CN101155811A - Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases - Google Patents

Abstract

The invention provides compounds of general formula wherein R and R<SUP>1</SUP> are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Description

The purposes of the disease of novel diazaspiroalkanes and their treatment CCR8 mediations

Technical field

The present invention relates to new diazaspiracyclic compounds, prepare their method, contain their pharmaceutical composition and their purposes in treatment.

Background technology

The initial stage of disease and secular organization restructuring and muscle deterioration depend on white corpuscle raising to inflammatory damage.Leukocyte recruitment relate to white corpuscle by blood vessel in pathological tissues migration and their activation, thereby cause the progress of disease.This potential mechanism (chemotaxis) of raising is similar to immune-mediated pathological conditions (being supersensitivity and autoimmune disorder) and other disease (being atherosclerosis and Parkinson's disease) of typical definition.Therefore, the white corpuscle intervention of raising to the inflammatory target tissue has constituted attracting new treatment principle.

Chemokine is that little 8-to 15-kDa secretes the extended familys (＞50 member) of property heparin in conjunction with polypeptide, and described heparin is leukocytic transportation of control and activation in conjunction with the basic function of polypeptide.According to the structural similarity of being enjoyed, they are different from typical chemoattractant (that is, N-formyl peptides, complement component, lipid molecule and the platelet activation factor of bacterial derivation).All chemokines all have four conserved cysteine residue that form disulfide linkage, and they are vital for the 3-D structure.Position according to preceding two halfcystines can further be divided into subclass to chemokine.Two main subclass are CC-chemokine (wherein halfcystine is adjacent) and CXC-cytokine (wherein halfcystine is separated by an amino acid).Two families in addition, C and CX3C chemokine are wanted much smaller and are included only one or several member.

The specific biological effect of chemokine comprises leukocyte recruitment, this specific biological effect be by with seven-family of striding film G-protein linked receptor (GPCRs) interacts and mediates.The length of these Chemokine Receptors is about 350 amino acid, is made of C-end in short extracellular N-end, seven-transmembrane fragment and the cell.This seven-transmembrane structural domain is an alpha-helical, and has ring (intracellular loop) and 3 extracellular loop (extracellular loop) in 3 cells between these structural domains.

Up to the present, 18 kinds of human chemokine receptors have been identified.Wherein, 11 kinds of CC-chemokine receptor are arranged, 5 kinds of CXC acceptors, a kind of CX3C acceptor and a kind of C acceptor.Usually, the CC chemokine is monocyte and lymphocytic potent chemoattractant, but is the weak activator of neutrophil.The multiple chemokine of some receptors bind, for example CCR1 is in conjunction with CCL3, CCL5, CCL7 and CCL8, however other Chemokine Receptors has more limited binding pattern.This ligand specificity and the Chemokine Receptors expression pattern on the particular leukocyte subclass has been explained adjusting, the limited and specific transportation of cell to inflammatory damage.Inflammatory cell is that the signal of the intracellular cytoplasmic tail mediation by Chemokine Receptors causes towards the chemotaxis of chemokine gradient.Downstream signal relates in particular to PI3K γ, MAPK and PKC approach.

Immunocyte occurred in the post-stimulatory 6-48 of allergen hour in locational gathering of allergic inflammation, and this gathering is the sign of allergic disease.Studies show that, detect antigen-specific C D4 in the lung tissue of the asthmatic patient after being exposed to allergen ⁺The T cell.Although compare with eosinophil, wetting property T cell quantitatively relatively seldom, compellent evidence has proved that the T cell plays an important role in the inflammatory processes of development people asthma.There is confidential relation between the TH2 cytokine levels that is produced by the T cell among the mankind, the serum level of IgE and the asthma morbidity.

Shown that people CCR8 acceptor and human chemokine CCL1 (I-309) interact.This chemokine is potent eosinophil, T cell and endotheliocyte chemistry decoy.In the presence of costimulatory signal (being CD28), after best TCR was crosslinked, this receptor had demonstrated instantaneous on polarized T H2 cell and has just regulated.CCR8 just regulates collaborative on activating T cell after the antigenic stimulation, shows the redistribution that it helps the inflammatory lesions of activated T cell to the inflammation tissue of expressing CCL1.In fact, the body inner model of supersensitivity airway inflammation has demonstrated effector T cell to the raising and dark blocking-up that the TH2 cytokine produces of inflammatory lung tissue, and the body inner model of described supersensitivity airway inflammation uses CCR8 to express insufficient mouse.In addition, the T cell of infiltration people air flue epithelium has been shown as the CCR8 positive in the allergen stimulating course.Importantly, the number that migrates to the submucosal CCR8 positive cell of air flue after allergen stimulates has demonstrated relevant with the minimizing of FEV1.

Consider the vital role that CCR8 is risen in the TH2 cell chemotaxis, and the importance of TH2 cell in supersensitivity illness such as asthma, CCR8 represents to be used for the treatment of the good target of the drug development of respiratory system disease (comprising asthma, chronic obstructive pulmonary disease and rhinitis).

International Patent Application WO 2005/040167 has been described has active diazaspiracyclic compounds to the CCR8 acceptor.

The desirable properties of the medicine that the CCR8 acceptor is worked is that it has high-effect, is for example suppressed the determined usefulness of ability of CCR8 receptor active by its.The metabolic stability of also expecting this medicine is good, thereby improves drug effect.To the metabolic stability of vitro human microsome is the indication of internal metabolism stability.

The present inventor has determined one group of compound, and it demonstrates to high-effect (definite with combining of CCR8 by suppressing CCL1) of CCR8 with to the unexpected combination of the metabolic good stability of vitro human microsome.

Summary of the invention

The invention provides formula (II) compound or its pharmacy acceptable salt:

Wherein R represents following group:

Or

R wherein ²And R ³Expression-NR independently ⁸-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH, or-COOH;

R ⁴And R ⁶Represent halogen, CF independently of one another ₃Or C _1-4Alkyl;

R ⁸Be hydrogen or C _1-4Alkyl;

P and q are 0,1 or 2 independently;

R ¹Represent following group:

Or

R ⁶And R ⁷Be hydrogen, methoxy or ethoxy independently.

No matter term " alkyl " is during separately or as another group a part of, comprises straight chain and branched-chain alkyl.

Be not subjected to any concrete one theory, think that carboxyl can help to improve metabolic stability, and the phenoxy group-benzyl on molecule right side can help to improve CCR8 usefulness.

Have high CCR8 usefulness and the compound of the particularly advantageous of vitro human microsome metabolic stability combination is found to be R ⁶And R ⁷Compound for methoxyl group.Therefore, in the specific embodiment of the present invention, R ⁶And R ⁷Be methoxyl group.

R ²And R ³Independently expression-NH-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH, or-COOH.Work as R ²And R ³Expression-O-(C _1-4Alkyl)-COOH, or-C _1-4During alkyl-COOH, preferred group is-O-CH ₂-COOH ,-O-(CH ₂) ₂-COOH ,-CH ₂-COOH or-(CH ₂) ₂-COOH.

In an embodiment of the invention, R ²And R ³Expression-O-CH independently ₂-COOH or-CH ₂-COOH.

In another embodiment of the present invention, R ²And R ³Expression-CH independently ₂-COOH.

R ⁴And R ⁵Represent halogen (for example chlorine, fluorine or bromine) independently of one another, CF ₃Or C _1-4Alkyl (for example methyl).Preferably, R ⁴And R ⁵Be halogen, more preferably chlorine or bromine.In an embodiment of the invention, R ⁴And R ⁵Be chlorine.

P and q are 0,1 or 2 independently.Preferably, p and q are 0 or 1.In embodiment, p and q are 0.In another embodiment, p and q are 1.

R ⁸Be hydrogen or C _1-4Alkyl (for example methyl).Preferably, R ⁸Be hydrogen.

In an embodiment of the invention, R represents

R wherein ²For-NH-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH or-COOH; And R ⁴' and R ⁴" represent halogen or hydrogen independently of one another.R ⁴' and R ⁴" for example all can be halogen (for example chlorine).Perhaps, R for example ⁴' can be halogen (for example chlorine), R ⁴" be hydrogen.

