KR100806478B1 - Formamide derivatives useful as adrenoceptor - Google Patents

Abstract

The present invention relates to a compound represented by the following formula (1), a method for preparing the same, an intermediate used in the preparation thereof, a composition containing the compound, the use of the compound, and a derivative thereof. The compounds according to the invention are useful for various diseases, disorders and symptoms, in particular inflammatory, allergic and respiratory diseases, disorders and symptoms:

Formula 1

Description

Formamide derivative useful as an adrenergic receptor {FORMAMIDE DERIVATIVES USEFUL AS ADRENOCEPTOR}

The present invention relates to the use of the β 2 agonist represented by the following formula (1), a preparation method thereof, a composition comprising the same, and a derivative thereof:

Where

R ¹ , R ² , n and Q ¹ have the meanings described below.

Adrenaline receptors are members of the super-family of giant G-protein coupled receptors. The adrenergic receptor subgroup is divided into α and β subgroups, wherein the β subgroup consists of at least three receptor subtypes, ie β1, β2 and β3. Adrenaline receptors exhibit different expression patterns in the tissues of various lineages and organs of mammals. β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells (e.g., smooth muscles of blood vessels, bronchus, uterus or intestine), while β3 adrenergic receptors are mainly expressed in adipose tissue (hence, β3 agonists are used to treat adiposis and diabetes) Be used), β1 adrenergic receptors are mainly expressed in cardiac tissue (hence β1 agonists are mainly used as cardiac agents).

Pathophysiology and treatment of airway diseases are extensively described in Chestnut, PJ, 1997, 111: 2, pp17S-26S and Bryan, SA et al., Expert Opinion on investigational drugs, 2000, 9: 1, pp25-42. Therefore, only a brief point will be described here in order to explain the background art.

Glucocorticoids, anti-leukotrienes, theophylline, chromones, anticholinergic drugs and β2 agonists have recently been used to treat allergic and nonallergic airway diseases such as asthma and chronic obstructive airway diseases (chronic obstructive pulmonary disease). Group of drugs. Treatment guidelines for such diseases include both short acting inhalation beta agonists and long acting inhalation beta 2 agonists. Rapidly expressing short acting β agonists are used for "rescue" bronchodilation, while long acting forms are sustained release and used for maintenance therapy.

Bronchodilation is mediated by the action of β2 adrenergic receptors expressed on airway smooth muscle cells, resulting in relaxation, resulting in bronchodilation. Thus, β agonists as functional antagonists can prevent and counteract the effects of all bronchoconstrictors, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandin, histamine and endothelin. Because β2 receptors are widely distributed in the airways, β2 agonists may affect other types of cells that play a role in asthma. For example, it has been reported that β2 agonists may stabilize mast cells. Inhibiting the release of bronchoconstrictor may be a way for β2 agonists to block bronchial contraction due to allergens, exercise and cold air. In addition, β2 agonists may reduce cholinergic-reflective bronchial contraction by inhibiting cholinergic neurotransmission in the human airways.

In addition to the airways, β2 adrenergic receptors are also expressed in other organs and tissues, so β2 agonists such as those described herein can cause neurological diseases, premature colic, congestive heart failure, depression, inflammatory skin diseases, allergic skin diseases, psoriasis, The treatment of proliferative skin diseases, other diseases such as glaucoma, and lowering the acidity of gastric juice can be applied to symptoms that help, in particular, stomach and peptic ulcers.

However, β2 agonists have been limited in their use due to low selectivity and high circulatory exposure and side effects mainly mediated by action at β2 adrenergic receptors expressed externally in the airways (muscle tremor, tachycardia, palpitations, arthropathy). Thus, there is a need for improvements to this type of drug.

Thus, there is still a need for novel β 2 agonists with appropriate pharmacological profiles, eg in terms of efficacy, selectivity, pharmacokinetics, and duration of action. In this regard, the present invention relates to novel β2 agonists.

Various formamide derivatives are already disclosed. US 2004/0006112, for example, discloses compounds having the following formula as β2 agonists:

US2003 / 0229058 discloses selective β 2 agonists having the formula:

However, any of the aforementioned formamide derivatives can be used as a pharmacological profile that can be used as an effective drug in the treatment of β2-mediated diseases and / or symptoms, such as allergic and non-allergic airway diseases, in particular diseases and / or symptoms by the inhalation route. Does not indicate.

The present invention relates to compounds of formula (1) or, where appropriate, pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic derivatives thereof:

Formula 1

Where

(CH ₂ ) _n -C (= O) Q ¹ group is in meta or para position,

R ¹ and R ² are independently H and C ₁ -C ₄ Selected from the group consisting of alkyl,

n is 0, 1 or 2,

(여기서, p는 1 또는 2이고, q는 1 또는 2이다),

및 ^*-NR⁸-Q²-A 기{여기서, Q²는 C₁-C₄ 알킬엔이고, R⁸는 H 또는 C₁-C₄ 알킬이고, A는 피리딜, C₃-C₁₀ 시클로알킬(시클로알킬은 1개 이상, 바람직하게는 1개, 2개, 3개 또는 4개의 탄소원자에 의해 임의로 가교결합된다), 테트라하이드로피라닐, 피페리디닐, 테트라하이드로티오피라닐,

또는

이다}로 이루어진 군으로부터 선택된 기이고, Q ¹ is optionally crosslinked by one carbon atom

Where p is 1 or 2 and q is 1 or 2,

And ^* -NR ⁸ -Q ² -A groups, wherein Q ² is C ₁ -C ₄ alkylene, R ⁸ is H or C ₁ -C ₄ alkyl, A is pyridyl, C ₃ -C ₁₀ cyclo Alkyl (cycloalkyl is optionally crosslinked by one or more, preferably one, two, three or four carbon atoms), tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl,

or

Group selected from the group consisting of

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CN, CO ₂ R ⁹ , CF ₃ , OCF ₃ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NHCOR ¹⁰ and phenyl, wherein the phenyl is OR ⁹ , halo and C ₁ -C ₄ Unsubstituted or substituted with 1 to 3 groups selected from the group consisting of alkyl,

R ⁹ and R ¹⁰ are the same or different and are selected from the group consisting of H and C ₁ -C ₄ alkyl,

* Represents a bonding position of a carbonyl group.

Compounds of formula (I) are β2 receptor agonists that are particularly useful in the treatment of β2-mediated diseases and / or symptoms, showing excellent efficacy, particularly when administered by the inhalation route.

In Formula 1, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylene represent a straight or branched group containing 1, 2, 3 or 4 carbon atoms. This also applies to substituents with substituents or other radicals such as O- (C ₁ -C ₄ ) alkyl radicals, S- (C ₁ -C ₄ ) alkyl radicals and the like. Examples of suitable (C ₁ -C ₄ ) alkyl radicals are methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec -butyl, tert -butyl. Examples of suitable O- (C ₁ -C ₄ ) alkyl radicals are methoxy, ethoxy, n -propyloxy, iso -propyloxy, n -butyloxy, iso -butyloxy, sec -butyloxy and tert -butyloxy have.

C ₃ -C ₁₀ cycloalkyl, wherein two or more carbon atoms are optionally crosslinked by one or more carbon atoms, is 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.

Finally, halo represents a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

구조에서와 같은 페닐기상의 자유결합은 페닐이 메타 또는 파라 위치에서 치환될 수 있음을 의미한다.In the following

Free bonding on the phenyl group as in the structure means that phenyl can be substituted in the meta or para position.

Compounds of Formula 1 may be prepared using conventional procedures, such as the methods illustrated below, wherein Q ¹ , Q ² , R ¹ , R ² , A and n are represented by Formula 1 unless otherwise noted. As defined for compounds of:

Formula 1

Amide derivatives of Formula 1 can be prepared by coupling an acid of Formula 2 with an amine of Formula 3, 3a, 3b, or 3c:

NHR ⁸ -Q ² -A

Coupling reactions are generally common in excess of these amines as acid acceptors such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N'-dicyclohexylka Optionally a catalyst (e.g. 1-hydroxybenzo) using a bodyimide or O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexaflourophosphate In the presence of triazole hydrate or 1-hydroxy-7-azabenzotriazole), optionally in the presence of a tertiary amine base such as N-methylmorpholine, triethylamine or diisopropylethylamine. The reaction can be carried out for 1 to 24 hours at 10-40 ° C. (room temperature) in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate.

The amine of the formula (3), (3a), (3b) or (3c) may be purchased commercially or conventional methods known to those skilled in the art from commercially available materials (e.g., reduction, oxidation, alkylation, coupling reactions by transition metals, protection, Deprotection and the like.

Acids of formula (2) can be prepared from the corresponding esters of formula (4) according to any method known to those skilled in the art that can produce acids from esters without modifying other portions of the molecule:

Where

Ra is a suitable acid protecting group, preferably a benzyl group or a (C ₁ -C ₄ ) alkyl group, including but not limited to methyl and ethyl. For example, the ester may be an aqueous acid or base at a temperature of 20-100 ° C. for 1-40 hours, optionally in the presence of a solvent or solvent mixture (eg water, 1,4-dioxane, tetrahydrofuran / water). (Eg, hydrogen chloride, potassium hydroxide, sodium hydroxide, lithium hydroxide) and may be hydrolyzed. Alternatively, when the ester is a benzyl group, the ester is 1 to 48 at a temperature of 20 to 50 ° C. in a suitable solvent (eg methanol, ethanol, 2M ammonia in methanol) in the presence of a suitable catalyst (eg palladium on carbon or palladium hydroxide on carbon). May be hydrogenated at 1-4 hydrogen pressure for a period of time.

Esters of Formula 4 may be prepared by reacting an amine of Formula 5, wherein Ra and n are as defined above, with a bromide of Formula 6:

In a typical procedure, the amine of formula 5 is optionally in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N, N-dimethylformamide, acetonitrile), optionally a suitable base (e.g. triethylamine , Diisopropylethylamine, potassium carbonate) at 80-120 ° C. for 12-48 hours with bromide.

The bromide of formula (6) can be prepared according to the method disclosed in Organic Process Research and Development 1998, 2, 96-99.

Amines in which R ¹ is Me and R ² H in Formula 5 are standard methodologies for cleaving nitrogen protecting groups as disclosed in TWGreene and PGMWuts, Protective Groups in Organic Synthesis Third Edition, John Wiley and Sons Inc., 1999. The bond between N and Rb and between N and Rc can be easily cleaved using to produce a free amine of formula 5 as a (R) or (S) enantiomer from the corresponding protected amine of formula Can be:

Where

Ra and n are as defined above,

Rb and Rc represent any suitable substituent such that HNRbRc is a chiral amine (eg, Rb may be hydrogen and Rc may be α-methylbenzyl).

Amines of formula 7 may be prepared as single diastereomers by reacting a ketone of formula 8 with an amine of formula HNRbRc:

Where

Ra, Rb, Rc and n are as described above.

In a conventional procedure, chiral intermediates are made by reaction of a ketone of formula 8 with an amine of formula HNRbRc, which is then reacted with an acid catalyst (optionally in the presence of a desiccant (e.g. molecular filter, magnesium sulfate). Example: acetic acid) in the presence of a suitable reducing agent such as sodium cyanoborohydride of formula NaCNBH ₃ or sodium triacetoxyborohydride of formula Na (OAc) ₃ BH to reduce the amine of formula 7 to the diastereomer It is produced as a mixture. The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane for 3 to 72 hours at a temperature of 20 to 80 ° C. The product is then converted to hydrochloride, nitrate and optionally crystallized from a suitable solvent or solvent mixture (e.g. isopropanol, ethyl acetate, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) to give a single compound of formula It is produced as a diastereomer of.

Ketones of n in Formula 8 may be prepared by palladium mediated coupling reaction of an aryl halide of Formula 9 with an oleate or an oleate equivalent:

Where

Ra is as described above,

Hal represents a halogen atom including, but not limited to bromine, iodine.

In a typical procedure, the aryl halides of formula 9 are palladium acetate / tri represented by suitable palladium catalysts (e.g., formula Pd (OAc) ₂ / P (o-Tol) ₃ in nonpolar solvents (e.g. toluene, benzene, hexane). Isopropenyl acetate in the presence of ortho -tolylphosphine) with tri-n-butyltin methoxide of the formula Bu ₃ SnOMe to react with tin enolate generated in situ. Preferably, the reaction is carried out at 80 to 110 ° C. for 6 to 16 hours.

The aryl halides of formula 9 can be obtained by esterifying the corresponding acid of formula 10 according to any method known to those skilled in the art with respect to preparing esters from acids without modifying other parts of the molecule:

Where

Hal is as described above.

In a conventional procedure, the acid of formula 10 is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as defined above, in the presence of an acid such as hydrogen chloride for 8-16 hours at a temperature of 10-40 ° C. (room temperature). Alternatively, the acid of formula 10 is reacted with a base (e.g. cesium carbonate or potassium carbonate) in an appropriate solvent such as N, N-dimethylformamide for 10-20 hours at a temperature of 10-40 ° C. (room temperature) and an alkyl halide (e.g. : Methyl iodide, benzyl bromide).

Acids of formula 10 are commercially available products.

Amines in which R ¹ and R ² are both C ₁ -C ₄ alkyl in Formula 5 may be prepared according to Scheme 1 below:

Where

R ¹ , R ² and Ra are as described above.

In a conventional procedure, the ester of formula 11 is reacted with “activated” alkyl (organometallic alkyl such as R ² MgBr, R ² MgCl or R ² Li) by the method described above to give the corresponding tertiary alcohol of formula 12 .

Subsequently, the tertiary alcohol of Formula 12 is treated with alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid (eg sulfuric acid, acetic acid) to form a protected intermediate, then as disclosed in the above-mentioned literature. Cleavage using standard methodology for cleaving nitrogen protecting groups. The resulting amino acid is then esterified using the method disclosed herein to yield an amine of formula (5).

Alternatively, an amine in Formula 5 wherein both R ¹ and R ² are C ₁ -C ₄ alkyl and n is 0 can be prepared according to Scheme 2:

Where

R ¹ , R ² and Ra are as described above.

In a conventional procedure, the ester of formula 13 is reacted with an "activated" alkyl (organometallic alkyl such as R ² MgBr, R ² MgCl or R ² Li) by the method described above to give the corresponding tertiary alcohol of formula 14 .

The 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 form a protected intermediate, followed by nitrogen as described in the aforementioned literature. Cleavage using standard methodology for cleaving protecting groups yields bromo amines of Formula 15.

The resulting bromoamine of Formula 15 may be prepared under the carbon monoxide atmosphere at elevated temperature (100 ° C.) and elevated pressure (100 psi) using RaOH (e.g., MeOH, EtOH, benzyl alcohol) as a solvent, or an auxiliary solvent such as DMF. Suitable palladium catalysts such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), palladium (II) acetate 1,1'-bis (diphenylphosphino) ferrocene], tris (di Benzylideneacetone) dipalladium (0), 2,2'-bis (diphenylphosphino) -1,1'-binaphtyldichloropalladium (II)} yields the ester of formula (5).

