CN101296701A

CN101296701A - A combination of compounds, which can be used in the treatment of respiratory diseases, especially chronic obstructive pulmonary disease (COPD) and asthma

Info

Publication number: CN101296701A
Application number: CNA2006800402380A
Authority: CN
Inventors: 托马斯·埃里克森; 约翰·汉森
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-08-26
Filing date: 2006-08-24
Publication date: 2008-10-29
Also published as: ZA200801407B

Abstract

The present invention provides pharmaceutical compositions comprising a glucocorticosteroid and a compound of formula: wherein m, R<1>, R<2>, R<3>, and R<4> are as defined in the specification, and their use in therapy.

Description

Be used for the treatment of respiratory system disease, especially the combination of compounds of chronic obstructive pulmonary disease (COPD) and asthma

Technical field

The present invention relates to be used for the treatment of respiratory system disease, the especially pharmaceutically active substances of chronic obstructive pulmonary disease (COPD) and asthma combination.

Background technology

The essential function of lung requires a kind of structure of fragility extensively to be exposed to comprise in pollutant, microorganism, allergen and the carcinogenic environment.The interactional host factor of the life style that results from selection and genetic constitution has influenced the response to this exposure.Injury or infection to lung can produce respiratory system disease (or respiratory disorder) widely.Multiple in these diseases has huge public health importance.Respiratory system disease comprises acute lung injury, adult respiratory distress syndrome (ARDS), occupational lung disease, pulmonary carcinoma, tuberculosis, fibre modification, pneumoconiosis, pneumonia, emphysema, chronic obstructive pulmonary disease (COPD) and asthma.

Modal respiratory system disease is an asthma.Asthma is commonly defined as the inflammatory illness of air flue, and clinical symptoms is caused by intermittent airflow obstruction.Clinical symptoms be stridulate, the outbreak of dyspnea and cough.As if it is a kind of chronic failure illness, and its prevalence and seriousness are all increasing.In the population of developed country, 15% child and 5% adult suffer from asthma according to estimates.Therefore, treatment should so that normal life becomes possibility, meanwhile provide the basis for treatment essence inflammation at controlling symptoms.

COPD is the term that expression one big class can be disturbed the pneumonopathy of eupnea.It is the disease of feature that present clinical criterion is defined as COPD with incomplete reversible flow limitation (airflow limitation).Flow limitation is progressive usually, and is relevant to the unusual inflammatory responses of deleterious particle and gas with lung again.The most important contribution source of this class granule and gas is smoking in the Western countries at least.COPD patient has multiple symptom, comprises that cough, short of breath and expectorant generate too much; This class symptom derives from a large amount of cellular compartments dysfunction of (comprising neutrophil cell, macrophage and epithelial cell).Two kinds of most important diseases that COPD is contained are chronic bronchitis and emphysema.

Chronic bronchitis is bronchial long-term inflammation, and causing mucus to generate increases and other variation.Patient's symptom is cough and expectoration.Chronic bronchitis can cause that more frequent and more serious respiratory system infection, bronchus narrow down and obstruction, dyspnea and Disability.

Emphysema are the chronic lung diseases that influence alveolar and/or minimum bronchus tip.Lung is lost its elasticity, so these zones of lung enlargement that becomes.The zone of these enlargements outmoded gas of bottling up can not exchange with fresh air effectively.This causes dyspnea, and may cause the oxygen supply deficiency to blood.Emphysema patient's cardinal symptom is a short of breath.

The therapeutic agent that is used for the treatment of respiratory system disease comprises glucocorticoid (glucocorticosteroid).Glucocorticoid (also claiming corticosteroid or glucocorticoid) is potent antiinflammatory.Although their definite mechanism of action it be unclear that, but the final result of glucocorticoid treatment is the quantity, activity of inflammatory cell and reduces to the motion of bronchial submucosa, causes that airway reactivity reduces.Glucocorticoid also can cause the bronchiolar epithelium lining to come off, and minimizing, vascular permeability reduce and mucous secretion reduces.

Although glucocorticoid treatment can produce important benefit, but the effect of these compositions often is far from satisfactory, particularly in treatment COPD.And although the use of steroid can cause therapeutic effect, but needs can use the steroid of low dosage, to minimize the generation and the seriousness of the side effect of not expecting that may be relevant with conventional administration.The problem that the steroid drug resistance obtains among the patient who suffers from respiratory system disease has also been given prominence in nearest research.For example, have been found that the smoker who suffers from asthma is insensitive to the corticosteroid therapy that short-term sucks, but the response difference between smoker and the non smoker as if because of the corticosteroid that high dose sucks reduce (Tomlinson et al., Thorax 2005; 60:282-287).Therefore, medically press for for example new therapy of COPD and asthma of anti-respiratory system disease, particularly have the therapy that disease relaxes potentiality.

WO01/98273 and WO03/051839 have described has pharmaceutically active, particularly chemokine receptors (especially MIP-1 α chemokine receptors) the active chemical compound of regulator, its salt and pharmaceutical preparation, and their potential uses in the treatment various diseases.

MIP-1 α chemokine receptors CCR1 (chemokine receptors 1) organizes camber to express in the sufferer of the disease (for example asthma and chronic obstructive pulmonary disease) of different autoimmune, inflammatory, proliferative, excess proliferative and immunology mediation.And the morbidity to respiratory system disease, for example COPD has contribution to inflammatory cell (for example neutrophil cell and monocyte/macrophage) owing to secretory protein hydrolytic enzyme, oxidant and pharmacologic mediator.These cells depend on CCR1 and raise in lung tissue and activatory function.

Surprisingly, have now found that, in the treatment of respiratory system disease, can observe unexpected useful therapeutic effect if be used in combination CCR1 receptor antagonist and glucocorticoid.For example, combination according to the present invention is considered to that to flow in the lung be effective especially reducing inflammatory cell.When with two kinds of active substances (perhaps in single pharmaceutical preparations or) or during successively or respectively via the administration of separated drug prepared product simultaneously, can observe useful effect via the prepared product that separates.

Summary of the invention

Thereby, the invention provides a kind of drug products (pharmaceutical product), its combination comprises

(a) first active component, it is formula (I) compound or pharmaceutically acceptable salt thereof

Wherein

M is 0,1 or 2;

Each R ¹Represent halogen or cyano group independently;

R ²Expression hydrogen atom or methyl;

R ³Expression C ₁-C ₄Alkyl; With

R ⁴The expression hydrogen or halogen; With

(b) second active component, it is a glucocorticoid.

Drug products of the present invention can for example be to mix the pharmaceutical composition that comprises first and second active component.Perhaps, drug products can be a test kit (kit) for example, it comprises the prepared product and the optional description of the prepared product (preparation) and second active component of first active component, and described description is used for giving described prepared product simultaneously, successively or separately to the patient that described needs are arranged.

In the context of the present specification, the moieties in alkyl substituent or the substituent group can be a straight or branched.

Integer m preferably 1 or 2.

Each R ¹Represent halogen (for example chlorine, fluorine, bromine or iodine) or cyano group independently.

In one embodiment of the invention, m is 1, R ¹Expression halogen atom, particularly chlorine atom.

In further embodiment, m is 1, R ¹Expression halogen atom (for example chlorine), it is positioned on the phenyl ring and linking group CH ₂4 of the carbon atom that connects.

R ²Expression hydrogen atom or methyl.In one embodiment of the invention, R ²The expression methyl.

R ³Expression C ₁-C ₄Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group).Usually, R ³Be methyl or ethyl, particularly methyl.

R ⁴Expression hydrogen or halogen (for example fluorine, chlorine, bromine or iodine).In embodiments of the present invention, R ⁴Expression hydrogen or chlorine.

Formula (I) chemical compound can exist with stereoisomeric forms in any ratio.Should be understood that all geometric isomers and the optical isomer of formula (I) chemical compound contained in the present invention, and these mixture of isomers, comprises the use of racemate.The use of tautomer and composition thereof also constitutes an aspect of of the present present invention.Preferred optical isomer is that (S)-enantiomer is (just at R ²The three-dimensional center that is connected with OH has the chemical compound of S configuration).

Formula of the present invention (I) chemical compound can utilize WO01/98273 and the described technology of WO03/051839 to synthesize.

Formula (I) chemical compound can use the form of its officinal salt, preferred acid addition salts, for example hydrochlorate, hydrobromate, phosphate, sulfate, acetate, Ascorbate, benzoate, fumarate, hemifumarate (hemifumarate), furoate, succinate, maleate, tartrate, citrate, oxalates, xinafoate (xinafoate), mesylate or right-toluene fulfonate.Officinal salt also comprises inner salt (amphion) form.Any appellation to formula (I) compound or its salt also contains the solvate of this compounds and the solvate of this class salt (for example hydrate).