In an embodiment of the invention, R represents

Or

R ²And R ³Independently expression-NH-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH or-COOH; R ⁴And R ⁵Represent halogen, CF independently of one another ₃Or C _1-4Alkyl; P and q are 0,1 or 2 independently; R ⁸Be hydrogen or C _1-4Alkyl; R ¹Represent following group:

R wherein ⁷Be hydrogen, methoxy or ethoxy.

In another embodiment, R represents

Or

R ²And R ³Independently expression-NH-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH, or-COOH; R ⁴And R ⁵Represent halogen, CF independently of one another ₃Or C _1-4Alkyl; P and q are 0,1 or 2 independently; R ⁸Be hydrogen or C _1-4Alkyl; R ¹Represent following group:

R wherein ⁶Be hydrogen, methoxy or ethoxy independently.

In another embodiment of the present invention, R represents

Or

R ²And R ³Independently expression-NH-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH or-COOH; R ⁴And R ⁵Represent halogen independently of one another; P and q are 0,1 or 2 independently; R ⁸Be hydrogen; R ¹Represent following group:

Or

R wherein ⁶And R ⁷Be hydrogen or methoxyl group independently.

It should be understood that formula (II) compound, the present invention includes all how much and optical isomers of formula (II) compound existing with stereoisomer form, with and composition thereof, comprise racemic compound.Tautomer and composition thereof also constitutes one aspect of the present invention.

The preferred compound of the present invention comprises:

(2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate,

(5-chloro-2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate,

(2-{[9-(3-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate,

[2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate,

[5-chloro-2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate,

4,5-two chloro-2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenylformic acid,

[2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] amino } (oxo) acetate,

[2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate,

2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenylformic acid,

[4-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenoxy group] acetate,

[2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenoxy group] acetate,

Or its pharmacy acceptable salt.

The present invention also provides the method for preparation formula (II) compound and salt thereof, and this method comprises

(a) make the compound of formula (III) and the compound reaction of formula (IV),

In the formula (III), R ¹Define suc as formula (II) is middle,

In the formula (IV), LG is suitable leavings group, and R ' is that different is R suc as formula defined R in (II) ²Be R ²' and R ³Be R ³', and R wherein ²' and R ³' expression-NH-C (O)-C (O)-OR independently ", O-(C _1-4Alkyl)-C (O)-OR " ,-C _1-4Alkyl-C (O)-OR " or-C (O)-OR ", R wherein " and be suitable blocking group, for example C ₁-C ₆Alkyl (preferable methyl or ethyl) and remove blocking group then to form corresponding acid functional group (R wherein for example ²' and R ³' be ester group, with ester group R ²' and R ³' be hydrolyzed into corresponding acid); Perhaps

(b) make the compound of formula V and the aldehyde cpd reaction of formula (VI),

In the formula V, R defines suc as formula institute in (II) or is its shielded deriveding group (protectedderivative),

In the formula (VI), R ¹Define suc as formula (II) is middle,

Perhaps

(c) make the compound of formula V of above definition and the compound reaction of formula (VII),

In the formula (VII), R ¹Define suc as formula (II) is middle, and LG is a leavings group.

Can following compound by method (d) preparation formula (III): make the compound (in the formula (VIII), P is a blocking group) of formula (VIII) and the compound reaction of formula defined above (VI), then remove blocking group P,

Also can following compound: make the compound of formula (VIII) and the compound reaction of formula defined above (VII), then remove blocking group P by method (e) preparation formula (III).

Can be following compound by method (f) preparation formula V: make the compound (in the formula (IX), P is suitable blocking group) of formula (IX) and the compound reaction of formula defined above (IV), then remove blocking group P

Can use standard linked reaction known in the art to carry out method (a).Suitable leavings group LG is preferably OH for for example OH or chlorine.Usually can use activating reagent to carry out linked reaction, described activating reagent is N-[(1H-1 for example, 2,3-benzotriazole-1-base oxygen base) (dimethylamino) methylene radical]-N-methyl ammonium hexafluorophosphate (HBTU), N-[(dimethylamino) (3H-[1,2,3] methylene radical triazolo [4,5-b] pyridin-3-yl oxygen base)]-N-methyl ammonium hexafluorophosphate (HATU) or (benzotriazole-1-base oxygen base) tripyrrole alkyl  hexafluorophosphate (PYBOP).Usually, in the presence of suitable alkali (for example triethylamine) and organic solvent (for example methylene dichloride), carry out this reaction in suitable temperature (for example room temperature).Work as R ²' and R ³' when being ester group, can for example carry out the degreasing reaction in the presence of the LiOH at alkali.

Can carry out method (b) by reduction amination method well known in the art.Usually, at sodium triacetoxy borohydride [NaBH (OAc) ₃] carry out this reaction under existing.Usually, in the presence of suitable alkali (for example triethylamine) and organic solvent (for example methylene dichloride), carry out this reaction in suitable temperature (for example room temperature).In the method, available suitable blocking group blocking group R.As an example, can be by the carboxylic acid functional among the form protection R that forms ester group COOP ', wherein P ' is suitable blocking group (for example methyl or ethyl).After the reaction, can remove blocking group to obtain carboxylic acid (for example under the situation of ester, ester hydrolysis is to obtain needed acid functional group (or its salt)).But, those skilled in the art will recognize that available other functional group (functional group except ester) protection R, when removing described other functional group, obtain needed acid functional group (or its salt).

Can in the presence of appropriate organic solvent (for example DMF), carry out method (c) in suitable temperature (for example room temperature).For the reaction of the type, it is known in the art using leavings group.The example of common leavings group is halogen, alkoxyl group, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base.Usually, this leavings group is a for example chlorine or bromine of halogen.The as above compound of the formula V that uses in the described guard method of method (b) (c).

Can carry out the coupling step of method (d) according to the condition of above-described method (b).Can carry out the coupling step of method (e) according to the condition of above-described method (c).Can carry out the coupling step of method (f) according to the condition of above-described method (a).The as above compound of the formula V that uses in the described guard method of method (b) (c).Method (d), (e) and (f) in the example of the typical blocking group P that uses be tert-butoxycarbonyl (t-boc).But, also can use other suitable blocking group.

' Protective Groups in Organic Chemistry ', PlenumPress (1973) and ' Protective Groups in Organic Synthesis ', 2nd edition, T.W.Greene﹠amp that J.W F.McOmie edits; P.G.M.Wuts has described the protection and the deprotection of functional group all sidedly among the Wiley-Interscience (1991).After the coupling, can remove blocking group P.

Formula (IV), (VI), (VII), (VIII) and compound (IX) or can buy, known in the literature, perhaps can easily prepare, shown in for example appended embodiment of described known technology by known technology.U.S. Pat 5451578 (Claremon etc.) has been described in the embodiment 1 of this patent and has been synthesized 3, the method for 9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester (is the compound (IX) of tert-butoxycarbonyl corresponding to P).

As long as mentioned intermediate can form salt in the method for the present invention, so above-described method of the present invention just comprises the intermediate that uses salt form or free form.

Following formula (II) compound can be changed into its pharmacy acceptable salt, be preferably base addition salt (or acid salt, described base addition salt is the salt of sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzyl star green grass or young crops (benzathine), chloroprocaine, choline, diethanolamine, thanomin, quadrol, meglumin, tromethane or PROCAINE HCL, PHARMA GRADE for example, and described acid salt is hydrochloride, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate or tosilate for example.

Formula (II) compound and pharmacy acceptable salt thereof can solvation the form form of hydration for example, and the form of solvation exists, and the present invention includes the form of all these solvations.

Should be appreciated that, formula (II) compound and salt thereof can be zwitterionic form exist, and when sour formal description, form existence that also can inner salt (zwitterionic).The statement of formula (II) and example of the present invention are contained acid and zwitterionic form, and with the mixture of all proportions.