Ketones with n = 2 in Formula 8 may be prepared by reducing the alkene of Formula 16:

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

Alkenes of Formula 16 may be prepared by reacting an activated olefin with a palladium mediated coupling reaction with an aryl halide of Formula 17:

In conventional procedures, the aryl halides of formula 17 are suitable solvents (eg, acetonitrile, N, N-dimethylformamide, toluene) for 8 to 24 hours at 40 to 110 ° C., optionally in the presence of a base such as triethylamine. Suitable palladium catalysts such as tetrakis (triphenylphosphine) palladium (0) of formula Pd (PPh ₃ ) ₄ , palladium acetate / tri-ortho- of formula Pd (OAc) ₂ / P (o-Tol) ₃ Coupling with a vinyl ester (eg methyl acrylate) in the presence of tolylphosphine or (diphenylphosphino) ferrocenyl palladium chloride of the formula dppfPdCl ₂ .

Ketones of formula 17 are commercially available products.

Alternatively, the compound of formula 1 may be prepared by reacting the bromide of formula 6 with an amine of formula 18:

Where

R ¹ , R ² , Q ¹ and n are as defined above in Formula 1 unless otherwise noted.

In conventional procedures, the amine of formula 18 is optionally used in a solvent or solvent mixture (at 80-120 ° C. for 12-48 hours, optionally in the presence of a suitable base such as triethylamine, diisopropylethylamine, potassium carbonate). Examples: dimethyl sulfoxide, toluene, N, N-dimethylformamide, acetonitrile) and the bromide of formula (6).

Amides of Formula 18 may be prepared by coupling the acid of Formula 19 comprising a suitable amine protecting group P1 with an amine of Formula 3, 3a, 3b or 3c:

Formula 3

NHR ⁸ -Q ² -A

Formula 3a

Formula 3b

Formula 3c

The coupling reaction is usually carried out in excess of the amine as an acid acceptor with conventional coupling reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N'-dicyclohex Silcarbodiimide), optionally in the presence of a catalyst such as 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole, optionally a tertiary amine base such as N-methylmo Pauline, triethylamine or diisopropylethylamine). The reaction can be carried out for 1 to 24 hours at 10-40 ° C. (room temperature) in a suitable solvent such as pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate.

The amine of Formula 3, 3a, 3b, or 3c may be purchased for commercial use, or conventional methods known to those skilled in the art from commercially available materials (eg, reduction, oxidation, alkylation, transition metal mediated coupling reactions, protection, deprotection, etc.). It can be prepared by).

Acids of formula 19 may be prepared from the corresponding esters of formula 5.

In Formula 19, both R ¹ and R ² are C ₁ -C ₄ Acids which are alkyl may be prepared from esters of formula 5 comprising a suitable amine protecting group P1 before or after the acid is formed according to any method known to those skilled in the art to prepare an acid from an ester without modifying other parts of the molecule. have:

Formula 5

Where

Ra is a suitable acid protecting group, preferably a (C ₁ -C ₄ ) alkyl group, including but not limited to methyl and ethyl.

For example, the ester may be an aqueous acid or base at a temperature of 20-100 ° C. for 1-40 hours, optionally in the presence of a solvent or solvent mixture (eg water, 1,4-dioxane, tetrahydrofuran / water). (Eg, hydrogen chloride, potassium hydroxide, sodium hydroxide, lithium hydroxide) and may be hydrolyzed.

Amines in which R ¹ and R ² are both hydrogen in Formula 5 can be prepared according to Scheme 3:

Where

R ¹ and R ² And Ra are as described above.

In conventional procedures the acid of formula 20 is preferentially reduced to the corresponding alcohol of formula 21 in the presence of an ester. This can be done by the formation of acyl imidazole or mixed anhydride, followed by reduction with sodium borohydride or other suitable reducing agent.

The primary alcohol of formula 21 is then converted to a leaving group such as mesylate, tosylate, bromide or iodide and substituted with a suitable amine nucleophile. Preferred nucleophiles are azide ions, which can then be reduced to primary amines via hydrogenation or reduced to triphenylphosphine. Still other nucleophiles may include ammonia or alkyl amines such as benzylamine or allylamine, after which the cleavage of the alkyl group results in the amine.

Alternatively, amides of formula 22 can be prepared as outlined above using standard amide bond formation reactions. The compound of formula 22 is then a suitable catalyst in the presence of a base (eg, N, N-diisopropylethylamine) in a solvent (N, N-dimethylformamide, acetonitrile) at 20-120 ° C. for 1-48 hours. (E.g., palladium (II) acetate) and phosphine (e.g. triphenylphosphine, tri-ortho-tolylphosphine) can be reacted with protected vinylamine (e.g. N-vinylphthalimide). . Alkenes of formula 23 may then be reduced to alkanes of formula 24 using standard hydrogenation conditions, and the phthalimide protecting group is removed using standard protecting group removal methods. The amine of Formula 25 may be reacted with the bromide of Formula 6 to produce a compound of Formula 1 under the conditions described above.

For some of the steps of the above-described process for preparing compounds of Formula 1, it may be necessary to protect reactive functional groups that do not react and consequently cleave the protecting groups. In this case, any compatible protective radical can be used. In particular, the protection and deprotection methods disclosed in TWGreene and PGMWuts, Protective Groups in Organic Synthesis , John Wiley and Sons Inc., 1999 or PJKocienski, Protecting groups , Georg Thieme Verlag, 1994 can be used.

Not only are the reactions used in the aforementioned methods and methods of preparing the new starting materials conventional and suitable reagents and reaction conditions for their implementation or preparation, but the separation procedures for the desired products are described in the above-mentioned literature and in the examples and preparations herein. It is known to those skilled in the art in connection with the examples.

또는

이다. 바람직하게 Q¹은 R³ 내지 R⁶중 하나는 OH이고 나머지는 H인

또는

이다. 바람직하게 Q¹은 A가

기(이때, R³, R⁴, R⁵, R⁶ 및 R⁷은 동일하거나 상이하며, H, C₁-C₄ 알킬, OR⁹, SR⁹, SOR⁹, SO₂R⁹, 할로, CN, CO₂R⁹, CF₃, OCF₃, SO₂NR⁹R¹⁰, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR¹⁰ 및 페닐로 이루어진 군으로부터 선택되며, 이때 상기 페닐은 R³ 내지 R⁷중 2 이상이 H인 경우 OR⁹, 할로 및 C₁-C₄ 알킬로 이루어진 군으로부터 선택된 1 내지 3개의 기로 치환되거나 치환되지 않고, R⁹와 R¹⁰은 동일하거나 상이하며 H 및 C₁-C₄ 알킬로 이루어진 군으로부터 선택된다)인 ^*-NH-Q²-A기이다.In addition, the compounds of formula (1) and intermediates for their preparation can be purified by various known methods, such as, for example, crystallization or chromatography. Preference is given to a subgroup of compounds of formula 1 containing the following substituents. Preferably Q ¹ is a ^* -NH-Q ² -A group wherein A is cyclohexyl or adamantyl, preferably Q ¹ is R ³ , R ⁴ , R ⁵ and R ⁶ are H

or

to be. Preferably Q ¹ is ^one of R ³ to R ⁶ is OH and the other is H

or

to be. Preferably Q ¹ is A

Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CN , CO ₂ R ⁹ , CF ₃ , OCF ₃ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NHCOR ¹⁰ and phenyl, wherein the phenyl is selected from R ³ to R ⁷ When at least 2 is H, it is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of OR ⁹ , halo and C ₁ -C ₄ alkyl, R ⁹ and R ¹⁰ are the same or different and H and C ₁ -C ₄ It is selected from the group consisting of alkyl) ^* -NH-Q ² -A group.

기(이때, R³, R⁴, R⁵, R⁶ 및 R⁷은 동일하거나 상이하며, H, OH, CH₃, OCH₃, OCF₃, OCH₂-CH₃, SCH₃, N(CH₃)₂, NH(C=O)CH₃, C(=O)NH₂, COOCH₃, SO₂CH₃, SO₂NH₂, 할로, CN, CF₃ 및 페닐로 이루어진 군으로부터 선택되고, 이때 상기 페닐은 R³ 내지 R⁷중 2 이상이 H인 경우 OH로 치환되거나 치환되지 않는다)인 ^*-NH-Q²-A기이다.More preferably, Q ¹ is A

Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, OH, CH ₃ , OCH ₃ , OCF ₃ , OCH ₂ -CH ₃ , SCH ₃ , N (CH ₃ ) ₂ , NH (C═O) CH ₃ , C (═O) NH ₂ , COOCH ₃ , SO ₂ CH ₃ , SO ₂ NH ₂ , halo, CN, CF ₃ and phenyl, wherein Phenyl is a ^* -NH-Q ² -A group, which is optionally substituted with OH when at least two of R ³ to R ⁷ are H.

기(이때, R³ 내지 R⁷중 하나가 OH, 또는 OH로 치환된 페닐이다)이다.In a preferred embodiment, A is

Group, wherein one of R ³ to R ⁷ is OH or phenyl substituted with OH.

기(이때, R³ 내지 R⁷중 하나가 OH, 또는 OH로 치환된 페닐이고, 다른 것은 R³ 내지 R⁷중 2 이상이 H인 경우 H, Cl 및 CH₃로 이루어진 군으로부터 선택된다)이다.In a preferred embodiment, A is

Group, wherein one of R ³ to R ⁷ is OH or phenyl substituted with OH and the other is selected from the group consisting of H, Cl and CH ₃ when at least two of R ³ to R ⁷ are H .

Preferably, A is naphthyl unsubstituted or substituted with OH.

Preferably, A is naphthyl substituted with OH.

In this group of compounds, the following substituents are particularly preferred: Q ² is —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- ; R ¹ is H or C ₁ -C ₄ alkyl and R ² is C ₁ -C ₄ alkyl; More preferably R ¹ is H or CH ₃ and R ² is H or CH ₃ ; n is 0 or 1; R ¹ is H and R ² is CH ₃ and n is 0 or 1; R ¹ is CH ₃ and R ² is CH ₃ and n is 0 or 1.

A compound of formula 1 as described in the Examples below, ie N-benzyl-2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Ethylamino] -2-methylpropyl} phenyl) acetamide; N- (3,4-dimethylbenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} phenyl) acetamide; N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} benzamide; N- [2- (2-chlorophenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (2-naphthalen-1-yl Ethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-methylphenyl) Ethyl] benzamide; N- [2- (2,6-dimethylphenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropyl} benzamide; N- [2- (2,3-dimethylphenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropylbenzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy -2,3-dimethylphenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-methoxy Phenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N-phenethyl-benzamide; N-cyclohexylmethyl-3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; N- [5-((1R) -2- {1,1-dimethyl-2- [3- (piperidine-1-carbonyl) phenyl] ethylamino} -1-hydroxyethyl] -2-hydro Hydroxyphenyl] formamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2 -(3-trifluoromethylphenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2 -Methylpropyl} -N- (3-phenylpropyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropyl} -N-indan-2-ylbenzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropyl} -N- (2-pyridin-2-ylethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydro Oxyethylamino] -2-methylpropyl} -N- [2- (4-sulfamoylphenyl) ethyl] benzamide; N- (4-dimethylaminobenzyl) -2- (3-{(2R ) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; N- [5- (2-{(1R ) -2- [3- (3,4-Dihydro-1H-isoquinolin-2-carbonyl) -phenyl] -1,1-dimethyl-ethylamino} -1-hydroxyethyl) -2-hydro Hydroxyphenyl] formamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (4 '-Hydroxybiphenyl-3-ylmethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2 -Methylpropyl} -N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydro Hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy-3-methylphenyl) ethyl] benzamide; N- (4-acetylaminobenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phene ) Acetamide; 4-{[2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetylamino ] Methyl} benzamide; N-adamantan-1-yl-3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benz Amides; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (2-hydroxy-naphthalene -1-ylmethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (4-hydroxy-3, 5-dimethylbenzyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (6-hydroxy-naphthalene- 2-ylmethyl) benzamide; N- (3,6-dichloro-2-hydroxybenzyl) -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropyl} benzamide; N- (3,4-dimethylbenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] ethyl} phenyl Acetamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy Phenyl) -2-methylpropyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (4'-hydroxybiphenyl -4-ylmethyl) benzamide; N-adamantan-1-yl-2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] Propyl} phenyl) acetamide; N- [5- (2- {2- [3- (10-aza-tricyclo [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-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4 ' -Hydroxybiphenyl-3-ylmethyl) acetamide; 4-{[2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -acetyl Amino] methyl} benzoic acid methyl ester; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxy phenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N -(4-trifluoroomethoxy-benzyl) acetamide; N- (2-chloro-4-hydroxybenzyl) -N-ethyl-2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; N- (2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Oxyethylamino] -2-methylpropyl} phenyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4- Hydroxy-3,5-dimethylbenzyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (2- Hydroxynaphthalen-1-ylmethyl) acetamide; N- (5-chloro-2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Oxyethylamino] propyl} phenyl) acetamide; N- (3,5-dichloro-2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2 -Hydroxyethylamino] propyl} phenyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (6- Hydroxynaphthalen-2-ylmethyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4 ' -Hydroxybiphenyl-4-ylmethyl) acetamide; N- (4-cyano-benzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} -phenyl) -acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -N- (4 Methanesulfonyl-benzyl) acetamide; 2- (3- {2-[(2R) -2- (3-formyl amino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (4- Methylsulfanyl-benzyl) acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -N- (4 -Trifluuromethyl-benzyl) acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (4 ' -Hydroxy-biphenyl-4-ylmethyl) acetamide; N- [2- (5-chloro-2-hydroxyphenyl) -ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Ethylamino] -2-methylpropyl} -benzamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (4 ' -Hydroxybiphenyl-3-ylmethyl) acetamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl)- 2-methylpropyl] -benzamide; N- (2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R)-(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; N- [2- (5-chloro-2-hydroxyphenyl) -ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Ethylamino] -2-methylpropyl} benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl)- 2-methylpropyl] benzamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (tetrahydro -Thiopyran-4-yl) acetamide; N- (5-chloro-2-hydroxybenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; And N- {5-[(1R) -2-((1R) -2- {3- [3- (3,4-dihydro- 1H -isoquinolin-2-yl) -3-oxopropyl] Phenyl} -1-methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide is particularly preferred.

According to one aspect of the invention, compounds in which the (CH ₂ ) _n -C (= 0) Q ¹ group in formula ¹ is in meta position are generally preferred.

Pharmaceutically acceptable salts of compounds of formula 1 include acid addition salts and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetates, adipates, aspartates, benzoates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, chamlates, citrates, cyclamates, edisylates, acylates, formates, pumas Glycetate, Glyconate, Glycuronate, Hexafluurophosphate, Hibenzate, Hydrochloride / chloride, Hydrobromide / bromide, Hydroiodide / Yodide, Hydrogen phosphate, Isethionate, D And L-lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen, Phosphate / potassium dihydrogen phosphate, pyroglutamate, saccharide, stearate, succinate, tannate, D- L- tartrate, include 1-hydroxy-2-naphthoate tosylate and benzoate over Four benzoate salt. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trometamine and zinc salts. In addition, hemisalts of acids and bases may be formed, such as hemisulphate and hemicalcium salts.

For suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany, 2002.

Pharmaceutically acceptable salts of the compounds of formula (1) include (i) a method of reacting a compound of formula (1) with a desired acid or base, (ii) removing an acidic or basic labile protecting group from a suitable precursor of the compound of formula (1) Or ring-opening a suitable cyclic precursor such as lactone or lactam with the desired acid or base, (iii) a salt of the compound of formula 1 by reaction with a suitable acid or base or by a suitable ion exchange column Can be prepared by one or more of three methods of converting the salts to other salts.

