MXPA01000561A - Therapeutic agents for allergic diseases - Google Patents

Abstract

Therapeutic and/or preventive agents for allergic diseases, particularly, allergy type I and IV reactions, inflammation, rhinitis, conjunctivitis, bronchial asthma, atopic diseases (such as dermatitis or enteritis) and allergic inflammation of digestive tract, which are characterized by containing metalloproteinase inhibitors as the active ingredient.

Description

AGENTS FOR THE TREATMENT OF ALLERGIC DISEASES Field of the Invention The present invention relates to anti-allergic agents, anti-inflammatory agents or prophylactic and / or therapeutic drugs for a disease selected from the group consisting of bronchial asthma, allergic rhinitis, atopic diseases, allergic gastroenterocolitis, allergic conjunctivitis, etc., which each comprising an effective amount of at least one member selected from metalloproteinase inhibitors. In still another aspect, the present invention relates to: (i) a method for obtaining an antiallergic and / or anti-inflammatory action, and / or a normalizing action on the physiological or biological responses related thereto, or (ii) a method for treating prophylactically and / or therapeutically at least one disease selected from the group consisting of bronchial asthma, allergic rhinitis, atopic diseases, allergic gastroenterocolitis, conjunctivitis Ref: 126512 allergic, etc., wherein said method comprises administering a prophylactically and / or therapeutically effective amount of at least one member selected from metalloproteinase inhibitors. Among them, the present invention relates particularly to antiallergic agents, anti-inflammatory agents, or prophylactic and / or therapeutic drugs for a disease selected from the group consisting of bronchial asthma, allergic rhinitis, atopic diseases, allergic gastroenterocolitis, with allergic untivitis. , etc., each comprising an effective amount of at least one member selected from the group consisting of a compound of the general formula (I) and a pharmaceutically acceptable salt or solvate thereof. In still another aspect, the present invention relates to: (i) a method for obtaining an antiallergic and / or anti-inflammatory action and / or a normalizing action on the physiological or biological responses related thereto, or (ii) a method for treating prophylactically and / or therapeutically at least one disease selected from the group consisting of bronchial asthma, allergic rhinitis, atopic diseases, Allergic gastroenterocolitis, allergic conjunctivitis, etc., wherein said method comprises administering a prophylactically and / or therapeutically effective amount of at least one member selected from the group consisting of a compound of the general formula (I) and a salt or solvate pharmaceutically acceptable thereof.

Background of the Invention Allergic reactions are classified according to their pathophysiological nature in four types: type I, type II, type III and type IV. Classically, type I, type II and type III allergies are included in the immediate type hypersensitivity depending on the interaction of antigens with humoral antibodies and type IV allergy is on delayed type hypersensitivity, based on the terms up to the beginning of it after the promotion with the antigen. Type I allergy is a reaction in which IgE antibodies participate and is also called anaphylaxis. Examples of type I allergic responses include bronchial asthma, atopic diseases (dermatitis, enteritis, etc.), allergic rhinitis, such as pollinosis, allergic conjunctivitis, food allergy, etc. Type II allergy is called cytotoxic allergy or stimulant allergy. This allergy type II participates in the onset of diseases including tissue disorders caused by transfusion of non-compatible erythrocytes, autoimmune hemolytic anemia, idiopathic thrombocytopenia, myasthenia gravis, Basedo's disease, etc. Thus, when IgM or IgG antibodies produced against extrinsic or intrinsic antigens are linked to the antigens on the target cells, the complements or phagocytes are activated and, as a result, the target cells are damaged. Now, when the antibodies are linked to the autoantigens such as the receptors on a cell surface and the like, the antibodies are poorly understood as ligands for the receptors, or the antibodies disturb the binding of the intrinsic ligands specific for the receptors, which the biological functions of the tissues are stimulated or suppressed and their homeostasis becomes confused. Type III allergy is called allergy-mediated immune complex or allergy type Arthus. Major disorders of this type III allergy include serum sickness, acute glomerulonephritis, lupus nephritis, hypersensitivity pneumonitis, etc. The IgG or IgM antibodies in blood are coupled with soluble antigens to form soluble immune complexes which are subsequently deposited in fixed sites, etc., which gives rise to acute inflammatory reactions. In this way, tissue damage is associated with the activation of the complements and phagocytes that result from the binding of immune complexes in tissues, etc., said immune complexes being formed by the coupling of IgG or IgM antibodies in blood. with soluble antigens. Type IV allergy is called a delayed or cell-mediated allergy. This covers contact dermatitis, metal allergy, tuberculin reaction, etc. The inflammatory symptoms characterized by erythema and induration become evident 24 to 72 hours after exposure to the antigen. The inflammation has been clinical and basically studied for many years, but many issues have remained unsolved. With respect to your concept, definition and classification, there are a variety of diverse opinions. In terms of pathology, inflammation refers to disease states accompanied by flushing (redness), heat (heating), tumor (swelling), pain and loss of function (inhibited function or loss). To date, by inflammation is expressed the response by a host against a damage or surgical intervention that damages the cells and tissues, including said response a regeneration process against the defective invasion, a repair reaction to the destructive tension and a reaction defensive to infectious tension. Such invasion is a matter or foreign body that is going to be discharged or excluded from the host regardless of its origin (extrinsic and intrinsic). Bronchial asthma is a chronic inflammatory disease of the respiratory tract. The inflammation of the respiratory tract is accompanied by a bronchial hyperreactivity, which causes a reversible obstruction of the respiratory tract in response to various stimulants; As a result, signs or symptoms such as stridor and dyspnea occur. In addition, characteristic features of bronchial asthma lie in airway inflammation histologically, presence of IgE antibodies to environmental antigens observed in a large number of patients immunologically, hyper-response of the respiratory tract physiologically and paroxysmal dyspnea, stridor and reversible contraction of the Respiratory tract (bronchospasm) clinically. It is probable that type I allergy participates in its onset; However, there are some documents that report that type IV allergy participates in the progress to chronic asthma and not treatable during the stage of inflammation of the respiratory tract. The complete cure of bronchial asthma is fundamentally difficult. In addition, severe and dangerous processes are likely to occur after asthma attacks. Consequently, there has been a demand for effective therapeutic methods for asthma. Atopic dermatitis is a peculiar dermatitis, for example, a disease that arises from an atopic diathesis as an antecedent and proceeds chronically. There is a document that reports that atopic dermatitis is accompanied by a significantly high titer of IgE antibody in the blood, similar to allergic diseases including allergic bronchial asthma in children, allergic rhinitis, urticaria, etc., which suggests a possibility that type I allergy participate in it. However, it has also been said that atopic dermatitis can not be explained by type I allergy alone and an abundance of features in atopic dermatitis have yet to be resolved. The histopathological changes in the skin with atopic dermatitis are very similar to those in allergic contact dermatitis which is a type IV allergy and, therefore, it is likely that atopic dermatitis is a disease where type I and type IV allergic responses are complicatedly intermixed. Its characteristic symptoms are on the face, hair, atrium, etc., itching similar to eczema of the skin and in the sites of the head and eyebrows can be observed erythema with yellowish white crust during a childish period, etc. , where in some cases the erythema accompanied by desquamation can occur in the trunk and lower extremities; Dry eczema on the trunk or itching of the skin at the joints of the legs and the like can also be observed. In children, Two types of cardinal symptoms are mainly noticed as follows: (a) dry eczema frequently generated on the trunk, particularly on the back and (b) licheniform eczema frequently generated on the skin at the joints of the legs and neck. Another characteristic is that, in the adolescent and adult stages, there is an abundance of severe cases of this disease that have not been naturally cured. Although the causes of these symptoms have not been fully clarified yet, it is believed that constitutional factors are mainly responsible in patients. Their examples are considered to be (a) a skin barrier disorder as a result of abnormal metabolism of lipids in skin tissues, (b) a high ability to produce IgE, and (c) an antibody production. for allergens, related to the above. When the skin on the sick sites (lichenified eczema, dry eczema, etc.) of patients suffering from atopic dermatitis is subjected to abrasion with a hard tool that has an obtuse edge, anemic white lines due to vasoconstriction are generated (white line dermatographism) but the red dermatological lines that are normally noticed in healthy people do not result. In addition, when acetylcholine or methacholine is intradermally injected, the patient's diseased sites generate pale spots, but they do not generate the erythema that normally occurs in healthy people. Such atopic dermatitis frequently progresses chronically and is intractable. In recent years, such clinical cases tend to increase. Therefore, there has been a demand for a safe and effective remedy for it. Allergic conjunctivitis is an inflammatory disease of the conjunctiva caused by an allergic reaction. Although this is mainly caused by a type I allergic reaction, it sometimes includes those that are caused by a type IV allergic reaction. There is a plethora of cases where pollens, ticks, household powders, fungi, hairs and hairs of animals, etc. They act as antigens, thereby leading to ocular irritation from which patients complain, as well as other symptoms such as conjunctival hyperemia and ocular discharge. When an ectocorneal disorder gets complicated with it, There may also be various symptoms such as a sensation of foreign substance, eye pain, lacrimation and reduced vision. Allergic rhinitis has three cardinal signs: onset of frequent sneezing, excessive watery nasal discharge and nasal obstruction, caused by an allergic reaction; In addition, this may be accompanied by systemic discomfort and irritation of the nasopharynx, eyes, etc. There have been few cases combined with other atopic diseases such as asthma, atopic conjunctivitis and atopic dermatitis. The inflammation of the allergic digestive tract (allergic gastroenterocolitis, allergic gastrointestinal inflammation or allergic inflammation of the intestine) is an inflammatory allergic disease on the surface of the digestive tracts and / or a state of digestive morbidity as one of the systemic allergic symptoms, induced for a antigen contained in food, etc. The elevated symptoms of this type of diseases include stomach pain, diarrhea, vomiting and inflammatory signs around or in the mouth, in the anal periphery, etc. For these patients to lead a normal daily life, it is necessary that each The substance that acts as an antigen must be specified and the antigen must also be removed from the materials taken by them such as food. In addition, in other allergic diseases (such as atopic dermatitis) where an allergic inflammation of the digestive tract manifests itself as one of the symptoms, it is also important to remove the specific antigen. However, it is very difficult to completely remove antigens from food, of the environment, etc. Therefore, there has been a demand for an effective and highly safe therapeutic agent for the same. Matrix metalloproteinases (MMPs) are a family of natural proteases and have Zn2 + in the active center. It has already been known that MMPs play an important role in the degradation of extracellular matrices in diseases accompanied by tissue destruction. So far, 17 MMPs have been known. The destruction of extracellular matrices by MMPs is one of the important causes of delayed healing of intractable diseases accompanied by tissue destruction. The activity of MMP is controlled by (a) a level regulated expression gene, (b) adjustment in conversion from a latent proforma to an active form by proteases, and (c) regulation of enzymatic activity by intrinsic inhibitors of MMPs, eg, tissue inhibitors of metalloproteinase (TIMPs) . Thus, it has been believed that an increase in MMP activity as such results from an imbalance of the amounts between the MMPs and the intrinsic inhibitors. For example, it has been reported that, with respect to the destruction of extracellular matrices by MMPs, etc., such TIMPs participate in rheumatoid arthritis, osteoarthritis, skin ulcer, tumor cell metastasis, etc. However, there has been no document that reports that MMP inhibitors and / or natural compounds and products (including fragments thereof) structurally similar to MMP inhibitors are effective in allergic diseases, particularly type I allergies. and / or type IV, inflammation, atopic diseases, such as atopic dermatitis and bronchial asthma. Conventional antiallergic agents, adrenocorticosteroids, agents antihistamines, etc., are used for drug therapy of allergic diseases. However, although anti-allergic agents of the prior art, antihistaminic agents and the like are effective in allergic reactions in the initial stage of type I allergy, mediated by chemical mediators such as histamine, which are not expected to be effective in the phases of chronic inflammation mediated by cells due to its nature. In addition, although adrenocorticosteroids are limited therapeutic agents for the phases of cell-mediated allergic reaction, there has also been a large number of prior art agents that are still resistant to such therapeutic use. Furthermore, when adrenocorticosteroids are continuously administered, very severe adverse reactions such as weakening (thinning) of the skin, immunosuppression and inhibition of adrenocortical hormone secretion in vi ve, or a sudden interruption or withdrawal of therapy are problematic due to a phenomenon of dependence on steroids, etc. Consequently, there are a large number of unfavorable aspects for clinical use. Patients (particularly patients adults) suffering from bronchial asthma, atopic diseases, allergic rhinitis, allergic conjunctivitis, food allergy and inflammatory skin diseases are increasing in recent years. Therefore, there has been a demand for new and safer drugs capable of broadly achieving the effects on acute, subacute, and / or chronic inflammatory responses, particularly on allergic diseases of type I and / or type IV. With regard to metalloproteinase inhibitors, there have been reports on the metastasis of tumor cells and the arthropathy that correlates with the destruction of extracellular matrices by MMPs, etc. However, there has been no document that reports that the metalloproteinase inhibitor acts effectively on diseases such as bronchial asthma and atopic diseases. Bronchial asthma is a disease in which there is stridor and paroxysmal dyspnea. When an asthma attack becomes severe, lung function that is almost normal at the no-attack stage decreases in terms of a forced expiratory volume in one second, or a of expiratory volume forced in one second to the forced vital capacity, after which obstructive ventilatory disorder is observed with an increase in the resistance of the respiratory tract, a decrease in the pulmonary flexibility, a decrease in the vital capacity, etc. Especially in the case of chronic bronchial asthma, the resistance of the respiratory tract increases due to the contraction of the bronchial smooth muscles, inflammation, thickening, edema, muciferous promotion of the mucosa of the respiratory tract, etc. In severe cases, death often occurs due to suffocation (death due to asthma) due to obstruction of the respiratory tract. As a first aid agent in such a case, a bronchodilator is used (ß-adrenergic agent, theophylline, etc.). With regard to metalloproteinase inhibitors, there has been no document that fully reports that its therapeutic effect on inflammatory edema is specifically evaluated, as mentioned above. In addition, it has not been fully known that they are able to prevent death by suffocation caused by attacks of bronchial asthma.

Description of the invention The present inventors have carried out extensive research paying particular attention to the fact that metalloproteinase inhibitors act on inflammatory edema in an inhibitory manner. As a result, the present inventors have succeeded in developing effective antiallergic agents (such as prophylactic and / or therapeutic agents for type I and / or type IV allergies and, in addition, prophylactic and / or therapeutic agents for inflammation) using effective compounds as the metalloproteinase inhibitors. In addition, the present inventors have tested the use of the metalloproteinase inhibitor compounds that the pharmacological action of the metalloproteinase inhibitor compounds can be effectively achieved in various experimental models of animals with inflammation. As a result, the present inventors have also found that the metalloproteinase inhibiting compounds have potent anti-inflammatory activities and excellent properties in terms of safety, etc. (for example, no loss of body weight is noted, no thinning of skin and no rebound phenomenon after interruption and / or discontinuation of drug administration). In addition, the present inventors have found that metalloproteinase inhibitors are clinically useful. In this way, the present invention is provided. The present inventors have also found that metalloproteinase inhibitors have excellent properties as the therapeutic agents for ventilatory disorders (which will sometimes result in death) caused by airway stenosis and airway obstruction, frequently observed at the beginning. of acute and severe bronchial asthma. In this way, therapeutic methods for such diseases are provided. An objective of the present invention is to provide a means to therapeutically treat cell-mediated inflammatory diseases and allergic diseases type I and / or type IV, to ameliorate the morbid signs or symptoms of such diseases, and / or to prevent an onset of such clinical signs and symptoms, with a pharmaceutical composition comprising an effective amount of metalloproteinase inhibitor compounds (metalloproteinase inhibitors). A particular objective of the present invention is to provide the therapy of patients suffering from bronchial asthma (including those who have become chronic), atopic dermatitis, hay fever, pollinosis, allergic rhinitis (including seasonal rhinitis), allergic conjunctivitis, (including seasonal conjunctivitis), allergic inflammation of the digestive tract, food allergy, inflammatory diseases of the skin, etc., and the improvement and / or prophylactic therapy of the signs or symptoms experienced by said patients, with a pharmaceutical composition comprising a effective amount of a metalloproteinase inhibitor. In addition, the pharmaceutical composition has several excellent characteristics in the therapy or improvement of airway stenosis and airway obstruction frequently observed in acute bronchial asthma, which worsens, and also in the prophylaxis and / or therapy of the respiratory tract. morbid conditions of it that have become chronic.