Formula (II) compound has the activity as medicine, particularly have as the active conditioning agent of Chemokine Receptors (especially CCR8), thereby can be used for handling the condition/disease that worsened or caused by the excessive of chemokine generation or imbalance institute among (treatment or the prevention) mankind or the non-human animal.The example of these condition/disease comprises:

(1) (respiratory tract) airway obstructive disease comprises: chronic obstructive pulmonary disease (COPD); Asthma such as bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, particularly chronic asthma or obstinate asthma (for example late period asthma and airway hyperreactivity); Bronchitis; Acute rhinitis, allergic rhinitis, atrophic rhinitis or chronic rhinitis comprise caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca and medicamentous rhinitis; Membranous rhinitis comprises croup (croupous) rhinitis, fibrinous rhinitis and pseudomembrane rhinitis or scrofulous rhinitis (scrofoulousrhinitis); The seasonal rhinitis comprises nervous rhinitis's (spring fever) and vasomotor rhinitis; Sarcoidosis; Farmer's lung and relevant disease; Fibroid lung and idiopathic interstitial pneumonia;

(2) (bone and joint) gout, rheumatoid arthritis, seronegative spondyloanthropathy (comprising ankylosing spondylitis, arthritic psoriasis and Lay Te Shi disease), behcet's disease (Behcet ' s disease), siogren's syndrome (Sjogren ' s syndrome) and Sjogren's syndrome disease;

(3) (skin) pruritus, scleroderma, otitis media (otitus), psoriasis, atopic dermatitis, contact dermatitis and other eczema dermatoses (eczematous dermitides), seborrheic dermatitis, lichen planus (Lichen planus), pemphigus, BP (bullous Pemphigus), epidermolysis bullosa (Epidermolysis bullosa), urticaria, angioedema, vasculitis, erythema, the skin eosinophilia, uveitis, alopecia areata and vernal conjunctivitis, lupus;

(4) (gi tract) coeliac disease, rectitis, eosinophilic gastroenteritis (eosinopilicgastro-enteritis), mastocytosis, inflammatory bowel such as Crohn's disease, ulcerative colitis, ileitis and enteritis can have food related allergic such as migraine, rhinitis and eczema away from the intestines effect;

(5) (maincenter and peripheral nervous system) neurodegenerative disease and dementia (for example alzheimer's disease, amyotrophic lateral sclerosis and other motor neuron, Creutz Fil spy-Jakob's disease (Creutzfeldt-Jacob ' s disease) and other proteolytic enzyme infectious diseases (prion disease), HIV encephalopathic (dull-witted compound the levying of AIDS), huntington's chorea, frontotemporal dementia, dementia with Lewy body and vascular dementia; Polyneural disease is as Guillain-Barr é syndrome, chronic inflammatory demyelination polyembryony neuropathy, many focuses motor neuron, neuroplexus pathology; The CNS demyelination, as multiple sclerosis, acute dissemination/hemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; Neuromuscular disorder is as myasthenia gravis and Lambert-Eaton syndrome (Lambert-Eaton syndrome); The vertebra obstacle is as tropical spasm paraparesis and stiff-man syndrome; Paraneoplastic syndrome is as cerebellum degeneration and encephalomyelitis; The CNS wound, migraine, apoplexy and rectification disease (correctum diseases) are as brain (ridge) film inflammation.

(6) (other tissue and systemic disease) hepatitis, vasculitis, arthritis vertebralis, vaginitis, glomerulonephritis, myositis, atherosclerosis, acquired immune deficiency syndrome (AIDS) (AIDS), lupus erythematosus, systemic lupus, systemic lupus erythematosus, struma lymphomatosa (Hashimoto ' s thyroiditis), type i diabetes, nephrotic syndrome, eosinophilic fasciitis, high IgE syndrome, lepromatous leprosy disease and congenital thrombopenia purpura; Postoperative adhesion and Sepsis.

(7) repulsion of (repulsion of allograft and heterograft) acute and chronic allograft and heterograft, for example repulsion after kidney, heart, liver, lung, marrow, skin and corneal transplantation; And chronic graft versus host disease;

(8) cancer, cancer knurl and metastases, comprise the transfer of bladder, mammary gland, colon, kidney, liver, lung, ovary, pancreas, stomach, uterine cervix, Tiroidina and dermatoma, particularly nonsmall-cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma.The hematopoiesis tumour of lymphatic system comprises acute lymphoblastic leukemia, B cell lymphoma and Burketts lymphoma, hodgkin lymphoma (Hodgkin ' s lymphoma), acute lymphocytoblast leukemia.The hematopoiesis tumour of myelocytic series comprises acute and chronic myelocytic leukemia and promyelocytic leukemia.The tumour in mesenchyme source comprises fibrosarcoma and rhabdosarcoma, and other tumour, comprises melanoma, spermocytoma, lopsided knurl (tetratocarcinoma), neuroblastoma and neurospongioma.

(9) by unbalance all diseases that cause and cause the atopy Inflammatory response to increase of immune generality.

(10) reperfusion injury in cystic fibrosis, heart, brain, periphery four limbs and other organ.

(11) burn and chronic skin ulcer.

(12) reproducibility disease (as ovulation, menstruation and implantation obstacle, premature labor (Pre-term labour), endometriosis)

(13) thrombosis

(14) infectious diseases such as HIV infect and other virus infection, infectation of bacteria.

Therefore, the invention provides above formula (II) compound or its pharmacy acceptable salt of definition that is used for the treatment of.

The invention provides formula (II) compound or its pharmacy acceptable salt as defined above on the other hand, preparation be used for the treatment of chemokine receptor activity wherein particularly the active adjusting of CCR8 be purposes in the medicine of useful human disease or illness.

In this specification sheets literary composition, unless there is specified otherwise different therewith, term " treatment " also comprises " prevention ".Term " treatment " and " in treatment " also should be done corresponding explanation.

The present invention also provides the method for the chemokine mediated disease of treatment, this chemokine and chemokine (particularly CCR8) receptors bind wherein, and described method comprises the formula of patient's drug treatment significant quantity (II) compound or its pharmacy acceptable salt.

The present invention also provides suffering from respiratory system disease such as asthma, COPD or rhinitis, or being in the method for this disease of patient treatment of above-mentioned disease danger, this method comprises (II) compound of formula as above or its pharmacy acceptable salt to patient's drug treatment significant quantity.

Use for the above-mentioned treatment mentioned, dosage can change with compound used therefor, administering mode, desired treatment and the illness of adaptation certainly.

Formula (II) compound and pharmacy acceptable salt thereof can use separately, but carry out administration with the form of pharmaceutical composition usually, in described pharmaceutical composition, formula (II) compound or its salt (activeconstituents) combines with pharmaceutically acceptable auxiliary agent, diluent or carrier.According to administering mode, pharmaceutical composition preferably includes 0.05～99%w (weight percent), 0.05～80%w more preferably, also 0.10～70%w more preferably, and even the activeconstituents of 0.10～50%w more preferably, all weight percents are based on whole compositions.

The present invention also provides a kind of pharmaceutical composition, comprises formula (II) compound or its pharmacy acceptable salt as preceding definition, and is combined with pharmaceutically acceptable auxiliary agent, diluent or carrier.

The present invention also provides a kind of method for preparing pharmaceutical composition of the present invention, comprises formula (II) compound or its pharmacy acceptable salt as preceding definition are mixed with pharmaceutically acceptable auxiliary agent, diluent or carrier.

Pharmaceutical composition can be with the form topical (for example delivering medicine to lung and/or air flue or skin) of solution, outstanding mixture, Sevoflurane hydrocarbon gas colloidal sol and dry powder formulations; Perhaps with the form oral administration of tablet, capsule, syrup, pulvis or granule, perhaps with the form parenteral admin of solution or outstanding mixture, perhaps through subcutaneous administration, perhaps with the form rectal administration or the percutaneous dosing of suppository.Preferably, compound oral administration of the present invention administration.

