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    • 专利摘要:
    An increase in the number of neutrophils and / or in a mammal, such as a human, comprising administering a PPARγ agonist such as Compound (I) to a mammal in need thereof in an effective, nontoxic and pharmaceutically acceptable amount. A method of treating a disease or disorder associated with hyperactivation.
    公开号:KR20010108506A
    申请号:KR1020017013106
    申请日:2000-04-17
    公开日:2001-12-07
    发明作者:콜린 허스튼 맥피
    申请人:피터 기딩스；스미스클라인비이참피이엘시이；
    IPC主号:
    专利说明:

    Novel Method of Treatment
    [2] European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives disclosed to have antihyperglycemic and hypolipidemic activity. One particular thiazolidinedione disclosed in EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (Hereinafter referred to as compound (I)). Example 1 of WO 94/05659 discloses certain salts of compound (I) comprising the maleate of compound (I).
    [3] Compound (I) is an example of one type of antihyperglycemic agent known as glitazone or thiazolidinedione.
    [4] In addition, European Patent Application Publication No. 0008203, No. 039421, No. 0032128, No. 0428312, No. 0489663, No. 055845, No. 0778775, No. 0204020, No. 0177353, 0319189, 0332331, 0332332, 0528734, 00508740, International Patent Application Publication Nos. 92/18501, 93/02079, 93/22445 and United States Patents 5104888 and 5478852 disclose certain thiazolidinediones.
    [5] The contents of the above mentioned publications are hereby incorporated by reference.
    [6] It is known that the γ-isomorphic form of the receptor activated with a peroxysomal proliferator (hereinafter referred to as PPARγ) is a member of the nuclear receptor superfamily including receptors of steroid hormones, thyroid hormones and retinoid hormones (Evans, Science 240, 889-895, (1988)]. See also Chalala et. al., Endocrinology 135, 798-800, 1994] it is known that PPARγ is expressed early in adipocyte differentiation. J. Biol. Chem., 270, 12963-12966, it is known that thiazolidinedione, such as compound (I), is a PPARγ agonist.
    [7] We have now found that PPARγ expression is significantly upregulated in activated neutrophils. Therefore, it is expected that PPARγ agonists can be used in diseases and disorders that require activated neutrophil action to inhibit neutrophil activity or suppression of numbers. Such diseases include the list including gout, arthritis, asthma, chronic obstructive pulmonary disease, irritable bowel syndrome, psoriasis and acne.
    [8] Neutrophils are also the major cell types that infiltrate the dermis and epidermal layers of the skin after moderate to severe UV exposure. The cells can cause tissue damage and create certain difficult situations that delay skin recovery. Therefore, it is contemplated that PPARγ agonists will be useful for the prevention and / or treatment of damage to the dermis and / or epidermal layer by excessive ultraviolet radiation or sun exposure. The agonists are also contemplated to assist in the recovery of the skin after such injury.
    [9] Thus, the present invention includes the administration of a PPARγ agonist such as Compound (I) to a mammal in need thereof in an effective, nontoxic and pharmaceutically acceptable amount, and thus increases the number of neutrophils in mammals such as humans, and ( Or) provide a method of treating a disease or disorder associated with hyperactivation.
    [10] In another aspect, the present invention provides the use of a PPARγ agonist, such as compound (I), for the manufacture of a medicament for the treatment of a disease or condition associated with an increase in the number of neutrophils and / or overactivation in a mammal such as a human. do.
    [11] Suitable examples of diseases or disorders associated with increased number of neutrophils and / or hyperactivation include diseases or disorders of the airways, bones, joints, skin, gastrointestinal tract, other tissues, and systemic diseases, allograft rejection and certain cancers. Especially a disease or condition of the airways. Especially diseases or disorders of bones and joints. Especially a disease or condition of the skin. Especially a disease or condition of the gastrointestinal tract. In particular diseases or disorders of other tissues and systemic diseases. In particular, it is a disease associated with allograft rejection. Especially certain cancers.