Thus, the present invention provides: (1) a prophylactic and / or therapeutic drug for allergic diseases, comprising an effective amount of at least one member selected from the metalloproteinase inhibitors; (2) the drug according to item (1) above which exerts a prophylactic and / or therapeutic action on the inflammation resulting from an allergic reaction; (3) the drug according to items (1) or (2) above for the prophylactic and / or therapeutic treatment of type I allergic disorders; (4) the drug according to items (1) or (2) above for the prophylactic and / or therapeutic treatment of type IV allergic disorders; (5) the drug according to items (1) or (2) above for the reduction of a blood antibody titer or the inhibition of the production of antibodies to prophylactically and / or therapeutically treat allergic diseases; (6) the drug according to clauses (1), (2) or (5) above to reduce the blood level of IgE or inhibit the production of IgE for treat prophylactically and / or therapeutically allergic diseases; (7) a prophylactic and / or therapeutic drug for bronchial asthma, comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (8) the drug according to subsection (7) above for the prophylactic and / or therapeutic treatment of chronic bronchial asthma; (9) a prophylactic and / or therapeutic drug for allergic rhinitis, comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (10) a prophylactic and / or therapeutic drug for atopic diseases, comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (11) the drug according to item (10) above for the prophylactic and / or therapeutic treatment of atopic dermatitis; (12) a prophylactic and / or therapeutic drug for allergic conjunctivitis, comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (13) a prophylactic and / or therapeutic drug for immediate, late and / or very late allergic responses, comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (14) a prophylactic and / or therapeutic drug for allergic gastroenteritis (allergic inflammation in the digestive tract) comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (15) A prophylactic and / or therapeutic drug for allergic diseases, comprising an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 is selected from the group consisting of hydrogen, hydroxyl, aryl- (alkylene of 1 to 6 carbon atoms) and a group of the formula: -A-SOn-B wherein A is alkylene of 1 to 6 carbon atoms carbon, B is selected from the group consisting of alkyl of 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, aryl and a heterocyclic radical, and n is zero, 0, 1 or 2; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms and alkylthio of 1 to 6 carbon atoms; R3 and R4, which may be identical or different, are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and aryl- (alkylene of 1 to 6 carbon atoms); R5 is a group of the formula: -YD or D wherein Y is selected from the group consisting of alkylene of 1 to 6 carbon atoms, imino oxygen, (alkylene of 1 to 6 carbon atoms) -imino, and D is select from the group consisting of a sulfonic acid residue, a phosphonic acid residue, amidino, acyl 1 to 6 carbon atoms, acylimidoyl, di (phosphono) methino and di (carboxy) methino; and R6 is selected from the group consisting of hydrogen, unsubstituted or optionally substituted benzyl, trialkylsilyl, tert-butyldiphenylsilyl, tetrahydropyranyl, tert-butyl and a hydroxyl protecting group; and a pharmaceutically acceptable salt or solvate thereof; (16) the drug according to the preceding paragraph (15) that exerts a prophylactic and / or therapeutic action on the inflammation that results from an allergic reaction; (17) the drug according to subsection (15) or (16) above for the prophylactic and / or therapeutic treatment of type I allergic disorders; (18) the drug according to subsection (15) or (16) above for the prophylactic and / or therapeutic treatment of type IV allergic disorders; (19) the drug according to subsection (15) or (16) above for reducing a blood antibody titer or inhibiting the production of antibodies to prophylactically and / or therapeutically treat allergic diseases; (20) the drug according to subsection (15), (16) or (19) above to reduce the blood level of IgE, or inhibit the production of IgE to treat prophylactically and / or therapeutically allergic diseases; (21) a prophylactic and / or therapeutic drug for bronchial asthma, comprising an effective amount of at least one member selected from the group consisting of the aforementioned compound (I), wherein R1 to R6, have all the same meanings as are defined in the above item (15), and a pharmaceutically acceptable salt or solvate thereof; (22) the drug according to subsection (21) above for the prophylactic and / or therapeutic treatment of chronic bronchial asthma; (23) a prophylactic and / or therapeutic drug for allergic rhinitis, comprising an effective amount of at least one member selected from the group consisting of the aforementioned compound (I), wherein R1 to R6, have all the same meanings as are defined in the above item (15), and a pharmaceutically acceptable salt or solvate thereof; (24) a prophylactic and / or therapeutic drug for atopic diseases, comprising an effective amount of at least one member selected from the group consisting of the aforementioned compound (I), wherein R1 to R6, have all the same meanings as defined in the above item (15), and a pharmaceutically acceptable salt or solvate thereof; (25) the drug according to subsection (-24) above, for the prophylactic and / or therapeutic treatment of atopic dermatitis; (26) A prophylactic and / or therapeutic drug for allergic conjunctivitis comprising an effective amount of at least one member selected from the group consisting of the aforementioned compound (I), wherein R1 to R6, have all the same meanings as defined in the above item (15), and a pharmaceutically acceptable salt or solvate thereof; (27) a prophylactic and / or therapeutic drug for immediate, late and / or very late allergic responses comprising an effective amount of at least one member selected from the group consisting of the aforementioned compound (I), wherein R1 to R6 , they all have the same meanings that defined in subsection (15) above, and a pharmaceutically acceptable salt or solvate thereof, said drug having the property of alleviating allergic symptoms wherein the allergic symptom is an immediate, delayed and / or very late phase response; and (28) a prophylactic and / or therapeutic drug for allergic gastroenteritis (allergic inflammation in the digestive tract) comprising an effective amount of at least one member selected from the group consisting of the compound (I) mentioned above, wherein R1 to R6, have all the same meanings as defined in the above item (15), and a pharmaceutically acceptable salt or solvate thereof. In still another aspect, the present invention provides: (29) the drug according to any of the items (15) to (28) above, wherein, with respect to the aforementioned formula (I), R1 is selected from the group consisting of hydrogen, hydroxyl, phenyl- (C 1 -C 6 -alkylene) unsubstituted or optionally substituted, thio- (C 1-6 -alkylene) with heterocyclic radical containing unsubstituted or optionally substituted sulfur, and (C 1 -C 6 alkylthio) - (C 1 -C 6 -alkylene) unsubstituted or optionally substituted; R2 is alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R3 and R4, which may be identical or different, are each independently selected from the group consisting of hydrogen, unsubstituted or optionally substituted phenyl; and unsubstituted or optionally substituted naphthyl; R5 is selected from the group consisting of a sulfuric acid residue, a sulfonic acid residue, a phosphoric acid residue, guanido, lower alkylene of 1 to 4 carbon atoms substituted with guanido, amidino, lower alkylene of 1 to 4 atoms carbon substituted with acylimidoylimino, lower alkylene of 1 to 4 carbon atoms substituted with acylimino; and R6 is hydrogen or a hydroxyl protecting group; (30) the drug according to any of the items (15) to (28) above wherein, with respect to the formula (I) mentioned above, R1 is selected from the group consisting of hydrogen, hydroxyl, phenyltrimethylene, thienylthiomethylene and isopropylthiomethylene; R2 is isopropyl or n-propyloxy; R3 is hydrogen; R 4 is selected from the group consisting of methyl, phenyl, p-methoxyphenyl and 1-naphthyl; R5 is selected from the group consisting of a sulfuric acid residue, a sulfonic acid residue, a phosphoric acid residue, guanido, guanidomethylene, amidino, acetimidoyliminomethylene, propionimidoylimethylene, benzimidoyliminomethylene, acetamidomethylene; and R6 is hydrogen; and (31) the drug according to any one of items (1) to (14) above, wherein the metalloproteinase inhibitor is selected from the group consisting of the compounds described in each example of the patent documents (patent journals). including patent publications and patent applications open to the public) as listed in Tables 1, 2, 3 and 4 herein. In still another aspect, the present invention provides: (32) the drug according to any of items (1) to (31) above, for alleviating acute inflammatory symptoms; (33) the drug according to any of items (1) to (31) above, for alleviating subacute inflammatory symptoms; (34) the drug according to any of items (1) to (31) above, for alleviating chronic inflammatory symptoms; (35) the drug according to any of the items (1) to (34) above, for improving an inflammatory symptom selected from the group consisting of: (i) those caused by at least one member selected from the group consisting of lymphocytes , mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells, etc .; (ii) those characterized by migration, infiltration, and / or accumulation of at least one member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells in diseased sites; Y (iii) those characterized by an increase in number or amount, or proliferation (development and production) / destruction of at least one cellular or non-cellular member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes , histiocytes, Langerhans cells, and connective tissue components in diseased sites; (36) the drug according to any of items (1) to (36) above, for improving an inflammatory symptom selected from the group consisting of: (i) those caused by at least one member selected from the group consisting of eosinophils , neutrophils and macrophages; and (ii) those caused by at least one member selected from the group consisting of eosinophils and neutrophils in the respiratory tract, nasal cavity, skin, conjunctiva and intestine; (37) the drug according to any of the items (1) to (36) above, to improve inflammatory edema; (38) the drug according to any of subsections (7), (8), (21) and (22) above to improve cyanosis due to airway obstruction or narrowing of the airways; (39) the drug according to any of the items (7), (8), (21) and (22) to improve cyanosis by muciparous promotion of the respiratory tract or contraction of the respiratory tract; (40) the drug according to any of the items (1) to (34) above, for applications comprising therapy aimed at the extinction of inflammatory symptoms or relief thereof or preventive therapy for the onset of symptoms inflammatory (41) a pharmaceutical product comprising not only an effective amount of at least one member selected from metalloproteinase inhibitors, but also having at least one biological activity selected from the group consisting of (i) migration inhibition, infiltration, and / or accumulation of eosinophils and / or neutrophils within the diseased sites; (ii) extinction, relief or prophylaxis of the symptoms of bronchial asthma and / or the symptoms of atopic dermatitis; (iii) Cyanosis extinction, relief or prophylaxis; and (iv) remedy for impaired hyper-response of the respiratory tract due to the symptoms of bronchial asthma; (42) a pharmaceutical product comprising not only an effective amount of at least one member selected from the group consisting of the aforementioned compound (I) wherein R1 to R6, have all the same meanings as defined in subsection (15) , and a pharmaceutically acceptable salt or solvate thereof, but also has at least one biological activity selected from the group consisting of (i) inhibition of migration, infiltration, and / or accumulation of eosinophils and / or neutrophils within the sites sick; (ii) extinction, relief or prophylaxis of the symptoms of bronchial asthma and / or the symptoms of atopic dermatitis; (iii) Cyanosis extinction, relief or prophylaxis; Y (iv) remedy for impaired hyper-response of the respiratory tract due to the symptoms of bronchial asthma; (43) the drug according to items (1) to (15) above for improving an allergic symptom, selected from the group consisting of (i) those caused by at least one member selected from the group consisting of lymphocytes, mast cells, eosinophils , basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells, etc .; (ii) those characterized by migration, infiltration, and / or accumulation of at least one member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells in diseased sites; and (iii) those characterized by an increase in number or amount, or proliferation (development and production) / destruction of at least one cellular or non-cellular member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells, and connective tissue components in diseased sites; (44) the drug according to items (1) to (15) above, for improving an allergic symptom selected from the group consisting of: (a) those caused by eosinophils; (b) those caused by macrophages; (c) those caused by neutrophils; (d) those caused by lymphocytes; (a) those caused by eosinophils and macrophages; and (f) those caused by eosinophils in the respiratory tract, nasal cavity, skin, conjunctiva or intestine; (45) the drug according to items (1) to (15) above, to improve a chronic allergic symptom; (46) the drug according to clauses (1) to (15) above, to improve a very late allergic symptom (very late phase allergic response); (47) the drug according to items (1) to (15) for applications comprising therapy directed at the extinction of the allergic symptoms or to the relief thereof in the treatment of the allergy, or preventive therapy for the onset of allergic symptoms; (48) a prophylactic and / or therapeutic drug for inflammation comprising an effective amount of at least one member selected from metalloproteinase inhibitors; (49) a prophylactic and / or therapeutic drug for inflammation comprising an effective amount of at least one member selected from the group consisting of the aforementioned compound (I), wherein R1 to R6, have all the same meanings as defined in subsection (15) above, and a pharmaceutically acceptable salt or solvate thereof; (50) the drug according to the clauses (48) or (49) above, which acts on the prophylaxis and / or therapy of inflammation via allergic reactions; (51) the drug according to any of the items (48) to (50) above, to alleviate an acute inflammatory symptom; (52) the drug according to any of the items (48) to (50) above, to alleviate a subacute inflammatory symptom; (53) the drug according to any of the items (48) to (50) above, to alleviate a chronic inflammatory symptom; (54) the drug according to any of the items (48) to (53) to ameliorate an inflammatory symptom selected from the group consisting of; (i) those caused by at least one member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells, etc .; (ii) those characterized by migration, infiltration, and / or accumulation of at least one member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells in diseased sites; and (iii) those characterized by an increase in number or amount, or proliferation (development and production) / destruction of at least one cellular or non-cellular member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, macrophages, monocytes, histiocytes, Langerhans cells, and connective tissue components in diseased sites; (55) the drug according to any of the above (48) to (53), to improve an inflammatory symptom selected from the group consisting of: (i) those caused by at least one member selected from the group consisting of eosinophils , neutrophils and macrophages; and (ii) those caused by at least one member selected from the group consisting of eosinophils and neutrophils in the respiratory tract, nasal cavity, skin, conjunctiva and intestine; (56) the drug according to any of subsections (48) to (50) above to improve inflammatory edema; and (57) the drug according to any of clauses (48) to (50) above for applications comprising therapy directed at the extinction of the inflammatory symptoms or the relief thereof, or preventive therapy for the initiation of the inflammatory symptoms. In still another aspect, the present invention provides: (58) the drug according to any of items (1) to (57) above, wherein the drug is in the form of a composition or pharmaceutical formulation suitable for oral, topical, and / or parenteral application; (59) the drug according to any of the items (1) to (58) above, suitable for administration or application by a route selected from the group consisting of the oral, intracellular, intravenous, intramuscular, subcutaneous, intracutaneous route, intraperitoneal, intrapleural, and intraspinal, an intratissular route, a route by instillation, an enteral route, a rectal route, routes by instillation in the ear, eye, or nose, and the plaster or application on the skin or mucosa; (60) the drug according to any one of items (1) to (59) above, which is a formulation selected from the group consisting of a pharmaceutical solution, a pharmaceutical dispersion, a semi-solid preparation, a particulate preparation, a shaped preparation , and extractive; and (61) the drug according to any of the items (1) to (60) above, wherein its dosage form is selected from the group consisting of tablet, coated tablet, sugar-coated tablet, pill, troche, hard capsule, soft capsule, microcapsule, implant, powder, granule, fine granule, injection, liquid and solution, elixir, emulsion , irrigation, syrup, medicated water, magma, milk, suspension, liniment, lotion, spray, dew, inhalation, nebulization, ointment, poultice, patch, paste, poultice, creams, medicated oil, suppository (eg, rectal suppository), tincture, dermatological water, ophthalmic solution, colunario, auristila, paint, transfusion, powders for solution for injection, lyophilized preparation, and conditioned gel. It is apparent that there are chiral carbon atoms designated with * in the compounds of the formula (I), as illustrated in the following formula: Thus, it should be understood that the compounds given in formula (I) above can include not only geometric isomers, stereoisomers, each optically active isomer, racemates, and tautomers thereof, but also metabolite derivatives thereof. All compounds, isomers, racemates, tautomers and derivatives thereof are intended to be within the scope of the present invention. In a preferred embodiment of the present invention, the chiral carbon atoms designated with * in the above compounds (I ') include the carbon atom (1) in the "R" or "S" configuration, the carbon atom (2) ) in the "R" configuration, the carbon atom (3) in the "S" configuration. The above objects and other objects, features, advantages, and aspects of the present invention are readily apparent to those skilled in the art from the following descriptions. It should be understood, however, that the description of the specification including the following best embodiments for carrying out the invention, the examples, etc., are illustrating the preferred embodiments of the present invention and are given solely for explanation thereof. Be apparent to the person skilled in the art that a large number of variations and / or alterations (or modifications) of this invention may be made, based on the knowledge from the description in the following parts and other parts of the specification, without departing from the spirit and scope thereof, as described herein. All patent publications and reference documents cited therein for illustrative purposes are incorporated herein by reference in the present disclosure. The term "and / or" used herein means the presence of (i) a connecting relationship together and (ii) a selectively connecting relationship. For example, in the case of "prophylactically and / or therapeutically" it is used in a sense such that said expression covers (i) "prophylactically and therapeutically" and (ii) "prophylactically or therapeutically". In other cases, the term "and / or" is used in the same sense that it covers (i) a relationship that connects together and (ii) a relationship that connects selectively, too.

Brief Description of the Drawings Figure 1 is a graph showing the kinetics of the development of atrial edema in experimental mouse atopic dermatitis models. Figure 2 is a graph showing chronologically the cell types and the numbers of infiltrated leukocytes within the inflamed sites of experimental mouse atopic dermatitis models. Figure 3 is a graph showing chronologically each atrial edema in mutant mice genetically deficient in mast cells (basophils) and mice (each having an identical genetic background) that have mast cells (basophiles). Figure 4 is a graph that chronologically shows each atrial edema in mutant mice genetically deficient in the thymus and mice (each having an identical genetic background) that have a thymus. Figure 5 is a graph that chronologically shows the kinetic changes in the development of atrial edema in response to the second promotion after the initial promotion. Figure 6 is a graph showing chronologically the inhibitory efficiencies on the development of atrial edema in an experimental mouse atopic dermatitis model. Figure 7 is a graph that chronologically shows the inhibitory efficiencies on atrial edema in models of experimental atopic dermatitis in mice. Figure 8 is a graph that chronologically shows the inhibitory efficiencies on the scraping behavior in experimental mouse atopic dermatitis models. Figure 9 is a graph that chronologically shows changes in body weight in experimental mouse atopic dermatitis models. Figure 10 is a graph showing chronologically the efficiencies on allergic dermatitis of spontaneously diseased NC / Jic mice. Figure 11 is a graph showing the efficiencies on experimental bronchial asthma models in guinea pigs.

Figure 12 is a graph showing the efficiencies on the contact type dermatitis (type IV) mouse models. Figure 13 is a graph showing the inhibitory efficiencies on leukocyte infiltration in models of allergic inflammation in guinea pigs (air bag models). Figure 14 is a graph showing the improvement of the efficiencies on the resistance within the nasal airways of the models of allergic rhinitis in guinea pigs.

