CN101052401A - Use of unsaturated quionoline or naphtalene derivatives as medicaments - Google Patents

Abstract

A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof; for use as a medicament (for example modulating the glucocorticoid receptor in a warm blooded animal), and pharmaceutical compositions comprising such compounds.

Description

Unsaturated quionoline or naphthalene derivatives are as the purposes of medicine

The present invention relates to unsaturated quionoline or naphthalene derivatives as the purposes of medicine (for example treating inflammatory conditions), use the method for this derivant and comprise the pharmaceutical composition of this analog derivative.

The hydrogen quinoline is disclosed among the EP-A1-0347960.

Known some nonsteroidal compound and glucocorticoid receptor (GR) (GR) interact, and because this interaction produces the inhibition (for example, referring to US6323199) of inflammation.This compounds shows tangible irrelevance (dissociation) between antiinflammatory and metabolism, this makes them be better than the steroidal and the non-steroidal glucocorticoid of early stage report.The invention provides other nonsteroidal compound, this chemical compound is used as the regulator (for example agonist, antagonist, partial agonist or partial antagonist) of glucocorticoid receptor (GR), and can have irrelevance between its antiinflammatory and metabolism.

The invention provides formula (I) chemical compound or its pharmaceutically acceptable salt and be used as medicine:

Wherein:

T is CH or N;

W, X, Y and Z are hydrogen, halogen, C independently _1-4Alkyl, C _1-4Alkoxyl, C _1-4Alkylthio group, CF ₃, OCF ₃, benzyloxy, nitro, cyano group, S (O) ₂NH ₂, C (O) (C _1-4Alkyl), C (O) NH ₂, NHC (O) (C _1-4Alkyl) or NR ¹⁰R ¹¹And W and X and/or Y and Z can be in conjunction with forming fused benzene rings or pyridine ring,

R ¹⁰And R ¹¹Be hydrogen, C independently _1-4Alkyl or C _3-7Cycloalkyl;

R ¹, R ²And R ³Be hydrogen or C independently _1-4Alkyl;

L is CH ₂Or C (O);

Key A is single or two keys.

Formula (I) chemical compound can exist with different isomeric form (as enantiomer, diastereomer, geometric isomer or tautomer).The present invention includes the purposes of whole mixture of the isomer of the purposes of all these class isomers and arbitrary proportion.

Suitable salt comprises acid-addition salts, example hydrochloric acid salt, hydrobromate, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalates, mesylate, tosilate, succinate, glutarate or malonate.

Formula (I) chemical compound can be used as solvate (as hydrate) and exists, and the present invention includes the purposes of all these kind solvent things.

Alkyl group and part are straight or branched, for example are methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl or the tert-butyl group.

Cycloalkyl is for example cyclopropyl, cyclopenta or cyclohexyl.

One concrete aspect in, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt as medicine, wherein: W and X are hydrogen; Y and Z are hydrogen or halogen (as fluorine or chlorine) independently; R ¹, R ²And R ³Be C independently _1-4Alkyl; L is CH ₂Or C (O); Key A is single or two keys.

In one aspect of the method, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt as medicine, wherein T is N.

In a further aspect, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt as medicine, wherein T is CH.

In also aspect one, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt as medicine, wherein W and X are hydrogen.

In one aspect of the method, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt as medicine, wherein Y and Z are hydrogen or halogen (as fluorine or chlorine) independently.

In a further aspect, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt, wherein R as medicine ¹, R ²And R ³Be C independently _1-4Alkyl.

One concrete aspect in, the invention provides as medicine formula (I) chemical compound or its pharmaceutically acceptable salt, wherein: T is N; W and X are hydrogen; Y and Z are hydrogen or halogen (as fluorine or chlorine) independently; R ¹, R ²And R ³Be C independently _1-4Alkyl; L is CH ₂Or C (O); Key A is single or two keys.