    [12] Suitable examples of airway diseases or disorders include obstructive airway disease, including chronic obstructive pulmonary disease (COPD); Asthma, such as bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma and dust asthma, especially chronic or refractory asthma (eg, late asthma and airway hypersensitivity); bronchitis; Acute allergic rhinitis, atrophic rhinitis and chronic rhinitis including casein rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and drug rhinitis; Membrane rhinitis and adenitis rhinitis, including croupous rhinitis, fibrous rhinitis, and mucosal rhinitis; Seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; Sarcoidosis, farmer's lung disease and related diseases, a list of diseases consisting of fibrotic pneumonia and idiopathic interstitial pneumonia. A particular disease or condition of the airways is considered to be each of the diseases of the list that do not include other diseases of the list.
    [13] Suitable examples of diseases or conditions of bone and joint include rheumatoid arthritis, serological negative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome ( Sjogren's syndrome and systemic sclerosis. Certain diseases or disorders of bone and joint are considered to be diseases of the above list which do not include other diseases of the above list.
    [14] Suitable examples of skin diseases or disorders include psoriasis, atopic dermatitis, contact dermatitis and other eczema dermatitis, seborrheic dermatitis, lichen planus, lactose, blistering dermatitis, bullous epidermal detachment, urticaria, vascular dermatitis, vasculitis, erythema And diseases on the list consisting of skin eosinophilia, uveitis, alopecia areata and spring conjunctivitis. A particular disease or condition of the skin is considered to be each of the diseases in the list that do not include other diseases in the list.
    [15] Suitable examples of gastrointestinal diseases or disorders include celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, and food-related allergies such as migraine, rhinitis and Includes diseases on the list of eczema. A particular disease or condition of the gastrointestinal tract is considered to be each of the diseases in the list that do not include other diseases in the list.
    [16] Suitable examples of other tissue diseases and systemic diseases include multiple sclerosis, arteriosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome And diseases on the list consisting of eosinophilic fasciitis, hyperimmunoglobulin E syndrome, nazona na, sezary syndrome and idiopathic thrombocytopenic purpura. Certain diseases or disorders of other tissues and certain systemic diseases are considered to be diseases of the above list, each of which does not include other diseases of the above list.
    [17] Suitable examples of diseases associated with allograft rejection include acute and chronic diseases following kidney, heart, liver, lung, bone marrow, skin and retinal transplantation; And chronic graft-versus-host disease. Certain diseases associated with allograft rejection are considered to be diseases of the list above that do not include other diseases on the list.
    [18] Suitable examples of cancer include cancers in the list consisting of non-small cell lung cancer (NSCLC) and squamous cell cancer. Particular cancer is non-small cell lung cancer. Particular cancer is squamous cell carcinoma.
    [19] In another aspect, a disease or condition on the list consisting of cystic fibrosis, stroke, reperfusion injury of the heart, brain, limbs and sepsis, gout, arthritis, asthma, chronic obstructive pulmonary disease, irritable bowel syndrome, psoriasis and acne are included. A particular disease or condition is considered to be each of the diseases in the list that do not include other diseases in the list.
    [20] As mentioned above, another disease of the skin associated with an increase in the number of neutrophils and / or overactivation is damage to the dermal dermis and / or epidermal layer by excessive ultraviolet radiation or sun exposure. Accordingly, the present invention also includes administering a PPARγ agonist, such as Compound (I), to a mammal in need thereof in an effective, nontoxic and pharmaceutically acceptable amount, such as excessive ultraviolet radiation or sunlight in a mammal, such as a human. Provided are methods of preventing and / or treating damage to skin dermis and / or epidermal layer by exposure.
    [21] The present invention also provides a method of promoting or assisting the recovery of the skin after said injury, comprising administering to a mammal in need thereof an effective, non-toxic and pharmaceutically acceptable amount such a PPARγ agonist such as Compound (I). to provide.
    [22] Suitable PPARγagonists are compound (I) or a pharmaceutically acceptable derivative thereof.
    [23] Other suitable PPARγ agonists include (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2- Yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2, 4-dione (or ciglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone )) And 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone), or pharmaceutically acceptable thereof Possible derivatives are included.
    [24] It will be understood that PPARγ agonists such as compound (I) are administered in pharmaceutically acceptable forms, including pharmaceutically acceptable derivatives.
