

An amine of formula (5), where H ¹ means Me and H ² means H, can be obtained as either (H) or (8) enantiomer from the corresponding protected amine of formula (7)

where Ha and η have the above meanings and Hb and Hc are any suitable substituents, so that HMBbc means a chiral amine (for example, bb may mean hydrogen and Hc may mean α-methylbenzyl), provided that the bonds between N and bb, N and Hc can easily be cleaved to give the free amine of formula (5) using a standard methodology for removing the nitrogen protecting groups, such as that specified in the Τ / руководстве manual. Szhepepe. Rto1essue Sgoirk ίη Otdashs 8upShek1k, third edition, and R.S.M. ^ u1k, ChoNp ^ 11eu apy 8opk, 1ps., 1999.

An amine of the formula (7) can be obtained in the form of a single diastereomer by reacting an amine of the formula HMBCH with a ketone of the formula (8)

About where Na, Hb, Hc and n have the above meanings.

According to a typical procedure, the interaction of a ketone of formula (8) with an amine of the formula ΗΝ№Κό results in a chiral intermediate, which, in turn, is reduced using a suitable reducing agent (for example, sodium cyanoborohydride of the formula No. 3.'ΝΒΗ ₃ or sodium triacetoxyborohydride of the formula No. (OAc) ₃ BH), optionally in the presence of a desiccant (e.g., molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g., acetic acid) to give an amine of formula (7) as a mixture of diastereomers. The reaction is usually carried out in a solvent, such as tetrahydrofuran or dichloromethane, at a temperature of 20-80 ° C for 3-72 hours. The resulting product is then converted to hydrochloride or nitrate and selectively crystallized from a suitable solvent or mixture of solvents (for example, isopropanol ethyl acetate, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) to give (7) as a single diastereomer.

A ketone of formula (8), where n = 1, can be obtained by palladium-mediated binding of aryl-logenide of formula (9)

where Na has the above meaning and Na1 represents a halogen atom that includes, but is not limited to, bromine and iodine, with an enolate or an equivalent of an enolate.

According to a typical procedure, the aryl halide of formula (9) is reacted with tin enolate obtained by ίη 8 and treatment of isopropenyl acetate with tri-n-butyl tin methoxide of the formula Vi ₃ 8pOMc. in the presence of a suitable palladium catalyst (palladium acetate / tri-orthotolylphosphine of the formula P6 (OAc) ₂ / P (o-To1) ₃ ) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the interaction is carried out at a temperature of 80-110 ° C for 6-16 hours

An aryl halide of formula (9) can be obtained by esterification of the corresponding acid of formula (10)

where H1 has the above meaning, in accordance with any technique well known to one of skill in the art to produce an ester from an acid, without modifying the rest of the molecule.

In a typical procedure, the acid of formula (10) is reacted with an alcohol solvent of the formula NaOH, where Na has the above meaning, in the presence of an acid, such as hydrogen chloride, at a temperature of 10-40 ° C (room temperature), for 8-16 hours. Alternatively, an acid of formula (10) is reacted with a base (e.g., cesium carbonate or potassium carbonate) and treated with an alkyl halide (e.g. methyl iodide, benzyl bromide) in a suitable solvent, such as Ν, Ν dimethylformamide, at a temperature of 10-40 ° C. (room The temperature) for 1-20 hours.

An acid of formula (10) is a commercial product.

The amine of formula (5) wherein H ¹ and H ^2, both, are _C1-C4 alkyl, can be prepared according to the following scheme:

where H ¹ , H ² and On have the above meanings.

In a typical procedure, an ester of formula (11) is reacted with an activated alkyl (organometallic alkyl such as H ² MdBr, H ² MdCl or H ² N) to give the corresponding tertiary alcohol of formula (12) using the above procedure.

The above tertiary alcohol of formula (12) is then treated with alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulfuric acid, acetic acid) to give a protected intermediate, which in turn is cleaved using a standard methodology for cleaving the protective nitrogen groups such as those given in the manuals. The resulting amino acid is then esterified using the process for preparing an amine of formula (5) as described herein.

Alternatively, the amine of formula (5) wherein H ¹ and H ^2, both, are _C1-C4 alkyl and n = 0 can be prepared according to the following scheme:

- 5 010133 where K ¹ , ² and On have the above meanings.

According to a typical procedure, an ester of formula (13) is reacted with activated alkyl (organometallic alkyl such as R ² MdBr, K ² MdC1 or R ² L1) to give the corresponding tertiary alcohol of formula (14) using the above procedure.

The above tertiary alcohol of formula (14) is then treated with alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulfuric acid, acetic acid) to give a protected intermediate, which, in turn, is cleaved using a standard methodology to remove the protective nitrogen groups, such as those given in the manuals, to produce bromamine (15).

The resulting bromamine (15) is treated using a suitable palladium catalyst (for example, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (11), [1,1'-bis (diphenylphosphino) ferrocene] palladium (11) acetate, tris (dibenzylideneacetone) dipalladium (0), 2,2'-bis (biphenylphosphino) -1,1'binaphthyldichloropalladium (P) in an atmosphere of carbon monoxide, using NaaOH as a solvent (e.g. MeOH, E1OH, benzyl alcohol) or, alternatively using a cosolvent, such as DMF, at elevated temperature (100 ° C) and pressure (100 psi), obtaining complex ether of formula (5).

A ketone of formula (8), where n = 2, can be obtained by reducing an alkene of formula (16)

In a typical procedure, a solution of an olefin of formula (16) in a suitable solvent (e.g., methanol, ethanol, ethyl acetate) is treated using a palladium catalyst (e.g., 10% palladium-on-charcoal) and stirred under a hydrogen atmosphere, optionally under elevated pressure (e.g. , 60 psi), at a temperature in the range between room temperature and 60 ° C, for 8-24 hours

An alkene of formula (16) can be prepared by palladium-mediated binding of an activated olefin to an aryl halide of formula (17)

In a typical procedure, aryl halide (17) is coupled to a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis (triphenylphosphine) palladium (O) of the formula Pb (PP ₃ ) ₄ , palladium acetate / tri-orthotolyl phosphine of the formula Pb (OAc ) ₂ / P (oTo1) ₃ or (diphenylphosphino) ferrocenyl palladium chloride of the formula brrGRbCPP) in a suitable solvent (e.g. acetonitrile, Ν, Ν-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine, at a temperature of 40-110 ° C, within 8-24 hours

A ketone of formula (17) is a commercial product.

Alternatively, a compound of formula (1) can be prepared by reacting a bromide of formula (6) and an amine of formula (18) 'toe ^{_ (0HL} ' _1G ^L '<">

About where K ¹ , ² , O 'and n are indicated above for compounds of formula (1), unless otherwise specified.

In a typical procedure, an amine of formula (18) is reacted with a bromide of formula (6), optionally in the presence of a solvent or mixture of solvents (e.g., dimethyl sulfoxide, toluene, Ν, Ν-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine , diisopropylethylamine, potassium carbonate), at a temperature of 80-120 ° C, for 12-48 hours

An amide of formula (18) can be prepared by coupling an acid of formula (19), including a suitable

- 6 010133

Binding is usually carried out with an excess of the above amine, as an acid receptor, using a standard binding agent (such as 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride or Ν, Ν'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1- hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole) and optionally in the presence of a tertiary amine as a base (for example, Ν-methylmorpholine, triethylamine or diisopropylethylamine). The interaction can occur in a suitable solvent, such as pyridine, Ν, Ν-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate, and at a temperature of 10-40 ° C (room temperature), for 1-24 hours

The above amine (3), (3 '), (3) or (3' '') is either commercially available or can be obtained using standard techniques well known to those skilled in the art (e.g., reduction, oxidation, alkylation , transition metal mediated binding, protection, deprotection, etc.) from a commercially available substance.

An acid of formula (19) can be obtained from the corresponding ester of formula (5).

Acid of Formula (19) wherein B ¹ and B ² both represent a _C1-C4 alkyl, can be prepared from the ester (5) incorporating a suitable, for amine protecting group P1, either before or after the acid formation

wherein Ba represents a suitable, protective for the acidic group group, preferably a _(C1-C4) alkyl group which includes, but is not limited to, methyl and ethyl, according to any technique well known to those skilled in the art to produce acid from ester, without modifying the rest of the molecule. For example, an ester can be hydrolyzed by treatment with aqueous acid or a base (e.g., hydrochloric acid, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or solvent mixture (e.g., water, 1,4-dioxane, tetrahydrofuran / water ), at a temperature of 20-100 ° C, for 1-40 hours

An amine of formula (5), where B ¹ and B ² , both, mean H, can be obtained in accordance with the following scheme:

where In ¹ , In ² and Ba have the above meanings.

In a typical procedure, the acid of formula (20) is preferably reduced to the corresponding alcohol (21) in the presence of an ester. This can be accomplished by the formation of an acylimidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.

The alcohol functional group of the above primary alcohol of formula (21) is then converted to a leaving group, such as mesylate, tosylate, bromide or iodide, and replaced with the corresponding amine as a nucleophile. A preferred nucleophile is an azide ion, which can then be reduced to a primary amine by hydrogenation or using triphenylphosphine. Alternative nucleophiles may include ammonia or alkylamines, such as benzylamine or allylamine, and subsequent cleavage of the alkyl group results in an amine.

(24)

- 7 010133

Alternatively, an amide of formula (22) can be prepared as previously indicated using standard reactions to form an amide bond. The compound of formula (22) can then be reacted with protected vinylamine (e.g., Ν-vinylphthalimide) in the presence of a suitable catalyst (e.g. palladium (P) acetate) and with phosphine (e.g. triphenylphosphine, tri-orthotolylphosphine) in the presence of a base (e.g. , Ν, Ν-diisopropylethylamine) in a solvent (for example, Ν, Ν-dimethylformamide, acetonitrile), at a temperature of 20-120 ° С, for 1-48 hours. The alkene of formula (23) can then be reduced to an alkane of the formula ( 24) using standard hydrogenation conditions and deprotect phthalimide group using a standard deprotection technique. An amine of formula (25) can be reacted with a bromide of formula (6) to give a compound of formula (1) using the previously described conditions.

For some of the steps of the process described above for preparing compounds of formula (1), it may be necessary to protect possible reactive functions that are undesirable for reacting and subsequently remove the above protecting groups. In this case, any compatible protective radical can be used. In particular, protection and deprotection methods such as those described by T. ^ can be applied. Szhepe and R.S.M. \ Ui15 (Rgssssrms Sgirz ίη Ogdashs 8up1ye818, Ιοίιη Khubeu apb 8opz, 1ps., 1999) or R.1. Kosheppsi (Rgo! Esbpd dgoirz, Seogd Tyue Ueg1ad, 1994).

All of the above reactions and methods for producing new starting materials used in the preceding methods are standard, and suitable reagents and reaction conditions for their fulfillment or preparation, as well as methods for isolating the desired products, are well known to those skilled in the art, with reference to the prior literature and In addition, examples and methods for obtaining.

Also, compounds of formula (1), as well as intermediates for their preparation, can be purified according to various well-known methods, such as, for example, crystallization or chromatography.

Subgroups of compounds of formula (1) containing the following substituents are preferred. Preferably, O 'is a group * -ΝΗ-ρ ² -Λ. where A is cyclohexyl or adamantyl. Preferably C ¹ means

where K ³ , K ⁴ , K ⁵ and K ⁶ mean N.

Preferably C ¹ means

where one of K ³ -K ⁶ means OH, and the others mean N.

Preferably C ¹ means a group * -ΝΗ-ρ ² -Α, where A means a group

where K ³ , K ⁴ , K ⁵ , K ⁶ and K ⁷ are the same or different and are selected from H, C1-C4 alkyl, OK ⁹ , 8K ⁹ , 8OK ⁹ , 8O2K ⁹ , halogen, ΟΝ, СО2К ⁹ , CP3, OCP ₃ , 8O ₂ PK ⁹ K ¹⁰ , SOB1K ⁹ K ¹⁰ , PK ⁹ K ¹⁰ , KHNSOK and phenyl optionally substituted by 1-3 groups selected from OK ⁹ , halogen and C1-C4 alkyl, provided that at least 2 of K ³ -K ⁷ are H; where K ⁹ and K ¹⁰ are the same or different and are selected from H or C1-C4 alkyl.

More preferably O ¹ means a group * -ΝΗ-Ο ^: -Α, where A means a group

- 8 010133 where K ³ , Z ⁴ , Z ⁵ , Z ⁶ and Z ⁷ are the same or different and are selected from H, OH, CH ₃ , OCH ₃ , OSB ₃ , OCH ₂ -CH ₃ , 8CH ₃ , S ( CH ₃ ) ₂ , \ (CO) CH _; . Ο (= Θ) ΝΗ _2, COOCH _3, gD ₂ CH _3, 8Ο ₂ ΝΗ _2, halogen, ΟΝ, SB _3, and phenyl optionally substituted with OH, with the proviso that at least 2 of R ³ -I ⁷ are N.

In a preferred embodiment, A means a group

where one of H ³ -H ⁷ means OH or phenyl substituted with OH. In a preferred embodiment, A means a group

where one of H ³ -J ⁷ means OH or phenyl substituted with OH, and the others are selected from H, C1 or CH ₃ , provided that at least 2 of H ³ -J ⁷ are N.

Preferably, A is naphthyl optionally substituted with OH.

Preferably, A is naphthyl substituted with OH.

In the above groups of compounds, the following substituents are particularly preferred:

O ² means —CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, —CH ₂ —C (CH ₃ ) ₂ - or —C (CH ₃ ) ₂ -, preferably —CH ₂ - or - (CH ₂ ) ₂ -;

I ¹ means H or C1-C4-alkyl and I ² means C1-C4-alkyl. More preferably, I ¹ means H or CH3 and I ² means H or CH3;

η means 0 or 1;

I ¹ means H, I ² means CH ₃ and η means 0 or 1;

I ¹ means CH3, I ² means CH3 and η means 0 or 1.

Particularly preferred are the compounds of formula (1) described in the Examples section below, that is, No. benzyl-2- (3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide;

No. (3,4-dimethylbenzyl) -2- (3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -

2-methylpropyl} phenyl) acetamide;

No. [2- (4-chlorophenyl) ethyl] -3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} benzamide;

No. [2- (2-chlorophenyl) ethyl] -3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№ (2-naphthalene-

1-yl-ethyl) benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№ [2- (4-methylphenyl) ethyl] benzamide;

No. [2- (2,6-dimethylphenyl) ethyl] -3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -

2-methylpropyl} benzamide;

No. [2- (2,3-dimethylphenyl) ethyl] -3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] 2-methylpropyl} benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№ [2- (4hydroxy-2,3-dimethylphenyl) ethyl] benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№ [2- (4methoxyphenyl) ethyl] benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl) -phenethylbenzamide;

No. cyclohexylmethyl-3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

No. [5 - ((1H) -2- {1,1-dimethyl-2- [3- (piperidin-1-carbonyl) phenyl] ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№ [2- (3trifluoromethylphenyl) ethyl] benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№ (3-phenylpropyl) benzamide;

3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -№indan-2

- 9 010133 ilbenzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (2-pyridin-2-yl-ethyl) benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4sulfamoylphenyl) ethyl] benzamide;

X- (4-dimethylaminobenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

X- [5- (2 - {(1B) -2- [3- (3,4-dihydro-1H-isoquinoline-2-carbonyl) phenyl] -1,1-dimethylethylamino} -1-hydroxyethyl) -2- hydroxyphenyl] formamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (4'-hydroxybiphenyl-3-methylmethyl) benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4hydroxy-2,5-dimethylphenyl) ethyl] benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4hydroxy-3-methylphenyl) ethyl] benzamide;

X- (4-acetylaminobenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

4- {[2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetylamino] methyl} benzamide;

X-adamantan-1-yl-3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (2-hydroxynaphthalen-1-ylmethyl) benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (4-hydroxy-3,5-dimethylbenzyl) benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (6-hydroxynaphthalen-2-ylmethyl) benzamide;

X- (3,6-dichloro-2-hydroxybenzyl) -3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

X- (3,4-dimethylbenzyl) -2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] ethyl} phenyl) acetamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4hydroxyphenyl) -2-methylpropyl] benzamide;

3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (4'-hydroxybiphenyl-4-ylmethyl) benzamide;

X-adamantan-1-yl-2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

X- [5- (2- {2- [3- (10-azatricyclo [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene-10-carbonyl) phenyl ] -1,1-dimethylethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide;

2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (4'-hydroxybiphenyl-3-ylmethyl) acetamide ;

4 - {[2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} phenyl) acetylamino] methyl} benzoic acid methyl ester;

2- (3- {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) X- (4-trifluoromethoxybenzyl) acetamide;

X- (2-chloro-4-hydroxybenzyl) -X-ethyl-2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2hydroxyethylamino] -2- methylpropyl} phenyl) acetamide;

X- (2-chloro-4-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide;

2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (4-hydroxy-3,5-dimethylbenzyl) acetamide;

2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (2-hydroxynaphthalen-1-ylmethyl) acetamide;

X- (5-chloro-2-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide ;

X- (3,5-dichloro-2-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl ) acetamide;

2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (6-hydroxynaphthalen-2-ylmethyl) acetamide;

2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (4'-hydroxybiphenyl-4-ylmethyl) acetamide ;

X- (4-cyanobenzyl) -2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-me

- 10 010133 tilpropyl} phenyl) acetamide;

2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) Y- (4-methanesulfonylbenzyl) acetamide;

2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) Y- (4-methylsulfanylbenzyl) acetamide;

2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) Y- (4-trifluoromethylbenzyl) acetamide;

2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) N- (4'-hydroxybiphenyl-4-ylmethyl) acetamide;

Y- [2- (5-chloro-2-hydroxyphenyl) ethyl] -3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) No. (4'-hydroxybiphenyl-3-ylmethyl) acetamide;

3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} -№ [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide;

No. (2-chloro-4-hydroxybenzyl) -2- (3 - {(2K) -2 - [(2K) - (2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

No. [2- (5-chloro-2-hydroxyphenyl) ethyl] -3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} -№ [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide;

2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) No. (tetrahydrothiopyran-4-yl) acetamide;

No. (5-chloro-2-hydroxybenzyl) -2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; and No. {5 - [(1K) -2 - ((1K) -2- {3- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropyl] phenyl} -1- methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide.

In accordance with one aspect of the present invention, compounds of formula (I) are generally preferred, wherein the group (CH ₂ ) _p —C (= O) p ¹ is in the meta position.

Pharmaceutically acceptable salts of the compounds of formula (1) include their acid and base addition salts.

Suitable acid addition salts are formed by acids which give non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, gibenzoate, gibenzate hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate, isethionate, Ό- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, 2-napzilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate , pyroglutamate, sugar, stearate, succinate, tannate, Ό- and b-tartrate, 1-hydroxy-2-n aphthoate, tosylate and xinafoate.

Suitable base salts are formed with bases which give non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemi-sulfate and hemi-calcium salts.

For a review of suitable salts, see 81a111 apb; Ryagtaseiyis1 8a1! S: Rregoreyes, 8e1es! Yup, apb Ize (^ jeu-usn, Huyeshepp. Segtapu, 2002).

Pharmaceutically acceptable salts of the compounds of formula (1) can be prepared in one or more of three ways:

(ί) reacting a compound of formula (1) with a desired acid or base;

(i) removing the acidic or basic labile protecting group from a suitable precursor of the compound of formula (1) or opening the ring of a suitable cyclic precursor, for example lactone or lactam, using the desired acid or base; or (iii) converting one salt of a compound of formula (1) into another by reacting with a suitable acid or base, or using a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the obtained salt can vary from completely ionized to almost non-ionized.

The compounds of this invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of this invention and a stoichiometric amount of 1 or more molecules of a pharmaceutically acceptable solvent, for example ethanol. The term hydrate is used when the above solvent is water.

Complexes, such as clathrates, inclusion complexes of le

- 11 010133 a proprietary host, where, unlike the aforementioned solvates, the drug and the host are in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts.

The resulting complexes can be ionized, partially ionized, or non-ionized. For a review of such complexes, see Na1eLi1ap, 1. Rjagt. 8sk, 64 (8), 1269-1288 (August, 1975).

Further, all references to compounds of formula (1) include references to their salts, solvates and complexes, and to solvates and complexes of their salts.

Compounds according to this invention include compounds of formula (1) as described above, including all their polymorphs and crystalline forms, their prodrug forms and their isomers (including optical, geometric and tautomeric isomers), as further described, and isotopically labeled compounds of formula (1 )

As indicated, the so-called prodrugs of the compounds of formula (1) are also included in the scope of this invention. So, some derivatives of the compounds of formula (1), which may or may not have significant pharmacological activity, when they are introduced into or applied to the body, can be converted to compounds of formula (1) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as prodrugs. Further information on the use of prodrugs can be found in Rgbgidz az Youe1 Beyuegu §u81et8, volume 14, AC8 8utrobst 8pe8 (T. Shdisy apb 81e11a) and Vyguegae Satega ίη Bgid Be81dp, Regdatop Rzegz, 1987. Atepsap Rhartasei11ca1 Abboaabop).

Prodrugs according to this invention can be, for example, obtained by substituting the corresponding functional groups present in the compounds of formula (1) with some residues known to the person skilled in the art in the form of pro-residues, as described, for example, in BeDpO & Rgobgids, N. Vipbdaagb (E1zeu1eg, 1985).

Some examples of prodrugs according to this invention include:

(ί) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, e.g. a compound wherein a hydrogen atom in a functional carboxylic acid group of compounds of formula (1) is substituted by _(C1-C8) -alkyl;

(ίί) where the compound of formula (1) contains an alcohol functionality (-OH), an ether thereof, for example the compound wherein the hydrogen atom in the alcohol functional group of the compound of formula (1) is substituted by _(C1-C6) -alkanoiloksimetilom; and (ίίί) when the compound of formula (1) contains a functional primary or secondary amino group (-ΝΗ ₂ or -ΝΗΚ, where K # H), its amide, for example, a compound where, as the case may be, 1 or both hydrogen atoms of a functional amino group the compounds of formula (1) is substituted (s) with (C1-Ci) alkanoyl.

Further examples of substituent groups according to the preceding examples and examples of other types of prodrugs can be found in the above references.

In addition, some compounds of formula (1) themselves can act as prodrugs of other compounds of formula (1).

Also included in the scope of the present invention are metabolites of the compounds of formula (1), i.e., compounds formed after the administration of a drug. Some examples of metabolites according to this invention include:

(ί) when the compound of formula (1) contains a methyl group, its hydroxymethyl derivative (—CH ₃ -> —CH ₂ OH);

(ίί) when the compound of formula (1) contains an alkoxyl group, its hydroxyl derivative (—OK> —OH);

(ίίί) when the compound of formula (1) contains a tertiary amino group, its secondary amino derivative (-ΧΗΙΓ> - \ HH or -ΝΗΚ. ² );

(ίν) when the compound of formula (1) contains a secondary amino group, its primary amino derivative (-ΝΗΒ ¹ > -ΝΗ ₂ );

(ν) when the compound of formula (1) contains a phenyl residue, its phenolic derivative (—PB> —PBON); and (νί) when the compound of formula (1) contains an amide group, its carboxyl derivative (-COXH;> COOH).

Compounds of formula (1) containing 1 or more asymmetric carbon atoms can exist as two or more stereoisomers. When the compound of formula (1) contains an alkenyl or alkenylene group, geometric cis / trans- (or Ζ / E-) isomers are possible. When the structural isomers are interconvertible due to the low energy barrier, tautomeric isomerism (tautomerism) may occur. It can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto or oxime group, or the so-called valence tautomerism in compounds that contain an aromatic residue. It follows that a single compound may exhibit more than one type of isomerism.

- 12 010133

The scope of the present invention includes all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more of them. Also included are acid or base addition salts where the counterion is optically active, for example ά-lactate or 1-lysine, or is racemic, for example b1-tartrate or 61-arginine.

Cis / trans isomers can be separated using standard methods well known to those skilled in the art, for example by chromatography and fractional crystallization.

Standard methods for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or separation of the racemate (or salt or derivative racemate) using, for example, chiral high performance liquid chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic residue, with an acid or base such (such as) tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure (e) enantiomer (s) in a manner well known to those skilled in the art.

The chiral compounds of this invention (and their chiral precursors) can be prepared in enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric mobile phase resin consisting of a hydrocarbon, usually heptane or hexane, containing 0-50 vol.% Isopropanol, usually 2-20 vol.%, and 0-5 vol.% alkylamine, usually 0.1 vol.% diethylamine. Concentration of the eluate leads to an enriched mixture.

Stereoisomeric conglomerates can be separated using standard techniques well known to those skilled in the art, see, for example, E. Eee1 81Geosyetschuyu £ Ogdashs Sohroiibk (^ 11еу, New York, 1994).

In accordance with one aspect of the present invention, generally preferred (. Κ, Κ) stereoisomer of formula below, wherein B ¹ is hydrogen and R ² represents a _C1-C4 alkyl, preferably methyl, and η and D 'are as defined above:

The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (1), wherein 1 or more atoms are replaced by atoms having the same atomic number, but the atomic mass or mass number is different from the atomic mass or mass number that prevails in nature.