The invention still further relates to conjoint therapy, wherein simultaneously or successive administration The compounds of this invention or its pharmacy acceptable salt, or comprise the pharmaceutical composition or the preparation of formula (II) compound or its salt, and the therapy and/or the medicament of any one disease in other treatment asthma, allergic rhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatory bowel, osteoarthritis or the osteoporosis.

Particularly, in order to treat inflammatory diseases, rheumatoid arthritis, psoriasis, inflammatory bowel, COPD, asthma and allergic rhinitis, The compounds of this invention can with such as following medicament associating: for example TNF-alpha inhibitor such as anti-TNF monoclonal antibody are (as Remicade, CDP-870 and D ₂E ₇) and TNF receptor immunoglobulin molecule (as Enbrel ); Non-selective COX-1/COX-2 inhibitor (for example piroxicam, diclofenac, propionic acid class such as Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP, fragrant that acids such as mefenamic acid, INDOMETHACIN (Indomethacin), sulindac, azapropazone, pyrazolone such as Phenylbutazone, salicylic acid such as acetylsalicylic acid); Cox 2 inhibitor (for example meloxicam, celecoxib, rofecoxib, valdecoxib and support are examined former times); The Rheumatrex of low dosage, leflunomide (lefunomide), ciclesonide, Oxychloroquine, d-Trolovol, auranofin or parenteral or oral golden preparation.

The invention still further relates to the combination of The compounds of this invention and following medicament: leukotrienes biosynthesis inhibitor, 5-lipoxidase (5-LO) inhibitor or 5-lipoxidase activated protein (FLAP) antagonist, for example abandon and stay logical (zileuton); ABT-761; Fenleuton (fenleuton); Tepoxalin (tepoxalin); Abbott-79175; Abbott-85761; N-(5-replaces)-thiophene-2-alkyl sulfamoyl; The 2,6 di t butyl phenol hydrazone; Methoxyl group tetrahydropyrans such as Zeneca ZD-2138; Compound S B-210661; 2-cyano group naphthalene compound such as L-739 that pyridyl replaces, 010; 2-cyano quinolines compound such as L-746,530; Indoles and quinoline compound such as MK-591, MK-886 and BAY x 1005.

The invention still further relates to The compounds of this invention and leukotrienes LTB ₄, LTC ₄, LTD ₄And LTE ₄The combination of receptor antagonist, this receptor antagonist is selected from thiodiphenylamine-3-ketone such as L-651,392; Amidino compounds such as CGS-25019c; Benzo  amine such as Ontazolast; Benzenyl amidine (benzenecarboximidamides) is as BIIL 284/260; With compound for example Zafirlukast, Ro 23-3544, Singulair, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAYx 7195.

The invention still further relates to the combination of The compounds of this invention and PDE4 inhibitor, described PDE4 inhibitor comprises the inhibitor of isoform PDE4D.

The invention still further relates to The compounds of this invention and antihistaminic H ₂The combination of receptor antagonist, described antagonist be alerlisin, Loratadine, Desloratadine, fexofenadine, astemizole, azelastine and Toldrin (chlorpheniramine) for example.

The invention still further relates to The compounds of this invention and stomach protectiveness H ₂The combination of receptor antagonist.

The invention still further relates to The compounds of this invention and α ₁-and α ₂The combination of-adrenoceptor agonists, vasoconstrictor, sympathomimetic, described medicament be propylhexedrine (propylhexedrine), synephrine, Phenylpropanolamine, pseudoephedrine, naphcon, Oxymetazoline Hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorephinephrine hydrochloride for example.

The invention still further relates to the combination of The compounds of this invention and anticholinergic agents, described anticholinergic agents is ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine and telenzepine for example.

The invention still further relates to The compounds of this invention and β ₁-to β ₄The combination of-adrenoceptor agonists, described receptor, agonist for example Orciprenaline, Racemic isoproterenol, norepinephrine (isoprenaline), salbutamol, salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline (orciprenaline), bitolterol mesilate and pirbuterol or methyl xanthine comprises theophylline and aminophylline, Sodium Cromoglicate, or muscarinic receptor (M1, M2 and M3) antagonist.

The present invention also further relates to the combination of compound of the present invention and insulin-like growth factor I type (IGF-1) stand-in.

The present invention also further relates to the combination of suction glucocorticosteroid of The compounds of this invention and the systemic side effects with minimizing, and described glucocorticosteroid is prednisone, prednisolone, flunisolide, Triamcinolone Acetonide, Viarox, budesonide, fluticasone propionate and furoic acid momisone for example.

The present invention also further relates to the combination of The compounds of this invention and matrix metalloproteinase (MMPs) inhibitor, and this matrix metalloproteinase is molten stromatin enzyme (stromelysins), collagenase and gelatinase, and proteoglycan enzyme (aggrecanase; Especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), molten stromatin enzyme-1 (MMP-3), molten stromatin enzyme-2 (MMP-10) and molten stromatin enzyme-3 (MMP-11) and MMP-12.

The present invention further also relates to being used in combination of other conditioning agent of The compounds of this invention and chemokine receptor function, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for C-C family), CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for C-X-C family) and CX ₃CR1 is (to C-X ₃-C family).

The present invention also further relates to The compounds of this invention and antiviral medication such as viracept see nelfinaivr (Viracept), AZT, acyclovir (aciclovir) and Famciclovir (famciclovir), and the combination of antimicrobial compounds such as Valant.

The present invention also further relates to The compounds of this invention and cardiovascular agent such as calcium channel blocker, fat-reducing medicament such as Statins, the special class (fibrates) of shellfish, beta-blocker, ACE inhibitor, Angiotensin-2 receptor antagonist, and the combination of anticoagulant.

The present invention also further relates to The compounds of this invention and CNS medicine such as thymoleptic (for example Sertraline), antiparkinsonism drug is (as selegiline, levodopa, Ropinirole (Requip), pramipexole, MAOB inhibitor such as Si Lanjilan (selegine) and rasagiline, comP inhibitor such as tolcapone (tasmar), the A-2 inhibitor, dopamine reuptake inhibitor, nmda antagonist, nicotinic agonist, dopamine agonist and neuronal nitric oxide synthase inhibitor), and anti-Alzheimer disease medicine such as E2020, tacrine, cox 2 inhibitor, the combination of propentofylline or metrifonate (metryfonate).

The present invention also further relates to the combination of The compounds of this invention and following medicine: (i) tryptase inhibitors; (ii) platelet activation factor (PAF) antagonist; (iii) interleukin is changed enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) the adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) kethepsin; (vii) map kinase inhibitor; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin-B ₁-and B ₂-receptor antagonist; (x) antigout agent is as colchicine; (xi) xanthine oxidase inhibitor is as Zyloric; (xii) uricosuric agent is as probenecid, sulfinpyrazone and benzbromarone; (xiii) tethelin succagoga; (xiv) transforming growth factor (TGF β); (xv) Thr6 PDGF BB (PDGF); (xvi) fibroblast growth factor, as basic fibroblast growth factor (basic fibroblast growthfactor, bFGF); (xvii) granulocyte-macrophage colony stimutaing factor (GM-CSF); (xviii) capsicum vegetable oil (capsaicin cream); (xix) tachykinin NK-1 ₁And NK ₃Receptor antagonist is selected from NKP-608C, SB-233412 (Talnetant) and D-4418; (xx) elastase inhibitor is selected from UT-77 and ZD-0892; (xxi) TNF α converting enzyme inhibitor (TACE); (xxii) inductive nitric oxide synthetase (iNOS) inhibitor or the chemoattractant receptor homolog molecule (CRTH2 antagonist) of (xxiii) expressing on the TH2 cell.

The compounds of this invention also can with osteoporosis agents, for example for example FK-506, rapamycin, Cyclosporine (cyclosporine), azathioprine and methotrexate coupling of raloxifene (roloxifene), droloxifene, Lasofoxifene or fosomax and immunosuppressor.