    [25] Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters and solvates as suitable PPARγ agonists.
    [26] Suitable pharmaceutically acceptable salts and solvates forms of compound (I) include those described in EP 0306228 and WO 94/05659. Preferred pharmaceutically acceptable salts of compound (I) are maleates. Preferred pharmaceutically acceptable solvates of compound (I) are hydrates.
    [27] Other pharmaceutically acceptable derivatives include standard references such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) or the publications mentioned above. Is disclosed.
    [28] PPARγ agonists can be prepared using known methods, such as those disclosed in the publications mentioned above.
    [29] Compound (I) and its pharmaceutically acceptable forms can be prepared using known methods, for example those disclosed in EP 0306228 and WO 94/05659.
    [30] Compound (I) may exist in one form of several tautomers, all of which are included in the term compound (I) as individual tautomeric forms or mixtures thereof. Since compound (I) contains chiral carbon atoms, it may exist in up to two stereoisomeric forms, and the term compound (I) includes both of these isomeric forms as individual isomers including racemates or as a mixture of isomers. do.
    [31] As used herein, the term 'pharmaceutically acceptable' includes both human and veterinary uses, for example the term 'pharmaceutically acceptable' includes veterinary acceptable compounds.
    [32] Reference to a scalar amount, including mg amounts of compound (I) in pharmaceutically acceptable form, refers to the scalar amount relative to compound (I) itself. For example, 2 mg of compound (I) in maleate form refers to the amount of maleate comprising 2 mg of compound (I).
    [33] Neutrophil activation can be seen using conventional methods as disclosed in Current Protocols in Immunology, Vol I, Suppl 1, Unit 6.12.3., Incorporated herein by reference.
    [34] Neutrophils can be isolated from human blood as described in Current Protocols in Immunology, Vol I, Suppl 1, Unit 7.23.1., Incorporated herein by reference.
    [35] In the methods of the invention, the active medicament is preferably administered in the form of a pharmaceutical composition.
    [36] Thus, in one aspect, the invention provides a treatment for a disease or condition associated with an increase in the number and / or overactivation of neutrophils in a mammal, such as a human, comprising a PPARγ agonist such as Compound (I) and a pharmaceutically acceptable carrier. Provided is a pharmaceutical composition for use in.
    [37] The composition can be prepared for a suitable method of administration, for example oral, parenteral, sublingual or transdermal administration.
    [38] The composition may be in the form of a liquid formulation such as tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, oral or sterile injectable solutions or suspensions.
    [39] For consistency of administration it is preferred that the compositions of the present invention are in unit dosage form.
    [40] Unit dosage forms for oral administration may be tablets and capsules, binders (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar, corn) Conventional excipients such as starch, calcium phosphate, sorbitol or glycine, tableting lubricants (e.g. magnesium stearate), disintegrants (e.g. starch, polyvinylpyrrolidone, starch glycolate or microcrystalline cellulose Or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.
    [41] The composition is preferably a unit dosage form comprising an appropriate amount for an appropriate daily dosage based on the particular compound selected and factors such as the nature and severity of the disease or disorder.
    [42] Appropriate dosages, including unit dosages of PPARγ agonists such as Compound (I), are described in the UK and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and in Martindale The Extra Pharmacopoeia (London, The Pharmaceutical). Known) and known dosages and unit doses of such compounds as described or referred to in the above references or in the publications mentioned above.
    [43] In the treatment of the present invention, the PPARγ agonist may be administered according to known therapies described or mentioned in the references as mentioned above or in the publications mentioned above.
    [44] In the treatment, the medicament may be administered 1 to 6 times a day, but most preferably 1 or 2 times a day.
    [45] Oral solid compositions can be prepared by conventional methods of blending, filling or tableting. The blending process may be repeated to distribute the active agent in the composition using a large amount of filler. Such a process is of course common in the art. Tablets may be coated according to methods known in conventional pharmaceutical preparation, in particular with enteric coatings.