All three reactions are typically carried out in solution. The resulting salt can be precipitated out of the solvent, collected by filtration or recovered by solvent evaporation. The degree of ionization of the resulting salt may vary from fully ionized to rarely ionized.

The compounds of the present invention may exist in both unsolvated and solvated compound forms. The term "solvent compound" is used herein to describe the stoichiometric amounts of one or more pharmaceutically acceptable solvent molecules, such as ethanol, and molecular complexes comprising a compound of the invention. The term 'hydrate' is used when the solvent is water.

The scope of the present invention includes complexes comprising clathrates, drug-hosts, in which case the drug and host are present in stoichiometric or non-stoichiometric amounts, unlike the solvates described above. Also included are drug complexes that contain two or more organic and / or inorganic components in stoichiometric or non stoichiometric amounts. The resulting complex may be ionized, partially ionized or not ionized. For such complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian, August 1975.

Reference to the compounds of formula (1) below include salts, solvates and complexes thereof, and also references to solvates and complexes of salts thereof.

Compounds of the present invention include polymorphs, crystalline forms, prodrugs and isomers (optical isomers, geometric isomers, tautomers) of the compounds of formula 1 as defined above and of compounds of formula 1 as defined below Isomers), and isotopically labeled compounds of the compound of formula (I).

As mentioned above, “prodrugs” of the compounds of Formula 1 are also within the scope of the present invention. Thus, some derivatives of the compounds of formula (I) with little or no pharmacological activity can be converted into compounds of formula (I) having the desired activity, for example by hydrolytic cleavage, when administered into or on the body. Such derivatives are called "prodrugs". Further information on prodrug use can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series, T. Higuchi and W. Stella and Biersible Carriers in Drug Design, Pergamon Press, 1987, ed. E.B. Roche, American Pharmaceutical Association.

Prodrugs according to the present invention are suitable for use by some of the known functional groups known to those skilled in the art as pro-moiety, for example as described in the Design of Prodrugs, H. Bungaard, Elsevier, 1985. It can be prepared by replacing with a residue.

In some examples of prodrugs according to the present invention (i) when the compound of formula 1 contains a carboxylic acid functional group (-COOH), the ester thereof, such as the hydrogen of the carboxylic acid functional group of the compound of formula 1 is (C ₁ -C ₈ ) alkyl (Ii) when the compound of formula 1 contains an alcohol functional group (-OH), the hydrogen of the ether, such as the alcohol functional group of the compound of formula 1, is replaced by (C ₁ -C ₆ ) alkanoyloxymethyl Compounds, and (iii) when the compound of formula 1 contains a primary or secondary amino functional group (-NH ₂ or -NHR, wherein R is not H), an amide thereof, such as the amino functional group of the compound of formula 1 Included are compounds in which one or two hydrogens of are replaced with (C ₁ -C ₁₀ ) alkanoils.

Further examples of alternative groups and other prodrug forms according to the above examples can be found in the aforementioned references.

In addition, some of the compounds of Formula 1 may act as prodrugs of other compounds of Formula 1.

Also included in the scope of the present invention are metabolites of the compound of formula 1, ie compounds formed in vivo upon drug administration. Some examples of metabolites according to the invention include (i) hydroxymethyl derivatives (-CH _3- > -CH ₂ OH) when the compound of formula 1 contains a methyl group; (ii) when the compound of formula 1 contains an alkoxy group, a hydroxy derivative thereof (-OR->-OH); (iii) where the compound of formula 1 contains a tertiary amino group, a secondary amino derivative thereof (-NR ¹ R ^2- > -NHR ¹ or -NHR ² ); (iv) if the compound of formula 1 contains a secondary amino group, a primary derivative thereof (-NHR ^1- > -NH ₂ ); (v) if the compound of formula 1 contains a phenyl moiety, -Ph-> PhOH) and (vi) When the compound of formula 1 contains an amide group, carboxylic acid derivatives thereof (-CONH _2- > COOH) are included.

Compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Cis / trans (or Z / E) geometric isomers are possible when the compound of formula 1 contains alkenyl or alkenylene groups. Tautomeric isomers ('tautomerization') can occur when the structural isomers are interconvertible by a low energy barrier. It may take the form of proton tautomerism, for example in compounds of formula (I) containing imino, keto or oxime groups, or the so-called valence tautomerism in compounds containing aromatic moieties. A single compound may represent one or more isomeric types.

The scope of the present invention includes all stereoisomers, geometric isomers and tautomeric forms of compounds of Formula 1 and mixtures of one or more thereof, including compounds exhibiting one or more isomeric types. Also included are acid addition or base salts in which the counterion has optical activity, such as racemic compounds such as d -lactate, l -lysine or dl -tartrate or dl -arginine.

Cis / trans isomers may be separated by conventional methods known to those skilled in the art, such as chromatography or fractional crystallization.

Conventional methods for the preparation / separation of each enantiomer include racemic compounds (or racemic compounds of salts or derivatives) using chiral synthesis from optically pure suitable precursors, or using, for example, chiral high pressure liquid chromatography (HPLC). Resolution).

Alternatively, the racemic compound (or racemic precursor) may be reacted with a suitable compound having optical activity, such as an alcohol, or an acid such as tartaric acid or 1-phenylethylamine if the compound of formula 1 has an acidic or basic moiety. Or with a base. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and either or both of the diastereomers can be converted to the corresponding pure enantiomer (s) by methods known to those skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) are hydrocarbons containing 0-50% by volume of isopropanol, typically 0-20% by volume and 0-5% by volume of alkylamine, typically 0.1% diethylamine, Chromatography on asymmetric resins, typically using a mobile phase consisting of heptane or hexane, can be obtained in enantiomeric rich form, typically using HPLC. Concentration of the eluate provides this rich mixture.

Stereoisomeric agglomerates can be separated by conventional methods known to those skilled in the art, see, eg, Stereochemistry of Organic Compounds, E.L.Eliel, Wiley, New York, 1994.

에서 R¹은 수소이고, R²가 C₁-C₄ 알킬, 바람직하게는 메틸이고, n과 Q¹은 전술한 바와 같은 (R,R) 입체이성체가 바람직하다.According to one aspect of the invention,

R ¹ is hydrogen, R ² is C ₁ -C ₄ alkyl, preferably methyl, and n and Q ¹ are the (R, R) stereoisomers as described above.

The present invention relates to pharmaceutically acceptable isotopically labeled pharmaceutically acceptable compounds of Formula 1 wherein one or more atoms have the same atomic number but the atomic mass is replaced by an atom having a mass or mass number different from the atomic mass or mass number It includes both compounds.

Examples of isotopes suitable for inclusion in the compounds of the 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 Cl, fluorine such as ¹⁸ F, iodine Such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorous such as ³² P and sulfur such as ³⁵ S.

Compounds of Formula 1 Labeled with Isotopes Several compounds, such as those containing radioisotopes, are useful in drug and / or matrix tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose because their incorporation is readily and quickly detected.

Substitution with heavier isotopes such as deuterium, ie ² H, may have therapeutic benefits resulting from greater metabolic stability, such as may be desirable in some circumstances as there is a therapeutic benefit of increased half-life in vivo or a decrease in required dose, for example. .

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

Isotopically labeled compounds of formula (I) are generally prepared by conventional methods known to those skilled in the art, or by using appropriate reactants labeled with isotopes instead of previously used unlabeled reactants. It may be prepared by a method similar to that described in.

Solvates are pharmaceutically acceptable according to the present invention is the solvent of crystallization may be isotopically substituted by, for example D ₂ O, d ₆ - acetone, and a, d ₆ -DMSO.

Compounds of formula (1) and their pharmaceutically acceptable salts and / or derivatives thereof are important compounds having pharmacological activity, these are the treatment and prevention of disorders, in particular allergy, in which the β2 receptor is involved or has an effect by the action of the β2 receptor Symptoms that can be helpful for lowering sexual and non-allergic airway diseases, as well as nervous system diseases, premature colic, congestive heart failure, depression, inflammatory skin diseases, allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma, and gastric acidity It is also suitable for the treatment of other diseases, such as but not limited to gastric ulcers and peptic ulcers.

The compounds of the present invention for pharmaceutical use can be administered as crystalline or amorphous products. These can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying and evaporation drying. Microwave or radio frequency drying may be used for this purpose.

The compounds of the invention may be administered alone, in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or in combination with one or more other drugs). In general, the compounds of the present invention are administered in a formulation combined with one or more pharmaceutically acceptable excipients. As used herein, the term "excipient" is used to describe any ingredient that is not a compound (s) of the present invention. The choice of excipient depends greatly on factors such as the specific method of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation are apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, 1995.

The compounds of the present invention can be administered orally. Oral administration may involve swallowing the compound into the gastrointestinal tract, and buccal administration or sublingual administration may include allowing the compound to enter the blood system directly through the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids or powders, lozenges (including those filled with liquid phases), chewing agents, multi- and nano-particulates, gels, solid solutions, liposomes, films , Ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as soft or hard capsule fillers and typically include carriers such as, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents. . Liquid formulations may also be prepared, for example, by reconstitution of a solid from a sachet.

The compounds of the present invention can also be used in fast-soluble, fast disintegrating dosage forms as described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, Liang and Chen, 2001.

In the case of tablet dosage forms the drug may comprise 1 to 80%, more typically 5 to 60% by weight of the dosage form, depending on the dose. In addition to the above drugs, the tablets generally contain tableting substances. Examples of tablet degradants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxy Propyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the decomposables comprise from 1 to 25% by weight, preferably from 5 to 20% by weight of the dosage form.

Binders are generally used to impart adhesion to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural gums, synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxy propyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate This may be included.

In addition, the tablet may optionally include surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. The surfactant, when present, may constitute 0.2-5% by weight of the tablet, and the fluidity increasing agent may constitute 0.2-1% by weight of the tablet.

In addition, tablets generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.25 to 10%, preferably 0.5 to 3% by weight of the tablet.

Other usable ingredients include antioxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain about 80% drug, about 10% to about 90% binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight tablet decomposer and about 0.25% to about 10% by weight lubricant.

Tablet blends may form tablets either directly or by roller compaction. The tablet blend or portion of the blend may be wet-, dry- or melt-granulated, melt solidified or extruded before tableting. The final formulation may comprise one or more layers and may or may not be coated. The final formulation may be encapsulated.

Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets, Vol 1, H. Lieberman and L. Lachman, Marcel Dekker, New York, 1980.

Consumable oral films for use in humans or livestock are typically in the form of flexible, water soluble or water swellable thin films and can be quickly dissolved or mucoadhesive, typically compounds of formula 1, film forming polymers, binders, solvents, humectants , Plasticizers, stabilizers, emulsifiers, viscosity modifiers and solvents. Some components of the formulation may exhibit one or more functions.

The compound of formula 1 may be water soluble or water insoluble. The water soluble compound typically comprises 1 to 80% by weight solute, more typically 20 to 50% by weight. Less water soluble compounds may be included in a larger proportion in the composition, typically up to 88% by weight of the solute. Alternatively, the compound of Formula 1 may be in the form of multiparticulate beads.

The film forming polymer may be selected from the group consisting of natural polysaccharides, proteins, synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically 30 to 80% by weight.

Other usable ingredients include antioxidants, colorants, flavors, flavor enhancers, preservatives, salivary gland promoters, coolants, co-solvents (including oils), emollients, fillers, defoamers, surfactants and taste-removing agents.

Films according to the invention are typically prepared by evaporating to dry a thin aqueous film coated on a peelable support or paper. This can be done in a drying oven or tunnel, typically a combined coating dryer or by lyophilization or vacuum.

Solid dosage forms for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, program release.

Modified release formulations suitable for the purposes of the present invention are disclosed in US Pat. No. 6,106,864. Details of other suitable release methods such as high energy dispersive and osmotic coated particles can be found in Pharmaceutical Technology On-line, 25 (2), 1-14, Verma et al., 2001. The use of chewing gum to carry out controlled release is disclosed in WO 00/35298.

The compounds of the invention may also be administered directly to the bloodstream, muscle or internal organs. Suitable methods for parenteral administration include intravenous administration, intraarterial administration, intraperitoneal administration, intradural administration, intraventricular administration, intraurethral administration, substernal administration, intracranial administration, intramuscular administration and subcutaneous administration. Devices suitable for parenteral administration include injection with a needle (including microneedles), injection without a needle, and injection method.

Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, hydrocarbons, and buffers (preferably at pH 3-9), and in some applications may be formulated with sterile water formulated as sterile non-aqueous solutions or having no pyrogen. It may be more suitable to be formulated in dry form for use with such a suitable vehicle.

Preparation of parenteral formulations under sterile conditions, such as by lyophilization, can be readily accomplished using standard pharmaceutical techniques known to those skilled in the art.

The solubility of the compound of formula 1 used in the preparation of parenteral solutions can be increased by using suitable formulation techniques such as incorporation of solubility enhancers.

Formulations for parenteral administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, program release. Thus, the compounds of the present invention may be formulated as solid, semisolid, or thixotropic liquids for administration as implanted depots that provide modified release of the active compounds. Examples of such formulations include drug coated stents and poly ( dl -lactic-coglycolic) acid (PGLA) microspheres.

In addition, the compounds of the invention may also be administered topically to the skin or mucosal layer, ie through the dermis or transdermal. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and Microemulsions are included. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be included, see, for example, J Pharm Sci, 88 (10), 955-958, Finnin and Morgan, October 1999.

Other methods of topical administration include electroporation, iontophoresis, negative electrophoresis, ultrasound therapy, microneedle injection or needle-free injections (e.g. Powderject®, Bioject®, etc.). Delivery by.

Formulations for topical administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, program release.

Compounds of the invention may be used in pressurized vessels with or without suitable propellants, such as 1,1,1,2-tetrafluuroethane or 1,1,1,2,3,3,3-heptafluuropropane , As an aerosol spray from a pump, spray, nebulizer (preferably an electrohydrator to generate fine vapors) or a nebulizer, or typically in dry powder form (alone, mixed In the form of an anhydrous blend with lactose or as a mixed component particle mixed with phospholipids such as phosphatidylcholine) or intranasally. For intranasal use the powder may comprise a biobinding agent such as chitosan or cyclodextrin.

Pressurized vessels, pumps, sprays, nebulizers or nebulizers are for example ethanol, aqueous ethanol, or other reagents suitable for dispersing, dissolving or sustaining the release of the active ingredient, dispersant (s) as a solvent, and sorbitan trioleate, oleic acid or It contains a solution or suspension of a compound of the invention comprising any surfactant such as oligolactic acid.

Prior to use in anhydrous powder or suspension formulations, the drug product is ground to a size (typically 5 microns or less) suitable for delivery by inhalation. This can be done by any suitable grinding method such as spiral jet milling, fluidized bed jet milling, supersonic fluid processing to produce nano-particles, high pressure homogenization or spray drying.

Cartridges for use in capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), blisters and inhalers or blowers are suitable powder bases, l -classes, such as the compounds of the invention, lactose or starch It may be formulated to contain a powder mix of performance modifiers such as isin, mannitol or magnesium stearate. Lactose may be in anhydrous form or in monohydrate form, preferably in monohydrate form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers using electrohydrodynamics to generate fine vapors may contain between 1 μg and 20 mg of the compound of the invention per actuation, with actuation volumes varying from 1 to 100 μl. Can be. Typical formulations may include a compound of formula 1, propylene glycol, sterile water, ethanol, sodium chloride. Other solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents such as menthol and levomenthol, or sweetening agents such as saccharin or saccharin sodium can be added to the formulations of the invention for inhalation / nasal administration.