Can use or improve disclosed method preparation formula (I) chemical compound in this area.The raw material of preparation method can maybe can prepare by literature method, improvement literature method commercial obtaining.

Because formula (I) chemical compound has the ability that is attached to glucocorticoid receptor (GR), so they can be used as antiinflammatory, and also demonstrate anti-contingency, immunosuppressant and anti proliferative effect.Therefore, formula (I) chemical compound can be used as the medicine of the following pathological state in treatment or the prevention mammal (as the people):

(i) with the pneumonopathy of inflammation, allergy and/or breeding:

The chronic obstructive pulmonary disease in source mainly is a bronchial asthma arbitrarily

The bronchitis of separate sources

The various forms of pneumonopathy of constructivity again (restructive lung disease) mainly are allergic pulmonary alveolitiss

Various forms of pulmonary edema mainly are toxic pulmonary edemas

Sarcoidosis (sarcoidoses) and granulomatosis (granulomatoses) are as the Boeck disease

(ii) with the rheumatism/autoimmune disease/degenerative joint disease of inflammation, allergy and/or breeding:

Various forms of rheumatism, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, collagenosis (collagenoses)

Reactive arthritis

The struvite soft tissue diseases in other source (inflammatory soft-tissuedisease)

Arthritis condition of illness (arthroses) in the degenerative joint disease

Traumatic arthritis (traumatic arthritide)

The collagenosis in other source, for example systemic lupus erythematosus (sle), scleroderma, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis

Xerodermosteosis (sj  gren ' s syndrome), still's syndrome (Still ' ssyndrome), Felty syndrome (Felty ' s syndrome)

(iii) the allergic effect with inflammation, allergy and/or breeding reacts:

Various forms of atopic reactions, for example vasodilation (Quincke ' sedema), pollinosis, insect bite, to medicament, blood spread out atopic reaction, anaphylactic shock, urticaria, the contact dermatitis of preparation (bloodderivative), contrast agent etc.

(iv) with the dermatosis of inflammation, allergy and/or breeding:

Atopic dermatitis (mainly being the child)

Psoriasis

Red spot disease (erythematous disease) is by triggerings such as for example radiation of Different Kinds of Pathogens, chemical substance, burns

Acid burn (acid burn)

Bullous dermatosis

Lichen sample disease

(for example the anaphylaxis source itches) itches

Seborrheic eczema

Rosacea (rosacea)

Pemphigus vulgaris

Hebra's disease

Erythema nodosum

Balanitis

Vulvitis

Inflammatory alopecia is as alopecia areata

Skin T-cell lymphoma

(v) with the nephropathy of inflammation, allergy and/or breeding:

Nephrotic syndrome

Various nephritis

(vi) with the hepatopathy of inflammation, allergy and/or breeding:

Acute hepatocyte division (acute liver cell decomposition)

The acute hepatitis of separate sources, for example virus, toxin or medicament cause,

Chronic aggressivity hepatitis and/or Chronic Intermittent hepatitis

(vii) with the gastrointestinal disease of inflammation, allergy and/or breeding:

Crohn disease (Crohn disease)

Ulcerative colitis

The gastroenteritis in other source, for example congenital sprue (native sprue)

(viii) with the rectum disease of inflammation, allergy and/or breeding:

Anal eczema (anal eczema)

Be full of cracks (fissure)

Haemorrhoids

The special property sent out proctitis

(ix) with the oculopathy of inflammation, allergy and/or breeding:

Allergia keratitis (allergic keratitis), uvea inflammatory iritis (uvenitisiritis)

Conjunctivitis

Blepharitis

Optic neuritis

Choroiditis

Sympathetic ophthalmia

(x) with the ear-nose-larynx district disease of inflammation, allergy and/or breeding:

Allergic rhinitis, pollinosis

External otitis is for example caused by contact dermatitis, infection etc.