Best Modalities for Carrying Out the Invention The present invention is characterized in that a compound (metalloproteinase inhibitor) having the property of inhibiting at least one member selected from metalloproteinases (including matrix metalloproteinases, MMPs) is used as an effective ingredient for pharmaceutical compositions. The present invention relates to pharmaceutical compositions in the therapy and / or prophylaxis of allergy, particularly applied to patients suffering from allergic diseases including diseases allergic type I and / or type IV, or pharmaceutical compositions to the specific site of people susceptible to allergy, including type I and / or type IV allergic responses. The present invention also relates to a method for the therapy and / or prophylaxis of allergy, which comprises the application thereof. In yet another embodiment, the present invention relates to pharmaceutical compositions capable of improving all immediate, late and very late allergic responses and symptoms, each comprising at least one member selected from metalloproteinase inhibitors. In addition, this relates to a method for therapy and / or prophylaxis using said composition. The present invention relates to the therapeutic and / or prophylactic agents for bronchial asthma, each comprising at least one member selected from metalloproteinase inhibitors. In addition, this refers to a method for the therapy and / or prophylaxis of bronchial asthma, which comprises administering the same to a subject. In still another aspect, this refers to the therapeutic and / or prophylactic agents for bronchial asthma, each comprising at least one selected member of metalloproteinase inhibitors and also a method for the therapy and / or prophylaxis of bronchial asthma, which comprises administering them to a subject. In addition, the present invention relates to the therapeutic and / or prophylactic agents for bronchial asthma, each comprising an effective amount of at least one member selected from the metalloproteinase inhibitors and also to a method for therapy and / or prophylaxis. of bronchial asthma, which comprises administering an effective amount thereof to a subject. In addition, the present invention relates to therapeutic and / or prophylactic agents for atopic diseases (including atopic dermatitis, atopic enteritis, etc.), each comprising an effective amount of at least one selected member of atopic inhibitors. metalloproteinase, and also a method for the prophylaxis and / or therapy of atopic diseases, comprising administering an effective amount thereof to a subject. Still further, the present invention relates to the therapeutic and / or prophylactic agents for allergic conjunctivitis, each comprising an effective amount of at least one member selected from metalloproteinase inhibitors, and also a method for the therapy and / or prophylaxis of allergic conjunctivitis, comprising administering an effective amount thereof to a subject. Still further, the present invention relates to the therapeutic and / or prophylactic agents for allergic inflammation of the digestive tract, each comprising an effective amount of at least one member selected from metalloproteinase inhibitors, and also a method for therapy and / or prophylaxis of allergic inflammation of the digestive tract, comprising administering an effective amount thereof to a subject. In addition, the present invention relates to anti-inflammatory agents, each comprising an effective amount of at least one member selected from metalloproteinase inhibitors, and also to a method for the therapy and / or prophylaxis of inflammation, which it comprises administering an effective amount thereof to a subject. In addition, the present invention provides pharmaceutical products for therapy or prophylaxis, characterized in that (A) the number of cells (in diseased areas) of a cell member selected from the group consisting of of lymphocytes, mast cells, eosinophils, basophils, neutrophils, monocytes, macrophages and the like and / or (B) Migration, infiltration or accumulation (towards the diseased areas) of a cell member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, monocytes, macrophages and the like and / or is abolished.

(C) suppression of antibody production (particularly IgE production) mediated by a cell member selected from the group consisting of lymphocytes, mast cells, eosinophils, basophils, neutrophils, monocytes, macrophages, Langerhans cells, etc., and / or the maintenance / increase of the blood content thereof and / or (D) the elimination, alleviation or prevention of cyanosis caused by the hypersecretion of mucus in the respiratory tract or spasm of the respiratory tract, and / or (E) the prevention of asthmatic death, etc. The present invention also provides a method for the therapy and / or prophylaxis of diseases or morbid states, comprising administering an effective amount thereof to a subject. The metalloproteinase inhibitor as used herein may include compounds (particularly synthetic compounds) each having an inhibitory activity against at least one member selected from the MMP family. Such MMP inhibitory compounds include compounds based on hydroxamic acid, carboxylic acid based compounds, phosphonic acid based compounds, thiol derivatives, etc. Examples of such compounds are compounds of the formula (I) and a pharmaceutically acceptable salt and solvate thereof. At least one member selected from the group consisting of the compounds (I) and the pharmaceutically acceptable salts and solvates thereof may be preferably used. Such a compound has a large number of excellent characteristics as a therapeutic agent for allergy, particularly as a therapeutic agent for type I and / or IV allergies etc. More preferably, the metalloproteinase inhibitor as used herein has an abundance of excellent characteristics such as a therapeutic agent for bronchial asthma, allergic rhinitis (including seasonal rhinitis), atopic diseases (including atopic dermatitis, atopic enteritis, etc.), conjunctivitis allergic (including conjunctivitis seasonal), allergic gastroenterocolitis, allergic peritonitis, inflammation of various organs, etc., and has a large number of excellent characteristics as a prophylactic agent for such diseases. Especially when allergic reactions take place in vivo, the complicated, multiple-stage processes participate in these and various host cells and biologically active factors participate in these, which are each different at a respective stage. It must be understood that it is difficult to evaluate, under such a morbid condition, what allergic reactions take place, what role a metalloproteinase inhibitor plays, what pharmacological or physiological activity it has and for what diseases it is effective. Furthermore, with regard to inflammation as a result of an IgE-mediated allergic response, it has been found that it appears in an immediate manner (Inflammatory responses are evident within several minutes to approximately 60 minutes after re-challenge with allergens) and in a delayed (delayed) manner (inflammatory responses become evident within approximately 24 to 72 hours after the challenge with allergens). However, the present inventors have found that, after immediate and delayed responses (immediate and late phase responses, IPR and LPR), a very late response (very late phase response; vLPR) becomes manifest. The present inventors have found that metalloproteinase inhibitors are effective for immediate inflammatory responses (IPR), late inflammatory responses (LPR) and / or very late inflammatory responses (vLPR). Thus, with respect to allergic reactions in the experimental models of atopic dermatitis, it has been noted that, after immediate and delayed responses, edema as a result of inflammatory responses, etc., is once relieved and then the Inflammatory responses manifest again, which are called "very late phase response". Thus, in the experimental models of atopic dermatitis, the immediate phase response becomes evident as the atrial edema that is an inflammatory symptom in the first hour after the challenge, and then the late phase response becomes evident as the edema headphones on day 1 after the challenge. After that, the edemas are once again relieved and then the auricular edema begins to manifest again from day 5 after the re-challenge as the very late phase response (vLPR) after which the inflammatory symptoms worsen. In this experimental system, it has been found that the peak of the very late phase response appears on days 7 and 10 and the inflammatory symptoms are gradually improved. With respect to the behavior of inflammatory cells, etc., in each response phase, it has been found that eosinophils, neutrophils, macrophages, etc., increase markedly in the late phase response. In addition, it has been found that an increase in eosinophils is very significant in the very late phase response and mast cells, lymphocytes and, especially, T cells also participate in it. It can be presumed that the alleviation of the allergic symptoms noted in this very late phase response is associated with an inhibition (suppression) of infiltrating or migrating eosinophils, etc., towards inflammatory tissues and / or a decrease in blood antibody titer. Under the circumstances where an agent effective in alleviating allergic symptoms has been claimed, it is believed that metalloproteinase inhibitors are useful as preventive and / or therapeutic agents not only to suppress immediate and delayed inflammation but also especially to alleviate very late (or post-late) inflammatory symptoms. ). In addition, it is believed that metalloproteinase inhibitors are useful for suppressing inflammation in allergic diseases that have become chronic and refractory. Furthermore, it is believed that metalloproteinase inhibitors are useful as prophylactic agents and / or therapeutic agents to suppress inflammation in allergic reactions in the acute and subacute stages. In addition, from the previous point of view, when it is considered that the late phase response and the very late phase response show similar states to the mechanism of initiation of the type IV allergy, it is believed that the metalloproteinase inhibitors are also useful as agents Therapeutics for allergic responses not only in type I allergies but also in type IV allergies, as well as their analogues.

Furthermore, in comparison to prednisolone, which is a known therapeutic agent for allergy, metalloproteinase inhibitors have a safer and more effective pharmacological effect in that regard, since they do not induce a decrease in body weight, a thinning of the skin and / or a rebound phenomenon after the interruption and / or withdrawal of steroid administration, etc. In a more preferred embodiment, the present invention relates to a pharmacological agent selected from the group consisting of antiallergic agents, agents against bronchial asthma and agents against allergic rhinitis (including seasonal rhinitis), atopic diseases (including atopic dermatitis, atopic enteritis, etc.), allergic conjunctivitis (including seasonal conjunctivitis), allergic inflammation of the digestive tract, allergic peritonitis and / or inflammation of various organs, and / or anti-inflammatory agents, comprising an effective amount of at least one member selected from the group consisting of the aforementioned compounds (I) and the pharmaceutically acceptable salts and solvates thereof, and also refers to a method for the therapy and / or prophylaxis of diseases or abnormal conditions, comprising the administration of said pharmacological agent to a subject. In connection with the present invention, suitable metalloproteinase inhibitors include, for example, the compounds as listed in Tables 1, 2, 3 and 4 herein.

TABLE 1 TABLE 1 (Continuation; TABLE 2 TABLE 2 (Continued) TABLE 3 TABLE 3 (Continued) TABLE 4 TABLE 4 (Continued) TABLE 4 (Continued) The metalloproteinase inhibitor includes, for example, those described in the examples of patent gazettes (including patent publications and patent applications open to the public) as listed in Tables 1 to 4 herein (note: in the Tables the examples are cited specifically with their example number). Among them, particularly noteworthy are the metalloproteinase inhibitors, for example: (A): 3 (S) -N-hydroxy-4- (4 - ((pyrid-4-yl) oxy) -benzenesulfonyl) -2, 2- dimethyl-tetrahydro-2H-l, 4-thiazine-3-carboxamide (WO 97/20824, example No. 1) (B): sodium salt of [4- (N-hydroxyamino) -2R-isobutyl-3S- ( 2-thiophenethiomethyl) succinyl] -L-phenylalanine-N-methylamide (WO 90/05719, example No. 11) (C): N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] hydrochloride (3 -picolyl) -amino] -3-methylbutanamide (EP 0606046 Al, example No. 1) (D): N2- [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-tert-leucine-N -methyl amide (GB 2287023A, example No. 10) (E): N- [2 (R) -isobutyl-3- (N '-hydroxycarbonylamino) -propanoyl] -tryptophan methylamide (WO) 94/22309, example No. 1) (F): l- [3-cyclopentyl-2 (R) - [1 (R) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2, 5 -dioxo-l-imidazolinyl) ethyl] propionyl] -piperidine (EP 0816341 Al, example No. 15), etc. The described contents (including the specific examples described and the specific compounds described in said examples) in the patent documents (patent gazettes including the Patent Publications and the Open Patent Applications to the Public) listed in Tables 1 to 4 in the present are incorporated by reference in the present description. Particularly preferable metalloproteinase inhibitors are the compounds (I) as mentioned above. The compounds (I) are those specifically described in W096 / 33968 (International Publication Date: October 31, 1996) or those that can be prepared through production processes as are described in this one. In one embodiment, the compounds (I) include the following (in connection with the aforementioned formula (I), each substituent has the following meaning): The "sulphonic acid residue" denotes -S03H.

The "sulfuric acid residue" denotes -OS03H. The "phosphonic acid residue" denotes -P03H2. The "phosphoric acid residue" denotes -OP03H2. The "amidino" denotes -C (= NH) NH2. The "guanido" denotes -NH-C (= NH) NH2. The "aminometi leño" denotes -CH2NH2. "Guanidomethylene" denotes -CH2-NH-C (= NH) NH2. "Acetamidomethylene" denotes -CH2NH-COCH3. The "acetimidoyliminomethylene" denotes -CH2-NH-C (= NH) CH3. The "propionimidoyliminomethylene" denotes -CH2-NH-C (= NH) CH2CH3. The benzimidoi 1 iminometi le or "denotes -CH2-NH-C (= NH) C6H5.The" di (phosphono) methino "denotes -CH [PO (OH) 2] 2 • The" di (carboxy) metho "denotes -CH (C02H) 2. "C 1-6 -alkyl" denotes a straight or branched chain alkyl group having 1 to 6 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl , secbutyl, terbutyl, pentyl, hexyl, etc., which may be unsubstituted or optionally substituted with one or more substituents selected from those given below for the substituents on the aryl group. The "alkylene of 1 to 6 carbon atoms" denotes - (CH2) n- (n = 1 to 6). The "imino" denotes -NH-. The "C1-C6-alkylene imino" denotes - (CH2) n-NH- (n = 1 to 6), preferably alkyleneimino of 1 to 3 carbon atoms ", and more preferably -CH2-NH-. acyl of 1 to 6 carbon atoms "denotes a straight or branched chain alkylaryl group having from 1 to 6 carbon atoms, including formyl, acetyl, n-propanoyl, n-butanoyl, etc." Acylimidoyl "denotes -C (= NH) - [(alkyl of 1 to 6 carbon atoms)] or -C (= NH) - (aryl) The "heterocyclic radical" denotes a saturated or unsaturated cyclic organic group containing at least one heteroatom selected from sulfur, oxygen, nitrogen, etc. Preferred examples of the heterocyclic radical include thienyl, thiazolyl, imidazolyl, pyridyl, etc., which may be unsubstituted or optionally substituted The "aryl" denotes an unsubstituted or optionally substituted aromatic ring such as phenyl, naphthyl and anthracenyl. The substituent on the aryl includes alkyl of 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, hydroxyl, amino, carboxyl, halogen, etc. When the aryl has two or more substituents, such substituents may be the same or different. The substituent on the heterocyclic radical is selected from those given herein for the substituents on the aryl. The "halogen" denotes a fluorine, chlorine, bromine, or iodine atom. As used herein for the term "hydroxyl protecting group" in connection with R6 with the compound (I), suitable protecting groups are those known to those skilled in the fields of organic synthesis, for example, selected from those that have been employed in technical fields including peptide synthesis, penicillin synthesis, cephalosporin synthesis, sugar synthesis, and the like. The "hydroxyl protecting groups" include those removable by treatment with water, those removable by hydrogenolysis, those removable with Lewis acid catalysts such as AICI3, those removable with zinc / acid. acetic, those removable with thiourea, those removable with acids or weak bases, and the like. Representative hydroxyl protecting groups include benzyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, 2-methoxyethoxymethyl, formyl, acetyl, chloroacetyl, dichloroacetyl, trifly, and the like. Such groups are any, as long as they are capable of forming, or are convertible to, a hydroxyl group, chemically or under biological conditions, for example, physiological conditions (eg, bioreactions such as oxidation, reduction, and hydrolysis, catalyzed by enzymes). in vivo and similar). In connection with the present invention, metalloproteinase inhibitors, e.g., compounds (I), can exist as alternative tautomers. There are several chiral centers in the compounds including the compounds (I) (as used herein) due to the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of optical isomers with respect to each chiral center. All mixtures of such isomers and each individual optical isomer are intended to be within the scope of the present invention.