Formulations for inhalation / nasal administration may be formulated for immediate release and / or modified release, eg using PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, program release.

For dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Units according to the invention are typically such that a metered dose containing 0.001 mg to 10 mg of the compound of formula 1 is administered or is a single puff. The total daily dose is typically 0.001 mg to 40 mg, which may be administered in a single dose or more generally in several divided doses throughout the day.

The compound of formula 1 is particularly suitable for inhalation administration.

The compounds of the present invention can be administered via the rectum or vagina, for example in the form of suppositories, suppositories or enemas. Cocoa butter is a typical suppository base, but various other materials may be suitably used.

Formulations for rectal / vaginal administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, program release.

The compounds of the present invention may also be administered directly to the eyes or ears, typically in the form of droplets of finely divided suspensions or solutions in isotonic sterile saline adjusted to pH. Other formulations suitable for ocular and ear administration include ointments, biodegradable (e.g. absorbent gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicle systems such as niosomes or liposomes. . Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid; Cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose; Or heteropolysaccharide polymers such as, for example, gelan gum, may be incorporated with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular / ear administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, program release.

The compounds of the present invention are also soluble polymer populations such as cyclodextrins and their suitable derivatives or polyethylene-glycol-containing polymers for improving solubility, dissolution rate, taste-removing, bioavailability and / or stability for use in the methods of administration described above. It can be combined with.

For example, drug-cyclodextrin complexes are known to be generally useful for most dosage forms and routes of administration. Both insert and non-insert complexes can be used. As an alternative to direct complexing with the drug, cyclodextrins can be used as auxiliary additives such as carriers, diluents or solubilizers. Α-, β- and γ-cyclodextrins are most commonly used for this purpose, examples of which can be found in International Patent Applications WO 91/11172, WO 94/02518 and WO 98/55148.

It may be desirable to administer a mixture of active compounds, for example, to treat a particular disease or condition, so that two or more pharmaceutical compositions (one or more of the pharmaceutical compositions contain a compound of the present invention) are suitable for the simultaneous administration of the compositions for convenience. Combinations of forms are within the scope of the present invention.

Thus, the kits of the present invention comprise two or more separate pharmaceutical compositions (one or more pharmaceutical compositions comprising a compound of formula 1 according to the invention) and means for separating and maintaining the composition, such as a container, a separate bottle or a separate Contains a foil packet. An example of such a kit is a conventional blister pack used for the packaging of tablets, capsules.

The kits of the present invention are particularly suitable for different parental forms, such as parenteral administration, for administering separate compositions at different dose times, or for titrating separate compositions against each other. For clarity, the kit generally includes instructions for administration and may have a so-called memory aid.

The total daily dose of a compound of the invention for administration to a human patient is typically from 0.001 to 5000 mg depending on the method of administration. For example, the intravenous daily dose may be only 0.001-40 mg. The total daily dose may be administered in one or divided doses and may, as directed by the physician, fall outside the ranges presented herein.

This dose is based on an average human having a mass of about 65-70 kg. The doctor may determine the dose for a person, such as an infant or elderly, who is out of weight.

For clarity, as used herein, "treatment" is intended to include healing, alleviation and prophylactic treatments.

According to another aspect of the invention, the compound of formula 1, pharmaceutically acceptable salts thereof, derivatives thereof and compositions thereof may be used in combination with one or more additional therapeutic agents to be co-administered to a patient so that (i) bronchial contraction, Specific specific purposes such as the treatment of pathophysiologically related diseases, including, but not limited to, inflammation, (iii) allergies, (iv) tissue destruction, (v) dyspnea, and signs and symptoms such as coughing Enable to get treatment results. In addition, the second and other additional therapeutic agents may be a compound of Formula 1, a pharmaceutically acceptable salt thereof, derivatives thereof and compositions thereof, or one or more β 2 agonists known to those skilled in the art. More typically, the second and other therapeutic agents are selected from different kinds of therapeutic agents.

As used herein in referring to a compound of Formula 1 and one or more other therapeutic agents, the terms "simultaneous administration", "simultaneously administered" and "in combination" are intended to indicate the following, and the dosage also indicates Including, each moiety can be administered via the same or different routes:

Co-administration of the compound (s) and therapeutic agent (s) of Formula 1 to a patient in need thereof, wherein the ingredients are formulated in a single dosage form such that the ingredients are administered to the patient substantially simultaneously; Substantially simultaneous administration of a combination of the compound (s) and therapeutic agent (s) of Formula 1 to a patient in need thereof, wherein the components are formulated separately in separate dosage forms but the components are substantially released simultaneously to the patient When administered to the patient at substantially the same time; Sequential administration of a combination of compound (s) and therapeutic agent (s) of Formula 1 to a patient in need thereof, wherein the components are formulated separately in separate dosage forms and administered sequentially to the patient with a significant time difference between each administration Causing the component to be released to the patient at substantially different times; Sequential administration of a combination of compound (s) and therapeutic agent (s) of Formula 1 to a patient in need thereof, wherein the ingredients are formulated in a single dosage form and the ingredients are released in a controlled manner simultaneously and / or with other Administered together, sequentially and / or in duplicate at time.

Suitable examples of compounds of Formula 1, pharmaceutically acceptable salts thereof, derivatives thereof, and other agents that may be used in combination with the compositions include (a) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygena Azeotropic antagonists (FLAP) antagonists, (b) leukotriene antagonists (LTRA) including LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ antagonists, (c) histamine receptor antagonists, including H1 and H3 antagonists, (d) decongestion use Vasoconstrictive sympathomimetic agonists as α ₁ and α ₂ -adrenergic receptor agonists, (e) muscarinic M3 receptor antagonists or anticholiners, (f) PDE inhibitors such as PDE3, PDE4 and PDE5 inhibitors, (g) Theophylline, (h) sodium chromoglycate, (i) COX inhibitors including both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), (j) oral and inhaled glucocorticosteroids, (k) Single with activity against endogenous inflammatory residues Ron antibody, (l) Anti-tumor necrosis factor (anti -TNF-α) material, (m) (n) adhesion molecule inhibitors including VLA-4 antagonists, kinin -B ₁ - and B ₂ - receptor antagonists, (o ) An immunosuppressant, (p) an inhibitor of matrix metalloprotease (MMP), (q) takininine NK ₁ , NK ₂ and NK ₃ receptor antagonists, (r) elastase inhibitors, (s) adenosine A2a receptor agonists, (t) urokinase inhibitors, (u) compounds acting on dopamine receptors, such as D2 agonists, (v) modulators of the NF _κ β pathway, such as IKK inhibitors, (w) modulators of the cytokine signaling pathway, such as p38 MAP kinases or syk kinases, drugs that may be classified as mucolytic or antitussives, (y) antibiotics, (z) HDAC inhibitors, and (aa) PI3 kinase inhibitors.

According to the invention, the compounds of formula 1 and H3 antagonists, muscarinic M3 receptor antagonists, PDE4 inhibitors, glucocorticoids, adenosine A2a receptor agonists, modulators of cytokine signaling pathways such as p38 MAP kinase or syk kinase, LTB ₄ , LTC ₄ Preferred are combinations with leukotriene antagonists (LTRA), including, LTD ₄ and LTE ₄ antagonists.

According to the invention, the compounds of formula (1) and glucocorticoids, in particular inhaled glucocorticosteroids with reduced systemic side effects such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, butdecoe Naid, fluticasone propionate, ciclesonide and mometasone puroate, or muscarinic M3 receptor antagonists, anticholinergic agents, such as especially the ipratropium salts, ie bromide, tiotropium salts, ie bromide, oxy More preferred are trophium salts, i.e. combinations with bromide, ferrenzepine and tellenepine.

As used herein, “treatment” is understood to include healing, alleviation and prophylactic treatments. The detailed description below relates to the therapeutic use to which the compound of formula 1 can be applied.

Compounds of formula (1) can interact with β2 receptors and have various therapeutic uses, as described below, because of the essential role that β2 receptors play in the physiology of all mammals.

Accordingly, another aspect of the invention relates to a compound of formula 1, pharmaceutically acceptable salts thereof, derivatives thereof and compositions thereof for use in the treatment of diseases, disorders and symptoms involving the β2 receptor. More specifically, the invention also relates to asthma with any form, etiology or pathogenesis, in particular atopic asthma, nonatopic asthma, allergic asthma, atopic bronchial asthma mediated by IgE, bronchial asthma, essential asthma, Intrinsic asthma, endogenous asthma due to pathophysiological disorders, exogenous asthma due to environmental factors, essential asthma due to unknown or unclear causes, non-topical asthma, bronchitis asthma, emphysema, asthma induced by exercise Asthma, allergen-induced asthma, cold-air-induced asthma, occupational asthma, infectious asthma due to bacteria, fungi, worms or viral infections, non-allergic asthma, early asthma, harsh breathing syndrome in infants and Asthma selected from the group consisting of bronchiolitis; Chronic or acute bronchial contraction, chronic bronchitis, small airway obstruction and emphysema; Obstructive or inflammatory airway disease of any form, etiology or pathogenesis, particularly chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated with or without COPD, Obstructive or inflammatory airway disease selected from the group consisting of COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness following other medications, and airway disease associated with pulmonary hypertension; Bronchitis in any form, etiology or pathogenesis, especially acute bronchitis, acute laryngeal bronchitis, arachidous bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthma bronchitis, proliferative bronchitis, staphylococcal bronchitis, streptococcal bronchitis and Bronchitis selected from the group consisting of alveolar bronchitis; Acute lung injury; Bronchiectasis of any form, etiology or pathogenesis, especially bronchiectasis, selected from the group consisting of cylindrical bronchiectasis, pocket-shaped bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis A compound of Formula 1, a pharmaceutically acceptable salt thereof, derivatives thereof and compositions thereof for use in the treatment of diseases, disorders and conditions selected from the group of the present invention.

Another aspect of the invention relates to the use of a compound of formula 1, a pharmaceutically acceptable salt thereof, derivatives thereof and compositions thereof for the manufacture of a drug having β 2 agonist activity. In particular, the present invention relates to compounds of formula 1, pharmaceutically acceptable salts thereof, derivatives thereof in the manufacture of a medicament for the treatment of diseases and / or symptoms mediated by β2, in particular the diseases and / or symptoms described above, and It relates to the use of the composition.

As a result, the present invention provides methods of particular interest for treating mammals, including humans, using an effective amount of a compound of Formula 1, a pharmaceutically acceptable salt thereof, derivatives thereof, and compositions thereof. More specifically, the present invention relates to a mammal including a human having the aforementioned diseases and / or symptoms, comprising administering to the mammal an effective amount of a compound of formula 1, a pharmaceutically acceptable salt thereof and / or a derivative thereof. Provided are methods of particular interest for treating β2-mediated diseases and / or symptoms in animals.

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

Preparation Example 1 (3-ethoxycarbonylmethylphenyl) acetic acid ethyl ester

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, then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (100 ml) and extracted with sodium bicarbonate (3 x 50 ml) and brine (3 x 50 ml). The organic phase was dried (MgSO ₄ ), concentrated in vacuo and the residue triturated with pentane to give the product (11.8 g).

Preparation Example 2 (3-ethoxycarbonylmethylphenyl) acetic acid

Preparation 1 product (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) were added with hydrochloric acid (12M, 4.9 ml). , 58.8 mmol) dropwise. The reaction mixture was stirred at reflux for 18 h, then cooled and concentrated to low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry was filtered. The filtrate was concentrated in vacuo and the residue was taken up in water and basified with sodium bicarbonate until the pH was neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5 x 30 ml) and brine (50 ml). The aqueous extracts were combined and acidified to pH 3 with 6M hydrochloric acid and extracted with diethyl ether (3 × 30 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo. The residue was triturated with pentane to give a colorless solid (10.8 g).

Preparation Example 3: [3- (2-hydroxy-2-methylpropyl) phenyl] acetic acid

Methyl magnesium chloride (51 ml of 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirring solution of Preparation 2 product (11.6 g, 51 mmol) in tetrahydrofuran (300 ml) at 0 ° C. under nitrogen (International Journal of Peptide and Protein Research, 1987, 29 (3), 331). The reaction was allowed to warm to room temperature overnight to form a white thick precipitate which was then carefully added water (50 ml) and 2N hydrochloric acid (80 ml). The aqueous layer was extracted with ethyl acetate (2 x 300 ml) and the combined organic layers were washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to afford the title compound (11.2 g) as a gold oil.

Preparation Example 4: (3- {2-[(chloroacetyl) amino] -2-methylpropyl} phenyl) acetic acid

2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of Preparation 3 product (16.0 g, 70 mmol) in acetic acid (33 ml) and cooled to 0 ° C. The resulting solution was treated with concentrated sulfuric acid (33 ml) and gradually warmed to room temperature. After 4 hours the reaction mixture was poured onto ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2 x 500 ml) and the combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to afford the title product (19.0 g) as a colorless solid.

Preparation Example 5 [3- (2-amino-2-methylpropyl) phenyl] acetic acid methyl ester

A solution of Preparation 4 product (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated under reflux for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethanol (150 ml) and saturated with hydrogen chloride gas and the resulting solution was heated to reflux for 16 h. 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 (MgSO ₄ ) and concentrated in vacuo. The residue was purified by strong cation exchange resin (2M solution of ammonia in methanol and then methanol) to give a yellow oil (2.68 g).

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

A solution of di-tert-butyldicarboxylate (8.19 g, 38.0 mmol) in dichloromethane (40 ml) was prepared in Trichloromethane (60 ml) at 0-5 ° C. with the product of Example 5 (8.4 g, 38.0 mmol) and tri Ethylamine (5.2 ml, 38.0 mmol) was added to the solution. The mixture was allowed to warm up to room temperature and then stirred overnight. The solvent was removed and the residue was treated with sodium carbonate solution and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine (3 × 20 ml) and dried (Na ₂ SO ₄ ). The product was purified by chromatography (0 to 80% ethyl acetate in hexane) to give a colorless oil, which was dissolved in diethyl ether (x 3) and evaporated (10.1 g).

Preparation Example 7 [3- (2-tert-butoxycarbonylamino-2-methylpropyl) phenyl] acetic acid

Preparation Example 6 The product (7.45 g, 23.0 mmol), sodium hydroxide solution (5M, 4.6 ml, 115 mmol), dioxane (30 ml) and water (8 ml) were stirred at room temperature for 18 hours. The solvent was removed, the material was dissolved in water, cooled and acidified to pH 3 with hydrochloric acid (2M). The product was extracted with ethyl acetate (3 x 30 ml) and the organic layer was washed with brine (3 x 30 ml) and dried (Na ₂ SO ₄ ). The resulting oil was dissolved in diethyl ether and evaporated to give a colorless gum (7.0 g).