Otitis media

(xi) with the sacred disease (Neurological disease) of inflammation, allergy and/or breeding:

Cerebral edema mainly is the cerebral edema that tumor causes

Multiple sclerosis

Acute encephalomyelitis

Multi-form convulsions, for example baby's salaam convulsion

(xii) with the hematopathy of inflammation, allergy and/or breeding:

Acquired hemolytic anemia (acquired haemolytic anemia)

The special property sent out thrombocytopenia (idiopathic thrombocytopenia)

(xiii) with the oncosis of inflammation, allergy and/or breeding:

Acute lymphoblastic leukemia (acute lymphatic leukaemia)

Malignant lymphoma

Lymphogranulomatosis (lymphogranulomatoses)

Lymphosarcoma

General property transfer (extensive metastase) is mainly in breast carcinoma and carcinoma of prostate

(xiv) with the endocrinopathy of inflammation, allergy and/or breeding:

Endocrine orbital disease (endocrine orbitopathy)

Thyroid toxicity outbreak (thyrotoxic crisis)

De Kuierwanshi thyroiditis (de Quervain ' s thyroiditis)

Chronic lymphocytic thyroiditis (Hashimoto ' s thyroiditis)

Hyperthyroidism

(vx) with the transplanting of inflammation, allergy and/or breeding;

(xvi) with the severe hemorrhagic shock (Severe shockcondition) of inflammation, allergy and/or breeding, anaphylactic shock for example

(xvii) with the alternative medicine of inflammation, allergy and/or breeding, have:

Congenital primary adrenal insufficiency, for example congenital adrenogenital syndrome

The day after tomorrow primary adrenal insufficiency, for example Addison disease ((meta-infective), tumor, transfer etc. after Adidison ' sdisease), autoimmune adrenalitis, the infection

Congenital Secondary cases adrenal insufficiency, for example congenital hypopituitarism

The Secondary cases adrenal insufficiency will for example infect back (meta-infective), tumor etc. the day after tomorrow

(xviii) with the vomiting of inflammation, allergy and/or breeding:

For example in the inductive vomiting of cytostatic agent with 5-HT ₃The combination of-antagonist.

Be without prejudice to above-mentioned, formula (I) chemical compound also can be used for treating disease, as: conn's syndrome (Conies syndrome), constitutional and Secondary cases aldosteronism, sodium retention increases, magnesium and potassium are drained increases (polyuria), hydropexis increases (increased water retention), hypertension (unicity systolic hypertension and mixed type contraction/relaxation phase hypertension), arrhythmia, myocardial fibrosis, myocardial infarction, barrett's syndrome (Bartter ' s Syndrome), with excessive catecholamine levels diseases associated, diastole and contraction congestive heart failure (CHF), peripheral blood vessel, diabetic nephropathy, liver cirrhosis (cirrhosis with edema and ascites) with edema and ascites, esophagus varices (oesophagealvaricies), Addison disease (Addison ' s Disease), myasthenia, the dermal melanin calmness increases, (weight loss) loses weight, hypotension, hypoglycemia, hypercortisolism (Cushing ' s Syndrome), fat, hypertension, glucose intolerance, hyperglycemia, diabetes, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disease, the tissue rejection relevant with organ transplantation, malignant diseases such as leukemia and lymphoma, acute adrenal insufficiency, adrenal,congenital hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, myeloid cell series suppress, immunoproliferation/apoptosis, the hpa axis function suppresses and regulates, hypercortisolism (hypercortisolemia), the Th1/Th2 cytokine balance is regulated, chronic nephropathy, apoplexy and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, the Secondary cases adrenal insufficiency, adrenal,congenital hyperplasia, cerebral edema, thrombocytopenia, the Little syndrome, systematicness inflammation (systemicinflammation), inflammatory bowel, systemic lupus erythematosus (sle), discoid lupus erythematosus (discoid lupuserythematosus), nodositas polyarthritis (polyartitis nodosa), Wegner granulomatosis (Wegener ' s granulomatosis), giant cell arthritis, rheumatoid arthritis, osteoarthritis, pollinosis, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis (exfoliativedermatitis), urticaria, vasodilation, chronic obstructive pulmonary disease, asthma, tendinitis, bursitis, Crohn disease, ulcerative colitis, ACAH, hepatitis, cinhosis, inflammatory alopecia (inflammatory scalp alopecia), panniculitis, psoriasis, inflammatory cyst (inflamedcyst), PG, pemphigus vulgaris, bullous pemphigoid, dermatomyositis, the eosinophilic fasciitis, relapsing polychondritis, struvite vasculitis, sarcoidosis Sweet disease, 1 type reactional leprosy, capillary hemangioma, lichen planus, erythema nodosum acne (erythema nodosum acne), hirsutism, toxic epidermal necrolysis (toxic epidermal necrolysis), erythema multiforme (erythema multiform), skin T-cell lymphoma, psychosis, cognitive disorder (as disturbance of memory), mood disorders (as depression and bipolar disorder), anxiety disorder and personality disorder.