Should be understood that formula (I) chemical compound and salt thereof can be used as amphion and exists.Thereby although describe and represent chemical compound with OH-form, but they also can exist with inner salt (amphion) form.The representation of formula of the present invention (I) and embodiment contains the mixture of hydroxyl and zwitterionic form and arbitrary proportion thereof.

In another embodiment of the invention, formula (I) chemical compound is selected from

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide,

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide,

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-the 2-hydroxypropyl) the oxygen base]-the 4-hydroxy phenyl } acetamide,

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-the 2-hydroxypropyl) the oxygen base]-the 4-hydroxy phenyl } propionic acid amide., perhaps

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } propionic acid amide.,

Or its officinal salt.

In another embodiment of the invention, formula (I) chemical compound is N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } salt of acetamide, for example hydrochlorate, hydrobromate, phosphate, sulfate, acetate, Ascorbate, benzoate, fumarate, hemifumarate, furoate, succinate, maleate, tartrate, citrate, oxalates, xinafoate, mesylate or right-toluene fulfonate.Salt with special good properties (for example favourable degree of crystallinity and be suitable for for example being formulated in other physical property that is administered to lung in the dry powder formulations) is N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } benzoate, fumarate or the hemifumarate of acetamide, comprise any form of the salt of mentioning among the embodiment.

In embodiments of the present invention, formula (I) compound or its salt has crystallographic property, for example at least 50% degree of crystallinity, at least 60% degree of crystallinity, at least 70% degree of crystallinity or at least 80% degree of crystallinity.X-ray diffraction technique by routine can be estimated degree of crystallinity.

In another embodiment of the invention, formula (I) compound or its salt is 50%, 60%, 70%, 80% or 90% to 95%, 96%, 97%, 98%, 99% or 100% degree of crystallinity.

It should be noted that, this paper is when expressing X-ray powder diffraction peak (° 2 θ), limit of error is consistent about the general rules (USP941) of X-ray diffraction with American Pharmacopeia---referring to United StatesPharmacopeia Convention.X-Ray Diffraction, General Test＜941〉.UnitedStates Pharmacopeia, 25th ed.Rockville, MD:United States PharmacopeialConvention; 2002:2088-2089.

In embodiments of the present invention, formula (I) chemical compound is N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } hemifumarate of acetamide, its shows following at least characteristic X-ray powder diffraction peak (expressing with ° 2 θ):

(1) 6.2,10.7 and 12.5, perhaps

(2) 6.2,10.7 and 18.8, perhaps

(3) 6.2,10.7 and 18.0, perhaps

(4) 6.2,10.7,12.5,18.0 and 18.8, perhaps

(5) 6.2,10.7,12.5,18.0,18.8,19.7 and 19.8.

In another embodiment of the invention, formula (I) chemical compound is N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } furoate of acetamide, its shows following at least characteristic X-ray powder diffraction peak (expressing with ° 2 θ):

(1) 6.3,11.0 and 12.7, perhaps

(2) 6.3,10.7 and 12.7, perhaps

(3) 6.3,11.0,12.7 and 15.9, perhaps

(4) 6.3,10.7,11.0,12.7,13.9,14.2 and 15.9, perhaps

(5) 6.3,10.7,11.0,12.7,15.9,17.7,19.1,19.7 and 25.5, perhaps

(6) 6.3,10.7,11.0,12.7,13.9,14.2,15.9,17.7,19.1,19.7,19.9,21.6 and 25.5.

(1) 6.7,11.0 and 13.4, perhaps

(2) 6.7,10.4,11.0 and 13.4, perhaps

(3) 6.7,10.4,12.4,13.4 and 13.7, perhaps

(4) 6.7,10.4,13.4 and 20.9, perhaps

(5) 6.7,10.4,11.0,12.4,13.4,13.7,15.6,16.0 and 17.6, perhaps

(6) 6.7,10.4,11.0,12.4,13.4,13.7,15.6,16.0,16.1,17.6,18.0,18.6,18.9,20.1,20.9 and 23.4.

In another embodiment of the invention, formula (I) chemical compound is N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } benzoate of acetamide, its shows following at least characteristic X-ray powder diffraction peak (expressing with ° 2 θ):

(1) 6.1,10.7 and 19.3, perhaps

(2) 6.1,12.2 and 14.1, perhaps

(3) 6.1,10.7,12.2,14.1,18.1 and 19.3, perhaps

(4) 6.1,10.7,12.2,14.1,15.7,18.1 and 19.3, perhaps

(5) 6.1,10.7,12.2,14.1,15.1 and 19.3, perhaps

(6) 6.1,10.7,12.2,14.1,15.1,15.7,18.1 and 19.3, perhaps

(7) 6.1,10.7,12.2,14.1,15.1,15.7,18.1,19.3,21.2 and 24.6.

(1) 6.5,9.3 and 10.5, perhaps

(2) 6.5,9.3,17.6 and 17.8, perhaps

(3) 6.5,9.3,10.5,12.0 and 12.4, perhaps

(4) 6.5,9.3,10.5,12.0,12.4,13.0,13.6,15.5,17.6 and 17.8, perhaps

(5) 6.5,13.0 and 20.2, perhaps

(6) 6.5,9.3,10.5,12.0,12.4,13.0,13.6,15.5,17.6,17.8 and 19.2, perhaps

(7) 6.5,9.3,10.5,12.0,12.4,13.0,13.6,15.5,17.6,17.8,19.2,20.2,22.8 and 26.0, perhaps

(8) 6.5,9.3,10.5,12.0,12.4,13.0,13.6,15.5,17.6,17.8,19.2,20.2,22.8,24.2,26.0 and 30.7.

In further embodiment of the present invention, formula (I) chemical compound is N-{5-chloro-2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } furoate or the benzoate of acetamide.

Second active component in the present invention's combination is a glucocorticoid.Glucocorticoid of the present invention can be any synthetic or naturally occurring glucocorticoid.The example that can be used for glucocorticoid of the present invention comprises budesonide, fluticasone (for example as propionic ester), mometasone (mometasone) (for example as furoate (furoate ester)), beclometasone (beclomethasone) is (for example as 17-propionic ester or 17, the 21-dipropionate), ciclesonide (ciclesonide), loteprednol (loteprednol) (for example as etabonate (etabonate)), sprinkle promise (etiprednol) (for example as the dichloroacetic acid ester) according to replacing, triamcinolone (triamcinolone) (for example as contracting acetone (acetonide)), flunisolide (flunisolide), zoticasone, flumoxonide (flumoxonide), rofleponide (rofleponide), butixocort (butixocort) (for example as propionic ester), prednisolone (prednisolone), prednisone (prednisone), tipredane (tipredane), according to WO 2002/12265, the steroid esters of WO 2002/12266 and WO2002/88167,6 α for example, 9 α-two fluoro-, 17 α-[(2-furyl carbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyls-3-oxo-androstane (androsta)-1,4-diene-17 β-thiocarboxylic acid S-fluoro methyl ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-propionyloxy-androstane-1,4-diene-17 β-thiocarboxylic acid S-(2-oxo-oxolane-3S-yl) ester and 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiazole-5-carbonyl) oxygen base]-3-oxo-androstane-1,4-diene-17 β-thiocarboxylic acid S-fluoro methyl ester; Steroid ester as described in the DE 4129535 those, those of steroid such as GSK870086, GSK685698, GSK799943 and WO 2002/00679, WO 2005/041980, or the like.

In the context of the present specification, except as otherwise noted, any appellation for glucocorticoid all comprises can be from all active salts, solvate or the derivant of described glucocorticoid generation.The salt that glucocorticoid is possible or the example of derivant comprise: sodium salt, sulfosalicylic acid salt, phosphate .gamma.-pyridinecarboxylic acid salt, acetate, propionate, dihydrogen orthophosphate, palmitate, pivalate, fumarate and pharmaceutically acceptable ester (C for example ₁-C ₆Arrcostab).Glucocorticoid and active salt thereof or derivant also can be their solvate forms, for example hydrate forms.

In one embodiment of the invention, glucocorticoid is a budesonide.The chemical name of budesonide is 16,17-[butylidene two (oxygen base)]-11,21-dihydroxy-pregnant steroid-1,4-diene-3,20-diketone.Budesonide and preparation example thereof be as being described in Arzneimittel-Forschung (1979), and 29 (11), among 1687-1690, DE 2,323,215 and the US 3,929,768.Present available budesonide formulation is commercially available ' Entocort '.