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

Preparation of 3,4-dichlorobenzylamine (1.30ml, 9.76mmol) Preparation Example 7 Compound (3.00g, 9.76mmol), hydroxybenzotriazole hydrate (1.50g, 9.76mmol), 1- (3-dimethylaminopropyl) To a 3-ethylcarbodiimide hydrochloride (1.87 g, 9.76 mmol) and triethylamine (4,07 ml, 11.2 mmol) solution was added and the resulting solution was stirred at room temperature for 18 hours. The solvent was removed and the crude was placed in ethyl acetate (50 ml) and water (30 ml), sodium carbonate solution (2 x 30 ml), brine (30 ml), hydrochloric acid (0.5 M, 2 x 30 ml) and brine (30 ml) ) And then dried (Na ₂ SO ₄ ). The resulting white solid was triturated with diethyl ether (3.1 g).

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

Prepared using the acid of Preparation Example 7 and using the method described in Preparation Example 8 and 3,4-dimethylbenzylamine.

Preparation Example 10 2- [3- (2-amino-2-methylpropyl) phenyl] -N- (3,4-dichlorobenzyl) acetamide

Preparation 8 Compound (3.0 g, 6.50 mmol) in dioxane (5 ml) was treated with hydrogen chloride (4M in dioxane, 20 ml) and the resulting solution was stirred for 18 h at room temperature. The solvent was removed, the compound was redissolved in methanol (x 2) and evaporated, and the resulting gum was suspended in diethyl ether (x 2) and evaporated to give a white solid having a melting point of 214 to 216 DEG C (methyl acetate-methanol). 2.7 g) was obtained.

Preparation Example 11 2- [3- (2-amino-2-methylpropyl) phenyl] -N- (3,4-dimethylbenzyl) acetamide

It prepared using the amide of Preparation Example 9 and the manufacturing method of Preparation Example 10.

Preparation Example 12 N- {2-benzyloxy-5-[(1R) -2-bromo-1- (tert-butyldimethylsilanyloxy) ethyl] phenyl} formamide

N- [2-benzyloxy-5- (2-bromo-1-hydroxyethyl) phenyl] formamide in N, N-dimethylformamide (25 ml) (Organic Process Research and Development 1998, 2, 96 Tert-butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol) and 4- (dimethylamino) pyridine (4.12 g, 11.8 mmol) under nitrogen at room temperature in a solution. 40 mg, 33 μmol) was added. The resulting solution was stirred overnight at room temperature, the solvent was removed and the product was taken up in ethyl acetate (70 ml). The organics were washed with water (100 ml) and the aqueous extracted with ethyl acetate (20 ml). The combined organics were washed with hydrochloric acid (2M, 50ml), brine (100ml) and dried (MgSO ₄ ). The crude material was purified by chromatography (5-25% ethyl acetate in pentane) to give a colorless oil (5.7 g).

Preparation Example 13: 2- (3- {2-[(2R) -2- (4-benzyloxy-3-formylaminophenyl) -2- (tert-butyl-dimethylsilaneyloxy) ethylamino] -2 -Methylpropyl} phenyl) -N- (3,4-dichlorobenzyl) acetamide

Preparation 12 Compound (500 mg, 1.08 mmol) and Preparation Example 10 compound (780 mg, 216 mmol) were heated and stirred at 90 ° C. for 24 hours. After cooling the material was dissolved in methanol and evaporated, the material was suspended in diethyl ether and the precipitate was filtered off. After evaporation of the filtrate the material was purified by chromatography (0-5% methanol in dichloromethane), suspended in diethylether (x 3) and evaporated to give a foam (425 mg).

Preparation Example 14 2- (3- {2-[(2R) -2- (4-benzyloxy-3-formylaminophenyl) -2- (tert-butyl- dimethylsilaneyloxy) ethylamino]- 2-methylpropyl} phenyl) -N- (3,4-dimethylbenzyl) acetamide

It was prepared using the amide in Preparation Example 13, the bromide in Preparation Example 12, and the method described in Preparation Example 11.

Preparation Example 15 N-benzyl-2- (3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino ] -2-methylpropyl} phenyl) acetamide

Preparation 13 compound (100 mg, 134 μmol) and palladium on carbon (10%, 20 mg) in methanol (10 ml) were hydrogenated at 50 psi / room temperature for 6 hours. The mixture was filtered through a filter aid and the solvent was removed. The material was suspended in sodium hydrogen carbonate solution and extracted with ethyl acetate (30 ml). The organic layer was washed with sodium bicarbonate solution, brine (2 x ml) and dried (Na ₂ SO ₄ ). The resulting material was suspended in diethyl ether (x 3) and evaporated to give a film (24 mg).

Preparation Example 16: 2- (3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] -2- Methylpropyl} phenyl) -N- (3,4-dimethylbenzyl) acetamide

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

Preparation Example 17 Methyl (3-bromophenyl) Acetate

Acetyl chloride (0.7 ml, 9.3 mmol) was added slowly to a solution of (3-bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0 ° C. nitrogen and the reaction was gradually warmed to room temperature for 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 afford the title compound (20.6 g) as a colorless oil.

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

Tributyltin methoxide (28.3 ml, 98 mmol), product of Preparation 17 (15.0 g, 65 mmol), isopropenyl acetate (10.8 ml, 98 mmol), palladium (II) acetate (750 mg, 3.30 mmol) and tri- Ortho-tolylphosphine (2.0 g, 6.5 mmol) was stirred in toluene (75 ml) at 100 ° C. for 5 hours. After cooling the reaction was diluted with ethyl acetate (150 ml) and 4M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered over Arbocel® and the organic phase was separated and concentrated in vacuo. The residue was then purified by column chromatography on silica gel eluting with diethyl ether: pentane from 0: 100 to 25:75 and then with dichloromethane to give the title compound as a pale yellow oil in 94% yield (12.6). g).

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

Product of Preparation 18 (8.5 g, 41.2 mmol), (R) -α-methylbenzylamine (4.8 ml, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) in dichloromethane (400 ml) And an acetic acid (2.2 ml, 38 mmol) solution was stirred for 48 h at room temperature. Saturated sodium hydrogen carbonate solution (200 ml) was added to quench the reaction mixture and stirred until boiling stopped. The aqueous phase was separated and extracted with dichloromethane (100 ml). The combined organic solutions were then dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting dichloromethane: methanol: ammonia from 99: 1: 0.1 to 95: 5: 0.5 yielded a 4: 1 mixture of diastereomers (given R, R) as pale yellow oil ( 8.71 g). Treatment with hydrogen chloride (40 ml of a 1M solution in methanol, 40 mmol) followed by three successive crystallizations (diisopropylether / methanol) gave the title compound as a white crystalline solid in 50% yield (5.68 g).

Preparation Example 20 Methyl {3-[(2R) -2-aminopropyl] phenyl} acetate

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

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

Using a method similar to the preparation of Preparation 6, the title compound of the yellow oil was obtained from the product of Preparation 20 and di-tertbutyl dicarboxylate in 97% yield.

Preparation Example 22: (3-{(2r) -2-[(tert-butoxycarbonyl) amino] propyl} phenyl) acetic acid

A mixture of Preparation 21 compound (8.31 g, 27.1 mmol) and lithium hydroxide solution (1M 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 was acidified to pH 2 with 2M hydrochloric acid. The mixture was then extracted with ethyl acetate (3 x 75 ml), the combined organic solutions washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound of the yellow oil in 82% yield (6.50 g). Obtained.

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

Preparation 22 Product (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) were stirred in dichloromethane (100 ml) at room temperature for 10 minutes. Benzyl alcohol (2.2 ml, 21.5 mmol) was added and the mixture was stirred at rt for 18 h. 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). Obtained).

Preparation Example 24 Benzyl {3-[(2R) -2-aminopropyl] phenyl} acetate

Hydrogen chloride (4M in dioxane, 5.43 ml, 21.72 mmol) was added to a solution of Preparation 23 product (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 dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow oil in 93% yield (2.85 g).

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

From the Preparation 12 product and Preparation 24 product, the title compound of brown oil was prepared in 25% yield using a method analogous to the preparation method of Preparation 13.

LRMS APCI m / z 667 [M + H] ⁺

Preparation Example 26 {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxy Phenyl] ethyl} amino) propyl] phenyl} acetic acid

Preparation 25 product (851 mg, 1.27 mmol) and 10% Pd / C (50 mg) were suspended in methanol and the mixture was stirred for 72 h at room temperature under 60 psi of hydrogen gas. The reaction mixture was then filtered on a Filter aid® and the filtrate was concentrated in vacuo to yield the title compound in brown foam in 94% yield (580 mg).

Preparation Example 27 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4- Hydroxyphenyl] ethyl} amino) propyl] phenyl} -N- [4- (dimethylamino) benzyl] acetamide

Preparation 26 product (100 mg, 206 μmol), hydroxybenzotriazole hydrate (32 mg, 206 μmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydro in N, N-dimethylformamide (2 ml) A mixture of chloride (40 mg, 206 μmol) and triethylamine (58 μl, 412 μmol) was stirred at room temperature for 10 minutes. Then 4- (dimethylamino) benzylamine (31 mg, 206 μmol) was added and the mixture was stirred at rt for 20 h. The solvent is then removed in vacuo, the residue is diluted with dichloromethane, washed with sodium bicarbonate solution (20 ml) and brine (20 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a brown gum. Was obtained in 10% yield (131 mg).

Preparation Examples 28 and 29:

A compound having the formula shown below was prepared from Preparation 26 product and a suitable amine using a method analogous to that described in Preparation 27. The reaction was observed by TLC analysis and stirred for 18-72 hours at room temperature.

Preparation Example 28 N- [4- (aminomethyl) phenyl] acetamide is described in J. Med. Chem. 46, 3116, 2003].

Preparation 29: 4- (aminomethyl) benzamide was prepared as described in WO02085860, p239.

Preparation Example 30 [3-((2R) -2-{[(1R) -1-phenylethyl] amino} propyl) phenyl] acetic acid

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

Preparation Example 31 N-1-adamantyl-2- [3-((2R) -2-{[(1R) -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 Preparation 30 product (10.7 g, 36.0 mmol) in dichloromethane (200 ml). Then 2-chloro-1,3-dimethylimidazolidinium hexaflourourophosphate (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. Dichloromethane: methanol: 0.88 ammonia was eluted at 95: 5: 0.5 and the residue was purified by column chromatography on silica gel to give the product in foam form in quantitative yield (17.6 g).

Preparation Example 32 N-1-adamantyl-2- {3-[(2R) -2-aminopropyl] phenyl} acetamide

Using the method analogous to the preparation in Preparation 20, the title compound was obtained in 92% yield from the Preparation 31 product.

Preparation Example 33 2- (3-{(2R) -2-[((2R) -2- [3- (acetylamino) -4- (benzyloxy) phenyl] -2-{[tert-butyl (dimethyl ) Ylyl] oxy} ethyl) amino] propyl} phenyl) -N-1-adamantylacetamide

A mixture of Preparation 12 product (696 mg, 1.5 mmol) and Preparation 32 product (978 mg, 3.0 mmol) in dichloromethane (0.5 ml) was heated at 90 ° C. for 5 minutes to evaporate dichloromethane. The reaction mixture was heated to melt at 90 ° C. for 18 h and cooled to room temperature. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia at 98: 2: 0.2 to give the title compound in pale foam form in 59% yield (630 mg).

Preparation Example 34 N-adamantan-1-yl-2- (3- {2-[(2R) -2-({(2R) -2- (tert-butyldimethylsilanyloxy) -2- (2) 3-formylamino-4-hydroxyphenyl) ethylamino] propyl} phenyl) acetamide

Using the method analogous to the preparation method of Preparation 20, the title compound was obtained in quantitative yield from 33 products in the preparation.

Preparation 35: 1- (3-bromophenyl) -2-methylpropan-2-ol

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

Preparation Example 36 N- [2- (3-bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide

Chloroacetonitrile (6.63 ml, 105 mmol) was added to the stirring solution of Preparation 35 product (12.0 g, 52.0 mmol) in acetic acid (25 ml) at room temperature. The resulting solution was cooled to 0 ° C. and concentrated sulfuric acid (25 ml) was added while keeping the temperature below 10 ° C. The resulting solution was stirred for 1 hour, poured onto ice and basified by addition of solid potassium carbonate. The product was extracted with ethyl acetate (2 x 500 ml) and the combined organic solutions washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to yield the title compound as an orange solid in quantitative yield (16.08 g).

Preparation Example 37 2- (3-Bromophenyl) -1,1-dimethylethylamine

The solution of Preparation 36 product (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was heated to reflux overnight. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo, basified with sodium hydroxide aqueous solution (1M, 450 ml) and extracted with dichloromethane (2 × 500 ml). The combined organic solutions were 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).

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

Preparation 37 The product (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 solutions were dried over sodium sulphate and concentrated in vacuo. The crude material was purified using a cation exchange column (using methanol and 2M ammonia in methanol), eluting dichloromethane and purified by flash column chromatography on silica gel to give the title compound as a brown oil in quantitative yield (7.23 g). Obtained.

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

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

Preparation 40 Benzyl 3- (2-amino-2-methylpropyl) benzoate hydrochloride

Using the preparation method similar to the preparation method of Preparation 24, the title compound was obtained in 91% yield from the Preparation Example 39 product.

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

A mixture of Preparation 40 product (1.81 g, 6.38 mmol), Preparation 12 product (2.96 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) in dimethyl sulfoxide (10 ml) was heated at 95 ° C. for 40 hours. It was. The cooled reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic solutions were washed with sodium hydrogen carbonate solution (50 ml) and brine (2 x 50 ml), dried over sodium sulphate and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel eluting with 50:50 dichloromethane: hexanes, then from 100: 0 to 98: 2 dichloromethane: methanol. The appropriate aliquot was evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel eluting with dichloromethane: methanol from 100: 0 to 98: 2 to give a yellow gum. The gum was azeotropic with diethyl ether (x 3) to give the title compound as a yellow gum in 20% yield (0.83 g).

Preparation Example 42 3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino ) -2-methylpropyl] benzoic acid

The title compound was prepared from the Preparation 41 product using a method similar to the preparation of Example 26. The crude product was azeotropic with diethyl ether (x 3) to give the title compound as a pale yellow solid in 97% yield.

Preparation Example 43: (4-hydroxy-2,5-dimethylphenyl) acetonitrile

The (4-methoxy-2,5-dimethylphenyl) acetonitrile (0.5 g, 2.9 mmol) solution in dichloromethane (10 ml) was cooled to -80 ° C and borontribromide (1M in dichloromethane, 14.3 ml) , 14.3 mmol). The reaction mixture was further stirred at −80 ° C. for 30 minutes and warmed 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. Purification by column chromatography on silica gel eluting with 20:80 to 33:67 ethyl acetate: pentane afforded the title compound as a colorless solid (0.28 g) in 60% dispersion yield in mineral oil.

Preparation Example 44 (4-hydroxy-2,3-dimethylphenyl) acetonitrile

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

Preparation Example 45 (4-hydroxy-3-methylphenyl) acetonitrile

A pale yellow solid title compound was prepared from (4-methoxy-3-methylphenyl) acetonitrile using a method similar to the preparation method of Preparation Example 43.

Preparation Example 46 4- (2-aminoethyl) -2,5-dimethylphenol

A solution of Preparation 43 product (0.28 g, 1.74 mmol) in ethanol (15 mL) was hydrogenated at 60 psi on Raney Nickel® (0.1 g, 50% w / w) for 16 hours. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified using methanol followed by cation exchange resin eluting with 1M ammonia in methanol to afford the title compound as a colorless oil.