Term used herein " congestive heart failure " (CHF) or " congestive heart disease " be meant that blood that heart can not effectively aspirate enough volumes satisfies the morbid state (disease state) of the cardiovascular system of bodily tissue and tract demand.Usually, CHF is characterised in that hydrops in left ventricular insufficiency (heart contraction imbalance) and the lung, the underlying cause is one or more hearts or cardiovascular disease state, comprises coronary artery disease, myocardial infarction, hypertension, diabetes, valvular heart disease and cardiomyopathy.Term " diastole congestive heart failure " is meant the impaired CHF morbid state of ability that is characterised in that heart is suitably lax and congested.On the contrary, term " contraction congestive heart failure " is meant and is characterised in that heart suitably shrinks and the impaired CHF morbid state of ability of spray blood.

Those skilled in the art will appreciate that physiological decease can be used as " chronic " symptom or " acute " outbreak exists.Term used herein " chronic " is meant slow development and the long-term disease that continues.Thereby when diagnosis and treatment chronic disease, treatment continues whole lysis.On the contrary, term " acute " is meant the deterioration incident or the outbreak of short process, is the catabasis then.Therefore, the treatment of physiological decease is not only considered acute attack but also consider chronic disease.In acute attack, when paresthesia epilepsy, give drug compound, just disconnected medicine when transference cure.

In one aspect of the method, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt and be used for the treatment of purposes in the medicine of glucocorticoid disease states mediated (for example above-mentioned disease) in preparation.

In aspect another, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt and be used for the treatment of purposes in the medicine of inflammation (for example arthritis) symptom in preparation.

In aspect another, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt and be used for the treatment of purposes in the medicine of symptoms of asthma in preparation.

In also on the one hand, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt and be used for the treatment of purposes in the medicine of dermatosis symptom in preparation.

In also on the one hand, the invention provides formula (I) chemical compound or its pharmaceutically acceptable salt and be used for the treatment of purposes in the medicine of COPD in preparation.

In aspect another, the invention provides the method for glucocorticoid receptor (GR) disease states mediated in the treatment mammal (as the people), comprise formula (I) chemical compound or its pharmaceutically acceptable salt the mammal effective dosage of this class treatment of needs.

In another aspect, the invention provides the method for inflammation (for example arthritis) symptom in the treatment mammal (as the people), comprise formula (I) chemical compound or its pharmaceutically acceptable salt the mammal effective dosage of this class treatment of needs.

In another aspect, the invention provides the method for asthma in the treatment mammal (as the people), comprise formula (I) chemical compound or its pharmaceutically acceptable salt the mammal effective dosage of this class treatment of needs.

In another aspect, the invention provides the method for dermatosis symptom in the treatment mammal (as the people), comprise formula (I) chemical compound or its pharmaceutically acceptable salt the mammal effective dosage of this class treatment of needs.