Examples of isotopes suitable for inclusion in the compounds of this invention include hydrogen isotopes such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ C1, fluorine such as E, iodine, such as I and I, nitrogen, such as N and Ν, oxygen, such as O, O and ¹⁸ O, phosphorus, such as ³² P, and sulfur, such as ³⁵ 8.

Some isotope-labeled compounds of formula (1), such as those including a radioactive isotope, are useful in studies on the distribution of drugs and / or substrates in tissues. The radioactive isotopes of tritium, that is, ³ N, and carbon-14, that is, ¹⁴ C, are especially suitable for this purpose because of their easy incorporation and quick method of determination.

Substitution with heavier isotopes such as deuterium, i.e., ² N, may provide some therapeutic benefits resulting from greater metabolic stability, for example, an increased ίη ugo half-life or reduced dosage requirements, and therefore this may be preferred in some cases.

18 15 13

Substitution with isotopes with positron emission, such as C, E, O, and Ν, may be suitable in the case of studies using positron emission topography (PET) to assess the binding of the receptor to the substrate.

Isotope-labeled compounds of formula (1) can usually be obtained using standard techniques known to a person skilled in the art, or by methods similar to those described in the accompanying examples and preparations, using suitable isotopically labeled reagents instead of unlabeled reagents used previously.

Pharmaceutically acceptable solvates of the present invention include those wherein the crystallization solvent may be isotopically substituted, for example E ₂ O, b ₆ -acetone, b ₆ -DMSO.

The compounds of formula (1), their pharmaceutically acceptable salts and / or derivatives, are useful pharmaceutically active compounds which are suitable for the treatment and prevention of numerous disorders in which the 32 receptor is involved or in which agonism thereof

- 13 010133 receptors can be effectively caused, in particular in allergic and non-allergic diseases of the respiratory tract, but also in the treatment of other diseases, such as, but not limited to, the nervous system, premature birth, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where a decrease in gastric acidity is necessary, especially with gastric and peptic ulcers.

The compounds of this invention for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, in the form of dense layers, powders or films using methods such as precipitation, crystallization, freeze-drying, spray drying or evaporative drying. For this purpose, you can use drying using microwaves or radio frequencies.

They can be administered alone or in combination with one or more other compounds according to this invention or in combination with one or more other drugs (or in the form of any combination thereof). Typically, they are administered in the form of a finished dosage form in combination with one or more pharmaceutically acceptable excipients. The term excipient is used here to describe any ingredient other than the compound (s) according to this invention. The choice of excipient to a large extent depends on factors such as the particular route of administration, the effect of the excipient on solubility and stability, and the type of dosage form.

Pharmaceutical compositions suitable for administering the compounds of the present invention and methods for their preparation are readily understood by one skilled in the art. Such compositions and methods for their preparation can be found, for example, in Nettdfp'k Ryagtaseibs1 Zaepsek, 19th edition (Mask Ryyyipd Sotrapu, 1995).

The compounds of this invention can be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used in which the compound enters the bloodstream directly from the oral cavity.

Formulations for oral administration include solid formulations, such as tablets; capsules containing particles, liquids or powders; lozenges (including liquid-filled), chewing gums, multi- and nano-particles, gels, solid solution, liposomes, films, ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as excipients in soft or hard capsules and usually include a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by diluting a solid form, for example from a sachet.

The compounds of the present invention can also be used in the form of rapidly dissolving, rapidly disintegrating dosage forms, such as those described by Apd ap Syp in Exrey Orshyup and Tyegareibs RaYupK 11 (6), 981-986 (2001).

In the case of tablet dosage forms, depending on the dose, the drug can be from 1 to 80 wt.% Based on the dosage form, more typically from 5 to 60 wt.% Based on the dosage form. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, substituted lower starch alkali hydroxymaxyl hydroxymaxyl hydroxymaxyl hydroxyl. Typically, the disintegrating agent is contained in the range from 1 to 25 wt.%, Preferably from 5 to 20 wt.%, Based on the dosage form.

Binders are usually used to impart a binder to a tablet. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic resins, polyvinylpyrrolidone, peptized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

Tablets may also contain diluents, such as lactose (monohydrate obtained by spray drying, monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silica and talc.

If present, surfactants may be contained in an amount of 0.2 to 5 wt.% Based on the tablet, and slippage agents may be contained in an amount of 0.2 to 1 wt.% Based on the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are usually contained in an amount of from 0.25 to 10 wt.%, Preferably from 0.5 to 3 wt.%, Based on the tablet.

- 14 010133

Other possible ingredients include antioxidants, colorants, flavors, preservatives, and taste masking agents.

Typical tablets contain about 80% of the drug, from about 10 to about 90 wt.% A binder, from about 0 to about 85 wt.% Diluent, from about 2 to about 10 wt.% Disintegrant and from about 0.25 to about 10 wt.% lubricant.

The tablet mixes can be compressed directly or using a tablet roll. Tablet mixtures or portions of the mixtures may, alternatively, be wet and dry granulated or thermogranulated, melt hardened or extruded before tabletting. The final finished dosage form may contain one or more layers and may be coated or uncoated; it can even be encapsulated.

Finished dosage forms in the form of tablets are considered N. Lebettap and L. Baptist in Paganaseis 1 Eau ^ ad Horn: TaBe (b, Volume 1 (Magse1 Eekkeg, New York, 1980).

Consumable oral films for use in human medicine or veterinary medicine are usually flexible, water-soluble or water-swellable thin-film dosage forms that can be rapidly dissolving or adhering to the mucous membrane and usually contain a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant , a plasticizer, stabilizer or emulsifier, a viscosity modifying agent and a solvent. Some components of the finished dosage form can perform more than one function.

The compound of formula (1) may be soluble in water or insoluble. The water-soluble compound typically comprises from 1 to 80% by weight, more typically from 20 to 50% by weight, based on the solute. Less soluble compounds can make up a much larger fraction of the composition, typically up to 88% by weight, based on the solute. Alternatively, the compound of formula (1) may be in the form of granules of a variety of microparticles.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is usually contained in the range from 0.01 to 99 wt.%, More typically in the range from 30 to 80 wt.%.

Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, salivating agents, refrigerants, cosolvents (including oils), emollients, fillers, antifoam additives, surfactants, and taste masking agents.

Films according to this invention are usually obtained by evaporative drying of thin aqueous films deposited on a peeling carrier material or paper. This can be achieved by oven or tunnel drying, usually in a combination chamber for drying and coating, or by freeze-drying, or vacuum drying.

Solid oral dosage forms can be prepared with immediate and / or modified release. Modified release formulations include sustained, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified release formulations for the purposes of this invention are described in US Pat. No. 6,106,864. Details of other suitable release methods, such as high-energy dispersions and osmotic and coated particles, are provided by Wegta et al., In Pbactaseis1 Tec1po1 Opt-1te, 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in \ UO 00/35298.

The compounds of this invention can also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrathoracic, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion devices.

Parenteral dosage forms are usually aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably up to pH 3-9), but for some applications they may be more suitably prepared as a sterile non-aqueous solution or as a dry form used in combination with a suitable diluent such as sterile non-pyrogenic water.

Obtaining parenteral dosage forms in sterile conditions, for example, by lyophilization can be easily carried out using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (1) used to prepare parenteral solutions can be increased by the use of suitable methods for preparing formulations, such as the inclusion of solubility enhancing agents.

Formulations for parenteral administration with immediate and / or modified release can be prepared. Finished dosage forms with modified you

- 15 010133 release include slow, sustained, pulsed, controlled, targeted and programmed release. Thus, the compounds according to this invention can be used to obtain the finished dosage form in solid, semi-solid form or in the form of a thixotropic liquid for administration as an implantable depot, providing a modified release of the active compound. Examples of such formulations include drug coated stents and poly (81 lactic acid with glycolic) acid microspheres (PCLL).

The compounds of this invention can also be administered locally through the skin or mucous membrane, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, tampons, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. You can include penetration enhancing agents - see, for example, Είηηίη apb Mogdap, 1. Rnagsh. 8cG, 88 (10), 955-958 (October, 1999).

Other methods of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and using a microneedle or needleless (for example, Po \\ ysg | ss! ^{| L1} . B | o) ss1 ™, etc.) injection.

Formulations for topical administration with immediate and / or modified release can be prepared. Modified release formulations include sustained, sustained, pulsed, controlled, targeted and programmed release.

The compounds of this invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (or separately as a mixture, for example a dry mixture with lactose, or as a mixed composite particle, for example mixed with phospholipids, such as phosphatidylcholine) from a dry inhaler powder or in the form of an aerosol spray from a pressure vessel, pump, sprayer, atomizer (preferably atomizer using electrohydrodynamics to produce thick fog) or atomizer using olzovaniem or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, for example chitosan or cyclodextrin.

A pressure vessel, pump, sprayer, atomizer or sprayer contains a solution or suspension of the compound (s) according to this invention, comprising, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, dissolving or prolonged release of the active substance, a propellant ( s) as a solvent (s) and optionally a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Before use in the finished dosage form in the form of a dry powder or suspension, the drug product is finely ground to a size suitable for administration by inhalation (usually less than 5 microns). This can be achieved using any suitable grinding method, such as using a spiral jet mill, a fluidized bed jet mill, supercritical fluidized treatment to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (prepared, for example, from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator to contain a powder mixture of a compound of this invention, a suitable powder base, such as lactose or starch, and a suitable modifier such as 1-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable formulation as a solution for use in a nebulizer using electrohydrodynamics to produce thick fog may contain from 1 μg to 20 mg of the compound of this invention per exposure, and the exposure volume may vary from 1 to 100 μl. A typical finished dosage form may contain a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, can be added to these dosage forms according to the invention for inhalation / intranasal administration.

Formulations for inhalation / intranasal administration with immediate and / or modified release can be prepared using, for example, RSL. Modified release formulations include sustained, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dispensers are installed by means of a valve that releases a metered amount. The dispensers of this invention are typically adapted to administer a metered dose or injection containing (d) 0.001-10 mg of the compound of formula (1). The total daily dose is usually in the range of 0.001 to 40 mg, and can be administered as a single dose or, more commonly, in divided doses throughout the day.

- 16 010133

The compounds of formula (1) are particularly suitable for administration by inhalation.

The compounds of this invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Formulations for rectal / vaginal administration with immediate and / or modified release can be prepared. Modified release formulations include sustained, sustained, pulsed, controlled, targeted and programmed release.

The compounds of this invention can also be administered directly to the eye or ear, usually in the form of drops of a micronized suspension or solution in an isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for ophthalmic and ear administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses, and corpuscular or vesicular systems, such as niosomes or liposomes . A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example hydroxypropyl methylcellulose, hydroxyethyl cellulose or methyl cellulose, or a heteropolysaccharide polymer, for example jelly gum, can be included with a preservative such as benzalkon. Such formulations can also be administered by iontophoresis.

Formulations for ocular / ear administration with immediate and / or modified release can be prepared. Modified release formulations include sustained, sustained, pulsed, controlled, targeted and programmed release.

The compounds of this invention can be combined with soluble macromolecular substances, such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste mask, bioavailability and / or stability for use in any of the above methods of administration .

Found that drug complexes with cyclodextrin, for example, are usually suitable for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an adjuvant, i.e. as a carrier, diluent or solubilizer. As a rule, the most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in international patent applications No.№ ¥ О 91/11172, \ УО 94/02518 and \ УО 98/55148.

Since it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to this invention, can conveniently be combined in the form a kit suitable for co-administration of the compositions.

Thus, a kit according to the invention contains two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) according to this invention, and means for separately storing the above compositions, such as a container, vessel with a septum or a divided foil bag. An example of such a kit is conventional transparent packaging used for packaging tablets, capsules, and the like.

The kit of the invention is particularly suitable for administering various dosage forms, for example parenterally, for administering individual compositions at different dosage intervals, or for titrating individual compositions against one another. To meet the conditions, the kit usually contains instructions for introduction and can be equipped with a so-called memo.

For administration to patients, the total daily dose of the compounds of this invention is usually in the range of 0.001-5000 mg, depending, of course, on the route of administration. For example, only an intravenous daily dose may require 0.001-40 mg. The total daily dose may be administered as a single dose or in divided doses and may, at the discretion of the physician, go beyond the typical range given here.

These doses are based on use for a normal subject having a body weight of about 65-70 kg. A competent physician can easily determine doses for subjects whose body weight is outside this range, such as children and the elderly.

For the avoidance of doubt, the recommendations given here regarding treatment include recommendations for reconstructive, palliative, and preventative treatment.

In accordance with another embodiment of the present invention, the compounds of formula (1) or pharmaceutically acceptable salts, derivatives or compositions thereof can also be used in combination with one or more additional therapeutic agents for co-administration to a patient to obtain some particularly desirable therapeutic end result, such such as the weakening of pathophysiologically relevant pathological processes, including but

- 17 010133 not limited to this: (ί) bronchostenosis, (ίί) inflammation, (ίίί) allergies, (ίν) tissue destruction, (ν) signs and symptoms, such as respiratory failure, cough. The second and more additional therapeutic agents may also be a compound of formula (1) or a pharmaceutically acceptable salt thereof, derivative forms or compositions, or one or more B2 agonists known in the art. More typically, the second and more additional therapeutic agents are selected from various classes of therapeutic agents.

As used here, under the terms co-administration, co-administered and combined with in relation to the compounds of formula (1) and one or more other therapeutic agents, it means that it refers to and includes the following:

the simultaneous administration of such a combination of the compound (s) of formula (1) and the therapeutic agent (s) to a patient in need of treatment, when such components are used together in the form of a single dosage form that releases the above components essentially in one and the same same time for the above patient;

essentially the simultaneous administration of such a combination of the compound (s) of formula (1) and the therapeutic agent (s) to a patient in need of treatment, when such components are used separately from each other in the form of separate dosage forms that are administered, essentially at the same time to the above patient, whereby the above components are released essentially at the same time for the above patient;

the sequential administration of such a combination of the compound (s) of formula (1) and the therapeutic agent (s) to a patient in need of treatment, when such components are used separately from each other in the form of separate dosage forms that are administered at successive intervals to the above patient, with a significant time interval between each introduction, as a result of which the above components are released essentially after different periods of time for the above patient; and sequentially administering such a combination of the compound (s) of formula (1) and the therapeutic agent (s) to a patient in need of treatment, when such components are used together in a single dosage form that releases the above components in a controlled manner, whereby they simultaneously are sequentially and / or co-administered over the same time and / or at different time periods to the above patient;

where each part can be entered either in the same or in different ways.

Suitable examples of other therapeutic agents that can be used in combination with the compound (s) of formula (1) or their pharmaceutically acceptable salts, derivatives or compositions include, but are not limited to:

(a) 5-lipoxygenase inhibitors (5-L0) or antagonists of the 5-lipoxygenase activating protein (BAP), (b) leukotriene antagonists (LTCAc), including LBT ₄ , LTC ₄ , LTP ₄ and LET ₄ antagonists, (c) antagonists histamine receptors, including H1 and NZ antagonists, (P) vasoconstrictor sympathomimetic agents a ₁ - and a ₂ adrenergic agonists for use as decongestants, (e) muscarinic MH receptor antagonists or anticholinergic agents, (I) ΡΌΕ- inhibitors, e.g. ΡΌΕ3-, ΡΌΕ4- and RPE5 inhibitors, (e) theophylline, (II) sodium chromoglycate , (ί) COX inhibitors, both non-selective and selective COX-1 or COX-2 inhibitors (ΝδΑΙΌδ), (ί) oral and inhaled glucocorticosteroids, (k) active monoclonal antibodies against endogenous inflammatory substances, ( l) agents against tumor necrosis factor (anti-TPR-a), (t) adhesion molecule inhibitors, including VLA-4 antagonists, (p) kinin-II and B ₂ receptor antagonists, (o) immunosuppressive agents, ( p) inhibitors of matrix metalloproteinases (ΜΜΡδ), (p. |) antagonists of tachykinin-ΝΚ! -, ΝΚ ₂ - and LK ₃ receptors, (d) inhibitors of elast basics, (§) adenosine A2a receptor agonists, (ΐ) urokinase inhibitors, (and) compounds that act on dopamine receptors, for example P2 agonists, (ν) ΝΡκβ pathway modulators, for example 1KK inhibitors, (those) modulators of cytokine signaling pathways, such as p38 MAP kinase or 5uk kinase, (x) agents that can be classified as mucolytic or antitussive, (y) antibiotics, (ζ) ΗΩΑΟ inhibitors, and

- 18 010133 (aa) P13 kinase inhibitors.

According to the present invention, further preferred combinations of compounds of formula (1) with H3 antagonists, antagonists of the muscarinic MH receptor,

REE4 inhibitor of, glucocorticosteroids, adenosine A2a agonists-receptor modulators of cytokine signaling pathways such as p38 MAP kinase or kinase cookies or leukotriene antagonists (TNAk) including antagonists TV _4, TS _{4, 4} TO and TE _4.

According to the present invention, further preferred combinations of compounds of formula (1) with glucocorticosteroids, in particular those administered by inhalation of glucocorticosteroids, with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamkinolone acetone, beclomethasone dipropionate, budesonide, flutamate azithromonazonate, maltutonazonate, mlamutonazone MH receptor or anticholinergic agents, including, in particular, ipratropium salts, namely bromide, tiotropium salts, and names of bromide, oksitropievye salts, namely bromide, perenzepin and telenzepine.

It is intended that all references given herein with respect to treatment include reconstitution, palliative, and prophylactic treatment. The following description relates to therapeutic applications for which the compounds of formula (1) may be intended.

The compounds of formula (1) are able to interact with the b2 receptor and, thus, have a wide range of therapeutic applications, as described below, since the b2 receptor plays an essential role in the physiology of all mammals.

Therefore, a further aspect according to the present invention relates to compounds of formula (1) or their pharmaceutically acceptable salts, derivative forms or compositions for use in the treatment of diseases, disorders and conditions in which the 2 receptor is involved. More specifically, the present invention also relates to compounds of formula (1) or their pharmaceutically acceptable salts, derivative forms or compositions for use in the treatment of diseases, disorders and conditions selected from the group consisting of any type of asthma, etiology or pathogenesis, in particular asthma , which is a disease selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial 1DE-mediated asthma, bronchial asthma, essential asthma, isti asthma, hereditary bronchial asthma caused by pathophysiological disorders, acquired bronchial asthma caused by environmental factors, essential asthma for an unknown or asymptomatic reason, non-atopic asthma, bronchodilator asthma, emphysematous asthma, asthma caused by exercise, asthma caused by allergen, asthma cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma , initial asthma, childhood asthmatic syndrome and bronchiolitis;

chronic or acute bronchostenosis, chronic bronchitis, minor obstruction of the airways and emphysema;

obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular obstructive or inflammatory disease of the respiratory tract, which is a disease selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (SORE), SORE, which includes chronic bronchitis , pulmonary emphysema or dyspnea, associated or unrelated to the SORE, SORE, which is characterized by irreversible progressive airway obstruction her, adult respiratory distress syndrome (ANE8), exacerbation of airway hyperresponsiveness resulting from other drug therapies, and airway disease that is associated with pulmonary hypertension;

bronchitis of any type, etiology or pathogenesis, in particular bronchitis, which is a disease selected from the group consisting of acute bronchitis, acute laryngeal-tracheal bronchitis, arachid bronchitis, catarrhal bronchitis, croupous bronchitis, dry bronchitis, infectious asthmatic bronchitis, industrial bronchitis, bronchitis caused by staphylococcus or streptococcus, and vesicular bronchitis;

severe lung injury;

bronchiectasis of any type, etiology or pathogenesis, in particular bronchiectasis, which is a disease selected from the group consisting of cylindrical bronchiectasis, saccular bronchiectasis, spindle-shaped bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular.

A still further aspect of the present invention also relates to the use of compounds of formula (1) or their pharmaceutically acceptable salts, derivative forms or compositions for the manufacture of a medicament having a B2 agonist activity. In particular, the present invention

- 19 010133 relates to the use of compounds of formula (1) or their pharmaceutically acceptable salts, derivatives or compositions for the manufacture of a medicament for the treatment of (^ -mediated diseases and / or conditions, in particular the diseases and / or conditions listed above.

As a result, the present invention relates to a particularly interesting method of treating a mammal, including a human, with an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof. More specifically, the present invention relates to a method of treatment of particular interest (^ -mediated diseases and / or conditions of a mammal, including humans, in particular diseases and / or conditions listed above, comprising administering to the above mammal an effective amount of a compound of formula (1), pharmaceutically acceptable salts and / or derivatives.

The following examples illustrate the preparation of compounds of formula (1).

Getting 1. Ethyl ether (3-ethoxycarbonylmethylphenyl) acetic acid.

N.

2,2 '- (1,3-Phenylene) diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol (100 ml) and the solution was treated dropwise with acetyl chloride (2.5 ml). The reaction mixture was stirred at reflux for 18 hours before cooling and concentration in vacuo. The residue was taken up in ethyl acetate (100 ml) and extracted with sodium bicarbonate solution (3x50 ml) and brine (3x50 ml). The organic phase was dried (Md8O _4), concentrated in vacuo and the residue was triturated with pentane to yield the product (11.8 g).

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, q), 7.24-7.36, (4H, m); LBM8 Ε8Ι (low resolution mass spectrometry with electron sputter ionization): t / ζ 251 [M + H] ⁺ .

Getting 2. (3-Ethoxycarbonylmethylphenyl) acetic acid.

BUT.

A solution of the compound from Preparation 1 (44.3 g, 177 mmol) and 2.2 '- (1,3-phenylene) diacetic acid (59.2 g, 308 mmol) in ethanol (24 ml) and dioxane (290 ml) treated dropwise with hydrochloric acid (12M, 4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours before cooling and concentration to a small volume. The reaction mixture was diluted with toluene (125 ml) and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the residue was treated with water and made basic with sodium bicarbonate until the pH became neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5x30 ml) and brine (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethyl ether (3x30 ml). The organic layers were combined, dried (Md8O ₄₎ and concentrated in vacuo. The residue was triturated in pentane to give a colorless solid (10.8 g).

Ή-NMR (SE ₃ OE, 400 MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, q), 7 18-7.32 (4H, m); LBM8 Ε8Ι: t / ζ 245 [M + Na] ⁺ .

Preparation 3. [3- (2-Hydroxy-2-methylpropyl) phenyl] acetic acid.

BUT.

-IT

Methylmagnesium chloride (51 ml of a 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirred solution of the compound from Preparation 2 (11.6 g, 51 mmol) (1p1cgpaPopa1 1game1 o! Réoie apy Prgoes vekeagsy, 1987, 29 (3), 331) in tetrahydrofuran (300 ml) at a temperature of 0 ° C in a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature overnight to form a white solid, and then water (50 ml) and 2N were carefully added. hydrochloric acid (80 ml).

The aqueous layer was extracted with ethyl acetate (2x300 ml) and the combined organic layers were washed with brine (50 ml), dried (sodium sulfate) and the solvent was removed in vacuo to give the title compound as a golden oil (11.2 g).

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m ); LBM8 Ε8Ι: t / ζ 209 [M + H] ⁺ .

Preparation 4. (3- {2 - [(Chloracetyl) amino] -2-methylpropyl} phenyl) acetic acid.

BUT.

C1

2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of the compound from Preparation 3 (16.0 g, mmol) in acetic acid (33 ml) and cooled to 0 ° C. The resulting solution was treated with concentrated sulfuric acid (33 ml) and allowed to gradually warm to room temperature. After 4 hours, the reaction mixture was poured onto ice and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate (2x500 ml) and the combined organic extracts were dried (Md ₈ O ₄ ) and concentrated in vacuo to give the title product as a colorless solid (19.0 g).

¹ H-NMR (SPS1 ₃ , 400 MHz) δ: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6 19 (1H, m); 7.067.31 (4H, m); LKM8 Ε8Ι: t / ζ 282 [M – H] ^- .

Preparation 5. Methyl ester of [3- (2-amino-2-methylpropyl) phenyl] acetic acid.

A solution of the compound from Preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated under reflux in a nitrogen atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature and was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethanol (150 ml), saturated with hydrogen chloride and the resulting solution was heated at reflux for 16 hours. The mixture was concentrated in vacuo and ethyl acetate (200 ml) and 5% aqueous sodium carbonate solution (200 ml) were added. . The organic phase was washed with brine (100 ml), dried (MgO ₄ ) and concentrated in vacuo. The residue was purified using a strong cation exchange resin (methanol and then a 2M solution of ammonia in methanol) to give a yellow oil (2.68 g).

Я-NMR (SPS1 ₃ , 400 MHz) δ: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7, 08-7.16 (3H, m); 7.23-7.27 (1H, m); LKM8 Ε8Ι: t / ζ 222 [M + H] ⁺ .

Preparation 6. [3- (2-Tert-butoxycarbonylamino-2-methylpropyl) phenyl] acetic acid methyl ester.