Preparation 47: 4- (2-Amino-ethyl) -2,3-dimethyl-phenol

Using the same method as in Preparation 46, the title compound as a colorless solid was prepared in 95% yield from the Preparation 44 product.

Preparation Example 48 4- (2-aminoethyl) -2-methylphenol

The title compound as a colorless oil was prepared from the product of Preparation 45 using a method similar to the preparation of Preparation 46.

Preparation 49: tert-butyl (3-iodobenzyl) carbamate

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

Preparation 50: tert-butyl [(4'-hydroxybiphenyl-3-yl) methyl] carbamate

Preparation 49 product (0.75 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.62 g, 4.50 mmol) and 1,1′-bis (diphenylphosphino) in N, N-dimethylformamide (14 ml) The ferrocenyl palladium (II) chloride (0.11 g, 0.14 mmol) solution was treated with 2M aqueous sodium carbonate solution (4 ml) and the resulting mixture was heated at 80 ° C. for 16 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 25:75 ethyl acetate: pentane to afford the title compound as a pale pink crystalline solid in quantitative yield (0.73 g).

Preparation 51: 3 '-(aminomethyl) biphenyl-4-ol hydrochloride

Preparation 50 The product (0.73 g, 2.43 mmol) was treated with 4M hydrochloric acid (6.1 ml, 24.3 mmol) in dioxane and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to afford the title compound as a colorless solid.

Preparation 52: 2-hydroxy-1-naphtamide

2-hydroxy-1-naphthoic acid (5.0 g, 26.6 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol) in tetrahydrofuran (70 ml) and The solution of 1-hydroxybenzotriazole (3.95 g, 29.2 mmol) was stirred at room temperature for 30 minutes and then 0.88 ammonia (6 ml) was added. The resulting suspension was stirred for 2 hours at room temperature. The reaction mixture was filtered and the filtrate was diluted with water (80 ml) and extracted with ethyl acetate (4 x 80 ml). The combined organic extracts were washed with water (2 x 50 ml) and brine (50 ml), dried over sodium sulfate and concentrated in vacuo to afford an orange oil. The oil was purified by column chromatography on silica gel eluting with 95: 5: 0.5 dichloromethane: methanol: 0.880 ammonia to give the title compound as a pink solid in 37% yield (1.83 g).

Preparation Example 53 3,5-dichloro-N-ethyl-2-hydroxybenzamide

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

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

Borane solution in tetrahydrofuran (1M 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). The resulting solution was heated to reflux for 16 h. The reaction mixture was cooled to room temperature, treated with 6N hydrochloric acid (20 ml) and heated an additional 30 minutes under reflux. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified using strong cation exchange resin eluting with methanol and then 2M ammonia in methanol to give an orange oil. The oil was treated with 1M hydrogen chloride (20 ml) in methanol and the reaction mixture was concentrated in vacuo to give the title compound as a pale yellow solid in quantitative yield (1.12 g).

Preparation 55: 2- (aminomethyl) -4-chlorophenol hydrochloride

The title compound was prepared from 5-chloro-2-hydroxybenzonitrile using a method similar to the preparation method of Preparation Example 54.

Preparation 56: 4 '-(aminomethyl) biphenyl-4-ol hydrochloride

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

Preparation Example 57 1- (aminomethyl) -2-naphthol

Borane solution in tetrahydrofuran (19.23 ml, 19.23 mmol in 1M solution) was added dropwise to a solution of amide (0.90 g, 4.81 mmol) in Preparation 52 in tetrahydrofuran (10 ml) and the reaction was heated at reflux for 2 hours. . The solution was cooled, treated with 6M hydrochloric acid (10 ml) and heated under reflux for another 2 hours. The resulting suspension was cooled to room temperature and the pH was adjusted to pH 9 by addition of 0.88 ammonia and extracted with ethyl acetate (3 x 50 ml). The combined organic solutions were washed with brine (20 ml), dried over sodium sulphate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia from 95: 5: 0.5 to 90: 10: 1 gave the title compound as a pink solid in 23% yield (0.19 g). .

Preparation 58: 2,4-dichloro-6-[(ethylamino) methyl] phenol

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

Preparation Examples 59-68

Compounds having the formulas were prepared from Preparation 42 products and appropriate amines using methods analogous to those described in Preparation 27. The reaction was observed by TLC analysis and stirred for 18-72 hours at room temperature.

Preparation Example 60 : Elution with dichloromethane: methanol: 0.88 ammonia of 96: 4: 0.3 was purified by column chromatography using a 12g Redisep® cartridge.

Preparation 62 : Further azeotroping with diethyl ether (x 3) afforded the desired product.

Preparation 68 : 6- (aminomethyl) -2-naphthalenol was prepared as described on page 19 of US20040204455.

Preparation 69: 3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino ) -2-methylpropyl] -N- [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide

4- (2-amino-1,1-dimethylethyl) phenol hydrochloride ( Acta Chem. Scand. 8, 1203, 1207; 1954) (41 mg, 0.21 mmol) was prepared in N, N-dimethylformamide (3 ml) Example 42 Product (100 mg, 0.21 mmol), O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexaflourophosphate (78 mg, 0.21 mmol) and tree To a mixture of ethylamine (35 μl, 0.4 mmol) was added and the mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution (3 x 20 ml) and brine (3 x 20 ml). The organic solution was dried over sodium sulfate and concentrated in vacuo to give the title compound as a brown foam in 54% yield.

LRMS ACPI m / z 634 [M + H] ⁺

Preparation Examples 70-76

Compounds having the formulas were prepared from Preparation 42 products and appropriate amines using methods analogous to those described in Preparation 69. The reaction was observed by TLC analysis and stirred for 18-72 hours at room temperature.

Preparation Example 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 for 16 hours. Heated. The reaction was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between saturated aqueous sodium hydrogen carbonate solution (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 yield the title compound as a pale yellow oil in quantitative yield (63.5 g).

Preparation Example 78 [3- (2-oxo-propyl) -phenyl] acetic acid ethyl ester

A solution of diester (44.3 g, 177 mmol) and 2,2 '-(1,3-phenylene) diacetic acid (59.2 g, 308 mmol) from Preparation 77 in ethanol (24 ml) and dioxane (290 ml) was added 12 M. Treated dropwise with 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 diluted with toluene (125 ml) and the resulting slurry was filtered. The filtrate was concentrated in vacuo and the residue was taken up in water and basified with sodium bicarbonate until the pH was neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5 x 30 ml) and brine (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethyl ether (3 × 30 ml). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with pentane to afford 27% yield of 10.8 g of a colorless solid of the title compound.

Preparation Example 79 [3- (2-hydroxy-2-methyl-propyl) -phenyl] acetic acid

Methyl magnesium chloride (51 ml of a 3M solution in tetrahydrofuran, 153 mmol) in Preparation 78 product (11.6 g, 51 mmol) in tetrahydrofuran (300 ml) at 0 ° C. (International Journal of Peptide and Protein Research, 1987, 29 ( 3), 331) was added dropwise to the stirring solution. The reaction was allowed to warm to room temperature overnight to form a thick white precipitate and carefully added water (50 ml) and 2N hydrochloric acid (80 ml). The aqueous layer was separated and extracted with ethyl acetate (2 x 300 ml). The combined organic solutions were washed with brine (50 ml), dried over sodium sulphate and concentrated in vacuo to afford 11.2 g of the title compound as a gold oil in quantitative yield.

Preparation 80: {3- [2- (2-Chloro-acetylamino) -2-methyl-propyl) -phenyl} acetic acid

2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of Preparation 79 product (16.0 g, 70 mmol) in acetic acid (33 ml). The resulting solution was cooled to 0 ° C. and treated with concentrated sulfuric acid (33 ml) and the reaction mixture was gradually warmed to room temperature. After 4 hours the reaction mixture was poured onto ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2 x 500 ml) and the combined organic solution extracts were dried over magnesium sulfate and concentrated in vacuo to give the title product as a colorless solid in 96% yield, 19.0 g.

Preparation Example 81 [3- (2-amino-2-methyl-propyl) -phenyl] acetic acid methyl ester

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

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

The title compound was prepared from the product of Preparation 81 using a preparation method similar to in Preparation 49 to give the title compound as a colorless oil in 81% yield.

Preparation Example 83: (3- {2-[(tert-butoxycarbonyl) amino] -2-methylpropyl} phenyl) acetic acid

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

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 of Preparation 83 (5.7 g, 18.6 mmol) in N, N-dimethylformamide (40 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in N, N-dimethylformamide (80 ml), treated with benzylbromide (3.18 g, 18.6 mmol) and stirred at rt for 3 h. The mixture was filtered, concentrated in vacuo, the residue dissolved in ethyl acetate (60 ml), washed with brine (60 ml), dried over magnesium sulfate and concentrated in vacuo to give 5.6 g of the title compound as a pale yellow oil in 76% yield. It was.

Preparation Example 85 Benzyl [3- (2-amino-2-methylpropyl) phenyl] acetate

Trifluoroacetic acid (30 ml) was added to the product of Preparation 84 (5.6 g, 14.1 mmol) and the mixture was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with dichloromethane (100 ml) and basified with saturated sodium hydrogen carbonate solution (300 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a yellow oil in 76% yield.

Preparation 86: benzyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (formylamino) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy) } Ethyl) amino] -2-methylpropyl} phenyl) acetate

Using the same preparation method as in Preparation 13, the title compound was obtained in 55% yield from the product of Preparation 12 and the product of Preparation 85.

Preparation 87: {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} Amino) -2-methylpropyl] phenyl} acetic acid

Using the preparation method similar to Preparation 26, the title compound was obtained in 93% yield from the product of Preparation 86.

Preparation Example 88 2-Chloro-N-ethyl-5-hydroxybenzamide

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

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

The title compound was prepared as a colorless solid from the product of Preparation 88 using the method of Preparation 57.

Preparation 90: 4-{[tert-butyl (dimethyl) silyl] oxy} -2-chlorobenzaldehyde

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) in N, N-dimethylformamide (40 ml) ) And N, N-dimethylaminopyridine (10 mg) solution were 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 was separated, washed with brine (50 ml), dried over sodium sulphate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with pentane: ethyl acetate of 75:25 to 67:33 gave 6.50 g of the title compound as a colorless oil in 75% yield.

Preparation 91: N- (4-{[tert-butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) prop-2-en-1-amine

The solution of aldehyde (6.50g, 24.0mmol) and allylamine (1.51g, 26.4mmol) of Preparation Example 90 in dichloromethane (60ml) was treated with sodium triacetoxyborohydride (7.6g, 35.6mmol). The suspension was stirred at rt for 16 h. 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 yield a yellow oil. Purification of the oil by column chromatography on silica gel eluting with pentane: ethyl acetate of 75:25 to 67:33 gave 2.80 g of the title compound as a colorless oil in 38% yield.

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

Preparation of Product 91 (2.8 g, 9.0 mmol), dimethylbarbituric acid (7.0 g, 45 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.08 mmol) in dichloromethane (80 ml) The solution was heated at reflux for 4 h. The cooled solution was 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 from 98: 2: 0 to 95: 5: 0.5 to give 1.70 g of the title compound as a colorless oil in 70% yield.

Preparation Examples 93-95

The compound having the following formula was prepared from the product of Preparation 87 and the appropriate amine using a method similar to that described in Preparation 27. The reaction was observed by TLC analysis and stirred for 18-72 hours at room temperature.

Preparation Example 96: 2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] Ethyl} amino) -2-methylpropyl] phenyl} -N- (2-chloro-4-hydroxy benzyl) acetamide

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

Preparation Example 97 2- (3-Bromophenyl) -N- (3,4-dimethylbenzyl) acetamide

Using a method similar to the preparation of Preparation 27, the title compound was obtained in 93% yield from 3,4-dimethylbenzylamine and 3-bromophenylacetic acid.

Preparation Example 98 N- (3,4-dimethylbenzyl) -2- {3-[(E) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl ) Vinyl] phenyl} acetamide

Product of Preparation 97 (5.0 g, 15 mmol), N-vinylphthalimide (2.62 g, 15.1 mmol) in acetonitrile (35 ml), tri-ortho-tolylphosphine (473 mg, 1.55 mmol), palladium (II) Acetate (98 mg, 0.4 mmol) and N, N-diisopropylethylamine (30 ml, 172 mmol) were heated at reflux for 16 h. The reaction mixture was cooled to room temperature and the precipitate was filtered off. The solid was dissolved in dichloromethane, activated charcoal was added and the solution was filtered through Celite®. The filtrate was concentrated in vacuo and the residue was recrystallized from hot dichloromethane / methanol to give 3.5 g of the title compound as a yellow solid in 55% yield.

Preparation Example 99 N- (3,4-dimethylbenzyl) -2- {3- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] phenyl Acetamide

The product of Preparation 98 (3.3 g, 7.7 mmol) and 10% palladium on carbon (1 g) were suspended in ethanol and the mixture was stirred for 16 h at room temperature under 50 psi of hydrogen gas. The reaction mixture was filtered through Avocel® and washed thoroughly with ethanol and the filtrate was concentrated in vacuo to give 1.7 g of the title product as a yellow solid in 52% yield.

Preparation Example 100 2- [3- (2-aminoethyl) phenyl] -N- (3,4-dimethylbenzyl) acetamide

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

Preparation Example 101 2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (formylamino) phenyl] -2-{[tert-butyl (dimethyl) silyl] Oxy} ethyl) amino] ethyl} phenyl) -N- (3,4-dimethylbenzyl) acetamide

Using the method similar to the preparation of Preparation 33, the title compound of yellow oil was obtained from the products of Preparation 12 and Preparation 100 in 37% yield.

Preparation Example 102: 2- {3- [2-({(2R) -2-{[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] Ethyl} amino) ethyl] phenyl} -N- (3,4-dimethylbenzyl) acetamide

Using a method similar to that of Preparation Example 20, the title compound of the white foam was obtained in 83% yield from the product of Preparation 101.

Preparation Examples 103-110

The compound having the following formula was prepared from the product of Preparation 87 and the appropriate amine using a method similar to that described in Preparation 27. The reaction was observed by TLC analysis and stirred for 18-72 hours at room temperature.

Preparation Examples 111-119

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (40 mg, 205 μmol) in dichloromethane (2 mL) Preparation 42 product (100 mg, 206 μmol), hydroxybenzotriazole hydrate (32 mg, 205 μmol) and triethylamine (0.55 μL, 412 μmol) were added, amine (205 μmol) was added and the mixture was stirred at room temperature for 18 hours. The solvent is removed in vacuo, the residue is diluted with ethyl acetate, washed with sodium bicarbonate solution (20 ml) and brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to form a film, followed by diethyl ether Suspension at (x 3) gave a foam.

* Means no evaporation from diethyl ether.

Preparation Example 122 N- {5-[(2R) -2- {2- [3- (10-Aza-tricyclo [6.3.1.0 ^* 2,7 ^* ] Dodeca-2 (7), 3,5-triene-10-carbonyl) phenyl] -1,1-dimethylethylamino} -1- (tert-butyldimethylsilanyloxy) ethyl] -2-hydro Oxyphenyl} formamide

The title compound was prepared using 10-aza-tricyclo [6.3.1.0 ^* 2,7 ^* ] dodeca-2 (7), 3,5-triene in a similar manner to the preparation method of Preparation 69.