Formula (I) chemical compound is worked as and the glucocorticoid coupling, presents surprising especially effect during particularly with the budesonide coupling.For example, interior animal experiment shows that glucocorticoid and formula (I) combination of compounds has significantly reduced inflammatory cell inflow (inflammatory cell influx) when two kinds of components have no significant effect pulmonary inflammatory dosage level separately.For this combination, cell flows into to reduce and adds with effect desired greater than two kinds of compositions.When with the combination of these compositions, viewed synergy can be used for for example reducing the therapeutic dose of steroid, perhaps obtains when using steroid separately reinforced effects to inflammation with identical dosage.When need be than the steroid of low dosage, for example in obtaining the chemical sproof individuality of these steroid, synergy can be particularly advantageous.

Drug products of the present invention can further randomly comprise the bronchodilator as the 3rd active component.Bronchodilator is lax and expansion bronchus passage and improve the medicine that circulation of air enters lung.The example of the bronchodilator that can use in the present invention comprises β ₂-agonist or anticholinergic compound.

β ₂-agonist (also claims beta2 (β ₂) adrenoreceptor agonists) can be used for by lax bronchial smooth muscle, reduce airway obstruction, reduce lung inflation excessively and reduce the symptom that short of breath alleviates respiratory system disease.β of the present invention ₂-agonist can be anyly can stimulate β ₂-receptor and the chemical compound or the material that serve as bronchodilator.The β that can use in the present invention ₂The example of-agonist comprises bambuterol (bambuterol), bitolterol (bitolterol), carbuterol (carbuterol), indenes Da Teluo (indacaterol), Clenbuterol (clenbuterol), fenoterol (fenoterol), formoterol, hexoprenaline (hexoprenaline), terbutaline diisobutyrate (ibuterol), pirbuterol (pirbuterol), procaterol (procaterol), reproterol (reproterol), salmaterol (salmeterol), sulfonterol (sulphonterol), terbutaline (terbutaline), tobuterol (tolubuterol), (chemical identification is 2 (1H)-quinolinoness to TA 2005,8-hydroxyl-5-[1-hydroxyl-2-[[2-(4-methoxyl group-phenyl)-1-Methylethyl]-amino] ethyl]-mono-hydrochloric salts; [R-(R ^*, R ^*)], also determine and be disclosed in United States Patent (USP) 4,579,854 (=CHF-4226) in) by Chemical Abstract Service RegistryNumber 137888-11-0; GSK159797; The formailide derivant, for example be disclosed in 3-among the WO 2002/76933 (4-{[6-((2R)-2-[3-(formamido group)-4-hydroxy phenyl]-the 2-hydroxyethyl amino) hexyl] the oxygen base-butyl)-benzsulfamide; Benzenesulfonamide derivatives for example is disclosed in 3-among the WO 2002/88167 (4-{[6-({ (2R)-2-hydroxyl-2-[4-hydroxyl-3-(hydroxyl-methyl) phenyl] ethyl } amino)-hexyl] oxygen base } butyl) benzsulfamide; The aryl aniline receptor stimulating agent for example is disclosed in the aryl aniline receptor stimulating agent among WO 2003/042164 and the WO2005/025555; And indole derivatives, for example be disclosed in the indole derivatives among the WO2004/032921.

On the one hand, β of the present invention ₂-agonist is a long-acting beta ₂-agonist, the just active β that continues more than 12 hours ₂-agonist.Long-acting beta ₂The example of-agonist comprises formoterol, bambuterol and salmaterol.

In the context of the present specification, except as otherwise noted, anyly (comprise β for bronchodilator ₂-agonist, long-acting beta ₂-agonist and anticholinergic compound) appellation comprise active salt, solvate or derivant and any enantiomer thereof that can generate from described bronchodilator, and the mixture of enantiomer comprises racemate.The possible salt or the example of derivant are acid-addition salts, for example hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, acetate, fumarate, succinate, lactate, citrate, tartrate, 1-hydroxyl-2-naphthalene-carboxylic acid salt, maleate and pharmaceutically acceptable ester (C for example ₁-C ₆Arrcostab).Bronchodilator (comprising its salt and derivant) also can be solvate forms, for example form of hydrate.

The example of anticholinergic compound comprises ipratropium (ipratropium) (for example ipratropium bromide), tiotropium (tiotropium) (for example tiotropium bromide), oxygen holder ammonium (oxitropium) (for example oxitropium bromide), tolterodine (tolterodine), AD-237 (Arakis) and is disclosed in quinuclidine derivant among the US 2003/0055080.

In embodiments of the present invention, bronchodilator is a formoterol.The chemical name of formoterol is N-[2-hydroxyl-5-[(1)-1-hydroxyl-2-[[(1)-2-(4-methoxyphenyl)-1-Methylethyl] amino] ethyl] phenyl]-Methanamide.The preparation example of formoterol is as being described among the WO 92/05147.As above clearly as can be known, term " formoterol " intention comprises its all officinal salts.In the one side of this embodiment, bronchodilator is a formoterol fumarate, for example formoterol fumarate dihydrate.

As what above emphasize, should be understood that the present invention is contained all optical isomers of formoterol and composition thereof, comprised the use of racemate.Thereby for example, N-[2-hydroxyl-5-[(1R)-1-hydroxyl-2-[[(1R)-2-(4-methoxyphenyl)-1-Methylethyl contained in term " formoterol "] amino] ethyl] phenyl]-Methanamide, N-[2-hydroxyl-5-[(1S)-1-hydroxyl-2-[[(1S)-2-(4-methoxyphenyl)-1-Methylethyl] amino] ethyl] phenyl]-mixture of Methanamide or these enantiomers, comprise racemate.

In further embodiment of the present invention, bronchodilator is indenes Da Teluo.As above clearly as can be known, term " indenes Da Teluo " intention comprises its all officinal salts, for example comprises maleic acid indenes Da Teluo and hydrochloric acid indenes Da Teluo.

Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof (first active component), glucocorticoid (second active component) and optional bronchodilator (the 3rd active component) (simultaneously), (sequentially) or separately (separately) administration successively simultaneously, the treatment respiratory system disease." successively " be meant active component administration in any order, after administration is a kind of, give the administration another kind immediately.If with they separate administration, then they still have required effect, but when administration in such a way, their dosing interval is generally less than 4 hours, ground preferably is at interval less than 2 hours, and ground more preferably is at interval less than 30 minutes, and optimum ground is at interval less than 10 minutes.

Can adopt conventional system's dosage form (systemic dosage form), the for example aqueous of tablet, capsule, pill, powder, aqueous or oily solution agent or suspensoid, emulsion and aseptic injection or oily solution agent or suspensoid, the oral or parenteral with active component of the present invention (for example intravenous, subcutaneous, intramuscular or intraarticular) administration.Active component also can be with the form topical (to lung and/or air flue) of solution, suspensoid, aerosol and dry powder formulations.These dosage forms will comprise one or more pharmaceutically acceptable compositions usually, and they can be selected from for example adjuvant, carrier, binding agent, lubricant, diluent, stabilizing agent, buffer agent, emulsifying agent, viscosity modifier, surfactant, antiseptic, correctives and coloring agent.As understood by one of ordinary skill in the art, the proper method of administration active component depends on multiple factor.

In one embodiment of the invention, active component is via the administration of separated drug prepared product.

Therefore, on the one hand, the invention provides a kind of test kit, it comprises the prepared product of first active component, first active component is the prepared product of formula (I) compound or pharmaceutically acceptable salt thereof and second active component, and second active component is a glucocorticoid, with optional description, described description is used for giving described prepared product simultaneously, successively or separately to the patient that described needs are arranged.Test kit can further randomly comprise the prepared product of the 3rd active component, and it is a bronchodilator.

In another embodiment, active component can be via the single pharmaceutical composition administration.Therefore, the present invention further provides pharmaceutical composition, its mixing comprises first active component, and it is formula (I) compound or pharmaceutically acceptable salt thereof and second active component, and it is a glucocorticoid.Pharmaceutical composition can further randomly comprise the 3rd active component, and it is a bronchodilator.The present invention also provides the method for pharmaceutical compositions, comprises first active component is mixed with second active component and the 3rd active component of choosing wantonly.

Pharmaceutical composition of the present invention can be prepared as follows: with first active component and second active component and pharmaceutically acceptable auxiliaries, diluent or carrier, and the 3rd optional active component mixes.Therefore, of the present invention further aspect, the method for pharmaceutical compositions is provided, comprise formula (I) compound or pharmaceutically acceptable salt thereof and glucocorticoid and pharmaceutically acceptable auxiliaries, diluent or carrier, and optional bronchodilator mixes.

Should be understood that according to the present invention, the therapeutic dose of every kind of active component of institute's administration is with the given activity composition that is adopted, the mode that gives active component and the disease of being treated or illness and different.

In one embodiment of the invention, first active component of the present invention, second active component (with the 3rd active component, are inhalation separately if present).In this respect, active component is simultaneously, sucks successively or separately.

Spread all in the application's the description, unless have in addition outside clear and definite different the qualification, the amount of used active component is meant unit dose.