A solution of di-tert-butyl dicarboxylate (8.19 g, 38.0 mmol) in dichloromethane (40 ml) was added to a solution of the compound from Preparation 5 (8.4 g, 38.0 mmol) and triethylamine (5.2 ml, 38 , 0 mmol) in dichloromethane (60 ml) at a temperature of 0-5 ° C. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed and the residue was treated with sodium carbonate solution and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine (3x20 ml) and dried (Na ₂ 8O ₄ ). The product was purified by chromatography (0-80% ethyl acetate in hexane) to give a colorless oil, which was dissolved in diethyl ether (3 times) and evaporated (10.1 g).

Я-NMR (SPS1 ₃ , 400 MHz) δ: 1.26 (6H, s), 1.46 (9H, s), 2.97 (2H, s), 3.60 (2H, s), 3, 68 (3H, s), 4.26 (1H, br.s), 7.05-7.07 (2H, m), 7.13-7.17 (1H, m), 7.22-7, 26 (1H, m); LKM8 Ε8Ι: t / ζ 344 [M + No.] ⁺ .

Preparation 7. [3- (2-tert-Butoxycarbonylamino-2-methylpropyl) phenyl] acetic acid.

The compound from Preparation 6 (7.45 g, 23.0 mmol), a solution of sodium hydroxide (5M, 4.6 ml, 115 mmol), dioxane (30 ml) and water (8 ml) were stirred at room temperature for 18 hours The solvent is removed and the product is dissolved in water, cooled and acidified to pH 3 with hydrochloric acid (2M). The product was extracted with ethyl acetate (3x30 ml) and the organic layers were washed with brine (3x30 ml) and dried (No. 8O ₄ ). The resulting oil was dissolved in diethyl ether and evaporated to give a colorless gum (7.0 g).

Ή-NMR (C1) ₃ O1U 400 MHz) δ: 1.23 (6H, s), 1.48 (9H, s), 2.96 (2H, s), 3.57 (2H, s), 7 04-7.06 (2H, m); 7.11-7.13 (1H, m); 7.18-7.22 (1H, m); LKM8 APC1 (low resolution mass spectrometry with chemical ionization at atmospheric pressure): t / ζ 308 [M + H] ⁺ .

Preparation 8. (2- {3 - [(3,4-Dichlorobenzylcarbamoyl) methyl] phenyl} -1,1-dimethylethyl) carbamic acid tert-butyl ester.

3,4-Dichlorobenzylamine (1.30 ml, 9.76 mmol) was added to a solution of the compound from Preparation 7 (3.00 g, 9.76 mmol), hydroxybenzotriazole hydrate (1.50 g, 9.76 mmol), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.87 g, 9.76 mmol) and triethylamine (4.07 ml, 11.2 mmol) and the resulting solution was stirred at room temperature for 18 hours. The solvent was removed and the crude product treated with ethyl acetate (50 ml) and washed with water (30 ml), sodium carbonate solution (2x30 ml), with

- 21 010133 with a left solution (30 ml), hydrochloric acid (0.5 M, 2x30 ml) and brine (30 ml) and then dried (Ν; · ι ₂ 8Ο ₄ ). The resulting white solid was triturated with diethyl ether (3.1 g).

Ή-NMR (SBS 1 _h , 400 MHz) δ: 1.25 (6H, s), 1.45 (9H, s), 2.97 (2H, s), 3.62 (2H, s), 4, 22 (1H, br.s), 4.34 (2H, d), 5.78 (1H, br.s), 6.99-7.01 (1H, dd), 7.04 (1H, s) 7.07-7.09 (1H, d), 7.12-7.14 (1H, d), 7.22 (1H, d), 7.27 (1H, d), 7.32 (1H , d); LKM8 APC1: t / ζ 465 [M + H] ⁺ .

Preparation 9. (2- {3 - [(3,4-dimethylbenzylcarbamoyl) methyl] phenyl} -1,1-dimethylethyl) carbamic acid tert-butyl ester.

Receive, using the acid from obtaining 7, and 3,4-dimethylbenzylamine, and the method described for obtaining 8.

Ή-NMR (SPS1 _h , 400 MHz) δ: 1.19 (6H, s), 1.46 (9H, s), 2.20 (6H, d), 2.95 (2H, s), 3, 59 (2H, s), 4.15 (1H, br.s), 4.32 (2H, d), 5.59 (1H, br.s), 6.86-6.93 (2H, m) 7.02-7.06 (3H, m); 7.13-7.15 (1H, d); 7.23-7.27 (1H, m); LKM8 APC1: t / ζ 425 [M + H] ⁺ .

Preparation 10. 2- [3- (2-Amino-2-methylpropyl) phenyl] -Y- (3,4-dichlorobenzyl) acetamide.

The compound from Preparation 8 (3.0 g, 6.50 mmol) in dioxane (5 ml) was treated with hydrogen chloride (4M solution in dioxane, 20 ml) and the resulting solution was allowed to stir at room temperature for 18 hours. The solvent was removed and the compound was repeated. dissolved in methanol (2 times) and evaporated, then the resulting resin was suspended in diethyl ether (2 times) and evaporated to give a white solid (2.7 g).

Melting point (ethyl acetate-methanol): 214-216 ° C (decomposition).

Ή-NMR (C1) _; O1U 400 MHz) δ: 1.33 (6H, s), 2.90 (2H, s), 3.59 (2H, s), 4.35 (2H, s), 7.13-7.19 ( 3H, m), 7.24-7.27 (1H, m), 7.31-7.38 (2H, m), 7.42 (1H, d); LKM8 E81: t / ζ 365 [M + H] ⁺ .

Preparation 11. 2- [3- (2-Amino-2-methylpropyl) phenyl] -Y- (3,4-dimethylbenzyl) acetamide.

Obtained using the amide from Production 9 and the method described for Production 10.

'H-NMR (C1) _; O1U 400 MHz) δ: 1.32 (6H, s), 2.21 (6H, s), 2.89 (2H, s), 3.56 (2H, s), 4.29 (2H, s) 6.957.05 (3H, m), 7.14-7.16 (2H, m), 7.24-7.26 (1H, m), 7.31-7.35 (1H, m); 1. HM8 E81: t / ζ 325 [M + H] ⁺ .

Preparation 12. No. {2-Benzyloxy-5 - [(1H) -2-bromo-1- (tert-butyldimethylsilanyloxy) ethyl] phenyl} formamide.

To a solution of No. [2-benzyloxy-5- (2-bromo-1-hydroxyethyl) phenyl] formamide (Ogdapu Rgosekke Neck apb Oetekrtepk 1998, 2, 96-99) (4.12 g, 11.8 mmol) in Ν, Ν-dimethylformamide (25 ml) at room temperature under nitrogen atmosphere add tert-butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol) and 4- (dimethylamino) pyridine (40 mg, 330 μmol). The resulting solution was stirred at room temperature overnight, the solvent was removed, and the product was treated with ethyl acetate (70 ml). The organic layers were washed with water (100 ml) and the aqueous layers were extracted with ethyl acetate (20 ml). The combined organic layers were washed with hydrochloric acid (2M, 50 ml), brine (100 ml) and dried (MgO ₄ ). The crude product was purified by chromatography (5-25% ethyl acetate in pentane) to give a colorless oil (5.7 g).

'H-NMR (SPS1 _h , 400 MHz) δ: -0.08 - -0.05 (3H, m), 0.09-0.11 (3H, s), 0.89-0.90 (9H , m), 3.38-3.55 (2Н, m), 3.78-3.84 (1Н, m), 5.06-5.11 (2Н, m), 6.90-6.97 (1H, m), 7.03-7.12 (1H, m), 7.24 (m), 7.36-7.43 (5H, m), 7.67-7.78 (m), 7.88 (d), 8.74 (d); 1. HM8 ARC1: t / ζ 464/466 [M + H] ⁺ .

- 22 010133

Preparation 13. 2- (3- {2 - [(2B) -2- (4-Benzyloxy-3-formylaminophenyl) -2- (tert-butyldimethylsilanyloxy) ethylamino] -2-methylpropyl} phenyl) -Y- (3, 4-dichlorobenzyl) acetamide.

The compound from Preparation 12 (500 mg, 1.08 mmol) and the compound from Preparation 10 (780 mg, 216 mmol) are heated and stirred at 90 ° C. for 24 hours. After cooling, the product is dissolved in methanol and evaporated, the product is suspended in diethyl ether and the precipitate is filtered off. The filtrate was evaporated and the product was purified by chromatography (0-5% methanol in dichloromethane) and then suspended in diethyl ether (3 times) and evaporated to give a foam (425 mg).

Я-NMR (СОЗОО, 400 MHz) δ: -0.20 - -0.18 (3Н, m), -0.04-0.00 (3Н, m), 0.78-0.81 (9Н, m), 1.01-1.03 (3H, m), 1.05 (3H, br.s), 2.62-2.74 (3H, m), 2.83-2.88 (1H, m), 3.52 (2H, d), 4.31 (2H, s), 4.68-4.71 (1H, m), 5.17-5.19 (2H, m), 7.00 -7.23 (7H, m), 7.29-7.41 (5H, m), 7.44-7.49 (2H, m), 8.57 (s); LBM8 Ε8Ι: t / ζ 748 [M + H] ⁺ .

HBM8 (high resolution mass spectrometry) ί. '. ₁ | Η ₅ | 01 _; Ν ₃ 0. ₁ 8ί: 748.3099 [M + H] ⁺ , found 748.3066. Preparation 14. 2- (3- {2 - [(2B) -2- (4-Benzyloxy-3-formylaminophenyl) -2- (tert-butyldimethylsilanyloxy) ethylamino] -2-methylpropyl} phenyl) -Y- (3, 4-dimethylbenzyl) acetamide.

Obtained using the amide from Preparation 13, the bromide from Production 12 and the method described for Production 11.

Я-NMR (SPS1 ₃ , 400 MHz) δ: -0.17 - -0.16 (3H, 2x s), -0.05 - -0.01 (3H, m), 0.78-0.82 (9H, m), 0.97-1.01 (6H, m), 2.19 (3H, s), 2.20 (3H, s), 2.56-2.90 (4H, m), 3.54-3.63 (2H, m), 4.28-4.35 (2H, m), 4.67-4.74 (1H, m),

5.06-5.09 (2H, m), 5.58-5.62 and 5.99-6.03 (1H, m), 6.87-7.25 (9H, m), 7.35 -7.44 (5H, m), 7.68-7.79 (1H, m), 8.30 (d), 8.43 (d), 8.71 (s), 8.74 (s) ; LBM8 Ε8Ι: t / ζ 748 [M + H] ⁺ .

HBM8 C ₄₃ H ₅₇ No. O ₄ 81: 708.4191 [M + H] ⁺ , found 708.4156.

Preparation 15. No. Benzyl-2- (3- {2 - [(2B) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydro-

The compound from Preparation 13 (100 mg, 134 μmol) and palladium-on-carbon (10%, 20 mg) in methanol (10 ml) was hydrogenated at a pressure of 50 psi at room temperature for 6 hours. Mixture filtered through filter aid and the solvent removed. The product was suspended in a solution of sodium bicarbonate and extracted with ethyl acetate (30 ml). The organic layers were washed with sodium bicarbonate solution, brine (2 ml) and dried (Na ₂ 8 O ₄ ). The resulting product was suspended in diethyl ether (3 times) and evaporated to give a film (24 mg).

Я-NMR (SOKHOU 400 MHz) δ: -0.19 (3H, s), -0.02 (3H, s), 0.79 (9H, s), 1.04, (3H, s), 1 07 (3H, s), 2.622.89 (4H, m), 3.48-3.56 (2H, dd), 4.35 (2H, s), 4.61 (1H, br.s), 4.69-4.72 (1H, m), 5.17-5.19 (2H, m), 6.79-6.85 (1H, m), 6.91-6.94 (1H, m ), 7.04-7.06 (1H, m), 7.11-7.28 (7H, m), 8.12 (1H, d), 8.27, 8.59 (1H, 2x s) ; LBM8 Ε8Ι: t / ζ 590 [M + H] ⁺ .

HBM8 C ₃₄ H ₄₇ No. O ₄ 81: 590.3402 [M + H] ⁺ , found 590.3409.

Preparation 16. 2- (3- {2 - [(2B) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphe- 010 0133 nyl) ethylamino] -2-methylpropyl} phenyl) -№ (3,4-dimethylbenzyl) acetamide.

Obtained using the amide from Preparation 14 and the method described for Preparation 15. The product was purified by chromatography (0-3.5% methanol in dichloromethane + 0.3% ammonia) to give a foam (85 mg).

Ή-NMR (C1); O1). 400 MHz) δ: -0.20 - -18 (3Н, m), -0.03-0.00 (3Н, m), 0.79-0.81 (9Н, m), 1.02-1 05 (6H, m), 2.19 (3H, s), 2.20 (3H, s), 2.61-2.73 (3H, m), 2.83-2.88 (1H, m ), 3.46 (2H, dd), 4.27 (2H, s), 4.65 (1H, dd), 6.78-7.22 (8H, m), 8.12 (d), 8 27 (8), 8.59 (s); 1.EM8 Ε8Ι: t / ζ 618 [M + H] ⁺ .

HBM8 0 ₃₆ Η ₅₁ Ν ₃ Ο ₄ 8ί: 618.3722 [M + H] ⁺ , found 618.3701.

Getting 17. Methyl (3-bromophenyl) acetate.

Acetyl chloride (0.7 ml, 9.3 mmol) is slowly added to a solution of (3-bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at a temperature of 0 ° C in a nitrogen atmosphere and the reaction mixture is left gradually warm to room temperature over 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colorless oil (20.6 g).

Я-NMR (СОС1 ₃ , 400 MHz) δ: 3.59 (2Н, s), 3.70 (3Н, s), 7.17-7.24 (2Н, m), 7.37-7.45 (2H, m); LKM8 Ε8Ι: t / ζ 253 [M + No.] ⁺ .

Preparation 18. Methyl [3- (2-oxopropyl) phenyl] acetate.

Tributyltin methoxide (28.3 ml, 98 mmol), product from Preparation 17 (15.0 g, 65 mmol), isopropenyl acetate (10.8 ml, 98 mmol), palladium (11) acetate (750 mg, 3.30 mmol ) and tri-orthotolylphosphine (2.0 g,

6.5 mmol) was stirred together in toluene (75 ml) at 100 ° C for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (150 ml) and 4M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered through ArboseG® and the organic phase was separated and concentrated in vacuo. The residue was then purified by silica gel column chromatography, eluting with a diethyl ether: pentane mixture from 0: 100 to 25:75, then with dichloromethane, to give the title compound as a pale yellow oil with a yield of 94%, 12.6 g.

Я-NMR (ΟΌΟ1 ₃ , 400 MHz) δ: 2.15 (3H, s), 3.61 (2H, s), 3.69 (5H, s), 7.10-7.13 (2H, m ), 7.19 (1H, d), 7.30 (1H, t); 1.EM8 Ε8Ι: t / ζ 229 [Μ + Ν] ⁺ .

Preparation 19. Methyl [3 - ((2K) -2 - {[(1K) -1-phenylethyl] amino} propyl) phenyl] acetate hydrochloride.

A solution of the product from Preparation 18 (8.5 g, 41.2 mmol), (K) -a-methylbenzylamine (4.8 ml, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 ml, 38 mmol) in dichloromethane (400 ml) was stirred at room temperature for 48 hours. The reaction mixture was quenched by the addition of a saturated sodium hydrogen carbonate solution (200 ml) and allowed to stir until gas evolution ceased. The aqueous phase is separated and extracted with dichloromethane (100 ml). The combined organic solution was then dried over magnesium sulfate and concentrated in vacuo. Purified by silica gel column chromatography, eluting with dichloromethane: methanol: ammonia in a ratio of 99: 1: 0.1 to 95: 5: 0.5 to obtain a mixture of diastereomers in a ratio of 4: 1 (large proportion B, B) in as a pale yellow oil (8.71 g). It is treated with hydrogen chloride (40 ml of a 1M solution in methanol, 40 mmol), then by three successive crystallizations (diisopropyl ether / methanol) to obtain the title compound as a white crystalline solid in 50% yield, 5.68 g.

Ή-NMR (400 MHz, CO ₃ OD): δ: 1.18 (3H, d), 1.68 (3H, d), 2.60-2.66 (1H, m), 3.15-3 26 (1H, m), 3.253.30 (1H, m), 3.31 (3H, s), 3.62 (2H, s), 4.59 (1H, q), 6.99-7, 02 (2H, m), 7.17 (1H, m), 7.25-7.28 (1H, m), 7.487.52 (5H, m); 1.EM8 Ε8Ι: t / ζ 312 [M + H] ⁺ .

- 24 010133

Preparation 20. Methyl {3 - [(2B) -2-aminopropyl] phenyl} acetate.

° -Sn ₃

A solution of the product from Preparation 19 (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) is heated at a temperature of 75 ° C in the presence of 20% palladium-on-carbon hydroxide (2.00 g) . After 90 minutes, the reaction mixture was cooled to room temperature, filtered through Arbose1® and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 0.88 ammonia (100 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a colorless oil in quantitative yield (4.78 g).

Я-NMR (400 MHz, СО ₃ OD): δ: 1.06 (3Н, d), 2.57-2.67 (2Н, m), 3.05-3.12 (1Н, m), 3 63 (2H, s), 3.67 (3H, s), 7.09-7.13 (3H, m), 7.23-7.27 (1H, t); LBM8 E81: t / ζ 208 [M + H] ⁺ .

Preparation 21. Methyl (3 - {(2B) -2 - [(tert-butoxycarbonyl) amino] propyl} phenyl) acetate.

The title compound was obtained from the product from Preparation 20 and di-tert-butyl dicarboxylate using a method similar to that in Preparation 6 as a yellow oil in a yield of 97%.

Ή-NMR (400 MHz, CO ₃ Cl ₃ ): δ: 1.07 (3H, d), 1.43 (9H, s), 2.61 (1H, dd), 2.81 (1H, dd) 3.60 (2H, s), 3.69 (3H, s), 3.89 (1H, br.s), 4.36 (1H, br.s), 7.06-7.19 (3H) m) 7.22-7.27 (1H, m); LKM8 APC1: t / ζ 306 [M-H] ^- .

Preparation 22. (3 - {(2B) -2 - [(tert-Butoxycarbonyl) amino] propyl} phenyl) acetic acid.

IT

A mixture of the compound from Preparation 21 (8.31 g, 27.1 mmol) and a solution of lithium hydroxide (1 M solution in water, 54 ml, 54 mmol) in tetrahydrofuran (100 ml) was stirred at room temperature for 20 hours. The reaction mixture was then concentrated in vacuo and the aqueous residue acidified with 2M hydrochloric acid to pH 2. Then the mixture was extracted with ethyl acetate (3x75 ml) and the combined organic solution was washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound as yellow oil with a yield of 82% (6.5 0 g).

Ή-NMR (400 MHz, CO ₃ Cl ₃ ): δ: 1.07 (3H, d), 1.40 (9H, s), 2.61 (1H, dd), 2.77-2.88 ( 1H, broad s), 3.62 (2H, s), 3.89 (1H, broad s), 4.39 (1H, broad s), 7.07-7.16 (3H, m) 7.22-7.27 (1H, m); LKM8 APC1: t / ζ 292 [M – H] ^- .

Preparation 23. Benzyl (3 - {(2B) -2 - [(tert-butoxycarbonyl) amino] propyl} phenyl) acetate.

Product from Preparation 22 (6.30 g, 21.5 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.14 g, 21.5 mmol), 1-hydroxybenzotriazole hydrate (3.30 g, 21, 5 mmol) and triethylamine (4.85 ml, 43 mmol) are stirred together in dichloromethane (100 ml) for 10 min at room temperature. Then benzyl alcohol (2.2 ml, 21.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. Then the reaction mixture was diluted with dichloromethane (50 ml), washed with sodium bicarbonate solution (100 ml) and brine (100 ml) ), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a clear oil in 50% yield, 4.16 g.

Ή-NMR (400 MHz, CO ₃ Cl ₃ ): δ: 1.04 (3H, d), 1.44 (9H, s), 2.59 (1H, dd), 2.81 (1H, dd) , 3.64 (2H, s), 3.87 (1H, s), 4.34 (1H, s), 5.13 (2H, s), 7.07-7.11 (2H , m) 7.13 (1H, brq), 7.22-7.27 (1H, m), 7.29-7.38 (5H, m); LKM8 APC1: t / ζ 382 [M – H] ^- .

Preparation 24. Benzyl {3 - [(2B) -2-aminopropyl] phenyl} acetate.

Hydrogen chloride (4M solution in dioxane, 5.43 ml, 21.72 mmol) was added to a solution of the product from Preparation 23 (4.16 g, 10.86 mmol) in dioxane (50 ml) and the resulting solution was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with sodium hydrogen carbonate solution (50 ml) and brine (50 ml). The organic solution was then dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow oil in 93% yield (2.85 g).

Ή-NMR (400 MHz, CO ₃ Cl ₃ ): δ: 1.09 (3H, d), 1.55 (2H, br.s), 2.48 (1H, dd), 2.66 (1H, dd), 3.10-3.18

- 25 010133 (1H, m), 3.65 (2H, s), 5.17 (2H, s), 7.09-7.13 (2H, m), 7.14-7.18 (1H, br.s.d), 7.24-7.38 (6H, m); LAM8 ARC1: t / ζ 284 [M – H] ^- .

Preparation 25. Benzyl (3 - {(2H) -2 - [((2H) -2- [4- (benzyloxy) -3- (formylamino) phenyl] -2 - {[tert-butyl (dimethyl) silyl] oxy } ethyl) amino] propyl} phenyl) acetate.

The title compound was obtained from the products from Preparation 12 and Preparation 24, using a method similar to that in Preparation 13, as a brown oil in 25% yield.

LKM8 APC1: t / ζ 667 [M + H] ⁺ .

Preparation 26. {3 - [(2H) -2 - ({(2H) -2 - {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino ) propyl] phenyl} acetic acid.

• N

The product from Preparation 25 (851 mg, 1.27 mmol) and 10% Pb / C (50 mg) was suspended in methanol and the mixture was stirred under a hydrogen atmosphere at a pressure of 60 psi. inch at room temperature for 72 hours. The reaction mixture was then filtered through filter aid® and the filtrate was concentrated in vacuo to afford the title product as a brown foam in 94% yield, 580 mg.

Ή-NMR (400 MHz, СОС1 ₃ ): δ: -0.09 (3Н, s), 0.08 (3Н, s), 0.88 (9Н, s), 1,12,1,24 (3Н , 2xd), 2.07-2.82 (2H, m), 2.99 (1H, dd), 3.18 (1H, dd), 3.60 (2H, s), 4.16-4, 22 (1H, m), 4.97-5.07 (1H, m), 6.87 (1H, d), 6.99-7.32 (6H, m), 7.93 (s), 8 17, (d), 8.33 (s); LYM8 APC1: t / ζ 487 [M + H] ^- .

Preparation 27. 2- {3 - [(2H) -2 - ({(2H) -2- {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl } amino) propyl] phenyl} -Y- [4- (dimethylamino) benzyl] acetamide.

BUT'

A mixture of the product from Preparation 26 (100 mg, 206 μmol), hydroxybenzotriazole hydrate (32 mg, 206 μmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (40 mg, 206 μmol) and triethylamine (58 μl, 412 μmol) in Ν, Ν-dimethylformamide (2 ml) was stirred at room temperature for 10 minutes. Then 4- (dimethylamino) benzylamine (31 mg, 206 μmol) was added and the mixture was stirred at room temperature for 20 hours. Then the solvent was removed in vacuo and the residue was diluted with dichloromethane, washed with sodium hydrogen carbonate solution (20 ml) and brine (20 ml) ), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown gum in 10% yield, 131 mg.

Ή-NMR (400 MHz, CO ₃ Cl ₃ ): 0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.08 (3H, m), 2 80-3.00 (10H, m), 3.47 (1H, m), 3.66 (2H, m), 4.23 (2H, m), 5.48 (1H, m), 6, 66 (1H, d), 6.70-7.23 (10H, m), 7.97 (m), 8.27 (s); LN8 ARC1: t / ζ 504 [M + H] ^- .

Receive 28-29.

The following compounds of the general formula indicated below are prepared from the product from Preparation 26 and the corresponding amine using a method similar to that described in Preparation 27. The reaction mixtures were monitored by thin layer chromatography and stirred at

- 26 010133 room temperature for 18-72 hours.

No. 01 Data Exit 28 DKM5 ARS1: t / ζ 632 [M-H] ‘ 99% 29th LXX / ' LKMZ ARS1: t / ζ 6618 [MH] ’ 99%

Getting 28.

Y- [4- (Aminomethyl) phenyl] acetamide can be prepared as described in 1. May. Siet., 46, 3116, 2003. Obtaining 29.

4- (Aminomethyl) benzamide can be obtained as described in UO 02085860, p.239.

Preparation 30. [3 - ((2K) -2 - {[(1K) -1-Phenylethyl] amino} propyl) phenyl] acetic acid.