The compounds of this invention can also with the existing medicine coupling that is used for the treatment of osteoarthritis.But the nonsteroidal anti-inflammatory agent (hereinafter being called NSAID) that the suitable drugs of coupling comprises standard is piroxicam, diclofenac for example, the propionic acid class is Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP for example, fragrant that acids such as mefenamic acid, INDOMETHACIN, sulindac, azapropazone, pyrazolone such as Phenylbutazone, salicylate such as acetylsalicylic acid; Cox 2 inhibitor for example celecoxib, valdecoxib, rofecoxib and support is examined former times, pain killer and intraarticular curative such as corticosteroid and hyaluronic acids such as Hyalgan and synvisc and P2X7 receptor antagonist.

Compound of the present invention also can be used for the treatment of the existing drug regimen of cancer and use.The suitable drug of use capable of being combined comprises:

(i) antiproliferative/antitumour drug and the combination thereof as being used for the medical science oncology, for example alkylating agent (as cis-platinum, carboplatin, endoxan, mustargen, L-PAM, Chlorambucil, busulfan or nitrosourea); (antifol for example is as fluorinated pyrimidine such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, Rheumatrex, cytosine arabinoside, hydroxyurea, gemcitabine or taxol (Taxol ) for metabolic antagonist; Antitumor antibiotics (for example anthracycline antibiotics, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu or Plicamycin); Antimitotic agent (catharanthus alkaloid class for example, as vincristine(VCR), vincaleucoblastine, vindesine and vinorelbine, and taxanes, as taxol or docetaxel); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin class, as Etoposide and teniposide, Amsacrine, topotecan or camptothecin);

(ii) cytostatic agent such as antiestrogen (tamoxifen for example, toremifene, raloxifene, droloxifene or iodoxyfene), estrogen receptor is born conditioning agent (as fulvestrant), antiandrogen (bicalutamide for example, flutamide, Nilutamide or cyproterone acetate), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide or buserelin), progestogens (as Magace), aromatase inhibitor (anastrozole for example, letrozole, vorozole (vorazole) or Exemestane) or 5 inhibitor such as finasteride;

The (iii) medicine (for example inhibitor of inhibitors of metalloproteinase such as Marimastat or UPA function of receptors) of anticancer invasion;

(iv) somatomedin depressant of functions, for example such as following inhibitor: growth factor antibodies, growth factor receptor antibody (for example anti--erbb2 antibody trastuzumab [HerceptinTM] and anti--erbb1 antibody Cetuximab [C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor or serine/threonine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor for example, as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) and 6-acryl amino-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), the inhibitor of for example platelet-derived growth factor family and for example inhibitor of pHGF family;

(v) anti-angiogenic agent, for example those suppress the medicine of vascular endothelial growth factor effect, (for example anti-VEGF antibody rhuMAb-VEGF [AvastinTM], for example those disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354) and the compound (for example inhibitor or the angiostatin of linomide, beta 2 integrin alpha v β 3 functions) that works with other mechanism;

(vi) vascular damages disclosed compound among agent such as combretastatin A4 or International Patent Application WO 99/02166, WO00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or the WO 02/08213;

(those materials of target spot such as ISIS 2503, anti--ras antisense thing are listed in vii) antisense therapy agent above for example being oriented to;

(viii) gene therapy method comprises that for example those use the method for Isocytosine deaminase, thymidine kinase or bacterium nitroreductase and increase the method for example multidrug resistance gene treatment of patient to chemotherapy or radiotherapy tolerance method, GDEPT (the enzyme prodrug treatment of the gene orientation) method that for example replaces aberrant gene such as unusual p53 or unusual BRCA1 or BRCA2; With

(ix) immunotherapy method, comprise the method that for example increases the patient tumors cell immunogenicity in vitro and in vivo, as with cytokine such as interleukin-22, interleukin 4 or rHuGM-CSF transfection, the method that reduces T-cell anergy, the immunocyte that uses transfection such as transfection cytokine dendritic cell method, use cytokine transfection tumor cell line method and use the method for antiidiotypic antibody.

With reference to following exemplary embodiment, further specify the present invention.

General method

The HPLC condition

A. method A

HPLC method A: utilize Agilent 1100 serial machines on Kromassil  C185 μ m3.0 * 100mm post, to carry out.Water is water/TFA (99.8/0.1), and organic phase is acetonitrile/TFA (99.92/0.08).Flow velocity is 1mL/min, and gradient is set to 10 to 100% organic phases, lasts 20 minutes.220,254 and 280nm detect.

B. method B

HPLC method B: utilize Agilent 1100 serial machines at XTerra  RP ₈Carry out on 5 μ m3.0 * 100mm post.Water is 15nM NH ₃The aqueous solution, organic phase is an acetonitrile.Flow velocity is 1mL/min, and gradient is set to 10 to 100% organic phases, lasts 20 minutes.220,254 and 280nm detect.

The raw material of embodiment 1 to 11

Intermediate A: 3-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane hydrochloride

A) 9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester

In room temperature, with 3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester hydrochloride (0.95g, 3.26mmol), the 2-phenoxy benzaldehyde (0.70g, 3.54mmol) and sodium triacetoxy borohydride (0.97g is 4.56mmol) at CH ₂Cl ₂(20mL), DMF (1.0mL) and Et ₃Stir 24h in the mixture of N (0.68mL).With Na ₂CO ₃(saturated aqueous solution) (30mL) is added in the reaction mixture.Use CH ₂Cl ₂Extract this product, wash with water, dry and evaporating solvent.With heptane/EtOAc 1: 1 and 2%Ft ₃The N wash-out by silica gel chromatography, obtains title compound (384mg).

¹H NMR(400MHz，CDCl ₃)：δ7.52(m，1H)，7.29(m，3H)，7.14(m，1H)，7.06(m，1H)，6.91(m，3H)，3.59(m，2H)，3.35(m，4H)，1.45(s，9H)，1.69-1.32(m，4H)

B) 3-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane hydrochloride

With 9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester (0.873g, 2.0mmol) be dissolved in THF (50mL) and HCl (dense) (15mL) in, and at this reaction mixture of stirring at room 2h.Behind the evaporating solvent, resistates is dissolved among toluene/MeOH 1: 1, and it is evaporated obtains title compound, be white glass attitude material (0.775g).

APCI-MS，m/z 337(MH ⁺)

Intermediate B: 3-[3-phenoxy benzyl]-3,9-diaza spiro [5.5] undecane dihydrochloride

A) 9-(3-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester

With 3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester hydrochloride (1.0g, 3.4mmol), 3-phenoxy benzaldehyde (0.75g, 3.8mmol), triethylamine (0.72mL, 5.2mmol), sodium triacetoxy borohydride (1.02g, 4.8mmol), the mixture heating up of ethylene dichloride (35mL) and dimethyl formamide (5mL) refluxes and spend the night.This reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate solution.Separate organic layer, and it is evaporated to dried.By silica gel chromatography, obtain title compound (0.71g, 47%).

APCI-MS m/z：437.3[MH+]

B) 3-(3-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane dihydrochloride

To 9-(3-phenoxy benzyl)-3, (0.71g adds the dense HCl of 5mL to 9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester in 50mL THF solution 1.6mmol).After stirring at room 2h, reaction mixture is evaporated, and with itself and methyl alcohol and toluene coevaporation three times.Obtain title compound, be white solid.

APCI-MS m/z：337.2[MH+]

Intermediate C:3-[2-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane dihydrochloride

A) 9-[2-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester

With 3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester hydrochloride (1.50g, 5.2mmol), 2-(2-methoxyl group phenoxy group) phenyl aldehyde (1.24g, 5.4mmol), triethylamine (1.08mL, 7.74mmol) and sodium triacetoxy borohydride (1.23g 5.8mmol) is dissolved in methylene dichloride (40mL) and the dry DMF (15mL).With AcOH with pH regulator to 4, and with this mixture in stirred overnight at room temperature.(1.0g 4.72mmol), and stirs 2h with this mixture at 40 ℃ to add another batch sodium triacetoxy borohydride.Dilute this mixture with EtOAc (150mL), and with sodium hydrogen carbonate solution, H ₂O and salt water washing are through Na ₂SO ₄Dry also evaporation.Use heptane: EtOAc 4: 1+2 volume %NEt ₃Wash-out by this crude product of silica gel chromatography, obtains title compound, is colorless oil (1.27g, 53%).