When inhalation, the dosage of first active component (formula (I) compound or pharmaceutically acceptable salt thereof) is generally following scope: 0.1 μ g to 10000 μ g, 0.1 to 5000 μ g, 0.1 to 1000 μ g, 0.1 to 500 μ g, 0.1 to 200 μ g, 0.1 to 200 μ g, 0.1 to 100 μ g, 0.1 to 50 μ g, 5 μ g to 5000 μ g, 5 to 1000 μ g, 5 to 500 μ g, 5 to 200 μ g, 5 to 100 μ g, 5 to 50 μ g, 10 to 5000 μ g, 10 to 1000 μ g, 10 to 500 μ g, 10 to 200 μ g, 10 to 100 μ g, 10 to 50 μ g, 20 to 5000 μ g, 20 to 1000 μ g, 20 to 500 μ g, 20 to 200 μ g, 20 to 100 μ g, 20 to 50 μ g, 50 to 5000 μ g, 50 to 1000 μ g, 50 to 500 μ g, 50 to 200 μ g, 50 to 100 μ g, 100 to 5000 μ g, 100 to 1000 μ g or 100 to 500 μ g.

First active component (formula (I) compound or pharmaceutically acceptable salt thereof) also can be taken orally.The CCR1 receptor antagonist of oral administration can for example be used in drug products or the test kit, and wherein other active component are inhalations.

When inhalation, the dosage of second active component (glucocorticoid) is generally following scope: from 0.1 μ g to 1000 μ g, 0.1 to 500 μ g, 0.1 to 200 μ g, 0.1 to 100 μ g, 0.1 to 50 μ g, 0.1 to 5 μ g, 5 to 1000 μ g, 5 to 500 μ g, 5 to 200 μ g, 5 to 50 μ g, 5 to 10 μ g, 10 to 1000 μ g, 10 to 500 μ g, 10 to 200 μ g, 10 to 100 μ g, 10 to 50 μ g, 20 to 1000 μ g, 20 to 500 μ g, 20 to 200 μ g, 20 to 100 μ g, 20 to 50 μ g, 50 to 1000 μ g, 50 to 500 μ g, 50 to 200 μ g, 50 to 100 μ g, 100 to 1000 μ g or 100 to 500 μ g.

In one embodiment, the amount of used first active component is in the scope of 1 μ g to 200 μ g, and the amount of second composition is in the scope of 1 μ g to 200 μ g.

The mol ratio of second active component and first active component usually can be in 1: 10 to 10: 1 scope in the dosage.Preferably, this ratio is in 1: 1 to 10: 1 scope, and then preferably in 5: 1 to 20: 1 scope.

When existing, the 3rd active component (bronchodilator) can be aptly through inhalation, and dosage is generally following scope: 0.1 to 100 μ g, 0.1 to 50 μ g, 0.1 to 40 μ g, 0.1 to 30 μ g, 0.1 to 20 μ g, 0.1 to 10 μ g, 5 to 100 μ g, 5 to 50 μ g, 5 to 40 μ g, 5 to 30 μ g, 5 to 20 μ g, 5 to 10 μ g, 10 to 100 μ g, 10 to 50 μ g, 10 to 40 μ g, 10 to 30 μ g or 10 to 20 μ g.In embodiments of the present invention, the dosage of the 3rd active component is in the scope of 1 to 30 μ g.

(with the 3rd active component, dosage if present) is generally to divide every day and gives for 1 to 4 time, and aptly once a day or twice, optimum ground once a day for first active component and second active component.

In one embodiment, the invention provides a kind of drug products, its combination comprises first active component, it is formula (I) compound or pharmaceutically acceptable salt thereof, with second active component, it is glucocorticoid and the 3rd optional active component, it is a bronchodilator, and wherein every kind of active component is formulated into inhalation.

Active component is aptly with the form inhalation (for example topical is to lung and/or air flue) of solution, suspensoid, aerosol or dry powder formulations.Administration can be that per os sucks or intranasal sucks.Active component preferably is suitable for from Diskus, pressurised metered dose inhalers or nebulizer together or administration respectively.

Active component can mix use with one or more pharmaceutically acceptable additives, diluent or carrier.The example of the diluent or carrier that is fit to comprises lactose (for example monohydrate), glucosan, mannitol or glucose.

Metered-dose inhaler device can be used for being dispersed in the active component of suitable propellant, wherein contains or does not have extra excipient (for example ethanol), surfactant, lubricant, antioxidant or a stabilizing agent.The propellant that is fit to comprises hydrocarbon, Chlorofluorocarbons and hydrofluoroalkane (for example Sevoflurane) propellant, the perhaps any mixture of described propellant.Preferred propellant is P134a and P227, and they can use separately separately or use with other propellants and/or surfactant and/or other excipient composition.Also can applying unit dosage or the atomizing aqueous suspensions of multiple dose dosage form, perhaps be preferably solution, the pH and/or the tension regulator that wherein contain or do not have to be fit to.

Diskus can be used for giving individually active component or give active component and the combination of pharmaceutically suitable carrier, when giving the combined situation of active component and pharmaceutically suitable carrier, with the powder of fine pulverizing or the form administration of ordered mixture.Diskus can be single dose or multiple dose, and can adopt dry powder or contain the capsule of powder.

When with each active component during together or respectively via the nebulizer administration, they can be the aqueous suspensions or the solvent version of atomizing, wherein contain or not have suitable pH or tension regulator, are single dose or multiple dose device.

Metered dose inhaler, nebulizer and powder inhaler are known, and multiple this class device is obtainable.

In embodiments of the present invention, can be with formula (I) compound or pharmaceutically acceptable salt thereof oral administration, and other active component inhalations.

The present invention further provides in treatment simultaneously, successively or the drug products of the present invention, test kit or the pharmaceutical composition that separately use.

The present invention further provides according to drug products of the present invention, test kit or pharmaceutical composition and be used for the treatment of respiratory system disease, especially the purposes in the medicine of chronic obstructive pulmonary disease or asthma in preparation.

The present invention further provides the method for treatment respiratory system disease, comprises patient while that these needs are arranged, gives successively or separately:

(a) first active component of (treatment is effectively) dosage, it is formula (I) compound or pharmaceutically acceptable salt thereof; With

(b) second active component of (treatment is effectively) dosage, it is a glucocorticoid; With optional

(c) the 3rd active component of (treatment effectively) dosage, it is a bronchodilator.

In the context of present specification, unless opposite specifying arranged in addition, term " treatment " also comprises " prevention ".Term " treatment " and " remedially " also can correspondingly explain.

It is relevant especially with the personnel's of the previous outbreak of suffering from described disease or disease treatment that prevention is considered to, or be considered to the increase danger that is in described disease or disease among personnel's treatment relevant especially.Be in the personnel among the danger that forms disease specific or disease, generally include those personnel of the family history with this disease or disease, or be defined as especially easily suffering from those personnel of this disease or disease by hereditism's test or screening.

Further understand the present invention now with reference to following illustrative embodiment, wherein

Fig. 1 shows that the cell that uses the present invention to be combined in the rat that LPS-stimulates flows into experimental result.

Conventional method

Record on Varian Unity Inova 400 or Varian Mercury VX 300 ¹H NMR spectrum, data are quoted with the form of δZhi, provide with the 1000000/umber (ppm) with respect to interior mark tetramethylsilane (TMS).

Use chloroform-d (δ _H7.27ppm), acetone-d ₆(δ H 2.05ppm) or DMSO-d ₆(δ _H2.50ppm) the center solvent peak as interior mark.

Be furnished with record low resolution mass spectrum and accurate mass measurement in the Agilent MSD 1100LC-MS system of APCI/ESI ionization chamber.

All solvent and commercially available reagent are laboratory-scale, and in statu quo use.

Use following abbreviation:

The DMSO dimethyl sulfoxide;

The DMF dinethylformamide;

The THF oxolane;

The TFA trifluoroacetic acid

The X-ray powder diffraction is analyzed

Can be according to standard method, prepared sample is carried out X-ray powder diffraction (XRPD) to be analyzed (referring to for example Giacovazzo et al., eds., Fundamentals of Crystallography, OxfordUniversity Press (1992), Jenkins ﹠amp; Snyder, eds., Introduction to X-Ray PowderDiffractometry, John Wiley ﹠amp; Sons, New York (1996), Bunn, ed., ChemicalCrystallography, Clarendon Press, London (1948) and Klug ﹠amp; Alexander eds., X-ray Diffraction Procedures, John Wiley ﹠amp; Sons, New York (1974)).