A solution of lithium hydroxide (1M solution in water, 90 ml, 90 mmol) was added to a solution of the product from Preparation 19 (13.50 g, 43.5 mmol) in methanol (200 ml), and the mixture was stirred at room temperature for 18 hours. Then, a 1M hydrochloric acid solution (90 ml) was added to the reaction mixture, and methanol was removed in vacuo. The resulting precipitate was filtered off and washed with water (20 ml) and ethanol / diethyl ether (20:80) to give the title compound as a solid in 91% yield, 11.8 g.

Ή-NMR (400 MHz, SEZOO) δ: 1.16 (3H, d), 1.62 (3H, d), 2.66-2.62 (1H, m), 3.13-3.26 ( 2H, m), 3.46 (2H, s), 4.48-4.56 (1H, q), 6.92 (1H, d), 7.19 (1H, s), 7.18-7 22 (2H, m); 7.45-7.52 (5H, m); LMP8 Ε8Ι: t / ζ 298 [M + H] ⁺ .

Preparation 31. Y-1-Adamantyl-2- [3 - ((2K) -2 - {[(1K) -1-phenylethyl] amino} propyl) phenyl] acetamide.

1-Adamantylamine (5.44 g, 36.0 mmol) and triethylamine (15 ml, 108 mmol) were added to a solution of the product from Preparation 30 (10.7 g, 36.0 mmol) in dichloromethane (200 ml). Then 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (10.0 g, 36.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane: methanol: 0.88 ammonia, 95: 5: 0.5, to obtain the product as a foam in quantitative yield, 17.6 g.

'H-NMR (400 MHz, C1O1)) δ: 0.89 (3H, d), 1.35 (3H, d), 1.65-1.75 (6H, m), 1.98 (6H, m), 2.04 (3H, m), 2.37-2.42 (1H, dd), 2.65-2.74 (1H, m), 2.95-3.00 (1H, dd) 3.36 (2H, s), 3.98 (1H, q), 6.89 (1H, d), 6.98 (1H, s), 7.09 (1H, d), 7.17 ( 1H, t), 7.22-7.27 (1H, m), 7.30-7.38 (4H, m); LMP8 Ε8Ι: t / ζ 431 [M + H] ⁺ .

Preparation 32. Y-1-Adamantyl-2- {3 - [(2K) -2-aminopropyl] phenyl} acetamide.

The title compound was prepared from the compound from Preparation 31, using a method similar to that in Preparation 20, as a solid in 92% yield.

Я-NMR (400 MHz, C1UO1)) δ: 1.09 (3Н, d), 1.66-1.72 (6Н, m), 2.00 (6Н, m), 2.03 (3Н, m ), 2.58-2.70 (2H, m), 3.10-3.16 (1H, q), 3.40 (2H, s), 7.05-7.28 (4H, m); LMP8 Ε8Ι: t / ζ 327 [M + H] ⁺ .

Preparation 33. 2- (3 - {(2K) -2 - [((2K) -2- [3- (Acetylamino) -4- (benzyloxy) phenyl] -2 - {[tert-butyl (dimer 27 010133 tyl) silyl] oxy} ethyl) amino] propyl} phenyl) -X-1-adamantylacetamide.

A mixture of the products from Preparation 12 (696 mg, 1.5 mmol) and Preparation 32 (978 mg, 3.0 mmol) in dichloromethane (0.5 ml) was heated at 90 ° C. for 5 minutes, leaving the dichloromethane to evaporate. The reaction mixture is then heated as a melt at 90 ° C. for 18 hours before cooling to room temperature. The crude product was then purified by column chromatography on silica gel, eluting with a dichloromethane: methanol: 0.88 ammonia mixture in a ratio of 98: 2: 0.2 to obtain the title compound as a pale yellow foam in 59% yield, 630 mg.

Я-NMR (400 MHz, CO ₃ OE) δ: -0.18 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.05-1.08 (d 3H), 1.66-1.72 (6H, m), 2.00 (6H, m), 2.02 (3H, m), 2.52-2.71 (3H, m), 2, 84-2.96 (2H, m), 3.36-3.41 (2H, m), 4.68-4.72 (1H, m), 5.20 (2H, s), 6.92- 7.18 (6H, m), 7.30-7.50 (5H, m), 8.22 (m), 8.36 (s), 8.54 (s); LMP8 Ε8Ι: t / ζ 710 [M + H] ⁺ .

Preparation 34. X-Adamantan-1-yl-2- (3- {2 - [(2B) -2 - ({(2B) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl ) ethylamino] propyl} phenyl) acetamide.

The title compound was obtained from the product from Preparation 33, using a method similar to that in Preparation 20, as a clear foam in quantitative yield.

Ή-NMR (400 MHz, C1XO1)! δ: -0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.04-1.06 (d, 3H), 1.69-1.70 (6H, m), 2.00 (6H, m), 2.03 (3H, m), 2.52-2.70 (3H, m), 2.88-2.94 (2H, m), 3.37-3.38 (2H, m), 4.64-4.69 (1H, m), 6.927.18 (6H, m), 8.00 (1H, d), 8.30 (s) 8.56 (s); 1. VM8 Ε8Ι: t / ζ 620 [M + H] ⁺ .

Preparation 35. 1- (3-Bromophenyl) -2-methylpropan-2-ol.

Methyl magnesium bromide (3M solution in diethyl ether, 51.6 ml, 155 mmol) is slowly added to a solution of 1- (3-bromophenyl) propan-2-one (15.0 g, 70 mmol) in anhydrous diethyl ether (200 ml) at at 0 ° C and the mixture was stirred for 3 hours. The reaction mixture was then re-cooled to 0 ° C and quenched slowly with a saturated aqueous solution of ammonium chloride. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual yellow oil was then purified by silica gel column chromatography, eluting with a dichloromethane: pentane: methanol mixture in a ratio of 90: 5: 5 to obtain a pale yellow oil in 83% yield, 13.26 g.

Ή-NMR (400 MHz, COC1 ₃ ) δ: 1.22 (6H, s), 1.42 (1H, br.s), 2.74 (2H, s), 7.15 (2H, m), 7.40 (2H, m). Getting 36. X- [2- (3-Bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide.

Chloroacetonitrile (6.63 ml, 105 mmol) was added to a stirred solution of the product from Preparation 35 (12.0 g, 52.0 mmol) in acetic acid (25 ml) at room temperature. The resulting solution was cooled to a temperature of 0 ° C and concentrated sulfuric acid (25 ml) was added while maintaining the temperature below 10 ° C. The resulting solution was allowed to stir for 1 h and then poured onto ice and made basic by adding solid potassium carbonate. The product was extracted with ethyl acetate (2x500 ml) and the combined organic solution was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to give the title compound as an orange solid in quantitative yield, 16.08 g.

Ή-NMR (400 MHz, COC1 ₃ ) δ: 1.37 (6H, s), 3.02 (2H, s), 3.94 (2H, s), 6.17 (1H, br.s), 7.08-7.03 (1H, d), 7.10-7.13 (1H, t), 7.26 (1H, s), 7.39-7.32 (1H, d); LBM8 Ε8Ι: t / ζ 306 [M + H] ⁺ .

- 28 010133

Microanalysis: С ₁₂ Н ₁₅ ВГС1ЫО: calculated: С, 47.32; H, 4.96; Ν, 4.60; Found: C, 47.26; H, 4.87; Ν, 4.65. Preparation 37. 2- (3-Bromophenyl) -1,1-dimethylethylamine.

A solution of the product from Preparation 36 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, made basic with an aqueous solution of sodium hydroxide (1M, 450 ml) and extracted with dichloromethane (2x500 ml). The combined organic solution was washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo to give the title compound as a black oil in 96% yield, 23 g.

Я-NMR (400 MHz, δ: 1.12 (6H, s), 1.84 (2H, br.s), 2.62 (2H, s), 7.16-7.08 (2H, m) 7.36-7.32 (2H, m); BBM8 E81: t / z 228 [M + H] ⁺ .

Preparation 38. [2- (3-Bromophenyl) -1,1-dimethylethyl] carbamic acid tert-Butyl ester.

The product from Preparation 37 (5.0 g, 22 mmol) was treated with di-tert-butyl dicarbonate (5.26 g, 24 mmol) in dichloromethane (50 ml) and stirred for 20 hours. The reaction mixture was washed with water (50 ml) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The crude product is purified using a cation exchange column (methanol, then 2M ammonia in methanol), then purified by flash column chromatography on silica gel eluting with dichloromethane to give the title compound as a brown oil in quantitative yield, 7.23 g .

Я-NMR (400 MHz, COCB) δ: 1.27 (6H, s) 1.50 (9H, s), 2.97 (2H, s), 4.24 (1H, br.s), 7, 05 (1H, d), 7,157.11 (1H, t), 7.30 (1H, s), 7.35 (1H, d); LBM8 E81: t / ζ 350 [Μ + ΝΗ ₄ ] ⁺ .

Preparation 39. Benzyl-3- {2 - [(tert-butoxycarbonyl) amino] -2-methylpropyl} benzoate.

A solution of the product from Preparation 38 (3.9 g, 12 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (11) (1.00 g, 1.3 mmol) and triethylamine (3.3 ml, 24 mmol) in benzyl alcohol (60 ml) was heated at a temperature of 100 ° C and a pressure of carbon monoxide of 100 psi for 5 hours. The cooled reaction mixture was then filtered through ArboseG 'and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate solution (50 ml) and brine (2x50 ml). The organic solution was then dried over sodium sulfate and concentrated in vacuo to give a dark oil. This oil was purified by silica gel column chromatography, eluting with a hexane: ethyl acetate mixture in a ratio of 100: 0 to 84:16, to give the title compound as a pale yellow oil in 61% yield, 2.81 g.

¹ H-NMR (400 MHz, COCB) δ: 1.25 (6H, s), 1.45 (9H, s), 3.05, (2H, s), 4.22 (1H, br.s) 5.35 (2H, s), 7.32-7.48 (7H, m), 7.86 (1H, s), 7.93-7.97 (1H, m).

Getting 40. Benzyl 3- (2-amino-2-methylpropyl) benzohydrochloride.

The title compound was obtained from the product from Preparation 39, using a method similar to that in Preparation 24, as a white solid in 91% yield.

¹ H-NMR (400 MHz, C1) _; O1)) δ: 1.33 (6H, s), 2.98 (2H, s), 5.37 (2H, s), 7.31-7.53 (7H, m), 7.93 (1H s) 8.00-8.04 (1H, m); LBM8 APC1: t / ζ 284 [M + H] ⁺ .

Preparation 41. Benzyl-3- {2 - [((2B) -2- [4- (benzyloxy) -3- (formylamino) phenyl] -2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) amino ] -2-methylpropyl} benzoate.

- 29 010133

A mixture of products from preparation 40 (1.81 g, 6.38 mmol), production 12 (2.96 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) in dimethyl sulfoxide (10 ml) heated at 95 ° C. for 40 hours. The cooled reaction mixture was then diluted with water (250 ml) and extracted with ethyl acetate (3x50 ml). The combined organic solution was washed with sodium bicarbonate solution (50 ml) and brine (2x50 ml), dried over sodium sulfate and concentrated in vacuo to give an orange oil. This oil is purified by column chromatography on silica gel, eluting with a 50:50 mixture of dichloromethane: hexane and then with a dichloromethane: methanol mixture in a ratio of 100: 0 to 98: 2. The appropriate fractions were evaporated under reduced pressure, and the residue was then purified by silica gel column chromatography, eluting with dichloromethane: methanol in a ratio of 100: 0 to 98: 2 to obtain a yellow gum. This resin was azeotroped with diethyl ether (3 times) to give the title compound as a yellow gum in 20% yield, 0.83 g.

Я-NMR (400 MHz, SES1 ₃ ): δ: -0.15 - -0.17 (3H, m), -0.03 (3H, s), 0.79-0.82 (9H, s) 1.01 (3H, s), 1.04 (3H, s), 2.62-2.86 (4H, m), 4.66-4.74 (1H, m), 5.06-5 07 (2H, m), 5.36 (2H, s), 6.88 (1H, d), 7.01-7.05 (1H, m), 7.27-7.50 (12H, m ), 7.74 (1H, m), 7.87-7.96 (2H, m), 8.39 (s), 8.40 (s), 8.76 (s), 8.78 (s) ); 1.1 NMR8 APC1: t / ζ 667 [M + H] ^- .

Preparation 42. 3- [2 - ({(2H) -2 - {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2-methylpropyl ] benzoic acid.

The title compound was obtained from the product from Preparation 41 using a method similar to that of Preparation 26. The crude product was then azeotroped with diethyl ether (3 times) to give the title compound as a pale yellow solid in yield 97 %

Ή-NMR (400 MHz, SE ₃ OE): δ: -0.12 (3H, s), 0.05 (3H, s), 0.81 (9H, s), 1.24 (6H, s) 2.98 (2H, dd), 3.263.30 (2H, m), 4.91 (1H, t), 6.89 (1H, d), 7.02 (1H, m), 7.37- 7.49 (2H, m), 7.85 (1H, br.s), 7.93-7.96 (1H, d), 8.11 (s, 1H), 8.32 (s), 8 , 61 (s); 1.1 NM8 Ε8Ι: t / ζ 487 [M + H] ^- .

Preparation 43. (4-Hydroxy-2,5-dimethylphenyl) acetonitrile.

A solution of (4-methoxy-2,5-dimethylphenyl) acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 ml) is cooled to -80 ° C and treated with boron tribromide (1M solution in dichloromethane, 14.3 ml, 14.3 mmol). The reaction mixture was stirred at -80 ° C for the next 30 minutes and then allowed to warm to room temperature for 2 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate solution (20 ml) and the organic layer was separated. The organic solution was washed with brine (20 ml), dried over sodium sulfate and concentrated in vacuo to give a pale brown solid. Purify by silica gel column chromatography, eluting with ethyl acetate: pentane in a ratio of 20:80 to 33:67 to obtain the title compound as a colorless solid in 60% yield, 0.28 g.

Ή-NMR (400 MHz, SEZOE) δ: 2.13 (3H, s), 2.23 (3H, s), 3.66 (2H, s), 6.60 (1H, s), 6.98 (1H, s); 1.1 NM8 Ε8Ι: t / ζ 160 [M-H] ^- .

Preparation 44. (4-Hydroxy-2,3-dimethylphenyl) acetonitrile.

The title compound was prepared from (4-methoxy-2,3-dimethylphenyl) acetonitrile using a method similar to that of Preparation 43 as a colorless solid in 94% yield.

Ή-NMR (400 MHz, SES1 ₃ ) δ: 2.20 (3H, s), 2.24 (3H, s), 3.62 (2H, s), 6.64 (1H, d), 7, 03 (1H, d); 1.1 NMR8 APC1: t / ζ 160 [M-H] ^- .

- 30 010133

Preparation 45. (4-Hydroxy-3-methylphenyl) acetonitrile.

The title compound was prepared from (4-methoxy-3-methylphenyl) acetonitrile using a method similar to that obtained in Preparation 43 as a pale yellow solid.

Ή-NMR (400 MHz, C1) C1 ₃ ) δ: 2.25 (3H, s), 3.65 (2H, s), 4.98 (1H, br.s), 6.76 (1H, d ), 7.01 (1H, d), 7.07 (1H, s); 1. VM8 Ε8Ι: t / ζ 146 [M-H] ^- .

Preparation 46. 4- (2-Aminoethyl) -2,5-dimethylphenol.

A solution of the product from Preparation 43 (0.28 g, 1.74 mmol) in ethanol (15 ml) was hydrogenated at a pressure of 60 psi using Raney Nickel (Kapeu No.ske®®) (0.1 g, 50% wt. ./mass.) for 16 hours. The reaction mixture is then filtered and the solvent removed in vacuo. The residue was purified using a cation exchange resin, eluting with methanol and then with a 1M solution of ammonia in methanol, to give the title compound as a colorless oil.

Я-NMR (400 MHz, C1UO1)) δ: 2.11 (3H, s), 2.19 (3H, s), 2.63-2.67 (2H, m), 2.72-2.76 (2H, m), 6.54 (1H, s), 6.81 (1H, s); 1. VM8 Ε8Ι: t / ζ 166 [M + H] ⁺ .

Preparation 47. 4- (2-Aminoethyl) -2,3-dimethylphenol.

The title compound was obtained from the product from Preparation 44, using a method similar to that obtained in Preparation 46, as a colorless solid in 95% yield.

Я-NMR (400 MHz, C1) C1 ₃ ) δ: 6.78 (1H, d), 6.55 (1H, d), 2.75-2.68 (4H, m), 2.19 (3H s) 2.12 (3H, s); LBM8 APC1: t / ζ 166 [M + H] ⁺ .

Preparation 48. 4- (2-Aminoethyl) -2-methylphenol.

The title compound was obtained from the product from Preparation 45, using a method similar to that in Preparation 46, as a colorless oil.

Я-NMR (400 MHz, C1UO1)) δ: 2.15 (3H, s), 2.60-2.64 (2H, m), 2.79-2.83 (2H, m), 6.66 (d, 1H), 6.82 (1H, d), 6.90 (1H, s); 1. VM8 Ε8Ι: t / ζ 152 [M + H] ⁺ .

Preparation 49. Tert-Butyl (3-iodobenzyl) carbamate.

A suspension of 3-iodobenzylamine hydrochloride (4.95 g, 18.4 mmol) in dichloromethane (100 ml) was treated with triethylamine (3.1 ml, 22 mmol) and di-tert-butyl dicarbonate (4.40 g, 20 mmol) and the resulting solution stirred at room temperature for 1.5 hours. The reaction mixture was then washed with 2M hydrochloric acid (30 ml), water (30 ml), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colorless quantitative solid yield, 6.43 g.

Я-NMR (400 MHz, C1) C1 ₃ ) δ: 1.46 (9H, s), 4.21-4.30 (2H, m), 4.79-4.89 (1H, br.s) 7.06 (1H, dd), 7.25 (1H, d), 7.60 (1H, d), 7.63 (1H, s); LBM8 Ε8Ι: t / ζ 332 [M-H] ^- .

Preparation 50. Tert-Butyl [(4'-hydroxybiphenyl-3-yl) methyl] carbamate.

A solution of the product from obtaining 49 (0.75 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.62 g,

4.50 mmol) and 1,1'-bis (diphenylphosphino) ferrocenyl palladium (11) chloride (0.11 g, 0.14 mmol) in Ν, Ν-di

- 31 010133 methylformamide (14 ml) was treated with a 2M aqueous solution of sodium carbonate (4 ml) and the resulting mixture was heated at 80 ° C for 16 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: pentane at a ratio of 25:75 to give the title compound as a pale pink crystalline solid in quantitative yield, 0.73 g.

^! H-NMR (400 MHz, SBS1 ₃ ) δ: 1.47 (9H, s), 4.33-4.41 (2H, m), 4.87-4.94 (1H, br.s), 6 89 (2H, d), 7.21 (1H, d), 7.37 (1H, dd), 7.43-7.45 (4H, m); LKM8 E81: t / ζ 298 [M-H] ^- .

Getting 51. 3 '- (Aminomethyl) biphenyl-4-olhydrochloride.

The product from Preparation 50 (0.73 g, 2.43 mmol) was treated with a 4M solution of hydrogen chloride in dioxane (6.1 ml, 24.3 mmol) and the resulting solution was allowed to stir at room temperature for 3 hours. The resulting mixture was then concentrated in vacuo to give the title compound as a colorless solid.

^! H-NMR (400 MHz, SB ₃ OB) δ: 4.17 (2H, s), 6.87 (2H, d), 7.34 (1H, d), 7.45-7.50 (3H, m), 7.61 (1H, d), 7.65 (1H, s); LKM8 E81: t / ζ 198 [M-H] ^- .

Getting 52. 2-Hydroxy-1-naphthamide.

A solution of 2-hydroxy-1-naphthoic acid (5.0 g, 26.6 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol) and 1-hydroxybenzotriazole (3, 95 g, 29.2 mmol) in tetrahydrofuran (70 ml) was stirred at room temperature for 30 minutes before adding 0.88 ammonia (6 ml). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the filtrate was diluted with water (80 ml) and extracted with ethyl acetate (4x80 ml). The combined organic extracts were washed with water (2x50 ml) and brine (50 ml), dried over sodium sulfate and concentrated in vacuo to give an orange oil. Purify the oil using silica gel column chromatography, eluting with dichloromethane: methanol: 0.880 ammonia in a ratio of 95: 5: 0.5, to give the title compound as a pink solid in 37% yield, 1.83 g.

^! H-NMR (400 MHz, SBS1 ₃ ) δ: 6.11-6.35 (2H, br.s), 7.17 (1H, d), 7.36 (-1H, dd), 7.54 ( 1H, dd), 7.79 (1H, d), 7.84 (1H, d), 8.22 (1H, d), 11.70-11.88 (1H, br.s); LKM8 E81: t / ζ 186 [M-H] ^- .

Getting 53. 3,5-Dichloro-Noethyl-2-hydroxybenzamide.

The title compound was prepared from 3,5-dichloro-2-hydroxybenzoic acid and ethylamine using a method similar to that in Preparation 52 to afford the title compound as a pale yellow solid.

^! H-NMR (400 MHz, SBS1 ₃ ) δ: 1.28 (3H, t), 3.47-3.54 (2H, m), 6.29-6.36 (1H, br.s), 7 27 (1H, d); 7.48 (1H, d); LKM8 E81: t / ζ 232 [M-H] ^- .

Preparation 54. 4- (Aminomethyl) -2,6-dimethylphenol hydrochloride.

A solution of borane in tetrahydrofuran (1M solution in tetrahydrofuran, 27.1 ml, 27.1 mmol) was added dropwise to a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 ml ) and the resulting solution was refluxed for 16 hours. The reaction mixture was cooled to room temperature, treated with 6n. hydrochloric acid (20 ml) and refluxed for the next 30 minutes. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was purified using a strong cation exchange resin, eluting with methanol and then with a 2M solution of ammonia in methanol to give an orange oil

- 32 010133 colors. This oil was then treated with a 1M solution of hydrogen chloride in methanol (20 ml) and the reaction mixture was concentrated in vacuo to give the title compound as a pale yellow solid in quantitative yield, 1.12 g.

'H-NMR (400 MHz, SES1 ₃ ) δ: 2.22 (6H, s), 3.75 (2H, s), 6, 90 (2H, s).

Preparation 55. 2- (Aminomethyl) -4-chlorophenol hydrochloride.

The title compound was prepared from 5-chloro-2-hydroxybenzonitrile using a method similar to that described in Preparation 54.

'H-NMR (400 MHz, SES1 ₃ ) δ: 4.08 (2H, s), 6.87 (1H, d), 7.27 (1H, d), 7.35 (1H, s); LKM8 APC1: t / ζ 156 [Μ-H] ^- .

Getting 56. 4 '- (Aminomethyl) biphenyl-4-olhydrochloride.

The title compound was prepared from 4'-hydroxybiphenyl-4-carbonitrile using a method similar to that of Preparation 54.

'H-NMR (400 MHz, SE ₃ OE) δ: 4.10 (s, 2H), 6.83 (d, 2H), 7.44-7.46 (m, 4H), 7.60 (d , 2H).

Preparation 57. 1- (Aminomethyl) -2-naphthol.

A solution of borane in tetrahydrofuran (19.23 ml of a 1M solution, 19.23 mmol) was added dropwise to a solution of amide from Preparation 52 (0.90 g, 4.81 mmol) in tetrahydrofuran (10 ml), and the reaction mixture was then refluxed refrigerator for 2 hours. The solution was cooled, treated with 6M hydrochloric acid (10 ml) and refluxed for the next 2 hours. The resulting suspension was cooled to room temperature and the pH was adjusted to pH 9 by adding 0.88 ammonia and extracted with ethyl acetate ( 3x50 ml). The combined organic solution was washed with brine (20 ml), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel column chromatography, eluting with dichloromethane: methanol: 0.88 ammonia in a ratio of 95: 5: 0.5 to 90: 10: 1, gives the title compound as a pink solid in yield 23%, 0.19 g.

'H-NMR (400 MHz, SE ₃ OE) δ: 4.41 (2H, s), 7.07 (1H, d), 7.23, (dd, 1H), 7.43 (1H, dd) 7.66 (1H, d); 7.72 (1H, d); 7.87 (1H, d); LKM8 Ε8Ι: t / ζ 174 [M + H] ⁺ .

Preparation 58. 2,4-Dichloro-6 - [(ethylamino) methyl] phenol.

A solution of the product from Preparation 53 (0.77 g, 3.29 mmol) in tetrahydrofuran (10 ml) was cooled to 0 ° C and treated with a borane-tetrahydrofuran complex (1 M solution in tetrahydrofuran, 9.9 ml, 9.9 mmol) . The resulting solution was allowed to warm to room temperature for 20 minutes and then refluxed for 16 hours. The reaction mixture was cooled to 0 ° C. and quenched by the addition of methanol. The resulting solution was allowed to warm to room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane (40 ml) and washed with water (2x10 ml), brine (10 ml), dried over sodium sulfate and concentrated in vacuo to give a colorless oil. Purification of the oil by silica gel column chromatography, eluting with methanol: dichloromethane in a ratio of 2:98 to 5:95, gave the title compound as a colorless solid in 74% yield, 0.53 g.