The compounds according to the present invention can also exist as separate enantiomers, as racemates, or as diastereomers. The compounds according to the present invention may also be in the form of solvates or acid addition salts. In addition, the compounds according to the present invention may be in the form of prodrugs, including those prodrugs of (i) compounds that contain an acid residue or acid group, such as a carboxyl radical and / or a hydroxyl radical and / or a basic group, such as an optionally substituted or unsubstituted amino radical or (ii) derivatives thereof. Prodrugs of the compounds according to the present invention include those compounds that can be transformed in vivo, for example by metabolic processes, including hydrolysis, oxidation, reduction, transesterification and the like, to produce the parent compounds of the formula (I), etc. The representatives of such prodrugs are derivatives of ester, ether, amide, alcohol, and amine, thereof. The metalloproteinase inhibitors, for example, the compounds (I) as used in the present may be in the form of solvates or salts (including the salts by addition of acid). In addition, these may include those salts derived from medicinal, pharmaceutically or physiologically acceptable acids and bases. These salts are not limited to, but include: those of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; occasionally, those of organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, citric acid, ascorbic acid, lactic acid, p-toluenesulfonic acid, methanesulfonic acid, fumaric acid, tartaric acid, and maleic acid; those of inorganic bases including alkali metal or alkaline earth metals such as sodium, potassium, calcium and magnesium, and ammonium, and those of organic bases including for example dialkylamines such as dimethylamine, and diethylamine, trialkylamines, dibenzylamine, ethanolamine, triethanolamine, morpholine , N-methylmorpholine, piperidine and the like. These compounds (e.g., the compounds (I)) can be converted to the salts of the pharmaceutical acids or bases or physiologically acceptable by conventional methods. Examples of such salts are those of inorganic acids, including hydrochloride, sulfate, and nitrate; depending on the particular inventive compound, those of organic acids, including acetate, oxalate, succinate, and maleate; those of alkali metals, including a sodium salt, and a potassium salt; those of alkaline earth metals, including a calcium salt; and similar. For example, the compounds of formula (I) related to the present invention, namely: sodium salt of N- [4- (N-hydroxyamino) -2 (R or S) - i sobuti lsuccinyl] -0- sul fo-L-shots in-N-methylamide (compound No. 1) sodium salt of N- [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-4'-sulfo-phenylalanine-N -methylamide (compound No. 2) sodium salt of N- [4-hydroxyamino) -2 (R) -isobutyl-3 (R or S) - (3-phenyl-trimethylene) succinyl] -0-sulfo-L- Tyrosine-N-methylamide (compound No. 3) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (RS) - (3-phenyl-trimethylene) succinyl] -N- sodium salt 4'-sulfophenylalanine-N-methylamide (compound No. 4) Sodium salt of N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (R or S) - (thienylthio-methylene) succinyl] -L-4 '-sulfophenylalanine-N-methylamide (compound No 5) N- [4- (N-hydroxyamino) -2 (R) -n-propyloxymethylene-3 (RS) -isopropylthiomethylene-succinyl] -L-4 '-sulfophenylalanine-N-methylamide salt (compound) No. 6) Sodium salt of N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (RS) - (3-phenyltrimethylene) succinyl] -0-sulfo-L-tyrosine-N-p-methoxyphenylamide (compound No. 7) N- [4- (N-hydroxyamino) -2 (R) -isobuty 1-3 (R or S) - (3-phenyltrimethylene) succinyl] -L-4 '-guanidophenylalanine-N-methylamide »l acetate (Compound No. 8) disodium salt of N- [4] - (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -0-phospho-L-tyros in-N-methylamide (compound No. 9) N- [4- (N-hydroxyamino) -2 (R) - i sobuti 1-3 (R or S) - (3-phenyltrimethylene) succinyl] -L-4'-acetimidoyliminomethylenephenylalanine-N-methylamide * l acetate (compound No. 10) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (R or S) - (3-phenyltrimethylene) succinyl] -L-4'-propionimidoyliminomethylenephenylalanine-N-methylamide "l acetate (compound No. 11) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (RS) - (3-phenyltrimethylene) succinyl] -L-4'-benzimidoyliminomethylenephenylalanine-N-methylamide * l acetate (compound No. 12) N- [4- (N-hydroxyamino) -2 (R) -isobuty 1-3 (RS) - (3-phenyl-trimethylene) succinyl] -L-4 '-acetamidomethylbenphenylalanine-N-methylamide (compound No. 13) ) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (RS) - (3-phenyltrimethylene) succinyl] -L-4'-guanidomethylenephenilalanin-N-methylamide »1-acetate (Compound No. 14) sodium salt of N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (R or S) - (3-phenyltrimethylene) succipyl] -0-sulfo-L-metatirosyn-N- methylamide (compound No. 15) N- [4- (N-hydroxyamino) -2 (R) -i sobuti 1-3 (S) -hydroxysuccinyl] -L-4'-guanine phenylalanine-N-methylamide »l acetate (compound No. 16) N- [4- (N-hydroxyamino) -2 (R) -i sobuti 1-3 (R or S) - (3-phenyltrimet ilen) succinyl] -L-4 '-amidinophenylalanin-N-methi lamide * l acetate (compound No. 17) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (RS) - (3-phenyltrimethylene) succinyl] -0-sulfo-L-tyrosin-N-1- sodium salt naft ilamide (compound No. 18) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (RS) - (3-phenyltrimethylene) succinyl] -L-4 '-guanidophenylalanine-N-phenylamide »! acetate (compound No. 19) N- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (R or S) - (3-phenyltrimethylene) succinyl] -L-4 '-guanidophenylalanine-N-methylamide * l hydrochloride (compound No. 20) N- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -L-4 '-guanido phenylalanine-N-methylamide »l sulfate (compound No. 21) N- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -L-4 '-guanidophenylalanine-N-methylamide * l acetate (compound No. 22) and other compounds are excellently active to inhibit MMPs and markedly improved in terms of solubility in water and oral bioavailability or included in such active groups compared to conventional compounds. These compounds can be easily applied to at least one member selected from the group consisting of diseases related to allergy and / or inflammation, bronchial asthma, allergic rhinitis, hay fever, pollinosis, atopic diseases, atopic enteritis or enterocolitis, allergic conjunctivitis. , allergic peritonitis, inflammation allergic gastrointestinal, inflammatory diseases observed in various organs, allergies to food substances, urticaria, various contact type dermatitis, graft versus host disease (GVH disease) occurred in organ transplantation, and the like, and have an aptitude to gain therapeutic advantages and / or prophylactics. The compounds (e.g., compounds (I)) as used herein may be used in combination with at least one member selected from the group consisting of antiallergic (antiallergic) agents and antiasthmatic agents known in the art. Anti-allergic agents and anti-asthmatic agents include, for example, sodium cromoglycate (1,3-bis (2-carboxychrom-5-yloxyl) -2-hydroxy-propane) disodium salt, tranilast (N- (3, 4- dimetoxicinamoyl) -anthra ine), ketotifen fumarate, azelastine hydrochloride, oxatomide, amlexanox, terfenadine, repirinast, ibudilast, tazanolast, pemirolast potassium, gold-sodium thiomalate, γ-globulin preparations, MS antigens, cortisone acetate, hydrocortisone , triamcinolone, dexamethasone, parametasone acetate, prednisolone, methylprednisolone, beclometasone dipropionate, ciproheptadine hydrochloride, homoclorcyclizine hydrochloride, tacrolimus, etc. The compounds (e.g., compounds (I)) as used herein may also be used in combination with at least one member selected from the group consisting of bronchodilators known in the art, including β2-adrenergic agonists such as ephedrine hydrochloride, Methylephedrine hydrochloride, orciprenaline sulfate, clenbuterol hydrochloride, chlorprenaline hydrochloride, salbutamol sulfate, fenoterol hydrobromide, tulobuterol, terbutaline sulfate, trimethoquinol hydrochloride, pirbuterol hydrochloride, formoterol fumarate, procaterol hydrochloride, hexoprenaline suflate and mabuterol hydrochloride; xanthine drugs such as theophylline and proxyphillin; anticholinergic agents such as ipratropium bromide; a2 blockers; methoxyphenamine hydrochloride, etc .; anticonvulsants known in the art, including oxymetebanol, isoaminyl citrate, oxeladin citrate, carbetapentane citrate, clofedanol hydrochloride, cloperastin hydrochloride, hydrobromide dextromethorphan, fominoben hydrochloride, dimemorfan phosphate, benproperine phosphate, etc .; expectorants known in the art, including lysozyme chloride, hydrochloride bromohexina, serapeptasa, pronase, acetylcysteine, carbocysteine, ambroxol hydrochloride, hydrochloride ethyl-L-cysteine hydrochloride eprazinona, guaifenesin, tipepidine hibenzate of, etc .; antihistaminic agents known in the art, including isothipendyl hydrochloride, diphenylpyraline, diphenhydramine hydrochloride, alimemazine tartrate, triprolidine hydrochloride, succinate embidrolina, clemastine fumarate, promethazine hydrochloride, chlorpheniramine maleate, mequitazine, etc .; anti-inflammatory agents (antiphlogistics), antimicrobial agents and antibiotics known in the art. When used as pharmacological agents, for example the compounds (I) and the salts thereof may be employed as pharmaceutical agents usually in the form of a pharmaceutical composition or of a preparation alone or in admixture with a variety of pharmacologically acceptable auxiliaries. For example, him compound (I), a salt thereof, etc., can be administered alone or in a form of a pharmaceutical composition or in a preparation in admixture with any of the various pharmaceutically acceptable auxiliaries. Preferably, it can be administered in the form of a suitable pharmaceutical composition or formulation, suitable for oral, topical, parenteral, or the like application. Any of the dosage forms (including those for inhalation and rectal administration) can be selected depending on the purpose. Parenteral administration includes topical, percutaneous, intravenous, intramuscular, subcutaneous, intracutaneous, and intraperitoneal routes. It is also possible to apply the drug directly to the affected sites, and, in a certain case, direct application is adequate. Preferably, the mammalian animals including human can receive the drug orally or parenterally (e.g., intracellularly, intravenously, intramuscularly, subcutaneously, intracuténeamente, intraperitoneally, intrapleurally, intraspinally, via an intra-tissue route, by instillation, enterally, rectally, by instillation into the ear, eye or nose, by poultice or application on the skin or mucosa, etc.). The specific dosage forms of the pharmaceutical preparations and the formulations include pharmaceutical solutions, pharmaceutical dispersions, semisolid preparations, particulate preparations, shaped preparations, extractables, etc. Examples of dosage forms are tablets, coated tablets, sugar-coated tablets, pills, troches, hard capsules, soft capsules, microcapsules, implants, powders, granules, fine granules, injections, liquids and solutions, elixirs, emulsions, irrigations , syrups, mixtures, suspensions, liniments, lotions, aerosols, sprays, inhalations, sprays, ointments, plasters, patches, pastes, cataplasms, creams, oleates, suppositories (e.g., rectal suppositories), tinctures, dermatologic waters, ophthalmic solutions, colunariums, auristilas, unturas, transfusions, powders for injection solutions, lyophilized preparations, conditioned gels, etc.

The pharmaceutical compositions can be formulated according to conventional techniques. For example, the pharmaceutical composition or formulation may comprise at least one of the compounds (I) of the present invention or a salt thereof alone or in mixture with the physiologically acceptable carriers, carriers, adjuvants, vehicles, excipients, diluents, etc. pharmaceutically acceptable The compound (I) of the present invention or a salt thereof is usually mixed with a simple member selected from the group consisting of physiologically permissible carriers., pharmaceutically acceptable carriers, adjuvants, vehicles, excipients, diluents, flavoring agents, perfuming agents, sweetening agents, extenders, antiseptics, stabilizers, binders, pH regulators, buffering agents, detergents (surfactants), bases, solvents, fillers, fillers, volume, solution adjuvants, solubilizers, tonicity agents, emulsifiers, suspending agents, dispersants, viscosity-increasing agents, thickening agents, gelling agents, stiffening agents, absorbents, adhesives, elastomers, plasticizers, disintegrators, aerosol propellants, preservatives, antioxidants, opacifying agents, humectants, emollients, fillers, softeners, all pharmaceutically acceptable, etc., or suitably in a combination thereof, depending on the need , to give a unit dosage form which is required for the pharmaceutical practices in general approved. Formulations suitable for oral application include solid compositions such as tablets, pills, capsules, powders, granules, and troches; fluid compositions such as solutions, syrups, and suspensions; etc. The aforementioned solid compositions can be formulated in admixture with any of the pharmaceutical auxiliaries. Such pharmaceutical auxiliaries include carriers such as dextran, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, caseins, albumin, synthetic or semi-synthetic polymers, glycerides, lactose, crystalline cellulose, microcrystalline cellulose, and shelac; binders such as dextrin, sucrose, crystalline cellulose, hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), gum arabic, tragacanth gum, calcium carbonate, gelatin, corn starch, polyvinylpyrrolidone, water, ethanol, glucose syrup and starch syrup; excipients such as starch (e.g., corn starch, etc.), lactose, sucrose, glucose, sodium chloride, calcium carbonate, carboxymethyl cellulose (CMC) and silicic acid; disintegrators such as starch (e.g., corn starch, potato starch, etc.), sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, gelatin, shelac, crystalline cellulose, calcium carbonate, sodium bicarbonate, tragacanth and phosphate gum of calcium; lubricants such as salts (for example, aluminum, potassium, sodium, calcium, magnesium) of stearic acid (for example, magnesium stearate), light anhydrous silicic acid, synthetic aluminum silicate, talc and microcrystalline cellulose; active surface agents (surfactants) such as polyoxyethylene sorbitan fatty acid esters and alkyl sulfates; capsule bases such as gelatin; sweetening agents (sweeteners) such as sucrose, lactose and saccharin; flavoring agents (flavoring agents) such as peppermint, cinnamon oil, orange oil, spearmint, cherry and cherry oil; other flavors; inhibitors of disintegration; absorption enhancers; stabilizers; preservatives such as parabens and sorbic acid; antioxidants such as ascorbic acid, α-tocopherol and cysteine; thickeners; etc. The tablets and pills can also be prepared by enteric coating. When the unit dosage form is a capsule, fluid carriers such as fats and oils may be contained in addition to the aforementioned materials. Representatives of such formulations are tablets and capsules, each of which is in the form of a dosage unit suitable for simple administration, and can be manufactured by ordinary techniques wherein customary additives are contained, as listed below. ahead. The tablet can be coated by customary techniques known for conventional pharmaceutical practices. (1) ordinary vehicles that serve as binders, including syrup, acacia, gelatin, sorbitol, tragacanth gum, or polyvinylpyrrolidone; (2) fillers, including lactose, sucrose, corn starch, calcium phosphate, sorbitol, and glycine; (3) lubricants for tablets, including for example magnesium stearate, talc, polyethylene glycol, and silica; and (4) disintegrators such as potato starch or acceptable wetting oils such as sodium lauryl sulfate. Fluid formulations may contain an inert diluent ordinarily used in the art, such as water. Representatives of the fluid formulations can be prepared in the form of a suspension, solution, emulsion, syrup, or elixir, wherein the water or oil is contained as a component, or provided in the form of an anhydrous product for reconstruction. in a liquid drug by adding water or a suitable vehicle just before use. Such fluid formulations may also contain any of the pharmaceutical auxiliaries, including for example suspending agents such as sorbitol, syrup, methylcellulose, carboxymethylcellulose, glucose syrup, gelatin and hydrogenated oils for diet; emulsifiers such as lecithin, sorbitan monooleate and acacia; non-aqueous vehicles (including diet oils) such as (i) vegetable oils including, for example, almond oil, fractionated coconut oil, etc., and (ii) oily esters including, for example, glycerin, propylene glycol, ethyl alcohol , etc.; customary additives including for example antiseptics (such as ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and sorbic acid), absorption enhancers, stabilizers, preservatives, and, as required, ordinary seasonings, sweetening agents (sweeteners), flavoring agents (flavoring agents), and / or coloring agents (colorants). In the formulations, the compounds of the present invention are applied in the form of compositions containing about 0.1 to 95 weight percent. Suitable formulations for parenteral routes include aseptic solutions or suspensions containing at least one component active in admixture with water or other pharmaceutically acceptable media. Examples of such parenteral formulations are injections. Preferred liquid carriers for injection generally include water, saline, dextrose solution, other related saccharide solutions, ethanol, glycols such as propylene glycol and polyethylene glycol, etc. For the preparation of injections, the active component of the present invention is usually mixed with any of the carriers such as distilled water, Ringer's solution, physiological saline solution, suitable dispersing agents, wetting agents, suspending agents, etc., to form formulations injectables including solutions, suspensions, emulsions, etc., by techniques known in the art. Examples of aqueous liquids for injection are a physiological saline solution and isotonic solutions containing glucose and other auxiliaries (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) wherein a suitable pharmaceutically acceptable auxiliary solubilizer is available. such as alcohol (e.g. ethanol, etc.), polyalcohol (e.g., propylene glycol, polyethylene glycol, etc.), nonionic surface active agent (eg, Polysorbate 80MR, HCO-50, etc.), etc., can be jointly used. Oily injectable liquids may include sesame oil, soy bean oil, etc., wherein benzyl benzoate, benzyl alcohol, etc., may be used together as auxiliary solubilizers. In addition, buffers (e.g., phosphate buffers, sodium acetate buffers, etc.), or agents for osmoregulation, analgesic agents (e.g., benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (e.g. example, human serum albumin, polyethylene glycol, etc.), preservatives (e.g., benzyl alcohol, phenol, etc.), antioxidants such as ascorbic acid, absorbable, etc. they can be composed with these too. The prepared injection solution is usually filled in suitable ampoules. Thus, not only are safe preparations made but also less toxic which can be administered to warm-blooded animals (e.g., humans, etc.), and the like. For parenteral administration, unit dose forms are prepared in solution or suspension, in sterile pharmaceutically acceptable fluids such as water, ethanol, and oils, in admixture with or without detergent and other pharmaceutically acceptable auxiliaries. The oily vehicle and the solvent used in the parenteral formulation can include synthetic or semi-synthetic mono-, di- or triglycerides; natural, semi-synthetic, or synthetic fats or oils; and fatty acids. Examples of such oily vehicles and solvents are vegetable oils such as peanut oil, corn oil, soybean oil, and sesame oil. For example, this injection can usually be prepared to form unit doses each containing approximately 0.1 to 10% by weight of the compound of the present invention. The formulation suitable for topical use or rectal application, includes ophthalmic solutions (eye drops), inhalants, ointments (ointments), suppositories, etc. Eye drops and other ophthalmic agents are prepared by conventional techniques, using pharmaceutically acceptable carriers. For inhalants, the compound of the present invention can be applied to the respiratory organs after dissolution alone or together with inert pharmaceutically acceptable carriers, in an aerosol or solution for nebulizers, or in the form of powders for inhalation. The ointments (ointments) are prepared by conventional techniques, in mixture with conventionally used pharmaceutical bases such as ointment bases (white petrolatum, paraffin, olive oil, macrogol 400, macrogol ointment, etc.). In ointments, the compounds of the present invention are applied in the form of comtions containing from about 0.001 to 30% by weight. Pharmaceuticals for topical application (including skin ointments) can be prepared in the form of a solution or suspension using aqueous or non-aqueous vehicles suitably sterilized. The additives used include buffering agents such as sodium bisulfite and disodium edetate; preservatives including antiseptic, antimicrobial and antifungal agents such as acetic acid, phenylmercuric nitrate, benzalkonium chloride and chlorhexidine; and thickeners such as hypromellose.

Suptories can be prepared by conventional techniques using carriers well known in the art, preferably suitable non-irritating excipients. Examples of excipients are those that are solid at room temperature but liquid at the rectal temperature, where such substances melt in the rectum to distribute a drug, such as polyethylene glycols, lanolin, cocoa butter, and triglycerides of fatty acid. In suptories, the compounds of the present invention are applied in the form of comtions containing from about 0.1 to 95% by weight. The compound, depending on the vehicle and the concentration used, can be either suspended or dissolved in the vehicle. Adjuvants such as a local anesthetic, a preservative and buffering agent can be dissolved in the vehicle. The aforementioned pharmaceutical preparations can be formulated in the form of comtions that usually contain about 0.001 to 95% by weight of the compound of the present invention. The levels of said compound or a salt thereof can vary within a wide range. The Specific levels and administration cycles for any particular patient will be employed depending on a variety of factors including the activity of the specific compounds employed, sex, age, body weight, general health, diet, time of administration, the route of administration, the rate of excretion, the combination with drugs, and the severity of the particular disease undergoing therapy. After oral administration, the effective dose levels of the active ingredients in the pharmaceutical comtions of the present invention can be varied depending on the disease being treated, the severity of the symptom being treated, the general condition and the previous medical history of a particular patient being treated, the route and administration cycle, etc. When administered to a mammalian patient (e.g., an adult person), an adequate daily dose will vary depending on the condition of the patient, but in general dose levels of about 0.01 to 500 mg will be suitably administered (more preferably from about 0.1 to 300 mg) of the compound (I) per kilogram of body weight per day. A parenteral dose suitable for a simple administration can be varied depending on the site being treated, the organ in question, the severity of the symptom in question, the general condition and the prior medical history of a particular patient in question. , of the route and the administration cycle, etc. For example, it is generally advantageous that the drugs can be injected intravenously, for example to an adult (taken as 60 kg), at a daily dose of about 0.001 mg to 6 g. (preferably from about 0.01 mg to 1 g) of the compound (I). For other animals, these can be administered in terms of a dose per 60 kg. A topical dose can be varied depending on the size of a sick site being treated. A typical dose for a simple ophthalmic application (per eye) is in the range of 0.01 to 100 mg of the compound (I). With respect to the therapeutic applications for inflammation, the active compound of the present invention can be administered orally or via injection to the diseased sites. For the manufacture of pharmaceutical compositions and pharmaceutical preparations, the additives, etc., the methods of preparation and the like can be suitably selected from those described in Nippon Yakkyokuho Kaisetsusho Henshu Iinkai (Ed.) "13th Ed. Nippon Yakkyokuho Kaisetsusho (Comments on the Pharmacopoeia of Japan, 13th Ed.), July 10, 1996, Hirokawa Pub. Co. , Tokyo Japan; Hisashi Ichibagade et al. (Ed.), "Pharmaceutical Research and Development (Ikuo Suzuki, editor in chief), Volume 12 (Pharmaceutical Necessities 1"), October 15, 1990, Hirokawa Pub. Co. , Tokyo Japan; ibid., Volume 12 (Pharmaceutical Necessities 2), October 28, 1990, Hirokawa Pub. Co. , Tokyo Japan; etc., depending on the need, and can be adapted by reference to the descriptions in these. For the terms (words) and / or abbreviations used in the specification and in the drawings, these are based on the meanings of the terms commonly used in the art.