In aspect another, the invention provides the method for COPD in the treatment mammal (as the people), comprise formula (I) chemical compound or its pharmaceutically acceptable salt the mammal effective dosage of this class treatment of needs.

For use formula (I) chemical compound or its pharmaceutically acceptable salt are used for mammiferous medical therapy, according to the standard drug practice described active component is mixed with pharmaceutical composition usually.

Therefore, in another aspect, the invention provides and comprise formula (I) chemical compound or its pharmaceutically acceptable salt (active component), and the pharmaceutical composition of pharmaceutically acceptable adjuvant, diluent or carrier.In aspect another, the invention provides the described method for compositions of preparation, comprise the mixed active composition, and pharmaceutically acceptable adjuvant, diluent or carrier.Depend on mode of administration, pharmaceutical composition can comprise 0.05-99%w (percetage by weight), for example 0.05-80%w, as the active component of 0.10-70%w (for example 0.10-50%w), and all wt percent is all based on whole compositionss.

For the disease of needs treatments, pharmaceutical composition of the present invention can be according to the standard mode administration, for example by local (as to lung and/or air flue or to skin), oral, rectum or parenteral.Therefore, formula (I) chemical compound or its pharmaceutically acceptable salt can be formulated into following form, for example aerosol, powder (for example dried or dispersible), tablet, capsule, syrup, granule, aqueous or oily solution or suspensoid, (lipid) emulsion, suppository, ointment, cream, drop or sterile injectable aqueous or oily solution or suspensoid.

Suitable drug compositions of the present invention is unit dosage form the sort of that is suitable for oral administration, for example comprises the tablet or the capsule of 0.1mg-1g active component.

In one aspect of the method, pharmaceutical composition of the present invention is for being fit to the sort of of intravenous, subcutaneous or intramuscular injection.

Can use buffer, pharmaceutically acceptable cosolvent such as Polyethylene Glycol, polypropylene glycol, glycerol or ethanol or chelating agent such as hydroxyl-propyl group beta-schardinger dextrin-to assist preparation.

Can obtain above-mentioned preparation by the conventional process of knowing in the drug world.Can carry out enteric coating to tablet by conventional means, the cellulose acetate-phthalate coating for example is provided.

The invention still further relates to therapeutic alliance or compositions, its Chinese style (I) chemical compound or its pharmaceutically acceptable salt or pharmaceutical composition that comprises formula (I) chemical compound or its pharmaceutically acceptable salt and the medicament that is used for the treatment of any above-mentioned disease be (may in same compositions) or administration successively simultaneously.

Especially, in order to treat inflammatory diseases (for example rheumatoid arthritis, COPD, asthma or allergic rhinitis), The compounds of this invention can with following medication combined use: the TNF-alpha inhibitor is (as anti-TNF monoclonal antibody (for example Remicade, CDP-870 and D ₂E ₇); Or TNF receptor immunoglobulin molecule (for example Enbrel ), nonselective COX-1/COX-2 inhibitor (for example piroxicam or diclofenac, the propanoic acid class is naproxen for example, flurbiprofen, fenoprofen, ketoprofen or ibuprofen, fragrant that acids is mefenamic acid for example, indometacin (Indomethacin), sulindac, azapropazone (azapropazone); Pyrazolone is Phenylbutazone for example, and Salicylate is aspirin for example); Cox 2 inhibitor (meloxicam for example, celecoxib, rofecoxib, valdecoxib or support are examined former times); The methotrexate of low dosage, leflunomide; Ciclesonide, oxychloroquine, d-penicillamine or auranofin, or parenteral or gold preparation for oral use (oral gold).