'H-NMR (400 MHz, SES1 ₃ ) δ: 1.17 (3H, t), 2.72 (2H, q), 3.98 (2H, s), 6.86 (1H, d), 7 23 (1H, d).

Receipts 59-68.

The following compounds of the general formula below are obtained from the product from Preparation 42 and the corresponding amine using a method similar to that described in Preparation 27. The reaction mixtures were monitored by thin layer chromatography and stirred at room temperature for 18-72 hours .

- 33 010133

No. 01 Data Exit 59 * H-NMR (400 MHz, € ϋ ₃ Οϋ) δ: -0.19 (S, s), -0.04 (S, s), 0.78 (S, s), 1.08 (S, s), 1.10 (ЗН, s), 2.65-2, 85 (4Н, m), 2.89 (2Н, t), 3.57 (2Н, t), 4.67 (1Н, dd ), 6.79 (1H, d), 6.93 (1H, dd}, 7.21-7.37 (6H, m), 7.59-7.65 (2H, m), 8.08 ( 1H, d), 8.29 (s); LV.MZ ARS1: t / g 624 [M + NC * 21% 60 p5- 'n-NMR (400 MHz, СОС1 ₃ ) δ: -0.23 (ЗН, s), -0.09 (ЗН, s), 0.71 (ЭН, s), 1.06 (ЗН, s) 1.08 (ZN, s), 2.18 (ZN, s), 2.26 (ZN, s), 2.60 - 2.82 (4H, m), 2.90-2.94 (2N, m ), 3.61-3.71 (2H, m), 4.61-4.65 (1H, m), 6.29-6.33 (1H, m), 6, 62-6, 64 (1H, m ), 6.85-6.89 (2H, m), 6.96 (1H, d), 7.18 (1H, s), 7.27-7.32 (2H, m), 7.40- 7.42 (1H, s), 7.78 (1H, s), 8.23 (1H, s), 9.62 (1H, br.s); ЪКМ5 АРС1: t / g 634 [M-H] ' 56% 61 * —ΗΝ — O ” LKM5 ARC1: t / ζ 668 [M + H] ⁺ 88% 62 3333 one GR.MZ ARS1: t / g 668 [M + H] * 48% 63 N.S. .on zhp GR.ME ARC1: t / ζ 634 [M + H] ⁺ 77% 64 Xxx ^sn ' 1kmZ ARS1: t / ζ 620 [M + H] * 96% 65 GC? BUT- LKMZ ARS1: t / ζ 642 [M + H] ⁺ 91% 66 ΣαΓ LWMZ ARS1: t / g 620 [M + H] ⁺ 95% 67 D lJhl _C1 LR.MZ ARS1: t / g 660 [M + H] * 89% 68 ^ ooh Τ, ΡΜΕ APC1: t / ζ 642 [M + H] * 91%

- 34 010133

Getting 60.

Purify by column chromatography using a 12 g cartridge of Kebscher®, eluting with dichloromethane: methanol: 0.88 ammonia in a ratio of 96: 4: 0.3.

Getting 62.

Then subjected to azeotropic distillation with diethyl ether (3 times), obtaining the desired product. Getting 68.

6- (Aminomethyl) -2-naphthalenol can be obtained as described in US patent No. 20040204455, p.19.

Preparation 69. 3- [2 - ({(2K) -2 - {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2-methylpropyl ] -No [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide.

4- (2-amino-1,1-dimethylethyl) phenol hydrochloride (Ac! A Cet. 8 Sep. 8, 1203, 1207, 1954) (41 mg, 0.21 mmol) was added to the product mixture from Preparation 42 (100 mg, 0.21 mmol), O- (1 H-benzotria ^,> ₍ ol-1-yl) -НН№№-tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol) and triethylamine (35 μl, 0.4 mmol) in Ν , Ν-dimethylformamide (3 ml) and the mixture was stirred for 18 h at room temperature.The solvent was then removed in vacuo and the residue was treated with ethyl acetate and washed with saturated sodium bicarbonate solution (3x20 ml) and brine (3x20 ml). The organic solution was then dried above sodium sulfate and concentrated in vacuo to give the title compound as a brown foam in 54% yield.

LKM8 APC1: t / ζ 634 [M + H] ⁺ .

Receipts 70-76.

The following compounds of the general formula below are prepared from the product from Preparation 42 and the corresponding amine using a method similar to that described in Preparation 69. The reaction mixtures were monitored by thin layer chromatography and stirred at room temperature for 18-72 hours. .

01 Data Exit 70 Ο-Ό- LKMZ ARS1: t / ζ 668 CM + H] * 96% 71 LNMZ ARS1: t / ζ 620 [M + H] ⁺ 89% 72 LNMZ ARS1: t / ζ 642 [M + H] ⁺ 84% 73 OU LWMZ APC1: t / ζ 626 [M + H] * 96% 74 LKMZ ARS1: t / ζ 660 [M + H] * 83% 75 £ hg LKMZ APC1: τη / ζ 642 [M + H] * 99% 76 1NMZ ARS1: t / ζ 668 [M + SC 80%

- 35 010133

Getting 77. Diethyl-2,2 '- (1,3-phenylene) diacetate.

Acetyl chloride (12.5 ml, 175 mmol) was added to a suspension of 2.2 '- (1,3-phenylene) diacetic acid (50.0 g, 260 mmol) in ethanol (500 ml) and the resulting solution was refluxed in for 16 hours. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between saturated aqueous sodium hydrogen carbonate (300 ml) and ethyl acetate (500 ml). The organic phase was separated and washed with water (200 ml) and brine (300 ml), dried over sodium sulfate and concentrated in vacuo to give the title compound as a pale yellow oil in quantitative yield, 63.5 g.

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, q), 7.24-7.36 (4H, m ); LKM8 Ε8Ι: t / ζ 251 [M + H] ⁺ .

Getting 78. Ethyl ester of [3- (2-oxopropyl) phenyl] acetic acid.

A solution of the diester obtained from 77 (44.3 g, 177 mmol) and 2.2 '- (1,3-phenylene) diacetic acid (59.2 g, 308 mmol) in ethanol (24 ml) and dioxane (290 ml ) is treated by adding dropwise 12M hydrochloric acid (4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours, cooled to room temperature and concentrated in vacuo. The reaction mixture was then diluted with toluene (125 ml) and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the residue was treated with water and made basic with sodium bicarbonate until the pH became neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5x30 ml) and brine (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethyl ether (3x30 ml). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in pentane to give the title compound as a colorless solid in 27% yield, 10.8 g.

Я-NMR (SEZOE, 400 MHz) δ: 1.25 (3Н, t), 3.60 (2Н, m), 3.63 (2Н, m), 4.15 (2Н, q), 7.18 -7.32 (4H, m); LKM8 Ε8Ι: t / ζ 245 [M + No.] ⁺ .

Getting 79. [3- (2-Hydroxy-2-methylpropyl) phenyl] acetic acid.

Methylmagnesium chloride (51 ml of a 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirred solution of the product from Preparation 78 (11.6 g, 51 mmol) (1p! (3), 331) in tetrahydrofuran (300 ml) at a temperature of 0 ° C. The reaction mixture was then allowed to warm to room temperature overnight to form a white solid, and then water (50 ml) and 2N were carefully added. hydrochloric acid (80 ml). The aqueous layer was separated and extracted with ethyl acetate (2x300 ml). The combined organic solution was washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo to give the title compound as a golden oil in quantitative yield, 11.2 g.

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m ); LKM8 Ε8Ι: t / ζ 209 [M + H] ⁺ .

Preparation 80. {3- [2- (2-Chloroacetylamino) -2-methylpropyl] phenyl} acetic acid.

2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of the product from Preparation 79 (16.0 g, 70 mmol) in acetic acid (33 ml). The resulting solution was cooled to 0 ° C, treated with concentrated sulfuric acid (33 ml) and the reaction mixture was allowed to gradually warm to room temperature. After 4 hours, the reaction mixture was poured onto ice and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate (2x500 ml) and the combined organic extraction solution was dried over magnesium sulfate and concentrated in vacuo to give the title product as a colorless solid in 96% yield, 19.0 g.

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6, 19 (1H, m); 7,067.31 (4H, m); LKM8 Ε8Ι: t / ζ 282 [M – H] ^- .

- 36 010133

Preparation 81. [3- (2-Amino-2-methylpropyl) phenyl] acetic acid methyl ester.

A solution of the product from Preparation 80 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was refluxed for 16 hours. The reaction mixture was then allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in methanol (150 ml) and saturated with gaseous hydrogen chloride. The resulting solution was refluxed for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate solution (200 ml). The organic phase is washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified using a strong cation exchange resin, eluting with methanol and then with a 2M solution of ammonia in methanol to give the title compound as a yellow oil in 67% yield, 2.68 g.

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7, 08-7.16 (3H, m); 7.23-7.27 (1H, m); LNM8 E81: t / z 222 [M + H] ⁺ .

Preparation 82. Methyl- (3- {2 - [(tert-butoxycarbonyl) amino] -2-methylpropyl} phenyl) acetate.

The title compound was obtained from the product from Preparation 81, using a method similar to that in Preparation 49 to afford the title compound as a colorless oil in 81% yield.

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.25 (6H, s), 1.45 (9H, s), 2.95 (2H, s), 3.60 (2H, s), 3, 70 (3H, s), 4.25 (1H, br.s), 7.02-7.06 (2H, m), 7.15 (1 H, d), 7.25 (1H, m); LNM8 E81: t / ζ 344 [M + No.] ⁺ .

Preparation 83. (3- {2 - [(tert-Butoxycarbonyl) amino] -2-methylpropyl} phenyl) acetic acid.

A 5M solution of sodium hydroxide (4.6 ml, 23 mmol) was added to a solution of the product from Preparation 82 (7.45 g, 23 mmol) in dioxane (30 ml) and water (8 ml) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in water and acidified to pH 3 with 2M hydrochloric acid. The mixture was then extracted with ethyl acetate (3x30 ml) and the combined organic solution was washed with brine (3x30 ml), dried over sodium sulfate and concentrated in vacuo to give an oil. This oil was then azeotroped with diethyl ether to give the title compound as a colorless gum in 99% yield, 7.0 g.

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.25 (6Н, s), 1.50 (9Н, s), 2.95 (2Н, s), 3.55 (2Н, s), 3, 65 (s, 1H), 7.05 (2H, m), 7.10 (1H, d), 7.20 (1H, m), 7.25 (1H, m).

Preparation 84. Benzyl- (3- {2 - [(tert-butoxycarbonyl) amino] -2-methylpropyl} phenyl) acetate.

Cesium carbonate (6.03 g, 18.6 mmol) was added to a solution of the product from Preparation 83 (5.7 g, 18.6 mmol) in Ν, Ν-dimethylformamide (40 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue was dissolved in Ν, Ν-dimethylformamide (80 ml), treated with benzyl bromide (3.18 g, 18.6 mmol) and stirred for 3 hours at room temperature. The mixture was then filtered and concentrated in vacuo and the residue was dissolved in ethyl acetate (60 ml), washed with brine (60 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a pale yellow oil in 76% yield 5.6 g

Я-NMR (SES1 ₃ , 400 MHz) δ: 1.25 (6H, s), 1.49 (9H, s), 2.98 (2H, s), 3.65 (2H, s), 4, 30 (s, 1H), 5.14 (2H, s), 7.06-7.10 (2H, d), 7.15-7.20 (1H, m), 7.22-7.39 ( 6H, m); LNM8 E81: t / z 396 [M-H] ^- .

Getting 85. Benzyl- [3- (2-amino-2-methylpropyl) phenyl] acetate.

Trifluoroacetic acid (30 ml) was added to the product from Preparation 84 (5.6 g, 14.1 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue diluted with dichloromethane (100 ml) and made basic with saturated sodium bicarbonate solution (300 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow oil in 76% yield.

'H-NMR (COC1 ₃ , 400 MHz) δ: 1.10 (6H, s), 1.50 (9H, s), 2.64 (2H, s), 3.66 (2H, s), 5 13 (2H, s), 7.077.12 (2H, d), 7.14-7.18 (1H, m), 7.22-7.38 (6H, m); LAM8 E81: t / ζ 298 [M + H] ⁺ .

Preparation 86. Benzyl- (3- {2 - [((2H) -2- [4- (benzyloxy) -3- (formylamino) phenyl] -2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetate.

The title compound was obtained from the products from Preparation 12 and Preparation 85, using a method similar to that in Production 13, in 55% yield.

'H-NMR (CBC1 ₃ , 400 MHz) δ: -0.20 (3H, m), -0.06 (3H, s), 0.78 (9H, s), 0.92 (3H, s) 0.95 (3H, s), 2.532.77 (4H, m), 3.57 (2H, s), 4.61-4.68 (1H, m), 5.01-5.02 (2H , m), 5.06 (2H, s), 6.84-6.87 (1H, m), 6.97-7.36 (14H, m), 7.62-7.70 (1H, m ), 8.33-8.35 (1H, m), 8.34 (s), 8.67 (s), 8.70 (s); LAM8 E81: t / ζ 681 [M + H] ^- .

Getting 87. {3- [2 - ({(2H) -2 - {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2- methylpropyl] phenyl} acetic acid

The title compound was obtained from the product from Preparation 86, using a method similar to that in Production 26, in 93% yield.

'H-NMR (400 MHz, COC1 ₃ ) δ: -0.06 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.00 (3H, s), 1.04 (3H, s), 2.582.88 (4H, m), 3.58 (2H, s), 4.64-4.67 (1H, m), 6.88-6.90 (1H, m), 6.95-6.98 (1H, m), 7.07-7.27 (5H, m), 8.04-8.05 (d), 8.25 (s), 9.55 (ears.s); LAM8 E81: t / ζ 501 [M + H] ^- .

Preparation 88. 2-Chloro-Y-ethyl-5-hydroxybenzamide.

The title compound was prepared from 2-chloro-5-hydroxybenzoic acid and ethylamine using a method similar to that in Preparation 52 as a colorless solid.

'H-NMR (400 MHz, COC1 ₃ ) δ: 1.22 (3H, t), 3.42-3.49 (2H, m), 6.48-6.52 (1H, m), 6, 80 (1H, dd), 7.13 (1H, d), 7.38 (1H, d); LAM8 E81: t / ζ 200 [M + H] ⁺ .

Preparation 89. 4-Chloro-3 - [(ethylamino) methyl] phenol.

The title compound was obtained from the product from Preparation 88, using the method as in Preparation 57, as a colorless solid.

'H-NMR (400 MHz, ί.Ό ₃ ΟΌ) δ: 1.15 (3H, t), 2.68 (2H, q), 3.79 (2H, s), 6.67-6.70 (1H, m), 6.84 (1H, d), 7.16 (1H, d).

- 38 010133

A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), tert-butyl (dimethyl) silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and Ν, Ν- dimethylaminopyridine (10 mg) in Ν, Ν-dimethylformamide (40 ml) was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase is separated, washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. Purify by silica gel column chromatography, eluting with a pentane: ethyl acetate mixture in a ratio of 75:25 to 67:33 to obtain the title compound as a colorless oil in 75% yield, 6.50 g.

'H-NMR (400 MHz, C1XT) δ: 0.25 (6H, s), 0.97 (9H, s), 6.80 (1H, dd), 6.87 (1H, d), 7, 84 (1H, d), 10.32 (1H, s).

Preparation 91. Ν- (4 - {[tert-Butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) prop-2-en-1-amine.

A solution of the aldehyde from Preparation 90 (6.50 g, 24.0 mmol) and allylamine (1.51 g, 26.4 mmol) in dichloromethane (60 ml) was treated with sodium triacetoxyborohydride (7.6 g, 35.6 mmol) and the resulting suspension was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (50 ml) was added and the organic layer was separated. The organic solution was washed with brine (50 ml), dried (sodium sulfate) and concentrated in vacuo to give a yellow oil. Purify the oil using silica gel column chromatography, eluting with a pentane: ethyl acetate mixture in a ratio of 75:25 to 67:33 to obtain the title compound as a colorless oil in 38% yield, 2.80 g.

'H-NMR (400 MHz, δ: 0.19 (6H, s), 0.97 (9H, s), 1.84 (1H, br.s), 3.26 (2H, d), 3, 81 (2H, s), 5.12 (1H, dd), 5.20 (1H, dd), 5.88-5.98 (1H, m), 6.71 (1H, dd), 6.85 -6.86 (1H, d), 7.24 (1H, d); LKM8 E81: t / z 312 [M + H] ⁺ .

Preparation 92. (4- {[tert-Butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) amine.

A solution of the product from Preparation 91 (2.8 g, 9.0 mmol), dimethyl barbituric acid (7.0 g, 45 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.08 mmol) in dichloromethane (80 ml) was refluxed for 4 hours. The cooled solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate (50 ml) and 1N. aqueous sodium hydroxide solution (50 ml). The organic layer was separated, washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.880 ammonia in a ratio of 98: 2: 0 to 95: 5: 0.5 to obtain the title compound as a colorless oil in 70% yield, 1, 70 g

'H-NMR (400 MHz, δ: 0.19 (6H, s), 0.97 (9H, s), 1.89 (2H, s), 3.85 (2H, s), 6.70 ( 1H, dd), 6.856.86 (1H, dd), 7.21 (1H, d).

Receipts 93-95.

The following compounds of the general formula below are obtained from the product from Preparation 87 and the corresponding amine using a method similar to that described in Preparation 27. The reaction mixtures were monitored by thin-layer chromatography and stirred at room temperature for 18-72 hours .

but'

- 39 010133

No. 01 Data Exit 93 ^ -NMR (400 MHz, С0 ₃ 0П) 8: -0.18 (ЗН, s), -0.07 (ЗН, s), 0.75 (9Н, s), 1.01 (ЗН, С) 1.04 (ZN, s), 2.59-2, 83 (4H, m), 3, 56-3, 58 (2H, m), 3.89 (ZN, 8), 4.41-4 53 (2H, m), 4.63-4.66 (1H, m), 6.80-6.82 (1H, m), 6.95-6, 98 (1H, m), 7.037.05 (1H, m), 7.09-7.11 (2H, m), 7.21-7.26 (4H, m), 7, 93-7, 69 (2H, d); LKM5 Ε5Ι: t / ζ 648 [M + H] ⁺ 41% 94 ^ -NMR (400 MHz, СО ₃ СУ) δ: -0.21 - - 0.16 (ЗН, m), -0.04-0.01 (ЗН, m), 0.76-0.83 ( EN, m), 1.02-1.09 (EN, m), 2.61-2.77 (ЗН, m>, 2.84-2.92 (1Н, s), 3.32-3, 38 (2H, m), 3.70, 3.81 (2H, 2xs), 4.55, 4.63 (2H, 2x0, 4.66, 4.72 (1H, m), 6.62-6 69 (1H, m), 6.78-6, 87 <2H, m>, 6.90-5.96 <1H, m), 6, 99-7.26 (5H, m), 8.07 -8.10 (1H, s), 8.29 (s), 8.60 (s); bp.MZ ARC1: t / ζ 668 [M + H] ⁺ 43% 95 'H-NMR (400 MHz, С0 ₃ 00) δ: -0.25 (ЗН, s), -0.09 (ЗН, s), 0.73 (EN, m>, 0.97 (ЗН, О , 0.99 (ZN, s), 2.56-2.83 (4H, m), 3, 47-3, 48 (2H, m), 4.31 (2H, s), 4, 59-4 , 53 (1H, m), 6.73, -7.41 (15H, m), 8.08 (s), 8.21 (s), 8.57 (s); KKM5 Ε5Ι: t / ζ 682 [M + H] ⁺ 54%

Preparation 96. 2- {3- [2 - ({(2K) -2- {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) - 2-methylpropyl] phenyl} -№ (2-chloro-4-hydroxybenzyl) acetamide.

The title compound was obtained from the products from Preparations 87 and 92, using a method similar to that of Preparation 27, as a brown foam in 62% yield.

Ή-NMR (400 MHz, ί.Ό ₃ ΟΌ) δ: -0.19 (3H, s), -0.03 (3H, s), 0.79 (9H, s), 1.01-1, 10 (6H, m), 2.62-2.76 (3H, m), 2.85 (1H, m), 3.37-3.92 (2H, m), 4.34 (2H, s) 4.66 (1H, m), 6.62 (1H, m), 6.78-6.82 (2H, m), 6.91 (1H, m), 7.02-7.23 (5H , m), 8.09-8.11 (1H, m), 8.27 (s), 8.59 (s); 1.EM8 ARC1: t / ζ 640 [M + H] ⁺ .

Preparation 97. 2- (3-Bromophenyl) -№ (3,4-dimethylbenzyl) acetamide.

The title compound was prepared from 3,4-dimethylbenzylamine and 3-bromophenylacetic acid using a method similar to that in Preparation 27 as a white solid in 93% yield.

Ή-NMR (400 MHz, SIS1 _; ) δ: 2.20 (6H, s), 3.50 (2H, s), 4.30 (2H, d), 5.80 (1H, br.s), 7.60-7.80 (7H, m);

- 40 010133

LKM8 E81: t / ζ 332 [M] ⁺ .

Preparation 98. No. (3,4-Dimethylbenzyl) -2- {3 - [(E) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) vinyl] phenyl} acetamide .

Product from Preparation 97 (5.0 g, 15 mmol), Ν-vinylphthalimide (2.62 g, 15.1 mmol), tri-orthotolylphosphine (473 mg, 1.55 mmol), palladium (11) acetate (98 mg 0.4 mmol) and Ν, Ν-diisopropylethylamine (30 ml, 172 mmol) in acetonitrile (35 ml) are refluxed for 16 hours. The reaction mixture is then cooled to room temperature and the precipitate is filtered off. The solid is then dissolved in dichloromethane, activated carbon is added and the solution is filtered through CeChe®. The filtrate was concentrated in vacuo and the residue was recrystallized from a hot dichloromethane / methanol mixture to give the title compound as a yellow solid in 55% yield, 3.5 g.

Ή-NMR (400 MHz, SES1 ₃ ) δ: 2.20 (6Н, s), 3.80 (2Н, s), 4.30 (2Н, d), 6.0 (1Н, br.s), 6.90 (2H, m), 7.01 (1H, m), 7.18 (1H, m), 7.26-7.40 (4H, m), 7.56-7.61 (1H, m), 7.75 (2H, m), 7.88 (2H, m).

Preparation 99. No. (3,4-Dimethylbenzyl) -2- {3- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] phenyl} acetamide.

The product from Preparation 98 (3.3 g, 7.7 mmol) and 10% palladium-on-charcoal (1 g) were suspended in ethanol and the mixture was stirred at 50 psi hydrogen pressure at room temperature for 16 h. The reaction mixture was then filtered through Arbose! ®, washed with ethanol and the filtrate was concentrated in vacuo to afford the title product as a yellow solid in 52% yield, 1.7 g.

Ή-NMR (400 MHz, SES1 ₃ ) δ: 2.20 (6Н, s), 2.95 (2Н, s), 3.60 (2Н, s), 3.90 (2Н, t), 4, 39 (2H, d), 5.95 (1H, br.s), 6.90-7.20 (8H, m), 7.60-7.70 (3H, m).

Preparation 100. 2- [3- (2-Aminoethyl) phenyl] -No (3,4-dimethylbenzyl) acetamide.

Hydrazine monohydrate (6 ml, 123.6 mmol) was added to a suspension of the product from Preparation 99 (3.5 g, 8.2 mmol) in ethanol (125 ml) and the mixture was refluxed for 4 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol: 0.88 ammonia, in a 95: 5: 1 ratio, to obtain the title compound with a yield of 57%, 1.4 g.

Я-NMR (400 MHz, CO ₃ OE) δ: 2.18 (6Н, s), 2.73 (2Н, m), 2.86 (2Н, m), 3.50 (2Н, s), 4 25 (2H, s); 6.877.25 (7H, m); LKM8 E81: t / ζ 297 [M + H] ⁺ .

Preparation 101. 2- (3- {2 - [((2B) -2- [4- (Benzyloxy) -3- (formylamino) phenyl] -2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] ethyl} phenyl) -№ (3,4-dimethylbenzyl) acetamide.

- 41 010133

The title compound was obtained from the products from Preparation 12 and Preparation 100, using a method similar to that in Preparation 33, as a yellow oil in 37% yield.

Ή-NMR (400 MHz, C1) _; O1)) δ: -0.18 (3H, s), -0.03 (3H, s), 0.80 (9H, s), 2.20 (6H, m), 2.80 (4H, m ), 3.40 (2H, s), 3.50 (2H, s), 4.25 (2H, s), 4.76 (1H, m), 5.18 (2H, s), 6.85 -7.45 (15H, m), 8.23 (s), 8.30 (s); LBM8 Ε8Ι: t / ζ 680 [M + H] ⁺ .

Preparation 102. 2- {3- [2 - ({(2B) -2 - {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) ethyl ] phenyl} -X- (3,4-dimethylbenzyl) acetamide.

The title compound was prepared from the product from Preparation 101, using a method similar to that in Preparation 20, as a white foam in 83% yield.