EXAMPLES The examples, for example, examples of biological assays, formulation examples, and preparation examples, of the present invention, which are provided solely for illustrative purposes, and not to limit the scope of the present invention, are described below. It should be understood that numerous variations, equivalents and modifications that could be within the scope of a person skilled in this art can be made without departing from the true spirit and scope of the invention.

Biological Test Example 1 Atrial Edema in the Experimental Model of Atopic Dermatitis Intravenous injection of an anti-2,4-dinitrophenol (DNP) Ab (Ab anti-DNP, monoclonal Ab IgE, its antibody titer was from 1: 512 to 1: 1024 for a reaction of heterogeneous passive cutaneous anaphylaxis in rat, using a Wistar rat) in a tail vein of female Balb / c mice (7 weeks of age, body weight: 17 to 20 g, purchased from JAPAN SLC, Inc.) at a dose of 1 ml per animal produced passive sensitization. Twenty-four hours after sensitization, 0.1% of 2,4-dinitrofluorobenzene (DNFB; Nacalai Tesque, Inc.) in ethanol was smeared on both sides of a pair of mouse atria at a dose of 10 μL per side for the challenge . Ovalbumin (OVA) was conjugated with DNP according to the method specified by Eisen et al.

(Eisen, H.N., et al., Journal of the American Chemical Society, 75: 4583-4585, 1953) and, as a result, approximately 3.5 molecules of DNP were coupled to one molecule of OVA. An aluminum hydroxide gel (Alum) was prepared according to the method specified by Levine et al. (Levine, B.B., et al., International Archives of Allergy, 39: 156-171, 1970). DNP-OVA (10 μg) was mixed perfectly with 1 mg of Alum and the resulting mixture was injected intraperitoneally into another group of mice, whereby active sensitization was induced. Two weeks later, 0.1% of DNFB in ethanol was smeared on both sides of a Pair of mouse ears for the challenge in the same way as mentioned above. Non-sensitized intact mice were smeared with 0.1% DNFB in ethanol on their ear in the same manner as mentioned above and served as a control group. Not only immediately before the challenge but also 1 hour, 5 hours, daily between days 1 and 14, and on day 16 after the challenge, the thickness of the ear was measured using a thickness gauge with marker (Peacook, Co. ). Each degree of atrial edema was calculated: Edema (Thickness of the Ear (Thickness of the Ear Handset After the Challenge, μm) - immediately before the Challenge, μm) The results are shown in Figure 1 for actively or passively sensitized mice and mice desensitized in terms of atrial edema (mean ± standard deviation, N = 6). It has been observed that (a) a type of atrial edema is at a maximum 1 hour after the challenge and at a minimum at 5 hours after the challenge, and (b) another type of atrial edema restarts after this and returns to reach a maximum 1 day after the challenge. The first corresponds to the "Immediate Phase Response (IPR)" and the last to the "Late Phase Response (LPR)", which have already been reported in the technique (Katayama, I., et al., Int. Arch. Allergy Appl. Immunol., 93: 148-154, 1990; Nagai, H., et al., Biol. Pharm. Bull., 18: 239-245, 1995; and Katayama, I., et al., Int. Arch. Allergy Immunol., 109: 390-397, 1996). To date, auricular edema different from the biphasic ones has not been reported. However, when atrial thickness measurement was continued after the late phase response in this Example, it was discovered that a new phase of atrial edema existed beginning on the day approximately 5, reaching a maximum on days approximately 7 a 10, and lasting until day 16 or after the dessert. This response is hereinafter referred to as "Very Late Phase Response (vLPR)". Figure 1 indicates that, similarly to IPR and LPR, vLPR is an atrial-dependent edema either of (1) active sensitization with an antigen or (2) passive sensitization by an intravenous injection of anti-DNP IgE Ab, in comparison to the auricular edemas in the group of mice not sensitized. It is shown that vLPR is observable independently of the modes of sensitization (active sensitization and passive sensitization) and its intensity, pattern and time course are equivalent.

Example 2 (1) Immunological Characteristics in Experimental Atopic Dermatitis The mice were passively sensitized with anti-DNP IgE Ab in the same manner as in Example 1. Twenty-four hours later, 0.1% DNFB in ethanol was smeared on both sides of a pair of mouse atria at a dose of μl per side for the challenge. After the challenge, the mice were sacrificed under ether anesthesia successively (0, 1 and 5 hours, and 1, 4, 8 and 24 days later) and a pair of mouse atria were surgically excised from each mouse. The tissues of the ear were fixed with 4% paraformaldehyde, embedded in paraffin, sliced with a microtome, and then dehydrated with a series of alcohols. After this, to evaluate the difference in the numbers of leukocytes present in the auricular tissues, the following staining was performed and the cells discriminable for each tension of the atrial slices with 5 mm in length, were observed under a microscope and counted: for the discrimination, staining with toluidino blue was used for the mast cells and basophils; staining with naphthol chloroacetate AS-D (staining with esterase) for neturophils, macrophages, etc .; and hematoxylin-eosin staining for eosinophils. The results are shown in Figure 2, where the data are expressed in terms of the mean ± standard deviation (N = 5). It was described that, one hour after the challenge (IPR), the cells positive to staining with toluidine blue and positive to esterase, were increased, and the eosinophils also did a little. It was noted that, thereafter, the numbers of cells positive to toluidine blue staining considered as caused by degranulation were gradually reduced 5 hours after challenge or after challenge. In addition, esterase-positive cells and eosinophils that were increased 1 hour after the challenge (IPR) were also reduced 5 hours after the challenge. A day after the challenge (LPR), esterase positive cells and eosinophils increased again. It is described that in this LPR the number of infiltrated eosinophils was markedly higher compared to that in IPR. Four days after the challenge, cells positive to staining with toluidine blue and esterase positive were restored to the levels immediately before the challenge. Furthermore, it is described that, 8 days after the challenge (vLPR), the toluidine blue and esterase positive staining cells increased a little, but the number of eosinophils increased extremely in comparison to these or to that of the eosinophils themselves before day 8 after the challenge. However, 24 days after the challenge the numbers of cells positive to toluidine blue staining, esterase positive cells and eosinophils became equivalent to those immediately before the challenge.

Example 3 (2) Immunological Characteristics in Experimental Atopic Dermatitis A role of mast cells in the development of atrial edema (IPR, LPR and vLPR) was evaluated using (1) a mutant mouse genetically deficient in mast cells (WBB6F1 W / Wv) and (2) a progenitor strain competent in mast cells, mouse (WBB6F1 + / +) that has an identical genetic background with it. In the same manner as in Example 1, the mice were passively sensitized with anti-DNP IgE Ab and challenged with 0.1% DNFB in ethanol 24 hours later. Immediately before the challenge, 1 and 5 hours, daily between days 1 to 15 and on day 17 after the challenge, the atrial thickness was measured in the same manner as in Example 1. Each amount of atrial edema was calculated. The results are shown in Figure 3, where the data are expressed in terms of the mean ± standard deviation (N = 6). Figure 3 indicates that atrial edemas 1 hour after challenge (IPR) were dependent on mast cells, but auricular edema on day 1 after challenge (LPR) they were independent of the mast cells. However, it is described that the auricular edemas starting on day 5 after the challenge (vLPR), were partially dependent on mast cells. In view of yet another aspect, it is suggested that atrial edema in vLPR is associated with one or several bioactive components / cell (s) different from mast cells.

Example 4 (3) Immunological Characteristics in Experimental Atopic Dermatitis Next, the role of the thymus in the development of atrial edema (IPR, LPR and vLPR) is evaluated using (1) a genetically deficient mutant mouse of the thymus (Balb / c nu / nu) and (2) a mouse (Balb / c) that he has a thymus and an identical genetic background with it. In the same manner as in Example 1, mice were passively sensitized with anti-DNP Ab IgE and then challenged with 0.1% DNFB in ethanol 24 hours later. Immediately before the challenge, at 1 and 5 o'clock, daily between days 1 to 9 and on days 11, 13 and 16 after the challenge, the atrial thickness in the same manner as in Example 1. Each of the amounts of atrial edema was calculated. The results are shown in Figure 4, where the data are expressed in terms of the mean ± standard deviation (N = 6). Figure 4 clearly indicates that both atrial edemas at 1 hour after the challenge (IPR) and 1 day after the challenge (LPR) were less dependent on the thymus, but a part of the auricular edemas starting on day 6 after the challenge (vLPR ) were dependent on the thymus. When the results in Examples 3 and 4 are summarized, it becomes apparent that (1) IPR is dependent on mast cells and less dependent on T cells, (2) LPR is dependent on T cells and dependent on mast cells, and (3) vLPR is associated with T cells and / or mast cells.

Example 5 (4) Immunological Characteristics in Experimental Atopic Dermatitis We examined how reattachment with DNFB before atrial swelling in vLPR could affect the development of atrial edema. In the same manner as in Example 1, Balb / c mice were passively sensitized with Ab IgE anti-DNP and then challenged with 0.1% DNFB in ethanol 24 hours later. The mice were subsequently smeared on both sides of a pair of their atria with 0.001%, 0.01% or 0.1% DNFB in ethanol at a dose of 10 μl per side 3 days later (on day 3 after the challenge). Immediately before challenge, at 1 and 5 hours, and daily between days 1 to 8 after the challenge, the atrial thickness was measured in the same manner as in Example 1. Each amount of atrial edema was measured. Three days after the first nail with DNFB, a second nail with DNFB was conducted, provided that the atrial thickness was similarly measured just before the second antrum, at 1 hour, and 5 hours after the anastomosis. for the calculation of each quantity of the auricular edema. It has been observed in Figure 5 that, 1 hour (IPR) and 1 day (LPR) later, the second nail with DNFB induces the auricular edemas similarly to the first challenge with DNFB. It is also apparent that the development of atrial edema in vLPR on day 7 after challenge with DNFB is increased dependently on the concentration of DNFB for the second unction. When consideration is given to its functional mechanism from another point of view, the following 3 points are deduced: (1) the second nail with DNFB acts merely as a chemotactic factor with respect to the development of atrial edema in vLPR, and the second nail with DNFB induces the most intense accumulation of leukocytes such as eosinophils, which makes the ear edemas worse; (2) the second nail with DNFB promotes degranulation from leukocytes such as eosinophils in atrial edema in a vLPR stage, thereby making the edemas auricular; I (3) the interaction of the second binding with DNFB with antibodies specifically reactive for DNFB, humoral factors such as components in the complement system activated by challenge with initial DNFB, and / or cellular components such as eosinophils, mast cells, T-cells, and antigen-presenting cells, leads to more accumulation of leukocytes such as those of the eosinophils, which makes the edemas auricular in vLPR worse, and (4) the second layer with DNFB interacts well with the antibodies specifically reactive for DNFB, liquid components such as components in the complement system activated by the initial challenge with DNFB, and / or cellular components such as eosinophils, T cells, mast cells, and antigen presenting cells, thereby making the edemas auricular in vLPR.

Example 6 (1) Efficacy against Experimental Atopic Dermatitis Balb / c mice were passively sensitized with Ab IgE anti-DNP from the same As in Example 1. Twenty-four hours later, 0.1% of DNFB in ethanol was smeared on both sides of a pair of mouse atria at a dose of 10 μl per side for the challenge. Twenty-four hours' and 2 hours before the challenge, each animal was given a solution of each test metalloproteinase inhibitor (Compounds No. 8 and 10, respectively, 60 mg / kg, once a day, subcutaneous administration) in saline. physiological injection or suspension of prednisolone (10 mg / kg, once daily, intraperitoneal administration) in 0.5% aqueous methylcellulose (5 animals per group). Immediately before the challenge, 1 hour and 1 day after challenge, atrial thickness was measured in the same manner as in Example 1. Each therapeutic efficacy is recorded as a percentage inhibition where "atrial edema (untreated group)" It is used as a control.

Inhibition of Atrial Edema (° /. = Ri - Atrial Edema (Treated Group), 100 f0 / \ Atrial Edema (Untreated Group) In Table 5, the data show that the test compounds have inhibitory actions on the development of atrial edema in IPR 1 hour and LPR on day 1 after the challenge. It is apparently shown that the percentage inhibition (efficacy) of each test metalloproteinase inhibitor (Compounds Nos. 8 and 10, respectively) is equivalent to or better than that of prednisolone.

TABLE 5 1) Efficacy on Experimental Atopic Dermatitis Compound No. Treatment% inhibition (name) IPR LPR Prednisolone 24 and 2 hours 36.8 29.9 Compound No. 8 before challenge 64.4 51.3 Compound No. 10 with DNFB 38.2 39.2 Example 7 (2) Efficacy Against the Experimental Model of Atopic Dermatitis Mice were sensitized with anti-DNP IgE Ab and then challenged by painting with 0.1% DNFB in ethanol on both sides of a pair of mouse auricles at a dose of 10 μl per side, 24 hours after sensitization in the same manner as in Example 1. At 24 and 2 hours before the challenge, and on days 1, 2, 3, 4 and 5 after the challenge, a solution of a test metalloproteinase inhibitor (Compound No. 8) was administered to each animal.; 60 mg / kg, once daily, subcutaneous administration) in physiological saline for injection or a prednisolone suspension (10 mg / kg, once a day, intraperitoneal administration) in 0.5% aqueous methylcellulose (5 animals per group ). Immediately before the challenge, and on day 7 after the challenge, the atrial thickness was similarly measured. Each therapeutic efficacy is recorded as a percent inhibition, where atrial edema in the untreated group is used as a control. The results (therapeutic efficacies) are summarized in Table 6, where the inhibitory actions on IgE-mediated atrial edema in the Very Late Phase Response are shown. (vLPR, day 7 after the challenge). Consequently, it has been found that the metalloproteinase inhibitor exerts an inhibitory action on the development of auricular edema. It is concluded that the metalloproteinase inhibitor is superior to prednisolone in terms of the inhibition of edema and is excellently potent.

TABLE 6 (2) Efficacy on Experimental Atopic Dermatitis Example 8 (3) Efficacy Against the Experimental Model of Atopic Dermatitis Mice were sensitized with anti-DNP IgE antibody and then challenged by painting with 0.1% DNFB in ethanol on both sides of a pair of mouse atria at a dose of 10 μl per each. side, 24 hours after sensitization in the same manner as in Example 1. On days 3, 4, 5, and 6 after the challenge, each animal was given a solution of each test metalloproteinase inhibitor (Compounds Nos. 8 and 10, respectively, 60 mg / kg, once daily, subcutaneous administration) in physiological saline for injection or a prednisolone suspension (10 mg / kg, once a day, intraperitoneal administration) in aqueous methylcellulose 0.5 % (5 animals per group). Immediately before the challenge, and on day 7 after the challenge, the thickness of the atrium was similarly measured. Each therapeutic efficacy is recorded as a percentage inhibition where atrial edema (untreated group) is used as a control. The results (therapeutic efficacies) are summarized in Table 3, where the inhibitory actions on IgE-mediated atrial edema in the Very Late Phase Response are shown. (vLPR; Day 7 after the challenge). Consequently, it has been found that metalloproteinase inhibitors exert an inhibitory action on the development of atrial edema. It is concluded that the MMP inhibitors are superior to prednisolone in terms of percent inhibition of edema and excellently powerful.

TABLE 7 (3) Efficacy on Experimental Atopic Dermatitis Example 9 (4) Efficacy Against the Experimental Model of Atopic Dermatitis Mice were sensitized with IgE anti-DNP antibody and then challenged by painting with 0.1% DNFB in ethanol on both sides of a pair of mouse atria at a dose of 10 μl per side, 24 hours after sensitization of the same way as in Example 1. Twenty-four hours and two hours before challenge, each animal (5 animals per group) was administered a solution of a test metalloproteinase inhibitor (Compound No. 8; 60 mg / kg, once daily, subcutaneous administration) in physiological saline for injection or a prednisolone suspension (10 mg / kg, once daily, intraperitoneal administration) in 0.5% aqueous methylcellulose. Immediately before the challenge, at 1 and 4 hours and on days 1, 3 and 7 after the challenge, the thickness of the atrium was measured similarly. From each atrial edema (μm) based on the thickness of the atrium immediately before challenge, a prophylactically therapeutic efficacy of the test compound was especially evaluated. The results (therapeutic efficacies) are summarized in Figure 6. The data indicate that the compound of the present invention has an inhibitory efficacy (average ± standard deviation) over the IgE-mediated atrial edema in the Immediate Phase Response (IPR; hour after the challenge), the Late Phase Response (LPR, 1 day after the challenge), and the Very Late Phase Response (vLPR, 7 days after the challenge). It is apparent that, in comparison to prednisolone, the metalloproteinase inhibitor (Compound No. 8) is endowed with an inhibitory activity of edema, equivalent to that of prednisolone in IPR and slightly and notably higher than that of prednisolone in LPR and vLPR, respectively, even where the drug is administered only in the pre-challenge stage.