The present invention further relates to chemical compound of the present invention and following drug regimen:

The leukotriene 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 sulfonamide; 2,6-two-tert-butyl phenol hydrazone; The methoxyl group Pentamethylene oxide. is Zeneca ZD-2138, SB-210661 for example; The 2-cyano group naphthalene compound of pyridine radicals-replacement, L-739 for example, 010; 2-cyano quinolines chemical compound, L-746 for example, 530; Indole and quinoline compound, MK-591 for example, MK-886, and BAYx1005;

Leukotriene LTB ₄, LTC ₄, LTD ₄And LTE ₄Receptor antagonist, be selected from: phenothiazine-3-ketone, L-651 for example, 392; Amidino compounds is CGS-25019c for example; Benzo  amine (benzoxalamine) is ontazolast for example; Benzenecarboximidamide (benzenecarboximidamides) is BIIL 284/260 for example; Chemical compound is zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAYx7195 for example;

The PDE4 inhibitor comprises the inhibitor of isoform PDE4D;

Antihistamine H ₁Receptor antagonist, for example alerlisin (cetirizine), loratadine (loratadine), Desloratadine (desloratadine), fexofenadine (fexofenadine), astemizole (astemizole), azelastine (zaelastine) and chlorphenamine (chlorpheniramine);

Stomach protectiveness H ₂Receptor antagonist;

α ₁-and α ₂-adrenoceptor agonists, vasoconstrictor, parasympathomimetic agent, for example propylhexedrine (propylhexedrine), phenylephrine (phenylephrine), phenylpropanolamine, pseudoephedrine (pseudoephedrine), naphazoline hydrochlorate (naphazolinehydrochloride), oxymetazoline hydrochloride (oxymetazoline hydrochloride), tetrahydrozoline (tetryzoline) hydrochlorate (tetrahydrozoline hydrochloride), xylometazoline hydrochloride (xylometazoline hydrochloride) and ethylnorephinephrine hydrochlorate;

Anticholinergic, for example ipratropium bromide (ipratropium bromide), tiotropium bromide (titropium bromide), oxitropium bromide (oxitropium bromide), pirenzepine (pirenzepine) and telenzepine (telenzepine);

β ₁-to β ₄-adrenoceptor agonists, for example orciprenaline (metaproterenol), isoproterenol (isoproterenol), norepinephrine (isoprenaline), albuterol (albutero), salbutamol (salbutamol), formoterol (formoterol), salmaterol (sameterol), terbutaline (terbutaline), orciprenaline (orciprenaline), Win-32784 (bitolterol mesylate) and pirbuterol (pirbuterol); Perhaps methylxanthine (methylxanthanine) comprises theophylline (theophylline) and aminophylline (aminophylline); Sodium cromoglicate (sodium cromoglycate); Or muscarinic receptor (muscarinic receptor) (M1, M2 and M3) antagonist;

Insulin-like growth factor I type (IGF-1) analogies;

Reduce the suction glucocorticoid of systemic side effects, for example prednisone (prednisone), prednisolone (prednisolone), flunisolide (flunisolide), triamcinolone acetonide (triamcinolone), beclomethasone (beclomethasone dipropionate), budesonide (budesonide), fluticasone propionate (fluticasone propionate) and furancarboxylic acid Mo Meisong (mometasone furoate);

Matrix metallo-proteinase inhibitor, the inhibitor of instant stromatin enzyme (stromelysins), collagenase and gelatinase and Dan Baijutang enzyme (aggrecanase); Collagenase-1 (MMP-1) particularly, 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 regulator of chemokine receptor function, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for C-C family); CXCR1, CXCR3, CXCR4 and CXCR5 (for C-X-C family) and to C-X ₃The CX of-C family ₃The CR1 receptor;

Osteoporosis agents, for example sieve is coughed up former times sweet smell, droloxifene, lasofoxifene or fosomax;

Immunosuppressant is FK-506, rapamycin (rapamycin), Cyclosporine (cyclosporine), azathioprine (azathiprine) and methotrexate (methotrexate) for example;