    [46] Oral liquid formulations may be in the form of emulsions, syrups or elixirs, for example, and may be provided as a dry product which is reconstituted with water or other suitable vehicle before use. Such liquid preparations include conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan monooleate or acacia; Non-aqueous vehicles (which may include edible oils), for example oily esters such as almond oil, fractionated coconut oil, glycerin, propylene glycol or esters of ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And, if desired, conventional flavoring or coloring agents.
    [47] Liquid unit dosage forms for parenteral administration are prepared using sterile vehicles, depending on the compound and concentration used, and may be suspended or dissolved in the vehicle. In the preparation of the solution, the compound may be dissolved in water for injection, filter sterilized and then filled and sealed in a suitable vial or ampoule. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. To improve stability, the composition can be filled into vials and then frozen, and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that compound (I) is suspended instead of dissolved in the vehicle and cannot be sterilized by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition so that the compound is uniformly distributed.
    [48] The composition may contain 0.1 to 99% by weight, preferably 10 to 60% by weight of the active substance, depending on the method of administration.
    [49] As mentioned, the PPARγ agonist may also be administered in a pharmaceutically acceptable form suitable for topical administration.
    [50] Topical administration of a PPARγ agonist is intended for the treatment of skin diseases or disorders, including the diseases listed above, and for preventing and / or preventing damage to the dermal dermis and / or epidermal layers by excessive ultraviolet or sunlight exposure. Especially suitable for treatment. Particular examples of skin diseases or disorders are psoriasis.
    [51] Accordingly, in a further aspect, the present invention also provides a pharmaceutical composition comprising a PPARγ agonist and a pharmaceutically acceptable carrier, suitable for topical administration, in particular for the treatment of skin diseases or disorders.
    [52] Pharmaceutically acceptable carriers suitable for topical administration include materials that are safe for topical or transdermal administration in humans or non-human mammals, and are compatible with the active compounds, and include solvents, diluents, preservatives, and penetration enhancers. , Polymers, buffers, flavorings, thickeners, gelling agents, surfactants and emulsifiers. Such substances are described in the UK and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press), Harry's Cosmeticology (Leonard Hill Books) and Drugs and Pharmaceutical Sciences, Vol 18, Dermatological Formulations "Percutaneous Absorption" by Brian W Barry, pub Marcel Deker (ISBN 0/8247/1729/5) or the above-mentioned publications.
    [53] For topical administration, the active ingredient may comprise 0.001 to 10% w / w, for example 1 to 2% w / w of the formulation. However, the active ingredient may not comprise as much as 10% w / w of the formulation, preferably less than 5% w / w, more preferably 0.1 to 1% w / w.
    [54] Compositions of the invention suitable for topical administration may be employed in conventional dosage forms suitable for topical administration, for example, lotions, liniments, gels, creams, ointments, eye drops, solutions, using the methods disclosed in the references cited above. Or as a spray.
    [55] Skin lotion or lining agents may also include drying accelerators such as alcohols or acetone and skin refreshing agents, and / or moisturizing agents such as glycerol or castor oil or peanut oil.
    [56] Creams, ointments or pastes according to the invention are semisolid formulations of the active ingredient for external application. The formulations may be prepared by mixing the active ingredient in powdered or powdered form alone or in a solution or suspension in an aqueous or non-aqueous liquid with an oily or non-oily base using a suitable machine. The base may be selected from the group consisting of hydrocarbons, such as hard, soft or liquid paraffins, glycerol, beeswax, metallic soaps, together with alcohols or macrogels such as propylene glycol; mucilage; Natural oils such as almond oil, corn oil, peanut oil, castor oil or olive oil; Woolen milk or derivatives thereof, or fatty acids such as stearic acid or oleic acid. The formulation may comprise any suitable surfactant, such as anionic, cationic or nonionic surfactants such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives, or inorganic materials such as siliceous silica, and other ingredients such as lanolin may also be included.