The X-ray powder diffraction figure that obtains the hemifumarate (for anhydrous form) of description in embodiment 1 as described below:

To use the secondary powder x-ray diffraction that focuses on of Bragg-Brentano of monochromatic CuK α radiation (45kV and 40mA) to be used for this analysis.First optics comprises Soller slit and automatic divergent slit (automatic divergence slit).The zero background board (zero background plate) of rotation is gone up the flat sample of preparation during measuring.Second optics comprises Soller slit, automatic anti-scatter slit, receives slit and monochromator.Diffracted signal detects with proportional xenon fill detector.With successive scan pattern, gather the diffraction pattern between 2 °≤2 θ≤40 °, the scanning stride is 0.016 ° of 2 θ, sweep speed be 4 ° of 2 θ/minute.The initial data of stored electrons form.Diffraction pattern original or that smoothing processing is crossed is estimated.

Panalytical X ' the pert PRO MPD θ-θ diffractometer of reflective-mode is used for above-mentioned measurement.Those skilled in the art can be provided with the instrument parameter of powder x-ray diffraction, thereby make it possible to gather and the suitable diffraction data of data that is provided.

The preparation of MIP-1 α chemokine receptor anagonists

Embodiment 1 (a)

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } preparation of acetamide hemifumarate (2: 1 salt)

Went through 15 minutes, to the rough N-{2-[((2S that stirs)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide (24.0g, 36.5mmol; As described in WO 03/051839 embodiment 1, obtain from corresponding salt extraction at pH 9 usefulness trifluoroacetic acids) methanol (240ml) solution, add fumaric acid (2.13g, methanol 18.3mmol) (55ml) solution.Observing when adding about 2/3rds fumaric acid solutions has precipitation to begin to generate.When adding whole fumaric acid solution, stop to stir, reactant mixture is spent the night in the flask of sealing in ambient temperature (20 ℃).The funnel precipitation separation with methanol wash (3x50ml), spends the night at 60 ℃ of vacuum dryings after filtration, obtains title salt, is pale solid (14.0g, 73%).

¹H NMR (399.99MHz, dmso) δ 8.91 (s, 1H), 7.48 (d, J=8.6Hz, 1H), 7.38 (d, J=8.5Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 6.50 (s, 1H), 6.42 (d, J=2.5Hz, 1H), 6.31 (dd, J=8.6,2.5Hz, 1H), 3.79 (s, strong coupling AB-systems, 2H), 3.44 (s, 2H), 2.88 (d, J=12.2Hz, 1H), 2.82-2.72 (m, 3H), 2.64-2.55 (m, 1H), 2.02 (s, 3H), 2.00-1.92 (m, 2H), 1.91-1.83 (m, 2H), 1.47-1.35 (m, 2H), 1.23 (s, 3H)

APCI-MS：m/z?462[MH+]

NMR confirms that the alkali and the stoichiometric proportion of acid are 2: 1.

Hemifumarate show following at least characteristic X-ray powder diffraction (XRPD) peak (expressing) with ° 2 θ (limit of error is consistent about the general rules (USP941) of X-ray diffraction with American Pharmacopeia---referring to United States Pharmacopeia Convention.X-Ray Diffraction, General Test＜941〉.United States Pharmacopeia, 25th ed.Rockville, MD:United StatesPharmacopeial Convention; 2002:2088-2089):

(1) 6.2,10.7 and 12.5, perhaps

(2) 6.2,10.7 and 18.8, perhaps

(3) 6.2,10.7 and 18.0, perhaps

(4) 6.2,10.7,12.5,18.0 and 18.8, perhaps

(5) 6.2,10.7,12.5,18.0,18.8,19.7 and 19.8.

Embodiment 1 (b)

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide benzoate (1: 1 salt), the preparation of A type

(a) with N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide (can be by WO 03/051839 described method preparation; 462mg, (244mg, ethyl acetate 2.0mmol) (10ml) solution mixes for (10ml) hot solution of ethyl acetate 1.0mmol) and benzoic acid.Make the gained mixture in the bottle of sealing, be cooled to ambient temperature (20 ℃).Find that the adularescent precipitation generates, and does not have muddiness.After the ambient temperature placement is spent the night, obtain precipitation, with ethyl acetate washing (3x10ml) precipitation, spend the night at 60 ℃ of vacuum dryings, obtain title salt, be pale solid (506mg, 86%).This salt contains the ethyl acetate of trace.

¹H NMR (399.99MHz, acetone-d ₆) δ 8.77 (s, 1H), 8.07-8.04 (m, 2H), 7.83 (d, J=8.7Hz, 1H), 7.55-7.50 (m, 1H), 7.46-7.41 (m, 2H), and 7.36-7.31 (m, 4H), 6.52 (d, J=2.6Hz, 1H), 6.40 (dd, J=8.7,2.6Hz, 1H), 3.97 (d, J=9.3Hz, 1H), 3.89 (d, J=9.3Hz, 1H), 3.48 (s, 2H), 3.29 (d, J=12.1Hz, 1H), 2.94 (d, J=12.2Hz, 1H), 2.91-2.77 (m, 3H), 2.09-2.00 (m, 4H), 1.98 (s, 3H), 1.72-1.59 (m, 2H), 1.30 (s, 3H)

APCI-MS：m/z?462[MH+]

NMR confirms that the alkali and the stoichiometric proportion of acid are 1: 1.

Prepare the more title salt of volume by following method:

(b) with N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide (4.0g, 8.65mmol) ethyl acetate (75ml) hot solution and benzoic acid (1.16g, ethyl acetate 9.5mmol) (75ml) solution mixes.When the gained mixture had been cooled to ambient temperature (20 ℃), the usefulness as above granule of (a) gained title salt was carried out kind of a crystalline substance to it, spent the night in the flask of sealing.Resulting precipitation is spent the night at 60 ℃ of vacuum dryings with ethyl acetate washing (3x50ml), obtains title salt, is pale solid (4.41g, 87%).This salt contains the ethyl acetate of trace.

Benzoate A type show following at least characteristic X-ray powder diffraction (XRPD) peak (expressing) with ° 2 θ (limit of error is consistent about the general rules (USP941) of X-ray diffraction with American Pharmacopeia---referring to United States Pharmacopeia Convention.X-Ray Diffraction, General Test＜941〉.United States Pharmacopeia, 25th ed.Rockville, MD:United StatesPharmacopeial Convention; 2002:2088-2089):

(1) 6.1,10.7 and 19.3, perhaps

(2) 6.1,12.2 and 14.1, perhaps

(3) 6.1,10.7,12.2,14.1,18.1 and 19.3, perhaps

(4) 6.1,10.7,12.2,14.1,15.7,18.1 and 19.3, perhaps

(5) 6.1,10.7,12.2,14.1,15.1 and 19.3, perhaps

(6) 6.1,10.7,12.2,14.1,15.1,15.7,18.1 and 19.3, perhaps

(7) 6.1,10.7,12.2,14.1,15.1,15.7,18.1,19.3,21.2 and 24.6.

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide benzoate (1: 1 salt), the preparation of Type B

(a) will place differential scanning calorimetry dish (having the lid that curls) by the benzoate (A type, 10 to 15mg) of embodiment 1 (b) method preparation, heat with the rate of heat addition of 5K/min, until the temperature that reaches 155 ℃.In case salt fusing (recording initial fusion temperature under used condition is 146.5 ℃) is cooled to ambient temperature (20 ℃) with melting the speed of sample with 5K/min.And then,, go through the scanning isothermal line of 148 ℃ of 10 minutes records until the temperature that reaches 151 ℃ with the rate of heat addition heated sample dish of 5K/min.To coil then and be cooled to ambient temperature rapidly, cause crystalline formation, with after X-ray powder diffraction (XRPD) turns out to be N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } novel crystal forms (Type B) of acetamide benzoate.Some amorphous benzoates may form the by-product of this method.

(b) the Type B salt in above-mentioned (a) also is prepared as follows: in bottle, the benzoate sample (A type) by embodiment 1 (b) method preparation of 20%w is dissolved in solvent, for example methanol (＞20mg/ml), ethanol (＞20mg/ml), normal propyl alcohol (＞20mg/ml), isopropyl alcohol (8.5mg/ml) or acetone (9.6mg/ml).The estimation dissolubility of the described salt of numeral in these solvents in the bracket.Sealed vial utilizes magnet at ambient temperature (20 ℃) homogenize suspension then.Insulated and stirred at least 7 days then with the products therefrom sample drying, is carried out the XRPD test.XRPD confirms that the A type has been converted into Type B fully.