LRMS APCI m / z 628 [M + H] ⁺

Preparation Example 123: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] -2-methylpropyl} -N- [2- (5-chloro-2-hydroxyphenyl) ethyl] benzamide

The title compound was prepared using 2- (2-aminoethyl) -4-chlorophenol in a similar manner to the preparation method of Preparation Example 69.

LRMS APCI m / z 640 [M + H] ⁺

Preparation Examples 124-128

Preparation 42 product (200 mg, 412 μmol), hydroxybenzotriazole hydrate (63 mg, 412 μmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79 mg, in dichloromethane (2 ml) 412 μmol) was added to a mixture of 412 μmol) and triethylamine (0.11 ml, 824 μmol), and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, the residue was diluted with ethyl acetate and washed with sodium bicarbonate solution (3 x 20 ml) and brine (3 x 20 ml) and dried (MgSO ₄ ). The crude material was purified by chromatography on silica gel eluting with 99.7: 0.3 dichloromethane: 0.88 ammonia. Appropriate aliquots were evaporated under reduced pressure, the residue was concentrated in vacuo, and the resulting white foam suspended in diethyl ether (x 3) and evaporated.

Preparation Example 129 3- (2-oxo-propyl) 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 (II) acetate (2.6 g, 11.6 mmol) And tri-ortho-tolylphosphine (7.1 g, 23.2 mmol) were stirred in toluene (350 ml) at 100 ° C. under nitrogen for 18 h. After cooling the reaction was treated with potassium fluoride solution (4M, 560 ml) and stirred for 2 hours. The resulting mixture was diluted with additional toluene (200 ml), filtered through Celite® and the filter pad was washed with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatography eluting with ethyl acetate: pentane from 10:90 to 20:80 to give the title compound (45.3 g) as an orange oil.

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

In the same manner as in Preparation 19, the title compound was prepared using the Preparation 129 product to give the title compound (27.3 g) as a colorless crystalline solid.

Preparation Example 131 Methyl {3-[(2R) -2-aminopropyl] phenyl} acetate

In the same manner as in Preparation 20, the title compound was prepared using the Preparation 130 product to give the title compound (8.48 g) as a pale yellow oil.

Preparation Example 132 3-((2R) -2-tert-butoxycarbonylaminopropyl) benzoic acid methyl ester

Preparative Example 131 A mixture of the product (5.00 g, 26.0 mmol), di-tert-butyldicarboxylate (6.22 g, 28.5 mmol) and sodium bicarbonate (4.35 g, 52 mmol) was prepared using 1,4-dioxane (100 ml) and Stir for 20 hours in a mixture of water (10 ml). The solvent was removed and the material was partitioned between ethyl acetate (200 ml) and hydrochloric acid (2M, 100 ml) and the organics washed with brine (100 ml) and dried (MgSO ₄ ). Removal of solvent gave a white solid (7.12 g, 93%).

Preparation Example 133 3-((2R) -2-tert-butoxycarbonylaminopropyl) benzoic acid

A mixture of Preparation 132 product (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 h. The reaction mixture was diluted with ethyl acetate (250 ml) and acidified to pH 2 with hydrochloric acid (2M). The aqueous phase was reextracted with ethyl acetate (150 ml) and the combined organics were washed with brine (300 ml) and dried (MgSO ₄ ). Filtration and removal of solvent gave 5.53 g (82%) of the title compound.

Preparation Example 134 3-((2R) -2-tert-butoxycarbonylaminopropyl) benzoic acid benzyl ester

Cesium carbonate (6.50 g, 19.8 mmol) in water (10 ml) was added to a solution of Preparation 133 product (5.50 g, 19.8 mmol) in N, N-dimethylformamide (50 ml), and the resulting mixture was allowed to stand at room temperature for 1 hour. Stirred at. Benzyl bromide (3.42 g, 19.8 mmol) was added and the mixture was stirred for 20 hours. Ethyl acetate (50 ml) was added and the suspension was filtered and the filtrate was washed with saturated brine (100 ml) and dried (MgSO ₄ ). Filtration and solvent removal gave 7.20 g of the title compound.

Preparation Example 135 3-((2R) -2-aminopropyl) benzoic acid benzyl ester

Preparation 134 product (7.20 g, 19.0 mmol) was treated with trifluoroacetic acid (35 ml) and the mixture was stirred for 20 h. Trifluoroacetic acid was removed in vacuo and dichloromethane (175 ml) was added. The mixture was basified with saturated sodium hydrogen carbonate (150 ml) and washed with sodium hydroxide (1M, 50 ml). The combined organics were washed with brine (150 ml) and dried (MgSO ₄ ) to give a brown oil (3.70 g, 72%).

Preparation Example 136: 3-{(2R) -2-[(2R) -2- (4-benzyloxy-3-formylaminophenyl) -2- (tert-butyldimethylsilanyloxy) ethylamino] propyl} Benzoic acid benzyl ester

The product of Preparation Example 135 (3.70 g, 13.8 mmol) and the product of Preparation Example 12 (3.20 g, 6.9 mmol) were heated to 90 ° C. for 26 hours. The mixture was cooled and diluted with dichloromethane (100 ml). The organics were washed with saturated sodium hydrogen carbonate (200 ml) and concentrated in vacuo. The crude material was purified by chromatography (x 2) eluting with 0: 100 to 40:60 ethyl acetate: heptane to give 2.0 g (52%) of the title compound.

LRMS APCI m / z 270 [M + H] ⁺

Preparation Example 137 3-{(2R) -2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] propyl} Benzoic acid

Preparative Example 136 product (2.0 g, 3.1 mmol) and palladium on carbon (10%, 205 mg) in methanol (100 ml) were hydrogenated at 60 psi / room temperature for 20 hours. Ammonia solution in methanol (2M, 50 ml) was added and the mixture was stirred for 2 minutes. The mixture was filtered through a filter aid (registered trademark), washed with ammonia solution in methanol (2M, 250 ml), and the resulting organics were concentrated to give a dark green solid. The crude material was purified by chromatography eluting with dichloromethane: methanol: 0.88 ammonia from 100: 0: 0 to 75: 20: 5 to give the title compound (131 mg) as a dark green solid.

Preparation Example 138: 3-{(2R) -2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] propyl} -N- [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide

Preparation of the title compound using 4- (2-amino-1, 1-dimethylethyl) phenol hydrochloride (see Acta Chem. Scand. 8, 1203, 1207; 1954) in a similar manner as in Preparation Example 27 It was.

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

3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4 g, 469 mmol) in acetonitrile (900 ml), palladium (II) acetate (7.9 g, 35.2 mmol), tri-ortho-tolylphosphine ( 21.4 g, 70.4 mmol) and triethylamine (82 ml) were heated under reflux in a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. Purification by flash column chromatography, eluting 90: 1 to 70:30 pentane: ethyl acetate, gave the title compound (54.3 g) as an orange oil.

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

The title compound of orange oil was prepared by the method of Preparation 26 using the Preparation 139 product.

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

The title compound as a white crystalline solid was prepared using the product of Preparation 140 in the same manner as in Preparation 19.

Preparation Example 142 3- {3-[(2R) -2-((1R) -1-phenylethylamino) propyl] phenyl} propionic acid

The product of Preparation Example 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 material dissolved in water, acidified to pH 6 with hydrochloric acid (2M) and solidified for 18 hours. The solid was filtered off and dried in vacuo (1.0 g, 36%). The filtrate was concentrated, tetrahydrofuran was added and the mixture was filtered. The filtrate was evaporated to leave a foam, which was suspended in diethyl ether (x3) to give a colorless foam (1.96 g, 70%).

Preparation Example 143 1- (3,4-dihydro-1H-isoquinolin-2-yl) -3- {3-[(2R) -2-((1R) -1-phenylethylamino) propyl] Phenyl} propan-1-one

Preparative Example 142 product (1.95 g, 6.27 mmol) and triethylamine (2.62 ml, 19.0 mmol) in dichloromethane (80 ml) were treated with 2-chloro-1,3-dimethylimidazoline hexaflourophosphate (1.75 g). , 6.27 mmol) and the resulting solution was stirred for 3 hours. The solvent was removed and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate (3 x 20 ml), brine (3 x 20 ml) and dried (Na ₂ SO ₄ ). After filtration and solvent removal the material was purified by chromatography eluting with dichloromethane: methanol: 0.88 ammonia from 99.7: 0: 0.3 to 96.7: 3: 0.3. The product was evaporated from diethyl ether (x3) to give a semi solid (2.3 g, 86%).

Preparation 144: 3- [3-((2R) -2-aminopropyl) phenyl] -1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one

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

Preparation Example 145 N- {2-benzyloxy-5-[(1R) -1- (tert-butyldimethylsilanyloxy) -2-((1R) -2- {3- [3- (3,4 -Dihydro-1H-isoquinolin-2-yl) -3-oxo-propyl] phenyl} -1-methylethylamino) ethyl] phenyl} formamide

The title compound was prepared (216 mg, 67%) using Preparation 144 and Preparation 12 product in a similar manner as in Preparation 136.

Preparation Example 146 N- {5-[(1R) -1- (tert-butyldimethylsilanyloxy) -2-((1R) -2- {3- [3- (3,4-dihydro-1H Isoquinolin-2-yl) -3-oxo-propyl] phenyl} -1-methylethylamino) ethyl] -2-hydroxyphenyl} formamide

Prepared using the method of preparation 15 and the amide of preparation 145 to obtain a brown foam (280 mg, 100%).

Example 1: N-benzyl-2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} Phenyl) acetamide

Compound (24 mg, 40 μmol), formic acid (0.5 ml), tetrahydrofuran (5 ml) and water (0.5 ml) of Preparation Example 15 were heated to 90 ° C. for 18 hours. Additional formic acid (0.5 ml) and tetrahydrofuran (5 ml) were added and the 18 h further heated. Solvent was removed and the product was purified by chromatography (0-10% methanol + 0.3% ammonia in dichloromethane). The product was dissolved in methanol (x3) and evaporated (10 mg).

Example 2: N- (3,4-dimethylbenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxy-phenyl) -2-hydroxyethyl Amino] -2-methylpropyl} phenyl) acetamide

It prepared by the method described in Example 1 using the amide of Preparation Example 16.

Example 3: N- [4- (dimethylamino) benzyl] -2- {3-[(2R) -2-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl ) -2-hydroxyethyl} amino) propyl] phenyl} acetamide

A mixture of Preparation 27 product (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 concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 100: 0: 0 to 90: 10: 1 dichloromethane: methanol: 0.88 ammonia to give the title compound of the brown foam in 36% yield. 18 mg were obtained.

Examples 4-12

The compound having the following formula was prepared using a method similar to the method described in Example 3. The appropriate starting material was treated with 1-1.1 equivalents of triethylamine trihydrofluoride at room temperature for 18-72 hours.

The crude compound was purified by column chromatography on silica gel eluting with 2M methanolic ammonia and then eluting with 90: 10: 1 dichloromethane: methanol: 0.88 ammonia. Thereafter, further azeotroping in methanol (x3) and diethyl ether (x3) gave the desired product as a white solid.

Examples 13-23

The compound having the following formula was prepared using a method similar to the method described in Example 3. The appropriate starting material was treated with 1-1.1 equivalents of triethylamine trihydrofluoride at room temperature for 18-72 hours.

In Example 14, the product was purified by azeotroping with 2M methanolic ammonia.

The crude compound was purified by column chromatography on silica gel eluting with 2M methanolic ammonia and then eluting with 90: 10: 1 dichloromethane: methanol: 0.88 ammonia. Thereafter, further azeotroping in methanol (x3) and diethyl ether (x3) gave the desired product as a white solid.

Examples 24-27

The compound having the following formula was prepared using a method similar to the method described in Example 3. The appropriate starting material was treated with 1-1.1 equivalents of triethylamine trihydrofluoride at room temperature for 18-72 hours.

Example 28 N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2- [3- (formylamino) phenyl] -2-hydroxyethyl} amino ) Propyl] phenyl} acetamide

A mixture of Preparation 34 product (500 mg, 0.81 mmol) and ammonium fluoride (200 mg, 5.4 mmol) in methanol (5 ml) and water (1.5 ml) was heated at 40 ° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 90: 10: 0.1 of dichloromethane: methanol: 0.88 ammonia to give the title compound in foam form in 84% yield, 347 mg.

Example 29 N- (3,4-dimethylbenzyl) -2- {3- [2-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxy Oxyethyl} amino) ethyl] phenyl} acetamide

The title compound was prepared from the Preparation 102 product using a similar method as in Examples 4 to 12.

Examples 30-37

The compound having the following formula was prepared using a method similar to the method described in Example 3. The appropriate starting material was treated with 1-1.1 equivalents of triethylamine trihydrofluoride at room temperature for 18-72 hours.

Examples 38-46

The appropriate amide, triethylamine trihydrofluoride (1 equiv) in tetrahydrofuran (5 ml) was stirred at room temperature for 2 days. The mixture was then concentrated in vacuo and the residue was treated with methanolic ammonia and evaporated (x3) to leave a foam, which was placed in 90: 10: 1 dichloromethane: methanol: 0.88 ammonia and filtered and then 90:10. Purification by column chromatography on silica gel eluting with 1: 1 dichloromethane: methanol: 0.88 ammonia afforded the title compound in the form of a film, which was dissolved in methanol, evaporated (x3), suspended in diethyl ether and evaporated ( x3) to give a white solid.

Examples 51-55

Compounds having the following formulas were prepared using methods analogous to those described in Example 3. The appropriate starting material was treated with 1-1.1 equivalents of triethylamine trihydrofluoride at room temperature for 18-72 hours.

Example 56: 3-{(2R) -2-[(2R) -2- [3- (formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} -N- [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide

In a similar manner to the method described in Examples 38 to 50, the title compound (35 mg, 31%) was obtained as a brown glass form from the product of Preparation 138.

Example 57: N- {5-[(1R) -2-((1R) -2- {3- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3- Oxopropyl] phenyl} -1-methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide

In a similar manner to the method described in Examples 38 to 50, the title compound (35 mg, 31%) was obtained as a brown glass form from the product of Preparation 138.

The compound of formula 1 acts as an effective β2 agonist, and as a result the ability to mediate smooth muscle relaxation can be determined by measuring the effect of β2 adrenergic receptor stimulation on the full-length stimulatory contraction of the guinea pig trachea strip. .

Guinea pig

Male Dunkin-Hartley guinea pigs (475-525 g) are killed by CO ₂ choking and femoral artery bleeding and organs are removed. Four tissue specimens are obtained from four animals, incised just below the larynx to take a 2.5 cm long organ. The cartilage on the opposite side of the tracheal muscle is cut to open the trachea, and a cross section of 3 to 4 cartilage widths is cut. The obtained strip tissue samples were suspended in a 5 ml organ bath by connecting the upper and lower cartilages with cotton yarns. The strip was in modified Krebs Ringer buffer (Sigma K0507) containing 3 μM of indomethacin (Sigma I7378), 10 μM of guanethidine (Sigma G8520) and 10 μM of athenol (Sigma A7655) for 20 minutes. Equilibrated without tension, heated to 37 ° C. and evaporated to 95% O ₂ /5% CO ₂ followed by 1 g initial tension. The test specimens were further equilibrated for an additional 30 to 45 minutes, during which time two tensions (up to 1 g) were applied again at 15 minute intervals. Changes in tension are recorded and observed through a standard isometric transducer connected to a data acquisition system (customized by Pfizer). After the tension had been equilibrated, the tissue was applied to the field stimulus (EFS) using parameters of 10 trains, 0.1 ms pulse width, 10 Hz and maximum voltage (25 V) every 2 minutes in succession throughout the experiment. EFS of cholinergic nerves after tracheal ganglion causes single phase contraction of smooth muscle and the height of single contraction is recorded. Peristaltic pumps throughout the experiment in the tissue bath except when the β2 agonist according to the present invention is added and the pump is stopped for cumulative amount time for the tissue bath and restarted for drug wash time after reaching the maximum response. The above-described Krebs Ringer buffer is continuously injected by the system (pump flow rate 7.5 ml / min).