Ή-NMR (400 MHz, C1) _; O1)) δ: -0.18 (3H, s), -0.05 (3H, s), 0.81 (9H, s), 2.18 (6H, m), 2.80 (4H, m ), 3.29 (2H, m), 3.51 (2H, s), 4.25 (2H, s), 4.70 (1H, m), 6.80 (1H, d), 6.91 -7.20 (9H, m), 8.03 (s), 8.25 (s); LBM8 Ε8Ι: t / ζ 590 [M + H] ⁺ .

Receive 103-110.

The following compounds of the general formula below are prepared from the product from Preparation 87 and the corresponding amine using a method similar to that described in Preparation 27. The reaction mixtures were monitored by thin layer chromatography and stirred at room temperature for 18-72 hours .

No.

104

Data

55%

Exit

66%

'H-NMR (400 MHz, SOzOO) 5: -0.25 (ZN, s), -0, 08 (ZN, c) g 0, 73 (EN, s), 0.97 (ZN, s), 0.99 (ZN, s) 2.37 (ZN, s), 2.56 -2.83 (4H, i), 3.39-3.45 (2H, m), 4.24 (2H, s), 4.60-4.63 (1H, m), 6.73- -6.79 (1H, m), 6.85 (1H, dd) 6, 97 (1H, d), 7.03 (1H, s), 6.97- -7.16 (6H, m), 8.04 (d), 3.21 (from) , 8.53 (s); Kommersant З3Ι: t / ζ 658

from) , 0, 98 (ZN, from) , 1.00 2,57- -2, 83 C4H, m) 3.48 4.37 (2H, from) , 4, 60- -4.63 6.73 (1H, d) 6, 85 (1H,

- 42 010133

'/ 17 (5H, m) 7.32 (2H, d) (2H, D) 8.04 (l), 8.22 8.52 (from); LKMZ ARS1: hl / Ζ

sp (400 MHz, SOZSGO) δ : -0.26 c), -0, 10 (ZN, from) , 0.72 s), 0.93 (ZN , from), 0 95 (ZN, 2.49-2.79 (4H g M) 3 46-3.47 m), 4.33 (2H , FROM) , 4, 58-4.61

H-NMR (400 MHz, SOzOO) δ: -0.24 (ZN, s), -0, 08 (ZN, from) , 0.74 (EN, s), 0.99 (ZN, s), 1,02 (ZN, s), 2.59-2.87 (4H, m), 3.47 (2H, m) 4.23 (2H, c), 4.62- 4.65 (1H, m) 6.65 (1H, D), 6.74 (1H, D) 6.90-6.95 (1H, m), 7.01- -Ί, ΟΊ (ZN, m), 7.10 (1H, s), 7.14- -7.24 (2H, m), 8.05 (1H, d), 8.22 (from) , 8.53 (s); Kommersant ARS1: t / ζ 640 [M + H] ⁺

N-NMR (400 MHz, SOZOO) δ: -0.24 (ZN, from) , -0.08 (ZN, s), 0.73 (EN, from), 1.00 (ZN , from) , 1.02 (ZN, c), 1 ί, 45- • 1.56 (2H , M) 2.01-2.04 (2H, m) 2.53-2.84 (8H, m), 3.38 (2H, FROM) , 3.58 (1H , FROM) , 4.60-4.63 (1H, m) 6.73 (1H , d) 6.85 (1H, DD) 6.97 (1H, d) 7.05-7.14 (ZN, m) 8.04 (1H , d) 6.24 (s), 8.53 (from) ; NNMZ ARS1: t / ζ 598 [M + H] +

1H-NMR (400 MHz, SOzOO) δ: -0.18 (ZN, from) , -0.02 (ZN, s), 0.80 (EN, from) , 1.05 (ZN, C), 1.07 (ZN, from) , 2, 61- 2.91 (4H, m), 3.08 (ZN, from) , 3,55 (2H, d), 4.45 (2H, from) , 4.66 42H dd) 6.79 (1H, d) 6, 91 (1H dd) 7.05 (1H, e) < 7.13 (1H, C), 7.15-7.25 (ZN, 'm) 7.45 (2H, d) 7.85 (2H, d), 8.10 (1H, d) 8.28 (s), 8.60 (from) ; bkmz ARS1 : t / ζ 668 [M + H] ⁺

- 43 010133

Receipts 111-119.

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (40 mg, 205 μmol) was added to a solution of the compound from Preparation 42 (100 mg, 206 μmol), hydroxybenzotriazole hydrate (32 mg, 205 μmol) and triethylamine (0.55 μl, 412 μmol) in dichloromethane (2 ml), then amine (205 μmol) was added and the mixture was stirred at room temperature for 18 hours. Then the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium bicarbonate solution (20 ml) and brine (20 ml), dried (No. ₂ 8О ₄ ) and concentrated in vacuo to obtain a film which Penetrate in diethyl ether (3 times) until a foam forms.

No. 01 Data Exit 111 of LKMZ Ε3Ι: w / ζ 590 [M + H] * 81% 112 ЕКМЗ АРС1: t / ζ 582 [M + H] * 74% 113 ,ABOUT ЕКМЗ АРС1: t / ζ 554 [M + H] * 94% 114 R KMZ ARS1: t / ζ 658 [M + H] * 87% 115 EKMZ ARS1: t / ζ 604 [M + H] * 83% 116 xo LWMZ APC1: t / ζ 602 [M + H] * 89% 117 --- 'Ί'Γ ЕКМЗ АРС1: t / ζ 591 [M + H] * 74% 118 LR.MZ ARC1: t / ζ 620 [M + H] * 90% 119 LKMZ ARS1: t / ζ 669 [M + H] * 80% 120 * AO LKMZ ARS1: t / ζ 602 [M + H] * 92% 121 * AO ЕКМЗ АРС1: t / ζ 620 [M + H] * 38%

* Do not evaporate from diethyl ether.

Preparation 122. No. {5 - [(2B) -2- {2- [3- (10-Azatricyclo [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene -10-carbonyl) phenyl] -1,1-dimethylethylamino] - 1- (tert-butyldimethylsilanyloxy) ethyl] -2-hydroxyphenyl} formamide.

- 44 010133

The title compound was prepared from 10-azatricyclo [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene using a method similar to that in Preparation 69.

LKM8 APC1: t / ζ 628 [M + H] ⁺ .

Preparation 123. 3- {2 - [(2B) -2- (tert-Butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] -2-methylpropyl} -№ [2- (5-chloro-2 -hydroxyphenyl) ethyl] benzamide.

The title compound was prepared from 2- (2-aminoethyl) -4-chlorophenol using a method similar to that of Preparation 69.

LKM8 APC1: t / ζ 640 [M + H] ⁺ .

Receipts 124-128.

Amine (412 μmol) is added to the mixture of the compound from Preparation 42 (200 mg, 412 μmol), hydroxybenzotriazole hydrate (63 mg, 412 μmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79 mg, 412 μmol) and triethylamine ( 0.11 ml, 824 μmol) in dichloromethane (2 ml) and the mixture was stirred at room temperature for 18 hours. Then the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium bicarbonate solution (3x20 ml) and brine (3x20 ml) , dried (Md ₈ O ₄ ). The crude product is purified by chromatography on silica gel, eluting with a mixture of dichloromethane: 0.88 ammonia in a ratio of 99.7: 0.3. The appropriate fractions were evaporated under reduced pressure and the residue was concentrated in vacuo, the resulting white foam was suspended in diethyl ether (3 times) and evaporated.

No. ίι Data Exit 124 CH ^H H-NMR (400 MHz, COC1 ₃ ) δ: -0.23 (S, s}, -0.09 (S, s), 0.69 (9H, s), 1.07 (S, s) 1.08 (ZN, s), 2.27 (ZN, s), 2.29 (ZN, s), 2.60-2.82 (4H, m), 2.98 (2H, t), 3.64-3.73 (2H, m), 4.61-4.65 (1H, m), 6.39 (1H, m}, 6, 84-7.42 (UN, m), 7, 80 (1H, s), 8.24 (1H, s), 9.70-9.80 (m); BEMZ ARC1 t / ζ 619 [M + H] ⁺ 63% 125 '-ΗΝ' ^ ίΡ but ² H-NMR (400 MHz, COC1 ₃ ) δ: -0.23 (3H, s), -0.09 (3H, s), 0.70 (9H, s), 1.02 (3H, s) 1.04 (ЗН, s), 2.60-2.79 (4Н, m), 3.09-3.12 (2Н, t), 3.74- 70%

- 45 010133

96%

3.79 (2H, m), 4.58-4.60 (ΙΗ, m}, 6.35-6, 39 (ΙΗ, μ), 6.88 (ΙΗ, D), 6.94 (ΙΗ, D), 7.10 (ΙΗ, s), 7.20-7.34 (4Η, m),

7.38-7.42 (2Η, Μ), 7.76 (ΙΗ,

C), 8.24 (ΙΗ, s), 9.76 (ΙΗ, s);

LKMZ ARS1 t / ζ 624 [M + H] * ¹ Η-NMR (400 MHz, COC13) δ:

-0.22 (ZN, s),  -0, 09 (ZN, 3 0.71 (EN, s). 1.20 (ZN, s), 1.22 (ZN, s). 2, 34 (6H, s), 2.61-2.78 (4H, - M) _g 3.00 (2H t), 3.56-3.60 (2H, m), 4.59- 4.62 (1H, m), 6, 39 -6.43 (1H i), 6.86 (1H, D) 6, 96-7.07 (ZN, m), 7.16 (1H, c), 7.28- 7, 33 (2H, m), 7.42 (1H, d), 7.77 (1H, s), 8, 24 (1H, s), 9.65 (1H, s); Kommersant APC1 t / ζ 618 [M + H] ⁺

¹ H-NMR (400 MHz, COC1 ₃ ) δ: -0.23 (ZN, s), -0, 09 (ZN, s), 0.70 (EN, s), 1.04 (ZN, s), 1.05 (ZN, s), 2.33 (ZN, s). 2.61-2.76 (4H, m), 2.88-2.92 (2H, t), 3.67-3.74 (2H, m), 4.57-4, 60 (1H, m), 6.25-6.29 (1H, m), 6.88 (1H, d), 6.98 (1H, d), 7.09-7.33 (7H, m). 7.75 (1H, s), 8.23 (1H, s), 9.82 (1H, s); BNMP APC1 πι / ζ 604

[M + H] * 'H-NMR (400 MHz, COC1 ₃ ] δ:

73%

nineteen%

-0.23 (ZN, s), -0.10 (ZN, s),

0.68 (EN, s), 1.03 (ZN, s),

1.04 (ZN, s), 2, 59-2, 76 (4H, m), 3, 42-3, 48 (2H, m), 3.803.94 (2H, m), 4.58-4, 61 (1H,

m), 6.30-6, 34 (1H, m), 6.89

(1H, d) 6, 98 (1H, d) 7.10 (1H, from) , 7.23- -7.60 (6H, m) 7.75 (1H, FROM) , 7.77 (1H, D) 8.15 (1H, D) 8.18 (1H, d) 9.77 (1H, from); BKMZ ARS1 t / ζ 640

[M + H] *

Preparation 129. 3- (2-Oxopropyl) benzoic acid methyl ester.

Tributyltin methoxide (80.3 ml, 279 mmol), methyl 3-bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium (11) acetate (2.6 g, 11 , 6 mmol) and tri-orthotolylphosphine (7.1 g, 23.2 mmol) are stirred together in toluene (350 ml) at a temperature of 100 ° C in nitrogen atmosphere for 18 hours. After cooling, the reaction mixture is treated with a solution of potassium fluoride (4M 560 ml) and stirred for 2 hours. The resulting mixture was then diluted with toluene (200 ml) and filtered through CeChe®, and the filter layer was washed with ethyl acetate. The organic phase is separated, dried (sodium sulfate) and

- 46 010133 concentrated in vacuo. The residue was purified by chromatography, eluting with ethyl acetate: pentane in a ratio of 10:90 to 20:80 to give the title compound (45.3 g) as an orange oil.

'H-NMR (400 MHz, C0Cl ₃ ) δ: 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43-7.37 (2H, m), 7.87 (1H, s), 7.95-7.93 (1H, d); LAM8 E81: t / ζ 215 [M + No.] ⁺ , 191 [M-H] ^- .

Preparation 130. 3 - [(2H) -2 - ((1H) -1-phenylethylamino) propyl] benzoic acid methyl ester hydrochloride.

The title compound was obtained from the compound from Preparation 129, using a method similar to that of Preparation 19 to obtain the title compound (27.3 g) as a colorless crystalline solid.

'H-NMR (400 MHz, C1) _; O1)) δ: 1.17-1.16, (3H, d), 1.71-1.69 (3H, d), 2.71-2.65 (1H, dd), 3.25-3 , 19 (1H, m), 3.43-3.38 (1H, dd), 190 (3H, s), 4.68-4.63 (1H, q), 7.35-7.33 (1 N, d), 7.45-7.42 (1H, dd), 7.55-7.49 (5H, m), 7.75 (1H, s), 7.92-7.90 (1H, e).

Preparation 131. Methyl {3 - [(2H) -2-aminopropyl] phenyl} acetate.

The title compound was prepared from the compound from Preparation 130, using a method similar to that in Preparation 20 to afford the title compound (8.48 g) as a pale yellow oil.

'H-NMR (400 MHz, COC1 ₃ ) δ: 1.14-1.12 (3H, d), 2.64-2.59 (1H, dd), 2.78-2.73 (1H, dd ), 3.26-3.17 (1H, m), 3.90 (3H, s), 7.38-7.34 (2H, m), 7.90-7.87 (2H, m); LAM8 E81: t / ζ 194 [M + H] ⁺ .

Preparation 132. 3 - ((2H) -2-tert-butoxycarbonylaminopropyl) benzoic acid methyl ester.

A mixture of the compound: from preparation 131 (5.00 g, 26.0 mmol), di-tert-butyl dicarboxylate (6.22 g,

28.5 mmol) and sodium bicarbonate (4.35 g, 52 mmol) was stirred in a mixture of 1,4-dioxane (100 ml) and water (10 ml) for 20 hours. The solvent was removed and the product was partitioned between ethyl acetate (200 ml) ) and hydrochloric acid (2M, 100 ml), the organic layers are washed with brine (100 ml) and dried (MgO ₄ ). Removal of the solvent gave a white solid (7.12 g, 93% yield).

'H-NMR (400 MHz, C1) _; O1)) δ: 1.09 (3H, d), 1.35 (9H, s), 2.73-2.79 (2H, m), 3.76-3.83 (1H, m), 3 89 (3H, s), 6.54 (1H, d), 7.26-7.46 (2H, m), 7.84-7.87 (2H, m); LM8: HS = 4.53 min, t / z 294 [M + H] ⁺ .

Preparation 133. 3 - ((2H) -2-tert-butoxycarbonylaminopropyl) benzoic acid.

A mixture of the compound from Preparation 132 (7.10 g, 24.3 mmol) and lithium hydroxide (1.00 M, 50.0 ml, 50.0 mmol) in tetrahydrofuran (100 ml) was stirred for 20 hours. The reaction mixture was diluted with ethyl acetate. (250 ml) and acidified with hydrochloric acid (2M) to pH 2. The aqueous phase is re-extracted with ethyl acetate (150 ml) and the combined organic layers are washed with brine (300 ml) and dried (MgO ₄ ). Filter and remove the solvent, yielding 5.53 g (82% yield) of the title compound.

'H-NMR (400 MHz, C1) _; O1)) δ: 1.10 (3H, d), 1.36 (9H, s), 2.82-2.81 (2H, m), 3.77-3.84 (1H, m), 7 35-7.45 (2H, m); 7.84-7.89 (2H, m); LYM8 APC1: t / ζ 278 [M-H] ^- .

Preparation 134. 3 - ((2H) -2-tert-butoxycarbonylaminopropyl) benzoic acid benzyl ester.

Cesium carbonate (6.50 g, 19.8 mmol) in water (10 ml) is added to a solution of the compound from

133 (5.50 g, 19.8 mmol) in Ν, Ν-dimethylformamide (50 ml) and the resulting mixture was stirred at room temperature

- 47 010133 at ambient temperature for 1 h. Then benzyl bromide (3.42 g, 19.8 mmol) was added and the mixture was stirred for 20 h. Ethyl acetate (50 ml) was added and the suspension was filtered off, the filtrate was washed with brine (100 ml) ) and dried (Md ₈ O ₄ ). After filtration and removal of solvent, 7.20 g of the title compound are obtained.

^! H-NMR (400 MHz, SbzOb) δ: 1.09 (3H, d), 1.32 (9H, s), 2.74 (2H, d), 2.7.5-2.83, (1H , m), 5.34 (2H, s), 7.29-7.40 (4H, m), 7.43-7.47 (3H, m), 7.85-7.90 (2H, m ); LRM8 ARC1: t / ζ 270 [Ν-VOSD

Preparation 135. 3 - ((2K) -2-aminopropyl) benzoic acid benzyl ester.

The compound from Preparation 134 (7.20 g, 19.0 mmol) was treated with trifluoroacetic acid (35 ml) and the mixture was allowed to stir for 20 hours. Trifluoroacetic acid was removed in vacuo and dichloromethane (175 ml) was added. The mixture was made basic with saturated sodium hydrogen carbonate solution (150 ml) and washed with sodium hydroxide solution (1M, 50 ml). The combined organic layers were washed with brine (150 ml) and dried (Md ₈ O ₄ ) to give a brown oil (3.70 g, 72% yield).

^! H-NMR (400 MHz, SB ₃ OB) δ: 1.04 (3H, d), 2.66 (2H, d), 3.05 (1H, dt), 5.33 (2H, s), 7 28-7.44 (7H, m); 7.86-7.90 (2H, m); LKM8 APC1: t / ζ 270 [M + H] ⁺ .

Preparation 136. 3 - {((2K) -2 - [(2K) -2- (4-benzyloxy-3-formylaminophenyl) -2- (tert-butyldimethylsilanyloxy) ethylamino] propyl} benzoic acid benzyl ester.

Compounds from Preparation 135 (3.70 g, 13.8 mmol) and Preparation 12 (3.20 g, 6.9 mmol) were heated at 90 ° C. for 26 hours. The mixture was allowed to cool and diluted with dichloromethane (100 ml). . The organic layers were washed with saturated sodium bicarbonate solution (200 ml) and concentrated in vacuo. The crude product was purified by chromatography (2 times), eluting with ethyl acetate: heptane in a ratio of 0: 100 to 40:60 to give 2.0 g (52% yield) of the title compound.

LMP8 APC1: t / ζ 270 [M + H] ⁺ .

Preparation 137. 3 - {(2K) -2 - [(2K) -2- (tert-Butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] propyl} benzoic acid.

NM

The compound from Preparation 136 (2.0 g, 3.1 mmol) and palladium-on-carbon (10%, 205 mg) in methanol (100 ml) was hydrogenated at 60 psi at room temperature for 20 h. A solution of ammonia in methanol (2M, 50 ml) was added and the mixture was allowed to mix for 2 minutes. The mixture was then filtered through filter aid, which was washed with a solution of ammonia in methanol (2M, 250 ml) and the resulting organic layers were concentrated to give a dark green solid. The crude product was purified by chromatography, eluting with dichloromethane: methanol: 0.88 ammonia in a ratio of 100: 0: 0 to 75: 20: 5 to give the title compound as a dark green solid (131 mg).

^! H-NMR (400 MHz, DMSO-b ₆ ) δ: -0.18 (3H, s), -0.06 (3H, s), 0.77 (9H, s), 0.89 (3H, d ), 2.61-2.68 (2H, m), 2.65-2.73 (2H, m), 2.80-2.86 (1H, m), 4.56-4.60 (1H , m), 6.75 (1H, d), 6.81 (1H, dd), 7.83 (2H, d), 7.70-7.75 (2H, m), 8.00 (d) 8.25 (s); 9.53 (s); LKM8 APC1: t / ζ 473 [M + H] ⁺ .

Preparation 138. 3 - {(2K) -2 - [(2K) -2- (tert-Butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] propyl} -№ [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide.

- 48 010133

The title compound was prepared from 4- (2-amino-1,1-dimethylethyl) phenol hydrochloride (Ac! A C11et. 8 ppb., 8, 1203, 1207, 1954) using a method similar to that obtained in Preparation 27.

Я-NMR (400 MHz, C1UO1)) δ: -0.24 (3H, s), -0.08 (3H, s), 0.76 (9H, s), 0.99, (3H, d) , 1.28 (6H, s), 2.54

2.92 (5H, m), 3.46 (2H, s), 4.60-4.63 (1H, m), 6.66-6.70 (3H, m), 6.77-6, 80 (1H, dd), 7.20-7.34 (4H, m), 7.45 (1H, s), 7.50 (1H, d), 7.92-7.93 (1H, d) 8.21 (s); 8.55 (s); LKM8 APC1: t / ζ 620 [M + H] ⁺ .

Preparation 139. Methyl- (2E) -3- [3- (2-oxopropyl) phenyl] acrylate.

ABOUT

A solution of 3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4 g, 469 mmol), palladium (P) acetate (7.9 g, 35.2 mmol), tri-orthotolylphosphine (21.4 g , 70.4 mmol) and triethylamine (82 ml) in acetonitrile (900 ml) were refluxed under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Purify by flash column chromatography, eluting with a pentane: ethyl acetate mixture in a ratio of 90:10 to 70:30 to give the title compound as an orange oil (54.3 g).

Ή-NMR (400 MHz, C1UO1)) δ: 2.15 (3H, s), 3.70 (2H, s), 3.77 (3H, s), 6.43-6.39 (1H, d ), 7.20-7.18 (1H, d), 7.34-7.31 (2H, t), 7.41-7.39 (1H, d), 7.66-7.62 (1H , d); LKM8 Ε8Ι: t / ζ 241 [M + No.] ⁺ , 217 [M-H] ^- .

Preparation 140. Methyl 3- [3- (2-oxopropyl) phenyl] propanoate.

Receive in accordance with the method used for obtaining 26, using the compound from obtaining 139, getting mentioned in the title compound as an orange oil.

Я-NMR (400 MHz, C1UO1)) δ: 2.14 (3H, s), 2.64-2.60 (2H, t), 2.96-2.92 (2H, t), 3-, 66 (5H, s), 7.05-7.04 (2H, d), 7.11-7.09 (1H, d), 7.27-7.23 (1H, q); LKM8 Ε8Ι: t / ζ 243 [M + No.] ⁺ , 219 [Ν-Η] ^- .

Preparation 141. Methyl- [3 - ((2K) -2 - {[(1K) -1-phenylethyl] amino} propyl) phenyl] propanoate hydrochloride.

Receive in accordance with the method used for obtaining 19, using the compound from obtaining 140, obtaining mentioned in the title compound as a crystalline white solid.

Я-NMR (400 MHz, C1UO1)) δ: 1.18-1.16 (3H, d), 1.71-1.69 (3H, d), 2.62-2.56 (3H, m) , 2.89-2.85 (2H, t), 3.20-3.12 (1H, m), 3.34-3.29 (1H, m), 3.61 (3H, s), 4 64-4.59 (1H, q), 6.92-6.91 (2H, d), 7.12-7.10 (1H, d), 7.23-7.19 (1H, t) 7.54-7.47 (5H, m); LKM8 Ε8Ι: t / ζ 326 [M + H] ⁺ .

Preparation 142. 3- {3 - [(2K) -2 - ((1K) -1-Phenylethylamino) propyl] phenyl} propionic acid.

The compound from Preparation 141 (3.25 g, 8.98 mmol) and sodium hydroxide (5M, 9.0 ml, 45.0 mmol) were stirred in 1,4-dioxane (40 ml) and water (40 ml) for 18 hours. The solvent was removed in vacuo and the product was dissolved in water, acidified with hydrochloric acid (2M) to pH 6, and it solidified for 18 hours. The solid was filtered off and dried in vacuum (1.0 g, 36% yield). The filtrate was concentrated and tetrahydrofuran was added and the mixture was filtered. The filtrate was evaporated to give a foam, which was suspended in diethyl ether (3 times) to give a colorless foam (1.96 g, 70% yield).

Я-NMR (400 MHz, C1UO1)) δ: 1.13 (3H, d), 1.62 (3H, d), 2.42 (2H, t), 2.55-2.64 (1H, m ), 2.84 (2H, t), 3.08-3.42 (2H, m), 4.46-4.52 (1H, m), 6.86 (1H, d), 6.98 ( 1H, s), 7.11-7.22 (2H, m), 7.45-7.52 (5H, m); BCM8 APC1: t / ζ 312 [M + H] ⁺ .

- 49 010133

Preparation 143. 1- (3,4-Dihydro-1H-isoquinolin-2-yl) -3- {3 - [(2K) -2 - ((1K) -1-phenylethylamino) propyl] phenyl} propan-1- it.