Be used for the treatment of the chemical compound that AIDS and/or HIV infect, for example: prevention or suppress virus protein gp120 in conjunction with the reagent of host cell CD4 { as soluble CD4 (recombinant); Anti-CD 4 antibodies (or modification/recombinant antibodies) is PRO542 for example; Anti-gp120 antibody (or modification/recombinant antibodies); Or disturb gp120 in conjunction with the another kind of reagent of CD4 BMS806} for example; Prevent to be utilized the reagent { as CXCR4 agonist or antagonist or anti--CXCR4 antibody } of the chemokine receptors of combination except that CCR5 by HIV virus; Disturb the chemical compound that merges between HIV peplos and the cell membrane { as anti-gp41 antibody; Enfuvirtide (T-20) or T-1249}; DC-SIGN (also being called CD209) inhibitor { as anti--DC-SIGN antibody or DC-SIGN binding inhibitors }; Nucleoside/nucleotide analogue reverse transcriptase inhibitor { for example zidovudine (AZT), nevirapine, didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), Abacavir, adefovirdipivoxil or tenofovir (for example be free alkali or for disoproxil fumarate) }; Non-nucleoside reverse transcriptase inhibitor { for example nevirapine, Delavirdine or efavirenz }; Protease inhibitor { for example ritonavir, indinavir, Saquinavir (for example free alkali or mesylate), nelfinavir (for example free alkali or mesylate), amprenavir, Lopinavir or atazanavir (for example free alkali or sulfate) }; The ribonucleotide reductase inhibitor is hydroxyurea for example; Or antiretroviral drugs emtricitabine for example;

The existing medicine that is used for the treatment of osteoarthritis, for example non-steroid class antiinflammatory (hereinafter being called NSAID) is piroxicam or diclofenac for example, and the propanoic acid class is naproxen for example, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fragrant that acids is mefenamic acid for example, indometacin, sulindac, azapropazone, pyrazolone is Phenylbutazone for example, and Salicylate is aspirin for example; Cox 2 inhibitor is celecoxib for example, rofecoxib, and valdecoxib and support are examined former times, and analgesic and intraarticular therapeutic agent be for example Hyalgan (hyalgan) and synvisc and P2X7 receptor antagonist of corticosteroid and hyalomitome acids for example.

The present invention further also relates to being used in combination of The compounds of this invention and following medicine: (i) tryptase inhibitors; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin is changed enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) the adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) cathepsin; (vii) map kinase inhibitor; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin-B ₁-and B ₂-receptor antagonist body; (x) gout agent, for example, colchicine; (xi) xanthine oxidase inhibitor, for example, allopurinol; (xii) uricosuric agent, for example probenecid or sulphur arsenic ketone or benzbromarone; (xiii) growth hormone succagoga; (xiv) transforming growth factor (TGF); (xv) platelet derived growth factor (PDGF); (xvi) fibroblast growth factor, for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) Fructus Capsici vegetable oil (capsaicin cream); (xix) tachykinin NK-1 ₁Or NK ₃Receptor antagonist for example is selected from NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor is selected from UT-77 and ZD-0892; (xxi) TNF α converting enzyme inhibitor (TACE); (xxii) the inductive nitric oxide synthase inhibitor activity (iNOS) or the chemoattractant receptor homolog molecule (CRTH2 antagonist) of (xxiii) expressing on the TH2 cell.

Below the chemical compound example formula (I) chemical compound has been described, and with their chemical abstracts registry no.

Human glucocorticoid receptor (GR) measures

Based on the commercial reagents box (Item Number P2893) of Panvera/Invitrogen, analyze.Analytical technology is a fluorescence polarization.Test kit utilizes recombined human GR ((Panvera, Item Number P2812), Fluoromone ^TMLabelling tracer (GS Red, Panvera, Item Number P2894) and stabilisation peptide 10X (Panvera, Item Number P2815).GR and stabilisation peptide reagent store down at-70 ℃, and GS Red stores down at-20 ℃.Also comprise 1M DTT (Panvera, Item Number P2325 store down at-20 ℃) and GR screening buffer 10X (Panvera, Item Number P2814 begin to store down at-70 ℃, but in case thaw just storage at room temperature) in the test kit.For all reagent, all avoid freeze/thaw repeatedly.GR screening buffer 10X comprises 100mM potassium phosphate, 200mM sodium molybdate, 1mM EDTA and 20%DMSO.