Example 10 (5) Efficacy Against the Experimental Model of Atopic Dermatitis Mice were sensitized with IgE anti-DNP antibody and then challenged by painting with 0.1% DNFB in ethanol on both sides of a pair of mouse atria at a dose of 10 μl per side, 24 hours after sensitization of the same manner as in Example 1. A solution of a test metalloproteinase inhibitor (Compound No. 8; 50 μg / orej a / dose, twice a day) in ethanol was painted on both sides of a pair of atria. mouse, 1 hour before the challenge, 0.25, 3, 4, 5 and 6 days after the challenge (5 animals per group). Immediately before the challenge, at 0.5, 1 and 4 hours, and on days 1, 3 and 7 after the challenge, the thickness of the atrium was measured similarly.

Each amount of atrial edema was calculated (mean ± standard deviation). The results (therapeutic efficacies) are summarized in Figure 7. The data show inhibitory efficiencies on IgE-mediated atrial edema in IPR (1 hour after challenge), LPR (1 day after challenge, and vLPR (7 days after challenge). challenge) It has been observed that the metalloproteinase inhibitor (Compound No. 8) is endowed with an inhibitory activity on the edema in any of IPR, LPR and vLPR It has been found that this exerts especially an excellent inhibitory activity on the development of the edema vLPR.

Example 11 (6) Efficacy against the Experimental Model of Atopic Dermatitis Passive mice were sensitized with anti-DNP IgE antibody and a pair of mouse atria were then challenged with 0.1% DNFB in ethanol 24 hours after sensitization, in the same manner as in Example 1. A solution of each inhibitor of test metalloproteinase (Compounds Nos. 20 and 21, respectively; μg / orej a / dose) in ethanol was smeared on both sides of a pair of mouse atria twice a day (morning and afternoon) 1 hour before the challenge, 6 hours, 1 to 6 days after challenge (5 animals per group). Each atrial edema was measured 1 hour, 1 day, and 7 or 8 days after the challenge based on the thickness of the atrium just before the challenge. Each percentage of inhibition of atrial edema (%) was calculated in the same manner as in example 6. The results (therapeutic efficacies) are summarized in Table 8. The data show the inhibitory efficiencies on the development of atrial edema in IPR ( 1 hour after the challenge), LPR (1 day after the challenge) and vLPR (7 or 8 days after the challenge). It is apparent that metalloproteinase inhibitors (Compounds Nos. 20 and 21) are biologically effective against the development of atrial edema in IPR, LPR and vLPR.

TABLE 8 (6) Efficacy on Experimental Atopic Dermatitis % inhibition IPR LPR vLPR Compound No. 20 56 58 31 Compound No. 21 31 22 35 Example 12 (1) Efficacy Against Scratch Behavior In the Experimental Model of Atopic Dermatitis Passive mice were sensitized with IgE anti-DNP antibody and then challenged by painting with 0.1% DNFB in ethanol on both sides of a pair of mouse atria 24 hours after challenge, in the same manner as in Example 1. Five minutes before the challenge, an ethanolic solution containing 0.3% of Compound No. 20 was painted on both sides of a pair of the atria at a dose of 10 μl for each side. Tacrolimus (Fujisawa Pharmaceutical Co., Ltd.) was used as a positive control drug. An ethanolic solution containing 0.1% of the drug was prepared positive control, just before use, and then painted on the mouse atria 1 hour before the challenge in the same way as for the paint of Compound No. 20. A negative control group was smeared with a solvent alone (6 animals per group). From the point immediately after the challenge, each mouse was individually housed in a shared acrylic cage, and observed by taking a video with no one to attend, up to 2 hours after the challenge (Inagaki, N., et al., The European Journal of Pharmacology, 367: 361-371, 1999). After finishing such a video recording, the scratching behavior by the mouse back legs to a pair of ears was visually examined for each mouse and the integrated scratching behaviors were counted for 6 durations after the challenge, for 20 minutes each; 0 to 20 minutes, 20 to 40 minutes, 40 to 60 minutes, 60 to 80 minutes, 80 to 100 minutes, and 100 to 120 minutes. In this experiment, an action from scratch to scratch the ear with the back leg of the mouse until a release of the hind leg is counted as a scratching behavior. As shown in Figure 8, the results indicate the effectiveness of the compounds inhibitors of metalloproteinase on mouse scratching behavior. A mouse scratching behavior (mean ± standard deviation) was most noticeable in the duration of 20 to 40 minutes after challenge. Compound No. 20 apparently inhibits the scratching behavior of the mouse. For its intensity, the inhibitory efficacy of the same in the post-challenge duration of 20 to 40 minutes (where scratching is more noticeable) is higher than that of tacrolimus. The results suggest that metalloproteinase inhibitors (Compound No. 20) inhibit itching due to an allergic reaction.

Example 13 (2) Efficacy against Scratch Behavior in the Experimental Model of Atopic Dermatitis Passive mice were sensitized with IgE anti-DNP antibody and then challenged with 0.1% DNFB in ethanol 24 hours after sensitization, in the same manner as in Example 12. One hour before the challenge, a 0.1% solution was smeared. % of a metalloproteinase inhibitor (Compound No. 20 or 21) in ethanol on both sides of a pair of atria at a dose of 10 μl per side. A negative control group was smeared with a solvent alone. From the point immediately after the challenge, each mouse was individually housed in a shared cage and observed by taking a video with no one to attend until 2 hours after this (3 animals per group). In the same manner as in Example 12, the scratching behaviors by the hind legs of the mouse were counted for every 15 minutes: 8 durations after the challenge; 0 to 15 minutes, 15 to 30 minutes, 30 to 45 minutes, 45 to 60 minutes, 60 to 75 minutes, 75 to 90 minutes, 90 to 105 minutes, and 105 to 120 minutes. The results are summarized in Table 9.

The data indicate the efficacy of the metalloproteinase inhibitor compounds on the scratch responses associated with the challenge (counts for the durations after the challenge of 15 to 30 minutes and 30 to 45 minutes): mean ± standard deviation (control groups with solvent) and percentage inhibition (treated groups). It is apparent that all metalloproteinase inhibitor compounds (Compounds Nos. 20 and 21) greatly alleviate the mouse scratching behaviors in the experimental model of atopic dermatitis.

Table 9 (2) Efficacy on Scratch Behavior in the Experimental Model of Atopic Dermatitis Conc. Behavior of% of (%) scrape (times) inhibition (mean ± Deviation) Control with 209.0 ± 70.4 solvent Compound No. 20 0.1 124.0 ± 43.6 40.7 Compound No. 21 0.1 96.0 ± 32.6 54.1 Example 1 Efficacy on Production of Antibody Induced by Peripheral Blood Mononuclear Cells from Healthy People Peripheral heparinized blood derived from a healthy person was diluted to a medium with phosphate buffered saline (PBS) and applied to density gradient centrifugation using Ficoll-Pague (Pharmacia Biotech) to give peripheral blood mononuclear cells (PBMC). After isolation, PBMC were rinsed with PBS, and suspended in RPMI 1640 (KK Nikken Seibutsu Igaku Kenkyujo) medium containing 10% fetal calf serum heat inactivated (1 x 106 cells / ml), followed by addition 0.05% of S t ure aphyl ococc us to us Cowan-I (SAC, CALBIOCHEM) and 10 units / ml of interleukin 2 (IL-2, Genzyme) for stimulation, as well as by simultaneous addition of inhibitor compound No. 8 of metalloproteinase (final concentration: 0.1, 1 and 10 μM). The mixtures were incubated in a 96-well microtiter plate at 37 ° C for 6 days in an atmosphere of 95% air and 5% C02. After incubation, supernatants were collected and quantitatively measured for IgG and IgM levels by an enzyme immunoassay (a method of sandwich immunoassay using two antibodies). IgG assay: A preparation that contained 500 μg / ml anti-human IgG antibody (F (ab ') 2 Cappel) in 50 mM sodium bicarbonate-sodium carbonate buffer (pH 9.6) was added to each well of a 96-well microtiter plate ( Nunc) at a rate of 100 μl / well. The plates they were allowed to stand overnight at 4 ° C, and then rinsed 3 times with PBS containing 0.05% of Tween 20. A one-quarter dilution of BlockAce (Snow Brand Milk Products Co., Ltd.) in PBS was added to the 96-well microtiter plates (300 μl / well) which were then allowed to stand overnight at 4 ° C, followed by rinsing in a similar manner. Then, a culture supernatant was serially diluted with a quarter-BlockAce dilution in PBS and a series of 100 μl / well dilutions were added to the 96-well microtiter plates, which were then allowed to stand at 25 ° C for 1 hour, followed by rinsing in a similar manner. After this, a dilution of 1-2500 of mouse anti-human IgG antibody, labeled with peroxidase was added.

(Zymed) at a rate of 100 μl / well to the 96-well microtiter plates, which were then allowed to stand at 25 ° C for 1 hour, followed by rinsing in a similar manner. A peroxidase staining kit (Sumitomo Bakelite) was added at a rate of 100 μl / well, to each well, which was subjected to an enzymatic reaction for 15 to 30 minutes at room temperature, followed by the addition of 1 N hydrochloric acid at a rate of 100 μl / well. The resulting colored product was measured for an optical density (OD) at 450 nm for a test wavelength and at 650 nm for a reference wavelength in a microplate reader. The IgG levels were calculated using a standard IgG calibration curve. IgM assay: The procedures for the IgG assay as mentioned above were repeated, except that the anti-human IgG antibody (F (ab ') _) was replaced with the anti-human IgM antibody (F (ab') 2, Cappel ) and mouse anti-human IgG antibody, labeled with peroxidase also for mouse anti-human IgM antibody, labeled with peroxidase (Zymed, dilution 1/2000). The IgM levels are obtained in the same way as for the IgG assay. Compound No. 8 MMP inhibitor (final concentration: 0.1, 1 and 10 μM) inhibited PBMC IgG production (percentage inhibition: 84.5% 96.1% and 96.0%). It also inhibited the production of IgM (percent inhibition: 32.9%, 68.1% and 63.4%). From these data it is presumed that the MMP inhibitor inhibits IgE production related to allergy similarly.

Example 15 (1) Efficacy on Mouse Body Weight Gain When drug therapy is applied, various side effects are observed. It is considered that one of the indices for this is a change in body weight. Consequently, to evaluate the collateral effect of each of the following test compounds, an action on body weight gains was examined. A solution of each test metalloproteinase inhibitor (Compound No. 8 or 10; 60 mg / kg; subcutaneous injection) in physiological saline for injection or prednisolone suspension (10 mg / kg; intraperitoneal injection) in aqueous methylcellulose 0.5% was administered to mice (5 animals per group) once a day for 6 days (Days 0, 1, 2, 3, 4 and 5). Then the mice were measured for their body weight. Each body weight gain was calculated on days 5, 7 and 10 after administration, based on body weight just before administration. Changes in body weight (mean ± standard deviation) are shown in Table 10.

The body weight gains in mice administered with each metalloproteinase inhibitor (Compounds Nos. 8 and 10) exceed those in the unmanaged group, while the body weight in the group administered with prednisolone is below that of the unmanaged group. In addition, it fails to recover to the level in the unmanaged group, even on day 5 after the suspension of administration (on day 10 after the start of administration).

TABLE 10 (1) Efficacy on the gain in body weight Compound Observation Day 5 Day 7 Day 10 None 0.50 + 0.23 0.80 ± 0.48 1.07 + 0.58 Prednisolone 0.00 + 0.26 0.03 ± 0.57 0.97 + 0.47 Metalloproteinase inhibitors Compound No. 8 0.57 + 0.61 0.77 ± 0.55 1.20 ± 0.26 Compound No. 10 1.08 ± 0.39 1.62 ± 0.26 1.40 ± 0.30 Example 16 (2) Efficacy on Body Weight Gain in Sensitized Mice Mice of the experimental atopic dermatitis model, sensitized in the same manner as in Example 1, were examined for influence on the gains in body weight. A solution of a test metalloproteinase inhibitor (Compound No. 8; 50 μg / orej a / dose, twice a day) in ethanol or a prednisolone solution (5 μg / orej a / dose, twice daily) in ethanol was administered to mice (5 animals per group) by stitching on both sides of a pair of atria, not only one hour before the challenge but also 0.25, 3, 4, 5 and 6 days after the challenge. Each mouse was measured for body weight not only immediately before the start of the anasthus, but also on days 1, 4 and 7 after the beginning of the unction. Each gain in body weight was calculated and considered as an indicator of an effect on changes in body weight affected by the treatments.

The changes in body weight (mean ± standard deviation) after said treatments are shown in Figure 9. It is apparent that the body weight gains in the group receiving the metalloproteinase inhibitor (Compound No. 8) is almost equivalent to that in the control group treated with solvent (ethanol seam), while the gain in body weight in the group treated with prednisolone is below that in the control group treated with solvent.

Example 17 Efficacy on Spontaneously Manifest Allergic Dermatitis in NC / Jic Mice Compound No. 8 was perfectly mixed with an equivalent mixture of polyethylene glycol 400 and polyethylene glycol 4000 to give an approximately homogeneous product. In this way, an ointment containing the test compound at a ratio of 0.1% was prepared. For the control groups, a base for ointment alone was used. Male NC / Jic mice (body weight, 24.1 to 31.9 g, age, 12 to 24 weeks of age, provider Clea Japan, Inc.) were verified for your health after the acquisition. Immediately after the health check, the mice were housed under conventional conditions until the dermatitis occurred. The heads of the mice surrounding the atrial portions were observed with the unaided eye once a day during the preparatory accommodation and, after a start in the ointment, once a day before the unction. The severity of spontaneous dermatitis was rated according to a pre-assigned classification table (Table 8) for the observation of dermatitis. The serial animals used in the experiment were selected from those showing signs of dermatitis with a score of 1 or 2 for 3 consecutive days or longer.

Table 11 Qualification Table for Dermatitis Observation The ointment was heated to approximately 37 ° C before administration, and spread openly on the diseased sites at 100 mg / dose / day. Seven weeks were established as a period of application of the drug. Scratching behavior by the front legs or hind legs to the affected portions with the dermatitis or the proximity of it, it was observed 30 minutes before the unction with the ointment in the last week (days 47 to 48) during the application period, and a total of the scratching behaviors were counted. The results are shown in Figure 10 and Table 12 (dermatitis score on day 49). The dermatitis score is apparently low in NC / Jic mice smeared with the ointments containing Compound No. 8, as compared to that in mice smeared with the ointment base alone. In addition, the scratching behaviors were also reduced (the base group with ointment, 126, 138, 206 scraping actions (average: 157 scraping actions); groups with ointment containing Compound No. 8, 19, 81, 177 scraping actions (average: 92 scraping actions)). These indicate that the drug inhibits the progression of spontaneously manifested dermatitis, and effectively alleviates the itching caused by it.

Table 12 Efficacy on Spontaneously Manifest Allergic Dermatitis in NC / Jic Mice Content Qualification Number of Animal Dermatitis (Average ± S.D. *) Ointment Base 0% 3 3.7 ± 0.6 Compound No. 8 0.1% 3 2.3 ± 1.5 S.D .: Standard Deviation Example 18 1) Efficacy on the Experimental Asthma Model Guinea pigs (female, Std: Hartley, 3 weeks old, weighing 200-250 g) were individually housed in a plastic chamber (width, 200 mm, depth, 300 mm, height, 167 mm). Aqueous ovalbumin (10 mg / ml) was administered to the guinea pigs once a day for 10 minute inhalation sensitization with a nebulizer (5B, Nippon Shoji KK: flow rate, 6 liters / minute) at a dose of 10 mg / ml for 8 consecutive days. On day 7 after the final sensitization, the guinea pigs were housed in a plastic chamber and inhaled using a nebulizer with an ovalbumin solution (10 mg / ml) in physiological saline for 1 minute, for the challenge (Matsumoto, T., et al., The Journal of Pharmacology and Experimental Therapeutics, 269: 1236-1244, 1994). The number of animals used in the experiment was adjusted to the extent that there were at least 6 as individuals escaping asthmatic death. A solution of a test metalloproteinase inhibitor (Compound No. 8, 15 mg / kg) in water for injection was administered subcutaneously twice, for example, 24 hours and 2 hours before challenge. Similarly, the solvent alone was also administered to a negative control group. A suspension of prednisolone (10 mg / kg) in 0.5% aqueous methylcellulose was administered orally twice, for example, 24 hours and 2 hours before the challenge. Similarly, the solvent was also only administered to another control group. Since the asthmatic death provoked by the challenge with the inhalation of the antigen was frequently observed approximately 2 to 3 minutes after the challenge, the efficacy was evaluated using at least 6 representative examples selected data among the test animals. The evaluation for efficiencies was conducted in terms of airway resistance. For this purpose, an apparatus dedicated to the measurement of airway resistance (K.K. Medical Agent) was used. The measurement includes placing a guinea pig in a test chamber under a non-anesthetized condition, applying sinusoidal pressure waves of 30 Hertz components to a part below the animal's neck from the back side of the chamber, measuring the waves Respiratory components of 30 Hertz components leaking through the mouth (volume of air flow of 30 Hertz passing through the respiratory tract) in front of the neck, and mechanically calculating the resistance of the respiratory tract. The measurement was carried out immediately before the first treatment with the drug (24 hours before the challenge), just before the challenge, 10 minutes, 1, 2, 4, 6 and 8 hours after the challenge. Figure 11 shows the results obtained in the aforementioned test. When attention is given to each control group with solvent, resistance of the respiratory tract it becomes maximum 1 and 6 hours after the challenge, which are referred to as "immediate response of the respiratory tract (IAR)" and "late response of the respiratory tract (LAR)", respectively. These two increases in airway resistance are caused by inflammation, hypertrophy, edema, mucus, etc., in the mucosa of the respiratory tract, indicating that there are bronchial asthmatic symptoms (narrowing of the respiratory tract). Among them, the increased numbers of eosinophils and neutrophils are notable in LAR (Matsumoto, T. et al., The Journal of Pharmacology and Experimental Therapeutics, 269: 1236-1244, 1994). The data show that subcutaneous administration of the metalloproteinase inhibitor (Compound No. 8) leads to significant reduction of increased resistance of the airways. The activity is approximately equal to or greater than that of prednisolone.