    [57] Eye drops according to the invention may comprise a sterile aqueous solution or an oily solution, or an aqueous or oily suspension, and may comprise a fungicide and / or fungicide and / or any other suitable preservative, and preferably a surfactant. It can be prepared by dissolving the active ingredient in a suitable aqueous solution. The resulting solution can then be clarified by filtration, transferred to a suitable container, sealed and then sterilized by autoclaving or holding at 98-100 ° C. for 30 minutes. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of fungicides and fungicides suitable for inclusion in eye drops include phenyl mercury nitrate or mercury phenyl mercury acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, dilute alcohol and propylene glycol.
    [58] In topical treatment, the medicament may be applied 1 to 6 times per day, but is most preferably applied once or twice a day.
    [59] The present invention also provides a pharmaceutical composition for topical administration, comprising a PPARγ agonist and a pharmaceutically acceptable carrier suitable for topical administration, for use as an active therapeutic agent.
    [60] The composition may be in the form of a pack containing written or printed instructions for use as needed.
    [61] The compositions can be found in references such as the British and American Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, 31st edition 341) And Harry's Cosmeticology (Leonard Hill Books) or the aforementioned publications, according to conventional methods.
    [62] The compositions or methods of the present invention in the above-mentioned dosage ranges did not exhibit toxicological side effects.
    [63] The following examples illustrate the invention and do not limit it in any way.
    [64] <Efficacy check>
    [65] The results shown in FIG. 1 showed that PPARγ mRNA increased rapidly and significantly while human neutrophils adhered to the culture dish (take data after 1 hour and 4 hours), which was further improved by treatment with GM-CSF (FIG. 1A ), The increase in gelatinase B mRNA expression observed 4 hours after neutrophil adhesion was reduced by treatment with Compound (I) 1 μM (FIG. 1B). Time Zero (T0) refers to the expression of intrinsic human neutrophils prior to adhesion.
    [66] 2 shows the inhibition of MMP-9 release by compound (I). Neutrophils were isolated to at least 98% purity by countercurrent centrifugal elutriation and maintained in RPMI 1640 + 1% BSA. Cells were cultured in 48 well plates and adhered to wells within 1 hour of plating. Compound (I) (named “BRL49653” in FIG. 2) was included at the beginning of the experiment. After 4 hours, the culture was removed and human MMP-9 ELISA assay (Amersham) was performed. The other four data were not suitable for direct comparison and for normalization the data were normalized to the percentage of control without compound. * Means that Student's t-test on the original data before standardization results in p <0.05. The IC 50 for inhibition of MMP-9 release by Compound (I) was 10.6 nM (calculated according to the 4-parameter log curve using Statisistica).
    [1] The present invention relates to a method of treatment, in particular a method of treating a disease or condition associated with an increase in the number of neutrophils and / or hyperactivation.
    权利要求:
    Claims (11)
    [1" claim-type="Currently amended] PPARγ agonists such as 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (compound (I)) are effective A method of treating a disease or condition associated with an increase in the number and / or hyperactivation of neutrophils in a mammal, such as a human, comprising administering to the mammal in need thereof a nontoxic and pharmaceutically acceptable amount.
    [2" claim-type="Currently amended] The method of claim 1, wherein the disease or condition associated with an increase in the number and / or overactivation of neutrophils is a disease or condition of the airways, bones, joints, skin, gastrointestinal tract, other tissues, and systemic diseases, allograft rejection and certain cancers. The method selected.
    [3" claim-type="Currently amended] The method of claim 1 or 2, wherein the disease or condition of the airway comprises obstructive airway disease, including chronic obstructive pulmonary disease (COPD); Asthma, such as bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma and dust asthma, especially chronic or refractory asthma; bronchitis; Acute allergic rhinitis, atrophic rhinitis and chronic rhinitis including casein rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and drug rhinitis; Membrane rhinitis and adenitis rhinitis, including croupous rhinitis, fibrous rhinitis, and mucosal rhinitis; Seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; Sarcoidosis, farmer's lung disease and related diseases, fibrotic pneumonia and idiopathic interstitial pneumonia.
    [4" claim-type="Currently amended] The disease or condition of the bone or joint according to claim 1, wherein the disease or condition of the bone and joint is rheumatoid arthritis, serological negative spondyloarthropathy, Behcet's disease, Sjogren's syndrome and systemic sclerosis. A method or disease in a composed list.