(c) the Type B salt in above-mentioned (a) also is prepared as follows: will be by benzoate (A the type) (22.0g of embodiment 1 (b) method preparation in round-bottomed flask, 37.7mmol) and benzoic acid (0.46g, 3.8mmol) be dissolved in the hot 2-propanol (190ml), obtain blush solution.Utilize the rotary evaporator rotary flask in 40 ℃ of water-baths, be cooled to 40 ℃ until solution, this moment, the crystal with some Type B salt carried out kind of a crystalline substance to it.Make water-bath slowly cool to ambient temperature and spend the night, the while rotary flask, the crystal with some Type B salt carries out kind of a crystalline substance to mixture once in a while.Pink that isolated at suction generated precipitation with 2-propanol washing (2x50ml), 100 ℃ of vacuum dryings 20 hours, obtains title salt (confirming through XRPD), is rose pink solid (18.5g, 84%).This salt contains the 2-propanol of trace.

¹H?NMR(299.95MHz，DMSO-d6)δ8.87(s，1H)，7.96-7.91(m，2H)，7.59-7.52(m，1H)，7.49-7.47(m，1H)，7.46-7.42(m，2H)，7.36(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，2H)，6.39(d，J＝2.5Hz，1H)，6.29(dd，J＝8.5，2.5Hz，1H)，3.78-3.72(m，2H)，3.41(s，2H)，2.79-2.66(m，4H)，1.98(s，3H)，1.97-1.88(m，2H)，1.85-1.76(m，2H)，1.41-1.25(m，2H)，1.19(s，3H)

APCI-MS：m/z?462[MH+]

The benzoate Type B show following at least characteristic X-ray powder diffraction (XRPD) peak (expressing) with ° 2 θ (limit of error is consistent about the general rules (USP941) of X-ray diffraction with American Pharmacopeia---referring to United States Pharmacopeia Convention.X-Ray Diffraction, General Test＜941〉.United States Pharmacopeia, 25th ed.Rockville, MD:United StatesPharmacopeial Convention; 2002:2088-2089):

(1) 6.5,9.3 and 10.5, perhaps

(2) 6.5,9.3,17.6 and 17.8, perhaps

(3) 6.5,9.3,10.5,12.0 and 12.4, perhaps

(4) 6.5,9.3,10.5,12.0,12.4,13.0,13.6,15.5,17.6 and 17.8, perhaps

(5) 6.5,13.0 and 20.2, perhaps

(6) 6.5,9.3,10.5,12.0,12.4,13.0,13.6,15.5,17.6,17.8 and 19.2, perhaps

Embodiment 1 (c)

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide furoate (1: 1 salt), the preparation of A type

(a) in bottle, to the N-{2-[((2S that stirs)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide (can be by WO 03/051839 described method preparation; 46mg, 0.1mmol) (23mg in methanol 0.2mmol) (0.2ml) solution, adds ether (5ml), sealed vial with furancarboxylic acid.The gained mixture was stirred 3 days, separate the precipitation that is generated,,, obtain pale solid (38mg) at vacuum drying with the ether washing.This solid contains title salt, is crystalline material, and some amorphous salts.Title salt contains the ether of trace.

¹H?NMR(299.946MHz，DMSO-d ₆)δ8.92(s，1H)，7.75-7.73(m，1H)，7.46(d，J＝8.6Hz，1H)，7.37(d，J＝4.4Hz，2H)，7.29(d，J＝4.4Hz，2H)，6.97-6.94(m，1H)，6.54(dd，J＝3.4，1.7Hz，1H)，6.40(d，J＝2.4Hz，1H)，6.29(dd，J＝8.6，2.4Hz，1H)，3.78(s，2H)，3.43(s，2H)，2.93(d，J＝12.1Hz，1H)，2.84-2.71(m，3H)，2.70-2.58(m，1H)，1.99(s，3H)，1.96-1.83(m，4H)，1.51-1.34(m，2H)，1.22(s，3H)

APCI-MS：m/z?462[MH+]

Prepare the more title salt of volume by following method:

(b) to the N-{2-[((2S that in bottle, contains)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide (230mg, 0.5mmol) methanol (0.5ml) solution in, adding furancarboxylic acid solid (62mg, 0.55mmol).Shake mixture, until obtaining solution.With solution usefulness ethyl acetate (6ml) dilution, the usefulness as above granule of (a) gained title salt is carried out kind of a crystalline substance to it, places in the bottle of sealing and spends the night.The gained precipitation with the ethyl acetate washing, is spent the night at 60 ℃ of vacuum dryings, obtain title salt, be pale solid (200mg, 70%).Title salt contains the ethyl acetate of trace.

¹H?NMR(299.946MHz，DMSO-d ₆)δ8.94(s，1H)，7.73-7.71(m，1H)，7.47(d，J＝8.6Hz，1H)，7.37(d，J＝8.4Hz，2H)，7.30(d，J＝8.4Hz，2H)，6.94-6.91(m，1H)，6.52(dd，J＝3.3，1.8Hz，1H)，6.40(d，J＝2.2Hz，1H)，6.30(dd，J＝8.6，2.2Hz，1H)，3.78(s，2H)，3.43(s，2H)，2.97(d，J＝11.9Hz，1H)，2.87-2.61(m，4H)，1.98(s，3H)，1.96-1.85(m，4H)，1.53-1.38(m，2H)，1.23(s，3H)

APCI-MS：m/z?462[MH+]

Furoate A type show following at least characteristic X-ray powder diffraction (XRPD) peak (expressing) with ° 2 θ (limit of error is consistent about the general rules (USP941) of X-ray diffraction with American Pharmacopeia---referring to the United States Pharmacopeia Convention.X-Ray Diffraction, General Test＜941〉.United States Pharmacopeia, 25th ed.Rockville, MD:United StatesPharmacopeial Convention; 2002:2088-2089):

(1) 6.3,11.0 and 12.7, perhaps

(2) 6.3,10.7 and 12.7, perhaps

(3) 6.3,11.0,12.7 and 15.9, perhaps

(4) 6.3,10.7,11.0,12.7,13.9,14.2 and 15.9, perhaps

(5) 6.3,10.7,11.0,12.7,15.9,17.7,19.1,19.7 and 25.5, perhaps

(6) 6.3,10.7,11.0,12.7,13.9,14.2,15.9,17.7,19.1,19.7,19.9,21.6 and 25.5.

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide furoate (1: 1 salt), the preparation of Type B

(a) Type B is prepared as follows: in bottle, the furoate sample (A type) by embodiment 1 (b) method preparation of 20%w is dissolved in solvent, for example ethanol (16mg/ml) or 2-butanols (8mg/ml).The estimation dissolubility of the described salt of numeral in these solvents in the bracket.Sealed vial utilizes magnet at ambient temperature (20 ℃) homogenize suspension then.Insulated and stirred at least 7 days then with the products therefrom sample drying, is carried out the XRPD test.XRPD confirms that the A type has been converted into Type B fully.

Prepare the more title salt of volume by following method:

(b) with N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide (46mg, 0.10mmol) 2-butanols (0.5ml) solution and furancarboxylic acid (12.5mg, 0.11mmol) 2-butanols (0.5ml) solution mix, carry out kind of a crystalline substance with some Type B crystal.With mixture in ambient temperature, in the bottle of sealing, placed 3 days.The gained precipitation with the washing of 2-butanols, is spent the night at 60 ℃ of vacuum dryings, obtain title salt, be pale solid.This salt contains the 2-butanols of trace.

NMR confirms that alkali and the character and the stoichiometric proportion of acid are 1: 1.

The furoate Type B show following at least characteristic X-ray powder diffraction (XRPD) peak (expressing) with ° 2 θ (limit of error is consistent about the general rules (USP941) of X-ray diffraction with American Pharmacopeia---referring to the United States Pharmacopeia Convention.X-Ray Diffraction, General Test＜941〉.United States Pharmacopeia, 25th ed.Rockville, MD:United StatesPharmacopeial Convention; 2002:2088-2089):

(1) 6.7,11.0 and 13.4, perhaps

(2) 6.7,10.4,11.0 and 13.4, perhaps

(3) 6.7,10.4,12.4,13.4 and 13.7, perhaps

(4) 6.7,10.4,13.4 and 20.9, perhaps

(5) 6.7,10.4,11.0,12.4,13.4,13.7,15.6,16.0 and 17.6, perhaps

Embodiment 2

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } propionic acid amide. two-trifluoroacetate.

(i) N-(2-hydroxyl-4-methoxyphenyl) propionic acid amide.

(600mg, 3.4mmol) dichloromethane (25mL) solution with triethylamine (3 equivalent) drips propionic andydride (1.1 equivalent) to ice-refrigerative 2-hydroxyl-4-aminoanisole HCl.Solution is placed 5h in ambient temperature.Water cancellation reaction separates each layer, and organic facies extracts (3x25mL) with 1N NaOH (aqueous solution).The pH of water is adjusted to 5 with dense HCl, with dichloromethane extraction (3x25mL).Organic facies is filtered through anhydrous sodium sulfate drying, and vacuum is removed, and obtains the subhead chemical compound, is brown solid (555mg, 83%).