Example 19 (2) Efficacy on the Experimental Asthma Model There is also a period of increase in airway resistance within several minutes after the challenge (before the manifestation of RAI) in Example 18 above. This was visually observed by a person who carried out such a test in terms of the appearance of cyanosis or death by suffocation (asthmatic death) due to obstruction of the respiratory tract. The percentage mortality due to the occurrence of cyanosis after challenge by antigen inhalation was obtained using all the data in Example 18. The results are shown in Table 13. with respect to death by suffocation due to fair cyanosis. after the challenge, no animal is present in the group treated with a metalloproteinase inhibitor (Compound No. 8).

Table 13 (2) Efficacy on the Experimental Model of Bronchial Asthma Example 20 (3) Efficacy on the Experimental Asthma Model Guinea pigs were sensitized with ovalbumin and asthma was induced on Day 7 after the final sensitization in the same manner as in Example 18. The number of animals used in the experiment was adjusted to the extent that there were at least 6 as individuals. that escape asthmatic death (8 to 11 animals / group). In the same manner as in Example 18, the animals were measured for the resistance of the tracks mechanically respiratory, and each percentage change (%) in airway resistance was calculated (each value just before the challenge was established as 100%). Each percentage improvement in airway resistance was calculated from the percentage changes in airway resistance according to the following formula: The number of animals killed by asthmatic death was recorded, which was observed within several minutes after the challenge, in the same way as in Example 19 and the mortality proportions were calculated (%, number of dead animals / number of animals tested x 100). A solution of a test metalloproteinase inhibitor of the present invention (Compound No. 22: 15 mg / kg or 30 mg / kg) in water for injection or the solvent alone as a negative control was administered to each animal subcutaneously twice, for example, 24 hours and 2 hours before the challenge. Similar to Example 18, prednisolone is used as a control drug, while the solvent alone was also a control for the prednisolone group. The results are shown in Table 14. The data show that subcutaneous administration of the metalloproteinase inhibitor (Compound No. 22) or oral administration of prednisolone leads to improvement over airway resistance immediately, 1 hour and 6 hours after of the challenge. With respect to improvement by the metalloproteinase inhibitor, it has an activity equal to or greater than prednisolone. For the metalloproteinase inhibitor, moderation in cyanosis is also observed. Regarding the number of dead animals associated with the induction of asthma, in comparison to prednisolone, it is demonstrated that the administration of the metalloproteinase inhibitor (Compound No. 22) leads to excellent results.

Table 14 (3) Efficacy on the Experimental Models of Bronchial Asthma L *: Respiratory resistance in control groups with solvent (% value before challenge, average + standard error) Example 21 Efficacy on Allergic Dermatitis Type IV The mice (male, Balb / c, 6 weeks old, weighing 20 to 25 g) were sensitized by applying a 3% solution of oxazolone (100 μl) abdominally. Six days after sensitization, a 0.5% solution of oxazolone in acetone was smeared on both sides of a right ear at a dose of 10 μl to give rise to atrial edema. An untreated group was smeared with the solvent (acetone) only on both sides of a left ear of the same mouse at 10 μl. At 24 hours after the induction of edema, each mouse was sacrificed with ether and one equivalent of each of the right and left atria was excised with a perforator (diameter: 6 mm). The sections of the left and right atrium were measured for their weight, and each percentage edema was calculated (Kazuo Ouchi (Ed.), "Seibutsu Yakukagaku Jikken Koza, Ensho To Allergy (Inflammation and Allergy) 1-1", 1993, Hirokawa Publishing Co., Japan).

Weight of the segment? Percent Right Earphone of edema (%) x 100 Weight of the Left Auricular Segment A solution of a test metalloproteinase inhibitor (Compound No. 8, 50 mg / ml) in ethanol was smeared on both sides of the right atrium at 10 μl per side twice, eg 0.5 hours before the induction of edema and 6 hours after the induction of edema. The solvent (ethanol) was only painted on a left atrium at the same dose (treated group). The non-sensitized mice were also treated for induction similarly, and then treated with the compound of the present invention, only followed by the examination for the potency of the compound of the present invention on the atria (non-sensitized group). The number of animals used in the test was adjusted to 4 per group. The results are shown in Figure 13, indicating the therapeutic power (mean ± standard deviation) on the development of atrial edema. It is apparent that the compound of the present invention alone, makes the atria almost free of swelling and / or thinning, and the administration of the metalloproteinase inhibitor (Compound No. 8) leads to the improvement of atrial edema.

Example 22 Efficacy (1) on Allergic Peritonitis Each efficacy on allergic peritonitis was examined according to the methods as described in Ouchi et al., "Seibutsu Yakukagaku Jikken Koza, Ensho To, Allergy (Inflammation and Allergy) 1-3", pp. 139 to 151, Hirokawa Publishing Co. , Japan and Spicer et al., The International Archives of Allergy and Applied Immunology, 81: 81-84, 1986. An extract of ambrosia pollen (Ambrosi to art emi si a efol ia) (1: 100, Torii Pharmaceutical Co. , Ltd.) was diluted to one tenth with physiological saline and administered subcutaneously to male Balb / c mice (7 weeks of age, 20 to 23 g, purchased from JAPAN SLC, Inc.) on days 0 and 1 at a time. single dose of 0.1 ml and also on days 6, 8 and 14 at a single dose of 0.2 ml for sensitization. On day 20 after the initial sensitization, a solution of antigen for induction (a mixture of the ambrosia pollen extract diluted to a tenth, mentioned above, 50 units / ml of potassium penicillin G, and 0.05 mg / ml of streptomycin sulfate) was administered intraperitoneally to each animal at a dose of 0.2 ml to give rise to allergic peritonitis. Compound No. 8 (30 mg / kg) or physiological saline solution (10 mg / kg) was administered intraperitoneally to each animal 5 minutes before induction, 3, 6 and 12 hours after induction. Twenty-four hours after induction, the mice were sacrificed under analgesia with ether and each peritoneal cavity was washed twice or three times with a washing medium (total volume: 5 ml, physiological saline containing 10 units / ml of heparin) . Peritoneal exudate (PEC) cells were harvested in a siliconized glass tube. The recovered washing medium was measured for its yield (ml) and the number of cells exudate therein by using the Turk solution and counting on a hemocytometer and a total PEC number was calculated. An aliquot of it was taken (an extension of approximately ,000 cells of PEC). The specimens for staining were prepared using Cytospin 3 (CHANDON), and the PEC stained with Dif-Quick solution (International Reagents Corporation). After staining, PEC was subjected to fractional beads under a microscope classified as eosinophils, neutrophils, lymphocytes / macrophages and basophils based on their shape and nature of staining (more than 500 PEC per specimen were randomly counted). Each cell ratio was as follows: 1.1% (eosinophils), 2.6% (neutrophils), 94.6% (lymphocytes / macrophages), and 1.7% (basophils) for mice administered with physiological / non-sensitized saline; and '10 .3% (eosinophils), 11.6% (neutrophils), 77.8% (lymphocytes / macrophages), and 0.3% (basophils) for mice administered with physiological / sensitized saline. Since the basophil occupancy rate of PEC was extremely low and the neutrophil occupancy rate of PEC varied sparingly, basophils and neutrophils were excluded from the subjects to be examined. After the count, the rates of inhibition of intraperitoneal exudation by the following formula, and they express as therapeutic efficiencies.

Speed of (%) = Inhibition xlOO These results clearly show that when Compound 8 was administered, it potentially inhibited the infiltration of eosinophils and lymphocytes / macrophages into the peritoneal cavity in response to challenge with ambrosia pollen extracts (e.g., 57.2% and 219.0% inhibition). , respectively). It is also apparent that this contributed to a decrease in the total number of PECs (143.8%).

Example 23 Efficacy (2) About Allergic Peritonitis A physiological saline solution containing ovalbumin (0.25 mg / ml) and an aluminum hydroxide gel (4 mg / ml) was administered subcutaneously to male Balb / c mice (7 weeks of age, 20 to 23 g, purchased from JAPAN SLC, Inc.,) twice at weekly intervals at a single dose of 0.4 ml for sensitization. On day 14 after the initial sensitization, each animal was administered intraperitoneally with a solution of antigen for induction (2.5 μg / ml) at a dose of 0.4 ml to give rise to allergic peritonitis. Compound No. 8 (30 mg / kg) or a negative control solvent, physiological saline solution (10 mg / kg), was administered intraperitoneally to each animal 5 minutes before induction, 3 and 6 hours after induction. Similar to Example 22, the perifoneal cavities were washed to recover PEC. The drained liquids were measured for their performance and total number of PEC in them. In the same manner as in Example 22, PEC were stained and subjected to fractional counting under a microscope, based on their shape. Each cell ratio was as follows: 1.5% (eosinophils), 1.1% (neutrophils), 97.3% (lymphocytes / macrophages), and 0.1% (basophils) for mice not sensitized / administered with physiological saline; and 24.3% (eosinophils), 7.4% (neutrophils), 68.2% (lymphocytes / macrophages), and 0.1% (basophils) for mice sensitized / administered with physiological saline. Similar to Example 22, basophils and neutrophils were excluded from the subjects to be examined. In the same manner as in Example 22, rates of inhibition of peritoneal exudation were calculated, and expressed as therapeutic efficiencies. It is clarified that Compound No. 8 markedly inhibits the infiltration of eosinophils and lymphocytes / macrophages into the peritoneal cavity in response to challenge with ovalbumin (56.3% and 74.9%, respectively). As a result, it greatly reduces the total PEC numbers (70.7%).

Example 24 Efficacy (3) on Allergic Peritonitis In the same manner as in Example 23, male Balb / c mice were sensitized with ovalbumin and an aluminum hydroxide gel, and, on Day 14 after initial sensitization, treated with an antigen solution to elevate allergic peritonitis . Compound No. 8 (30 mg / kg) or a negative control solvent, physiological saline solution (10 ml / kg) was administered subcutaneously to each animal 6 hours and 5 minutes before induction, respectively. Similar to Example 22, the perifoneal cavities were washed to recover PEC 24 hours after induction. The drained liquids were measured for their performance and total number of PEC in them. In the same manner as in Example 22, PEC was stained and subjected to fractional counting under a microscope based on its shape. Each cell proportion was as follows: 1.2% (eosinophils), 0.6% (neutrophils), 97.2% (lymphocytes / macrophages), and 1.0% (basophils) for mice administered with physiological / non-sensitized saline; and 21.9% (eosinophils), 0.9% (neutrophils), 76.8% (lymphocytes / macrophages), and 0.4% (basophils) for mice sensitized / administered with physiological saline. Similar to Example 22, basophils and neutrophils were excluded from the subjects to be examined. In the same manner as in Example 22, inhibition rates of intraperitoneal exudation were calculated and expressed as the therapeutic efficacies.

It is clarified that Compound No. 8 markedly inhibited the infiltration of eosinophils and lymphocytes / macrophages into the peritoneal cavity in response to challenge with ovalbumin (38.6% and 91.2%, respectively). As a result, it greatly reduces the total PEC numbers (68.5%). It is suggested by a line of the results obtained in Examples 22, 23 and 24 that the efficiencies of Compound No. 8 are equivalent and significant even if the compound is administered topically to the site of inflammation (intraperitoneal route) or subcutaneously to the different tissues from the inflammatory regions.

Example 25 Efficacy (4) on Allergic Peritonitis In the same manner as in Example 23, the mice were actively sensitized with ovalbumin and alum and, on day 14 after initial sensitization, challenged with an inducer antigen solution. A test metalloproteinase inhibitor compound (Compound No. 20: 30 mg / kg) or a negative control solvent, physiological saline (10 ml / kg), was administered subcutaneously to each animal 6, 3 hours, and 5 minutes before induction, 3, and 6 hours after induction. At 24 hours after induction, a physiological saline solution (containing heparin) was injected intraperitoneally at 4 ml / mouse for peritoneal lavage. An aliquot of the recovered washing medium was taken, and not only was it measured for a PEC density but also stained for PEC, followed by fractional counting. Each effect of the compound on the total number of PEC (density of PEC x 4 ml), and the eosinophils and lymphocytes / macrophages are shown in Table 15. Almost similarly to Examples 22 to 24, the total number of PEC and numbers of eosinophils and lymphocytes / macrophages in the peritoneal cavity are reduced.

Table 15 Efficacy on Allergic Peritonitis in Model Animals Rate of inhibition of leukocyte exudate (%) Total number Eosinophils PEC macrophages Lymphocytes Compound No. 20 49.6 38.9 55.1 E p e 26 Efficacy (5) on Allergic peritonitis Each efficacy on intraperitoneal exudation of neutrophils was examined according to the methods as described in Ouchi et al., "Seibutsu Yakukagaku Jikken Koza, Ensho To Allergy (Inflammation and Allergy) 1-3", pp. 139 to 151, Hirokawa Publishing Co. , Japan and Spicer et al., The International Archives of Allergy and Applied Immunology, 81: 81-84, 1986. In the same manner as in Example 23, male Balb / c mice were sensitized with ovalbumin and a sodium hydroxide gel. aluminum and, on day 14 after the initial sensitization, challenged by an antigen solution to elevate allergic peritonitis. Each test metalloproteinase inhibitor (Compound No. 20 or 21: 30 mg / kg) or a negative control solvent, physiological saline solution (10 ml / kg), was administered subcutaneously to each animal 1 hour before induction, and hours after the induction. At 6 hours after induction, peritoneal lavage was performed similarly to Example 22, measured for a PEC density, and counted for the total number of PEC. In the same manner as in Example 22, PEC was stained, and subjected to fractional counting under a microscope classified as neutrophils, eosinophils, lymphocytes / macrophages and basophils, based on their shape and nature of staining. Each cell ratio was as follows: 2.3% (neutrophils), 1.1% (eosinophils), 95.4% (lymphocytes / macrophages), and 1.2% (basophils) for mice not sensitized / administered with physiological saline; and 5.7% (neutrophils), 11.9% (eosinophils), 81.3% (lymphocytes / macrophages), and 1.1% (basophils) for mice sensitized / administered with physiological saline. By a similar line of reasoning in Example 22, basophils were excluded from the subject to be examined. In the same manner as in Example 22, inhibition rates of intraperitoneal exudation were calculated and expressed as therapeutic efficiencies. These results are summarized in Table 16.

The data indicate that metalloproteinase inhibitors (Compounds Nos. 20 and 21) not only potently inhibit the infiltration of eosinophils, etc., but also markedly inhibit the infiltration of neutrophils into the peritoneal cavity in response to challenge with ovalbumin. As a result, these strongly reduce the total numbers of PEC.

Table 16 Efficacy on Allergic Peritonitis in Model Animals Rate of inhibition of leukocyte exudate (%) Total number Eosinophils PEC Neutrophils Compound No. 20 40.9 38.4 41.4 Compound No. 21 38.6 - 27.1 Example 27 Efficacy on the Allergic Inflammation Model (Air Bag Model) Compound No. 8 was dissolved in physiological saline to make the final concentration of 2.5 mg / ml (equal to 10 mg / kg) or 7.5 mg / ml (equal to 30 mg / kg) and administered in an air bag of animals or intraperitoneally at a dose of 4 ml / kg. Dexamethasone was also dissolved in physiological saline to make the final concentration of 25 μg / ml (equal to 0.1 mg / kg) and administered in an animal air bag at a dose of 4 ml / kg. Administration in such an air bag was conducted simultaneously with the second challenge, while intraperitoneal administration was 30 minutes before the second challenge. Acetylated bovine serum albumin, diazo-coupled with arsanilic acid (ABA-AcBSA) was prepared according to the methods of Ouchi et al., And Tabachnick et al., As described in Ouchi et al., "Seibutsu Yakukagaku Jikken Koza , Ensho To Allergy (Inflammation and Allergy) 1-2", pp. 194 to 206, Hirokawa Publishing Co., Japan and tabchnick et al., The JOURNAL OF BIOLOGICAL CHEMISTRY, 234: 1726-1730, 1959, and mixed with a complete Freund's adjuvant (Difco) at an equal ratio. The mixture was treated using a connection type glass syringe to form an emulsion which was used as a sensitization solution. A 2% aqueous solution of carboxymethylcellulose (CMC) containing 0.5 mg / ml of ABA-AcBSA, 52 μg / ml of polymyxin B sulfate (Sigma), 0.1 mg / ml of sodium sulfate was used as an initial challenge solution. streptomycin (Meiji Seika Kaisha, Ltd.) and 0.1 mg / ml potassium penicillin G (Meiji Seika Kaisha, Ltd.). A physiological saline solution containing 3 mg / ml of ABA-AcBSA, 52 μg / ml of polymyxin B sulfate, 0.1 mg / ml of streptomycin sulfate and 0.1 mg / ml of potassium penicillin G as a second challenge solution was used. . Male rats with shaved hair (Crj: Sprague-Dawley line IGS, 5 weeks old) were treated by intradermal injection of the sensitization solution at a dose of 0.1 ml (equivalent to 5 mg of ABA-AcBSA) with a needle subcutaneous 1/4 in 5 different sites of the dorsal skin (2 sites for the shoulder and 3 sites for the lumbus). Nine days after sensitization, 10 ml of air was injected subcutaneously with a 1/4 subcutaneous needle into the dorsal skin to form an oval air pocket. One day later, 4 ml of the initial challenge solution was injected with a 1/1 subcutaneous needle to elevate the allergic inflammation. Five days after the initial challenge, 1 ml of the second challenge solution was injected with a 1/3 subcutaneous needle to elevate recrudescent inflammation. Eight hours after the second challenge, the rats were sacrificed by exsanguination to recover the exudates in the air bag. The recovered exudates were measured by the dye exclusion method using a hematocytometer and the number of leukocytes exuded was counted. Figure 13 shows the results, demonstrating that leukocyte infiltration within an air pocket was significantly inhibited either via direct inoculation into the air pocket or subcutaneous administration of Compound No. 8 (statistical analysis by a test of multicomparación: *, significant with less than 5% risk, and * *, significant with less than 1% risk). In addition, its efficacy is roughly equivalent to that of dexamethasone.