Test compound (1 μ L) and tester (1 μ L) in 100%DMSO are joined (Greiner is low, and volume black is flat, Item Number 784076) on the black polystyrene 384-orifice plate.0% tester is 100%DMSO, and 100% tester is 10 μ M dexamethasone.With background solution (8 μ L; Measure buffer 10X, stabilisation peptide, DTT and ice-cold MQ water) join in this bottom outlet.With GS Red solution (7 μ L; Measure buffer 10X, stabilisation peptide, DTT, GS Red and icy water) join in the institute this bottom outlet is porose.With GR solution (7 μ L; Measure buffer 10X, stabilisation peptide, DTT, GR and icy water) solution join institute porose in.Sealing plate, and in the dark at room temperature cultivated 2 hours.In Analyst plate readout instrument (LJL Biosystems/Molecular Devices Corporation) or other can write down on the similar plate readout instrument of fluorescence polarization plate reading (dichroic mirror is at the 561nm place for excitation wavelength 530nm, emission wavelength 590nm).Use XLfit model 205 to calculate the IC50 value.

Chemical compound	IC 50(nM)
		CAS120109-44-6	240

Claims (10)

1. be used as formula (I) chemical compound or its pharmaceutically acceptable salt of medicine:

Wherein:

T is CH or N;

W, X, Y and Z are hydrogen, halogen, C independently _1-4Alkyl, C _1-4Alkoxyl, C _1-4Alkylthio group, CF ₃, OCF ₃, benzyloxy, nitro, cyano group, S (O) ₂NH ₂, C (O) (C _1-4Alkyl), C (O) NH ₂, NHC (O) (C _1-4Alkyl) or NR ¹⁰R ¹¹And W and X and/or Y and Z can be in conjunction with forming fused benzene rings or pyridine ring,

R ¹⁰And R ¹¹Be hydrogen, C independently _1-4Alkyl or C _3-7Cycloalkyl;

R ¹, R ²And R ³Be hydrogen or C independently _1-4Alkyl;

L is CH ₂Or C (O);

Key A is single or two keys.

2. formula (I) chemical compound as medicine as claimed in claim 1, wherein T is N.

3. formula (I) chemical compound as medicine as claimed in claim 1, wherein T is CH.

4. as claim 1,2 or 3 described formula (I) chemical compounds as medicine, wherein W and X are hydrogen.

5. as claim 1,2,3 or 4 described formula (I) chemical compounds as medicine, wherein Y and Z are hydrogen or halogen independently.

6. as claim 1,2,3,4 or 5 described formula (I) chemical compound, wherein R as medicine ¹, R ²And R ³Be C independently _1-4Alkyl.

7. formula (I) chemical compound as medicine as claimed in claim 1, wherein: T is N; W and X are hydrogen; Y and Z are hydrogen or halogen independently; R ¹, R ²And R ³Be C independently _1-4Alkyl; L is CH ₂Or C (O); Key A is singly-bound or two key.

8. formula (I) chemical compound as claimed in claim 1 or its pharmaceutically acceptable salt are used for the treatment of purposes in the medicine of glucocorticoid disease states mediated in preparation.

9. the method for glucocorticoid receptor (GR) disease states mediated in the treatment mammal comprises formula as claimed in claim 1 (I) chemical compound or its pharmaceutically acceptable salt to the mammal effective dosage of this treatment of needs.

10. a pharmaceutical composition comprises formula as claimed in claim 1 (I) chemical compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable adjuvant, diluent or carrier.