¹H NMR(400MHz，DMSO-D ₆)δ7.42(dd，J＝7.5，1.5Hz，1H)，7.17-7.10(m，3H)，7.04(td，J＝7.4，0.9Hz，1H)，6.95-6.88(m，2H)，6.84(d，J＝7.6Hz，1H)，6.58(d，J＝8.0Hz，1H)，3.74(s，3H)，3.54(s，2H)，3.30-3.23(m，6H)，2.40-2.34(m，4H)，1.46-1.40(m，12H)，1.38(s，11H)，1.34-1.29(m，14H)

APCI-MS m/z：467.3[MH+]

B) 3-[2-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane dihydrochloride

Part oily matter a) is dissolved among the THF (100mL), and adds dense HCl (20mL), with mixture stirring at room 1 hour.Evaporating solvent, and with twice of this crude product and toluene and ethanol evaporation to remove the water of trace, obtain 1.59g (quantitatively) title compound, be lilac oily matter.Some toluene (12wt%) are still stayed in this compound, even it does not disappear behind 24h under vacuum yet.

¹H NMR (400MHz, CD ₃OD) δ 7.57 (dd, J=7.6,1.6Hz, 1H), 7.38-7.27 (m, 2H), (7.24-7.08 m, 7H (+toluene)), 7.05 (td, J=7.7,1.4Hz, 1H), 6.60 (d, J=8.3Hz, 1H), 4.55 (s, 2H), 3.75 (s, 3H), and 3.64-3.49 (m, 4H), 3.25-3.19 (m, 4H), (2.32 s, 2H (toluene)), 2.06 (d, J=14.7Hz, 2H), 1.95 (t, J=5.9Hz, 2H), 1.89-1.62 (m, 6H)

APCI-MS m/z：367.5[MH+]

Intermediate D:3-[3-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane dihydrochloride

A) 3-(2-methoxyl group phenoxy group) phenyl aldehyde

With (3-formyl radical phenyl) boric acid (5.0g, 33mmol) and methyl catechol (2.8g, 22mmol) with Cu (OAc) ₂(4.0g 22mmol), anhydrous methylene chloride (150mL) solution of 4  molecular sieves and pyridine (9mL) mixes, stirs the mixture that obtains in room temperature and spends the night.Filter and concentrated reaction mixture.By silica gel chromatography, obtain title compound, be oily matter (1.7g, 23%).

¹H NMR(400MHz，CDCl ₃)δ9.95(s，1H)，7.58-7.54(m，1H)，7.47(t，J＝7.8Hz，1H)，7.38-7.34(m，1H)，7.26-7.19(m，2H)，7.08-7.02(m，2H)，7.01-6.95(m，1H)，3.82(s，3H)

GC-MS m/z：228.0[M]

B) 9-[3-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester

With 3,9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester hydrochloride (1.4g, 5.0mmol), 3-(2-methoxyl group phenoxy group) phenyl aldehyde (1.7g, 7.5mmol), triethylamine (1mL, 7.5mmol), sodium triacetoxy borohydride (1.6g, 7.5mmol) and the acetonitrile reflux spend the night.Reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate solution.Separate organic layer, and it is evaporated to dried.By silica gel chromatography, obtain title compound (1.5g, 64%).

¹H NMR(400MHz，DMSO-D ₆)δ7.26-7.14(m，3H)，7.04-6.90(m，3H)，6.76(s，1H)，6.71-6.66(m，1H)，3.39(s，2H)，3.31(s，5H)，3.29-3.23(m，4H)，2.33-2.25(m，4H)，1.43-1.36(m，11H)，1.35-1.27(m，4H)

APCI-MS m/z：467.3[MH+]

C) 3-[3-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane dihydrochloride

To 9-[3-(2-methoxyl group phenoxy group) benzyl]-3, (1.6g 3.4mmol) in the solution in 50mL THF, adds the dense HCl of 7mL to 9-diaza spiro [5.5] undecane-3-carboxylic acid tert-butyl ester.After stirring at room 2h, evaporation reaction mixture, and with methyl alcohol and toluene coevaporation three times.Obtain title compound, be white solid.

¹H NMR(400MHz，DMSO-D ₆)δ7.37(t，J＝7.9Hz，1H)，7.29(d，J＝7.7Hz，1H)，7.26-7.16(m，2H)，7.14(s，1H)，7.10-7.05(m，1H)，7.02-6.96(m，1H)，6.88-6.81(m，1H)，4.25(d，J＝5.4Hz，2H)，3.73(s，3H)，3.13-2.94(m，8H)，1.88-1.64(m，6H)，1.56-1.47(m，2H)

APCI-MS m/z：367.2[MH+]

Embodiment 1

(2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate

With intermediate A (88mg, 0.20mmol), 2-(2-methoxyl group-2-oxoethyl) phenylformic acid (47mg, 0.24mmol), triethylamine (200 μ l, 1.4mmol), the N-[(dimethylamino) (3H-[1,2,3] triazolo [4,5-b] pyridin-3-yl oxygen base) methylene radical]-N-methyl ammonium hexafluorophosphate (HATU, 91mg, 0.24mmol) and the mixture of methylene dichloride (2mL) stir 1h in envrionment temperature, then the evaporation.By column chromatography purifying (SiO ₂, gradient EtOAc/MeOH/Et ₃N 100/0/0 to 79/20/1) the crude product methyl ester, with LiOH (44mg, 1.8mmol), THF (2mL), MeOH (1mL) and water (1mL) is added to and contains the steaming in the fraction of intermediate ester.Stir this mixture 2h in envrionment temperature, add acetate (1mL), with preparation HPLC (RP-18, gradient acetonitrile/water/NH ₄OAc 10/90/0.1 to 95/5/0.1) purified product, obtain title compound, be white solid (45mg, 45%).

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): δ 7.47 (d, J=6.4Hz, 1H), 7.41-7.22 (m, 6H), 7.15 (t, J=7.2Hz, 2H), 7.06 (s, 1H), 6.90-6.85 (m, 3H), 3.92-3.80 (m, 1H), 3.61-3.38 (m, 5H), and 3.28-3.21 (m, 2H), 2.56-2.40 (m, 4H), 1.69-1.26 (m, 8H)

APCI-MS m/z：499.3[MH+]

HPLC (method A) RT:7.88 minute

Embodiment 2

(5-chloro-2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate

Use the method for embodiment 1, different is to use intermediate A and 4-chloro-2-[2-methoxyl group-1-(methoxycarbonyl)-2-oxoethyl] phenylformic acid is as raw material, the preparation title compound.At 50 ℃ intermediate (5-chloro-2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) dimethyl malonate is hydrolyzed, obtains product, be white solid.

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): δ 7.59 (dd, 1H), 7.45-7.37 (m, 4H), 7.27 (dd, 1H), 7.20 (dd, 2H), 7.14 (d, 1H), 7.09-7.02 (m, 2H), 6.87 (d, 1H), 4.30 (s, 2H), 3.73 (d, 2H), 3.52 (dd, 2H), 3.28-3.12 (m, 6H), 1.85-1.30 (m, 8H)

APCI-MS m/z：542.9[MH+]

HPLC (method A) RT:9.00 minute

HPLC (method B) RT:5.95 minute

Embodiment 3

(2-{[9-(3-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate

Use the method for embodiment 1, different is to use intermediate B and 2-(2-methoxyl group-2-oxoethyl) phenylformic acid as raw material, and the preparation title compound obtains the product into white solid.