Example 28 Efficacy on Allergic Rhinitis Guinea pigs (males, Std: Hartley, 3 weeks old) were housed and fed in an aluminum cage at a rate of up to 5 animals per cage. After acclimation for 1 week, the guinea pigs were administered intravenously with an anti-ovalbumin antibody (Nihon Bioresearch Inc., Hajima Institute, antibody titre by a homologous passive cutaneous anaphylaxis reaction of 3 hours, 1: 8192) prepared from According to the Orange & Moore (Orange, R.P. and Moore, E. G., The Journal of Immunology 116: p.392-397, 1976) in his atrial vein at a dose of 0.3 ml / animal for passive sensitization. Twenty-four to twenty-six hours after sensitization under fasting conditions and free access to drinking water, the sensitized guinea pigs were anesthetized with urethane (1.2 g / kg, intraperitoneal administration), fixed in a supine position, and the necks were excised cervically for expose the tracheae. A polyethylene tube (No. 8, Hibiki) was inserted from the excised portion of the trachea to the side of the nasal cavity, followed by ligature. A Cotton ball impregnated with glycerin was packaged inside the oral cavity so that no air escaped from the nasal cavity into the oral cavity. To maintain breathing, a polyethylene cannula (No. 8, Hibiki) was inserted in the pulmonary side and the polyethylene cannula was inserted in the side of the nasal cavity, and was installed with a Y-type cannula connected to a three-way cap. tracks. The animals were ventilated with 5 ml of air by ventilation at a rate of 60 beats / minute via a Harvard Rodent Respirator (Model 683, Harvard) from one end of the Y-type cannula. A ventilatory overflow from the other end of the Type Y cannula under isobaric loads (10 cm H20) was taken as an index for the resistance of the nasal airways to a bronchospasm transducer (7020, Ugo basile). The variations of the ventilatory overflow were quantitatively recorded in a recticoder (RECTI-HORIZ-8K, Nippon Denki Sanei K.K.) for 20 minutes after challenge with the antigen. The height of the wave (cm) was measured on recording papers and the value of the resistance of the nasal airways was calculated according to the following formula: Percentage increase (%) in Nasal Resistance of Respiratory Pathways xlOO Compound No. 8 was dissolved in water for injection and injected subcutaneously one hour before the induction of rhinitis: 15 mg / kg and 5 ml / kg (N = 5). A solvent was only administered to a control group (N = 10). The results (mean ± standard deviation) are shown in Figure 14. It is apparent that the administration of Compound No. 8 markedly improves an increase in nasal resistance of the airways due to challenge with the antigen.

Formulation Example 1 An ointment was prepared that contained the following ingredients, according to conventional techniques: Ingredients Quantity White Petrolatum 97 g Liquid Paraffin 2 g Compound No. 22 1.0 g Total Quantity 100 g Formulation Example 2 An ointment was prepared that contained the following ingredients, according to conventional techniques: Ingredients Amount Petrolat - white 97 g Purified lanolin 2 g Compound No. 20 1.0 g Total Quantity 100 g Formulation Example 3 An ointment was prepared that contained the following ingredients, according to conventional techniques: Ingredients Quantity White petrolatum 97 g Purified lanolin 2 g Compound No. 21 1.0 g Total Quantity 100 g Formulation Example 4 An ointment was prepared that contained the following ingredients, according to conventional techniques: Ingredients Quantity White Petrolatum 99 g Compound No. 10 1.0 g Total Quantity 100 g Formulation Example 5 An ophthalmic drop containing the following ingredients was prepared according to conventional techniques: Ingredients Amount Compound No. 20 1.0 g Sodium Chloride 0.33 g Sterile Purified Water c. s. s Total Volume 100 ml Formulation Example 6 An ophthalmic drop containing the following ingredients was prepared according to conventional techniques: Ingredients Amount Compound No. 21 1.0 g Sodium Chloride 0.26 g Anhydrous Sodium Dihydrogenphosphate 0.56 g Disodium Phosphate Anhydrous 0.28 g Benzalkonium Chloride Aqueous at 0.002% q.s.s.

Total Volume 100 ml Formulation Example 7 An ophthalmic drop containing the following ingredients was prepared according to conventional techniques: Ingredients Amount Compound No. 8 1.0 g Sodium Chloride 0.33 g Anhydrous Sodium Sulfite 0.10 g Sterile Purified Water q.s. Total Volume 100 ml Formulation Example 8 A preparation for injection containing the following ingredients was formulated according to conventional techniques: Ingredients Quantity Compound No. 20 2.0 g Distilled Water for Injection c.s. Total Volume 100 ml Formulation Example 9 A preparation for injection containing the following ingredients was formulated according to conventional techniques: Ingredients Amount Compound No. 21 2.0 g Sodium Chloride 0.9 g Distilled Water for Injection c.s. Total Volume 100 ml Formulation Example 10 Preparation for Solutions A formula for a single dose is: Ingredients Quantity Compound No. 8 1.0 g Human serum albumin 0.05 g Lactose 1 g Saline Physiological Solution for Injection c.s. Total Volume 50 ml All the ingredients are mixed and dissolved to give a preparation for injection.

Formulation Example 11 Ointment Preparation A variety of ointment bases conventionally known in the art can be used in ointment preparations. For example, Compound No. 20 can be formulated in admixture with a macrogol ointment according to the following processes: To the macrogol ointment which is prepared by mixing macrogol 400 with macrogol 4000 is equivalently added ethyl p-hydroxybenzoate ( 5 mg) and Compound No. 20 (10 mg) to make the total amount of 10 g. The mixture was mixed perfectly according to conventional techniques to provide an ointment.

Formulation Example 12 Preparation for Solutions A physiological saline solution containing 0.005% benzalkonium chloride (0.15 M aqueous sodium chloride containing 0.005% benzalkonium chloride, pH 7.2) is added to Compound No. 21 to make its final concentration of 1.0%. The resulting solution is sterilized through a membrane filter with a pore size of 0.1 μm and refrigerated (4 ° C) until use.

Formulation Example 13 Preparation for Tablets Tablets each containing Compound No. 10 (30.0 mg) are formulated according to conventional techniques. A formula for tablets is: Ingredients Amount Compound No. 10 30.0 mg Hydroxypropylcellulose 5.0 mg Magnesium stearate 0.5 mg Corn starch 24.5 mg Lactose c.s. Total Quantity 150.0 mg Formulation Example 14 Preparation for Tablets Tablets each containing Compound No. 20 (50.0 mg) are formulated according to conventional techniques. A formula for tablets is: Ingredients Amount Compound No. 20 50.0 mg Fine cellulose powder 25.0 mg Corn starch 40.0 mg Talcum 5.0 mg Magnesium stearate 0.5 mg Lactose c.s. Total amount 170.0 mg Formulation Example 15 Preparation for Inhalation Powders Compound No. 21 (1.5 g) and lactose (60 g) are pulverized to form fine powders, respectively, and mixed thoroughly under stirring to provide a homogeneous mixture as a powder. The resulting mixture is packaged in capsules so that each capsule can contain 500 μg of Compound No. 21. The drugs are inhaled by the use of an insufflator whe the capsule is adjusted before use.

Formulation Example 16 Preparation for Inhalation Powders A powder is formulated by spraying each ingredient, to form a fine powder, and then all the resulting powders are mixed thoroughly under agitation to provide a homogeneous mixture. A formula for inhalation powders is: Ingredients Amount Compound No. 8 2.0 g Starch 30.0 g Talcum 5.0 g Magnesium stearate 1.0 g Lactose c.s. Total Quantity 100.0 g Possibility of Industrial Application The present invention provides pharmaceutical compositions that exert allergic or anti-inflammatory actions, or prophylactic and / or therapeutic efficacy on bronchial asthma or atopic diseases, which comprise as an active ingredient at least one member selected from the metalloproteinase inhibitors. Pharmaceutical products that contain an effective amount of metalloproteinase inhibitors can be applied to allergy therapy, especially to a sick site of patients affected with allergy, including allergy type I and / or type IV, etc., or a predetermined site of allergic people, including allergy type I and / or type IV, etc., which leads to an excellent or significant effect on them. The drugs are effective in the treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, pollinosis, atopic diseases (for example, atopic dermatitis, atopic enteritis, etc.), allergy to food substances, hives, various hypersensitivities. contact, injure-versus-host disease (GVH disease) occurred in the transplant of organs, etc. Pharmaceutical products containing an effective amount of the metalloproteinase inhibitors can be applied to the therapy and / or prophylaxis of inflammation, whereby an advantageous effect is exerted on it. The application of such drugs leads to (A) reduction of cells (such as lymphocytes, neutrophils, mast cells, eosinophils, basophils, macrophages and monocytes) in a diseased site, and / or (B) relief of inflammatory symptoms caused by migration, infiltration or accumulation of cells (such as lymphocytes, neutrophils, mast cells, eosinophils, basophils, macrophages and monocytes) to the diseased site, (C) inhibition of pathophysiological functions in cells (such as lymphocytes, neutrophils, mast cells, eosinophils, basophils, macrophages, monocytes, Langerhans cells and dendritic cells), and / or (D) blood level reduction or inhibition of antibody production, especially IgE. Accordingly, the drugs are useful in the prophylaxis and / or therapy of illnesses, disorders or disease conditions at the site.

While the present invention has been specifically described in detail with reference to certain embodiments and examples thereof, it may be apparent that it is possible to practice it in other ways. In light of the description, it will be understood that various modifications and variations are within the spirit and scope of the appended claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (28)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A prophylactic and / or therapeutic drug for allergic diseases, characterized in that it comprises an effective amount of at least one member selected from metalloproteinase inhibitors.

2. The drug according to claim 1, characterized in that it exerts a prophylactic and / or therapeutic action on the inflammation resulting from an allergic reaction.

3. The drug according to claim 1 or 2, characterized in that it is for the prophylactic and / or therapeutic treatment of type I allergic disorders.

4. The drug according to claim 1 6 2, characterized in that it is for the prophylactic and / or therapeutic treatment of type IV allergic disorders.

5. The drug according to claim 1, characterized in that it is for the reduction of a blood antibody titer or the inhibition of the production of antibodies to prophylactically and / or therapeutically treat allergic diseases.

6. The drug according to claim 1, 2 or 5, characterized in that it is for the reduction of the blood level of IgE or the inhibition of IgE production to treat prophylactically and / or therapeutically allergic diseases.

7. A prophylactic and / or therapeutic drug for bronchial asthma, characterized in that it comprises an effective amount of at least one member selected from metalloproteinase inhibitors.

8. The drug according to claim 7, characterized in that it is for the prophylactic and / or therapeutic treatment of chronic bronchial asthma.

9. A prophylactic and / or therapeutic drug for allergic rhinitis, characterized in that it comprises an effective amount of at least one member selected from metalloproteinase inhibitors.

10. A prophylactic and / or therapeutic drug for atopic diseases, characterized in that it comprises an effective amount of at least one selected member of metalloproteinase inhibitors.

11. The drug according to claim 10, characterized in that it is for the prophylactic and / or therapeutic treatment of atopic dermatitis.

12. A prophylactic and / or therapeutic drug for allergic conjunctivitis, characterized in that it comprises an effective amount of at least one member selected from metalloproteinase inhibitors.

13. A prophylactic and / or therapeutic drug for immediate, late and / or very late allergic responses, characterized in that it comprises an effective amount of at least one member selected from metalloproteinase inhibitors.

14. A prophylactic and / or therapeutic drug for allergic gastroenteritis (allergic inflammation in the digestive tract), characterized in that it comprises an effective amount of at least one member selected from metalloproteinase inhibitors.

15. A prophylactic and / or therapeutic drug for allergic diseases, characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 is selected from the group consisting of hydrogen, hydroxyl, aryl (alkylene of 1 to 6 carbon atoms) and a group of the formula: -A-SOn-B wherein A is alkylene of 1 to 6 carbon atoms , B is selected from the group consisting of alkyl of 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, aryl and a heterocyclic radical and n is 0, 1 or 2; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms and alkylthio of 1 to 6 carbon atoms; R3 and R4, which may be identical or different, are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and aryl- (alkylene of 1 to 6 carbon atoms); R5 is a group of the formula -YD or D wherein Y is selected from the group consisting of alkylene of 1 to 6 carbon atoms, oxygen, imino, (alkylene of 1 to 6 carbon atoms) -imino, and D is select from the group consisting of a sulfonic acid residue, a phosphonic acid residue, amidino, acyl 1 to 6 carbon atoms, acylimidoyl, di- (phosphono) methino and di (carboxy) -methine; and R6 is selected from the group consisting of hydrogen, unsubstituted or optionally substituted benzyl, trialkylsilyl, tert-butyldiphenylsilyl, tetrahydropyranyl, tert-butyl, and a hydroxyl protecting group; and a pharmaceutically acceptable salt or solvate thereof.

16. The drug according to claim 15, characterized in that it exerts a prophylactic and / or therapeutic action on the inflammation resulting from an allergic reaction.

17. The drug according to claim 15 or 16, characterized in that it is for the prophylactic and / or therapeutic treatment of type I allergic disorders.

18. The drug according to claim 15 or 16, characterized in that it is for the prophylactic and / or therapeutic treatment of type IV allergic disorders.

19. The drug according to claim 15 or 16, characterized in that it is for the reduction of a blood antibody titer or for the inhibition of the production of antibodies to treat prophylactically and / or therapeutically allergic diseases.

20. The drug according to claim 15, 16 or 19, characterized in that it is for the reduction of the blood level of IgE or the inhibition of the production of IgE to treat prophylactically and / or therapeutically allergic diseases.

21. A prophylactic and / or therapeutic drug for bronchial asthma, characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 to R6 have all the same meanings as defined in claim 15, and a pharmaceutically acceptable salt or solvate thereof.

22. The drug according to claim 21, characterized in that it is for the prophylactic and / or therapeutic treatment of chronic bronchial asthma.

23. A prophylactic and / or therapeutic drug for allergic rhinitis, characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 to R6 have all the same meanings as defined in claim 15, and a pharmaceutically acceptable salt or solvate thereof.

24. A prophylactic and / or therapeutic drug for atopic diseases, characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 to R6 have all the same meanings as defined in claim 15, and a pharmaceutically acceptable salt or solvate of the same.

25. The drug according to claim 24, characterized in that it is for the prophylactic and / or therapeutic treatment of atopic dermatitis.

26. A prophylactic and / or therapeutic drug for allergic conjunctivitis, characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 to R6 have all the same meanings as defined in claim 15, and a pharmaceutically acceptable salt or solvate thereof.

27. A prophylactic and / or therapeutic drug for immediate late and / or very late allergic responses, characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 to R6 have all the same meanings as defined in claim 15, and a pharmaceutically acceptable salt or solvate thereof.

28. A prophylactic and / or therapeutic drug for allergic gastroenteritis (allergic inflammation in the digestive tract), characterized in that it comprises an effective amount of at least one member selected from the group consisting of a compound having the following formula (I): wherein R1 to R6 have all the same meanings as defined in claim 15, and a pharmaceutically acceptable salt or solvate thereof. SUMMARY OF THE INVENTION The anti-inflammatory agents, antiallergic agents, drugs particularly prophylactically and / or therapeutically effective for allergic conditions type I and / or IV, and additional pharmaceuticals for treating prophylactic and / or therapeutically bronchial asthma, atopic diseases, are described. etc. The drugs of the invention comprise a prophylactic and / or therapeutically effective amount of a metalloproteinase inhibitor, which is active in the prophylaxis and / or allergy therapy, especially allergy type I and / or IV, etc. The drugs are active in the prophylactic and / or therapeutic treatment of inflammation, rhinitis, conjunctivitis, bronchial asthma, atopic diseases (including dermatitis, enteritis, etc.), or allergic gastroenterocolitis (allergic inflammation in the digestive tract) ). The application of such drugs leads to (A) cell reduction (such as lymphocytes, neutrophils, mast cells, eosinophils, basophils, macrophages and monocytes) in a disease site, and / or (B) the relief of inflammatory symptoms caused by migration, infiltration or accumulation of cells (such as lymphocytes, neutrophils, mast cells, eosinophils, basophils, macrophages and monocytes) for (or in) the diseased site, (C) the inhibition of pathophysiological functions in cells (such as lymphocytes, neutrophils, mast cells, eosinophils, basophils, macrophages, monocytes, Langerhans cells and dendritic cells) and / or (D) the reduction of the blood level or the inhibition of the production of antibodies, especially IgE. Accordingly, the drugs are useful in the prophylaxis and / or therapy of illnesses, disorders or disease conditions at the site.