¹H?NMR(300MHz，CDCl ₃-d ₆)δ7.04(b)，6.83(d，J＝8.4，1H)，6.58(d，J＝2.8，1H)，6.43(dd，J ₁＝8.4，J ₂＝2.8，1H)，3.77(s，3H)，2.49(q，J＝7.6，2H)，1.29(t，J＝7.5，3H)；APCI-MS：m/z?196[MH ⁺].

(ii) N-(5-chloro-2-hydroxyl-4-methoxyphenyl) propionic acid amide.

(500mg, 2.6mmol) DMF (5mL) solution with dimethyl formamide hydrochlorate (1 equivalent) adds a MCPBA (70%, 1 equivalent) by part to ice-refrigerative N-(2-hydroxyl-4-methoxyphenyl) propionic acid amide..With reactant mixture restir 5 minutes, use 1M NaHCO then ₃(aqueous solution) (50mL) cancellation.Water washs with ethyl acetate (50mL).Organic facies is washed with water (3x25mL), drying, vacuum is removed, and obtains the subhead chemical compound, is purple solid (408mg, 71%).

¹H NMR (300MHz, acetone-d ₆) δ 9.68 (b, 1H), 9.12 (b, 1H), 7.37 (s, 1H), 6.62 (s, 1H), 3.83 (s, 3H), 2.49 (q, J=7.7,2H), 1.18 (t, J=7.5,3H); APCI-MS:m/z 229[M ⁺].

(iii) N-(5-chloro-4-methoxyl group-2-{[(2S)-methyl oxirane-2-yl] methoxyl group } phenyl) propionic acid amide.

With N-(5-chloro-2-hydroxyl-4-methoxyphenyl) propionic acid amide. (202mg, 0.88mmol), [(2S)-2-methyl oxirane-2-yl] methyl 3-nitrobenzene-sulfonic acid ester (1 equivalent) and the suspension of cesium carbonate (1.2 equivalent) in DMF (4mL) be in stirring at room 4h.Water (50mL) and ethyl acetate (50mL) separating mixture.Organic facies is washed with water (2x30mL), drying, vacuum is removed, and obtains the subhead chemical compound, is pale solid (249mg, 95%).

¹H?NMR(300MHz，CDCl3)δ8.43(s，1H)，7.80(b，1H)，6.61(s，1H)，4.14(m，1H)，3.98(m，1H)，3.85(s，3H)，2.94(m，1H)，2.79(m，1H)，2.42(q，J＝7.6，2H)，1.47(s，3H)，1.25(t，J＝7.5，3H)；APCI-MS：m/z?299[MH+].

(iv) N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl third Base) oxygen base]-the 4-hydroxy phenyl } propionic acid amide. two-trifluoroacetate

(50mg, 0.2mmol) acetonitrile (5mL) solution with N-(5-chloro-4-methoxyl group-2-{[(2S)-methyl oxirane-2-yl] methoxyl group } phenyl) propionic acid amide. (1 equivalent) adds lithium perchlorate (10 equivalent) to 1-(4-benzyl chloride base)-piperidin-4-yl amine.Make reaction mixture refluxed 18h.Reactant mixture is poured over (Bond Elut on the MEGABE-SCX post

, 5g, 20mL).This post is at first used methanol wash (3x10mL), and usefulness ammonia/carbinol mixture washing subsequently (1/20,3x10mL).Compile alkaline layer, solvent removed in vacuo obtains N-{5-chloro-2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-the 2-hydroxypropyl) the oxygen base]-the 4-methoxyphenyl } propionic acid amide., be light brown oil (100mg, 86%), is dissolved in dichloromethane (4mL) again.Solution is cooled to 0 ℃, drips 1M BBr ₃Dichloromethane solution (1mL).Reactant mixture is stirred 18h, use the methanol cancellation then.Solvent removed in vacuo, residue is through anti-phase preparation HPLC purification (use contains the acetonitrile of 0.1%TFA and water gradient as mobile phase).The fraction that lyophilization compiled obtains title product, is amorphous white solid (38mg, 39%).

¹H NMR (300MHz, the δ 8.66 (broad peak) of acetone-d6), 8.09 (3,1H), 7.60 (d, J=8.4,4H), 7.47 (d, J=8.4,4H), 6.78 (s, 1H), 4.41 (s, 2H), 4.10-3.93 (m, 2H), and 3.70-3.65 (m, 4H), 3.44-2.39 (m, 1H), 3.20 (m, 2H), 2.52-2.37 (m, 6H), 1.38 (s, 3H), 1.10 (t, J=7.5,3H); APCI-MS:m/z 510[MH+].

Embodiment 3

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide two-trifluoroacetate.

Synthetic to be similar to embodiment 2 described, but 2-hydroxyl-4-aminoanisole HCl and acetic anhydride (1.1 equivalent) are reacted.

¹H NMR (300MHz, acetone-d ₆) δ 8.77 (s, 1H), 8.06 (s, 1H), 7.61 (d, J=8.2Hz, 2H), 7.47 (d, J=8.6Hz, 2H), 6.79 (s, 1H), 4.43 (s, 2H), 4.08 (d, J=9.9Hz, 1H), 3.94 (d, J=9.9Hz, 1H), 3.79-3.61 (m, 3H), 3.68 (d, J=12.5Hz, 1H), 3.42 (d, J=12.7Hz, 1H), 3.32-3.13 (m, 2H), 2.63-2.48 (m, 2H), 2.49-2.29 (m, 2H), 2.08 (s, 3H), 1.38 (s, 3H); APCI-MS:m/z 496[MH ⁺].

Embodiment 4

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-the 2-hydroxypropyl) the oxygen base]-the 4-hydroxy phenyl } acetamide two-trifluoroacetate.

Synthetic to be similar to embodiment 3 described, but N-(5-chloro-2-hydroxyl-4-methoxyphenyl) acetamide and S-(+)-glycidyl nitrobenzene-sulfonic acid ester (1 equivalent) are reacted.

¹H NMR (300MHz, acetone-d ₆) δ 8.64 (broad peak, NH), 8.21 (s, 1H), 7.59 (d, J=9.0Hz, 2H), 7.47 (d, J=9.0Hz, 2H), 6.74 (s, 1H), 4.41-4.35 (m, 3H), 4.13-4.01 (m, 2H), 3.69-3.40 (m, 5H), 3.14 (m, 2H), 2.55-2.47 (m, 2H), 2.31 (m, 2H), 2.09 (s, 3H); APCI-MS:m/z 482[MH ⁺].

Embodiment 5

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-the 2-hydroxypropyl) the oxygen base]-the 4-hydroxy phenyl } propionic acid amide. two-trifluoroacetate.

Synthetic to be similar to embodiment 2 described, but N-(5-chloro-2-hydroxyl-4-methoxyphenyl) acetamide and S-(+)-glycidyl nitrobenzene-sulfonic acid ester (1 equivalent) are reacted.

¹H NMR (300MHz, DMSO-d ₆) δ 10.05 (broad peak), 9.78 (broad peaks), 9.79 (broad peaks), 9.00 (broad peaks), 8.88 (broad peaks), 7.79 (m, 1H), 7.62-7.50 (m, 4H), 6.63 (s, 1H), 5.98 (broad peaks), 4.29 (m, 2H), 4.16 (m, 1H), 3.95-3.88 (m, 2H), 341-2.97 (m, 7H), 2.35-2.22 (m, 4H), 1.82-1.75 (m, 2H), 1.07 (m, 3H); APCI-MS:m/z 496[MH ⁺].

People CCR1 is in conjunction with mensuration

Film

Use the HEK293 cell (HEK-CCR1) (available from ECACC) of stably express recombined human CCR1, preparation comprises the cell membrane of CCR1.Film is stored in-70 ℃.Every batch film concentration is adjusted into the bonded 33pM[of 10% specificity ¹²⁵I] MIP-1 α.

In conjunction with measuring

The HEK-CCR1 film is diluted in is added with 17500 units/L bacitracin (Sigma, Cat NoB1025) mensuration pH of buffer 7.4 (137mM NaCl (Merck, Cat No 1.06404), 5.7mM glucose (Sigma, Cat No G5400), 2.7mM KCl (Sigma, Cat No P-9333), 0.36mMNaH ₂PO ₄* H ₂O (Merck, Cat No 1.06346), 10mM HEPES (Sigma, Cat NoH3375), 0.1% (w/v) gelatin (Sigma, Cat No G2625)) in, 100 these diluents of μ L are added in each hole of 96 hole screen plates (the opaque Millipore cat of 0.45 μ m no MHVB N4550).Add the mensuration buffer (comprising 10%DMSO) of 12 μ L chemical compounds, making final compound concentration is 1 * 10 ^-5.5To 1 * 10 ^-9.5M.Comprise the cold people of 12 μ l recombinate MIP-1 α (270-LD-050, R﹠amp in some hole (not having chemical compound); D Systems, Oxford, UK) (ultimate density in being supplemented with the mensuration buffer of 10%DMSO is 10nM) is as non-specific binding contrast (NSB).The mensuration buffer that 12 μ l is had 10%DMSO adds to some hole (not having chemical compound), to detect maximum combined (B0).