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): δ 7.597.43-7.22 (m, 6H), 7.19-7.04 (m, 3H), 6.99-6.93 (m, 3H), 6.90-6.85 (m, 1H), 3.92-3.81 (m, 1H), 3.64-3.38 (m, 5H), 3.29-3.23 (m, 2H), 2.51-2.35 (m, 4H), 1.68-1.31 (m, 8H)

APCI-MS m/z：449.7[MH+]

HPLC (method A) RT:8.02 minute

Embodiment 4

[2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate

Use the method for embodiment 1, different is to use intermediate C and 2-(2-methoxyl group-2-oxoethyl) phenylformic acid as raw material, and the preparation title compound obtains the product into white solid.

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): δ 7.40 (t, 2H), 7.33 (t, 1H), 7.24 (t, 1H), 7.18-7.08 (m, 3H), 7.02 (t, 1H), 6.96-6.86 (m, 2H), 6.59 (d, 1H), 3.92-3.82 (m, 1H), 3.76 (s, 3H), 3.69 (s, 2H), 3.63-3.39 (m, 3H), 3.29-3.23 (m, 2H), 2.63-2.50 (m, 4H), 1.68-1.31 (m, 8H)

APCI-MS m/z：529.3[MH+]

HPLC (method A) RT:8.10 minute

HPLC (method B) RT:5.09 minute

Embodiment 5

[5-chloro-2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate

Use the method for embodiment 1, different is to use intermediate C and 4-chloro-2-[2-methoxyl group-1-(methoxycarbonyl)-2-oxoethyl] phenylformic acid is as raw material, and the preparation title compound obtains the product into white solid.

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): δ 7.40 (t, J=7.1Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.24 (t, J=7.4Hz, 1H), 7.18-7.07 (m, 4H), 7.02 (t, J=7.4Hz, 1H), 6.95-6.86 (m, 2H), 6.59 (d, J=8.2Hz, 1H), 3.92-3.83 (m, 1H), 3.76 (s, 3H), 3.69 (s, 2H), and 3.63-3.39 (m, 3H), 3.29-3.23 (m, 2H), 2.64-2.49 (m, 4H), and 1.70-1.44 (m, 7H), 1.40-1.30 (m, 1H)

APCI-MS m/z：563.5[MH+]

HPLC (method A) RT:8.68 minute

HPLC (method B) RT:5.34 minute

Embodiment 6

4,5-two chloro-2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenylformic acid

With intermediate C (88mg, 0.20mmol), 5,6-two chloro-2-cumarones-1,3-diketone (48mg, 0.22mmol), triethylamine (100 μ l, 0.70mmol) and the mixture of methylene dichloride (1mL) stir 1h in envrionment temperature, evaporate then and with preparation HPLC (RP-18, gradient acetonitrile/water/NH ₄OAc10/90/0.1 to 95/5/0.1) this product of purifying obtains the product (97mg) into white solid.

¹H NMR(400MHz，CD ₃OD)：δ7.99(s，1H)，7.36-7.26(m，2H)，7.16(dd，1H)，7.11-7.05(m，2H)，7.01-6.83(m，4H)，4.14(s，2H)，3.73-3.53(m，5H)，3.27-3.00(m，6H)，1.82-1.27(m，8H)

APCI-MS m/z：583.4[MH+]

HPLC (method A) RT:9.54 minute

HPLC (method B) RT:7.22 minute

Embodiment 7

[2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] amino } (oxo) acetate

According to the acid amides coupling method of embodiment 1, use intermediate C and 2-benzaminic acid, preparation [2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] amine.To this aniline (110mg, add in 0.22mmol) chlorine (oxo) methyl acetate (30 μ L, 0.32mmol), triethylamine (40 μ L, 0.29mmol) and THF (2mL).After the envrionment temperature 30 minutes, (120mg 5mmol), and stirs 2h with 50 ℃ in mixture to add entry (2mL), methyl alcohol (1mL) and lithium hydroxide.By adding acetate and ammoniacal liquor, with pH regulator to 5, and with preparation HPLC (RP-18, gradient acetonitrile/water/NH ₄OAc 10/90/0.1 to 95/5/0.1) purified product, obtain product (31mg, 28%) into white solid.

¹H NMR(400MHz，DMSO-D ₆)：δ10.12(s，1H)，8.19(s，1H)，7.58(d，J＝7.1Hz，1H)，7.39(t，J＝9.2Hz，1H)，7.34-7.17(m，4H)，7.16-7.05(m，3H)，7.01(t，J＝7.6Hz，1H)，6.52(d，J＝8.1Hz，1H)，4.49-4.22(m，2H)，3.76-3.47(m，5H)，3.25-2.90(m，6H)，1.89-1.03(m，8H)

APCI-MS m/z：557.9[MH+]

HPLC (method A) RT:7.64 minute

HPLC (method B) RT:5.63 minute

Embodiment 8

[2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate

Use the method for embodiment 1, different is to use intermediate D and 2-(2-methoxyl group-2-oxoethyl) phenylformic acid as raw material, and the preparation title compound obtains the product into white solid.

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): 7.40 (d, J=1H), 7.34 (t, J=1H), 7.28-7.08 (m, 5H), 7.01-6.92 (m, 3H), 6.83 (s, 1H), 6.75 (d, 1H), 3.93-3.83 (m, 1H), 3.86 (s, 3H), 3.62-3.40 (m, 5H), 3.29-3.24 (m, 2H), 2.50-2.34 (m, 4H), 1.68-1.45 (m, 7H), 1.40-1.30 (m, 1H)

APCI-MS m/z：529.5[MH+]

HPLC (method A) RT:7.74 minute

Embodiment 9

2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenylformic acid

Use the method for embodiment 6, different is to use intermediate D and 2-cumarone-1, and the 3-diketone is as raw material, and the preparation title compound obtains the product into white solid.

¹H NMR(400MHz，DMSO-D ₆)：δ9.14-8.98(m，1H)，7.84(d，1H)，7.60-7.52(m，1H)，7.39-6.98(m，9H)，6.55-6.48(m，1H)，4.45(d，2H)，3.75-3.66(m，3H)，3.64-3.45(m，2H)，3.30-2.92(m，4H)，1.97-1.05(m，10H)

APCI-MS m/z：515.9[MH+]

HPLC (method A) RT:7.55 minute

HPLC (method B) RT:5.79 minute

Embodiment 10

[4-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenoxy group] acetate

Use the method for embodiment 1, different is to use intermediate D and 4-(2-methoxyl group-2-oxo oxyethyl group) phenylformic acid as raw material, and the preparation title compound obtains the product into white solid.

APCI-MS m/z：544.9[MH+]

HPLC (method A) RT:7.57 minute

Embodiment 11

[2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenoxy group] acetate

Use the method for embodiment 1, different is to use intermediate D and 2-(2-methoxyl group-2-oxo oxyethyl group) phenylformic acid as raw material, and the preparation title compound obtains the product into white solid.

¹(400MHz is added with the CD of NaOD to H NMR ₃OD): δ 7.36 (s, 1H), 7.26-7.15 (m, 3H), 7.11 (d, J=7.9Hz, 1H), 7.04-6.91 (m, 5H), 6.83 (s, 1H), 6.76 (s, 1H), 4.43 (d, J=21.0Hz, 2H), 3.81-3.66 (m, 5H), 3.47 (s, 2H), 3.42-3.22 (m, 2H), 2.49-2.35 (m, 4H), 1.66-1.46 (m, 7H), 1.43-1.33 (m, 1H)

APCI-MS m/z：544.9[MH+]

HPLC (method A) RT:8.02 minute

HPLC (method B) RT:5.57 minute

Pharmacology data

CCL1 SPA is in conjunction with mensuration

Recombinate the film (ES-136-M) of CHO-K1 cell of chemokine CCR8 acceptor transfection available from Euroscreen from the people.With this film preparation at-70 ℃, in 7.5mM Tris-Cl pH 7.5,12.5mMMgCl ₂, 0.3mM EDTA, 1mM EGTA stores until use in the 250mM sucrose.