    [5" claim-type="Currently amended] The skin disease or condition according to any one of claims 1 to 3, wherein the skin disease or condition is psoriasis, atopic dermatitis, contact dermatitis and other eczema dermatitis, seborrheic dermatitis, squamous tachycardia, ileal swelling, bullous pulmonary blister, A method or disease on the list consisting of epidermal detachment, urticaria, vascular dermatosis, vasculitis, erythema, cutaneous eosinophilia, uveitis, alopecia areata and spring conjunctivitis.
    [6" claim-type="Currently amended] The gastrointestinal disease or condition according to any one of claims 1 to 3, wherein the gastrointestinal disease or disease is not related to celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis and the digestive tract, A disease or condition on the list consisting of allergies associated with the disease.
    [7" claim-type="Currently amended] The disease according to any one of claims 1 to 3, wherein the diseases of other tissues and systemic diseases are multiple sclerosis, arteriosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, Hashimoto's thyroiditis ), Myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyperimmunoglobulin E syndrome, nazona syndrome, sezary syndrome and idiopathic thrombocytopenic purpura .
    [8" claim-type="Currently amended] The disease according to any one of claims 1 to 3, wherein the disease associated with allograft rejection comprises acute and chronic diseases following kidney, heart, liver, lung, bone marrow, skin and retinal transplantation; And chronic graft-versus-host disease.
    [9" claim-type="Currently amended] The method of claim 1, wherein the cancer is a cancer in the list consisting of non-small cell lung cancer (NSCLC) and squamous cell carcinoma.
    [10" claim-type="Currently amended] The PPARγ agonist according to any one of claims 1 to 9, wherein the PPARγ agonist is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2 , 4-dione (compound (I)) or a pharmaceutically acceptable derivative thereof.
    [11" claim-type="Currently amended] The method according to any one of claims 1 to 9, wherein the PPARγ agonist is 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione ( Or pioglitazone).
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    同族专利:
    公开号 | 公开日
    ES2256003T3|2006-07-16|
    PL364720A1|2004-12-13|
    CZ20013688A3|2003-03-12|
    NO20014950L|2001-12-13|
    DE60026508D1|2006-05-04|
    AU4583000A|2000-11-02|
    EP1274407A2|2003-01-15|
    DZ3151A1|2000-10-19|
    WO2000062766A3|2002-10-31|
    EP1593379A3|2007-10-31|
    YU77901A|2005-07-19|
    GB9908647D0|1999-06-09|
    CA2370127A1|2000-10-26|
    CN1413105A|2003-04-23|
    HRP20010746A2|2002-10-31|
    DK1274407T3|2006-06-26|
    AT319437T|2006-03-15|
    HU0300479A2|2003-07-28|
    ZA200108446B|2003-08-27|
    ID30339A|2001-11-22|
    IL145875D0|2002-07-25|
    BR0009776A|2002-06-04|
    SK14532001A3|2002-02-05|
    EP1274407B1|2006-03-08|
    TR200102977T2|2002-09-23|
    MA25351A1|2001-12-31|
    EP1593379A2|2005-11-09|
    EA200101089A1|2002-10-31|
    JP2003516310A|2003-05-13|
    WO2000062766A2|2000-10-26|
    DE60026508T2|2006-11-16|
    MXPA01010428A|2002-05-06|
    NO20014950D0|2001-10-11|
    PT1274407E|2006-06-30|
    AP200102291A0|2001-12-31|
    BG106104A|2002-05-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-04-15|Priority to GB9908647.2
    1999-04-15|Priority to GBGB9908647.2A
    2000-04-17|Application filed by 피터 기딩스, 스미스클라인비이참피이엘시이
    2000-04-17|Priority to PCT/GB2000/001499
    2001-12-07|Publication of KR20010108506A
    优先权:
    申请号 | 申请日 | 专利标题
    GB9908647.2|1999-04-15|
    GBGB9908647.2A|GB9908647D0|1999-04-15|1999-04-15|Novel compounds|
    PCT/GB2000/001499|WO2000062766A2|1999-04-15|2000-04-17|Uses of ppar-gamma agonists in neutrophil-induced diseases|
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