With 12 μ l[ ¹²⁵I] MIP-1 α add to institute porose in, making its ultimate density that is diluted in each hole in measuring buffer is 33pM.Then, the plate that will have a lid in room temperature was hatched 1.5 hours.After hatching, (MultiScreen Resist Vacuum Manifold System Millipore) empties each hole to vacuum filtration, measures the buffer washing once with 200 μ l.After the washing, the extra 50 μ L scintillation solutions of porose acceptance (OptiPhase " Supermix ", Wallac Oy, Turko, Finland).Use Wallac Trilux1450MicroBeta enumerator, measure bonded [ ¹²⁵I] MIP-1 α.Window is provided with (windows setting): low high 1020,1 minutes counting/holes of 5-.

Calculate displacement percentage ratio and IC ₅₀

Following equation is used for calculating displacement percentage ratio.

Displacement percentage ratio=1-((cpm test-cpm NSB)/(cpm B0-cpm NSB))

Wherein

Cpm test=contain film and chemical compound and [ ¹²⁵I] average cpm (counting of per minute) in the duplicate hole of MIP-1 α;

NSB=contain film and MIP-1 α and [ ¹²⁵I] average cpm in the hole of MIP-1 α (non-specific binding);

B0=contain film and measure buffer and [ ¹²⁵I] average cpm in the hole of MIP-1 α (maximum combined).

Use becomes 4-parameter l ogistics function based on the program XLfit (2.0.9 version) of Excel with data fitting, derives to produce 50% metathetical chemical compound molar concentration (IC ₅₀).

All embodiment 1 to 5 chemical compound all has the IC less than 20nM ₅₀Value.

Inflammatory cell in the LPS-stimulation in rats flows into experiment

By the effect of monitoring to total cell number in bronchus of rat alveolar wass (BAL) liquid that stimulates with (i.t.) in lipopolysaccharide (LPS) trachea, measure CCR1 receptor antagonist (N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide hemifumarate (2: 1 salt), here be called compd A), budesonide, and their combination effect (N=10 rat/disposal group) that inflammatory cell is flowed into.

Method

LPS instils: with rat with enflurane (Efrane) anesthesia, with supine position on 30 ° the plate of tilting, head-up.Utilize modified metal sleeve pipe i.t. to give saline (0.9%NaCl) solution of LPS (lipopolysaccharide B.E.coli 026:B6) (2.5 μ g/ml) or independent saline (negative control), volume is 200 μ L.Make rat keep this position until reviving.

The preparation of solution: will be dissolved in ethanol through the budesonide of homogenize, and mix with 0.9%NaCl solution then, ultimate density is 0.002mg budesonide/mL.Compd A is dissolved in 0.9%NaCl solution, and ultimate density is 0.034mg compd A/mL.Be prepared as follows budesonide/compd A mix preparation, compd A is dissolved in the budesonide suspension, ultimate density is 0.034mg compd A/mL and 0.002mg budesonide/mL.

Dispose: to animal intratracheal instillation budesonide/compd A (0.002/0.034mg/kg) or independent budesonide (0.002mg/kg) or independent compd A (0.34mg/kg) or brinish solution (1mL/kg) (negative and positive control animal).Under slight anesthesia (Efrane), dispose, reach lung to guarantee solution.30min before LPS instils gives medicine.

Stop: LPS stimulated back 4 hours, and (60mg/ml, Apoteksbolaget Sweden) (0.3mL) reach 1-2min with the mixture (1: 1) of PBS to inject pentobarbital in rat peritoneum.

Bronchoalveolar lavage (BAL): after the termination, carry out BAL twice with PBS.BAL liquid is centrifugal, cell precipitation is suspended among the PBS again.The sum of counting BAL cell in the SYSMEX cell counter.

Experimental result as shown in Figure 1.Among Fig. 1, " saline/saline " rat is represented usefulness saline treatment and the negative control rat that stimulates with saline." saline/LPS " animal is represented usefulness saline treatment and the positive control rat that stimulates with LPS.Its excess-three group is all handled with specific drug and is stimulated with LPS.

Claims

1. drug products, its combination comprises

Wherein

M is 0,1 or 2;

Each R ¹Represent halogen or cyano group independently;

R ²Expression hydrogen atom or methyl;

R ³Expression C ₁-C ₄Alkyl; With

R ⁴The expression hydrogen or halogen; With

(b) second active component, it is a glucocorticoid.

2. the product of claim 1, wherein R ¹It is halogen.

3. the product of claim 1 or claim 2, wherein R ⁴Be hydrogen or chlorine.

4. the product of claim 1 or claim 2, wherein R ⁴Be hydrogen.

5. each product, wherein R during aforesaid right requires ³Be methyl or ethyl.

6. each product during aforesaid right requires, wherein said first active component is selected from

N-{2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide;

N-{5-chloro-2-[((2S)-and 3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } acetamide;

Or its officinal salt.

7. each product during aforesaid right requires, wherein said first active component is a salt, and described salt is selected from N-{2-[((2S)-3-{[1-(4-benzyl chloride base) piperidin-4-yl] amino }-2-hydroxy-2-methyl propyl group) the oxygen base]-the 4-hydroxy phenyl } benzoate, furoate or the hemifumarate of acetamide.

8. each product during aforesaid right requires, wherein glucocorticoid is a budesonide.

9. each product during aforesaid right requires, it further comprises the 3rd active component, and it is a bronchodilator.

10. the product of claim 9, wherein said the 3rd active component is β ₂-agonist.

11. the product of claim 10, wherein said the 3rd active component is selected from formoterol or indenes Da Teluo.

12. the product of claim 11, wherein said the 3rd active component is a formoterol.

13. the product of claim 12, wherein said the 3rd active component is a formoterol fumarate dihydrate.

Each product during 14. aforesaid right requires, it is the form that is suitable for inhalation.

Each product during 15. aforesaid right requires, it is used for the treatment of.

16. each product was used for the treatment of purposes in the medicine of respiratory system disease in preparation during aforesaid right required.

17. the purposes of claim 16, wherein said respiratory system disease is a chronic obstructive pulmonary disease.

18. the purposes of claim 16, wherein said respiratory system disease is an asthma.

19. the method for treatment respiratory system disease, this method comprise patient's while that described needs are arranged, give successively or separately:

(a) first active component of (treatment is effectively) dosage, it is as each defined formula (I) compound or pharmaceutically acceptable salt thereof in the claim 1 to 7;

(b) second active component of (treatment is effectively) dosage, it is a glucocorticoid; Randomly

20. test kit, it comprises the prepared product of first active component, first active component is as each defined formula (I) compound or pharmaceutically acceptable salt thereof in the claim 1 to 7, prepared product with second active component, second active component is a glucocorticoid, with optional description, described description is used for giving described prepared product simultaneously, successively or separately to the patient that described needs are arranged.

21. the test kit of claim 20, wherein said first active component is selected from

Or its officinal salt.

22. the test kit of claim 20 or claim 21, wherein glucocorticoid is a budesonide.

23. each test kit in the claim 20 to 21, it further comprises the prepared product of the 3rd active component, and the 3rd active component is a bronchodilator.

24. the test kit of claim 23, wherein said the 3rd active component is β ₂-agonist.

25. the test kit of claim 24, wherein said the 3rd active component are formoterol or indenes Da Teluo.

26. the test kit of claim 25, wherein said the 3rd active component is a formoterol.

27. the test kit of claim 26, wherein said the 3rd active component is a formoterol fumarate dihydrate.

28. pharmaceutical composition, its mixing comprises first active component, and it is that it is a glucocorticoid as each defined formula (I) compound or pharmaceutically acceptable salt thereof and second active component in the claim 1 to 7.

29. the compositions of claim 28, wherein said first active component is selected from

Or its officinal salt.

30. the compositions of claim 28 or claim 29, wherein glucocorticoid is a budesonide.

31. each compositions in the claim 29 to 30 further comprises the prepared product of the 3rd active component, the 3rd active component is a bronchodilator.

32. the compositions of claim 31, wherein said the 3rd active component is β ₂-agonist.

33. the compositions of claim 31, wherein said the 3rd active component are formoterol or indenes Da Teluo.

34. the compositions of claim 32, wherein said the 3rd active component is a formoterol.

35. the compositions of claim 34, wherein said the 3rd active component is a formoterol fumarate dihydrate.