S'=7.4 mensuration damping fluid (50mM HEPES, 1mM CaCl with CCR8 film (50.6mg/ml) at pH ₂* 2H ₂O, 5mM MgCl ₂* 6H ₂O, 75mM NaCl, 0.1%BSA) in, use wheat germ agglutinin SPA pearl (4.05mg/ml) to cultivate in advance 2 hours on ice.In DMSO,, prepare 10-dose point-response curve (ultimate density 50 μ M, 16.7 μ M, 5.6 μ M, 1.9 μ M, 0.62 μ M, 0.21 μ M, 0.069 μ M, 0.023 μ M) with 1: 3 serial dilution compound.In screen plate (polystyrene NBS plate, Costar Corning 3604), the DMSO solution of 1 μ, 1 compound is transferred in each hole.The DMSO of 1 μ l is joined in the blank hole, and the unlabelled CCL1 of 1 μ l (300nM) is joined in the background control wells.SPA pearl-film mixture of 50 μ l is joined in each hole.At last, with 50 μ l (30pM) ¹²⁵I CCL1 (2000Ci/mM) joins in each hole.Then this plate was cultivated 90 minutes in room temperature while vibrate (700rpm), cultivated 30 minutes under the situation that does not have in room temperature subsequently to vibrate.In Wallac MicroBeta counter with 2 minutes/hole to this plate reading.

People's microsome stability is measured

Mensuration is carried out in potassium phosphate buffer (pH 7.4) with 96-deep-well plates form, and microsomal protein matter (Xenotech) concentration is that 1mg/mL, compound concentration are that 2.5 μ M, NADPH concentration are 2mM.Taking-up is carried out protein precipitation with 1% acetate/acetonitrile and is stopped enzymatic reaction at the sample of four time points (0,5,15 and 30 minute).On the temperature-constant plate (37 ℃) that places on the Tecan worktable, cultivate, and all fluid operatedly carry out with machine.After sample is centrifugal, supernatant liquor is accumulated one group 4 parts, then analyze with the liquid chromatography tandem mass spectrum detection method (LC/MS/MS) of using many reaction detection (MRM).Initial linear by compound disappearance curve partly calculates data, is expressed as intrinsic clearance (CL _Int), μ l/min/mg protein.

Table 1 and 2 is illustrated in above-mentioned CCL1SPA in conjunction with measuring the result who in (with the IC50 value representation) and the people's microsome stability mensuration compound of above embodiment 1 to 11 is tested.The data of four control compounds (A, B, X and Y) also are shown.

The comparative example A, B, X and Y are as follows:

A:(2-{[9-(2-isobutoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate

B:2-{[9-(2-isobutoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenylformic acid

X:3-(4-chlorobenzene formacyl)-9-[2-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane

Y:3-(4-chlorobenzene formacyl)-9-[3-(2-methoxyl group phenoxy group) benzyl]-3,9-diaza spiro [5.5] undecane

Table 1

Embodiment number	IC50(μM)
		A	1.06
B	1.37
		1	0.643
2	0.196
		3	0.144
4	0.058

5	0.017
		6	0.081
7	0.100
		8	0.042
9	0.071
		10	0.405
11	0.520

Table 2

Embodiment number	Intrinsic clearance (μ l/min/mg)
		1	＜10
2	＜10
		3	＜10
4	＜10
		5	＜10
6	16
		7	＜10
8	＜10
		9	＜10
10	＜10
		11	＜10
X	＞200
		Y	＞200

Claims (20)

1. formula (II) compound or its pharmacy acceptable salt:

Wherein R represents following group:

Or

R wherein ²And R ³Expression-NR independently ⁸-C (O)-COOH ,-O-(C _1-4Alkyl)-COOH ,-C _1-4Alkyl-COOH, or-COOH;

R ⁴And R ⁵Represent halogen, CF independently of one another ₃Or C _1-4Alkyl;

P and q are 0,1 or 2 independently;

R ⁸Expression hydrogen or C _1-4Alkyl;

R ¹Represent following group:

Or

And

R ⁶And R ⁷Be hydrogen, methoxy or ethoxy independently.

2. the compound of claim 1, wherein R is

And

R wherein ², R ⁴With p as defined in claim 1.

3. claim 1 or 2 compound, wherein R ⁶And R ⁷Represent methoxyl group independently.

4. each compound of aforementioned claim, wherein R ⁴And R ⁵Represent halogen independently.

5. each compound of aforementioned claim, wherein R ²And R ³Independently expression-NH-C (O)-COOH ,-O-CH ₂-COOH or-CH ₂-COOH.

6. each compound of aforementioned claim, wherein R ²And R ³Expression-CH independently ₂-COOH.

7. the formula of claim 1 (II) compound or its pharmacy acceptable salt, wherein said compound is selected from:

(2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate,

(5-chloro-2-{[9-(2-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate,

(2-{[9-(3-phenoxy benzyl)-3,9-diaza spiro [5.5] undecane-3-yl] carbonyl } phenyl) acetate,

[2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate,

[5-chloro-2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate,

4,5-two chloro-2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenylformic acid,

[2-(9-[2-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] amino } (oxo) acetate,

[2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenyl] acetate,

2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenylformic acid,

[4-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenoxy group] acetate, or

[2-(9-[3-(2-methoxyl group phenoxy group) benzyl] and-3,9-diaza spiro [5.5] undecane-3-yl } carbonyl) phenoxy group] acetate.

8. pharmaceutical composition, it comprise in the claim 1 to 7 each described formula (II) compound or its pharmaceutically acceptable and, and be combined with pharmaceutically acceptable auxiliary agent, diluent or carrier.

9. the method for preparing the described pharmaceutical composition of claim 8, it comprises each described formula (II) compound or its pharmacy acceptable salt or solvate in the claim 1 to 7, mixes with pharmaceutically acceptable auxiliary agent, diluent or carrier.

10. each described formula (II) compound or its pharmacy acceptable salt in the claim 1 to 7, it is used for the treatment of.

11. each described formula (II) compound or the purposes of its pharmacy acceptable salt in the medicine that preparation is used for the treatment of in the claim 1 to 7.

12. each described formula (II) compound or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of asthma in preparation in the claim 1 to 7.

13. each described formula (II) compound or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of chronic obstructive pulmonary disease in preparation in the claim 1 to 7.

14. each described formula (II) compound or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of rhinitis in preparation in the claim 1 to 7.

15. each described formula (II) compound or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of chemokine mediated disease in preparation in the claim 1 to 7.

16. treat the method for chemokine mediated disease, wherein this chemokine combines with one or more Chemokine Receptors, and this method comprises each described formula (II) compound or its pharmacy acceptable salt in the claim 1 to 7 of patient's drug treatment significant quantity.

17. the method for claim 16, wherein Chemokine Receptors is the CCR8 acceptor.

18. the method for treatment respiratory system disease, this method comprises each described formula (II) compound or its pharmacy acceptable salt in the claim 1 to 7 of patient's drug treatment significant quantity.

19. the method for claim 18, wherein respiratory system disease is selected from asthma and chronic obstructive pulmonary disease.

20. the method for formula (II) compound or its salt of preparation claim 1, it comprises:

(a) make the compound of formula (III) and the compound reaction of formula (IV),

In the formula (III), R ¹Define suc as formula (II) is middle,

In the formula (IV), LG is suitable leavings group, and R ' is that different is R suc as formula defined R in (II) ²Be R ²', R ³Be R ³', and R wherein ²' and R ³' expression-NH-C (O)-C (O)-OR independently ", O-(C _1-4Alkyl)-C (O)-OR " ,-C _1-4Alkyl-C (O)-OR " or-C (O)-OR ", R wherein " and be suitable blocking group, remove blocking group then to form corresponding acid functional group; Perhaps

(b) make the compound of formula V and the aldehyde cpd reaction of formula (VI),

In the formula V, R defines suc as formula institute in (II) or is its shielded deriveding group,

In the formula (VI), R ¹Suc as formula defining in (II), perhaps

(c) make the compound of defined formula V in above (b) and the compound reaction of formula (VII),

In the formula (VII), R ¹Define suc as formula (II) is middle, and LG is a leavings group.