The compound from Preparation 142 (1.95 g, 6.27 mmol), triethylamine (2.62 ml, 19.0 mmol) in dichloromethane (80 ml) was treated with 2-chloro-1,3-dimethylimidazoline hexafluorophosphate (1.75 g, 6.27 mmol) and the resulting solution was allowed to stir for 3 hours. The solvent was removed and the residue was treated with ethyl acetate and washed with saturated sodium bicarbonate solution (3x20 ml), brine (3x20 ml) and dried (Na ₂ 8 O ₄ ). After filtering and removing the solvent, the product is purified by chromatography, eluting with a mixture of dichloromethane: methanol: 0.88 ammonia in a ratio of 99.7: 0: 0.3 to 96.7: 3: 0.3. The product was evaporated from diethyl ether (3 times) to give a semi-solid (2.3 g, 86% yield).

'H-NMR (400 MHz, CCCCH) δ: 0.88 (3H, d), 1.30 (3H, d), 2.42-2.50 (1H, m), 2.64-2.98 (8H, m), 3.55-3.62 (1H, m), 3.78-3.96 (2H, m), 4.51 (1H, s), 4.72 (1H, s), 6.88-7.38 (13H, m); BCM8 APC1: t / ζ 427 [M + H] ⁺ .

Preparation 144. 3- [3 - ((2K) -2-Aminopropyl) phenyl] -1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one.

The compound from Preparation 143 (2.20 g, 5.16 mmol), ammonium formate (1.63 g, 26.0 mmol) and palladium hydroxide (500 mg) in ethanol (40 ml) are heated and stirred at 70 ° C. for 4 hours. The mixture was filtered through filter aid and the solvent was removed. The product is purified by chromatography, eluting with dichloromethane: methanol: 0.88 ammonia in a ratio of 99.7: 0: 0.3 to 94.7: 5: 0.3 to obtain a colorless oil, which is evaporated from diethyl ether (3 times) (1.26 g, yield 76%).

'H-NMR (400 MHz, CCC1 _; ) δ: rotamers 1.10 / 1.11 (3H, 2x d), 2.43-2.48 (1H, m), 2.62-2.76 (3H , m), 2,782.86 (2Н, m), 2.96-3.02 (2Н, m), 3.08-3.18 (1Н, m), 3.58 (1Н, t), 3, 81 (1H, t), 4.53 / 4.73 (2H, 2x s), 6.98-7.24 (8H, m); BCM8 APC1: t / ζ 323 [M + H] ⁺ .

Preparation 145. Y- {2-Benzyloxy-5 - [(1K) -1- (tert-butyldimethylsilanyloxy) -2 - ((1K) -2- {3- [3- (3,4-dihydro-1H-isoquinoline) -2-yl) -3-oxopropyl] phenyl} -1-methylethylamino) ethyl] phenyl} formamide.

The title compound was prepared from compounds of Preparation 144 and Preparation 12, using a method similar to that of Preparation 136 (216 mg, 67% yield).

'H-NMR (400 MHz, C1) _; O1)) δ: rotamers -0.19 (3H, s), -0.01 (3H, s), 0.82 (9H, s), 0.98-1.04 (3H, s), 2, 48-2.96 (11H, m), 3.57-3.62 / 3.72-3.76 (2H, m), 4.53-4.70 (3H, m), 5.18 (2H , m), 6.87-6.97 (3H, m), 6.99-7.18 (7H, m), 7.28-7.39 10 (3H, m), 7.45-7, 60 (2H, m), 8.20 (d), 8.31 (d); BCM8 APC1: t / ζ 707 [M + H] ⁺ .

Preparation 146. L- {5 - [(1K) -1- (tert-Butyldimethylsilanyloxy) -2 - ((1K) -2- {3- [3- (3,4-dihydro-1H-isoquinolin-2-yl ) -3-oxopropyl] phenyl} -1-methylethylamino) ethyl] -2-hydroxyphenyl} formamide.

Obtained using the amide from Preparation 145 and the method described in Preparation 15 to afford a brown foam (280 mg, 100% yield).

'H-NMR (400 MHz, C1) _; O1)) δ: rotamers -0.14 (3H, s), -0.03 (3H, s), 0.84 (9H, s), 1.08-1.12 (3H, m), 2, 54-3.20 (11H, m), 3.60-3.65 / 3.74-3.77 (2H, 2x t), 4.56-4.66 (2H, 2x s), 4.78 -4.84 (1H, m), 6.80-7.24 (1H, m),

- 50 010133

8.10 (s); 8.31 (s); BCM8 APC1: t / ζ 617 [M + H] ⁺ .

Example 1. No. Benzyl-2- (3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} phenyl) acetamide.

The compound from Preparation 15 (24 mg, 40 μmol), formic acid (0.5 ml), tetrahydrofuran (5 ml) and water (0.5 ml) are heated at 90 ° C. for 18 hours. A further aliquot of formic is then added. acid (0.5 ml) and tetrahydrofuran (5 ml) and continue to heat for the next 18 hours. The solvent is removed and the product is purified by chromatography (0-10% methanol in dichloromethane + 0.3% ammonia). The product was dissolved in methanol (3 times) and evaporated (10 mg).

'H-NMR ((ΊΧΟΙλ 400 MHz) δ: 1.05-1.09 (6H, m), 2.69-2.78 (2H, m), 2.78-2.83 (1H, m) 2.87-2.93 (1H,

m), 3.53 (2H, s), 4.35 (2H, s), 4.65 (1H, dd), 6.82-6.86 (1H, m), 6.99 (1H, dd ), 7.03-7.06 (1H, m), 7.13-7.28 (7H, m), 8.08 (d), 8.28 (s), 8.55 (s), 8 , 61 (s); HHM8 C ₂₈ N _sz No., O ₄ : 476.2544 [M + H] ⁺ , found: 476.2533.

Example 2. No. (3,4-Dimethylbenzyl) -2- (3- {2 - [(2H) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide.

Obtained using the amide from Preparation 16 and the method described in the case of Example 1.

'H-NMR ((ΊΧΟΙλ 400 MHz) δ: 1.05-1.08 (6H, m), 2.18 (3H, s), 2.19 (3H, s), 2.67-2.94 (4H, m), 3.52 (2H, s), 4.27 (2H, s), 4.62 (1H, dd), 4.65 (1H, dd), 6.81-7.06 ( 6H, m), 7.12-7.24 (3H, m), 8.07 (d), 8.27 (s), 8.55 (s), 8.61 (s); MS (APC1) : t / ζ 504 [M + H] ⁺ ; NKM8 С ₃₀ Н ₃₇ ЩО ₄ : 504.2857 [M + Н] ⁺ , found: 504.2842.

Example 3. Ν- [4- (Dimethylamino) benzyl] -2- {3 - [(2H) -2 - ({(2H) -2- [3 - (formylamino) -4-hydroxyphenyl] 2-hydroxyethyl} amino ) propyl] phenyl} acetamide.

A mixture of the product from Preparation 27 (131 mg, 0.21 mmol) and triethylamine trihydrofluoride (16 μl, 0.10 mmol) in tetrahydrofuran (2 ml) was stirred at room temperature for 3 days. The mixture was then concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol: 0.88 ammonia in a ratio of 100: 0: 0 to 90: 10: 1 to obtain the title compound as a brown foam. with a yield of 36%, 18 mg.

'H-NMR (400 MHz, C1XC1 _; ) δ: 1.07 (3H, m), 2.57 (1H, dd), 2.67-2.76 (2H, m), 2.85-2, 99 (2H, m), 2.87 (6H, s), 3.47 (1H, m), 4.23 (2H, s), 4.68 (1H, dd), 6.67-6.71 (2H, m), 6.77-6.79 (2H, d), 6.90 (1H, m), 6.97-7.70 (m, 6H), 7.97 (d), 8, 27 (s), 8.35 (s); LKM8 APC1: t / ζ 619 [M + H] ^- .

Examples 4-12.

The following compounds of the general formula indicated below are prepared using a method similar to that described for Example 3. The corresponding starting material is treated with 1-1.1 eq. triethylamine trihydrofluoride at room temperature for 18-72 hours

- 51 010133

Η-NMR 400 MHz, CoNSO δ:

!, 83-2.93 (2H, m) 3.13 H), 3.49 (2H, FROM) , 4.30 c), 4.64- -4.69 (1H, m) (1H, d), 6, 89 (1H, dd) (1H, d). 7.06 (1H, m) • 7.19 (4H, m) 7.45 (2H, ', 99 (d), 8.03 (from) , 8.28

1.09 (ZN, D) 2.60 (1H, dd), 2.74- • 2.82 (2H, m), 2.9C-2.96 (1H, m) 3.00-3.08 (1H, m), 3.53 (2H, c) 4.40 (2H, s), 4.61 (1H, DD), 6.78 (1H, d), 6, 91 (1H, DD), 7.02 (1H, d), 7.08- • 7.10 (1H, m), 7.12-7.25 (ZN, m) 7.29 (2H, D), 7.78 (2H, D) 7.99 (d) 8.28 (s), 8.56 (from) LKM5 ARS1: γγι / ζ 503 [MH] -

• 3.02 (5H, m) 3.47 4.18 (2H, • m) 4,56- m) 6.76-7.22 (8H, (1H, from), 8.27 (from) ,

[from)

m) 3.46 (2H, from), 4,54- (1H, m), 4.78 (2H, from) , 7.40 (8H, m), 7.66 -7.74 m) 7.85-7.91 (1H, m) (1H, c), 8.27 (from) , 8.54 Bkm5 APC1: τη / ζ 528 [M + H]

- 52 010133

*12 _B , N / A> Ή-NMR (400 MHz, δ: 1.05, 1.06 (3Н, d), 2.46-2.98 (5Н, m), 3.51 (2Н, s), 4.36 (2Н, s), 4.52-4.60 (1H, m), 6, 75-7.25 (UN, m), 7.39-7.47 (4H, m), 7.96 (1H, s) , 8.27 (s), 8.54 (s); BKM8 ARS1: ιϊι / ζ 554 [M + H] ⁺ 35%

* The crude compounds are subjected to azeotropic distillation with a 2M solution of ammonia in methanol before purification by column chromatography on silica gel, eluting with a mixture of dichloromethane: methanol: 0.88 ammonia in a ratio of 90: 10: 1. It is then subjected to subsequent azeotropic distillation with methanol (3 times) and diethyl ether (3 times) to obtain the desired products as white solids.

Examples 13-23.

The following compounds of the general formula indicated below are prepared using a method similar to that described for Example 3. The corresponding starting material is treated with 1-1.1 eq. triethylamine trihydrofluoride at room temperature for 18-72 hours

n

No. 01 Data Exit thirteen ^X H-NMR (400 MHz, CO ₃ OO) δ: 1.09, 1.10 (ZN, 2xs), 1.14, 1.16 (ZN, 2: xs), 2.76-3.04 ( 6H, m), 3.56 (2H, m), 4.67 (1H, dd), 6.84 (1H, d), 7.02 (1H, m), 7.20-7.28 (4H , m), 7.33-7.40 (2H, m), 7.60-7.67 (2H, m), 8.12 (1H, d), 8.29 (s), 8.64 ( from); LKMZ Ε3Ι: t / ζ 534 [M + Ia] ⁺ 65% 14 RNz Ή-NMR (400 MHz, ΟΌ ₃ θδ) δ7 1.0b (S, s), 1.13 (S, s), 2.10 (S, s), 2.21 (S, s), 2, 70- 3.02 (6H, m), 3.51 (2H, t), 4.62-4.68 (1H, m), 6.79-6.81 (1H, m), 6, 82- 6, 87 (2H, m), 7.01-7.07 (1H, m), 7.31-7.39 (2H, m), 7.69 (2H, m), 8.09 (1H, s), 8.29 (s), 8.63 (s); LNM5 APC1: t / ζ 520 [M + H] ⁺ 90% *fifteen -—ΗΝ— Ή-NMR (400 MHz, СО ₃ СУ) δ: 1.06 (ЗН, s), 1.12 (ЗН, s), 2.722.98 (4Н, m), 4.58-4, 67 (ЗН, m) 6, 77-7. 00 (4H, m), 7.167.73 (UN, m), 8.04 (1H, s), 8.27 (s), 8.59 (s); DIRECT APC1: t / ζ 554 [M + H] ' ¹ ' 39% sixteen Я-NMR (400 MHz, SEZOO) δ: 1.06 (S, s), 1.13 (S, s), 2.723.00 (4H, m), 4.54-4.70 (S, m) 6, 78-6, 86 (ZN, m), 6.976.99 (1H, d), 7, 34-7, 58 (8H, m), 7.71-7.76 (2H, m), 8 05 (1H, s), 8.27 (s), 8.59 (s); LMPZ APC1: t / ζ 554 [M + H] ⁺ 41% * 17 Я-NMR (400 MHz, СО ₃ СУ) δ: 1.09 (S, s), 1.16 (S, s), 2.08 (S, s), 2.21 (S, s), 2.753 06 (6H, m), 3.45-3.51 (2H, m), 4.66-4.71 (1H, m), 6.53 (1H, s), 6, 83-6, 88 (ZN, m), 7.02-7.04 (1H, m), 7.32-7.41 (2H, m), 7.63-7.68 (2H, m), 40%

- 53 010133

Οϋ, Οϋ) δ: 1,06

43% [Μ + Η]

Example 14

Subjected to azeotropic distillation with a 2M solution of ammonia in methanol before purification.

* The crude compounds are subjected to azeotropic distillation with a 2M solution of ammonia in methanol before purification by column chromatography on silica gel, eluting with a mixture of dichloromethane: methanol: 0.88 ammonia in a ratio of 90: 10: 1. It is then subjected to subsequent azeotropic distillation with methanol (3 times) and diethyl ether (3 times) to obtain the desired products as white solids.

Examples 24-27.

The following compounds of the general formula indicated below are prepared using a method similar to that described for Example 3. The corresponding starting material is treated with 1-1.1 eq. triethylamine trihydrofluoride at room temperature for 18-72 hours

- 54 010133

No. 01 Data Exit 24 ^X H-NMR (400 MHz, SOzOO) δ: 1.01 (S, s), 1.03 (S, s), 2.63-2.87 (4H, m), 3.52 (2H, s ), 3.84 (3H, s), 4.38 (2H, s), 4.56-4.60 (1H, m), 6.78-6.80 (1H, m), 6.94- 6.97 (1H, m), 7.00-7.02 (1H, m), 7.11-7.20 (4H, m), 7.26-7.29 (2H, m), 7, 87-7.89 (2H, d), 7.98-7.99 (d), 8.21 (s), 8.54 (s); ВВМЗ Ε3Ι: t / ζ 534 [M + H] ' 75% 25 / ^{b X} H-NMR (400 MHz, SBS1z) δ: 0.96-1.04 (9H, m), 2.60-2.88 (4H, m), 3.16-3.33 (2H, m) 3.66, 3.79 (2H, 2hc), 4.61, 4.66 (2H, 2x C), 4.64, 4.79 (1H, m), 6.56 (1H, m), 6, 73-6, 79 (2H, m), 6.92-7.19 (6H, m), 7.98 (1H, m), 8.23 (s), 8.65 (s); LKMS APC1 μ / ζ 554 [M + H] ⁺ 41% 26 „„ / -SUCHE- " ^X H-NMR (400 MHz, COC1 ₃ ) δ: 0.98 (3H, s), 1.00 (3H, s), 2.61-2.84 (4H, m), 3.48 (2H, s), 4.30 (2H, s), 4.54-4.57 (1H, m), 6.75-6.77 (3H, m), 6.91-6.94 (1H, m) 6.96-6.99 (1H, m), 7.08-7.18 (6H, m), 7.33-7.40 (4H, m), 7.98 (s), 8.21 (s) 8.56 (s); LKMS EC1 μ / ζ 568 [M + H] ⁺ 93% 27 but ^X H-NMR (400 MHz, SOzOO) δ; 1.05 (ZN, s), 1.08 (ZN, s), 2.66-2.93 (4H, m), 3.52 (2H, m), 4.34 (2H, s), 4 61 (1H, m) 6.81 (1H, m), 6.79 (1H, d), 6.81 (1H, d), 6.99-7.22 (6H, m), 8.06 (1H, d), 8.28 (s), 8.61 (s); ШМЗАРС1: τη / ζ 526 [M + H] * 44%

Example 28. No.’-Adamantyl-2- {3 - [(2K) -2 - ({(2K) -2- [3- (formylamino) phenyl] -2-hydroxyethyl} amino) propyl] phenyl} acetamide.

A mixture of the product from Preparation 34 (500 mg, 0.8 'mmol) and ammonium fluoride (200 mg, 5.4 mmol) in methanol (5 ml) and water (', 5 ml) is heated at a temperature of 40 ° C for ' 8 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with a 90: 10: 0.1 dichloromethane methanol U ammonia mixture, to give the title compound as a foam in 84% yield, 347 mg

'H-NMR (400 MHz, SB3OB) δ: 1.05-1.10 (m, 3H), 1.64-1.74 (6H, m), 1.98-2.03 (9H, m) 2.36-2.98 (5H, m), 3.36 (2H, s), 4.46-4.60 ('H, m), 6.46-7.20 (6H, m), 7.96 ('H, s), 8.28 (s), 8.56 (s); LKM8 E81: t / ζ 506 [M + H] ⁺ .

Example 29. N- (3.4-Dimethylbenzyl) -2- {3- [2 - ({(2K) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxy

- 55 010133 ethyl} amino) ethyl] phenyl} acetamide.

The title compound was obtained from the product from Preparation 102, using a method similar to that for Examples 4-12, as a solid.

Я-NMR (400 MHz, SI.OO) δ: 2.20 (6Н, m), 3.00 (2Н, m), 3.18 (2Н, m), 3.28 (2Н, m), 3 56 (2H, s), 4.28 (2H, s), 4.81 (1H, m), 6.81 (1H, d), 6.98 (2H, m), 7.05 (2H, m), 7.20 (4H, m), 7.30 (1H, t), 8.10 (s), 8.30 (s); LBM8 Ε8Ι: t / ζ 476 [M + H] ⁺ .

Examples 30-37.

The following compounds of the general formula indicated below are prepared using a method similar to that described for Example 3. The corresponding starting material is treated with 1-1.1 eq. triethylamine trihydrofluoride at room temperature for 18-72 hours

8.64 (s); LBME APC1: t / ζ 544 [M + H] *

Ή-NMR (400 MHz. CoNSU)

FROM), 0.97 (ZN, s), 2.33 (ZN, 2,56- -2, 81 (4H, m), 3.43 (2H, 4.21 (2H, s), 4.52-4.55 (1H, 6.73 (1H, m), 6.89-6.95 (2H, 7.03- • 7.13 (7H, m), 7.98 (d)

(ZN, from) 2.60-2.85 (2H, from) 4.36 (2H, (1H, m) 6.75 (1H, dd) 6, 98 (1H, d). m) 7, 31 (2H, d), 8.00 (d ), 8.22 (s).

Ή-NMR (400 MHz, Οϋ ₃ Ο0) δ: 1.00 (S, s), 1.02 (S, s), 2.62-2.86 (4H, m), 3.47 (2H, s), 4.30 (2H, s), 4.55-4.58 (1H, m), 6.82 (1H, d), 6.99 (1H, dd), 7.04 (1H, d) ), 7.14-7.23 (5H, m), 7.29 (1H, s), 7.31 (1H, s), 8.07 (1H, d), 8.29 (s), 8 , 64 (s); LKMZ ARS1: t / ζ 560 [M + H] ⁺ ^ H-NMR (400 MHz, SBROO) δ: 0.93 (ZN, s), 0.96 (ZN, s), 2.51-2.83 (4H, m), 3.47 (2H, s), 4.34 (2H, s), 4.52- 4.55 (1H, m), 6.73-6.76 (ZN, m), 6.90-6.97 (2H, m), 7.04-

- 56 010133

LKMZ ARS1: t / ζ 563 [M + H] * ^ H-NMRCHOO MHz, C0 ₃ 00) δ: '~ 0.99 50Ϊ (S, s), 1.01 (S, s), 2.61- 2.86 (4H, m), 3.47 (2H, s), 4.23 (2H,

s), 4.55-4.58 (1H, m), 6.64-6.66 (1H, m), 6.75-6.79 (1H, m), 6.927.16 (8H, m) 7.99 (1H, d), 8.22 (s), 8.54 (s); LEM5 ARC1: t / ζ 526 [M + H] ⁺

Ή-NMR (400 MHz, SOzOO) δ: 1.02 40Ϊ (ЗН, s), 1.04 (ЗН, s), 1.44-1.55 (2Н, m), 2.00-2.04 (2H, s), 2.522.87 (8H, m), 2.39 (2H, s), 3.553.61 (1H, m), 4.56-4.59 (1H, m),

6.76 (1H, d), 6, 93-6, 98 (2H, m),

7.07-7.16 (3H, m), 8.00 (1H, d),

8.23 (s); 8.55 (s); LKMZ ARS1:

t / ζ 486 [M + H] ⁺ * H-NMR (400 MHz, SECB) δ: 1.06 (3H, s), 1.08 (3H, s), 2.67-2.95 (4H, m), 3.07 (ЗН, s), 3.56 (2Н,

s), 4.45 (2H, s), 4.60 (1H, dd),

6.81 (1H, d), 6.98 (1H, dd), 7.04 (1H, d), 7.14-7.25 (4H, m), 7.44 (2H, d), 7 84 (2H, d), 8.06 (1H,

d), 8.28 (s), 8.61 (s);

LEM8 ARC1: t / ζ 554 [M + H] *

Examples 38-46.

The corresponding amides, triethylamine trihydrofluoride (1 equiv.) In tetrahydrofuran (5 ml), are stirred at room temperature for 2 days. The mixture was then concentrated in vacuo and the residue was treated with a methanol solution of ammonia and evaporated (3 times) to obtain a foam which was treated with a mixture of dichloromethane: methanol: 0.88 ammonia in a ratio of 90: 10: 1, filtered, then purified by column chromatography on silica gel , eluting with dichloromethane: methanol: 0.88 ammonia in a 90: 10: 1 ratio, to obtain the title compound as a film, which was dissolved in methanol and evaporated (3 times), then suspended in diethyl ether and evaporated (3 times) getting solid b logo color.

No. <21 Data Exit 38 Я-NMR (400 MHz, CO.sub.N.S.) δ: 1.07 (3H, s), 1.14 (3H, s), 2.73-3.00 (6H, m), 3.57-3.62 ( 2H, m), 4.644.70 (1H, m), 6.83 (1H, d), 7.017.05 (1H, m), 7.16-7.40 (7H, m), 7.61-7 67 (2H, m), 8.09 (1H, d), 8.29 (s), 8.63 (s); LKMZ ARS1: t / ζ 476 [M + H] ⁺ 52% 39 Я-NMR (400 MHz, SC ₃ O) δ: 0.941.34 (11Н, m), 1.58-1.80 (6Н, m), 2.74-3.00 (4Н, m), 3, 14-3.30 (2H, m), 4.65-4.69 (1H, m), 6.83 (1H, d), 7.02-7.06 (1H, m), 7.32- 7.31 (2H, m), 7.37-7.73 (2H, m), 8.07 (1H, d), 8.30 (s), 8.63 (s); LKMZ ARS1: t / ζ 468 [M + H] ⁺ 65% 40 .0 Ή-NMR (400 MHz, SC ₃ O) δ: 1.09 (ЗН, s), 1.11 (ЗН, s), 1.46-1.80 (6Н, m), 2.76-2, 95 (4H, m), 3.35 (2H, broad s), 3.69 (2H, broad s), 4.62-4.65 (1H, m), 6.82 (1H, d) 6.99-7.02 (1H, m), 7.18-7.30 (3H, m), 7.33-7.37 (1H, m), 8.04 (1H, s). 69%

- 57 010133

(ZN, from) , 1,11 (ZN, c) 2 :, 69- 3, 03 (6H, m) 3.47- 3, 67 (2H, m) 4.63- 4, 67 (1H, m) 6, 82 (1H, d) 7.00- 7.06 (1H, m) 7.30- • 7.64 (8H, m) 8.08 (1H, from) , 8.29 (from) , 8.63 (from) ; Kommersant ARS1 : t / ζ 542 [M + H] *

Ή-NMR (400 MHz, Οϋ ₃ ΟΟ) δ: 1.05 (ZN, s), 1.13 (ZN, from) , 1.88-1.98 (2H, m), 2.64-2.80 (4H, m), 2.89 3.00 (2H, m), 3.38- • h 46 (2H, m), 4.63-4.67 (1H, m), 6, 81 (1H, d), 6.98-7.08 (1H, m), 7, 10-7.30 (5H. m) 7.30-7.40 (2H, m) , 7.62-7.70 (2H, m), 8.08 (1H, from) , 8.27 (s), 8.61 (s); LKMZ ARS1: t / ζ 488 [M + H] ⁺

 from) , 1.13 (ZN, c) 2 , 71-3.04 from) , 4.50-4.80 (2H, m), 6.80 d) 6.96-7.06 (1H, m), 7.11 ) (4H, m), 7.31- -7.42 (2H, m), 3-7.71 (2H, m), 8.06 (1H, d), ' (from), 8.61 (s); : Bmz APC1: p / ζ [M + H] ⁺

from) , 1.11 (ZN, from) , 2.70-2.97 m) 3.06 (2H, T) 3.71 (2H, 4.64 -4.68 (1H, m) 6.82-6.86

m), 7 , 00-7.06 (1H, m), 7.19 (4H, m), 7.61- -7.64 (2H, m), (1H, t), 8.08 (1H, c), 8.28 8.45 (1H, d), 8.63 (from) ; APC1: : t / ζ 477 [M + H) G

from) , 1.12 (ZN, s), 2.70-3.00 m) 3,50-3, 60 (2H, m), 3.74 from) , 4.63-4.66 (1 N, m), 6.80- (ZN, m), 7.00-7.06 (1 N , m) (2H, d) 7.30-7.39 (2H, m) 7, 65 (2H, m), 8.09 (1H, FROM), (from) , 8.63 (s); LKMZ ARS1: t / ζ

Ή-NMR (400 MHz, SBROO) δ: 1.13 (ZN, s), 1.18 (ZN, from) , 2.75-3.06 (6H, m), 3, 62 (2H, T) 4.68-4.75 (1H, m), 6, 85 (1H, D) g 7.03 (1H, D), 7.37 -7.45 (4H, m) 7.62-7.70 (2H, M), 7.80 (2H, D) 8.12 (1H, s), 8.30 (from) , 8.64 (from) RMZ ARS t / ζ 555 [M + H] ⁺

: -4.73 (1H, m) 6, 87 (1H, dd) 1-7.15 (ZN, m) 7.20- -7, 30 (2H, 7.82-7.87 (1H, m), ί 3.09 (1H, 8.28 (s), 8.63 (from); Bnmz ARS1

D) 7.03 (1H, D) 7.31- ' m) 7.58-7.62 (2H, m), 1 from) , 8.30 (s). 8.63 (s);

- 58 010133

KMZ ARS1: t / ζ 506 [M + H] ⁺ 49 -CP ^ -NMR (400 MHz, C0 ₃ 00) δ: 1.001.08 (6H, m), 2.0q (1H, d), 2.262.38 (1H, m), 2.63-3.30 (7H, m), 3.40-3.58 (2H, m), 4.46-4.56 (1H, d), 4.60-4, 68 (1H, m), 6.58-6.68 ( 2H, m), 6.80-6, 90 (1H, m), 6,967.34 (7H, i), 8.08 (1H, s), 8.30 (s), 8.63 (s); LMPZ APC1: t / ζ 514 [M + H] * nineteen% fifty 'H-NMR (400 MHz, SBROO) δ: 1.10 (ZN, s), 1.14 (ZN, s), 2.27-3.00 (6H, m), 3.57-3, 60 (2gt, t), 4.63- 4.71 (1H, m), 6.71 (1H, d), 6.82 (1H, d), 6.99-7.09 (ZN, m), 7.32- 7.39 (2H, m), 7.61-7.67 (2H, m), 8.08 (1H, s), 8.29 (s), 8.63 (s); LMPZ APC1: t / ζ 526 [M + H] * 17%

Examples 51-55.