Experimental Plan for Activity and Potency Assessment

After EFS equilibration, the peristaltic pump is stopped and primed with a 300 nM single dose of isoprenaline (Sigma 15627) to determine the maximum response to inhibition of contractile EFS response. Thereafter, the isoprenaline is washed for 40 minutes. After initial sensitization and washout recovery, the concentration is incremented in half-logs to create a standard curve for isoprenal for all tissues for cumulative bolus addition to tissue baths (isoprelinin curve 1). . The concentration range used is 1 ^e-9 to 1 ^e / 3 ^e-6 M. At the end of the isoprenin curve, the preparation is washed again for 40 minutes before starting the second curve for isoprenin (internal control) or β2 agonist according to the invention. β2 agonist response is expressed as% inhibition of EFS response. Data for β2 agonists were normalized by indicating inhibition as the maximum percent inhibition by isoprenin in curve 1. The EC ₅₀ value of the β 2 agonist according to the invention refers to the compound concentration required to produce a 1/2 maximal effect. The data of β2 agonists according to the present invention are expressed as relative titers to isoprenin, defined as the ratio (EC ₅₀ β2 agonist) / (EC ₅₀ isoprenulin).

Identification of β2 Mediated Functional Activity

   The β2-agonist activity of the test compound was confirmed by the study design described above, but prior to preparing the curve for the β2-agonist according to the present invention, the preliminary sample was pre-cultured with 300 nM ICI 118551 (selective β2 antagonist) (at least 45 minutes). For the β2-mediated effect, allowing the test compound dose response curve to proceed to the right.

According to another embodiment, the agonist titer of the compound of formula (1) on the β2 receptor may also be determined by measuring the concentration of the compound according to the invention necessary to exhibit a ½ maximal effect on the β2 receptor (EC ₅₀ ).

Compound preparation method

Dilute 10 mM / 100% DMSO (dimethylsulfoxide) stock of the compound to the desired top dose in 4% DMSO. These peak doses are all used to create a 10 point semilog dilution curve at 4% DMSO. Isoprelinin (Sigma, I-5627) was used as standard in all experiments for control wells on each plate. Data is expressed as% isoprenal response.

Cell culture

10% bovine CHO (Chinese hamster ovary) cells (Kobika et al., PNAS 84: 46-50, 1987, and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhβ2) that recombinantly express human β2 adrenergic receptors. Dulvecose with added fetal serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg / ml Geneticin (Sigma, G7034) and 10 μg / ml Puromycin (Sigma, P8833) (Dulbeccos) MEM / NUT MIX F12 (Gibco, 21331-020). The cells were seeded to exhibit about 90% confluency for the test.

Analytical Method

Each dose of compound, 25 μl / well, was transferred to cAMP-flashplate (Flashplate®, NEN, SMP004B) with base control 1% DMSO and maximum control 100 nM isoprenin. It was diluted 1: 2 by adding 25 μl / well PBS. Cells were trypsinized (0.25% sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to produce 1 × 10 ⁶ cells / ml CHOhB2. Compounds were incubated with 50 μl / well of cells for 1 hour. Cells were digested by addition of 100 μl / well detection buffer (NEN, SMP004B) containing 0.18 μCi / ml ¹²⁵ I-cAMP (NEN, NEX-130) and the plates were incubated for another 2 hours at room temperature. The amount of ¹²⁵ I-cAMP bound to the Flashplate® was quantified at normal measurement efficiency for 1 minute using Topcount NXT (Packard). Dose response curves were expressed as% isoprenin activity and corrected using a four parameter sigmoid fit.

As a result, it was found that the compound of formula 1 according to the present invention illustrated in Examples 1 to 57 exhibits β2 cAMP EC ₅₀ of less than 5 nM.

Claims (25)

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof: Formula 1

Where (CH ₂ ) _n -C (= O) Q ¹ group is in meta or para position, R ¹ and R ² are independently H and C ₁ -C ₄ Selected from the group consisting of alkyl, n is 0, 1 or 2, Q ¹ is optionally crosslinked by one carbon atom

Where p is 1 or 2 and q is 1 or 2,

And * -NR ⁸ -Q ² -A groups, wherein Q ² is C ₁ -C ₄ alkylene, R ⁸ is H or C ₁ -C ₄ alkyl, A is pyridyl, C ₃ -C ₁₀ cyclo Alkyl, wherein cycloalkyl is optionally crosslinked by one or more carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl,

or

Is a group selected from the group consisting of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CO ₂ R ⁹ , CF ₃ , CN, OCF ₃ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NHCOR ¹⁰ and phenyl, wherein the phenyl is OR ⁹ , halo and C ₁ -C ₄ Unsubstituted or substituted with 1 to 3 groups selected from the group consisting of alkyl, R ⁹ and R ¹⁰ are the same or different and are selected from the group consisting of H and C ₁ -C ₄ alkyl, * Represents a bonding position of a carbonyl group. The method of claim 1, A compound or a pharmaceutically acceptable salt thereof, wherein Q ¹ is A-cyclohexyl or adamantyl, and is a ^* -NH-Q ² -A group. The method of claim 1, Q ¹ is A

The group ^* -NH-Q ² -A, wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CN, CO ₂ R ⁹ , CF ₃ , OCF ₃ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NHCOR ¹⁰ and phenyl, wherein The phenyl is not substituted or substituted with 1 to 3 groups selected from the group consisting of OR ⁹ , halo and C ₁ -C ₄ alkyl when two or more of R ³ to R ⁷ is H, and R ⁹ and R ¹⁰ are the same. Or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of H and C ₁ -C ₄ alkyl. The method of claim 3, wherein Q ¹ is A

Group ^* -NH-Q ² -A group, wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, OH, CH ₃ , OCH ₃ , OCF ₃ , OCH ₂ -CH ₃ , SCH ₃ , N (CH ₃ ) ₂ , NH (C═O) CH ₃ , C (═O) NH ₂ , COOCH ₃ , SO ₂ CH ₃ , SO ₂ NH ₂ , CN, halo, CF ₃ and phenyl And phenyl is substituted or unsubstituted with OH, or a pharmaceutically acceptable salt thereof. The method of claim 1, A

And wherein one of R ³ to R ⁷ is OH, or phenyl substituted with OH, or a pharmaceutically acceptable salt thereof. The method of claim 1, A compound or a pharmaceutically acceptable salt thereof, wherein A is naphthyl unsubstituted or substituted with OH. The method according to any one of claims 1 to 6, Q ² is —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, —CH ₂ —C (CH ₃ ) ₂ — or —C (CH ₃ ) ₂ — or a pharmaceutical thereof Acceptable salts. The method of claim 7, wherein Or a pharmaceutically acceptable salt thereof. Q ² is -CH _2- . The method of claim 1, Q ¹

or

Wherein R ³ , R ⁴ , R ^5, and R ⁶ are H, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 to 6, A compound or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or C ₁ -C ₄ alkyl and R ² is C ₁ -C ₄ alkyl. The method of claim 10, R ¹ is H or CH ₃ and R ² is H or CH ₃ ; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. delete The method according to any one of claims 1 to 6, A compound or a pharmaceutically acceptable salt thereof, wherein the (CH ₂ ) nC (= 0) Q ¹ group is in the meta position. The method of claim 1, N-benzyl-2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide ; N- (3,4-dimethylbenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} phenyl) acetamide; N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} benzamide; N- [2- (2-chlorophenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (2-naphthalen-1-yl Ethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-methylphenyl) Ethyl] benzamide; N- [2- (2,6-dimethylphenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropyl} benzamide; N- [2- (2,3-dimethylphenyl) ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropylbenzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy -2,3-dimethylphenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-methoxy Phenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N-phenethyl-benzamide; N-cyclohexylmethyl-3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; N- [5-((1R) -2- {1,1-dimethyl-2- [3- (piperidine-1-carbonyl) phenyl] ethylamino} -1-hydroxyethyl] -2-hydro Oxyphenyl] formamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (3-triples Oromethylphenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (3-phenylpropyl) benzamide ; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N-indan-2-ylbenzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (2-pyridin-2-yl Ethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-sulfamoyl Phenyl) ethyl] benzamide; N- (4-dimethylaminobenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] Propyl} phenyl) acetamide; N- [5- (2-{(1R) -2- [3- (3,4-dihydro-1H-isoquinolin-2-carbonyl) -phenyl] -1,1-dimethyl-ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (4'-hydroxybiphenyl -3-ylmethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy -2,5-dimethylphenyl) ethyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy -3-methylphenyl) ethyl] benzamide; N- (4-acetylaminobenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] Propyl} phenyl) acetamide; 4-{[2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetylamino ] Methyl} benzamide; N-adamantan-1-yl-3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benz Amides; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (2-hydroxy-naphthalene- 1-ylmethyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (4-hydroxy-3, 5-dimethylbenzyl) benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (6-hydroxy-naphthalene- 2-ylmethyl) benzamide; N- (3,6-dichloro-2-hydroxybenzyl) -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-methylpropyl} benzamide; N- (3,4-dimethylbenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] ethyl} phenyl Acetamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy Phenyl) -2-methylpropyl] benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -N- (4'-hydroxybiphenyl -4-ylmethyl) benzamide; N-adamantan-1-yl-2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] Propyl} phenyl) acetamide; N- [5- (2- {2- [3- (10-aza-tricyclo [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-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4 ' -Hydroxybiphenyl-3-ylmethyl) acetamide; 4-{[2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -acetyl Amino] methyl} benzoic acid methyl ester; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N -(4-trifluoroomethoxy-benzyl) acetamide; N- (2-chloro-4-hydroxybenzyl) -N-ethyl-2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; N- (2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Oxyethylamino] -2-methylpropyl} -phenyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4- Hydroxy-3,5-dimethylbenzyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (2- Hydroxynaphthalen-1-ylmethyl) acetamide; N- (5-chloro-2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Oxyethylamino] propyl} phenyl) acetamide; N- (3,5-dichloro-2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2 -Hydroxyethylamino] propyl} phenyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (6- Hydroxynaphthalen-2-ylmethyl) acetamide; 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4 ' -Hydroxybiphenyl-4-ylmethyl) acetamide; N- (4-cyano-benzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} -phenyl) -acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -N- (4 Methanesulfonyl-benzyl) -acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -N- (4 -Methylsulfanyl-benzyl) -acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -N- (4 -Trifluuromethyl-benzyl) -acetamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (4 ' -Hydroxy-biphenyl-4-ylmethyl) acetamide; N- [2- (5-chloro-2-hydroxyphenyl) -ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Ethylamino] -2-methylpropyl} -benzamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (4 ' -Hydroxybiphenyl-3-ylmethyl) -acetamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl)- 2-methylpropyl] -benzamide; N- (2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R)-(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; N- [2- (5-chloro-2-hydroxyphenyl) -ethyl] -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Ethylamino] -2-methylpropyl} benzamide; 3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl)- 2-methylpropyl] -benzamide; 2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -N- (tetrahydro -Thiopyran-4-yl) acetamide; N- (5-chloro-2-hydroxybenzyl) -2- (3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; And N- {5-[(1R) -2-((1R) -2- {3- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropyl] phenyl } -1-methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide or a pharmaceutically acceptable salt thereof. Asthma, chronic or acute bronchial contraction, chronic bronchitis, small airway obstruction, emphysema, obstructive or inflammatory airway, comprising the compound of formula 1 according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof A pharmaceutical composition for the treatment of a disease, disorder or condition selected from the group consisting of diseases, bronchitis, acute lung injury and bronchiectasis. delete The method of claim 16, Asthma is atopic asthma, nonatopic asthma, allergic asthma, atopic bronchial asthma mediated by IgE, bronchial asthma, essential asthma, true asthma, endogenous asthma due to pathophysiological disorders, exogenous asthma due to environmental factors, Essential asthma, non-topical asthma, bronchitis asthma, emphysema, asthma by unknown or unknown causes, asthma induced by exercise, asthma induced by allergens, asthma induced by cold air, occupation Selected from the group consisting of infectious asthma, non-allergic asthma, early asthma, rough respiratory syndrome in infants and bronchiolitis due to sexual asthma, bacteria, fungi, antigens or viral infections; COPD characterized by obstructive or inflammatory airway disease characterized by chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated with or without COPD, irreversible progressive airway obstruction Adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness after other drug treatments and airway disease associated with pulmonary hypertension; Bronchitis is selected from the group consisting of acute bronchitis, acute laryngeal bronchitis, arachidous bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthma bronchitis, proliferative bronchitis, staphylococcal bronchitis, streptococcal bronchitis and alveolar bronchitis; The bronchiectasis is selected from the group consisting of cylindrical bronchiectasis, pocket-shaped bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis. delete The compound according to any one of claims 1 to 6, (a) 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, (b) leukotriene antagonist (LTRA) ), (c) histamine receptor antagonists, (d) vasoconstrictive sympathomimetic agents as α ₁ -and α ₂ -adrenergic receptor agonists for use in decongestion, (e) muscarinic M3 receptor antagonists or anticholiners, (f ) PDE inhibitor, (g) theophylline, (h) sodium chromoglycate, (i) COX inhibitor, (j) oral and inhaled glucocorticoids, (k) monoclonal antibodies with activity against endogenous inflammatory moieties, (l) anti-tumor necrosis factor (anti-TNF-α) substances, (m) adhesion molecule inhibitors, (n) kinin-B ₁ -and B ₂ -receptor antagonists, (o) immunosuppressants, (p) matrix metal Inhibitors of loprotease (MMP), (q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists, (r) elastase inhibitors, (s) ah To didanosine A2a receptor agonists, (t) urokinase inhibitor, (u) dopamine compounds acting on the receptor, (v) modulators of NF _κ β modulators, (w) cytokine signaling pathways of the path, (x) mucilage solubilizing or antitussives A combination of drugs which can be classified as (y) antibiotics, (z) HDAC inhibitors, and (aa) PI3 kinase inhibitors. N- (5-chloro-2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxy Oxyethylamino] propyl} acetamide or a pharmaceutically acceptable salt thereof. 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl-N- (4-hydroxy Hydroxy-3,5-dimethylbenzyl) acetamide or a pharmaceutically acceptable salt thereof. 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl-N- (6-hydroxy Loxynaphthalen-2-ylmethyl) acetamide or a pharmaceutically acceptable salt thereof. 2- (3-{(2R) -2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl-N- (4'- Hydroxybiphenyl-4-ylmethyl) acetamide or a pharmaceutically acceptable salt thereof. N- [2- (4-chlorophenyl) ethyl) -3- {2-[(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Methylpropyl} benzamide or a pharmaceutically acceptable salt thereof.