The following compounds of the general formula indicated below are prepared using a method similar to that described for Example 3. The corresponding starting material is treated with

1-1.1 eq. triethylamine trihydrofluoride at room temperature for 18-72 hours

^ -NMR (400 MHz, Οϋ ₃ Οϋ) δ: 1.04 (ZN, from) , 1.12 (ZN, c) 2 , 68- 3, 02 (4 N, m) 3, 62- 3, 97 (2H, m) 3.70- 3.74 (2H, m) 4.64- • 4.68 (1H, m) 6.83 (1H, d)> 7, 02 (1H, d) 7.34- 7.48 (6H, m) 7, 62 (1H, FROM) , 7, 65- 7, 67 (1H, m) 7.72- -7.76 (1H, m) 7, 80 -7.84 (1H, m) 8.18 (1H, 8), 8.20 (1H, d) 8.29 (from) , 8.62 (from); Ι1Ε.Μ5 ARS1 : t / ζ 526 [M + H] ⁺

- 59 010133

Example 56. 3 - {(2K) -2 - [(2K) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} -Y [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide.

The title compound was obtained from the product from Preparation 138, using a method similar to that for Examples 38-50, as a brown glassy substance (35 mg, 31% yield).

'H-NMR (400 MHz, C1) _; O1)) δ: 1.03 (3H, d), 1.27 (6H, s), 2.56-2.90 (4H, m), 3.45 (2H, s), 4.55-4 58 (1H, m), 6.67-6.72 (3H, m), 6.85-6.87 (1H, m), 7.19-7.26 10 (5H, m), 7, 38 (1H, s), 7.43 (1H, d), 7.91 (d), 8.21 (s), 8.51 (s); LMP8 APC1: t / ζ 506 [M + H] ⁺ .

Example 57. L- {5 - [(1K) -2 - ((1K) -2- {3- [3- (3,4-Dihydro-1H-isoquinolin-2-yl) -3-oxopropyl] phenyl} -1methylethylamino) - '-hydroxyethyl] -2-hydroxyphenyl} formamide.

ΗΝ

The title compound was obtained from the product from Preparation 138, using a method similar to that for Examples 38-50, as a brown glassy substance (35 mg, 31% yield).

'H-NMR (400 MHz, C1) _; O1)) δ: 1.00-1.05 (3H, m), 2.48-2.92 (11H, m), 3.59 (1H, t), 3.73 (1H, t), 4 54-465 (3H, m), 6.75-7.18 (10H, m), 7.97 (s), 8.28 (d), 8.56 (d); LBM8 APC1: t / ζ 502 [M + H] ⁺ .

The ability of the compounds of formula (1) to act as effective B2 agonists, therefore, mediating smooth muscle relaxation, can be determined by measuring the stimulation effect of beta-2 adrenergic receptors in an electric field that stimulates the contraction of the bands of the guinea pig trachea.

Guinea pig trachea

Piict-Nagyeu male guinea pigs (475-525 g) were sacrificed by asphyxiation with CO ₂ , bled through the femoral artery and the trachea was separated. Four preparations were obtained from each animal, starting from dissection directly below the larynx and extraction of a 2.5-cm trachea segment. A part of the trachea was opened by dissection of the cartilage opposite the tracheal muscle, then transverse sections were made and 3-4 wide cartilage rings were cut out. The resulting band preparations were suspended in 5 ml organ baths using cotton threads linking the upper and lower cartilage bands. The bands were balanced, without stretching, for 20 min, in a modified buffer KGLK Ktdeg (81 dtA K0507) containing 3 μM indomethacin (81 dtA 37 7378), 10 μM guanethidine (81 dtA 68520) and 10 μM atenolol (8 unit A7655) ° C and saturated with a mixture of 95% O ₂ /5% CO ₂ before applying the initial stretching with a load of 1 g. The preparations were left to balance for the next 30-45 minutes, during which they were repeatedly stretched (up to 1 g) twice at 15-minute intervals . Tensile changes were recorded and monitored using standard isometric sensors associated with a data acquisition system (typically manufactured by RPheg). Following equilibration after stretching, the tissues were stimulated with an electric field (ΕΡ8) using the following parameters: series of 10 s every 2 min, pulse duration 0.1 ms, 10 Hz and the exact maximum electric voltage (25 V), constantly during experiment. ΕΡ8 tracheal postganglionic cholinergic nerves were obtained with single-phase smooth muscle contractions and the highest point of seizures was recorded. The organ baths were continuously replenished with the aforementioned KrKbK1ideg buffer using a peristaltic pump system (pumping at a flow rate of 7.5 ml / min) during the whole experiment, except when a beta-2 agonist according to the present invention was added; then the pump was stopped for the duration of the cumulative dose in the bath and started again after the maximum response achieved during the washing period.

The experimental protocol for evaluating the effectiveness and efficiency

After balancing to ΕΡ8, the peristaltic pump was stopped and the preparations were primed with a single dose in the amount of 300 nM isoprenaline (8pcs Ι5627) to establish the maximum response in terms of inhibiting the contractile response to ΕΡ8. Then isoprenaline was washed in

- 60 010133 for 40 minutes Following priming and regeneration by washing, a standard curve for isoprenaline was obtained in the case of all tissues (isoprenaline curve 1) by cumulative, bolus addition to the bath using semi-log concentration increases. A concentration range from 1 ^e-9 to 1 ^e / 3 ^e-6 M was used. Upon completion of the isoprenaline curve, the preparations were washed again for 40 minutes before the second curve began, either for isoprenaline (as an internal control) or for beta-2 agonist according to the present invention. Beta-2 agonist responses were expressed as percent inhibition of the response to EP8. The data for the beta-2 agonist was normalized by expressing the inhibition as a percentage of the maximum inhibition caused by isoprenaline according to curve 1. The IC ₅₀ (EC ₅₀ ) value for the beta-2 agonist according to the present invention refers to the concentration of the compound necessary to achieve a half-maximum effect. The data for the beta-2 agonists of the present invention were then expressed as relative efficacy compared to isoprenaline as determined by the ratio (IC ₅₀ beta-2 agonist) / (IC ₅₀ isoprenaline).

Confirmation of beta-2-mediated functional activity

The activity of the test compounds as a beta-2 agonist was confirmed using the above protocol, however, before constructing a curve for the beta-2 agonist according to the present invention, the preparations were preincubated (for at least 45 minutes) with 300 nM 1C1 118551 (selective B2 antagonist), which in the case of a beta-2-mediated effect leads to a shift to the right of the response curve to the dose of the test compound.

According to another alternative, the agonist activity of the compounds of formula (1) at the b2 receptor can also be determined by measuring the concentration of the compound of the present invention necessary to achieve a half-maximum effect (IC ₅₀ ) for the b2 receptor.

Preparation of the compound mM / 100% DMSO (dimethyl sulfoxide) of the initial solution of the compound was diluted to the required dose limit in 4% DMSO. This dose limit was used to construct a 10-point semi-log dilution curve, all in 4% DMSO. Isoprenaline (81dta, 1-5627) was used as a standard in each experiment and for control wells of each plate. Data were expressed as a response in% isoprenaline.

Cell culture

CHO cells (Chinese hamster ovary) recombinantly expressing the human B2 adrenergic receptor (KoBka et al., PNA8 84: 46-50, 1987 and Voi \ zeg et al., Mo1. Ryagtaso 33: 133-139, 1988, SNOiv2), cultivated in Dulbecco's environment MEM / ΝυΤ M1X P12 (61Lco, 21331-020), supplemented with 10% fetal calf serum (81dta, P4135, catalog number 90K8404, sample 09/04), 2 mM glutamine (81dta, 67513), 500 μg / ml geneticin (81dta, 67034) and 10 μg / ml puromycin (81dta, P8833). Cells were seeded, yielding approximately 90% confluency for testing.

Analysis method

Each dose of the compound, 25 μl per well, was transferred to cAMP-P1a8Yp1a! E® (ΝΉΝ, 8MP004B) with 1% DMSO as the main control and 100 nM isoprenaline as the maximum control. Diluted 1: 2 by adding phosphate-buffered saline at 25 μl per well. The cells were trypsinized (0.25% 81 dtA, T4049), washed with phosphate-buffered saline (61bCO, 14040-174) and resuspended in stimulation buffer (S, 8MP004B) to give 1 x 10 ⁶ cells / ml CHO11B2. Compounds were incubated with cells at 50 μl per well for 1 h. Then, the cells were lysed by adding 100 μl per well for determination buffer (ΝΉΝ, 8MP004B) containing 0.18 μCi / ml ¹²⁵ 1-cAMP (ΝΉΝ, ΝΞΧ- 130), and the plates were incubated at room temperature for the next 2 hours. The amount of ¹²⁵ 1-cAMP bound to P1a8Yp1a! E® was measured using Torsoip! ΝΧΤ (Raskagb), with a standard calculation of efficiency for 1 min. Dose response data were expressed as% isoprenaline activity and a sigmoidal curve was constructed using four parameters.

Thus, it was found that the compounds of formula (1) according to the present invention, which are illustrated above in Examples 1-57, show 32-cAMP IR ₅₀ below 5 nM.

Claims (25)

1. The compound of General formula (1) - 61 010133 where (CH ^ -C ^ O ^ -group is in the meta or para position, B ¹ and B ^{2 are} independently selected from H and C ₁ -C ₄ alkyl; η means 0, 1 or 2; where p means 1 or 2 and s. | means 1 or 2, and in the above group 2 carbon atoms of a saturated nitrogen-containing heterocycle are optionally connected by a methylene bridge, and the * -IV ^8- p ² -A groups, where 0 ° means C1-C4 alkylene, B ⁸ means H or C1-C _4- alkyl and A is pyridyl, C ₃ -C ₁₀ -cycloalkyl, wherein the above cycloalkyl is optionally bridged at 1 or more carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, or a group B ³ , B ⁴ , B ⁵ , B ⁶ and B ⁷ are the same or different and are selected from H, C1-C4 alkyl, OB ⁹ , 8B ⁹ , 8OB ⁹ , 8O2B ⁹ , halogen, CO2B ⁹ , CE3, SI , OSE ₃ , 8O ₂ IV ⁹ V ¹⁰ , СОМВ ⁹ В ¹⁰ , MV ⁹ В ¹⁰ , INSOV ¹⁰ and phenyl optionally substituted by 1-3 groups selected from OB ⁹ , halogen and C ₁ -C ₄ alkyl; B ⁹ and B ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl and * represents the point of attachment of a carbonyl group; or, accordingly, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations. 2. The compound according to claim 1, where O ¹ means a group * -ΝΗ-ρ ^: -Λ. where A is cyclohexyl or adamantyl. 3. The compound according to claim 1, where O ¹ means a group * -IN-p ² -A, where A means a group where B ³ , B ⁴ , B ⁵ , B ⁶ and B ⁷ are the same or different and are selected from H , С1-С4-alkyl, ОВ ⁹ , 8В ⁹ , 8OB ⁹ , 8О2В ⁹ , halogen, SI, СО2В ⁹ , CE3, ОСС ₃ , 8О ₂ ИВ ⁹ В ¹⁰ , СОМВ ⁹ В ¹⁰ , ИВ ⁹ ^ ⁰ , INSOV ¹⁰ and phenyl optionally substituted with 1-3 groups selected from OB ⁹ , halogen and C ₁ -C ₄ alkyl, with the proviso that at least 2 of B ³ -B ⁷ are H; where B ⁹ and B ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl. 4. The compound according to claim 3, where O ¹ means a group * -IN-p ² -A, where A means a group where B ³ , B ⁴ , B ⁵ , B ⁶ and B ⁷ are the same or different and are selected from H , OH, CH3, OCH3, OCE ₃ , OCH2-CH ₃ , 8CH ₃ , I (CH ₃ ) 2, I (C = O) CH ₃ , C (O) \ N, COOCH ₃ , 8O2CH ₃ , 8O _; \ 1 With SI, halogen, CE ₃ and phenyl optionally substituted by OH. 5. The compound according to claim 1, where a means a group - 62 010133 where one of K ³ -K ⁷ means OH or phenyl substituted with OH. 6. The compound according to claim 1, where A means naphthyl, optionally substituted by OH. 7. The compound according to any one of claims 1 to 6, where O ² means —CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, —CH ₂ —C (CH ₃ ) ₂ - or - C (CH ₃ ) ₂ -. 8. The compound according to claim 7, where O ² means —CH ₂ -. 9. The compound according to claim 1, where O ¹ means where K ³ , K ⁴ , K ⁵ and K ⁶ mean N. 10. The compound according to any one of claims ¹ to ⁹ , where K ¹ means H or C ¹ -C 4 -alkyl and K ² means C 1 -C 4 -alkyl. 11. The compound of claim 10, where K ¹ means H or CH3 and K ² means H or CH3. 12. The compound according to claims 1-11, where η means 0 or 1. 13. (K, K) -Stereoisomer of the compound according to any one of claims 1 to 12. 14. The compound according to any one of claims 1 to 13, where (CH ₂ ) _p —C (= O) 0 ¹ group is in the meta position. 15. The compound according to claim 1, selected from the group consisting of No. benzyl-2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl } phenyl) acetamide; No. (3,4-dimethylbenzyl) -2- (3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] - 2-methylpropyl} phenyl) acetamide; No. [2- (4-chlorophenyl) ethyl] -3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} benzamide; No. [2- (2-chlorophenyl) ethyl] -3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- (2-naphthalen-1-yl-ethyl) benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- [2- (4methylphenyl) ethyl] benzamide; No. [2- (2,6-dimethylphenyl) ethyl] -3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; No. [2- (2,3-dimethylphenyl) ethyl] -3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- [2- (4hydroxy-2,3-dimethylphenyl) ethyl] benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- [2- (4methoxyphenyl) ethyl] benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A-phenethylbenzamide; No. cyclohexylmethyl-3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} benzamide; No. [5 - ((1K) -2- {1,1-dimethyl-2- [3- (piperidin-1-carbonyl) phenyl] ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- [2- (3trifluoromethylphenyl) ethyl] benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- (3-phenylpropyl) benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A-indan-2ylbenzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- (2-pyridin2-yl-ethyl) benzamide; 3- {2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} A- [2- (4sulfamoylphenyl) ethyl] benzamide; No. (4-dimethylaminobenzyl) -2- (3 - {(2K) -2 - [(2K) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy - 63 010133 ethylamino] propyl} phenyl) acetamide; X- [5- (2 - {(1B) -2- [3- (3,4-dihydro-1H-isoquinoline-2-carbonyl) phenyl] -1,1-dimethylethylamino} -1-hydroxyethyl) -2- hydroxyphenyl] formamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (4'-hydroxybiphenyl-3-methylmethyl) benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4hydroxy-2,5-dimethylphenyl) ethyl] benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4hydroxy-3-methylphenyl) ethyl] benzamide; X- (4-acetylaminobenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; 4- {[2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetylamino] methyl} benzamide; X-adamantan-1-yl-3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (2-hydroxynaphthalen-1-ylmethyl) benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (4-hydroxy-3,5-dimethylbenzyl) benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (6-hydroxynaphthalen-2-ylmethyl) benzamide; X- (3,6-dichloro-2-hydroxybenzyl) -3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; X- (3,4-dimethylbenzyl) -2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] ethyl} phenyl) acetamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- [2- (4hydroxyphenyl) -2-methylpropyl] benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -X- (4'-hydroxybiphenyl-4-ylmethyl) benzamide; X-adamantan-1-yl-2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; X- [5- (2- {2- [3- (10-azatricyclo [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene-10-carbonyl) phenyl ] -1,1-dimethylethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide; 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (4'-hydroxybiphenyl-3-ylmethyl) acetamide ; 4- {[2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2methylpropyl} phenyl) acetylamino] methyl} benzoic acid methyl ester; 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) X- (4-trifluoromethoxybenzyl) acetamide; X- (2-chloro-4-hydroxybenzyl) -X-ethyl-2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2hydroxyethylamino] -2- methylpropyl} phenyl) acetamide; X- (2-chloro-4-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (4-hydroxy-3,5-dimethylbenzyl) acetamide; 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (2-hydroxynaphthalen-1-ylmethyl) acetamide; X- (5-chloro-2-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide ; X- (3,5-dichloro-2-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl ) acetamide; 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (6-hydroxynaphthalen-2-ylmethyl) acetamide; 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -X (4'-hydroxybiphenyl-4-ylmethyl) acetamide ; X- (4-cyanobenzyl) -2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; 2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) X- (4-methanesulfonylbenzyl) acetamide; 2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) X- (4-methylsulfanylbenzyl) acetamide; 2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - 64 010133 No. (4-trifluoromethylbenzyl) acetamide; 2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) No. (4'-hydroxybiphenyl-4-ylmethyl) acetamide; No. [2- (5-chloro-2-hydroxyphenyl) ethyl] -3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; 2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) No. (4'-hydroxybiphenyl-3-ylmethyl) acetamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} -№ [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide; No. (2-chloro-4-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) - (2K.) - 2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl } phenyl) acetamide; No. [2- (5-chloro-2-hydroxyphenyl) ethyl] -3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; 3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} -№ [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide; 2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) No. (tetrahydrothiopyran-4-yl) acetamide; No. (5-chloro-2-hydroxybenzyl) -2- (3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide and No. {5 - [(1B) -2 - ((1B) -2- {3- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropyl] phenyl} -1-methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide. 16. A pharmaceutical composition comprising at least an effective amount of a compound of formula (1) according to any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof. 17. The use of the compounds of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, as a medicine. 18. The use of a compound of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of diseases, disorders and conditions selected from the group consisting of any type of asthma, etiology or pathogenesis, in particular asthma, which is a disease selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial Ι ^ Ε-mediated asthma, bronchial asthma, essential asthma, true asthma, hereditary bronchial asthma caused by pathophysiological disorders, acquired bronchial asthma caused by environmental factors, essential asthma for an unknown or asymptomatic reason, bronchodilator asthma, emphysematous asthma, asthma caused by exercise, asthma caused by an allergen, asthma caused by cold air, occupational asthma, infection asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, initial asthma, childhood asthmatic syndrome ohms and bronchiolitis; chronic or acute bronchostenosis, chronic bronchitis, minor obstruction of the airways and emphysema; obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular obstructive or inflammatory disease of the respiratory tract, which is a disease selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (SORE). SORE. which includes chronic bronchitis, pulmonary emphysema, or shortness of breath associated with or unrelated to the SORE, SORE, which is characterized by irreversible progressive obstruction of the respiratory tract, adult respiratory distress syndrome (AKE8), exacerbation of airway hyperresponsiveness resulting from other medications, and respiratory tract disease, which is associated with pulmonary hypertension; bronchitis of any type, etiology or pathogenesis, in particular bronchitis, which is a disease selected from the group consisting of acute bronchitis, acute laryngeal-tracheal bronchitis, arachid bronchitis, catarrhal bronchitis, croupous bronchitis, dry bronchitis, infectious asthmatic bronchitis, industrial bronchitis, bronchitis caused by staphylococcus or streptococcus, and vesicular bronchitis; severe lung injury; bronchiectasis of any type, etiology or pathogenesis, in particular bronchiectasis, which is a disease selected from the group consisting of cylindrical bronchiectasis, saccular bronchiectasis, spindle-shaped bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular. 19. A method of treating a mammal, including a human, (2-agonist, comprising treating the above mammal with an effective amount of a compound of formula (1) according to any one of claims 1-15, or a pharmaceutically acceptable salt, derivative form or composition thereof. - 65 010133 20. The combination of a compound according to any one of claims 1 to 15 with other (s) therapeutic (s) agent (s) selected (s) from the group consisting of: (a) 5-lipoxygenase inhibitors (5-L0) or antagonists of the 5-lipoxygenase activating protein (ELP), (b) leukotriene antagonists (LTPLs), including LTP ₄ , LTC ₄ , LTO ₄ and L ₄ antagonists, (c) antagonists histamine receptors, including H1 and H3 antagonists, (b) vasoconstrictor sympathomimetic agents, α! - agonists, and a ₂ adrenoreceptors for use as decongestants, (f) muscarinic M3 receptor antagonists or anticholinergic agents, (ί) ΡΌΕ- inhibitors, e.g. ΡΌΕ3-, ΡΌΕ4- and P ^ Ε5-inhibitors, (e) theophylline, (1) chromoglyc sodium, (ί) COX inhibitors, both non-selective and selective COX-1 or COX-2 inhibitors (Ν8ΆΙΌ8), (ί) oral and administered by inhalation of glucocorticosteroids, (k) active monoclonal antibodies against endogenous inflammatory substances , (l) anti-tumor necrosis factor agents (anti-TIE-a), (t) adhesion molecule inhibitors, including UL-4 antagonists, (p) kinin-β and B ₂ receptor antagonists, (o) immunosuppressive agents , (p) inhibitors of matrix metalloproteinases (MMPs), (p. |) antagonists of tachykinin-ΝΚι-, ΝΚ ₂ - and KK ₃ receptors, (g) elastase inhibitors, (§) adenosine A2a receptor agonists, (I) urokinase inhibitors, (and) compounds that act on dopamine receptors, such as O2 agonists, (ν) ΝΕκβ pathway modulators, such as ΙΚΚ-inhibitors, (those ) modulators of cytokine signaling pathways, such as p38 MAP kinase or zuc kinase, (x) agents that can be classified as mucolytic or antitussive, (y) antibiotics, (ζ) NOLS inhibitors and (aa) P13 kinase inhibitors. 21. The compound of the formula N- (5-chloro-2-hydroxybenzyl) -2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl } phenyl) acetamide or a pharmaceutically acceptable salt or solvate thereof. 22. The compound of the formula 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -Y- (4-hydroxy-3 , 5-dimethylbenzyl) acetamide or a pharmaceutically acceptable salt or solvate thereof. 23. The compound of formula 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -Y- (6-hydroxynaphthalene-2 -ylmethyl) acetamide or a pharmaceutically acceptable salt or solvate thereof. 24. A compound of the formula 2- (3 - {(2B) -2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -Y- (4'-hydroxybiphenyl- 4-ylmethyl) acetamide or a pharmaceutically acceptable salt or solvate thereof. 25. The compound of the formula N- [2- (4-chlorophenyl) ethyl] -3- {2 - [(2B) -2- (3-formylamino-4-hydroxyphenyl) 2-hydroxyethylamino] -2-methylpropyl} benzamide or its a pharmaceutically acceptable salt or solvate.